Kathleen Poston, MD, MS

All Publications

• Neuronal alpha-Synuclein Disease integrated staging system performance in PPMI, PASADENA, and SPARK baseline cohorts. NPJ Parkinson's disease Dam, T., Pagano, G., Brumm, M. C., Gochanour, C., Poston, K. L., Weintraub, D., Chahine, L. M., Coffey, C., Tanner, C. M., Kopil, C. M., Xiao, Y., Chowdhury, S., Concha-Marambio, L., DiBiaso, P., Foroud, T., Frasier, M., Jennings, D., Kieburtz, K., Merchant, K., Mollenhauer, B., Montine, T. J., Nudelman, K., Seibyl, J., Sherer, T., Singleton, A., Stephenson, D., Stern, M., Soto, C., Tolosa, E., Siderowf, A., Dunn, B., Simuni, T., Marek, K. 2024; 10 (1): 178

  Abstract

  The Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with Lewy body pathology and stage them based on underlying biology and increasing degree of functional impairment. Utilizing data from the PPMI, PASADENA, and SPARK studies, we developed and applied biologic and clinical data-informed definitions for the NSD-ISS across the disease continuum. Individuals enrolled as Parkinson's disease, Prodromal, or Healthy Controls were defined and staged based on biological, clinical, and functional anchors at baseline. Across the three studies 1741 participants had SAA data and of these 1030 (59%) were S+ consistent with NSD. Among sporadic PD, 683/736 (93%) were NSD, and the distribution for Stages 2B, 3, and 4 was 25%, 63%, and 9%, respectively. Median (95% CI) time to developing a clinically meaningful outcome was 8.3 (6.2, 10.1), 5.9 (4.1, 6.0), and 2.4 (1.0, 4.0) years for baseline stage 2B, 3, and 4, respectively. We propose pilot biologic and clinical anchors for NSD-ISS. Our results highlight the baseline heterogeneity of individuals currently defined as early PD. Baseline stage predicts time to progression to clinically meaningful milestones. Further research on validation of the anchors in longitudinal cohorts is necessary.

  View details for DOI 10.1038/s41531-024-00789-w

  View details for PubMedID 39333167

  View details for PubMedCentralID 10627170

• The Parkinson's Disease Composite of Executive Functioning: A Measure for Detecting Cognitive Decline in Clinical Trials. Neurology Young, C. B., Cholerton, B., Smith, A. M., Shahid-Besanti, M., Abdelnour, C., Mormino, E. C., Hu, S. C., Chung, K. A., Peterson, A., Rosenthal, L., Pantelyat, A., Dawson, T. M., Quinn, J., Zabetian, C. P., Montine, T. J., Poston, K. L. 2024; 103 (2): e209609

  Abstract

  Executive functioning is one of the first domains to be impaired in Parkinson disease (PD), and the majority of patients with PD eventually develop dementia. Thus, developing a cognitive endpoint measure specifically assessing executive functioning is critical for PD clinical trials. The objective of this study was to develop a cognitive composite measure that is sensitive to decline in executive functioning for use in PD clinical trials.We used cross-sectional and longitudinal follow-up data from PD participants enrolled in the PD Cognitive Genetics Consortium, a multicenter setting focused on PD. All PD participants with Trail Making Test, Digit Symbol, Letter-Number Sequencing, Semantic Fluency, and Phonemic Fluency neuropsychological data collected from March 2010 to February 2020 were included. Baseline executive functioning data were used to create the Parkinson's Disease Composite of Executive Functioning (PaCEF) through confirmatory factor analysis. We examined the changes in the PaCEF over time, how well baseline PaCEF predicts time to cognitive progression, and the required sample size estimates for PD clinical trials. PaCEF results were compared with the Montreal Cognitive Assessment (MoCA), individual tests forming the PaCEF, and tests of visuospatial, language, and memory functioning.A total of 841 participants (251 no cognitive impairment [NCI], 480 mild cognitive impairment [MCI], and 110 dementia) with baseline data were included, of which the mean (SD) age was 67.1 (8.9) years and 270 were women (32%). Five hundred forty five PD participants had longitudinal neuropsychological data spanning 9 years (mean [SD] 4.5 [2.2] years) and were included in analyses examining cognitive decline. A 1-factor model of executive functioning with excellent fit (comparative fit index = 0.993, Tucker-Lewis index = 0.989, and root mean square error of approximation = 0.044) was used to calculate the PaCEF. The average annual change in PaCEF ranged from 0.246 points per year for PD-NCI participants who remained cognitively unimpaired to -0.821 points per year for PD-MCI participants who progressed to dementia. For PD-MCI, baseline PaCEF, but not baseline MoCA, significantly predicted time to dementia. Sample size estimates were 69%-73% smaller for PD-NCI trials and 16%-19% smaller for PD-MCI trials when using the PaCEF rather than MoCA as the endpoint.The PaCEF is a sensitive measure of executive functioning decline in PD and will be especially beneficial for PD clinical trials.

  View details for DOI 10.1212/WNL.0000000000209609

  View details for PubMedID 38870440

• Concerns with the new biological research criteria for synucleinopathy - Authors' reply. The Lancet. Neurology Simuni, T., Chahine, L. M., Weintraub, D., Poston, K. M., Kopil, C. M., Dunn, B., Marek, K. 2024; 23 (7): 663-666

  View details for DOI 10.1016/S1474-4422(24)00233-3

  View details for PubMedID 38876741

• Plasma pTau181 Reveals a Pathological Signature that Predicts Cognitive Outcomes in Lewy Body Disease. Annals of neurology Abdelnour, C., Young, C. B., Shahid-Besanti, M., Smith, A., Wilson, E. N., Ramos Benitez, J., Vossler, H., Plastini, M. J., Winer, J. R., Kerchner, G. A., Cholerton, B., Andreasson, K. I., Henderson, V. W., Yutsis, M., Montine, T. J., Tian, L., Mormino, E. C., Poston, K. L. 2024

  Abstract

  To determine whether plasma phosphorylated-Tau181 (pTau181) could be used as a diagnostic biomarker of concurrent Alzheimer's disease neuropathologic change (ADNC) or amyloidosis alone, as well as a prognostic, monitoring, and susceptibility/risk biomarker for clinical outcomes in Lewy body disease (LBD).We studied 565 participants: 94 LBD with normal cognition, 83 LBD with abnormal cognition, 114 with Alzheimer's disease, and 274 cognitively normal. Plasma pTau181 levels were measured with the Lumipulse G platform. Diagnostic accuracy for concurrent ADNC and amyloidosis was assessed with Receiver Operating Characteristic curves in a subset of participants with CSF pTau181/Aβ42, and CSF Aβ42/Aβ40 or amyloid-β PET, respectively. Linear mixed effects models were used to examine the associations between baseline and longitudinal plasma pTau181 levels and clinical outcomes.Plasma pTau181 predicted concurrent ADNC and amyloidosis in LBD with abnormal cognition with 87% and 72% accuracy, respectively. In LBD patients with abnormal cognition, higher baseline plasma pTau181 was associated with worse baseline MoCA and CDR-SB, as well as accelerated decline in CDR-SB. Additionally, in this group, rapid increases in plasma pTau181 over 3 years predicted a faster decline in CDR-SB and memory. In LBD patients with normal cognition, there was no association between baseline or longitudinal plasma pTau181 levels and clinical outcomes; however, elevated pTau181 at baseline increased the risk of conversion to cognitive impairment.Our findings suggest that plasma pTau181 is a promising biomarker for concurrent ADNC and amyloidosis in LBD. Furthermore, plasma pTau181 holds potential as a prognostic, monitoring, and susceptibility/risk biomarker, predicting disease progression in LBD. ANN NEUROL 2024.

  View details for DOI 10.1002/ana.27003

  View details for PubMedID 38888142

• Comprehensive proteomics of CSF, plasma, and urine identify DDC and other biomarkers of early Parkinson's disease. Acta neuropathologica Rutledge, J., Lehallier, B., Zarifkar, P., Losada, P. M., Shahid-Besanti, M., Western, D., Gorijala, P., Ryman, S., Yutsis, M., Deutsch, G. K., Mormino, E., Trelle, A., Wagner, A. D., Kerchner, G. A., Tian, L., Cruchaga, C., Henderson, V. W., Montine, T. J., Borghammer, P., Wyss-Coray, T., Poston, K. L. 2024; 147 (1): 52

  Abstract

  Parkinson's disease (PD) starts at the molecular and cellular level long before motor symptoms appear, yet there are no early-stage molecular biomarkers for diagnosis, prognosis prediction, or monitoring therapeutic response. This lack of biomarkers greatly impedes patient care and translational research-L-DOPA remains the standard of care more than 50 years after its introduction. Here, we performed a large-scale, multi-tissue, and multi-platform proteomics study to identify new biomarkers for early diagnosis and disease monitoring in PD. We analyzed 4877 cerebrospinal fluid, blood plasma, and urine samples from participants across seven cohorts using three orthogonal proteomics methods: Olink proximity extension assay, SomaScan aptamer precipitation assay, and liquid chromatography-mass spectrometry proteomics. We discovered that hundreds of proteins were upregulated in the CSF, blood, or urine of PD patients, prodromal PD patients with DAT deficit and REM sleep behavior disorder or anosmia, and non-manifesting genetic carriers of LRRK2 and GBA mutations. We nominate multiple novel hits across our analyses as promising markers of early PD, including DOPA decarboxylase (DDC), also known as L-aromatic acid decarboxylase (AADC), sulfatase-modifying factor 1 (SUMF1), dipeptidyl peptidase 2/7 (DPP7), glutamyl aminopeptidase (ENPEP), WAP four-disulfide core domain 2 (WFDC2), and others. DDC, which catalyzes the final step in dopamine synthesis, particularly stands out as a novel hit with a compelling mechanistic link to PD pathogenesis. DDC is consistently upregulated in the CSF and urine of treatment-naïve PD, prodromal PD, and GBA or LRRK2 carrier participants by all three proteomics methods. We show that CSF DDC levels correlate with clinical symptom severity in treatment-naïve PD patients and can be used to accurately diagnose PD and prodromal PD. This suggests that urine and CSF DDC could be a promising diagnostic and prognostic marker with utility in both clinical care and translational research.

  View details for DOI 10.1007/s00401-024-02706-0

  View details for PubMedID 38467937

  View details for PubMedCentralID 3995906

• Multiple biomarkers improve diagnostic accuracy across Lewy body and Alzheimer's disease spectra. Annals of clinical and translational neurology Plastini, M. J., Abdelnour, C., Young, C. B., Wilson, E. N., Shahid-Besanti, M., Lamoureux, J., Andreasson, K. I., Kerchner, G. A., Montine, T. J., Henderson, V. W., Poston, K. L. 2024

  Abstract

  More than half of neurodegenerative disease patients have multiple pathologies at autopsy; however, most receive one diagnosis during life. We used the α-synuclein seed amplification assay (αSyn-SAA) and CSF biomarkers for amyloidosis and Alzheimer's disease (AD) neuropathological change (ADNC) to determine the frequency of co-pathologies in participants clinically diagnosed with Lewy body (LB) disease or AD.Using receiver operating characteristic analyses on retrospective CSF samples from 150 participants determined αSyn-SAA accuracy, sensitivity, and specificity for identifying clinically defined LB disease and predicting future change in clinical diagnosis. CSF biomarkers helped determine the frequency of concomitant Lewy body pathology, ADNC, and/or amyloidosis in participants with LB disease and AD, across clinical spectra.Following a decade-long follow-up, the clinically or autopsy-defined diagnosis changed for nine participants. αSyn-SAA demonstrated improved accuracy (91.3%), sensitivity (89.3%), and specificity (93.3%) for identifying LB disease compared to all non-LB disease, highlighting the limitations of clinical diagnosis alone. When examining biomarkers of co-pathology, amyloidosis was present in 18%, 48%, and 71% (χ2 (2) = 13.56, p = 0.001) and AD biomarkers were present in 0%, 8.7%, and 42.9% (χ2 (2) = 18.44, p < 0.001) of LB disease participants with different stages of cognitive impairment respectively. Co-occurring biomarkers for αSyn-SAA and amyloidosis were present in 12% and 14% of AD compared to 43% and 57% LB disease participants with different stages of cognitive impairment (χ2 (3) = 13.87, p = 0.003).Our study shows that using a combination of αSyn-SAA and AD biomarkers can identify people with αSyn, ADNC, and co-pathology better and earlier than traditional clinical diagnostic criteria alone.

  View details for DOI 10.1002/acn3.52034

  View details for PubMedID 38436140

• A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research. The Lancet. Neurology Simuni, T., Chahine, L. M., Poston, K., Brumm, M., Buracchio, T., Campbell, M., Chowdhury, S., Coffey, C., Concha-Marambio, L., Dam, T., DiBiaso, P., Foroud, T., Frasier, M., Gochanour, C., Jennings, D., Kieburtz, K., Kopil, C. M., Merchant, K., Mollenhauer, B., Montine, T., Nudelman, K., Pagano, G., Seibyl, J., Sherer, T., Singleton, A., Stephenson, D., Stern, M., Soto, C., Tanner, C. M., Tolosa, E., Weintraub, D., Xiao, Y., Siderowf, A., Dunn, B., Marek, K. 2024; 23 (2): 178-190

  Abstract

  Parkinson's disease and dementia with Lewy bodies are currently defined by their clinical features, with α-synuclein pathology as the gold standard to establish the definitive diagnosis. We propose that, given biomarker advances enabling accurate detection of pathological α-synuclein (ie, misfolded and aggregated) in CSF using the seed amplification assay, it is time to redefine Parkinson's disease and dementia with Lewy bodies as neuronal α-synuclein disease rather than as clinical syndromes. This major shift from a clinical to a biological definition of Parkinson's disease and dementia with Lewy bodies takes advantage of the availability of tools to assess the gold standard for diagnosis of neuronal α-synuclein (n-αsyn) in human beings during life. Neuronal α-synuclein disease is defined by the presence of pathological n-αsyn species detected in vivo (S; the first biological anchor) regardless of the presence of any specific clinical syndrome. On the basis of this definition, we propose that individuals with pathological n-αsyn aggregates are at risk for dopaminergic neuronal dysfunction (D; the second biological anchor). Our biological definition establishes a staging system, the neuronal α-synuclein disease integrated staging system (NSD-ISS), rooted in the biological anchors (S and D) and the degree of functional impairment caused by clinical signs or symptoms. Stages 0-1 occur without signs or symptoms and are defined by the presence of pathogenic variants in the SNCA gene (stage 0), S alone (stage 1A), or S and D (stage 1B). The presence of clinical manifestations marks the transition to stage 2 and beyond. Stage 2 is characterised by subtle signs or symptoms but without functional impairment. Stages 2B-6 require both S and D and stage-specific increases in functional impairment. A biological definition of neuronal α-synuclein disease and an NSD-ISS research framework are essential to enable interventional trials at early disease stages. The NSD-ISS will evolve to include the incorporation of data-driven definitions of stage-specific functional anchors and additional biomarkers as they emerge and are validated. Presently, the NSD-ISS is intended for research use only; its application in the clinical setting is premature and inappropriate.

  View details for DOI 10.1016/S1474-4422(23)00405-2

  View details for PubMedID 38267190

• Assessment of heterogeneity among participants in the Parkinson?s Progression Markers Initiative cohort using a-synuclein seed amplification: a cross-sectional study LANCET NEUROLOGY Siderowf, A., Concha-Marambio, L., Lafontant, D., Farris, C. M., Ma, Y., Urenia, P. A., Nguyen, H., Alcalay, R. N., Chahine, L. M., Foroud, T., Galasko, D., Kieburtz, K., Merchant, K., Mollenhauer, B., Poston, K. L., Seibyl, J., Simuni, T., Tanner, C. M., Weintraub, D., Videnovic, A., Choi, S., Kurth, R., Caspell-Garcia, C., Coffey, C. S., Frasier, M., Oliveira, L. A., Hutten, S. J., Sherer, T., Marek, K., Soto, C., Parkinsons Progression Marker 2023; 22 (5): 407-417

  View details for Web of Science ID 000989704800001

• Illusory Responses across the Lewy Body Disease Spectrum ANNALS OF NEUROLOGY Shahid, M., Rawls, A., Ramirez, V., Ryman, S., Santini, V. E., Yang, L., Sha, S. J., Hall, J. N., Montine, T. J., Lin, A., Tian, L., Henderson, V. W., Cholerton, B., Yutsis, M., Poston, K. L. 2023

  View details for DOI 10.1002/ana.26574

  View details for Web of Science ID 000925056000001

• Parkinson's Progression Markers Initiative brain autopsy program. Parkinsonism & related disorders Bukhari, S. A., Nudelman, K. N., Rumbaugh, M., Richeson, P., Fox, E. J., Montine, K. S., Aldecoa, I., Garrido, A., Franz, J., Stadelmann, C., Vonsattel, J. P., Poston, K. L., Foroud, T. M., Montine, T. J. 2022; 101: 62-65

  Abstract

  We report on the initial 17 (11 male:6 female) brain autopsies from across Europe and the United States in the Parkinson's Progression Markers Initiative (PPMI). Clinical diagnoses were Parkinson's disease (n = 15), multiple system atrophy (n = 1), and Dementia with Lewy bodies (n = 1); average age of death = 72 ± 8 yr. Cognitive assessment at last evaluation was 5 with normal cognition, 7 with mild cognitive impairment, and 5 with dementia. Genetic assessment showed 4 participants were heterozygous or homozygous for GBA N370S and 3 were heterozygous carriers for LRRK2 R1441G or G2019S; 1 was an APOE ε2 carrier and 5 were APOE ε4 carriers. Longitudinal DAT neuroimaging as well as CSF and plasma biomarker data are summarized. Neuropathologic examination confirmed all clinical diagnoses and showed the expected frequencies of common comorbidities; no evidence of chronic traumatic encephalopathy was observed. Thus, brain autopsy data can provide confirmation, clarification, and new insights into the PD progression observed during life. As it grows, the PPMI brain autopsy program will provide a deeply-annotated research resource to the community of investigators focused on developing biomarkers for PD progression.

  View details for DOI 10.1016/j.parkreldis.2022.06.017

  View details for PubMedID 35803091

• Multimodal deep learning for Alzheimer's disease dementia assessment. Nature communications Qiu, S., Miller, M. I., Joshi, P. S., Lee, J. C., Xue, C., Ni, Y., Wang, Y., De Anda-Duran, I., Hwang, P. H., Cramer, J. A., Dwyer, B. C., Hao, H., Kaku, M. C., Kedar, S., Lee, P. H., Mian, A. Z., Murman, D. L., O'Shea, S., Paul, A. B., Saint-Hilaire, M., Alton Sartor, E., Saxena, A. R., Shih, L. C., Small, J. E., Smith, M. J., Swaminathan, A., Takahashi, C. E., Taraschenko, O., You, H., Yuan, J., Zhou, Y., Zhu, S., Alosco, M. L., Mez, J., Stein, T. D., Poston, K. L., Au, R., Kolachalama, V. B. 2022; 13 (1): 3404

  Abstract

  Worldwide, there are nearly 10 million new cases of dementia annually, of which Alzheimer's disease (AD) is the most common. New measures are needed to improve the diagnosis of individuals with cognitive impairment due to various etiologies. Here, we report a deep learning framework that accomplishes multiple diagnostic steps in successive fashion to identify persons with normal cognition (NC), mild cognitive impairment (MCI), AD, and non-AD dementias (nADD). We demonstrate a range of models capable of accepting flexible combinations of routinely collected clinical information, including demographics, medical history, neuropsychological testing, neuroimaging, and functional assessments. We then show that these frameworks compare favorably with the diagnostic accuracy of practicing neurologists and neuroradiologists. Lastly, we apply interpretability methods in computer vision to show that disease-specific patterns detected by our models track distinct patterns of degenerative changes throughout the brain and correspond closely with the presence of neuropathological lesions on autopsy. Our work demonstrates methodologies for validating computational predictions with established standards of medical diagnosis.

  View details for DOI 10.1038/s41467-022-31037-5

  View details for PubMedID 35725739

• Single-synapse analyses of Alzheimer's disease implicate pathologic tau, DJ1, CD47, and ApoE. Science advances Phongpreecha, T., Gajera, C. R., Liu, C. C., Vijayaragavan, K., Chang, A. L., Becker, M., Fallahzadeh, R., Fernandez, R., Postupna, N., Sherfield, E., Tebaykin, D., Latimer, C., Shively, C. A., Register, T. C., Craft, S., Montine, K. S., Fox, E. J., Poston, K. L., Keene, C. D., Angelo, M., Bendall, S. C., Aghaeepour, N., Montine, T. J. 1800; 7 (51): eabk0473

  Abstract

  [Figure: see text].

  View details for DOI 10.1126/sciadv.abk0473

  View details for PubMedID 34910503

• CD4+ T cells contribute to neurodegeneration in Lewy body dementia. Science (New York, N.Y.) Gate, D., Tapp, E., Leventhal, O., Shahid, M., Nonninger, T. J., Yang, A. C., Strempfl, K., Unger, M. S., Fehlmann, T., Oh, H., Channappa, D., Henderson, V. W., Keller, A., Aigner, L., Galasko, D. R., Davis, M. M., Poston, K. L., Wyss-Coray, T. 2021: eabf7266

  Abstract

  [Figure: see text].

  View details for DOI 10.1126/science.abf7266

  View details for PubMedID 34648304

• Cognition at Each Stage of Lewy Body Disease with Co-occurring Alzheimer's Disease Pathology. Journal of Alzheimer's disease : JAD Ryman, S. G., Yutsis, M., Tian, L., Henderson, V. W., Montine, T. J., Salmon, D. P., Galasko, D., Poston, K. L. 2021

  Abstract

  BACKGROUND: Alzheimer's disease neuropathologic change (ADNC) may contribute to dementia in patients with Lewy body disease (LBD) pathology.OBJECTIVE: To examine how co-occurring ADNC impacts domain specific cognitive impairments at each pathologic stage (brainstem, limbic, cerebral cortical) of LBD.METHODS: 2,433 participants with antemortem longitudinal neuropsychological assessment and postmortem neuropathological assessment from the National Alzheimer's Coordinating Center's Uniform Data Set were characterized based on the evaluation of ADNC and LBD. Longitudinal mixed-models were used to derive measures of cumulative cognitive deficit for each cognitive domain at each pathologic stage of LBD (brainstem, limbic, and cerebral cortical).RESULTS: 111 participants with a pathologic diagnosis of LBD, 741 participants with combined LBD and ADNC, 1,357 participants with ADNC only, and 224 with no pathology (healthy controls) were included in the analyses. In the executive/visuospatial domain, combined LBD and ADNC showed worse deficits than LBD only when Lewy bodies were confined to the brainstem, but no difference when Lewy bodies extended to the limbic or cerebral cortical regions. The cerebral cortical LBD only group exhibited greater executive/visuospatial deficits than the ADNC only group. By contrast, the ADNC only group and the combined pathology group both demonstrated significantly greater cumulative memory deficits relative to Lewy body disease only, regardless of stage.CONCLUSION: The impact of co-occurring ADNC on antemortem cumulative cognitive deficits varies not only by domain but also on the pathological stage of Lewy bodies. Our findings stress the cognitive impact of different patterns of neuropathological progression in Lewy body diseases.

  View details for DOI 10.3233/JAD-201187

  View details for PubMedID 33646154

• Single-cell peripheral immunoprofiling of Alzheimer's and Parkinson's diseases. Science advances Phongpreecha, T., Fernandez, R., Mrdjen, D., Culos, A., Gajera, C. R., Wawro, A. M., Stanley, N., Gaudilliere, B., Poston, K. L., Aghaeepour, N., Montine, T. J. 2020; 6 (48)

  Abstract

  Peripheral blood mononuclear cells (PBMCs) may provide insight into the pathogenesis of Alzheimer's disease (AD) or Parkinson's disease (PD). We investigated PBMC samples from 132 well-characterized research participants using seven canonical immune stimulants, mass cytometric identification of 35 PBMC subsets, and single-cell quantification of 15 intracellular signaling markers, followed by machine learning model development to increase predictive power. From these, three main intracellular signaling pathways were identified specifically in PBMC subsets from people with AD versus controls: reduced activation of PLCgamma2 across many cell types and stimulations and selectively variable activation of STAT1 and STAT5, depending on stimulant and cell type. Our findings functionally buttress the now multiply-validated observation that a rare coding variant in PLCG2 is associated with a decreased risk of AD. Together, these data suggest enhanced PLCgamma2 activity as a potential new therapeutic target for AD with a readily accessible pharmacodynamic biomarker.

  View details for DOI 10.1126/sciadv.abd5575

  View details for PubMedID 33239300

• Soluble TREM2 is elevated in Parkinson's disease subgroups with increased CSF tau. Brain : a journal of neurology Wilson, E. N., Swarovski, M. S., Linortner, P. n., Shahid, M. n., Zuckerman, A. J., Wang, Q. n., Channappa, D. n., Minhas, P. S., Mhatre, S. D., Plowey, E. D., Quinn, J. F., Zabetian, C. P., Tian, L. n., Longo, F. M., Cholerton, B. n., Montine, T. J., Poston, K. L., Andreasson, K. I. 2020

  Abstract

  Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease and affects 1% of the population above 60 years old. Although Parkinson's disease commonly manifests with motor symptoms, a majority of patients with Parkinson's disease subsequently develop cognitive impairment, which often progresses to dementia, a major cause of morbidity and disability. Parkinson's disease is characterized by α-synuclein accumulation that frequently associates with amyloid-β and tau fibrils, the hallmarks of Alzheimer's disease neuropathological changes; this co-occurrence suggests that onset of cognitive decline in Parkinson's disease may be associated with appearance of pathological amyloid-β and/or tau. Recent studies have highlighted the appearance of the soluble form of the triggering receptor expressed on myeloid cells 2 (sTREM2) receptor in CSF during development of Alzheimer's disease. Given the known association of microglial activation with advancing Parkinson's disease, we investigated whether CSF and/or plasma sTREM2 differed between CSF biomarker-defined Parkinson's disease participant subgroups. In this cross-sectional study, we examined 165 participants consisting of 17 cognitively normal elderly subjects, 45 patients with Parkinson's disease with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF amyloid-β and tau levels revealed that CSF sTREM2 concentrations were elevated in Parkinson's disease subgroups with a positive tau CSF biomarker signature, but not in Parkinson's disease subgroups with a positive CSF amyloid-β biomarker signature. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in Parkinson's disease.

  View details for DOI 10.1093/brain/awaa021

  View details for PubMedID 32065223

• Multivariate prediction of dementia in Parkinson's disease. NPJ Parkinson's disease Phongpreecha, T. n., Cholerton, B. n., Mata, I. F., Zabetian, C. P., Poston, K. L., Aghaeepour, N. n., Tian, L. n., Quinn, J. F., Chung, K. A., Hiller, A. L., Hu, S. C., Edwards, K. L., Montine, T. J. 2020; 6: 20

  Abstract

  Cognitive impairment in Parkinson's disease (PD) is pervasive with potentially devastating effects. Identification of those at risk for cognitive decline is vital to identify and implement appropriate interventions. Robust multivariate approaches, including fixed-effect, mixed-effect, and multitask learning models, were used to study associations between biological, clinical, and cognitive factors and for predicting cognitive status longitudinally in a well-characterized prevalent PD cohort (n = 827). Age, disease duration, sex, and GBA status were the primary biological factors associated with cognitive status and progression to dementia. Specific cognitive tests were better predictors of subsequent cognitive status for cognitively unimpaired and dementia groups. However, these models could not accurately predict future mild cognitive impairment (PD-MCI). Data collected from a large PD cohort thus revealed the primary biological and cognitive factors associated with dementia, and provide clinicians with data to aid in the identification of risk for dementia. Sex differences and their potential relationship to genetic status are also discussed.

  View details for DOI 10.1038/s41531-020-00121-2

  View details for PubMedID 32885039

  View details for PubMedCentralID PMC7447766

• Tau PET imaging with 18F-PI-2620 in aging and neurodegenerative diseases. European journal of nuclear medicine and molecular imaging Mormino, E. C., Toueg, T. N., Azevedo, C. n., Castillo, J. B., Guo, W. n., Nadiadwala, A. n., Corso, N. K., Hall, J. N., Fan, A. n., Trelle, A. N., Harrison, M. B., Hunt, M. P., Sha, S. J., Deutsch, G. n., James, M. n., Fredericks, C. A., Koran, M. E., Zeineh, M. n., Poston, K. n., Greicius, M. D., Khalighi, M. n., Davidzon, G. A., Shen, B. n., Zaharchuk, G. n., Wagner, A. D., Chin, F. T. 2020

  Abstract

  In vivo measurement of the spatial distribution of neurofibrillary tangle pathology is critical for early diagnosis and disease monitoring of Alzheimer's disease (AD).Forty-nine participants were scanned with 18F-PI-2620 PET to examine the distribution of this novel PET ligand throughout the course of AD: 36 older healthy controls (HC) (age range 61 to 86), 11 beta-amyloid+ (Aβ+) participants with cognitive impairment (CI; clinical diagnosis of either mild cognitive impairment or AD dementia, age range 57 to 86), and 2 participants with semantic variant primary progressive aphasia (svPPA, age 66 and 78). Group differences in brain regions relevant in AD (medial temporal lobe, posterior cingulate cortex, and lateral parietal cortex) were examined using standardized uptake value ratios (SUVRs) normalized to the inferior gray matter of the cerebellum.SUVRs in target regions were relatively stable 60 to 90 min post-injection, with the exception of very high binders who continued to show increases over time. Robust elevations in 18F-PI-2620 were observed between HC and Aβ+ CI across all AD regions. Within the HC group, older age was associated with subtle elevations in target regions. Mildly elevated focal uptake was observed in the anterior temporal pole in one svPPA patient.Preliminary results suggest strong differences in the medial temporal lobe and cortical regions known to be impacted in AD using 18F-PI-2620 in patients along the AD trajectory. This work confirms that 18F-PI-2620 holds promise as a tool to visualize tau aggregations in AD.

  View details for DOI 10.1007/s00259-020-04923-7

  View details for PubMedID 32572562

• Substantia Nigra Volume Dissociates Bradykinesia and Rigidity from Tremor in Parkinson's Disease: A 7 Tesla Imaging Study. Journal of Parkinson's disease Poston, K. L., Ua Cruadhlaoich, M. A., Santoso, L. F., Bernstein, J. D., Liu, T., Wang, Y., Rutt, B., Kerchner, G. A., Zeineh, M. M. 2020; 10 (2): 591–604

  Abstract

  BACKGROUND: In postmortem analysis of late stage Parkinson's disease (PD) neuronal loss in the substantial nigra (SN) correlates with the antemortem severity of bradykinesia and rigidity, but not tremor.OBJECTIVE: To investigate the relationship between midbrain nuclei volume as an in vivo biomarker for surviving neurons in mild-to-moderate patients using 7.0 Tesla MRI.METHODS: We performed ultra-high resolution quantitative susceptibility mapping (QSM) on the midbrain in 32 PD participants with less than 10 years duration and 8 healthy controls. Following blinded manual segmentation, the individual volumes of the SN, subthalamic nucleus, and red nucleus were measured. We then determined the associations between the midbrain nuclei and clinical metrics (age, disease duration, MDS-UPDRS motor score, and subscores for bradykinesia/rigidity, tremor, and postural instability/gait difficulty).RESULTS: We found that smaller SN correlated with longer disease duration (r = -0.49, p = 0.004), more severe MDS-UPDRS motor score (r = -0.42, p = 0.016), and more severe bradykinesia-rigidity subscore (r = -0.47, p = 0.007), but not tremor or postural instability/gait difficulty subscores. In a hemi-body analysis, bradykinesia-rigidity severity only correlated with SN contralateral to the less-affected hemi-body, and not contralateral to the more-affected hemi-body, possibly reflecting the greatest change in dopamine neuron loss early in disease. Multivariate generalized estimating equation model confirmed that bradykinesia-rigidity severity, age, and disease duration, but not tremor severity, predicted SN volume.CONCLUSIONS: In mild-to-moderate PD, SN volume relates to motor manifestations in a motor domain-specific and laterality-dependent manner. Non-invasive in vivo 7.0 Tesla QSM may serve as a biomarker in longitudinal studies of SN atrophy and in studies of people at risk for developing PD.

  View details for DOI 10.3233/JPD-191890

  View details for PubMedID 32250317

• Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson's Progression Markers Initiative (PPMI): a cross-sectional study. The Lancet. Neurology Simuni, T., Uribe, L., Cho, H. R., Caspell-Garcia, C., Coffey, C. S., Siderowf, A., Trojanowski, J. Q., Shaw, L. M., Seibyl, J., Singleton, A., Toga, A. W., Galasko, D., Foroud, T., Tosun, D., Poston, K., Weintraub, D., Mollenhauer, B., Tanner, C. M., Kieburtz, K., Chahine, L. M., Reimer, A., Hutten, S. J., Bressman, S., Marek, K., PPMI Investigators, Arnedo, V., Clark, A., Fraiser, M., Kopil, C., Chowdhury, S., Sherer, T., Daegele, N., Casaceli, C., Dorsey, R., Wilson, R., Mahes, S., Salerno, C., Crawford, K., Casalin, P., Malferrari, G., Weisz, M. G., Orr-Urtreger, A., Montine, T., Baglieri, C., Christini, A., Russell, D., Dahodwala, N., Giladi, N., Factor, S., Hogarth, P., Standaert, D., Hauser, R., Jankovic, J., Saint-Hilaire, M., Richard, I., Shprecher, D., Fernandez, H., Brockmann, K., Rosenthal, L., Barone, P., Espay, A., Rowe, D., Marder, K., Santiago, A., Hu, S., Isaacson, S., Corvol, J., Ruiz Martinez, J., Tolosa, E., Tai, Y., Politis, M., Smejdir, D., Rees, L., Williams, K., Kausar, F., Williams, K., Richardson, W., Willeke, D., Peacock, S., Sommerfeld, B., Freed, A., Wakeman, K., Blair, C., Guthrie, S., Harrell, L., Hunter, C., Thomas, C., James, R., Zimmerman, G., Brown, V., Mule, J., Hilt, E., Ribb, K., Ainscough, S., Wethington, M., Ranola, M., Mejia Santana, H., Moreno, J., Raymond, D., Speketer, K., Carvajal, L., Carvalo, S., Croitoru, I., Garrido, A., Payne, L. M., Viswanth, V., Severt, L., Facheris, M., Soares, H., Mintun, M. A., Cedarbaum, J., Taylor, P., Biglan, K., Vandenbroucke, E., Haider Sheikh, Z., Bingol, B., Fischer, T., Sardi, P., Forrat, R., Reith, A., Egebjerg, J., Ahlberg Hillert, G., Saba, B., Min, C., Umek, R., Mather, J., De Santi, S., Post, A., Boess, F., Taylor, K., Grachev, I., Avbersek, A., Muglia, P., Merchant, K., Tauscher, J. 2019

  Abstract

  BACKGROUND: The Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's disease that correlate with reduced DAT binding.METHODS: This cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65% of putamen striatal binding ratio expected for the individual's age. We used t tests, chi2 tests, and Fisher's exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number NCT01141023.FINDINGS: Between Jan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60% were female. Of the 286 (73%) non-manifesting carriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson's Disease Rating Scale (total score 4·6 [SD 4·4] healthy controls vs 8·4 [7·3] LRRK2 vs 9·5 [9·2] GBA, p<0·0001 for both comparisons) and the Scale for Outcomes for PD - autonomic function (5·8 [3·7] vs 8·1 [5·9] and 8·4 [6·0], p<0·0001 for both comparisons). There was no difference in daytime sleepiness, anxiety, depression, impulsive-compulsive disorders, blood pressure, urate, and rapid eye movement (REM) behaviour disorder scores. Hyposmia was significantly more common only in LRRK2 non-manifesting carriers (69 [36%] of 194 healthy controls vs 114 [55%] of 208 LRRK2 non-manifesting carriers; p=0·0003). Finally, GBA but not LRRK2 non-manifesting carriers showed increased DAT striatal binding ratios compared with healthy controls in the caudate (healthy controls 2·98 [SD 0·63] vs GBA 3·26 [0·63]; p<0·0001), putamen (2·15 [0·56] vs 2·48 [0·52]; p<0·0001), and striatum (2·56 [0·57] vs 2·87 [0·55]; p<0·0001).INTERPRETATION: Our data show evidence of subtle motor and non-motor signs of Parkinson's disease in non-manifesting carriers compared with healthy controls that can precede DAT deficit. Longitudinal data will be essential to confirm these findings and define the trajectory and predictors for development of Parkinson's disease.FUNDING: Michael J Fox Foundation for Parkinson's Research.

  View details for DOI 10.1016/S1474-4422(19)30319-9

  View details for PubMedID 31678032

• An increased rate of longitudinal cognitive decline is observed in Parkinson's disease patients with low CSF ASS42 and an APOE epsilon4 allele. Neurobiology of disease Shahid, M., Kim, J., Leaver, K., Hendershott, T., Zhu, D., Cholerton, B., Henderson, V. W., Tian, L., Poston, K. L. 2019

  Abstract

  OBJECTIVE: Low concentrations of cerebrospinal fluid (CSF) amyloid-beta (Abeta-42) are associated with increased risk of cognitive decline in Parkinson's disease (PD). We sought to determine whether APOE genotype modifies the rate of cognitive decline in PD patients with low CSF Abeta-42 compared to patients with normal levels.METHODS: The Parkinson's Progression Markers Initiative is a longitudinal, ongoing study of de novo PD participants, which includes APOE genotyping, CSF Abeta-42 determinations, and neuropsychological assessments. We used linear mixed effects models in three PD groups (PD participants with low CSF Abeta at baseline, PD participants with normal CSF Abeta, and both groups combined). Having at least one copy of the APOE ɛ4 allele, time, and the interaction of APOE ɛ4 and time were predictor variables for cognitive change, adjusting for age, gender and education.RESULTS: 423 de novo PD participants were followed up to 5 years with annual cognitive assessments. 103 participants had low baseline CSF Abeta-42 (39 APOE epsilon4+, 64 APOE epsilon4-). Compared to participants with normal CSF Abeta-42, those with low CSF Abeta-42 declined faster on most cognitive tests. Within the low CSF Abeta-42 group, APOE epsilon4+ participants had faster rates of decline on the Montreal Cognitive Assessment (primary outcome; 0.57 points annual decline, p = .005; 5-year standardized change of 1.2) and the Symbol Digit Modalities Test (1.4 points annual decline, p = .002; 5-year standardized change of 0.72).DISCUSSION: PD patients with low CSF Abeta-42 and APOE epsilon4+ showed a higher rate of cognitive decline early in the disease. Tests of global cognition (Montreal Cognitive Assessment) and processing speed (Symbol Digit Modalities Test) were the most sensitive to early cognitive decline. Results suggest that CSF Abeta-42 and APOE epsilon4 might interact to promote early cognitive changes in PD patients.

  View details for PubMedID 30826425

• Longitudinal Change of Clinical and Biological Measures in Early Parkinson's Disease: Parkinson's Progression Markers Initiative Cohort MOVEMENT DISORDERS Simuni, T., Siderowf, A., Lasch, S., Coffey, C. S., Caspell-Garcia, C., Jennings, D., Tanner, C. M., Trojanowski, J. Q., Shaw, L. M., Seibyl, J., Schuff, N., Singleton, A., Kieburtz, K., Toga, A. W., Mollenhauer, B., Galasko, D., Chahine, L. M., Weintraub, D., Foroud, T., Tosun, D., Poston, K., Arnedo, V., Frasier, M., Sherer, T., Chowdhury, S., Marek, K., Parkinson's Progression Marker Ini 2018; 33 (5): 771–82

  Abstract

  The objective of this study was to assess longitudinal change in clinical and dopamine transporter imaging outcomes in early, untreated PD.We describe 5-year longitudinal change of the MDS-UPDRS and other clinical measures using results from the Parkinson's Progression Markers Initiative, a longitudinal cohort study of early Parkinson's disease (PD) participants untreated at baseline. We also provide data on the longitudinal change in dopamine transporter 123-I Ioflupane striatal binding and correlation between the 2 measures.A total of 423 PD participants were recruited, and 358 remain in the study at year 5. Baseline MDS-UPDRS total score was 32.4 (standard deviation 13.1), and the average annual change (assessed medications OFF for the treated participants) was 7.45 (11.6), 3.11 (11.7), 4(11.9), 4.7 (11.1), and 1.74(11.9) for years 1, 2, 3, 4, and 5, respectively (P < .0001 for the change over time), with a steeper change in year 1. Dopaminergic therapy had a significant effect on the change of MDS-UPDRS. There was a significant longitudinal change in dopamine transporter binding in all striatal regions (P < .001). There was a significant but weak correlation between MDS-UPDRS and dopamine transporter binding at baseline and years 1, 2, and 4, but no correlation between the rate of change of the 2 variables.We present 5-year longitudinal data on the change of the MDS-UPDRS and other clinical and dopamine transporter imaging outcome measures in early PD. These data can be used for sample size estimates for interventional studies in the de novo PD population. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

  View details for PubMedID 29572948

  View details for PubMedCentralID PMC6001458

• Compensatory neural mechanisms in cognitively unimpaired Parkinson disease. Annals of neurology Poston, K. L., YorkWilliams, S., Zhang, K., Cai, W., Everling, D., Tayim, F. M., Llanes, S., Menon, V. 2016; 79 (3): 448-463

  Abstract

  Cognitive impairments in Parkinson's disease (PD) are thought to be caused in part by dopamine dysregulation. However, even when nigrostriatal dopamine neuron loss is severe enough to cause motor symptoms, many patients remain cognitively unimpaired. It is unclear what brain mechanisms allow these patients to remain cognitively unimpaired despite substantial dopamine dysregulation.31 cognitively unimpaired PD participants OFF dopaminergic-medications were scanned using fMRI while they performed a working memory task, along with 23 controls. We first compared the PD_OFF medication group with controls to determine whether PD participants engage compensatory frontostriatal mechanisms during working memory. We then studied the same PD participants ON dopaminergic-medications to determine whether these compensatory brain changes are altered with dopamine.Controls and PD showed working memory load-dependent activation in the bilateral putamen, anterior-dorsal insula, supplementary motor area, and anterior cingulate cortex. Compared to controls, PD_OFF showed compensatory hyper-activation of bilateral putamen and posterior insula, and machine learning algorithms identified robust differences in putamen activation patterns. Compared to PD_OFF, PD_ON showed reduced compensatory activation in the putamen. Loss of compensatory hyper-activation ON dopaminergic-medication correlated with slower performance on the working memory task and slower cognitive speed on the Symbol Digit Modality Test.Our results provide novel evidence that PD patients maintain normal cognitive performance through compensatory hyper-activation of the putamen. Dopaminergic-medication down-regulates this hyper-activation and the degree of down-regulation predicts behavior. Identifying cognitive compensatory mechanisms in PD is important for understanding how some patients maintain intact cognitive performance, despite nigrostriatal dopamine loss. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ana.24585

  View details for PubMedID 26696272

• Differential diagnosis of parkinsonism: a metabolic imaging study using pattern analysis LANCET NEUROLOGY Tang, C. C., Poston, K. L., Eckert, T., Feigin, A., Frucht, S., Gudesblatt, M., Dhawan, V., Lesser, M., Vonsattel, J., Fahn, S., Eidelberg, D. 2010; 9 (2): 149-158

  Abstract

  Idiopathic Parkinson's disease can present with symptoms similar to those of multiple system atrophy or progressive supranuclear palsy. We aimed to assess whether metabolic brain imaging combined with spatial covariance analysis could accurately discriminate patients with parkinsonism who had different underlying disorders.Between January, 1998, and December, 2006, patients from the New York area who had parkinsonian features but uncertain clinical diagnosis had fluorine-18-labelled-fluorodeoxyglucose-PET at The Feinstein Institute for Medical Research. We developed an automated image-based classification procedure to differentiate individual patients with idiopathic Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. For each patient, the likelihood of having each of the three diseases was calculated by use of multiple disease-related patterns with logistic regression and leave-one-out cross-validation. Each patient was classified according to criteria defined by receiver-operating-characteristic analysis. After imaging, patients were assessed by blinded movement disorders specialists for a mean of 2.6 years before a final clinical diagnosis was made. The accuracy of the initial image-based classification was assessed by comparison with the final clinical diagnosis.167 patients were assessed. Image-based classification for idiopathic Parkinson's disease had 84% sensitivity, 97% specificity, 98% positive predictive value (PPV), and 82% negative predictive value (NPV). Imaging classifications were also accurate for multiple system atrophy (85% sensitivity, 96% specificity, 97% PPV, and 83% NPV) and progressive supranuclear palsy (88% sensitivity, 94% specificity, 91% PPV, and 92% NPV).Automated image-based classification has high specificity in distinguishing between parkinsonian disorders and could help in selecting treatment for early-stage patients and identifying participants for clinical trials.National Institutes of Health and General Clinical Research Center at The Feinstein Institute for Medical Research.

  View details for DOI 10.1016/S1474-4422(10)70002-8

  View details for Web of Science ID 000273922000012

  View details for PubMedID 20061183

• Elevated tau in the piriform cortex in Alzheimer's but not Parkinson's disease using PET-MR. Alzheimer's & dementia (Amsterdam, Netherlands) Moein Taghavi, H., Karimpoor, M., van Staalduinen, E. K., Young, C. B., Georgiadis, M., Leventis, S., Carlson, M., Romero, A., Trelle, A., Vossler, H., Yutsis, M., Rosenberg, J., Davidzon, G. A., Zaharchuk, G., Poston, K., Wagner, A. D., Henderson, V. W., Mormino, E., Zeineh, M. 2024; 16 (4): e70040

  Abstract

  Olfactory dysfunction can be an early sign of Alzheimer's disease (AD). We used tau positron emission tomography-magnetic resonance (PET-MR) to analyze a key region of the olfactory circuit, the piriform cortex, in comparison to the adjacent medial temporal lobe.Using co-registered magnetic resonance imaging (MRI) and 18F-PI-2620 tau PET-MR scans in 94 older adults, we computed tau uptake in the piriform-periamygdaloid cortex, amygdala, entorhinal-perirhinal cortices, and hippocampus.We found an ordinal cross-sectional increase in piriform cortex tau uptake with increasing disease severity (amyloid-negative controls, amyloid-positive controls, mild cognitive impairment [MCI] and AD), comparable to entorhinal-perirhinal cortex. Amyloid-positive controls showed significantly greater tau uptake than amyloid-negative controls. Negative correlations were present between memory performance and piriform uptake. Piriform uptake was not elevated in cognitively unimpaired Parkinson's disease.Cross-sectionally, there is an early increase in tau uptake in the piriform cortex in AD but not in Parkinson's disease.Positron emission tomography-magnetic resonance (PET-MR) analysis of the piriform cortex sheds light on its role as a potential early region affected by neurodegenerative disorders underlying olfactory dysfunction.Uptake of tau tracer was elevated in the piriform cortex in Alzheimer's disease (AD) and mild cognitive impairment (MCI) but not in Parkinson's disease (PD).Memory performance was worse with greater piriform uptake.

  View details for DOI 10.1002/dad2.70040

  View details for PubMedID 39583648

  View details for PubMedCentralID PMC11585164

• A worldwide study of subcortical shape as a marker for clinical staging in Parkinson's disease. NPJ Parkinson's disease Laansma, M. A., Zhao, Y., van Heese, E. M., Bright, J. K., Owens-Walton, C., Al-Bachari, S., Anderson, T. J., Assogna, F., van Balkom, T. D., Berendse, H. W., Cendes, F., Dalrymple-Alford, J. C., Debove, I., Dirkx, M. F., Druzgal, J., Emsley, H. C., Fouche, J. P., Garraux, G., Guimarães, R. P., Helmich, R. C., Hu, M., van den Heuvel, O. A., Isaev, D., Kim, H. B., Klein, J. C., Lochner, C., McMillan, C. T., Melzer, T. R., Newman, B., Parkes, L. M., Pellicano, C., Piras, F., Pitcher, T. L., Poston, K. L., Rango, M., Ribeiro, L. F., Rocha, C. S., Rummel, C., Santos, L. S., Schmidt, R., Schwingenschuh, P., Squarcina, L., Stein, D. J., Vecchio, D., Vriend, C., Wang, J., Weintraub, D., Wiest, R., Yasuda, C. L., Jahanshad, N., Thompson, P. M., van der Werf, Y. D., Gutman, B. A. 2024; 10 (1): 223

  Abstract

  Alterations in subcortical brain regions are linked to motor and non-motor symptoms in Parkinson's disease (PD). However, associations between clinical expression and regional morphological abnormalities of the basal ganglia, thalamus, amygdala and hippocampus are not well established. We analyzed 3D T1-weighted brain MRI and clinical data from 2525 individuals with PD and 1326 controls from 22 global sources in the ENIGMA-PD consortium. We investigated disease effects using mass univariate and multivariate models on the medial thickness of 27,120 vertices of seven bilateral subcortical structures. Shape differences were observed across all Hoehn and Yahr (HY) stages, as well as correlations with motor and cognitive symptoms. Notably, we observed incrementally thinner putamen from HY1, caudate nucleus and amygdala from HY2, hippocampus, nucleus accumbens, and thalamus from HY3, and globus pallidus from HY4-5. Subregions of the thalami were thicker in HY1 and HY2. Largely congruent patterns were associated with a longer time since diagnosis and worse motor symptoms and cognitive performance. Multivariate regression revealed patterns predictive of disease stage. These cross-sectional findings provide new insights into PD subcortical degeneration by demonstrating patterns of disease stage-specific morphology, largely consistent with ongoing degeneration.

  View details for DOI 10.1038/s41531-024-00825-9

  View details for PubMedID 39557903

  View details for PubMedCentralID PMC11574005

• Parkinson's disease is characterized by vitamin B6-dependent inflammatory kynurenine pathway dysfunction. Research square Wilson, E., Umans, J., Swarovski, M., Minhas, P., Midttun, Ø., Ulvik, A. A., Shahid-Besanti, M., Linortner, P., Mhatre, S., Wang, Q., Channappa, D., Corso, N., Tian, L., Fredericks, C., Kerchner, G., Plowey, E., Cholerton, B., Ueland, P., Zabetian, C., Gray, N., Quinn, J., Montine, T., Sha, S., Longo, F., Wolk, D., Chen-Plotkin, A., Henderson, V., Wyss-Coray, T., Wagner, A., Mormino, E., Aghaeepour, N., Poston, K., Andreasson, K. 2024

  Abstract

  Parkinson's disease (PD) is a complex multisystem disorder clinically characterized by motor, non-motor, and premotor manifestations. Pathologically, PD involves neuronal loss in the substantia nigra, striatal dopamine deficiency, and accumulation of intracellular inclusions containing aggregates of α-synuclein. Recent studies demonstrate that PD is associated with dysregulated metabolic flux through the kynurenine pathway (KP), in which tryptophan is converted to kynurenine (KYN), and KYN is subsequently metabolized to neuroactive compounds quinolinic acid (QA) and kynurenic acid (KA). This multicenter study used highly sensitive liquid chromatography-tandem mass-spectrometry to compare blood and cerebral spinal fluid (CSF) KP metabolites between 158 unimpaired older adults and 177 participants with PD. Results indicate that increased neuroexcitatory QA/KA ratio in both plasma and CSF of PD participants associated with peripheral and cerebral inflammation and vitamin B6 deficiency. Furthermore, increased QA tracked with CSF tau and severity of both motor and non-motor PD clinical dysfunction. Importantly, plasma and CSF kynurenine metabolites classified PD participants with a high degree of accuracy (AUC = 0.897). Finally, analysis of metabolite data revealed subgroups with distinct KP profiles, and these were subsequently found to display distinct PD clinical features. Together, these data further support the hypothesis that the KP serves as a site of brain and periphery crosstalk, integrating B-vitamin status, inflammation and metabolism to ultimately influence PD clinical manifestation.

  View details for DOI 10.21203/rs.3.rs-4980210/v1

  View details for PubMedID 39399688

  View details for PubMedCentralID PMC11469709

• Neuronal alpha-Synuclein Disease Integrated Staging System performance in PPMI, PASADENA, and SPARK baseline cohorts. medRxiv : the preprint server for health sciences Dam, T., Pagano, G., Brumm, M. C., Gochanour, C., Poston, K. L., Weintraub, D., Chahine, L. M., Coffey, C., Tanner, C. M., Kopil, C. M., Xiao, Y., Chowdhury, S., Concha-Marambio, L., DiBiaso, P., Foroud, T., Frasier, M., Jennings, D., Kieburtz, K., Merchant, K., Mollenhauer, B., Montine, T. J., Nudelman, K., Seibyl, J., Sherer, T., Singleton, A., Stephenson, D., Stern, M., Soto, C., Tolosa, E., Siderowf, A., Dunn, B., Simuni, T., Marek, K. 2024

  Abstract

  The Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with Lewy body pathology and stage them based on underlying biology and increasing degree of functional impairment. Utilizing data from the PPMI, PASADENA and SPARK studies, we developed and applied biologic and clinical data-informed definitions for the NSD-ISS across the disease continuum. Individuals enrolled as Parkinson's disease, Prodromal, or Healthy Controls were defined and staged based on biological, clinical, and functional anchors at baseline. Across the three studies 1,741 participants had SAA data and of these 1,030 (59%) were S+ consistent with NSD. Among sporadic PD, 683/736 (93%) were NSD, and the distribution for Stages 2B, 3, and 4 was 25%, 63%, and 9%, respectively. Median (95% CI) time to developing a clinically meaningful outcome was 8.3 (6.2, 10.1), 5.9 (4.1, 6.0), and 2.4 (1.0, 4.0) years for baseline stage 2B, 3, and 4, respectively. We propose pilot biologic and clinical anchors for NSD-ISS. Our results highlight the baseline heterogeneity of individuals currently defined as early PD. Baseline stage predicts time to progression to clinically meaningful milestones. Further research on validation of the anchors in longitudinal cohorts is necessary.

  View details for DOI 10.1101/2024.02.14.24302818

  View details for PubMedID 39314957

  View details for PubMedCentralID PMC11419206

• A worldwide study of white matter microstructural alterations in people living with Parkinson's disease. NPJ Parkinson's disease Owens-Walton, C., Nir, T. M., Al-Bachari, S., Ambrogi, S., Anderson, T. J., Aventurato, Í. K., Cendes, F., Chen, Y. L., Ciullo, V., Cook, P., Dalrymple-Alford, J. C., Dirkx, M. F., Druzgal, J., Emsley, H. C., Guimarães, R., Haroon, H. A., Helmich, R. C., Hu, M. T., Johansson, M. E., Kim, H. B., Klein, J. C., Laansma, M., Lawrence, K. E., Lochner, C., Mackay, C., McMillan, C. T., Melzer, T. R., Nabulsi, L., Newman, B., Opriessnig, P., Parkes, L. M., Pellicano, C., Piras, F., Piras, F., Pirpamer, L., Pitcher, T. L., Poston, K. L., Roos, A., Silva, L. S., Schmidt, R., Schwingenschuh, P., Shahid-Besanti, M., Spalletta, G., Stein, D. J., Thomopoulos, S. I., Tosun, D., Tsai, C. C., van den Heuvel, O. A., van Heese, E., Vecchio, D., Villalón-Reina, J. E., Vriend, C., Wang, J. J., Wu, Y. R., Yasuda, C. L., Thompson, P. M., Jahanshad, N., van der Werf, Y. 2024; 10 (1): 151

  Abstract

  The progression of Parkinson's disease (PD) is associated with microstructural alterations in neural pathways, contributing to both motor and cognitive decline. However, conflicting findings have emerged due to the use of heterogeneous methods in small studies. Here we performed a large diffusion MRI study in PD, integrating data from 17 cohorts worldwide, to identify stage-specific profiles of white matter differences. Diffusion-weighted MRI data from 1654 participants diagnosed with PD (age: 20-89 years; 33% female) and 885 controls (age: 19-84 years; 47% female) were analyzed using the ENIGMA-DTI protocol to evaluate white matter microstructure. Skeletonized maps of fractional anisotropy (FA) and mean diffusivity (MD) were compared across Hoehn and Yahr (HY) disease groups and controls to reveal the profile of white matter alterations at different stages. We found an enhanced, more widespread pattern of microstructural alterations with each stage of PD, with eventually lower FA and higher MD in almost all regions of interest: Cohen's d effect sizes reached d = -1.01 for FA differences in the fornix at PD HY Stage 4/5. The early PD signature in HY stage 1 included higher FA and lower MD across the entire white matter skeleton, in a direction opposite to that typical of other neurodegenerative diseases. FA and MD were associated with motor and non-motor clinical dysfunction. While overridden by degenerative changes in the later stages of PD, early PD is associated with paradoxically higher FA and lower MD in PD, consistent with early compensatory changes associated with the disorder.

  View details for DOI 10.1038/s41531-024-00758-3

  View details for PubMedID 39128907

  View details for PubMedCentralID PMC11317500

• Data-driven discovery of movement-linked heterogeneity in neurodegenerative diseases NATURE MACHINE INTELLIGENCE Endo, M., Nerrise, F., Zhao, Q., Sullivan, E. V., Fei-Fei, L., Henderson, V. W., Pohl, K. M., Poston, K. L., Adeli, E. 2024

  View details for DOI 10.1038/s42256-024-00882-y

  View details for Web of Science ID 001287474600001

• Single-cell peripheral immunoprofiling of lewy body and Parkinson's disease in a multi-site cohort. Molecular neurodegeneration Phongpreecha, T., Mathi, K., Cholerton, B., Fox, E. J., Sigal, N., Espinosa, C., Reincke, M., Chung, P., Hwang, L. J., Gajera, C. R., Berson, E., Perna, A., Xie, F., Shu, C. H., Hazra, D., Channappa, D., Dunn, J. E., Kipp, L. B., Poston, K. L., Montine, K. S., Maecker, H. T., Aghaeepour, N., Montine, T. J. 2024; 19 (1): 59

  Abstract

  Multiple lines of evidence support peripheral organs in the initiation or progression of Lewy body disease (LBD), a spectrum of neurodegenerative diagnoses that include Parkinson's Disease (PD) without or with dementia (PDD) and dementia with Lewy bodies (DLB). However, the potential contribution of the peripheral immune response to LBD remains unclear. This study aims to characterize peripheral immune responses unique to participants with LBD at single-cell resolution to highlight potential biomarkers and increase mechanistic understanding of LBD pathogenesis in humans.In a case-control study, peripheral mononuclear cell (PBMC) samples from research participants were randomly sampled from multiple sites across the United States. The diagnosis groups comprise healthy controls (HC, n = 159), LBD (n = 110), Alzheimer's disease dementia (ADD, n = 97), other neurodegenerative disease controls (NDC, n = 19), and immune disease controls (IDC, n = 14). PBMCs were activated with three stimulants (LPS, IL-6, and IFNa) or remained at basal state, stained by 13 surface markers and 7 intracellular signal markers, and analyzed by flow cytometry, which generated 1,184 immune features after gating.The model classified LBD from HC with an AUROC of 0.87 ± 0.06 and AUPRC of 0.80 ± 0.06. Without retraining, the same model was able to distinguish LBD from ADD, NDC, and IDC. Model predictions were driven by pPLCγ2, p38, and pSTAT5 signals from specific cell populations under specific activation. The immune responses characteristic for LBD were not associated with other common medical conditions related to the risk of LBD or dementia, such as sleep disorders, hypertension, or diabetes.Quantification of PBMC immune response from multisite research participants yielded a unique pattern for LBD compared to HC, multiple related neurodegenerative diseases, and autoimmune diseases thereby highlighting potential biomarkers and mechanisms of disease.

  View details for DOI 10.1186/s13024-024-00748-2

  View details for PubMedID 39090623

  View details for PubMedCentralID 9739123

• LRRK2-Associated Parkinsonism With and Without In Vivo Evidence of Alpha-Synuclein Aggregates. medRxiv : the preprint server for health sciences Chahine, L. M., Lafontant, D. E., Ho Choi, S., Iwaki, H., Blauwendraat, C., Singleton, A. B., Brumm, M. C., Alcalay, R. N., Merchant, K., Nudelman, K. N., Dagher, A., Vo, A., Tao, Q., Venuto, C. S., Kieburtz, K., Poston, K. L., Bressman, S., Gonzalez-Latapi, P., Avants, B., Coffey, C., Jennings, D., Tolosa, E., Siderowf, A., Marek, K., Simuni, T. 2024

  Abstract

  Among LRRK2-associated parkinsonism cases with nigral degeneration, over two-thirds demonstrate evidence of pathologic alpha-synuclein, but many do not. Understanding the clinical phenotype and underlying biology in such individuals is critical for therapeutic development. Our objective was to compare clinical and biomarker features, and rate of progression over 4 years follow-up, among LRRK2-associated parkinsonism cases with and without in vivo evidence of alpha-synuclein aggregates.Data were from the Parkinson's Progression Markers Initiative, a multicenter prospective cohort study. The sample included individuals diagnosed with Parkinson disease with pathogenic variants in LRRK2. Presence of CSF alpha-synuclein aggregation was assessed with seed amplification assay. A range of clinician- and patient- reported outcome assessments were administered. Biomarkers included dopamine transporter SPECT scan, CSF amyloid-beta1-42, total tau, phospho-tau181, urine bis(monoacylglycerol)phosphate levels, and serum neurofilament light chain. Linear mixed effects models examined differences in trajectory in CSF negative and positive groups.148 LRRK2-parkinsonism cases (86% with G2019S variant), 46 negative and 102 positive for CSF alpha-synuclein seed amplification assay were included. At baseline, the negative group were older than the positive group (median [interquartile range] 69.1 [65.2-72.3] vs 61.5 [55.6-66.9] years, p<0.001) and a greater proportion were female (28 (61%) vs 43 (42%), p=0.035). Despite being older, the negative group had similar duration since diagnosis, and similar motor rating scale (16 [11-23] vs 16 [10-22], p=0.480) though lower levodopa equivalents. Only 13 (29%) of the negative group were hyposmic, compared to 75 (77%) of the positive group. Lowest putamen dopamine transporter binding expected for age and sex was greater in the negative vs positive groups (0.36 [0.29-0.45] vs 0.26 [0.22-0.37], p<0.001). Serum neurofilament light chain was higher in the negative group compared to the positive group (17.10 [13.60-22.10] vs 10.50 [8.43-14.70]; age-adjusted p-value=0.013). In terms of longitudinal change, the negative group remained stable in functional rating scale score in contrast to the positive group who had a significant increase (worsening) of 0.729 per year (p=0.037), but no other differences in trajectory were found.Among individuals diagnosed with Parkinson disease with pathogenic variants in the LRRK2 gene, we found clinical and biomarker differences in cases without versus with in vivo evidence of CSF alpha-synuclein aggregates. LRRK2 parkinsonism cases without evidence of alpha-synuclein aggregates as a group exhibit less severe motor manifestations and decline may have more significant cognitive dysfunction. The underlying biology in LRRK2-parkinsonism cases without evidence of alpha-synuclein aggregates requires further investigation.

  View details for DOI 10.1101/2024.07.22.24310806

  View details for PubMedID 39108519

  View details for PubMedCentralID PMC11302724

• Florbetaben amyloid PET acquisition time: Influence on Centiloids and interpretation. Alzheimer's & dementia : the journal of the Alzheimer's Association Johns, E., Vossler, H. A., Young, C. B., Carlson, M. L., Winer, J. R., Younes, K., Park, J., Rathmann-Bloch, J., Smith, V., Harrison, T. M., Landau, S., Henderson, V., Wagner, A., Sha, S. J., Zeineh, M., Zaharchuk, G., Poston, K. L., Davidzon, G. A., Mormino, E. C. 2024

  Abstract

  Amyloid positron emission tomography (PET) acquisition timing impacts quantification.In florbetaben (FBB) PET scans of 245 adults with and without cognitive impairment, we investigated the impact of post-injection acquisition time on Centiloids (CLs) across five reference regions. CL equations for FBB were derived using standard methods, using FBB data collected between 90 and 110 min with paired Pittsburgh compound B data. Linear mixed models and t-tests evaluated the impact of acquisition time on CL increases.CL values increased significantly over the scan using the whole cerebellum, cerebellar gray matter, and brainstem as reference regions, particularly in amyloid-positive individuals. In contrast, CLs based on white matter-containing reference regions decreased across the scan.The quantification of CLs in FBB PET imaging is influenced by both the overall scan acquisition time and the choice of reference region. Standardized acquisition protocols or the application of acquisition time-specific CL equations should be implemented in clinical protocols.Acquisition timing affects florbetaben positron emission tomography (PET) scan quantification, especially in amyloid-positive participants. The impact of acquisition timing on quantification varies across common reference regions. Consistent acquisitions and/or appropriate post-injection adjustments are needed to ensure comparability of PET data.

  View details for DOI 10.1002/alz.13893

  View details for PubMedID 38962867

• AI-based differential diagnosis of dementia etiologies on multimodal data. Nature medicine Xue, C., Kowshik, S. S., Lteif, D., Puducheri, S., Jasodanand, V. H., Zhou, O. T., Walia, A. S., Guney, O. B., Zhang, J. D., Pham, S. T., Kaliaev, A., Andreu-Arasa, V. C., Dwyer, B. C., Farris, C. W., Hao, H., Kedar, S., Mian, A. Z., Murman, D. L., O'Shea, S. A., Paul, A. B., Rohatgi, S., Saint-Hilaire, M. H., Sartor, E. A., Setty, B. N., Small, J. E., Swaminathan, A., Taraschenko, O., Yuan, J., Zhou, Y., Zhu, S., Karjadi, C., Alvin Ang, T. F., Bargal, S. A., Plummer, B. A., Poston, K. L., Ahangaran, M., Au, R., Kolachalama, V. B. 2024

  Abstract

  Differential diagnosis of dementia remains a challenge in neurology due to symptom overlap across etiologies, yet it is crucial for formulating early, personalized management strategies. Here, we present an artificial intelligence (AI) model that harnesses a broad array of data, including demographics, individual and family medical history, medication use, neuropsychological assessments, functional evaluations and multimodal neuroimaging, to identify the etiologies contributing to dementia in individuals. The study, drawing on 51,269 participants across 9 independent, geographically diverse datasets, facilitated the identification of 10 distinct dementia etiologies. It aligns diagnoses with similar management strategies, ensuring robust predictions even with incomplete data. Our model achieved a microaveraged area under the receiver operating characteristic curve (AUROC) of 0.94 in classifying individuals with normal cognition, mild cognitive impairment and dementia. Also, the microaveraged AUROC was 0.96 in differentiating the dementia etiologies. Our model demonstrated proficiency in addressing mixed dementia cases, with a mean AUROC of 0.78 for two co-occurring pathologies. In a randomly selected subset of 100 cases, the AUROC of neurologist assessments augmented by our AI model exceeded neurologist-only evaluations by 26.25%. Furthermore, our model predictions aligned with biomarker evidence and its associations with different proteinopathies were substantiated through postmortem findings. Our framework has the potential to be integrated as a screening tool for dementia in clinical settings and drug trials. Further prospective studies are needed to confirm its ability to improve patient care.

  View details for DOI 10.1038/s41591-024-03118-z

  View details for PubMedID 38965435

  View details for PubMedCentralID 7305953

• Development of highly multiplex targeted proteomics assays in biofluids using the Stellar mass spectrometer. bioRxiv : the preprint server for biology Plubell, D. L., Remes, P. M., Wu, C. C., Jacob, C. C., Merrihew, G. E., Hsu, C., Shulman, N., MacLean, B. X., Heil, L., Poston, K., Montine, T., MacCoss, M. J. 2024

  Abstract

  The development of targeted assays that monitor biomedically relevant proteins is an important step in bridging discovery experiments to large scale clinical studies. Targeted assays are currently unable to scale to hundreds or thousands of targets. We demonstrate the generation of large-scale assays using a novel hybrid nominal mass instrument. The scale of these assays is achievable with the Stellar™ mass spectrometer through the accommodation of shifting retention times by real-time alignment, while being sensitive and fast enough to handle many concurrent targets. Assays were constructed using precursor information from gas-phase fractionated (GPF) data-independent acquisition (DIA). We demonstrate the ability to schedule methods from an orbitrap and linear ion trap acquired GPF DIA library and compare the quantification of a matrix-matched calibration curve from orbitrap DIA and linear ion trap parallel reaction monitoring (PRM). Two applications of these proposed workflows are shown with a cerebrospinal fluid (CSF) neurodegenerative disease protein PRM assay and with a Mag-Net enriched plasma extracellular vesicle (EV) protein survey PRM assay.

  View details for DOI 10.1101/2024.06.04.597431

  View details for PubMedID 38895256

  View details for PubMedCentralID PMC11185584

• Data Independent Acquisition to Inform the Development of Targeted Proteomics Assays Using a Triple Quadrupole Mass Spectrometer. bioRxiv : the preprint server for biology Plubell, D. L., Huang, E., Spencer, S. E., Poston, K., Montine, T. J., MacCoss, M. J. 2024

  Abstract

  Mass spectrometry based targeted proteomics methods provide sensitive and high-throughput analysis of selected proteins. To develop a targeted bottom-up proteomics assay, peptides must be evaluated as proxies for the measurement of a protein or proteoform in a biological matrix. Candidate peptide selection typically relies on predetermined biochemical properties, data from semi-stochastic sampling, or by empirical measurements. These strategies require extensive testing and method refinement due to the difficulties associated with prediction of peptide response in the biological matrix of interest. Gas-phase fractionated (GPF) narrow window data-independent acquisition (DIA) aids in the development of reproducible selected reaction monitoring (SRM) assays by providing matrix-specific information on peptide detectability and quantification by mass spectrometry. To demonstrate the suitability of DIA data for selecting peptide targets, we reimplement a portion of an existing assay to measure 98 Alzheimer's disease proteins in cerebrospinal fluid (CSF). Peptides were selected from GPF-DIA based on signal intensity and reproducibility. The resulting SRM assay exhibits similar quantitative precision to published data, despite the inclusion of different peptides between the assays. This workflow enables development of new assays without additional up-front data acquisition, demonstrated here through generation of a separate assay for an unrelated set of proteins in CSF from the same dataset.

  View details for DOI 10.1101/2024.05.29.596554

  View details for PubMedID 38853953

  View details for PubMedCentralID PMC11160738

• Subthalamic nucleus-language network connectivity predicts dopaminergic modulation of speech function in Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America Cai, W., Young, C. B., Yuan, R., Lee, B., Ryman, S., Kim, J., Yang, L., Levine, T. F., Henderson, V. W., Poston, K. L., Menon, V. 2024; 121 (22): e2316149121

  Abstract

  Speech impediments are a prominent yet understudied symptom of Parkinson's disease (PD). While the subthalamic nucleus (STN) is an established clinical target for treating motor symptoms, these interventions can lead to further worsening of speech. The interplay between dopaminergic medication, STN circuitry, and their downstream effects on speech in PD is not yet fully understood. Here, we investigate the effect of dopaminergic medication on STN circuitry and probe its association with speech and cognitive functions in PD patients. We found that changes in intrinsic functional connectivity of the STN were associated with alterations in speech functions in PD. Interestingly, this relationship was characterized by altered functional connectivity of the dorsolateral and ventromedial subdivisions of the STN with the language network. Crucially, medication-induced changes in functional connectivity between the STN's dorsolateral subdivision and key regions in the language network, including the left inferior frontal cortex and the left superior temporal gyrus, correlated with alterations on a standardized neuropsychological test requiring oral responses. This relation was not observed in the written version of the same test. Furthermore, changes in functional connectivity between STN and language regions predicted the medication's downstream effects on speech-related cognitive performance. These findings reveal a previously unidentified brain mechanism through which dopaminergic medication influences speech function in PD. Our study sheds light into the subcortical-cortical circuit mechanisms underlying impaired speech control in PD. The insights gained here could inform treatment strategies aimed at mitigating speech deficits in PD and enhancing the quality of life for affected individuals.

  View details for DOI 10.1073/pnas.2316149121

  View details for PubMedID 38768342

• Longitudinal Network Changes and Phenoconversion Risk in Isolated REM Sleep Behavior Disorder. Research square Eidelberg, D., Tang, C., Nakano, Y., Vo, A., Nguyen, N., Schindlbeck, K., Poston, K., Gagnon, J. F., Postuma, R., Niethammer, M., Ma, Y., Peng, S., Dhawan, V. 2024

  Abstract

  Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal syndrome for Parkinson's disease (PD) and related α-synucleinopathies. We conducted a longitudinal imaging study of network changes in iRBD and their relationship to phenoconversion. Expression levels for the PD-related motor and cognitive networks (PDRP and PDCP) were measured at baseline, 2 and 4 years, along with dopamine transporter (DAT) binding. PDRP and PDCP expression increased over time, with higher values in the former network. While abnormal functional connections were identified initially within the PDRP, others bridging the two networks appeared later. A model based on the rates of PDRP progression and putamen dopamine loss predicted phenoconversion within 1.2 years in individuals with iRBD. In aggregate, the data suggest that maladaptive reorganization of brain networks takes place in iRBD years before phenoconversion. Network expression and DAT binding measures can be used together to assess phenoconversion risk in these individuals.

  View details for DOI 10.21203/rs.3.rs-4427198/v1

  View details for PubMedID 38853923

  View details for PubMedCentralID PMC11160876

• Mag-Net: Rapid enrichment of membrane-bound particles enables high coverage quantitative analysis of the plasma proteome. bioRxiv : the preprint server for biology Wu, C. C., Tsantilas, K. A., Park, J., Plubell, D., Sanders, J. A., Naicker, P., Govender, I., Buthelezi, S., Stoychev, S., Jordaan, J., Merrihew, G., Huang, E., Parker, E. D., Riffle, M., Hoofnagle, A. N., Noble, W. S., Poston, K. L., Montine, T. J., MacCoss, M. J. 2024

  Abstract

  Membrane-bound particles in plasma are composed of exosomes, microvesicles, and apoptotic bodies and represent ~1-2% of the total protein composition. Proteomic interrogation of this subset of plasma proteins augments the representation of tissue-specific proteins, representing a "liquid biopsy," while enabling the detection of proteins that would otherwise be beyond the dynamic range of liquid chromatography-tandem mass spectrometry of unfractionated plasma. We have developed an enrichment strategy (Mag-Net) using hyper-porous strong-anion exchange magnetic microparticles to sieve membrane-bound particles from plasma. The Mag-Net method is robust, reproducible, inexpensive, and requires <100 muL plasma input. Coupled to a quantitative data-independent mass spectrometry analytical strategy, we demonstrate that we can collect results for >37,000 peptides from >4,000 plasma proteins with high precision. Using this analytical pipeline on a small cohort of patients with neurodegenerative disease and healthy age-matched controls, we discovered 204 proteins that differentiate (q-value < 0.05) patients with Alzheimer's disease dementia (ADD) from those without ADD. Our method also discovered 310 proteins that were different between Parkinson's disease and those with either ADD or healthy cognitively normal individuals. Using machine learning we were able to distinguish between ADD and not ADD with a mean ROC AUC = 0.98 ± 0.06.

  View details for DOI 10.1101/2023.06.10.544439

  View details for PubMedID 38617345

• AI-based differential diagnosis of dementia etiologies on multimodal data. medRxiv : the preprint server for health sciences Xue, C., Kowshik, S. S., Lteif, D., Puducheri, S., Jasodanand, V. H., Zhou, O. T., Walia, A. S., Guney, O. B., Zhang, J. D., Pham, S. T., Kaliaev, A., Andreu-Arasa, V. C., Dwyer, B. C., Farris, C. W., Hao, H., Kedar, S., Mian, A. Z., Murman, D. L., O'Shea, S. A., Paul, A. B., Rohatgi, S., Saint-Hilaire, M. H., Sartor, E. A., Setty, B. N., Small, J. E., Swaminathan, A., Taraschenko, O., Yuan, J., Zhou, Y., Zhu, S., Karjadi, C., Ang, T. F., Bargal, S. A., Plummer, B. A., Poston, K. L., Ahangaran, M., Au, R., Kolachalama, V. B. 2024

  Abstract

  Differential diagnosis of dementia remains a challenge in neurology due to symptom overlap across etiologies, yet it is crucial for formulating early, personalized management strategies. Here, we present an AI model that harnesses a broad array of data, including demographics, individual and family medical history, medication use, neuropsychological assessments, functional evaluations, and multimodal neuroimaging, to identify the etiologies contributing to dementia in individuals. The study, drawing on 51,269 participants across 9 independent, geographically diverse datasets, facilitated the identification of 10 distinct dementia etiologies. It aligns diagnoses with similar management strategies, ensuring robust predictions even with incomplete data. Our model achieved a micro-averaged area under the receiver operating characteristic curve (AUROC) of 0.94 in classifying individuals with normal cognition, mild cognitive impairment and dementia. Also, the micro-averaged AUROC was 0.96 in differentiating the dementia etiologies. Our model demonstrated proficiency in addressing mixed dementia cases, with a mean AUROC of 0.78 for two co-occurring pathologies. In a randomly selected subset of 100 cases, the AUROC of neurologist assessments augmented by our AI model exceeded neurologist-only evaluations by 26.25%. Furthermore, our model predictions aligned with biomarker evidence and its associations with different proteinopathies were substantiated through postmortem findings. Our framework has the potential to be integrated as a screening tool for dementia in various clinical settings and drug trials, with promising implications for person-level management.

  View details for DOI 10.1101/2024.02.08.24302531

  View details for PubMedID 38585870

  View details for PubMedCentralID PMC10996713

• Impaired 24-h activity patterns are associated with an increased risk of Alzheimer's disease, Parkinson's disease, and cognitive decline. Alzheimer's research & therapy Winer, J. R., Lok, R., Weed, L., He, Z., Poston, K. L., Mormino, E. C., Zeitzer, J. M. 2024; 16 (1): 35

  Abstract

  Sleep-wake regulating circuits are affected during prodromal stages in the pathological progression of both Alzheimer's disease (AD) and Parkinson's disease (PD), and this disturbance can be measured passively using wearable devices. Our objective was to determine whether accelerometer-based measures of 24-h activity are associated with subsequent development of AD, PD, and cognitive decline.This study obtained UK Biobank data from 82,829 individuals with wrist-worn accelerometer data aged 40 to 79 years with a mean (± SD) follow-up of 6.8 (± 0.9) years. Outcomes were accelerometer-derived measures of 24-h activity (derived by cosinor, nonparametric, and functional principal component methods), incident AD and PD diagnosis (obtained through hospitalization or primary care records), and prospective longitudinal cognitive testing.One hundred eighty-seven individuals progressed to AD and 265 to PD. Interdaily stability (a measure of regularity, hazard ratio [HR] per SD increase 1.25, 95% confidence interval [CI] 1.05-1.48), diurnal amplitude (HR 0.79, CI 0.65-0.96), mesor (mean activity; HR 0.77, CI 0.59-0.998), and activity during most active 10 h (HR 0.75, CI 0.61-0.94), were associated with risk of AD. Diurnal amplitude (HR 0.28, CI 0.23-0.34), mesor (HR 0.13, CI 0.10-0.16), activity during least active 5 h (HR 0.24, CI 0.08-0.69), and activity during most active 10 h (HR 0.20, CI 0.16-0.25) were associated with risk of PD. Several measures were additionally predictive of longitudinal cognitive test performance.In this community-based longitudinal study, accelerometer-derived metrics were associated with elevated risk of AD, PD, and accelerated cognitive decline. These findings suggest 24-h rhythm integrity, as measured by affordable, non-invasive wearable devices, may serve as a scalable early marker of neurodegenerative disease.

  View details for DOI 10.1186/s13195-024-01411-0

  View details for PubMedID 38355598

  View details for PubMedCentralID 4163039

• Speech patterns during memory recall relates to early tau burden across adulthood. Alzheimer's & dementia : the journal of the Alzheimer's Association Young, C. B., Smith, V., Karjadi, C., Grogan, S. M., Ang, T. F., Insel, P. S., Henderson, V. W., Sumner, M., Poston, K. L., Au, R., Mormino, E. C. 2024

  Abstract

  Early cognitive decline may manifest in subtle differences in speech.We examined 238 cognitively unimpaired adults from the Framingham Heart Study (32-75 years) who completed amyloid and tau PET imaging. Speech patterns during delayed recall of a story memory task were quantified via five speech markers, and their associations with global amyloid status and regional tau signal were examined.Total utterance time, number of between-utterance pauses, speech rate, and percentage of unique words significantly correlated with delayed recall score although the shared variance was low (2%-15%). Delayed recall score was not significantly different between β-amyoid-positive (Aβ+) and -negative (Aβ-) groups and was not associated with regional tau signal. However, longer and more between-utterance pauses, and slower speech rate were associated with increased tau signal across medial temporal and early neocortical regions.Subtle speech changes during memory recall may reflect cognitive impairment associated with early Alzheimer's disease pathology.Speech during delayed memory recall relates to tau PET signal across adulthood. Delayed memory recall score was not associated with tau PET signal. Speech shows greater sensitivity to detecting subtle cognitive changes associated with early tau accumulation. Our cohort spans adulthood, while most PET imaging studies focus on older adults.

  View details for DOI 10.1002/alz.13731

  View details for PubMedID 38348772

• Evaluation of ATNPDFramework and Biofluid Markers to Predict Cognitive Decline in Early Parkinson Disease. Neurology Cousins, K. A., Irwin, D. J., Tropea, T. F., Rhodes, E., Phillips, J., Chen-Plotkin, A. S., Brumm, M. C., Coffey, C. S., Kang, J. H., Simuni, T., Foroud, T. M., Toga, A. W., Tanner, C. M., Kieburtz, K. D., Mollenhauer, B., Galasko, D., Hutten, S., Weintraub, D., Siderowf, A. D., Marek, K., Poston, K. L., Shaw, L. M., Parkinson's Progression Markers Initiative 2024; 102 (4): e208033

  Abstract

  BACKGROUND AND OBJECTIVES: In Parkinson disease (PD), Alzheimer disease (AD) copathology is common and clinically relevant. However, the longitudinal progression of AD CSF biomarkers-beta-amyloid 1-42 (Abeta42), phosphorylated tau 181 (p-tau181), and total tau (t-tau)-in PD is poorly understood and may be distinct from clinical AD. Moreover, it is unclear whether CSF p-tau181 and serum neurofilament light (NfL) have added prognostic utility in PD, when combined with CSF Abeta42. First, we describe longitudinal trajectories of biofluid markers in PD. Second, we modified the AD beta-amyloid/tau/neurodegeneration (ATN) framework for application in PD (ATNPD) using CSF Abeta42 (A), p-tau181 (T), and serum NfL (N) and tested ATNPD prediction of longitudinal cognitive decline in PD.METHODS: Participants were selected from the Parkinson's Progression Markers Initiative cohort, clinically diagnosed with sporadic PD or as controls, and followed up annually for 5 years. Linear mixed-effects models (LMEMs) tested the interaction of diagnosis with longitudinal trajectories of analytes (log transformed, false discovery rate [FDR] corrected). In patients with PD, LMEMs tested how baseline ATNPD status (AD [A+T+N±] vs not) predicted clinical outcomes, including Montreal Cognitive Assessment (MoCA; rank transformed, FDR corrected).RESULTS: Participants were 364 patients with PD and 168 controls, with comparable baseline mean (±SD) age (patients with PD = 62 ± 10 years; controls = 61 ± 11 years]; Mann-Whitney Wilcoxon: p = 0.4) and sex distribution (patients with PD = 231 male individuals [63%]; controls = 107 male individuals [64%]; chi2: p = 1). Patients with PD had overall lower CSF p-tau181 (beta = -0.16, 95% CI -0.23 to -0.092, p = 2.2e-05) and t-tau than controls (beta = -0.13, 95% CI -0.19 to -0.065, p = 4e-04), but not Abeta42 (p = 0.061) or NfL (p = 0.32). Over time, patients with PD had greater increases in serum NfL than controls (beta = 0.035, 95% CI 0.022 to 0.048, p = 9.8e-07); slopes of patients with PD did not differ from those of controls for CSF Abeta42 (p = 0.18), p-tau181 (p = 1), or t-tau (p = 0.96). Using ATNPD, PD classified as A+T+N± (n = 32; 9%) had worse cognitive decline on global MoCA (beta = -73, 95% CI -110 to -37, p = 0.00077) than all other ATNPD statuses including A+ alone (A+T-N-; n = 75; 21%).DISCUSSION: In patients with early PD, CSF p-tau181 and t-tau were low compared with those in controls and did not increase over 5 years of follow-up. Our study shows that classification using modified ATNPD (incorporating CSF Abeta42, CSF p-tau181, and serum NfL) can identify biologically relevant subgroups of PD to improve prediction of cognitive decline in early PD.

  View details for DOI 10.1212/WNL.0000000000208033

  View details for PubMedID 38306599

• Post-translational modifications linked to preclinical Alzheimer's disease-related pathological and cognitive changes. Alzheimer's & dementia : the journal of the Alzheimer's Association Abiose, O., Rutledge, J., Moran-Losada, P., Belloy, M. E., Wilson, E. N., He, Z., Trelle, A. N., Channappa, D., Romero, A., Park, J., Yutsis, M. V., Sha, S. J., Andreasson, K. I., Poston, K. L., Henderson, V. W., Wagner, A. D., Wyss-Coray, T., Mormino, E. C. 2023

  Abstract

  In this study, we leverage proteomic techniques to identify communities of proteins underlying Alzheimer's disease (AD) risk among clinically unimpaired (CU) older adults.We constructed a protein co-expression network using 3869 cerebrospinal fluid (CSF) proteins quantified by SomaLogic, Inc., in a cohort of participants along the AD clinical spectrum. We then replicated this network in an independent cohort of CU older adults and related these modules to clinically-relevant outcomes.We discovered modules enriched for phosphorylation and ubiquitination that were associated with abnormal amyloid status, as well as p-tau181 (M4: β = 2.44, p < 0.001, M7: β = 2.57, p < 0.001) and executive function performance (M4: β = -2.00, p = 0.005, M7: β = -2.39, p < 0.001).In leveraging CSF proteomic data from individuals spanning the clinical spectrum of AD, we highlight the importance of post-translational modifications for early cognitive and pathological changes.

  View details for DOI 10.1002/alz.13576

  View details for PubMedID 38146099

• Reliability of remote National Alzheimer's Coordinating Center Uniform Data Set data. Alzheimer's & dementia (Amsterdam, Netherlands) Smith, V., Younes, K., Poston, K. L., Mormino, E. C., Young, C. B. 2023; 15 (4): e12498

  Abstract

  The National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) neuropsychological battery is being used to track cognition in participants across the country, but it is unknown if scores obtained through remote administration can be combined with data obtained in person.The remote UDS battery includes the blind version of the Montreal Cognitive Assessment (MoCA), Number Span, Semantic and Phonemic Fluency, and Craft Story. For these tests, we assessed intraclass correlation coefficients (ICCs) between in-person and remote scores in 3838 participants with both in-person and remote UDS assessments, and we compared annual score changes between modalities in a subset that had two remote assessments.All tests exhibited moderate to good reliability between modalities (ICCs = 0.590-0.787). Annual score changes were also comparable between modalities except for Craft Story Immediate Recall, Semantic Fluency, and Phonemic Fluency.Our findings generally support combining remote and in-person scores for the majority of UDS tests.

  View details for DOI 10.1002/dad2.12498

  View details for PubMedID 38034852

  View details for PubMedCentralID PMC10687343

• Cerebellar Volume and Disease Staging in Parkinson's Disease: An ENIGMA-PD Study. Movement disorders : official journal of the Movement Disorder Society Kerestes, R., Laansma, M. A., Owens-Walton, C., Perry, A., van Heese, E. M., Al-Bachari, S., Anderson, T. J., Assogna, F., Aventurato, Í. K., van Balkom, T. D., Berendse, H. W., van den Berg, K. R., Betts, R., Brioschi, R., Carr, J., Cendes, F., Clark, L. R., Dalrymple-Alford, J. C., Dirkx, M. F., Druzgal, J., Durrant, H., Emsley, H. C., Garraux, G., Haroon, H. A., Helmich, R. C., van den Heuvel, O. A., João, R. B., Johansson, M. E., Khachatryan, S. G., Lochner, C., McMillan, C. T., Melzer, T. R., Mosley, P. E., Newman, B., Opriessnig, P., Parkes, L. M., Pellicano, C., Piras, F., Pitcher, T. L., Poston, K. L., Rango, M., Roos, A., Rummel, C., Schmidt, R., Schwingenschuh, P., Silva, L. S., Smith, V., Squarcina, L., Stein, D. J., Tavadyan, Z., Tsai, C. C., Vecchio, D., Vriend, C., Wang, J. J., Wiest, R., Yasuda, C. L., Young, C. B., Jahanshad, N., Thompson, P. M., van der Werf, Y. D., Harding, I. H. 2023

  Abstract

  Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non-motor functioning remain to be elucidated.To quantify cross-sectional regional cerebellar lobule volumes using three dimensional T1-weighted anatomical brain magnetic resonance imaging from the global ENIGMA-PD working group.Cerebellar parcellation was performed using a deep learning-based approach from 2487 people with PD and 1212 age and sex-matched controls across 22 sites. Linear mixed effects models compared total and regional cerebellar volume in people with PD at each Hoehn and Yahr (HY) disease stage, to an age- and sex- matched control group. Associations with motor symptom severity and Montreal Cognitive Assessment scores were investigated.Overall, people with PD had a regionally smaller posterior lobe (dmax  = -0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (dmax  = 0.28) in people with PD in HY stage 1 compared to controls. In contrast, smaller bilateral lobule VII volume in the posterior lobe was observed in HY stages 3, 4, and 5 (dmax  = -0.76), which was incrementally lower with higher disease stage. Within PD, cognitively impaired individuals had lower total cerebellar volume compared to cognitively normal individuals (d = -0.17).We provide evidence of a dissociation between anterior "motor" lobe and posterior "non-motor" lobe cerebellar regions in PD. Whereas less severe stages of the disease are associated with larger motor lobe regions, more severe stages of the disease are marked by smaller non-motor regions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

  View details for DOI 10.1002/mds.29611

  View details for PubMedID 37964373

• Quantitative estimate of cognitive resilience and its medical and genetic associations. Alzheimer's research & therapy Phongpreecha, T., Godrich, D., Berson, E., Espinosa, C., Kim, Y., Cholerton, B., Chang, A. L., Mataraso, S., Bukhari, S. A., Perna, A., Yakabi, K., Montine, K. S., Poston, K. L., Mormino, E., White, L., Beecham, G., Aghaeepour, N., Montine, T. J. 2023; 15 (1): 192

  Abstract

  We have proposed that cognitive resilience (CR) counteracts brain damage from Alzheimer's disease (AD) or AD-related dementias such that older individuals who harbor neurodegenerative disease burden sufficient to cause dementia remain cognitively normal. However, CR traditionally is considered a binary trait, capturing only the most extreme examples, and is often inconsistently defined.This study addressed existing discrepancies and shortcomings of the current CR definition by proposing a framework for defining CR as a continuous variable for each neuropsychological test. The linear equations clarified CR's relationship to closely related terms, including cognitive function, reserve, compensation, and damage. Primarily, resilience is defined as a function of cognitive performance and damage from neuropathologic damage. As such, the study utilized data from 844 individuals (age = 79 ± 12, 44% female) in the National Alzheimer's Coordinating Center cohort that met our inclusion criteria of comprehensive lesion rankings for 17 neuropathologic features and complete neuropsychological test results. Machine learning models and GWAS then were used to identify medical and genetic factors that are associated with CR.CR varied across five cognitive assessments and was greater in female participants, associated with longer survival, and weakly associated with educational attainment or APOE ε4 allele. In contrast, damage was strongly associated with APOE ε4 allele (P value < 0.0001). Major predictors of CR were cardiovascular health and social interactions, as well as the absence of behavioral symptoms.Our framework explicitly decoupled the effects of CR from neuropathologic damage. Characterizations and genetic association study of these two components suggest that the underlying CR mechanism has minimal overlap with the disease mechanism. Moreover, the identified medical features associated with CR suggest modifiable features to counteract clinical expression of damage and maintain cognitive function in older individuals.

  View details for DOI 10.1186/s13195-023-01329-z

  View details for PubMedID 37926851

  View details for PubMedCentralID 6410486

• An Explainable Geometric-Weighted Graph Attention Network for Identifying Functional Networks Associated with Gait Impairment. Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention Nerrise, F., Zhao, Q., Poston, K. L., Pohl, K. M., Adeli, E. 2023; 14221: 723-733

  Abstract

  One of the hallmark symptoms of Parkinson's Disease (PD) is the progressive loss of postural reflexes, which eventually leads to gait difficulties and balance problems. Identifying disruptions in brain function associated with gait impairment could be crucial in better understanding PD motor progression, thus advancing the development of more effective and personalized therapeutics. In this work, we present an explainable, geometric, weighted-graph attention neural network (xGW-GAT) to identify functional networks predictive of the progression of gait difficulties in individuals with PD. xGW-GAT predicts the multi-class gait impairment on the MDS-Unified PD Rating Scale (MDS-UPDRS). Our computational- and data-efficient model represents functional connectomes as symmetric positive definite (SPD) matrices on a Riemannian manifold to explicitly encode pairwise interactions of entire connectomes, based on which we learn an attention mask yielding individual- and group-level explainability. Applied to our resting-state functional MRI (rs-fMRI) dataset of individuals with PD, xGW-GAT identifies functional connectivity patterns associated with gait impairment in PD and offers interpretable explanations of functional subnetworks associated with motor impairment. Our model successfully outperforms several existing methods while simultaneously revealing clinically-relevant connectivity patterns. The source code is available at https://github.com/favour-nerrise/xGW-GAT.

  View details for DOI 10.1007/978-3-031-43895-0_68

  View details for PubMedID 37982132

  View details for PubMedCentralID PMC10657737

• Prediction of Phenoconversion Time in REM Sleep Behavior Disorder (RBD) with Brain Metabolic Network and Dopaminergic Imaging: A Longitudinal Study Tang, C. C., Schindlbeck, K., Nakano, Y., Niethammer, M., Dhawan, V., Poston, K., Eidelberg, D. WILEY. 2023: S189-S190

  View details for Web of Science ID 001084474200322

• ATN_PD Framework Using Biofluid Markers Predicts Cognitive Decline in Early Parkinson's Disease Cousins, K. Q., Irwin, D. J., Tropea, T. F., Rhodes, E., Phillips, J. S., Chen-Plotkin, A. S., Brumm, M. C., Coffey, C. S., Kang, J., Simuni, T., Foroud, T., Toga, A. W., Tanner, C. M., Kieburtz, K., Mollenhauer, B., Galasko, D. R., Hutten, S., Weintraub, D., Siderowf, A., Marek, K., Kollmorgen, G., Poston, K. L., Shaw, L. M. WILEY. 2023: S169

  View details for Web of Science ID 001084474200276

• An Explainable Geometric-Weighted Graph Attention Network for Identifying Functional Networks Associated with Gait Impairment. ArXiv Nerrise, F., Zhao, Q., Poston, K. L., Pohl, K. M., Adeli, E. 2023

  Abstract

  One of the hallmark symptoms of Parkinson's Disease (PD) is the progressive loss of postural reflexes, which eventually leads to gait difficulties and balance problems. Identifying disruptions in brain function associated with gait impairment could be crucial in better understanding PD motor progression, thus advancing the development of more effective and personalized therapeutics. In this work, we present an explainable, geometric, weighted-graph attention neural network (xGW-GAT) to identify functional networks predictive of the progression of gait difficulties in individuals with PD. xGW-GAT predicts the multi-class gait impairment on the MDS-Unified PD Rating Scale (MDS-UPDRS). Our computational- and data-efficient model represents functional connectomes as symmetric positive definite (SPD) matrices on a Riemannian manifold to explicitly encode pairwise interactions of entire connectomes, based on which we learn an attention mask yielding individual- and group-level explain-ability. Applied to our resting-state functional MRI (rs-fMRI) dataset of individuals with PD, xGW-GAT identifies functional connectivity patterns associated with gait impairment in PD and offers interpretable explanations of functional subnetworks associated with motor impairment. Our model successfully outperforms several existing methods while simultaneously revealing clinically-relevant connectivity patterns. The source code is available at https://github.com/favour-nerrise/xGW-GAT.

  View details for PubMedID 37547656

  View details for PubMedCentralID PMC10402187

• Parkinson's Progression Markers Initiative: A Milestone-Based Strategy to Monitor Parkinson's Disease Progression. Journal of Parkinson's disease Brumm, M. C., Siderowf, A., Simuni, T., Burghardt, E., Choi, S. H., Caspell-Garcia, C., Chahine, L. M., Mollenhauer, B., Foroud, T., Galasko, D., Merchant, K., Arnedo, V., Hutten, S. J., O'Grady, A. N., Poston, K. L., Tanner, C. M., Weintraub, D., Kieburtz, K., Marek, K., Coffey, C. S. 2023

  Abstract

  Identifying a meaningful progression metric for Parkinson's disease (PD) that reflects heterogeneity remains a challenge.To assess the frequency and baseline predictors of progression to clinically relevant motor and non-motor PD milestones.Using data from the Parkinson's Progression Markers Initiative (PPMI) de novo PD cohort, we monitored 25 milestones across six domains ("walking and balance"; "motor complications"; "cognition"; "autonomic dysfunction"; "functional dependence"; "activities of daily living"). Milestones were intended to be severe enough to reflect meaningful disability. We assessed the proportion of participants reaching any milestone; evaluated which occurred most frequently; and conducted a time-to-first-event analysis exploring whether baseline characteristics were associated with progression.Half of participants reached at least one milestone within five years. Milestones within the cognitive, functional dependence, and autonomic dysfunction domains were reached most often. Among participants who reached a milestone at an annual follow-up visit and remained active in the study, 82% continued to meet criteria for any milestone at one or more subsequent annual visits and 55% did so at the next annual visit. In multivariable analysis, baseline features predicting faster time to reaching a milestone included age (p <  0.0001), greater MDS-UPDRS total scores (p <  0.0001), higher GDS-15 depression scores (p = 0.0341), lower dopamine transporter binding (p = 0.0043), and lower CSF total α-synuclein levels (p = 0.0033). Symptomatic treatment was not significantly associated with reaching a milestone (p = 0.1639).Clinically relevant milestones occur frequently, even in early PD. Milestones were significantly associated with baseline clinical and biological markers, but not with symptomatic treatment. Further studies are necessary to validate these results, further assess the stability of milestones, and explore translating them into an outcome measure suitable for observational and therapeutic studies.

  View details for DOI 10.3233/JPD-223433

  View details for PubMedID 37458046

• Metrologically Traceable Quantification of 3 Apolipoprotein E Isoforms in Cerebrospinal Fluid. Clinical chemistry Huynh, H., Kuch, K., Orquillas, A., Forrest, K., Barahona-Carrillo, L., Keene, D., Henderson, V. W., Wagner, A. D., Poston, K. L., Montine, T. J., Lin, A., Tian, L., MacCoss, M. J., Emrick, M. A., Hoofnagle, A. N. 2023

  Abstract

  BACKGROUND: APOE genotype is associated with Alzheimer disease. Thus, the concentration of apolipoprotein E (apoE) isoforms in cerebrospinal fluid (CSF) could be altered in dementia. However, conflicting results have been obtained in different studies. Carefully validated and standardized assays could improve the interpretation of research findings, allow their replication in other laboratories, and generalize their application.METHODS: To evaluate this hypothesis, we aimed to develop, validate, and standardize a new measurement procedure using LC-MS/MS. Purified recombinant apoE protein standards (E2, E3, E4) were thoroughly characterized and used to assign the concentration of a matrix-matched calibration material that contained each apoE isoform, which ensured the metrological traceability of results.RESULTS: The assay of each isoform in human CSF was precise (≤11%CV) and of moderate throughput (approximately 80 samples per day). It demonstrated good linearity and parallelism for lumbar CSF, ventricular CSF, and bovine CSF. The use of an SI-traceable matrix-matched calibrator enabled precise and accurate measurements. There was no association observed between total apoE concentration and the number of Ɛ4 alleles in a cohort of 322 participants. However, the concentration of each isoform was significantly different in heterozygotes, with E4 > E3 > E2. Isoform concentrations were associated with cognitive and motor symptoms but contributed negligibly to a predictive model of cognitive impairment that included established CSF biomarkers.CONCLUSIONS: Our method simultaneously measures each apoE isoform in human CSF with excellent precision and accuracy. A secondary matrix-matched material has been developed and is available to other laboratories to improve interlaboratory agreement.

  View details for DOI 10.1093/clinchem/hvad056

  View details for PubMedID 37279935

• Impact of the Dopamine System on Long-Term Cognitive Impairment in Parkinson Disease: An Exploratory Study. Movement disorders clinical practice Weintraub, D., Picillo, M., Cho, H. R., Caspell-Garcia, C., Blauwendraat, C., Brown, E. G., Chahine, L. M., Coffey, C. S., Dobkin, R. D., Foroud, T., Galasko, D., Kieburtz, K., Marek, K., Merchant, K., Mollenhauer, B., Poston, K. L., Simuni, T., Siderowf, A., Singleton, A., Seibyl, J., Tanner, C. M. 2023; 10 (6): 943-955

  Abstract

  Little is known about the impact of the dopamine system on development of cognitive impairment (CI) in Parkinson disease (PD).We used data from a multi-site, international, prospective cohort study to explore the impact of dopamine system-related biomarkers on CI in PD.PD participants were assessed annually from disease onset out to 7 years, and CI determined by applying cut-offs to four measures: (1) Montreal Cognitive Assessment; (2) detailed neuropsychological test battery; (3) Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) cognition score; and (4) site investigator diagnosis of CI (mild cognitive impairment or dementia). The dopamine system was assessed by serial Iodine-123 Ioflupane dopamine transporter (DAT) imaging, genotyping, and levodopa equivalent daily dose (LEDD) recorded at each assessment. Multivariate longitudinal analyses, with adjustment for multiple comparisons, determined the association between dopamine system-related biomarkers and CI, including persistent impairment.Demographic and clinical variables associated with CI were higher age, male sex, lower education, non-White race, higher depression and anxiety scores and higher MDS-UPDRS motor score. For the dopamine system, lower baseline mean striatum dopamine transporter values (P range 0.003-0.005) and higher LEDD over time (P range <0.001-0.01) were significantly associated with increased risk for CI.Our results provide preliminary evidence that alterations in the dopamine system predict development of clinically-relevant, cognitive impairment in Parkinson's disease. If replicated and determined to be causative, they demonstrate that the dopamine system is instrumental to cognitive health status throughout the disease course.Parkinson's Progression Markers Initiative is registered with ClinicalTrials.gov (NCT01141023).

  View details for DOI 10.1002/mdc3.13751

  View details for PubMedID 37332638

  View details for PubMedCentralID PMC10272925

• Reduced and Delayed Cerebrovascular Reactivity in Patients with Parkinson's Disease. Movement disorders : official journal of the Movement Disorder Society Ryman, S. G., Shaff, N., Dodd, A., Nitschke, S., Wertz, C., Julio, K., Suarez Cedeno, G., Deligtisch, A., Erhardt, E., Lin, H., Vakhtin, A., Poston, K. L., Tarawneh, R., Pirio Richardson, S., Mayer, A. 2023

  Abstract

  Cerebrovascular dysfunction in Parkinson's disease (PD) is heterogeneous and may contribute to disease pathophysiology or progression. There is a need to understand the mechanisms by which cerebrovascular dysfunction is altered in participants with PD.The objective of this study is to test the hypothesis that participants with PD exhibit a significant reduction in the ability of the cerebral vessels to dilate in response to vasoactive challenges relative to healthy controls (HC).The current study uses a vasodilatory challenge while participants undergo functional magnetic resonance imaging to quantify the amplitude and delay of cerebrovascular reactivity in participants with PD relative to age and sex-matched HC. An analysis of covariance was used to evaluate differences in cerebrovascular reactivity amplitude and latency between PD participants and HC.A significant main effect of group was observed for whole-brain cerebrovascular reactivity amplitude (F(1, 28)  = 4.38, p = 0.046, Hedge's g = 0.73) and latency (F(1, 28)  = 16.35, p < 0.001, Hedge's g = 1.42). Participants with PD exhibited reduced whole-brain amplitude and increased latencies in cerebrovascular reactivity relative to HC. The evaluation of regional effects indicates that the largest effects were observed in the cuneus, precuneus, and parietal regions.PD participants exhibited reduced and delayed cerebrovascular reactivity. This dysfunction may play an important role in chronic hypoxia, neuroinflammation, and protein aggregation, mechanisms that could lead to disease progression. Cerebrovascular reactivity may serve as an important biomarker and target for future interventions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

  View details for DOI 10.1002/mds.29429

  View details for PubMedID 37157056

• Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study. The Lancet. Neurology Siderowf, A., Concha-Marambio, L., Lafontant, D. E., Farris, C. M., Ma, Y., Urenia, P. A., Nguyen, H., Alcalay, R. N., Chahine, L. M., Foroud, T., Galasko, D., Kieburtz, K., Merchant, K., Mollenhauer, B., Poston, K. L., Seibyl, J., Simuni, T., Tanner, C. M., Weintraub, D., Videnovic, A., Choi, S. H., Kurth, R., Caspell-Garcia, C., Coffey, C. S., Frasier, M., Oliveira, L. M., Hutten, S. J., Sherer, T., Marek, K., Soto, C. 2023; 22 (5): 407-417

  Abstract

  Emerging evidence shows that α-synuclein seed amplification assays (SAAs) have the potential to differentiate people with Parkinson's disease from healthy controls. We used the well characterised, multicentre Parkinson's Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of the α-synuclein SAA and to examine whether the assay identifies heterogeneity among patients and enables the early identification of at-risk groups.This cross-sectional analysis is based on assessments done at enrolment for PPMI participants (including people with sporadic Parkinson's disease from LRRK2 and GBA variants, healthy controls, prodromal individuals with either rapid eye movement sleep behaviour disorder (RBD) or hyposmia, and non-manifesting carriers of LRRK2 and GBA variants) from 33 participating academic neurology outpatient practices worldwide (in Austria, Canada, France, Germany, Greece, Israel, Italy, the Netherlands, Norway, Spain, the UK, and the USA). α-synuclein SAA analysis of CSF was performed using previously described methods. We assessed the sensitivity and specificity of the α-synuclein SAA in participants with Parkinson's disease and healthy controls, including subgroups based on genetic and clinical features. We established the frequency of positive α-synuclein SAA results in prodromal participants (RBD and hyposmia) and non-manifesting carriers of genetic variants associated with Parkinson's disease, and compared α-synuclein SAA to clinical measures and other biomarkers. We used odds ratio estimates with 95% CIs to measure the association between α-synuclein SAA status and categorical measures, and two-sample 95% CIs from the resampling method to assess differences in medians between α-synuclein SAA positive and negative participants for continuous measures. A linear regression model was used to control for potential confounders such as age and sex.This analysis included 1123 participants who were enrolled between July 7, 2010, and July 4, 2019. Of these, 545 had Parkinson's disease, 163 were healthy controls, 54 were participants with scans without evidence of dopaminergic deficit, 51 were prodromal participants, and 310 were non-manifesting carriers. Sensitivity for Parkinson's disease was 87·7% (95% CI 84·9-90·5), and specificity for healthy controls was 96·3% (93·4-99·2). The sensitivity of the α-synuclein SAA in sporadic Parkinson's disease with the typical olfactory deficit was 98·6% (96·4-99·4). The proportion of positive α-synuclein SAA was lower than this figure in subgroups including LRRK2 Parkinson's disease (67·5% [59·2-75·8]) and participants with sporadic Parkinson's disease without olfactory deficit (78·3% [69·8-86·7]). Participants with LRRK2 variant and normal olfaction had an even lower α-synuclein SAA positivity rate (34·7% [21·4-48·0]). Among prodromal and at-risk groups, 44 (86%) of 51 of participants with RBD or hyposmia had positive α-synuclein SAA (16 of 18 with hyposmia, and 28 of 33 with RBD). 25 (8%) of 310 non-manifesting carriers (14 of 159 [9%] LRRK2 and 11 of 151 [7%] GBA) were positive.This study represents the largest analysis so far of the α-synuclein SAA for the biochemical diagnosis of Parkinson's disease. Our results show that the assay classifies people with Parkinson's disease with high sensitivity and specificity, provides information about molecular heterogeneity, and detects prodromal individuals before diagnosis. These findings suggest a crucial role for the α-synuclein SAA in therapeutic development, both to identify pathologically defined subgroups of people with Parkinson's disease and to establish biomarker-defined at-risk cohorts.PPMI is funded by the Michael J Fox Foundation for Parkinson's Research and funding partners, including: Abbvie, AcureX, Aligning Science Across Parkinson's, Amathus Therapeutics, Avid Radiopharmaceuticals, Bial Biotech, Biohaven, Biogen, BioLegend, Bristol-Myers Squibb, Calico Labs, Celgene, Cerevel, Coave, DaCapo Brainscience, 4D Pharma, Denali, Edmond J Safra Foundation, Eli Lilly, GE Healthcare, Genentech, GlaxoSmithKline, Golub Capital, Insitro, Janssen Neuroscience, Lundbeck, Merck, Meso Scale Discovery, Neurocrine Biosciences, Prevail Therapeutics, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, VanquaBio, Verily, Voyager Therapeutics, and Yumanity.

  View details for DOI 10.1016/S1474-4422(23)00109-6

  View details for PubMedID 37059509

• Impact of the Dopamine System on Long-Term Cognitive Impairment in Parkinson Disease: An Exploratory Study MOVEMENT DISORDERS CLINICAL PRACTICE Weintraub, D., Picillo, M., Cho, H., Caspell-Garcia, C., Blauwendraat, C., Brown, E. G., Chahine, L. M., Coffey, C. S., Dobkin, R. D., Foroud, T., Galasko, D., Kieburtz, K., Marek, K., Merchant, K., Mollenhauer, B., Poston, K. L., Simuni, T., Siderowf, A., Singleton, A., Seibyl, J., Tanner, C. M., Parkinsons Progression Markers In 2023

  View details for DOI 10.1002/mdc3.13751

  View details for Web of Science ID 000975830100001

• Episodic memory deficit in HIV infection: common phenotype with Parkinson's disease, different neural substrates. Brain structure & function Fama, R., Müller-Oehring, E. M., Levine, T. F., Sullivan, E. V., Sassoon, S. A., Asok, P., Brontë-Stewart, H. M., Poston, K. L., Pohl, K. M., Pfefferbaum, A., Schulte, T. 2023

  Abstract

  Episodic memory deficits occur in people living with HIV (PLWH) and individuals with Parkinson's disease (PD). Given known effects of HIV and PD on frontolimbic systems, episodic memory deficits are often attributed to executive dysfunction. Although executive dysfunction, evidenced as retrieval deficits, is relevant to mnemonic deficits, learning deficits may also contribute. Here, the California Verbal Learning Test-II, administered to 42 PLWH, 41 PD participants, and 37 controls, assessed learning and retrieval using measures of free recall, cued recall, and recognition. Executive function was assessed with a composite score comprising Stroop Color-Word Reading and Backward Digit Spans. Neurostructural correlates were examined with MRI of frontal (precentral, superior, orbital, middle, inferior, supplemental motor, medial) and limbic (hippocampus, thalamus) volumes. HIV and PD groups were impaired relative to controls on learning and free and cued recall trials but did not differ on recognition or retention of learned material. In no case did executive functioning solely account for the observed mnemonic deficits or brain-performance relations. Critically, the shared learning and retrieval deficits in HIV and PD were related to different substrates of frontolimbic mnemonic neurocircuitry. Specifically, diminished learning and poorer free and cued recall were related to smaller orbitofrontal volume in PLWH but not PD, whereas diminished learning in PD but not PLWH was related to smaller frontal superior volume. In PD, poorer recognition correlated with smaller thalamic volume and poorer retention to hippocampal volume. Although memory deficits were similar, the neural correlates in HIV and PD suggest different pathogenic mechanisms.

  View details for DOI 10.1007/s00429-023-02626-x

  View details for PubMedID 37069296

  View details for PubMedCentralID 9804536

• Dementia with Lewy Bodies Drug Therapies in Clinical Trials: Systematic Review up to 2022. Neurology and therapy Abdelnour, C., Gonzalez, M. C., Gibson, L. L., Poston, K. L., Ballard, C. G., Cummings, J. L., Aarsland, D. 2023

  Abstract

  Reviews of randomized clinical trials (RCTs) in dementia with Lewy bodies (DLB) are essential for informing ongoing research efforts of symptomatic therapies and potentially disease-modifying therapies (DMTs).We performed a systematic review of all clinical trials conducted until September 27, 2022, by examining 3 international registries: ClinicalTrials.gov, the European Union Drug Regulating Authorities Clinical Trials Database, and the International Clinical Trials Registry Platform, to identify drugs in trials in DLB.We found 25 agents in 40 trials assessing symptomatic treatments and DMTs for DLB: 7 phase 3, 31 phase 2, and 2 phase 1 trials. We found an active pipeline for drug development in DLB, with most ongoing clinical trials in phase 2. We identified a recent trend towards including participants at the prodromal stages, although more than half of active clinical trials will enroll mild to moderate dementia patients. Additionally, repurposed agents are frequently tested, representing 65% of clinical trials.Current challenges in DLB clinical trials include the need for disease-specific outcome measures and biomarkers, and improving representation of global and diverse populations.

  View details for DOI 10.1007/s40120-023-00467-8

  View details for PubMedID 37017910

  View details for PubMedCentralID 6823159

• Cognitive Impairment in Neurodegenerative Movement Disorders. Seminars in neurology Abdelnour, C., Poston, K. L. 2023

  Abstract

  Patients with neurodegenerative movement disorders can develop cognitive impairment during the disease. Cognitive symptoms have been associated with decreased quality of life, higher caregiver burden, and earlier institutionalization, and are therefore critical for physicians to understand and address. The evaluation of cognitive performance of patients with neurodegenerative movement disorders is important for providing adequate diagnosis, management, prognosis, and support patients and their caregivers. In this review, we discuss the features of the cognitive impairment profile of commonly encountered movement disorders: Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, corticobasal syndrome, and Huntington's disease. In addition, we provide neurologists with practical guidance and evaluation tools for the assessment and management of these challenging patients.

  View details for DOI 10.1055/s-0043-1764204

  View details for PubMedID 36940727

• Synaptic Density and Glucose Consumption in Patients with Lewy Body Diseases: An [11 C]UCB-J and [18 F]FDG PET Study. Movement disorders : official journal of the Movement Disorder Society Andersen, K. B., Hansen, A. K., Schacht, A. C., Horsager, J., Gottrup, H., Klit, H., Danielsen, E. H., Poston, K. L., Pavese, N., Brooks, D. J., Borghammer, P. 2023

  Abstract

  BACKGROUND: Patients with Lewy body diseases exhibit variable degrees of cortical and subcortical hypometabolism. However, the underlying causes behind this progressive hypometabolism remain unresolved. Generalized synaptic degeneration may be one key contributor.OBJECTIVE: The objective of this study was to investigate whether local cortical synaptic loss is proportionally linked to the magnitude of hypometabolism in Lewy body disease.METHOD: Using in vivo positron emission tomography (PET) we investigated cerebral glucose metabolism and quantified the density of cerebral synapses, as measured with [18 F]fluorodeoxyglucose ([18 F]FDG) PET and [11 C]UCB-J, respectively. Volumes-of-interest were defined on magnetic resonance T1 scans and regional standard uptake value ratios-1 values were obtained for 14 pre-selected brain regions. Between-group comparisons were conducted at voxel-level.RESULTS: We observed regional differences in both synaptic density and cerebral glucose consumption in our cohorts of non-demented and demented patients with Parkinson's disease or dementia with Lewy bodies compared to healthy subjects. Additionally, voxel-wise comparisons showed a clear difference in cortical regions between demented patients and controls for both tracers. Importantly, our findings strongly suggested that the magnitude of reduced glucose uptake exceeded the magnitude of reduced cortical synaptic density.CONCLUSION: Here, we investigated the relationship between in vivo glucose uptake and the magnitude of synaptic density as measured using [18 F]FDG PET and [11 C]UCB-J PET in Lewy body patients. The magnitude of reduced [18 F]FDG uptake was greater than the corresponding decline in [11 C]UCB-J binding. Therefore, the progressive hypometabolism seen in Lewy body disorders cannot be fully explained by generalized synaptic degeneration. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

  View details for DOI 10.1002/mds.29375

  View details for PubMedID 36905188

• Listening session with the US Food and Drug Administration, Lewy Body Dementia Association, and an expert panel ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS Sabbagh, M. N., Taylor, A., Galasko, D., Galvin, J. E., Goldman, J. G., Leverenz, J. B., Poston, K. L., Boeve, B. F., Irwin, D. J., Quinn, J. F. 2023; 9 (1): e12375

  Abstract

  The regulatory path for drug approval is increasingly well defined. Drugs for the treatment of Alzheimer disease (AD) need to show statistically significant benefit over placebo with respect to cognitive and functional measures, with the Clinical Dementia Rating scale and Alzheimer's Disease Assessment Scale-Cognitive Subscale being among the most often used instruments in AD clinical trials. In contrast, there are no validated instruments for use in clinical trials of drugs for the treatment of dementia with Lewy bodies. This poses challenges for drug development because the regulatory pathway to drug approval requires demonstrable efficacy measures. In December 2021, the Lewy Body Dementia Association advisory group met with representatives from the US Food and Drug Administration to discuss the lack of approved drugs and treatments, discernment of efficacy measures, and identification of biomarkers.The Lewy Body with Dementia Association convened a listening session with the US Food and Drug Administration on dementia with Lewy bodies (DLB) and clinical trial design.Gaps include DLB-specific measures, alpha synuclein biomarkers, and coexisting pathologies.DLB clinical trial design should focus on clinical value and disease specificity.

  View details for DOI 10.1002/trc2.12375

  View details for Web of Science ID 000929340500001

  View details for PubMedID 36873923

  View details for PubMedCentralID PMC9983146

• Prediction of neuropathologic lesions from clinical data. Alzheimer's & dementia : the journal of the Alzheimer's Association Phongpreecha, T., Cholerton, B., Bhukari, S., Chang, A. L., De Francesco, D., Thuraiappah, M., Godrich, D., Perna, A., Becker, M. G., Ravindra, N. G., Espinosa, C., Kim, Y., Berson, E., Mataraso, S., Sha, S. J., Fox, E. J., Montine, K. S., Baker, L. D., Craft, S., White, L., Poston, K. L., Beecham, G., Aghaeepour, N., Montine, T. J. 2023

  Abstract

  Post-mortem analysis provides definitive diagnoses of neurodegenerative diseases; however, only a few can be diagnosed during life.This study employed statistical tools and machine learning to predict 17 neuropathologic lesions from a cohort of 6518 individuals using 381 clinical features (Table S1). The multisite data allowed validation of the model's robustness by splitting train/test sets by clinical sites. A similar study was performed for predicting Alzheimer's disease (AD) neuropathologic change without specific comorbidities.Prediction results show high performance for certain lesions that match or exceed that of research annotation. Neurodegenerative comorbidities in addition to AD neuropathologic change resulted in compounded, but disproportionate, effects across cognitive domains as the comorbidity number increased.Certain clinical features could be strongly associated with multiple neurodegenerative diseases, others were lesion-specific, and some were divergent between lesions. Our approach could benefit clinical research, and genetic and biomarker research by enriching cohorts for desired lesions.

  View details for DOI 10.1002/alz.12921

  View details for PubMedID 36681388

• APOE effects on regional tau in preclinical Alzheimer's disease. Molecular neurodegeneration Young, C. B., Johns, E., Kennedy, G., Belloy, M. E., Insel, P. S., Greicius, M. D., Sperling, R. A., Johnson, K. A., Poston, K. L., Mormino, E. C., Alzheimers Disease Neuroimaging Initiative, A4 Study Team 2023; 18 (1): 1

  Abstract

  BACKGROUND: APOE variants are strongly associated with abnormal amyloid aggregation and additional direct effects of APOE on tau aggregation are reported in animal and human cell models. The degree to which these effects are present in humans when individuals are clinically unimpaired (CU) but have abnormal amyloid (Abeta+) remains unclear.METHODS: We analyzed data from CU individuals in the Anti-Amyloid Treatment in Asymptomatic AD (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Amyloid PET data were available for 4486 participants (3163 Abeta-, 1323 Abeta+) and tau PET data were available for a subset of 447 participants (55 Abeta-, 392 Abeta+). Linear models examined APOE (number of e2 and e4 alleles) associations with global amyloid and regional tau burden in medial temporal lobe (entorhinal, amygdala) and early neocortical regions (inferior temporal, inferior parietal, precuneus). Consistency of APOE4 effects on regional tau were examined in 220 Abeta+CU and mild cognitive impairment (MCI) participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI).RESULTS: APOE2 and APOE4 were associated with lower and higher amyloid positivity rates, respectively. Among Abeta+CU, e2 and e4 were associated with reduced (-12 centiloidsper allele) and greater (+15 centiloidsper allele) continuous amyloid burden, respectively. APOE2 was associated with reduced regional tau in all regions (-0.05 to -0.09 SUVR per allele), whereas APOE4 was associated with greater regional tau (+0.02 to +0.07 SUVR per allele). APOE differences were confirmed by contrasting e3/e3 with e2/e3 and e3/e4. Mediation analyses among Abeta+s showed that direct effects of e2 on regional tau were present in medial temporal lobe and early neocortical regions, beyond an indirect pathway mediated by continuous amyloid burden. For e4, direct effects on regional tau were only significant in medial temporal lobe. The magnitude of protective e2 effects on regional tau was consistent across brain regions, whereas detrimental e4 effects were greatest in medial temporal lobe. APOE4 patterns were confirmed in Abeta+ADNI participants.CONCLUSIONS: APOE influences early regional tau PET burden, above and beyond effects related to cross-sectional amyloid PET burden. Therapeutic strategies targeting underlying mechanisms related to APOE may modify tau accumulation among Abeta+individuals.

  View details for DOI 10.1186/s13024-022-00590-4

  View details for PubMedID 36597122

• Computerized cognitive practice effects in relation to amyloid and tau in preclinical Alzheimer's disease: Results from a multi-site cohort. Alzheimer's & dementia (Amsterdam, Netherlands) Young, C. B., Mormino, E. C., Poston, K. L., Johnson, K. A., Rentz, D. M., Sperling, R. A., Papp, K. V. 2023; 15 (1): e12414

  Abstract

  Scalable cognitive paradigms that provide metrics such as the Computerized Cognitive Composite (C3) may be sensitive enough to relate to Alzheimer's disease biomarkers in the preclinical clinically unimpaired (CU) stage. We examined CU older adults (n=3287) who completed alternate versions of the C3 approximately 51 days apart. A subset of CU with abnormal amyloid also completed tau positron emission tomography (PET) imaging. C3 initial performance and practice effects were examined in relation to amyloid status and continuous regional tau burden. Initial C3 performance was associated with amyloid status across all participants, and with tau burden in the medial temporal lobe and early cortical regions in CU with abnormal amyloid. Short-term practice effects were associated with reduced tau in these regions in CU with abnormal amyloid, but were not associated with amyloid status. Thus, computerized cognitive testing repeated over a short follow-up period provides additional insights into early Alzheimer's disease processes.

  View details for DOI 10.1002/dad2.12414

  View details for PubMedID 36950699

• Longitudinal hippocampal subfields, CSF biomarkers, and cognition in patients with Parkinson disease. Clinical parkinsonism & related disorders Erhardt, E., Horner, A., Shaff, N., Wertz, C., Nitschke, S., Vakhtin, A., Mayer, A., Adair, J., Knoefel, J., Rosenberg, G., Poston, K., Suarez Cedeno, G., Deligtisch, A., Pirio Richardson, S., Ryman, S. 2023; 9: 100199

  Abstract

  Objective: Hippocampal atrophy is an indicator of emerging dementia in PD, though it is unclear whether cerebral spinal fluid (CSF) Abeta-42, t-tau, or alpha-syn predict hippocampal subfield atrophy in a de novo cohort of PD patients. To examine whether levels of CSF alpha-synuclein (alpha-syn), beta-amyloid 1-42 (Abeta-42), or total-tau (t-tau) are associated with hippocampal subfield volumes over time.Methods: We identified a subset of Parkinson's Progression Markers Initiative (PPMI) de novo PD patients with longitudinal T1-weighted imaging (baseline plus at least two additional visits across 12, 24, and 48months) and CSF biomarkers available at baseline. We performed cross-sectional, regression, and linear mixed model analyses to evaluate the baseline and longitudinal CSF biomarkers, hippocampal subfields, and cognition. A false discovery rate (FDR) was used to correct for multiple comparisons.Results: 88 PD-CN and 21 PD-MCI had high quality longitudinal data. PD-MCI patients exhibited reduced bilateral CA1 volumes relative to PD-CN, though there were no significant differences in CSF biomarkers between these groups. Relationships between CSF biomarkers and hippocampal subfields changed over time, with a general pattern that lower CSF Abeta-42, higher t-tau and higher alpha-syn were associated with smaller hippocampal subfields, primarily in the right hemisphere.Conclusion: We replicated prior reports that demonstrated reduced CA1 volumes in PD-MCI in a de novo PD cohort. CSF biomarkers were associated with individual subfields, with evidence that the increased CSF t-tau was associated with smaller subiculum volumes at baseline and over time, though there was no clear indication that the subfields associated with cognition (CA1 and HATA) were associated with CSF biomarkers.

  View details for DOI 10.1016/j.prdoa.2023.100199

  View details for PubMedID 38107672

• Gait and balance in apolipoprotein Ɛ4 allele carriers in older adults and Parkinson's disease. Clinical parkinsonism & related disorders Morris, R., Martini, D. N., Kelly, V. E., Smulders, K., Ramsey, K., Hiller, A., Chung, K. A., Hu, S., Zabetian, C. P., Poston, K. L., Mata, I. F., Edwards, K. L., Lapidus, J., Cholerton, B., Montine, T. J., Quinn, J. F., Horak, F. 2023; 9: 100201

  Abstract

  Background: Gait and balance impairments are among the most troublesome and heterogeneous in Parkinson's disease (PD). This heterogeneity may, in part, reflect genetic variation. The apolipoprotein E (APOE) gene has three major allelic variants (epsilon2, epsilon3 and epsilon4). Previous work has demonstrated that older adult (OA) APOE epsilon4 carriers demonstrate gait deficits. This study compared gait and balance measures between APOE epsilon4 carriers and non-carriers in both OA and PD.Methods: 334 people with PD (81 APOE epsilon4 carriers and 253 non-carriers) and 144 OA (41 carriers and 103 non-carriers) were recruited. Gait and balance were assessed using body-worn inertial sensors. Two-way analyses of covariance (ANCOVA) compared gait and balance characteristics between APOE epsilon4 carriers and non-carriers in people with PD and OA, controlling for age, gender, and testing site.Results: Gait and balance were worse in people with PD compared to OA. However, there were no differences between APOE epsilon4 carriers and non-carriers in either the OA or PD group. In addition, there were no significant group (OA/PD) by APOE epsilon4 status (carrier/non-carrier) interaction effects for any measures of gait or balance.Conclusions: Although we found expected impairments in gait and balance in PD compared to OA, gait and balance characteristics did not differ between APOE epsilon4 carriers and non-carriers in either group. While APOE status did not impact gait and balance in this cross-sectional study, future work is needed to determine whether progression of gait and balance deficits is faster in PD APOE Ɛ4 carriers.

  View details for DOI 10.1016/j.prdoa.2023.100201

  View details for PubMedID 37252677

• Performance of a fully-automated Lumipulse plasma phospho-tau181 assay for Alzheimer's disease. Alzheimer's research & therapy Wilson, E. N., Young, C. B., Ramos Benitez, J., Swarovski, M. S., Feinstein, I., Vandijck, M., Le Guen, Y., Kasireddy, N. M., Shahid, M., Corso, N. K., Wang, Q., Kennedy, G., Trelle, A. N., Lind, B., Channappa, D., Belnap, M., Ramirez, V., Skylar-Scott, I., Younes, K., Yutsis, M. V., Le Bastard, N., Quinn, J. F., van Dyck, C. H., Nairn, A., Fredericks, C. A., Tian, L., Kerchner, G. A., Montine, T. J., Sha, S. J., Davidzon, G., Henderson, V. W., Longo, F. M., Greicius, M. D., Wagner, A. D., Wyss-Coray, T., Poston, K. L., Mormino, E. C., Andreasson, K. I. 2022; 14 (1): 172

  Abstract

  BACKGROUND: The recent promise of disease-modifying therapies for Alzheimer's disease (AD) has reinforced the need for accurate biomarkers for early disease detection, diagnosis and treatment monitoring. Advances in the development of novel blood-based biomarkers for AD have revealed that plasma levels of tau phosphorylated at various residues are specific and sensitive to AD dementia. However, the currently available tests have shortcomings in access, throughput, and scalability that limit widespread implementation.METHODS: We evaluated the diagnostic and prognostic performance of a high-throughput and fully-automated Lumipulse plasma p-tau181 assay for the detection of AD. Plasma from older clinically unimpaired individuals (CU, n = 463) and patients with mild cognitive impairment (MCI, n = 107) or AD dementia (n = 78) were obtained from the longitudinal Stanford University Alzheimer's Disease Research Center (ADRC) and the Stanford Aging and Memory Study (SAMS) cohorts. We evaluated the discriminative accuracy of plasma p-tau181 for clinical AD diagnosis, association with amyloid beta peptides and p-tau181 concentrations in CSF, association with amyloid positron emission tomography (PET), and ability to predict longitudinal cognitive and functional change.RESULTS: The assay showed robust performance in differentiating AD from control participants (AUC 0.959, CI: 0.912 to 0.990), and was strongly associated with CSF p-tau181, CSF Abeta42/Abeta40 ratio, and amyloid-PET global SUVRs. Associations between plasma p-tau181 with CSF biomarkers were significant when examined separately in Abeta+ and Abeta- groups. Plasma p-tau181 significantly increased over time in CU and AD diagnostic groups. After controlling for clinical diagnosis, age, sex, and education, baseline plasma p-tau181 predicted change in MoCA overall and change in CDR Sum of Boxes in the AD group over follow-up of up to 5 years.CONCLUSIONS: This fully-automated and available blood-based biomarker assay therefore may be useful for early detection, diagnosis, prognosis, and treatment monitoring of AD.

  View details for DOI 10.1186/s13195-022-01116-2

  View details for PubMedID 36371232

• GaitForeMer: Self-Supervised Pre-Training of Transformers via Human Motion Forecasting for Few-Shot Gait Impairment Severity Estimation. Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention Endo, M., Poston, K. L., Sullivan, E. V., Fei-Fei, L., Pohl, K. M., Adeli, E. 2022; 13438: 130-139

  Abstract

  Parkinson's disease (PD) is a neurological disorder that has a variety of observable motor-related symptoms such as slow movement, tremor, muscular rigidity, and impaired posture. PD is typically diagnosed by evaluating the severity of motor impairments according to scoring systems such as the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Automated severity prediction using video recordings of individuals provides a promising route for non-intrusive monitoring of motor impairments. However, the limited size of PD gait data hinders model ability and clinical potential. Because of this clinical data scarcity and inspired by the recent advances in self-supervised large-scale language models like GPT-3, we use human motion forecasting as an effective self-supervised pre-training task for the estimation of motor impairment severity. We introduce GaitForeMer, Gait Forecasting and impairment estimation transforMer, which is first pre-trained on public datasets to forecast gait movements and then applied to clinical data to predict MDS-UPDRS gait impairment severity. Our method outperforms previous approaches that rely solely on clinical data by a large margin, achieving an F1 score of 0.76, precision of 0.79, and recall of 0.75. Using GaitForeMer, we show how public human movement data repositories can assist clinical use cases through learning universal motion representations. The code is available at https://github.com/markendo/GaitForeMer.

  View details for DOI 10.1007/978-3-031-16452-1_13

  View details for PubMedID 36342887

  View details for PubMedCentralID PMC9635991

• Cognition as a mediator for gait and balance impairments in GBA-related Parkinson's disease. NPJ Parkinson's disease Morris, R., Martini, D. N., Ramsey, K., Kelly, V. E., Smulders, K., Hiller, A., Chung, K. A., Hu, S., Zabetian, C. P., Poston, K. L., Mata, I. F., Edwards, K. L., Lapidus, J., Cholerton, B., Montine, T. J., Quinn, J. F., Horak, F. 2022; 8 (1): 78

  Abstract

  The extent to which the heterogeneity of gait and balance problems in PD may be explained by genetic variation is unknown. Variants in the glucocerebrosidase (GBA) gene are the strongest known genetic risk factor for PD and are associated with greater motor and cognitive severity. However, the impact of GBA variants on comprehensive measures of gait and balance and their relationship to cognition remains unknown. We aimed to determine differences in gait and balance impairments in those with and without GBA variants (mutation carriers and E326K polymorphism) and explore direct and indirect effects of GBA status on gait, balance, and cognition. 332 participants, 43 of whom had GBA variants, were recruited. Participants completed a comprehensive, objective assessment of gait and standing balance using body-worn inertial sensors. Group differences in gait and balance between PD with and without GBA variants were assessed with linear regression, adjusting for age, gender, clinical testing site, disease duration, and apolipoprotein E (APOE) ɛ4 status. Structural equation modeling (SEM) explored direct relationships between GBA status and gait and balance and indirect relationships between GBA status and gait and balance via cognition. The GBA variant group had more impaired gait (pace and variability) and balance (sway area/jerk and sway velocity), than the non-GBA variant group. SEM demonstrated cognition as a mediator of GBA status on gait and balance. The close relationships among GBA, gait/balance, and cognition suggest potential for novel therapeutics to target the GBA pathway and/or cognition to improve mobility in PD GBA variants.

  View details for DOI 10.1038/s41531-022-00344-5

  View details for PubMedID 35725575

• ISOLATED REM SLEEP BEHAVIOR DISORDER IS ASSOCIATED WITH 24-HOUR RHYTHM DISRUPTION Winer, J., Lok, R., Cahuas, A., Bueno, F., Poston, K., Mormino, E., Zeitzer, J., During, E. OXFORD UNIV PRESS INC. 2022: A125

  View details for Web of Science ID 000838094800278

• Divergent Cortical Tau Positron Emission Tomography Patterns Among Patients With Preclinical Alzheimer Disease. JAMA neurology Young, C. B., Winer, J. R., Younes, K., Cody, K. A., Betthauser, T. J., Johnson, S. C., Schultz, A., Sperling, R. A., Greicius, M. D., Cobos, I., Poston, K. L., Mormino, E. C., Alzheimers Disease Neuroimaging Initiative and the Harvard Aging Brain Study, Weiner, M. W., Aisen, P., Petersen, R., Jack, C. R., Jagust, W., Trojanowki, J. Q., Toga, A. W., Beckett, L., Green, R. C., Saykin, A. J., Morris, J. C., Perrin, R. J., Shaw, L. M., Khachaturian, Z., Carrillo, M., Potter, W., Barnes, L., Bernard, M., Gonzalez, H., Ho, C., Hsiao, J. K., Jackson, J., Masliah, E., Masterman, D., Okonkwo, O., Ryan, L., Silverberg, N., Fleisher, A., Sacrey, D. T., Fockler, J., Conti, C., Veitch, D., Neuhaus, J., Jin, C., Nosheny, R., Ashford, M., Flenniken, D., Kormos, A., Montine, T., Rafii, M., Raman, R., Jimenez, G., Donohue, M., Gessert, D., Salazar, J., Zimmerman, C., Cabrera, Y., Walter, S., Miller, G., Coker, G., Clanton, T., Hergesheimer, L., Smith, S., Adegoke, O., Mahboubi, P., Moore, S., Pizzola, J., Shaffer, E., Harvey, D., Forghanian-Arani, A., Borowski, B., Ward, C., Schwarz, C., Jones, D., Gunter, J., Kantarci, K., Senjem, M., Vemuri, P., Reid, R., Fox, N. C., Malone, I., Thompson, P., Thomopoulos, S. I., Nir, T. M., Jahanshad, N., DeCarli, C., Knaack, A., Fletcher, E., Tosun-Turgut, D., Chen, S. R., Choe, M., Crawford, K., Yuschkevich, P. A., Das, S., Koeppe, R. A., Reiman, E. M., Chen, K., Mathis, C., Landau, S., Cairns, N. J., Householder, E., Franklin, E., Bernhardt, H., Taylor-Reinwald, L., Korecka, M., Figurski, M., Neu, S., Nho, K., Risacher, S. L., Apostolova, L. G., Shen, L., Foroud, T. M., Nudelman, K., Faber, K., Wilmes, K., Thal, L., Johnson, K. A., Sperling, R. A. 2022

  Abstract

  Importance: Characterization of early tau deposition in individuals with preclinical Alzheimer disease (AD) is critical for prevention trials that aim to select individuals at risk for AD and halt the progression of disease.Objective: To evaluate the prevalence of cortical tau positron emission tomography (PET) heterogeneity in a large cohort of clinically unimpaired older adults with elevated beta-amyloid (A+).Design, Setting, and Participants: This cross-sectional study examined prerandomized tau PET, amyloid PET, structural magnetic resonance imaging, demographic, and cognitive data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study from April 2014 to December 2017. Follow-up analyses used observational tau PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Harvard Aging Brain Study (HABS), and the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center (together hereinafter referred to as Wisconsin) to evaluate consistency. Participants were clinically unimpaired at the study visit closest to the tau PET scan and had available amyloid and tau PET data (A4 Study, n=447; ADNI, n=433; HABS, n=190; and Wisconsin, n=328). No participants who met eligibility criteria were excluded. Data were analyzed from May 11, 2021, to January 25, 2022.Main Outcomes and Measures: Individuals with preclinical AD with heterogeneous cortical tau PET patterns (A+T cortical+) were identified by examining asymmetrical cortical tau signal and disproportionate cortical tau signal relative to medial temporal lobe (MTL) tau. Voxelwise tau patterns, amyloid, neurodegeneration, cognition, and demographic characteristics were examined.Results: The 447 A4 participants (A+ group, 392; and normal beta-amyloid group, 55), with a mean (SD) age of 71.8 (4.8) years, included 239 women (54%). A total of 36 individuals in the A+ group (9% of the A+ group) exhibited heterogeneous cortical tau patterns and were further categorized into 3 subtypes: asymmetrical left, precuneus dominant, and asymmetrical right. A total of 116 individuals in the A+ group (30% of the A+ group) showed elevated MTL tau (A+T MTL+). Individuals in the A+T cortical+ group were younger than those in the A+T MTL+ group (t61.867=-2.597; P=.03). Across the A+T cortical+ and A+T MTL+ groups, increased regional tau was associated with reduced hippocampal volume and MTL thickness but not with cortical thickness. Memory scores were comparable between the A+T cortical+ and A+T MTL+ groups, whereas executive functioning scores were lower for the A+T cortical+ group than for the A+T MTL+ group. The prevalence of the A+T cortical+ group and tau patterns within the A+T cortical+ group were consistent in ADNI, HABS, and Wisconsin.Conclusions and Relevance: This study suggests that early tau deposition may follow multiple trajectories during preclinical AD and may involve several cortical regions. Staging procedures, especially those based on neuropathology, that assume a uniform trajectory across individuals are insufficient for disease monitoring with tau imaging.

  View details for DOI 10.1001/jamaneurol.2022.0676

  View details for PubMedID 35435938

• Dopaminergic medication normalizes aberrant cognitive control circuit signalling in Parkinson's disease. Brain : a journal of neurology Cai, W., Young, C. B., Yuan, R., Lee, B., Ryman, S., Kim, J., Yang, L., Henderson, V. W., Poston, K. L., Menon, V. 2022

  Abstract

  Dopaminergic medication is widely used to alleviate motor symptoms of Parkinson's disease (PD), but these medications also impact cognition with significant variability across patients. It is hypothesized that dopaminergic medication impacts cognition and working memory in PD by modulating frontoparietal-basal ganglia cognitive control circuits, but little is known about the underlying causal signalling mechanisms and their relation to individual differences in response to dopaminergic medication. Here we use a novel state-space computational model with ultra-fast (490 msec resolution) fMRI to investigate dynamic causal signalling in frontoparietal-basal ganglia circuits associated with working memory in 44 PD patients ON and OFF dopaminergic medication, as well as matched 36 healthy controls. Our analysis revealed aberrant causal signaling in frontoparietal-basal ganglia circuits in PD patients OFF medication. Importantly, aberrant signaling was normalized by dopaminergic medication and a novel quantitative distance measure predicted individual differences in cognitive change associated with medication in PD patients. These findings were specific to causal signaling measures, as no such effects were detected with conventional non-causal connectivity measures. Our analysis also identified a specific frontoparietal causal signaling pathway from right middle frontal gyrus to right posterior parietal cortex that is impaired in PD. Unlike in healthy controls, the strength of causal interactions in this pathway did not increase with working memory load and the strength of load-dependent causal weights was not related to individual differences in working memory task performance in PD patients OFF medication. However, dopaminergic medication in PD patients reinstated the relation with working memory performance. Our findings provide new insights into aberrant causal brain circuit dynamics during working memory and identify mechanisms by which dopaminergic medication normalizes cognitive control circuits.

  View details for DOI 10.1093/brain/awac007

  View details for PubMedID 35357463

• Neuroimaging approaches to cognition in Parkinson's disease. Progress in brain research Montaser-Kouhsari, L., Young, C. B., Poston, K. L. 2022; 269 (1): 257-286

  Abstract

  While direct visualization of Lewy body accumulation within the brain is not yet possible in living Parkinson's disease patients, brain imaging studies offer insights into how the buildup of Lewy body pathology impacts different regions of the brain. Unlike biological biomarkers and purely behavioral research, these brain imaging studies therefore offer a unique opportunity to relate brain localization to cognitive function and dysfunction in living patients. Magnetic resonance imaging studies can reveal physical changes in brain structure as they relate to different cognitive domains and task specific impairments. Functional imaging studies use a combination of task and resting state magnetic resonance imaging, as well as positron emission tomography and single photon emission computed tomography, and can be used to determine changes in blood flow, neuronal activation and neurochemical changes in the brain associated with PD cognition and cognitive impairments. Other unique advantages to brain imaging studies are the ability to monitor changes in brain structure and function longitudinally as patients progress and the ability to study changes in brain function when patients are exposed to different pharmacological manipulations. This is particularly true when assessing the effects of dopaminergic replacement therapy on cognitive function in Parkinson's disease patients. Together, this chapter will describe imaging studies that have helped identify structural and functional brain changes associated with cognition, cognitive impairment, and dementia in Parkinson's disease.

  View details for DOI 10.1016/bs.pbr.2022.01.008

  View details for PubMedID 35248197

• GaitForeMer: Self-supervised Pre-training of Transformers via Human Motion Forecasting for Few-Shot Gait Impairment Severity Estimation Endo, M., Poston, K. L., Sullivan, E. V., Fei-Fei, L., Pohl, K. M., Adeli, E., Wang, L., Dou, Q., Fletcher, P. T., Speidel, S., Li, S. SPRINGER INTERNATIONAL PUBLISHING AG. 2022: 130-139

  View details for DOI 10.1007/978-3-031-16452-1_13

  View details for Web of Science ID 000867418200013

• Neurofunctional characteristics of executive control in older people with HIV infection: a comparison with Parkinson's disease. Brain imaging and behavior Müller-Oehring, E. M., Hong, J. Y., Poston, K. L., Brontë-Stewart, H. M., Sullivan, E. V., McGlynn, L., Schulte, T. 2022

  Abstract

  Expression of executive dysfunctions is marked by substantial heterogeneity in people living with HIV infection (PLWH) and attributed to neuropathological degradation of frontostriatal circuitry with age and disease. We compared the neurophysiology of executive function in older PLWH and Parkinson's disease (PD), both affecting frontostriatal systems. Thirty-one older PLWH, 35 individuals with PD, and 28 older healthy controls underwent executive task-activated fMRI, neuropsychological testing, and a clinical motor exam. fMRI task conditions distinguished cognitive control operations, invoking a lateral frontoparietal network, and motor control operations, activating a cerebellar-precentral-medial prefrontal network. HIV-specific findings denoted a prominent sensorimotor hypoactivation during cognitive control and striatal hypoactivation during motor control related to CD4+ T cell count and HIV disease duration. Activation deficits overlapped for PLWH and PD, relative to controls, in dorsolateral frontal, medial frontal, and middle cingulate cortices for cognitive control, and in limbic, frontal, parietal, and cerebellar regions for motor control. Thus, despite well-controlled HIV infection, frontostriatal and sensorimotor activation deficits occurred during executive control in older PLWH. Overlapping activation deficits in posterior cingulate and hippocampal regions point toward similarities in mesocorticolimbic system aberrations among older PLWH and PD. The extent of pathophysiology in PLWH was associated with variations in immune system health, neural signature consistent with subclinical parkinsonism, and mild neurocognitive impairment. The failure to adequately engage these pathways could be an early sign for cognitive and motor functional decline in the aging population of PLWH.

  View details for DOI 10.1007/s11682-022-00645-6

  View details for PubMedID 35294979

• Low soluble amyloid-beta 42 is associated with smaller brain volume in Parkinson's disease. Parkinsonism & related disorders Espay, A. J., Lafontant, D., Poston, K. L., Caspell-Garcia, C., Marsili, L., Cho, H. R., McDaniel, C., Kim, N., Coffey, C. S., Mahajan, A., Ezzat, K., Sturchio, A., Parkinson's Progression Markers Initiative 2021; 92: 15-21

  Abstract

  INTRODUCTION: We sought to examine whether levels of soluble alpha-synuclein (alpha-syn), amyloid-beta (Abeta42), phosphorylated tau (p-tau), and total tau (t-tau), as measured in cerebrospinal fluid (CSF), are associated with changes in brain volume in Parkinson's disease.METHODS: We assessed the 4-year change in total brain volume (n=99) and baseline CSF alpha-syn, Abeta42, p-tau, and t-tau of Parkinson Progression Markers Initiative participants. We used linear mixed models to assess the longitudinal effect of baseline CSF biomarkers on total and regional brain volume and thickness as well as linear regression for cross-sectional analyses at baseline and year 2. All models were adjusted for age and gender; brain volume models also adjusted for baseline intracranial volume. Bonferroni correction was applied.RESULTS: The 4-year change in total brain volume was -21.2mm3 (95% confidence interval, -26.1, -16.3). There were no significant associations between the 4-year change in total brain volume and baseline levels of any CSF biomarker (all p-values > 0.05). On cross-sectional analyses, CSF Abeta42 was linearly associated with total brain volume at baseline (R2=0.60, p=0.0004) and at year 2 (R2=0.66, p<0.0001), with CSF Abeta42<1100pg/ml, the threshold for brain amyloid pathology, associated with smaller total brain volume at baseline (p=0.0010) and at year 2 (p=0.0002). CSF alpha-syn was linearly associated with total brain volume at baseline (R2=0.58, p=0.0044) but not at year 2 (R2=0.58, p=0.1342).CONCLUSION: Reduction in soluble Abeta42 is associated with lower total brain volume in Parkinson's disease.

  View details for DOI 10.1016/j.parkreldis.2021.10.010

  View details for PubMedID 34656902

• Latent brain state dynamics and cognitive flexibility in older adults. Progress in neurobiology Lee, B., Cai, W., Young, C. B., Yuan, R., Ryman, S., Kim, J., Santini, V., Henderson, V. W., Poston, K. L., Menon, V. 2021: 102180

  Abstract

  Cognitive impairment in older adults is a rapidly growing public health concern as the elderly population dramatically grows worldwide. While it is generally assumed that cognitive deficits in older adults are associated with reduced brain flexibility, quantitative evidence has been lacking. Here, we investigate brain flexibility in healthy older adults (ages 60-85) using a novel Bayesian switching dynamical system algorithm and ultrafast temporal resolution (490msec) whole-brain fMRI data during performance of a Sternberg working memory task. We identify latent brain states and characterize their dynamic temporal properties, including state transitions, associated with encoding, maintenance, and retrieval. Crucially, we demonstrate that brain inflexibility is associated with slower and more fragmented transitions between latent brain states, and that brain inflexibility mediates the relation between age and cognitive inflexibility. Our study provides a novel neurocomputational framework for investigating latent dynamic circuit processes underlying brain flexibility and cognition in the context of aging.

  View details for DOI 10.1016/j.pneurobio.2021.102180

  View details for PubMedID 34627994

• Influence of Common Reference Regions on Regional Tau Patterns in Cross-Sectional and Longitudinal [18F]-AV-1451 PET Data. NeuroImage Young, C. B., Landau, S. M., Harrison, T. M., Poston, K. L., Mormino, E. C., ADNI 2021: 118553

  Abstract

  Tau PET has allowed for critical insights into in vivo patterns of tau accumulation and change in individuals early in the Alzheimer's disease (AD) continuum. A key methodological step in tau PET analyses is the selection of a reference region, but there is not yet consensus on the optimal region especially for longitudinal tau PET analyses. This study examines how reference region selection influences results related to disease stage at baseline and over time. Longitudinal [18F]-AV1451 PET scans were examined using several common reference regions (e.g., eroded subcortical white matter, inferior cerebellar gray matter) in 62 clinically unimpaired amyloid negative (CU A-) individuals, 73 CU amyloid positive (CU A+) individuals, and 64 amyloid positive individuals with mild cognitive impairment (MCI A+) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cross-sectionally, both reference regions resulted in robust group differences between CU A-, CU A+, and MCI A+ groups, along with significant associations with CSF phosphorylated tau (pTau-181). However, these results were more focally specific and akin to Braak Staging using eroded white matter, whereas effects with inferior cerebellum were globally distributed across most cortical regions. Longitudinally, utilization of eroded white matter revealed significant accumulation greater than zero across more regions whereas change over time was diminished using inferior cerebellum. Interestingly, the inferior temporal target region seemed most robust to reference region selection with expected cross-sectional and longitudinal signal across both reference regions. With few exceptions, baseline tau did not significantly predict longitudinal change in tau in the same region regardless of reference region. In summary, reference region selection deserves further evaluation as this methodological step may lead to disparate findings. Inferior cerebellar gray matter may be more sensitive to cross-sectional flortaucipir differences, whereas eroded subcortical white matter may be more sensitive for longitudinal analyses examining regional patterns of change.

  View details for DOI 10.1016/j.neuroimage.2021.118553

  View details for PubMedID 34487825

• Association of Short and Long Sleep Duration With Amyloid-beta Burden and Cognition in Aging. JAMA neurology Winer, J. R., Deters, K. D., Kennedy, G., Jin, M., Goldstein-Piekarski, A., Poston, K. L., Mormino, E. C. 2021

  Abstract

  Importance: Disrupted sleep is common in aging and is associated with cognition. Age-related changes to sleep are associated with multiple causes, including early Alzheimer disease pathology (amyloid beta [Abeta]), depression, and cardiovascular disease.Objective: To investigate the associations between self-reported sleep duration and brain Abeta burden as well as the demographic, cognitive, and lifestyle variables in adults with normal cognition.Design, Setting, and Participants: This cross-sectional study obtained data from participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study, which is being conducted in 67 sites in the United States, Canada, Australia, and Japan. The sample for this analysis consisted of individuals aged 65 to 85 years who underwent an Abeta positron emission tomography (PET) scan, had complete apolipoprotein E (APOE) genotype data, and were identified as clinically normal (per a Clinical Dementia Rating score of 0) and cognitively unimpaired (per a Mini-Mental State Examination score of 25 to 30 and Logical Memory Delayed Recall test score of 6 to 18). Data were analyzed from April 3, 2020, to June 20, 2021.Main Outcomes and Measures: The outcome was self-reported nightly sleep duration (grouped by short sleep duration: ≤6 hours, normal sleep duration: 7-8 hours, and long sleep duration: ≥9 hours) compared with demographic characteristics, Abeta burden (as measured with a fluorine 18-labeled-florbetapir PET scan), objective and subjective cognitive function measures, and lifestyle variables.Results: The 4417 participants in the study included 2618 women (59%) and had a mean (SD) age of 71.3 (4.7) years. Self-reported shorter sleep duration was linearly associated with higher Abeta burden (beta [SE]=-0.01 [0.00]; P=.005), and short sleep duration was associated with reduced cognition that was mostly in memory domains. No difference in Abeta was found between long and normal sleep duration groups (beta [SE]=0.00[0.01]; P=.99). However, compared with normal sleep duration, both short and long sleep durations were associated with higher body mass index (short vs normal sleep duration: beta [SE]=0.48 [0.17], P=.01; long vs normal sleep duration: beta [SE]=0.97 [0.31], P=.002), depressive symptoms (short vs normal sleep duration: beta [SE]=0.31 [0.05], P<.001; long vs normal sleep duration: beta [SE]=0.39 [0.09], P<.001), and daytime napping (short vs normal sleep duration: beta [SE]=2.66 [0.77], P=.001; long vs normal sleep duration: beta [SE]=3.62 [1.38], P=.01). Long sleep duration was associated with worse performance across multiple cognitive domains.Conclusions and Relevance: In this cross-sectional study, both short and long sleep durations were associated with worse outcomes for older adults, such as greater Abeta burden, greater depressive symptoms, higher body mass index, and cognitive decline, emphasizing the importance of maintaining adequate sleep.

  View details for DOI 10.1001/jamaneurol.2021.2876

  View details for PubMedID 34459862

• Semantic fluency and processing speed are reduced in non-cognitively impaired participants with Parkinson's disease. Journal of clinical and experimental neuropsychology Cholerton, B. A., Poston, K. L., Yang, L., Rosenthal, L. S., Dawson, T. M., Pantelyat, A., Edwards, K. L., Tian, L., Quinn, J. F., Chung, K. A., Hiller, A. L., Hu, S., Montine, T. J., Zabetian, C. P. 2021: 1-12

  Abstract

  Introduction: Parkinson's disease (PD) is associated with a range of cognitive deficits. Few studies have carefully examined the subtle impacts of PD on cognition among patients who do not meet formal criteria for MCI or dementia. The aim of the current study was thus to describe the impact of PD on cognition in those without cognitive impairment in a well-characterized cohort.Methods: Non-cognitively impaired participants (122 with PD, 122 age- and sex-matched healthy volunteers) underwent extensive cognitive testing. Linear regression analyses compared diagnostic group performance across cognitive measures. For cognitive tasks that were significantly different between groups, additional analyses examined group differences restricting the group inclusion to PD participants with mild motor symptoms or disease duration less than 10years.Results: Processing speed and semantic verbal fluency were significantly lower in the PD group (B =-3.77, 95% CIs [-5.76 to -1.77], p <.001, and B =-2.02, 95% CIs [-3.12, -0.92], p <.001, respectively), even after excluding those with moderate to severe motor symptoms (B =-2.73, 95% CIs [-4.94 to -0.53], p =.015 and B =-2.11, 95% CIs [-3.32 to -0.91], p <.001, respectively) or longer disease duration (B =-3.89, 95% CIs [-6.14 to -1.63], p <.001 and B =-1.58, 95% CIs [-2.78 to -0.37], p =.010, respectively). Semantic verbal fluency remained significantly negatively associated with PD diagnosis after controlling for processing speed (B =-1.66, 95% CIs [-2.79 to -0.53], p =.004).Conclusions: Subtle decline in specific cognitive domains may be present among people diagnosed with PD but without evidence to support a formal cognitive diagnosis. These results suggest the importance of early awareness of the potential for diminishing aspects of cognition in PD even among those without mild cognitive impairment or dementia.

  View details for DOI 10.1080/13803395.2021.1927995

  View details for PubMedID 34355669

• High cerebrospinal amyloid-β 42 is associated with normal cognition in individuals with brain amyloidosis. EClinicalMedicine Sturchio, A., Dwivedi, A. K., Young, C. B., Malm, T., Marsili, L., Sharma, J. S., Mahajan, A., Hill, E. J., Andaloussi, S. E., Poston, K. L., Manfredsson, F. P., Schneider, L. S., Ezzat, K., Espay, A. J. 2021; 38: 100988

  Abstract

  Brain amyloidosis does not invariably predict dementia. We hypothesized that high soluble 42-amino acid β amyloid (Aβ42) peptide levels are associated with normal cognition and hippocampal volume despite increasing brain amyloidosis.This cross-sectional study of 598 amyloid-positive participants in the Alzheimer's Disease Neuroimaging Initiative cohort examined whether levels of soluble Aβ42 are higher in amyloid-positive normal cognition (NC) individuals compared to mild cognitive impairment (MCI) and Alzheimer's disease (AD) and whether this relationship applies to neuropsychological assessments and hippocampal volume measured within the same year. All subjects were evaluated between June 2010 and February 2019. Brain amyloid positivity was defined as positron emission tomography-based standard uptake value ratio (SUVR) ≥1.08 for [18] F-florbetaben or 1.11 for [18]F-florbetapir, with higher SUVR indicating more brain amyloidosis. Analyses were adjusted for age, sex, education, APOE4, p-tau, t-tau, and centiloids levels.Higher soluble Aβ42 levels were observed in NC (864.00 pg/ml) than in MCI (768.60 pg/ml) or AD (617.46 pg/ml), with the relationship between NC, MCI, and AD maintained across all amyloid tertiles. In adjusted analysis, there was a larger absolute effect size of soluble Aβ42 than SUVR for NC (0.82 vs. 0.40) and MCI (0.60 vs. 0.26) versus AD. Each standard deviation increase in Aβ42 was associated with greater odds of NC than AD (adjusted odds ratio, 6.26; p < 0.001) or MCI (1.42; p = 0.006). Higher soluble Aβ42 levels were also associated with better neuropsychological function and larger hippocampal volume.Normal cognition and hippocampal volume are associated with preservation of high soluble Aβ42 levels despite increasing brain amyloidosis.Please refer to the Funding section at the end of the article.

  View details for DOI 10.1016/j.eclinm.2021.100988

  View details for PubMedID 34505023

  View details for PubMedCentralID PMC8413261

• The effects of mood and cognition on daily functioning and quality of life in older people living with HIV and people with Parkinson's disease. Neuropsychology Patel, S. S., Muller-Oehring, E. M., DeVaughn, S., Fama, R., Bronte-Stewart, H. M., Poston, K. L., Schulte, T. 2021

  Abstract

  OBJECTIVE: In light of the increased longevity of people living with HIV infection (PLWH) undergoing antiretroviral therapy (ART), the present study aimed to determine the effects of mood disturbances alongside cognitive and motor symptoms on activities of daily living (ADLs) and quality of life (QOL) in older PLWH in comparison to an aging control sample without notable medical history (CTL) and individuals with Parkinson's disease (PD).METHOD: Forty-one PLWH, 41 individuals with PD, and 37 CTL, aged 45-79 years, underwent neuropsychological, psychological, and neurological assessment including depressive and anxiety symptoms, physical (ADL-p) and instrumental (ADL-i) daily activities, Unified Parkinson's Disease Rating Scale motor ADLs (ADL-UPDRS-II), QOL, and cognitive and motor functions. Hierarchical regression analyses assessed the relative contribution of predictors including demographics, disease-related factors, comorbid conditions, and mood-related factors for ADL and QOL scales.RESULTS: PLWH and PD participants reported more depressive symptoms and higher anxiety and worse QOL and ADL-i than CTL. The PD group had greater ADL-p and motor-related ADL-UPDRS-II difficulties than PLWH and CTL groups. In PLWH, medical comorbidities and alcohol use disorder (AUD)/substance use disorder (SUD) histories significantly contributed to poor physical and motor ADLs. Mood scores, particularly depressive symptoms, were independent predictors of poor QOL and most ADLs in both clinical groups, above the contribution of cognitive compromise.CONCLUSIONS: Mood symptoms contribute significantly to poor ADLs and QOL in people aging with chronic diseases such as long-term HIV infection and PD. Comprehensive assessment and treatment of mood symptoms are recommended for ensuring optimal functional independence and life quality. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

  View details for DOI 10.1037/neu0000760

  View details for PubMedID 34323563

• International Multicenter Analysis of Brain Structure Across Clinical Stages of Parkinson's Disease. Movement disorders : official journal of the Movement Disorder Society Laansma, M. A., Bright, J. K., Al-Bachari, S., Anderson, T. J., Ard, T., Assogna, F., Baquero, K. A., Berendse, H. W., Blair, J., Cendes, F., Dalrymple-Alford, J. C., de Bie, R. M., Debove, I., Dirkx, M. F., Druzgal, J., Emsley, H. C., Garraux, G., Guimaraes, R. P., Gutman, B. A., Helmich, R. C., Klein, J. C., Mackay, C. E., McMillan, C. T., Melzer, T. R., Parkes, L. M., Piras, F., Pitcher, T. L., Poston, K. L., Rango, M., Ribeiro, L. F., Rocha, C. S., Rummel, C., Santos, L. S., Schmidt, R., Schwingenschuh, P., Spalletta, G., Squarcina, L., van den Heuvel, O. A., Vriend, C., Wang, J., Weintraub, D., Wiest, R., Yasuda, C. L., Jahanshad, N., Thompson, P. M., van der Werf, Y. D., ENIGMA-Parkinson's Study 2021

  Abstract

  BACKGROUND: Brain structure abnormalities throughout the course of Parkinson's disease have yet to be fully elucidated.OBJECTIVE: Using a multicenter approach and harmonized analysis methods, we aimed to shed light on Parkinson's disease stage-specific profiles of pathology, as suggested by in vivo neuroimaging.METHODS: Individual brain MRI and clinical data from 2357 Parkinson's disease patients and 1182 healthy controls were collected from 19 sources. We analyzed regional cortical thickness, cortical surface area, and subcortical volume using mixed-effects models. Patients grouped according to Hoehn and Yahr stage were compared with age- and sex-matched controls. Within the patient sample, we investigated associations with Montreal Cognitive Assessment score.RESULTS: Overall, patients showed a thinner cortex in 38 of 68 regions compared with controls (dmax =-0.20, dmin =-0.09). The bilateral putamen (dleft =-0.14, dright =-0.14) and left amygdala (d=-0.13) were smaller in patients, whereas the left thalamus was larger (d=0.13). Analysis of staging demonstrated an initial presentation of thinner occipital, parietal, and temporal cortices, extending toward rostrally located cortical regions with increased disease severity. From stage 2 and onward, the bilateral putamen and amygdala were consistently smaller with larger differences denoting each increment. Poorer cognition was associated with widespread cortical thinning and lower volumes of core limbic structures.CONCLUSIONS: Our findings offer robust and novel imaging signatures that are generally incremental across but in certain regions specific to disease stages. Our findings highlight the importance of adequately powered multicenter collaborations.

  View details for DOI 10.1002/mds.28706

  View details for PubMedID 34288137

• Longitudinal Analysis of Multiple Neurotransmitter Metabolites in Cerebrospinal Fluid in Early Parkinson's Disease. Movement disorders : official journal of the Movement Disorder Society Kremer, T., Taylor, K. I., Siebourg-Polster, J., Gerken, T., Staempfli, A., Czech, C., Dukart, J., Galasko, D., Foroud, T., Chahine, L. M., Coffey, C. S., Simuni, T., Weintraub, D., Seibyl, J., Poston, K. L., Toga, A. W., Tanner, C. M., Marek, K., Hutten, S. J., Dziadek, S., Trenkwalder, C., Pagano, G., Mollenhauer, B. 2021

  Abstract

  BACKGROUND: Cerebrospinal fluid (CSF) levels of monoamine metabolites may represent biomarkers of Parkinson's disease (PD).OBJECTIVE: The aim of this study was quantification of multiple metabolites in CSF from PD versus healthy control subjects (HCs), including longitudinal analysis.METHODS: Absolute levels of multiple monoamine metabolites in CSF were quantified by liquid chromatography coupled with tandem mass spectrometry from 161 individuals with early PD and 115 HCs from the Parkinson's Progression Marker Initiative and de novo PD (DeNoPA) studies.RESULTS: Baseline levels of homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were lower in individuals with PD compared with HCs. HVA levels correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale total scores (P<0.01). Both HVA/dopamine and DOPAC/dopamine levels correlated with caudate nucleus and raw DOPAC with putamen dopamine transporter single-photon emission computed tomography uptake ratios (P<0.01). No metabolite changed over 2years in drug-naive individuals, but some changed on starting levodopa treatment.CONCLUSIONS: HVA and DOPAC CSF levels mirrored nigrostriatal pathway damage, confirming the central role of dopaminergic degeneration in early PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

  View details for DOI 10.1002/mds.28608

  View details for PubMedID 33942926

• Neuropathological correlation supports automated image-based differential diagnosis in parkinsonism. European journal of nuclear medicine and molecular imaging Schindlbeck, K. A., Gupta, D. K., Tang, C. C., O'Shea, S. A., Poston, K. L., Choi, Y. Y., Dhawan, V., Vonsattel, J., Fahn, S., Eidelberg, D. 2021

  Abstract

  PURPOSE: Up to 25% of patients diagnosed as idiopathic Parkinson's disease (IPD) have an atypical parkinsonian syndrome (APS). We had previously validated an automated image-based algorithm to discriminate between IPD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). While the algorithm was accurate with respect to the final clinical diagnosis after long-term expert follow-up, its relationship to the initial referral diagnosis and to the neuropathological gold standard is not known.METHODS: Patients with an uncertain diagnosis of parkinsonism were referred for 18F-fluorodeoxyglucose (FDG) PET to classify patients as IPD or as APS based on the automated algorithm. Patients were followed by a movement disorder specialist and subsequently underwent neuropathological examination. The image-based classification was compared to the neuropathological diagnosis in 15 patients with parkinsonism.RESULTS: At the time of referral to PET, the clinical impression was only 66.7% accurate. The algorithm correctly identified 80% of the cases as IPD or APS (p=0.02) and 87.5% of the APS cases as MSA or PSP (p=0.03). The final clinical diagnosis was 93.3% accurate (p<0.001), but needed several years of expert follow-up.CONCLUSION: The image-based classifications agreed well with autopsy and can help to improve diagnostic accuracy during the period of clinical uncertainty.

  View details for DOI 10.1007/s00259-021-05302-6

  View details for PubMedID 33839891

• Deep sequencing of sncRNAs reveals hallmarks and regulatory modules of the transcriptome during Parkinson's disease progression NATURE AGING Kern, F., Fehlmann, T., Violich, I., Alsop, E., Hutchins, E., Kahraman, M., Grammes, N. L., Guimaraes, P., Backes, C., Poston, K. L., Casey, B., Balling, R., Geffers, L., Krueger, R., Galasko, D., Mollenhauer, B., Meese, E., Wyss-Coray, T., Craig, D. W., Van Keuren-Jensen, K., Keller, A. 2021; 1 (3): 309-+

  View details for DOI 10.1038/s43587-021-00042-6

  View details for Web of Science ID 000899149700009

• Deep sequencing of sncRNAs reveals hallmarks and regulatory modules of the transcriptome during Parkinson's disease progression. Nature aging Kern, F., Fehlmann, T., Violich, I., Alsop, E., Hutchins, E., Kahraman, M., Grammes, N. L., Guimarães, P., Backes, C., Poston, K. L., Casey, B., Balling, R., Geffers, L., Krüger, R., Galasko, D., Mollenhauer, B., Meese, E., Wyss-Coray, T., Craig, D. W., Van Keuren-Jensen, K., Keller, A. 2021; 1 (3): 309-322

  Abstract

  Noncoding RNAs have diagnostic and prognostic importance in Parkinson's disease (PD). We studied circulating small noncoding RNAs (sncRNAs) in two large-scale longitudinal PD cohorts (Parkinson's Progression Markers Initiative (PPMI) and Luxembourg Parkinson's Study (NCER-PD)) and modeled their impact on the transcriptome. Sequencing of sncRNAs in 5,450 blood samples of 1,614 individuals in PPMI yielded 323 billion reads, most of which mapped to microRNAs but covered also other RNA classes such as piwi-interacting RNAs, ribosomal RNAs and small nucleolar RNAs. Dysregulated microRNAs associated with disease and disease progression occur in two distinct waves in the third and seventh decade of life. Originating predominantly from immune cells, they resemble a systemic inflammation response and mitochondrial dysfunction, two hallmarks of PD. Profiling 1,553 samples from 1,024 individuals in the NCER-PD cohort validated biomarkers and main findings by an independent technology. Finally, network analysis of sncRNA and transcriptome sequencing from PPMI identified regulatory modules emerging in patients with progressing PD.

  View details for DOI 10.1038/s43587-021-00042-6

  View details for PubMedID 37118411

  View details for PubMedCentralID 2930111

• Cognitive impairment in Parkinson's disease is associated with Default Mode Network subsystem connectivity and cerebrospinal fluid Aβ. Parkinsonism & related disorders Zarifkar, P. n., Kim, J. n., La, C. n., Zhang, K. n., YorkWilliams, S. n., Levine, T. F., Tian, L. n., Borghammer, P. n., Poston, K. L. 2021; 83: 71–78

  Abstract

  To identify clinically implementable biomarkers of cognitive impairment in Parkinson's Disease (PD) derived from resting state-functional MRI (rs-fMRI) and CSF protein analysis.In this single-center longitudinal cohort study, we analyzed rs-fMRI and CSF biomarkers from 50 PD patients (23 cognitively normal, 18 mild cognitive impairment, 9 dementia) and 19 controls, who completed comprehensive neuropsychological testing. A subgroup of participants returned for follow-up cognitive assessments three years later. From rs-fMRI, we studied the connectivity within two distinct Default Mode Network subsystems: left-to-right hippocampus (LHC-RHC) and medial prefrontal cortex-to-posterior cingulate cortex (mPFC-PCC). We used regression analyses to determine whether imaging (LHC-RHC, mPFC-PCC), clinical (CSF Aβ-42:40, disease duration), and demographic (age, sex, education) variables were associated with global and domain-specific cognitive impairments.LHC-RHC (F3,67 = 3.41,p=0.023) and CSF Aβ-42:40 (χ2(3) = 8.77,p = 0.033) were reduced across more cognitively impaired PD groups. Notably, LHC-RHC connectivity was significantly associated with all global and domain-specific cognitive impairments (attention/executive, episodic memory, visuospatial, and language) at the baseline visit. In an exploratory longitudinal analysis, mPFC-PCC was associated with future global and episodic memory impairment.We used biomarker techniques that are readily available in clinical and research facilities to shed light on the pathophysiologic basis of cognitive impairment in PD. Our findings suggest that there is a functionally distinct role of the hippocampal subsystem within the DMN resting state network, and that intrinsic connectivity between the hippocampi is critically related to a broad range of cognitive functions in PD.

  View details for DOI 10.1016/j.parkreldis.2021.01.002

  View details for PubMedID 33484978

• Fluid and Tissue Biomarkers of Lewy Body Dementia: Report of an LBDA Symposium. Frontiers in neurology Scott, G. D., Arnold, M. R., Beach, T. G., Gibbons, C. H., Kanthasamy, A. G., Lebovitz, R. M., Lemstra, A. W., Shaw, L. M., Teunissen, C. E., Zetterberg, H., Taylor, A. S., Graham, T. C., Boeve, B. F., Gomperts, S. N., Graff-Radford, N. R., Moussa, C., Poston, K. L., Rosenthal, L. S., Sabbagh, M. N., Walsh, R. R., Weber, M. T., Armstrong, M. J., Bang, J. A., Bozoki, A. C., Domoto-Reilly, K., Duda, J. E., Fleisher, J. E., Galasko, D. R., Galvin, J. E., Goldman, J. G., Holden, S. K., Honig, L. S., Huddleston, D. E., Leverenz, J. B., Litvan, I., Manning, C. A., Marder, K. S., Pantelyat, A. Y., Pelak, V. S., Scharre, D. W., Sha, S. J., Shill, H. A., Mari, Z., Quinn, J. F., Irwin, D. J. 2021; 12: 805135

  Abstract

  The Lewy Body Dementia Association (LBDA) held a virtual event, the LBDA Biofluid/Tissue Biomarker Symposium, on January 25, 2021, to present advances in biomarkers for Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLBs) and Parkinson's disease dementia (PDD). The meeting featured eight internationally known scientists from Europe and the United States and attracted over 200 scientists and physicians from academic centers, the National Institutes of Health, and the pharmaceutical industry. Methods for confirming and quantifying the presence of Lewy body and Alzheimer's pathology and novel biomarkers were discussed.

  View details for DOI 10.3389/fneur.2021.805135

  View details for PubMedID 35173668

• Quantifying Parkinson's disease motor severity under uncertainty using MDS-UPDRS videos. Medical image analysis Lu, M., Zhao, Q., Poston, K. L., Sullivan, E. V., Pfefferbaum, A., Shahid, M., Katz, M., Kouhsari, L. M., Schulman, K., Milstein, A., Niebles, J. C., Henderson, V. W., Fei-Fei, L., Pohl, K. M., Adeli, E. 2021; 73: 102179

  Abstract

  Parkinson's disease (PD) is a brain disorder that primarily affects motor function, leading to slow movement, tremor, and stiffness, as well as postural instability and difficulty with walking/balance. The severity of PD motor impairments is clinically assessed by part III of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), a universally-accepted rating scale. However, experts often disagree on the exact scoring of individuals. In the presence of label noise, training a machine learning model using only scores from a single rater may introduce bias, while training models with multiple noisy ratings is a challenging task due to the inter-rater variabilities. In this paper, we introduce an ordinal focal neural network to estimate the MDS-UPDRS scores from input videos, to leverage the ordinal nature of MDS-UPDRS scores and combat class imbalance. To handle multiple noisy labels per exam, the training of the network is regularized via rater confusion estimation (RCE), which encodes the rating habits and skills of raters via a confusion matrix. We apply our pipeline to estimate MDS-UPDRS test scores from their video recordings including gait (with multiple Raters, R=3) and finger tapping scores (single rater). On a sizable clinical dataset for the gait test (N=55), we obtained a classification accuracy of 72% with majority vote as ground-truth, and an accuracy of ∼84% of our model predicting at least one of the raters' scores. Our work demonstrates how computer-assisted technologies can be used to track patients and their motor impairments, even when there is uncertainty in the clinical ratings. The latest version of the code will be available at https://github.com/mlu355/PD-Motor-Severity-Estimation.

  View details for DOI 10.1016/j.media.2021.102179

  View details for PubMedID 34340101

• Vision-based Estimation of MDS-UPDRS Gait Scores for Assessing Parkinson's Disease Motor Severity. Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention Lu, M., Poston, K., Pfefferbaum, A., Sullivan, E. V., Fei-Fei, L., Pohl, K. M., Niebles, J. C., Adeli, E. 2020; 12263: 637–47

  Abstract

  Parkinson's disease (PD) is a progressive neurological disorder primarily affecting motor function resulting in tremor at rest, rigidity, bradykinesia, and postural instability. The physical severity of PD impairments can be quantified through the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), a widely used clinical rating scale. Accurate and quantitative assessment of disease progression is critical to developing a treatment that slows or stops further advancement of the disease. Prior work has mainly focused on dopamine transport neuroimaging for diagnosis or costly and intrusive wearables evaluating motor impairments. For the first time, we propose a computer vision-based model that observes non-intrusive video recordings of individuals, extracts their 3D body skeletons, tracks them through time, and classifies the movements according to the MDS-UPDRS gait scores. Experimental results show that our proposed method performs significantly better than chance and competing methods with an F 1-score of 0.83 and a balanced accuracy of 81%. This is the first benchmark for classifying PD patients based on MDS-UPDRS gait severity and could be an objective biomarker for disease severity. Our work demonstrates how computer-assisted technologies can be used to non-intrusively monitor patients and their motor impairments. The code is available at https://github.com/mlu355/PD-Motor-Severity-Estimation.

  View details for DOI 10.1007/978-3-030-59716-0_61

  View details for PubMedID 33103164

• White Matter Hyperintensities Related to Parkinson's Disease Executive Function. Movement disorders clinical practice Linortner, P., McDaniel, C., Shahid, M., Levine, T. F., Tian, L., Cholerton, B., Poston, K. L. 2020; 7 (6): 629-638

  Abstract

  People with Parkinson's disease (PD) can develop multidomain cognitive impairments; however, it is unclear whether different pathologies underlie domain-specific cognitive dysfunction.We investigated the contribution of vascular copathology severity and location, as measured by MRI white matter hyperintensities (WMHs), to domain-specific cognitive impairment in PD.We studied 85 PD (66.6 ± 9.2 years) and 18 control (65.9 ± 6.6) participants. Using the Fazekas scale for rating the severity of WMH, we subdivided PD into 14 PD-WMH+ and 71 PD-WMH-. Participants underwent global, executive, visuospatial, episodic memory, and language testing. We performed nonparametric permutation testing to create WMH probability maps based on PD-WMH group and cognitive test performance.The PD-WMH+ group showed worse global and executive cognitive performance than the PD-WMH- group. On individual tests, the PD-WMH+ group showed worse Montreal Cognitive Assessment (MoCA), Stroop, Symbol Digit Modalities Test (SDMT), and Digit Span scores. WMH probability maps showed that in the PD-WMH+ group, worse Stroop was associated with lesions centered around the corticospinal tract (CST), forceps major, inferior-fronto-occipital fasciculus, and superior longitudinal fasciculus; worse SDMT with lesions around the CST, forceps major, and posterior corona radiata; worse Digit Span with lesions around the posterior corona radiata; and worse MoCA with lesions around the CST.We found that WMH severity was associated with PD executive dysfunction, including worse attention, working memory, and processing speed. Disruption of key white matter tracts in proximity to vascular lesions could contribute to these specific cognitive impairments. Early treatment of vascular disease might mitigate some executive dysfunction in a subset of patients with PD.

  View details for DOI 10.1002/mdc3.12956

  View details for PubMedID 32775508

  View details for PubMedCentralID PMC7396844

• Hallucinations and Development of Dementia in Parkinson's Disease. Journal of Parkinson's disease Gryc, W., Roberts, K. A., Zabetian, C. P., Weintraub, D., Trojanowski, J. Q., Quinn, J. F., Hiller, A. L., Chung, K. A., Poston, K. L., Yang, L., Hu, S., Edwards, K. L., Montine, T. J., Cholerton, B. A. 2020

  Abstract

  Neuropsychiatric symptoms are common in Parkinson's disease (PD). We investigated the relationship between neuropsychiatric symptoms and current and future diagnosis of PD dementia (PDD). Individuals with PD who had a study partner were enrolled (n = 696). Study partners were administered the Neuropsychiatric Inventory or Neuropsychiatric Inventory Questionnaire at baseline. Participants were assigned a cognitive diagnosis at baseline and follow up visits. Hallucinations were significantly associated with a diagnosis of PDD cross-sectionally (p < 0.001) and with shortened time to dementia longitudinally among initially nondemented participants (n = 444; p = 0.005). Screening for hallucinations may be useful for assessing risk of dementia in participants with PD.

  View details for DOI 10.3233/JPD-202116

  View details for PubMedID 32741842

• Clinical and Dopamine Transporter Imaging Characteristics of Leucine Rich Repeat Kinase 2 (LRRK2) and Glucosylceramidase Beta (GBA) Parkinson's Disease Participants in the Parkinson's Progression Markers Initiative: A Cross-Sectional Study MOVEMENT DISORDERS Simuni, T., Brumm, M. C., Uribe, L., Caspell-Garcia, C., Coffey, C. S., Siderowf, A., Alcalay, R. N., Trojanowski, J. Q., Shaw, L. M., Seibyl, J., Singleton, A., Toga, A. W., Galasko, D., Foroud, T., Nudelman, K., Tosun-Turgut, D., Poston, K., Weintraub, D., Mollenhauer, B., Tanner, C. M., Kieburtz, K., Chahine, L. M., Reimer, A., Hutten, S., Bressman, S., Marek, K., Parkinson's Progression Markers I 2020; 35 (5): 833–44

  View details for DOI 10.1002/mds.2798910.1002/mds.27989

  View details for Web of Science ID 000532910200019

• White Matter Hyperintensities Related to Parkinson's Disease Executive Function MOVEMENT DISORDERS CLINICAL PRACTICE Linortner, P., McDaniel, C., Shahid, M., Levine, T. F., Tian, L., Cholerton, B., Poston, K. L. 2020

  View details for DOI 10.1002/mdc3.12956

  View details for Web of Science ID 000529623200001

• Alterations of Brain Signal Oscillations in Older Individuals with HIV Infection and Parkinson's Disease. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology Muller-Oehring, E. M., Hong, J., Hughes, R. L., Kwon, D., Bronte-Stewart, H. M., Poston, K. L., Schulte, T. 2020

  Abstract

  More than 30years after the human immunodeficiency virus (HIV) epidemic, HIV patients are now aging due to the advances of antiretroviral therapy. With immunosenescence and the susceptibility of dopamine-rich basal ganglia regions to HIV-related injury, older HIV patients may show neurofunctional deficits similar to patients with Parkinson's disease (PD). We examined the amplitudes of low frequency fluctuations (ALFF) across different frequency bands of the BOLD signal in 30 older HIV-infected individuals, 33 older healthy controls, and 36 PD patients. Participants underwent resting-state fMRI, neuropsychological testing, and a clinical motor exam. HIV patients mainly showed abnormalities in cortical ALFF with reduced prefrontal amplitudes and enhanced sensorimotor and inferior temporal amplitudes. Frontal hypoactivation was overlapping for HIV and PD groups and different from controls. PD patients further exhibited reduced pallidum amplitudes compared to the other groups. In the HIV group, lower pallidum amplitudes were associated with lower CD4+ nadir and CD4+ T cell counts. Abnormalities in ALFF dynamics were largely associated with cognitive and motor functioning in HIV and PD groups. The disruption of neurofunctional frequency dynamics in subcortical-cortical circuits could contribute to the development of cognitive and motor dysfunction and serve as a biomarker for monitoring disease progression with immunosenescence. Graphical Abstract.

  View details for DOI 10.1007/s11481-020-09914-x

  View details for PubMedID 32291601

• PPMI 2.O New Science/New Cohorts - Transforming PPMI Marek, K., Siderowf, A., Kieburtz, K., Coffey, C., Foroud, T., Chahine, L., Poston, K., Mollenhauer, B., Galasko, D., Arnedo, V., Simuni, T., Tanner, C. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058005069

• APOE epsilon 4-related differences in visuospatial impairment in female Parkinson's Disease patients Rawls, A., Yang, L., Chung, K., Hiller, A., Espay, A., Revilla, F., Devoto, J., Goldman, J., Stebbins, G., Bernard, B., Wszolek, Z., Ross, O., Dickson, D., Rosenthal, L., Dawson, T., Albert, M., Factor, S., Weintraub, D., Trojanowski, J., Van Deerlin, V., Simuni, T., Lubbe, S., Mencacci, N., Hu, S., Leverenz, J., Quinn, J., Montine, T., Zabetian, C., Poston, K., Cholerton, B. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058001085

• Modeling PD Progression in the PPMI Cohort: Implications for Clinical Trial Design Coffey, C., Brumm, M., Siderowf, A., Simuni, T., Galasko, D., Mollenhauer, B., Chahine, L., Arnedo, V., Frasier, M., Tanner, C., Poston, K., Weintraub, D., Hutten, S. J., Kieburtz, K., Marek, K., Daegle, N. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058007098

• Participant and Study Partner Reported Impact of Cognition on Functional Activities in Parkinson's Disease MOVEMENT DISORDERS CLINICAL PRACTICE Cholerton, B., Poston, K. L., Tian, L., Quinn, J. F., Chung, K. A., Hiller, A. L., Hu, S., Specketer, K., Montine, T. J., Edwards, K. L., Zabetian, C. P. 2020; 7 (1): 61–69

  Abstract

  Cognitive dysfunction is common in Parkinson's disease (PD) and associated with reduced functional abilities and increased dependence. To date, however, little is known about the relationship between performance of instrumental activities of daily living (IADLs) and cognitive stages in PD, and there are conflicting reports as to whether declines in specific cognitive domains predict IADL impairment.Participants with PD were drawn from the Pacific Udall Center and included in the study if both participant and study partner IADL ratings and cognitive tests were completed (n = 192). Logistic regression analyses were performed to determine whether participant and/or study partner rating predicted mild cognitive impairment or dementia. Correlations are reported for the relationship between participant/study partner IADL reports as well as for specific cognitive tests.Although both participant and study partner ratings of IADL performance were associated with a diagnosis of PD with dementia, only participant self-rating of functional ability was significantly associated with a diagnosis of PD with mild cognitive impairment. Functional ability correlated most strongly with measures of processing speed, auditory working memory, and immediate verbal recall for both the participant and study partner ratings.For participants with PD in the early stages of cognitive decline, self-rating may be more sensitive to the impact of cognitive changes on IADL function than ratings made by a knowledgeable study partner. Changes in executive function, processing speed, and learning may indicate a higher likelihood of IADL impairment. Careful assessment of cognition and IADL performance is recommended to permit individualized interventions prior to significant disability.

  View details for DOI 10.1002/mdc3.12870

  View details for Web of Science ID 000507324100010

  View details for PubMedID 31970213

  View details for PubMedCentralID PMC6962683

• Multivariate prediction of dementia in Parkinson's disease. NPJ Parkinson's disease Phongpreecha, T., Cholerton, B., Mata, I. F., Zabetian, C. P., Poston, K. L., Aghaeepour, N., Tian, L., Quinn, J. F., Chung, K. A., Hiller, A. L., Hu, S. C., Edwards, K. L., Montine, T. J. 2020; 6 (1): 20

  Abstract

  Cognitive impairment in Parkinson's disease (PD) is pervasive with potentially devastating effects. Identification of those at risk for cognitive decline is vital to identify and implement appropriate interventions. Robust multivariate approaches, including fixed-effect, mixed-effect, and multitask learning models, were used to study associations between biological, clinical, and cognitive factors and for predicting cognitive status longitudinally in a well-characterized prevalent PD cohort (n = 827). Age, disease duration, sex, and GBA status were the primary biological factors associated with cognitive status and progression to dementia. Specific cognitive tests were better predictors of subsequent cognitive status for cognitively unimpaired and dementia groups. However, these models could not accurately predict future mild cognitive impairment (PD-MCI). Data collected from a large PD cohort thus revealed the primary biological and cognitive factors associated with dementia, and provide clinicians with data to aid in the identification of risk for dementia. Sex differences and their potential relationship to genetic status are also discussed.

  View details for DOI 10.1038/s41531-020-00121-2

  View details for PubMedID 34429432

• Mnemonic Similarity Task to study episodic memory in Parkinson's disease. Clinical parkinsonism & related disorders Das, T., Kim, N., McDaniel, C., Poston, K. L. 2020; 3: 100062

  Abstract

  Introduction: Parkinson's disease (PD) patients commonly experience episodic memory impairments, which are associated with an increased risk of dementia. The Mnemonic Similarity Task (MST) is a well-validated test to investigate episodic memory changes in healthy aging and in neurodegenerative diseases but has not been studied in PD patients.Methods: In the MST task, participants respond during a testing phase whether visualized images are "repeat", "similar", or "new", compared to images previously shown during an encoding phase. We tested 17 PD without cognitive impairment (level-II criteria), both off (PD-OFF) and on (PD-ON) dopaminergic medications; and compared PD-OFF with 17 age- and education-matched healthy controls (HC).Results: We found no influence of dopaminergic medications nor of disease on MST reaction time for any responses ("repeat", "similar", and "new") during the test phase. However, response probabilities showed that the MST is sensitive to subtle PD-related memory impairments. Specifically, PD-OFF responded more frequently with 'repeat', instead of 'similar' during lure trials, compared to HC (p = 0.030). This finding was still significant after correcting for response bias using the Recognition Index (p = 0.005).Conclusions: PD patients perform the MST without interference from bradykinesia or other PD-related motor symptoms. Our findings suggest that PD patients who do not meet criteria for mild cognitive impairment can have subtle recall or recognition impairments, which can be identified using the MST. We propose the MST as a well-tolerated and sensitive cognitive task in future studies of episodic memory impairment and progressive memory dysfunction in people with PD.

  View details for DOI 10.1016/j.prdoa.2020.100062

  View details for PubMedID 34316643

• Dopamine transporter imaging predicts clinically-defined α-synucleinopathy in REM sleep behavior disorder. Annals of clinical and translational neurology Chahine, L. M., Brumm, M. C., Caspell-Garcia, C. n., Oertel, W. n., Mollenhauer, B. n., Amara, A. n., Fernandez-Arcos, A. n., Tolosa, E. n., Simonet, C. n., Hogl, B. n., Videnovic, A. n., Hutten, S. J., Tanner, C. n., Weintraub, D. n., Burghardt, E. n., Coffey, C. n., Cho, H. R., Kieburtz, K. n., Poston, K. L., Merchant, K. n., Galasko, D. n., Foroud, T. n., Siderowf, A. n., Marek, K. n., Simuni, T. n., Iranzo, A. n. 2020

  Abstract

  Individuals with idiopathic rapid eye movement sleep behavior disorder (iRBD) are at high risk for a clinical diagnosis of an α-synucleinopathy (aSN). They could serve as a key population for disease-modifying trials. Abnormal dopamine transporter (DAT) imaging is a strong candidate biomarker for risk of aSN diagnosis in iRBD. Our primary objective was to identify a quantitative measure of DAT imaging that predicts diagnosis of clinically-defined aSN in iRBD.The sample included individuals with iRBD, early Parkinson's Disease (PD), and healthy controls (HC) enrolled in the Parkinson Progression Marker Initiative, a longitudinal, observational, international, multicenter study. The iRBD cohort was enriched with individuals with abnormal DAT binding at baseline. Motor and nonmotor measures were compared across groups. DAT specific binding ratios (SBR) were used to calculate the percent of expected DAT binding for age and sex using normative data from HCs. Receiver operative characteristic analyses identified a baseline DAT binding cutoff that distinguishes iRBD participants diagnosed with an aSN in follow-up versus those not diagnosed.The sample included 38 with iRBD, 205 with PD, and 92 HC who underwent DAT-SPECT at baseline. Over 4.7 years of mean follow-up, 14 (36.84%) with iRBD were clinically diagnosed with aSN. Risk of aSN diagnosis was significantly elevated among those with baseline putamen SBR ≤ 48% of that expected for age and sex, relative to those above this cutoff (hazard ratio = 17.8 [95%CI: 3.79-83.3], P = 0.0003).We demonstrate the utility of DAT SBR to identify individuals with iRBD with increased short-term risk of an aSN diagnosis.

  View details for DOI 10.1002/acn3.51269

  View details for PubMedID 33321002

• Quantitative Digitography Measures Fine Motor Disturbances in Chronically Treated HIV Similar to Parkinson’s Disease Frontier in Aging Neuroscience Prabhakar, V., Martin, T., Müller-Oehring, E. M., Goodcase, R., Schulte, T., Poston, K. L., Brontë-Stewart, H. M. 2020: 539598

  Abstract

  Introduction: Motor and cognitive deficits were compared in aging, chronically treated human immunodeficiency virus (HIV) people, people with mild-to-moderate stage Parkinson's disease (PD), and healthy controls. Methods: Groups consisted of 36 people with PD, 28 with HIV infection, and 28 healthy controls. Motor function was assessed with the Unified Parkinson's Disease Rating Scale (MDS-UPDRS-III) and a rapid alternating finger tapping (RAFT) task on an engineered keyboard known as Quantitative Digitography (QDG). Executive function, verbal memory, and visuospatial processing were assessed using standard neuropsychological tests. Results: HIV demonstrated RAFT deficits similar to PD such as reduced amplitude (P = 0.023) and greater amplitude variability (P = 0.019) in the index finger when compared to controls. This fine motor disturbance correlated with HIV's immune health, measured by their CD4+ T cell count (P < 0.01). The UPDRS did not yield motor differences between HIV and controls. Executive function and verbal memory were impaired in HIV (P = 0.006, P = 0.016, respectively), but not in PD; visuospatial processing was similarly impaired in HIV and PD (P < 0.05) although motor deficits predominated in PD. Conclusions: Fine motor bradykinesia measured quantitatively by QDG RAFT holds promise as a marker of motor decline related to current immune health in aging HIV patients and may be useful in longitudinal studies regarding mechanisms of immunosenescence vs. potential toxicity of combination antiretroviral therapy (cART) in this population. Additionally, motor and cognitive networks in HIV may be affected differently as the disease progresses as observed in the differential patterns of impairment between HIV and PD, providing insight into the mechanisms of brain deterioration in HIV.

  View details for DOI 10.3389/fnagi.2020.539598

  View details for PubMedCentralID PMC7575770

• Cognitive and motor deficits in older adults with HIV infection: Comparison with normal ageing and Parkinson's disease. Journal of neuropsychology Müller-Oehring, E. M., Fama, R. n., Levine, T. F., Hardcastle, C. n., Goodcase, R. n., Martin, T. n., Prabhakar, V. n., Brontë-Stewart, H. M., Poston, K. L., Sullivan, E. V., Schulte, T. n. 2020

  Abstract

  Despite the life-extending success of antiretroviral pharmacotherapy in HIV infection (HIV), the prevalence of mild cognitive impairment in HIV remains high. Near-normal life expectancy invokes an emerging role for age-infection interaction and a potential synergy between immunosenescence and HIV-related health factors, increasing risk of cognitive and motor impairment associated with degradation in corticostriatal circuits. These neural systems are also compromised in Parkinson's disease (PD), which could help model the cognitive deficit pattern in HIV. This cross-sectional study examined three groups, age 45-79 years: 42 HIV, 41 PD, and 37 control (CTRL) participants, tested at Stanford University Medical School and SRI International. Neuropsychological tests assessed executive function (EF), information processing speed (IPS), episodic memory (MEM), visuospatial processing (VSP), and upper motor (MOT) speed and dexterity. The HIV and PD deficit profiles were similar for EF, MEM, and VSP. Although only the PD group was impaired on MOT compared with CTRL, MOT scores were related to cognitive scores in HIV but not PD. Performance was not related to depressive symptoms, socioeconomic status, or CD4+ T-cell counts. The overlap of HIV-PD cognitive deficits implicates frontostriatal disruption in both conditions. The motor-cognitive score relation in HIV provides further support for the hypothesis that these processes share similar underlying mechanisms in HIV infection possibly expressed with or exacerbated by ageing.

  View details for DOI 10.1111/jnp.12227

  View details for PubMedID 33029951

• Sensorimotor Inhibition and Mobility in Genetic Subgroups of Parkinson's Disease. Frontiers in neurology Martini, D. N., Morris, R. n., Kelly, V. E., Hiller, A. n., Chung, K. A., Hu, S. C., Zabetian, C. P., Oakley, J. n., Poston, K. n., Mata, I. F., Edwards, K. L., Lapidus, J. A., Grabowski, T. J., Montine, T. J., Quinn, J. F., Horak, F. n. 2020; 11: 893

  Abstract

  Background: Mobility and sensorimotor inhibition impairments are heterogeneous in Parkinson's disease (PD). Genetics may contribute to this heterogeneity since the apolipoprotein (APOE) ε4 allele and glucocerebrosidase (GBA) gene variants have been related to mobility impairments in otherwise healthy older adult (OA) and PD cohorts. The purpose of this study is to determine if APOE or GBA genetic status affects sensorimotor inhibition and whether the relationship between sensorimotor inhibition and mobility differs in genetic sub-groups of PD. Methods: Ninety-three participants with idiopathic PD (53 non-carriers; 23 ε4 carriers; 17 GBA variants) and 72 OA (45 non-carriers; 27 ε4 carriers) had sensorimotor inhibition characterized by short-latency afferent inhibition. Mobility was assessed in four gait domains (pace/turning, rhythm, trunk, variability) and two postural sway domains (area/jerkiness and velocity) using inertial sensors. Results: Sensorimotor inhibition was worse in the PD than OA group, with no effect of genetic status. Gait pace/turning was slower and variability was higher (p < 0.01) in PD compared to OA. Postural sway area/jerkiness (p < 0.01) and velocity (p < 0.01) were also worse in the PD than OA group. Genetic status was not significantly related to any gait or postural sway domain. Sensorimotor inhibition was significantly correlated with gait variability (r = 0.27; p = 0.02) and trunk movement (r = 0.23; p = 0.045) in the PD group. In PD non-carriers, sensorimotor inhibition related to variability (r = 0.35; p = 0.010) and trunk movement (r = 0.31; p = 0.025). In the PD ε4 group, sensorimotor inhibition only related to rhythm (r = 0.47; p = 0.024), while sensorimotor inhibition related to pace/turning (r = -0.49; p = 0.046) and rhythm (r = 0.59; p = 0.013) in the PD GBA group. Sensorimotor inhibition was significantly correlated with gait pace/turning (r = -0.27; p = 0.04) in the OA group. There was no relationship between sensorimotor inhibition and postural sway. Conclusion: ε4 and GBA genetic status did not affect sensorimotor inhibition or mobility impairments in this PD cohort. However, worse sensorimotor inhibition was associated with gait variability in PD non-carriers, but with gait rhythm in PD ε4 carriers and with gait rhythm and pace in PD with GBA variants. Impaired sensorimotor inhibition had a larger effect on mobility in people with PD than OA and affected different domains of mobility depending on genetic status.

  View details for DOI 10.3389/fneur.2020.00893

  View details for PubMedID 33013627

  View details for PubMedCentralID PMC7498564

• Clinical and Dopamine Transporter Imaging Characteristics of Leucine- Rich Repeat Kinase 2 (LRRK2) and Glucosylceramidase Beta (GBA) Parkinson's Disease Participants in the Parkinson's Progression Markers Initiative: A Cross-Sectional Study. Movement disorders : official journal of the Movement Disorder Society Simuni, T. n., Brumm, M. C., Uribe, L. n., Caspell-Garcia, C. n., Coffey, C. S., Siderowf, A. n., Alcalay, R. n., Trojanowski, J. Q., Shaw, L. M., Seibyl, J. n., Singleton, A. n., Toga, A. W., Galasko, D. n., Foroud, T. n., Nudelman, K. n., Tosun-Turgut, D. n., Poston, K. n., Weintraub, D. n., Mollenhauer, B. n., Tanner, C. M., Kieburtz, K. n., Chahine, L. M., Reimer, A. n., Hutten, S. n., Bressman, S. n., Marek, K. n. 2020

  Abstract

  There are limited data on the phenotypic and dopamine transporter (DAT) imaging characterization of the Parkinson's disease (PD) patients with leucine rich kinase 2 (LRRK2) and glucosylceramidase beta (GBA) mutations.The objective of this study was to examine baseline clinical and DAT imaging characteristics in GBA and LRRK2 mutation carriers with early PD compared with sporadic PD.The Parkinson's Progression Markers Initiative is an ongoing observational longitudinal study that enrolled participants with sporadic PD, LRRK2 and GBA PD carriers from 33 sites worldwide. All participants are assessed annually with a battery of motor and nonmotor scales, 123-I Ioflupane DAT imaging, and biologic variables.We assessed 158 LRRK2 (89% G2019S), 80 GBA (89 %N370S), and 361 sporadic PD participants with the mean (standard deviation) disease duration of 2.9 (1.9), 3.1 (2.0), and 2.6 (0.6) years, respectively. When compared with sporadic PD, the GBA PD patients had no difference in any motor, cognitive, or autonomic features. The LRRK2 PD patients had less motor disability and lower rapid eye movement behavior disorder questionnaire scores, but no meaningful difference in cognitive or autonomic features. Both genetic cohorts had a higher score on the impulse control disorders scale when compared with sporadic PD, but no difference in other psychiatric features. Both genetic PD cohorts had less loss of dopamine transporter on DAT imaging when compared with sporadic PD.We confirm previous reports of milder phenotype associated with LRRK2-PD. A previously reported more aggressive phenotype in GBA-PD is not evident early in the disease in N370s carriers. This observation identifies a window for potential disease-modifying interventions. Longitudinal data will be essential to define the slope of progression for both genetic cohorts.ClinicalTrials.gov (NCT01141023). © 2020 International Parkinson and Movement Disorder Society.

  View details for DOI 10.1002/mds.27989

  View details for PubMedID 32073681

• Amyloid Deposition on PET Correlates with CSF Biomarkers and Cognitive Dysfunction in Parkinson's Disease Kim, J., Linortner, P., Toueg, T., Mormino, E. C., Poston, K. L. WILEY. 2019: S177

  View details for Web of Science ID 000488891800301

• Establishing a framework for neuropathological correlates and glymphatic system functioning in Parkinson's disease. Neuroscience and biobehavioral reviews Sundaram, S., Hughes, R. L., Peterson, E., Muller-Oehring, E. M., Bronte-Stewart, H. M., Poston, K. L., Faerman, A., Bhowmick, C., Schulte, T. 2019

  Abstract

  Recent evidence has advanced our understanding of the function of sleep to include removal of neurotoxic protein aggregates via the glymphatic system. However, most research on the glymphatic system utilizes animal models, and the function of waste clearance processes in humans remains unclear. Understanding glymphatic function offers new insight into the development of neurodegenerative diseases that result from toxic protein inclusions, particularly those characterized by neuropathological sleep dysfunction, like Parkinson's disease (PD). In PD, we propose that glymphatic flow may be compromised due to the combined neurotoxic effects of alpha-synuclein protein aggregates and deteriorated dopaminergic neurons that are linked to altered REM sleep, circadian rhythms, and clock gene dysfunction. This review highlights the importance of understanding the functional role of glymphatic system disturbance in neurodegenerative disorders and the subsequent clinical and neuropathological effects on disease progression. Future research initiatives utilizing noninvasive brain imaging methods in human subjects with PD are warranted, as in vivo identification of functional biomarkers in glymphatic system functioning may improve clinical diagnosis and treatment of PD.

  View details for DOI 10.1016/j.neubiorev.2019.05.016

  View details for PubMedID 31132378

• Feasibility and safety of lumbar puncture in the Parkinson's disease research participants: Parkinson's Progression Marker Initiative (PPMI) PARKINSONISM & RELATED DISORDERS Prakash, N., Caspell-Garcia, C., Coffey, C., Siderowf, A., Tanner, C. M., Kieburtz, K., Mollenhauer, B., Galasko, D., Merchant, K., Foroud, T., Chahine, L. M., Weintraub, D., Casaceli, C., Dorsey, R., Wilson, R., Herzog, M., Daegele, N., Arnedo, V., Frasier, M., Sherer, T., Marek, K., Frank, S., Jennings, D., Simuni, T., Marek, K., Siderowf, A., Seibyl, J., Coffey, C., Tanner, C., Tosun-Turgut, D., Simunir, T., Shaw, L., Trojanowski, J., Singleton, A., Kieburtz, K., Toga, A., Mollenhauer, B., Galasko, D., Poewe, W., Foroud, T., Poston, K., Sherer, T., Chowdhury, S., Frasier, M., Kopil, C., Arnedo, V., Marek, K., Daegele, N., Casaceli, C., Dorsey, R., Wilson, R., Mahes, S., Seibyl, J., Salerno, C., Coffey, C., Caspell-Garcia, C., Toga, A., Crawford, K., Foroud, T., Casalin, P., Malferrari, G., Weisz, M., Orr-Urtreger, A., Trojanowski, J., Shaw, L., Singleton, A., Foroud, T., Foroud, T., Montine, T., Russell, D., Tanner, C., Simuni, T., Dahodwala, N., Mollenhauer, B., Galasko, D., Poewe, W., Giladi, N., Factor, S., Hogarth, P., Standaert, D., Hauser, R., Jankovic, J., Saint-Hilaire, M., Richard, I., Shprecher, D., Fernandez, H., Brockmann, K., Rosenthal, L., Barone, P., Espay, A., Rowe, D., Marder, K., Santiago, A., Bressman, S., Hu, S., Isaacson, S., Corvol, J., Ruiz Martinez, J., Tolosa, E., Tai, Y., Politis, M., Smejdir, D., Rees, L., Williams, K., Kausar, F., Williams, K., Richardson, W., Willeke, D., Peacock, S., Heim, B., Mirelman, A., Sommerfeld, B., Freed, A., Wakeman, K., Blair, C., Guthrie, S., Harrell, L., Hunter, C., Thomas, C., James, R., Zimmerman, G., Brown, V., Mule, J., Hilt, E., Ribb, K., Ainscough, S., Wethington, M., Ranola, M., Santana, H., Moreno, J., Raymond, D., Speketer, K., Carvajal, L., Carvalho, S., Croitoru, I., Garrido, A., Payne, L., Viswanth, V., Severt, L., Facheris, M., Soares, H., Mintun, M. A., Cedarbaum, J., Taylor, P., Biglan, K., Vandenbroucke, E., Sheikh, Z., Bingol, B., Fischer, T., Sardi, P., Forrat, R., Reith, A., Egebjerg, J., Hillert, G., Saba, B., Min, C., Umek, R., Mather, J., De Santi, S., Post, A., Boess, F., Taylor, K., Grachev, I., Avbersek, A., Muglia, P., Merchant, K., Tauscher, J., Parkinsons Progression Markers, Study Cores, Site Investigators, Ind Sci Advisory Board 2019; 62: 201–9

  Abstract

  To determine the feasibility, safety and tolerability of lumbar punctures (LPs) in research participants with early Parkinson disease (PD), subjects without evidence of dopaminergic deficiency (SWEDDs) and healthy volunteers (HC).Cerebrospinal fluid (CSF) analysis is becoming an essential part of the biomarkers discovery effort in PD with still limited data on safety and feasibility of serial LPs in PD participants.Parkinson's Progression Marker Initiative (PPMI) is a longitudinal observation study designed to identify PD progression biomarkers. All PPMI participants undergo LP at baseline, 6, 12 months and yearly thereafter. CSF collection is performed by a trained investigator using predominantly atraumatic needles. Adverse events (AEs) are monitored by phone one week after LP completion. We analyzed safety data from baseline LPs.PPMI enrolled 683 participants (423 PD/196 HC/64 SWEDDs) from 23 study sites. CSF was collected at baseline in 97.5% of participants, of whom 5.4% underwent collection under fluoroscopy. 23% participants reported any related AEs, 68% of all AE were mild while 5.6% were severe. The most common AEs were headaches (13%) and low back pain (6.5%) and both occurred more commonly in HC and SWEDDs compared to PD participants. Factors associated with higher incidence of AEs across the cohorts included female gender, younger age and use of traumatic needles with larger diameter. AEs largely did not impact compliance with the future LPs.LPs are safe and feasible in PD research participants. Specific LP techniques (needle type and gauge) may reduce the overall incidence of AEs.

  View details for DOI 10.1016/j.parkreldis.2018.12.025

  View details for Web of Science ID 000476961700032

  View details for PubMedID 30738748

• Episodic recognition memory and the hippocampus in Parkinson's disease: A review CORTEX Das, T., Hwang, J. J., Poston, K. L. 2019; 113: 191–209

  View details for DOI 10.1016/j.cortex.2018.11.021

  View details for Web of Science ID 000465366800016

• Self-reported physical activity levels and clinical progression in early Parkinson's disease PARKINSONISM & RELATED DISORDERS Amara, A. W., Chahine, L., Seedorff, N., Caspell-Garcia, C. J., Coffey, C., Simuni, T., Marek, K., Daegelel, N., Tanner, C., Simuni, T., Coffey, C., Kieburtz, K., Wilsons, R., Mollenhauer, B., Galasko, D., Foroud, T., Chahine, L., Siderowf, A., Seibyl, J., Toga, A., Singleton, A., Weintraub, D., Trojanowski, J., Shaw, L., Tosun-Turgut, D., Poston, K., Bressman, S., Merchant, K. M., Poewe, W., Sherer, T., Chowdhury, S., Frasier, M., Kopil, C., Naito, A., Arnedo, V., Dorsey, R., Casaceli, C., Daegele, N., Albani, J., Caspell-Garcia, C., Uribe, L., Foster, E., Long, J., Seedorff, N., Crawford, K., Smiths, D., Casalin, P., Malferrari, G., Halter, C., Heathers, L., Russell, D., Factor, S., Hogarth, P., Standaert, D., Amara, A., Hauser, R., Jankovic, J., Dahodwala, N., Stern, M., Hu, S., Todd, G., Saunders-Pullman, R., Richard, I., Saint-Hilaire, M. H., Seppi, K., Shill, H., Fernandez, H., Trenkwalder, C., Oertel, W., Berg, D., Brockman, K., Wurster, I., Rosenthal, L., Tai, Y., Pavese, N., Barone, P., Isaacson, S., Espay, A., Rowe, D., Brandabur, M., Tetrud, J., Liang, G., Iranzo, A., Tolosa, E., Marder, K., Sanchez, M., Stefanis, L., Jose Marti, M., Ruiz Martinez, J., Corvol, J., Assly, J., Brillman, S., Giladi, N., Smejdir, D., Pelaggi, J., Kausar, F., Rees, L., Sommerfield, B., Freed, A., Blair, C., Williams, K., Zimmerman, G., Guthrie, S., Rawlins, A., Donhar, L., Hunter, C., Tran, B., Darin, A., Linder, C., Baca, M., Venkov, H., Thomas, C., James, R., Heim, B., Deritis, P., Sprenger, F., Raymond, D., Willeke, D., Obradov, Z., Mule, J., Monahan, N., Gauss, K., Fontaine, D., Szpak, D., Mccoy, A., Dunlop, B., Payne, L., Ainscough, S., Carvajal, L., Silverstein, R., Espay, K., Ranola, M., Mondragon Rezola, E., Mejia Santana, H., Stamelou, M., Garrido, A., Carvalho, S., Kristiansen, A., Specketer, K., Mirlman, A., Facheris, M., Soares, H., Mintun, M. A., Cedarbaum, J., Taylor, P., Jennings, D., Slieker, L., McBride, B., Watson, C., Montagut, E., Sheikh, Z., Bingol, B., Forrat, R., Sardi, P., Fischer, T., Reith, A. D., Egebjerg, J., Larsen, L., Breysse, N., Meulien, D., Saba, B., Kiyasova, V., Min, C., McAvoy, T., Umek, R., Iredale, P., Edgerton, J., De Sand, S., Czech, C., Boess, F., Sevigny, J., Kremer, T., Grachev, I., Merchant, K., Avbersek, A., Muglia, P., Stewart, A., Prashad, R., Taucher, J., Parkinsons Progression Markers 2019; 61: 118–25

  Abstract

  This study investigates longitudinal changes in self-reported physical activity, measured by Physical Activity Scale of the Elderly (PASE), in early Parkinson's disease (PD) and matched healthy control (HC) participants in the Parkinson's Progression Marker Initiative (PPMI) and evaluates associations between physical activity and PD progression.PPMI is a prospective, longitudinal study evaluating markers of progression in PD participants who are unmedicated at enrollment. PASE, a self-reported measure of physical activity, was administered to early PD (N = 380) and HC (N = 174). PASE was introduced after study launch and therefore administered at years 2, 3, and 4. PASE scores for PD and HC were compared with t-tests and changes over time were evaluated with generalized estimating equations.There were no differences in activity levels between PD and HC at any time point. However, PD participants had a longitudinal decrease in PASE from years two to four (p = 0.034), while HC did not (p = 0.89). In exploratory analyses controlling for age, sex, and disease duration, higher self-reported activity at year 2 were associated with slower progression of motor symptoms (p = 0.018), ADL performance (p < 0.0001), depression (p = 0.001), anxiety (p = 0.002), and cognitive decline (p = 0.016) over two years. These findings remained significant after adjusting for disease severity.There are no differences in self-reported physical activity between HC and early PD, but activity levels decline longitudinally in PD. Exploratory analyses show that higher self-reported physical activity is associated with less disease progression. Therefore, interventions to increase physical activity in early PD could potentially modify the disease course.

  View details for DOI 10.1016/j.parkreldis.2018.11.006

  View details for Web of Science ID 000468719900021

  View details for PubMedID 30554993

• Cognitive Performance in Parkinson's Disease in the Brain Health Registry. Journal of Alzheimer's disease : JAD Cholerton, B., Weiner, M. W., Nosheny, R. L., Poston, K. L., Scott Mackin, R., Tian, L., Ashford, J. W., Montine, T. J. 2019

  Abstract

  The study of cognition in Parkinson's disease (PD) traditionally requires exhaustive recruitment strategies. The current study examines data collected by the Brain Health Registry (BHR) to determine whether ongoing efforts to improve the recruitment base for therapeutic trials in Alzheimer's disease may be similarly effective for PD research, and whether online cognitive measurements can discriminate between participants who do and do not report a PD diagnosis. Participants enrolled in the BHR (age ≥50) with self-reported PD data and online cognitive testing available were included (n = 11,813). Associations between baseline cognitive variables and diagnostic group were analyzed using logistic regression. Linear mixed effects models were used to analyze longitudinal data. A total of 634 participants reported PD diagnosis at baseline with no self-reported cognitive impairment and completed cognitive testing. Measures of visual learning and memory, processing speed, attention, and working memory discriminated between self-reported PD and non-PD participants after correcting for multiple comparisons (p values <  0.006). Scores on all cognitive tests improved over time in PD and controls with the exception of processing speed, which remained stable in participants with PD while improving in those without. We demonstrate that a novel online approach to recruitment and longitudinal follow-up of study participants is effective for those with self-reported PD, and that significant differences exist between those with and without a reported diagnosis of PD on computerized cognitive measures. These results have important implications for recruitment of participants with PD into targeted therapeutic trials or large-scale genetic and cognitive studies.

  View details for PubMedID 30909225

• Lewy Body Dementia Association's Research Centers of Excellence Program: Inaugural Meeting Proceedings. Alzheimer's research & therapy Peterson, B., Armstrong, M., Galasko, D., Galvin, J. E., Goldman, J., Irwin, D., Paulson, H., Kaufer, D., Leverenz, J., Lunde, A., McKeith, I. G., Siderowf, A., Taylor, A., Amodeo, K., Barrett, M., Domoto-Reilly, K., Duda, J., Gomperts, S., Graff-Radford, N., Holden, S., Honig, L., Huddleston, D., Lippa, C., Litvan, I., Manning, C., Marder, K., Moussa, C., Onyike, C., Pagan, F., Pantelyat, A., Pelak, V., Poston, K., Quinn, J., Richard, I., Rosenthal, L. S., Sabbagh, M., Scharre, D., Sha, S., Shill, H., Torres-Yaghi, Y., Christie, T., Graham, T., Richards, I., Koehler, M., Boeve, B. 2019; 11 (1): 23

  Abstract

  The first Lewy Body Dementia Association (LBDA) Research Centers of Excellence (RCOE) Investigator's meeting was held on December 14, 2017, in New Orleans. The program was established to increase patient access to clinical experts on Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), and to create a clinical trials-ready network. Four working groups (WG) were created to pursue the LBDA RCOE aims: (1) increase access to high-quality clinical care, (2) increase access to support for people living with LBD and their caregivers, (3) increase knowledge of LBD among medical and allied (or other) professionals, and (4) create infrastructure for a clinical trials-ready network as well as resources to advance the study of new therapeutics.

  View details for PubMedID 30867052

• Lewy Body Dementia Association's Research Centers of Excellence Program: Inaugural Meeting Proceedings ALZHEIMERS RESEARCH & THERAPY Peterson, B., Armstrong, M., Galasko, D., Galvin, J. E., Goldman, J., Irwin, D., Paulson, H., Kaufer, D., Leverenz, J., Lunde, A., McKeith, I. G., Siderowf, A., Taylor, A., Amodeo, K., Barrett, M., Domoto-Reilly, K., Duda, J., Gomperts, S., Graff-Radford, N., Holden, S., Honig, L., Huddleston, D., Lippa, C., Litvan, I., Manning, C., Marder, K., Moussa, C., Onyike, C., Pagan, F., Pantelyat, A., Pelak, V., Poston, K., Quinn, J., Richard, I., Rosenthal, L. S., Sabbagh, M., Scharre, D., Sha, S., Shill, H., Torres-Yaghi, Y., Christie, T., Graham, T., Richards, I., Koehler, M., Boeve, B. 2019; 11

  View details for DOI 10.1186/s13195-019-0476-1

  View details for Web of Science ID 000461298700002

• Ultra-Low-Dose F-18-Florbetaben Amyloid PET Imaging Using Deep Learning with Multi-Contrast MRI Inputs RADIOLOGY Chen, K. T., Gong, E., Macruz, F., Xu, J., Boumis, A., Khalighi, M., Poston, K. L., Sha, S. J., Greicius, M. D., Mormino, E., Pauly, J. M., Srinivas, S., Zaharchuk, G. 2019; 290 (3): 649–56

  View details for DOI 10.1148/radiol.2018180940

  View details for Web of Science ID 000459261900009

• Comparative sensitivity of the MoCA and Mattis Dementia Rating Scale-2 in Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society Hendershott, T. R., Zhu, D., Llanes, S., Zabetian, C. P., Quinn, J., Edwards, K. L., Leverenz, J. B., Montine, T., Cholerton, B., Poston, K. L. 2019; 34 (2): 285–91

  Abstract

  BACKGROUND: Clinicians and researchers commonly use global cognitive assessments to screen for impairment. Currently there are no published studies directly comparing the sensitivity and specificity of the Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 in PD. The objective of this study was to identify the relative sensitivity and specificity of the Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 in PD.METHODS: The Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 were administered to training and validation cohorts. Cutoff scores were determined within the training cohort (n = 85) to optimize sensitivity and specificity for cognitive impairment and were applied to an independent validation cohort (n = 521).RESULTS: The Montreal Cognitive Assessment was consistently sensitive across training and validation cohorts (90.0% and 80.3%, respectively), whereas the Mattis Dementia Rating Scale-2 was not (87.5% and 60.3%, respectively). In individual domains, the Montreal Cognitive Assessment remained sensitive to memory and visuospatial impairments (91.9% and 87.8%, respectively), whereas the Mattis Dementia Rating Scale-2 was sensitive to executive impairments (86.2%).CONCLUSION: The Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 demonstrated individual strengths. Future work should focus on developing domain-specific cognitive screening tools for PD. © 2018 International Parkinson and Movement Disorder Society.

  View details for PubMedID 30776152

• Information Processing Deficit in Older Adults With HIV Infection: A Comparison With Parkinson's Disease NEUROPSYCHOLOGY Sundaram, S., Mueller-Oehring, E. M., Fama, R., Bronte-Stewart, H. M., Poston, K. L., Goodcase, R., Martin, T., Prabhakar, V., Karpf, J., Schulte, T. 2019; 33 (2): 157–68

  View details for DOI 10.1037/neu0000500

  View details for Web of Science ID 000457254300002

• Hippocampal CA1 subfield predicts episodic memory impairment in Parkinson's disease. NeuroImage. Clinical La, C. n., Linortner, P. n., Bernstein, J. D., Ua Cruadhlaoich, M. A., Fenesy, M. n., Deutsch, G. K., Rutt, B. K., Tian, L. n., Wagner, A. D., Zeineh, M. n., Kerchner, G. A., Poston, K. L. 2019; 23: 101824

  Abstract

  Parkinson's disease (PD) episodic memory impairments are common; however, it is not known whether these impairments are due to hippocampal pathology. Hippocampal Lewy-bodies emerge by Braak stage 4, but are not uniformly distributed. For instance, hippocampal CA1 Lewy-body pathology has been specifically associated with pre-mortem episodic memory performance in demented patients. By contrast, the dentate gyrus (DG) is relatively free of Lewy-body pathology. In this study, we used ultra-high field 7-Tesla to measure hippocampal subfields in vivo and determine if these measures predict episodic memory impairment in PD during life.We studied 29 participants with PD (age 65.5 ± 7.8 years; disease duration 4.5 ± 3.0 years) and 8 matched-healthy controls (age 67.9 ± 6.8 years), who completed comprehensive neuropsychological testing and MRI. With 7-Tesla MRI, we used validated segmentation techniques to estimate CA1 stratum pyramidale (CA1-SP) and stratum radiatum lacunosum moleculare (CA1-SRLM) thickness, dentate gyrus/CA3 (DG/CA3) area, and whole hippocampus area. We used linear regression, which included imaging and clinical measures (age, duration, education, gender, and CSF), to determine the best predictors of episodic memory impairment in PD.In our cohort, 62.1% of participants with PD had normal cognition, 27.6% had mild cognitive impairment, and 10.3% had dementia. Using 7-Tesla MRI, we found that smaller CA1-SP thickness was significantly associated with poorer immediate memory, delayed memory, and delayed cued memory; by contrast, whole hippocampus area, DG/CA3 area, and CA1-SRLM thickness did not significantly predict memory. Age-adjusted linear regression models revealed that CA1-SP predicted immediate memory (beta[standard error]10.895[4.215], p < .05), delayed memory (12.740[5.014], p < .05), and delayed cued memory (12.801[3.991], p < .05). In the fully-adjusted models, which included all five clinical measures as covariates, only CA1-SP remained a significant predictor of delayed cued memory (13.436[4.651], p < .05).In PD, we found hippocampal CA1-SP subfield thickness estimated on 7-Tesla MRI scans was the best predictor of episodic memory impairment, even when controlling for confounding clinical measures. Our results imply that ultra-high field imaging could be a sensitive measure to identify changes in hippocampal subfields and thus probe the neuroanatomical underpinnings of episodic memory impairments in patients with PD.

  View details for PubMedID 31054380

• Cognitive associations with comprehensive gait and static balance measures in Parkinson's disease. Parkinsonism & related disorders Morris, R. n., Martini, D. N., Smulders, K. n., Kelly, V. E., Zabetian, C. P., Poston, K. n., Hiller, A. n., Chung, K. A., Yang, L. n., Hu, S. C., Edwards, K. L., Cholerton, B. n., Grabowski, T. J., Montine, T. J., Quinn, J. F., Horak, F. n. 2019; 69: 104–10

  Abstract

  Gait and balance impairments are cardinal features of Parkinson's disease (PD) that require cognitive input. However, the extent to which specific gait and balance characteristics relate to cognition in PD is unclear. In addition, independent models of gait and balance have not been developed from the same cohort. We aimed to i) develop models of gait and balance in a large PD cohort and ii) determine which gait and balance characteristics best related to cognition.One hundred and ninety-eight people with PD were recruited to the Pacific Udall Center. Using six inertial sensors (APDM, Inc.), comprehensive gait measurements were collected over a 2-min continuous walk and comprehensive static balance measures were collected during a 60-second standing task. Six domains of cognition were assessed: global cognition, attention, executive function, language, memory, and visuospatial function. Correlations and hierarchical linear regression determined independent associations.Principal components analysis identified a gait model containing four domains accounting for 80.1% of total variance: pace/turning, rhythm, variability, and trunk. The balance model contained four independent domains accounting for 84.5% of total variance: sway area/jerkiness, sway velocity, sway frequency anteroposterior, and sway frequency mediolateral. Gait domains of pace/turning and variability were strongly associated with attention and executive function. Sway area and jerkiness of balance associated with attention and visuospatial function.Gait and balance characteristics were associated with specific types of cognition. The specific relationships between gait or balance with cognitive functions suggests shared cerebral cortical circuitry for mobility and cognitive functions.

  View details for DOI 10.1016/j.parkreldis.2019.06.014

  View details for PubMedID 31731260

• Predicting Progression in Parkinson's Disease Using Baseline and 1-Year Change Measures JOURNAL OF PARKINSONS DISEASE Chahine, L. M., Siderowf, A., Barnes, J., Seedorff, N., Caspell-Garcia, C., Simuni, T., Coffey, C. S., Galasko, D., Mollenhauer, B., Arnedo, V., Daegele, N., Frasier, M., Tanner, C., Kieburtz, K., Marek, K., Seibyl, J., Coffey, C., Tosun-Turgut, D., Shaw, L., Trojanowski, J., Singleton, A., Toga, A., Chahine, L., Poewe, W., Foroud, T., Poston, K., Sherer, T., Chowdhury, S., Kopil, C., Casaceli, C., Dorsey, R., Wilson, R., Mahes, S., Salerno, C., Crawford, K., Casalin, P., Malferrari, G., Weisz, M., Orr-Urtreger, A., Montine, T., Russell, D., Dahodwala, N., Giladi, N., Factor, S., Hogarth, P., Standaert, D., Hauser, R., Jankovic, J., Saint-Hilaire, M., Richard, I., Shprecher, D., Fernandez, H., Brockmann, K., Rosenthal, L., Barone, P., Espay, A., Rowe, D., Marder, K., Santiago, A., Bressman, S., Hu, S., Isaacson, S., Corvol, J., Ruiz Martinez, J., Tolosa, E., Tai, Y., Politis, M., Smejdir, D., Rees, L., Williams, K., Kausar, F., Richardson, W., Willeke, D., Peacock, S., Sommerfeld, B., Freed, A., Wakeman, K., Blair, C., Guthrie, S., Harrell, L., Hunter, C., Thomas, C., James, R., Zimmerman, G., Brown, V., Mule, J., Hilt, E., Ribb, K., Ainscough, S., Wethington, M., Ranola, M., Santana, H., Moreno, J., Raymond, D., Speketer, K., Carvajal, L., Carvalho, S., Croitoru, I., Garrido, A., Payne, L., Viswanth, V., Severt, L., Facheris, M., Soares, H., Mintun, M. A., Cedarbaum, J., Taylor, P., Biglan, K., Vandenbroucke, E., Sheikh, Z., Bingol, B., Fischer, T., Sardi, P., Forrat, R., Reith, A., Egebjerg, J., Hillert, G., Saba, B., Min, C., Umek, R., Mather, J., De Santi, S., Post, A., Boess, F., Taylor, K., Grachev, I., Avbersek, A., Muglia, P., Merchant, K., Tauscher, J., Parkinsons Progression Markers Ini 2019; 9 (4): 665–79

  Abstract

  Improved prediction of Parkinson's disease (PD) progression is needed to support clinical decision-making and to accelerate research trials.To examine whether baseline measures and their 1-year change predict longer-term progression in early PD.Parkinson's Progression Markers Initiative study data were used. Participants had disease duration ≤2 years, abnormal dopamine transporter (DAT) imaging, and were untreated with PD medications. Baseline and 1-year change in clinical, cerebrospinal fluid (CSF), and imaging measures were evaluated as candidate predictors of longer-term (up to 5 years) change in Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score and DAT specific binding ratios (SBR) using linear mixed-effects models.Among 413 PD participants, median follow-up was 5 years. Change in MDS-UPDRS from year-2 to last follow-up was associated with disease duration (β= 0.351; 95% CI = 0.146, 0.555), male gender (β= 3.090; 95% CI = 0.310, 5.869), and baseline (β= -0.199; 95% CI = -0.315, -0.082) and 1-year change (β= 0.540; 95% CI = 0.423, 0.658) in MDS-UPDRS; predictors in the model accounted for 17.6% of the variance in outcome. Predictors of percent change in mean SBR from year-2 to last follow-up included baseline rapid eye movement sleep behavior disorder score (β= -0.6229; 95% CI = -1.2910, 0.0452), baseline (β= 7.232; 95% CI = 2.268, 12.195) and 1-year change (β= 45.918; 95% CI = 35.994,55.843) in mean striatum SBR, and 1-year change in autonomic symptom score (β= -0.325;95% CI = -0.695, 0.045); predictors in the model accounted for 44.1% of the variance.Baseline clinical, CSF, and imaging measures in early PD predicted change in MDS-UPDRS and dopamine-transporter binding, but the predictive value of the models was low. Adding the short-term change of possible predictors improved the predictive value, especially for modeling change in dopamine-transporter binding.

  View details for DOI 10.3233/JPD-181518

  View details for Web of Science ID 000489899800003

  View details for PubMedID 31450510

• MRI biomarkers of motor and non-motor symptoms in Parkinson's disease. Parkinsonism & related disorders Ryman, S. G., Poston, K. L. 2019

  Abstract

  Parkinson's disease is a heterogeneous disorder with both motor and non-motor symptoms that contribute to functional impairment. To develop effective, disease modifying treatments for these symptoms, biomarkers are necessary to detect neuropathological changes early in the disease course and monitor changes over time. Advances in MRI scan sequences and analytical techniques present numerous promising metrics to detect changes within the nigrostriatal system, implicated in the cardinal motor symptoms of the disease, and detect broader dysfunction involved in the non-motor symptoms, such as cognitive impairment. There is emerging evidence that iron sensitive, neuromelanin sensitive, diffusion sensitive, and resting state functional magnetic imaging measures can capture changes within the nigrostriatal system. Iron, neuromelanin, and diffusion sensitive measures demonstrate high specificity and sensitivity in distinguishing Parkinson's disease relative to controls, with inconsistent results differentiating Parkinson's disease relative to atypical parkinsonian disorders. They may also serve as useful monitoring biomarkers, with each possibly detecting different aspects of the disease course (early nigrosome changes versus broader substantia nigra changes). Investigations of non-motor symptoms, such as cognitive impairment, require careful consideration of the nature of cognitive deficits to characterize regional and network specific impairment. While the early, executive dysfunction observed is consistent with nigrostriatal degeneration, the memory and visuospatial impairments, the harbingers of a dementia process reflect dopaminergic independent dysfunction involving broader regions of the brain.

  View details for DOI 10.1016/j.parkreldis.2019.10.002

  View details for PubMedID 31629653

• Hippocampal CA1 subfield predicts episodic memory impairment in Parkinson's disease NEUROIMAGE-CLINICAL La, C., Linortner, P., Bernstein, J. D., Cruadhlaoich, M., Fenesy, M., Deutsch, G. K., Rutt, B. K., Tian, L., Wagner, A. D., Zeineh, M., Kerchner, G. A., Poston, K. L. 2019; 23

  View details for DOI 10.1016/j.nicl.2019.101824

  View details for Web of Science ID 000485804400029

• Cognitive Performance in Parkinson's Disease in the Brain Health Registry JOURNAL OF ALZHEIMERS DISEASE Cholerton, B., Weiner, M. W., Nosheny, R. L., Poston, K. L., Mackin, R., Tian, L., Ashford, J., Montine, T. J. 2019; 68 (3): 1029–38

  View details for DOI 10.3233/JAD-181009

  View details for Web of Science ID 000464031500013

• Ultra-Low-Dose 18F-Florbetaben Amyloid PET Imaging Using Deep Learning with Multi-Contrast MRI Inputs. Radiology Chen, K. T., Gong, E., de Carvalho Macruz, F. B., Xu, J., Boumis, A., Khalighi, M., Poston, K. L., Sha, S. J., Greicius, M. D., Mormino, E., Pauly, J. M., Srinivas, S., Zaharchuk, G. 2018: 180940

  Abstract

  Purpose To reduce radiotracer requirements for amyloid PET/MRI without sacrificing diagnostic quality by using deep learning methods. Materials and Methods Forty data sets from 39 patients (mean age ± standard deviation [SD], 67 years ± 8), including 16 male patients and 23 female patients (mean age, 66 years ± 6 and 68 years ± 9, respectively), who underwent simultaneous amyloid (fluorine 18 [18F]-florbetaben) PET/MRI examinations were acquired from March 2016 through October 2017 and retrospectively analyzed. One hundredth of the raw list-mode PET data were randomly chosen to simulate a low-dose (1%) acquisition. Convolutional neural networks were implemented with low-dose PET and multiple MR images (PET-plus-MR model) or with low-dose PET alone (PET-only) as inputs to predict full-dose PET images. Quality of the synthesized images was evaluated while Bland-Altman plots assessed the agreement of regional standard uptake value ratios (SUVRs) between image types. Two readers scored image quality on a five-point scale (5 = excellent) and determined amyloid status (positive or negative). Statistical analyses were carried out to assess the difference of image quality metrics and reader agreement and to determine confidence intervals (CIs) for reading results. Results The synthesized images (especially from the PET-plus-MR model) showed marked improvement on all quality metrics compared with the low-dose image. All PET-plus-MR images scored 3 or higher, with proportions of images rated greater than 3 similar to those for the full-dose images (-10% difference [eight of 80 readings], 95% CI: -15%, -5%). Accuracy for amyloid status was high (71 of 80 readings [89%]) and similar to intrareader reproducibility of full-dose images (73 of 80 [91%]). The PET-plus-MR model also had the smallest mean and variance for SUVR difference to full-dose images. Conclusion Simultaneously acquired MRI and ultra-low-dose PET data can be used to synthesize full-dose-like amyloid PET images. © RSNA, 2018 Online supplemental material is available for this article.

  View details for PubMedID 30526350

• Episodic recognition memory and the hippocampus in Parkinson's disease: A review. Cortex; a journal devoted to the study of the nervous system and behavior Das, T., Hwang, J. J., Poston, K. L. 2018; 113: 191–209

  Abstract

  Parkinson's disease is a progressive neurodegenerative disorder of aging. The hallmark pathophysiology includes the development of neuronal Lewy bodies in the substantia nigra of the midbrain with subsequent loss of dopaminergic neurons. These neuronal losses lead to the characteristic motor symptoms of bradykinesia, rigidity, and rest tremor. In addition to these cardinal motor symptoms patients with PD experience a wide range of non-motor symptoms, the most important being cognitive impairments that in many circumstances lead to dementia. People with PD experience a wide range of cognitive impairments; in this review we will focus on memory impairment in PD and specifically episodic memory, which are memories of day-to-day events of life. Importantly, these memory impairments severely impact the lives of patients and caregivers alike. Traditionally episodic memory is considered to be markedly dependent on the hippocampus; therefore, it is important to understand the exact nature of PD episodic memory deficits in relation to hippocampal function and dysfunction. In this review, we discuss an aspect of episodic memory called recognition memory and its subcomponents called recollection and familiarity. Recognition memory is believed to be impaired in PD; thus, we discuss what aspects of the hippocampus are expected to be deficient in function as they relate to these recognition memory impairments. In addition to the hippocampus as a whole, we will discuss the role of hippocampal subfields in recognition memory impairments.

  View details for PubMedID 30660957

• The Parkinson's progression markers initiative (PPMI) - establishing a PD biomarker cohort. Annals of clinical and translational neurology Marek, K., Chowdhury, S., Siderowf, A., Lasch, S., Coffey, C. S., Caspell-Garcia, C., Simuni, T., Jennings, D., Tanner, C. M., Trojanowski, J. Q., Shaw, L. M., Seibyl, J., Schuff, N., Singleton, A., Kieburtz, K., Toga, A. W., Mollenhauer, B., Galasko, D., Chahine, L. M., Weintraub, D., Foroud, T., Tosun-Turgut, D., Poston, K., Arnedo, V., Frasier, M., Sherer, T., Parkinson's Progression Markers Initiative, Bressman, S., Merchant, M., Poewe, W., Kopil, C., Naito, A., Dorsey, R., Casaceli, C., Daegele, N., Albani, J., Uribe, L., Foster, E., Long, J., Seedorff, N., Crawford, K., Smith, D., Casalin, P., Malferrari, G., Halter, C., Heathers, L., Russell, D., Factor, S., Hogarth, P., Amara, A., Hauser, R., Jankovic, J., Stern, M., Hu, S., Todd, G., Saunders-Pullman, R., Richard, I., Saint-Hilaire, H., Seppi, K., Shill, H., Fernandez, H., Trenkwalder, C., Oertel, W., Berg, D., Brockman, K., Wurster, I., Rosenthal, L., Tai, Y., Pavese, N., Barone, P., Isaacson, S., Espay, A., Rowe, D., Brandabur, M., Tetrud, J., Liang, G., Iranzo, A., Tolosa, E., Marder, K., de Sanchez, M., Stefanis, L., Marti, M., Martinez, J., Corvol, J., Assly, O., Brillman, S., Giladi, N., Smejdir, D., Pelaggi, J., Kausar, F., Rees, L., Sommerfield, B., Cresswell, M., Blair, C., Williams, K., Zimmerman, G., Guthrie, S., Rawlins, A., Donharl, L., Hunter, C., Tran, B., Darin, A., Venkov, H., Thomas, C., James, R., Heim, B., Deritis, P., Sprenger, F., Raymond, D., Willeke, D., Obradov, Z., Mule, J., Monahan, N., Gauss, K., Fontaine, D., Szpak, D., McCoy, A., Dunlop, B., Payne, L., Ainscough, S., Carvajal, L., Silverstein, R., Espay, K., Ranola, M., Rezola, E., Santana, H., Stamelou, M., Garrido, A., Carvalho, S., Kristiansen, G., Specketer, K., Mirlman, A., Facheris, M., Soares, H., Mintun, A., Cedarbaum, J., Taylor, P., Jennings, D., Slieker, L., McBride, B., Watson, C., Montagut, E., Sheikh, Z., Bingol, B., Forrat, R., Sardi, P., Fischer, T., Reith, D., Egebjerg, J., Larsen, L., Breysse, N., Meulien, D., Saba, B., Kiyasova, V., Min, C., McAvoy, T., Umek, R., Iredale, P., Edgerton, J., Santi, D., Czech, C., Boess, F., Sevigny, J., Kremer, T., Grachev, I., Merchant, K., Avbersek, A., Muglia, P., Stewart, A., Prashad, R., Taucher, J. 2018; 5 (12): 1460–77

  Abstract

  Objective: The Parkinson's Progression Markers Initiative (PPMI) is an observational, international study designed to establish biomarker-defined cohorts and identify clinical, imaging, genetic, and biospecimen Parkinson's disease (PD) progression markers to accelerate disease-modifying therapeutic trials.Methods: A total of 423 untreated PD, 196 Healthy Control (HC) and 64 SWEDD (scans without evidence of dopaminergic deficit) subjects were enrolled at 24 sites. To enroll PD subjects as early as possible following diagnosis, subjects were eligible with only asymmetric bradykinesia or tremor plus a dopamine transporter (DAT) binding deficit on SPECT imaging. Acquisition of data was standardized as detailed at www.ppmi-info.org.Results: Approximately 9% of enrolled subjects had a single PD sign at baseline. DAT imaging excluded 16% of potential PD subjects with SWEDD. The total MDS-UPDRS for PD was 32.4 compared to 4.6 for HC and 28.2 for SWEDD. On average, PD subjects demonstrated 45% and 68% reduction in mean striatal and contralateral putamen Specific Binding Ratios (SBR), respectively. Cerebrospinal fluid (CSF) was acquired from >97% of all subjects. CSF (PD/HC/SWEDD pg/mL) alpha-synuclein (1845/2204/2141) was reduced in PD vs HC or SWEDD (P<0.03). Similarly, t-tau (45/53) and p-tau (16/18) were reduced in PD versus HC (P<0.01).Interpretation: PPMI has detailed the biomarker signature for an early PD cohort defined by clinical features and imaging biomarkers. This strategy provides the framework to establish biomarker cohorts and to define longitudinal progression biomarkers to support future PD treatment trials.

  View details for PubMedID 30564614

• The Parkinson's progression markers initiative (PPMI) - establishing a PD biomarker cohort ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY Marek, K., Chowdhury, S., Siderowf, A., Lasch, S., Coffey, C. S., Caspell-Garcia, C., Simuni, T., Jennings, D., Tanner, C. M., Trojanowski, J. Q., Shaw, L. M., Seibyl, J., Schuff, N., Singleton, A., Kieburtz, K., Toga, A. W., Mollenhauer, B., Galasko, D., Chahine, L. M., Weintraub, D., Foroud, T., Tosun-Turgut, D., Poston, K., Arnedo, V., Frasier, M., Sherer, T., Parkinsons Progression Markers In 2018; 5 (12): 1460–77

  View details for DOI 10.1002/acn3.644

  View details for Web of Science ID 000453056900001

• Information processing deficit in older adults with HIV infection: A comparison with Parkinson's disease. Neuropsychology Sundaram, S., Muller-Oehring, E. M., Fama, R., Bronte-Stewart, H. M., Poston, K. L., Goodcase, R., Martin, T., Prabhakar, V., Karpf, J., Schulte, T. 2018

  Abstract

  OBJECTIVE: Individuals with HIV treated with antiretroviral therapy can expect to reach average life span, making them susceptible to combined disease and aging effects on cognitive and motor functions. Slowed processing speed in HIV is a concern for cognitive and everyday functioning and is sensitive to declines in aging. We hypothesized that information processing (IP) deficits, over and above that expected with normal aging, would occur in older HIV patients similar to those observed in Parkinson's disease (PD) patients, with both conditions affecting frontostriatal pathways.METHOD: Groups comprised 26 individuals with HIV infection, 29 with mild-to-moderate PD, and 21 healthy controls (C). Speed of IP was assessed with the oral version of the Symbol Digit Modalities Test and the color naming condition of the Golden Stroop Task.RESULTS: The HIV group was impaired on speed of IP tasks compared with both the C and PD groups. Even after controlling for normal aging effects, older age in the HIV group correlated with IP slowing. Slower IP speed was associated with poorer general cognitive ability and more extrapyramidal motor signs in older HIV-infected individuals.CONCLUSIONS: The notable effects of impaired IP speed, over and above neurotypical age-related declines, indicate that older HIV-infected individuals may have an enhanced vulnerability for developing nonmotor and motor symptoms despite antiretroviral therapy. Assessing for oral IP speed may provide the unique opportunity to identify early signs of progressive clinical declines in HIV. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

  View details for PubMedID 30475047

• Dopamine-related dissociation of cortical and subcortical brain activations in cognitively unimpaired Parkinson's disease patients OFF and ON medications NEUROPSYCHOLOGIA Kim, J., Zhang, K., Cai, W., YorkWilliams, S., Cruadhlaoich, M., Llanes, S., Menon, V., Poston, K. L. 2018; 119: 24–33

  View details for DOI 10.1016/j.neuropsychologia.2018.07.024

  View details for Web of Science ID 000450543800003

• Dopamine-Related Dissociation of Cortical and Subcortical Brain Activations in Cognitively Unimpaired Parkinson's Disease Patients OFF and ON Medications. Neuropsychologia Kim, J., Zhang, K., Cai, W., YorkWilliams, S., I Ua Cruadhlaoich, M. A., Llanes, S., Menon, V., Poston, K. L. 2018

  Abstract

  BACKGROUND: Despite dopaminergic depletion that is severe enough to cause the motor symptoms of Parkinson's disease (PD), many patients remain cognitively unimpaired. Little is known about brain mechanisms underlying such preserved cognitive abilities and their alteration by dopaminergic medications.OBJECTIVES: We investigated brain activations underlying dopamine-related differences in cognitive function using a unique experimental design with PD patients off and on dopaminergic medications. We tested the dopamine overdose hypothesis, which posits that the excess of exogenous dopamine in the frontal cortical regions can impair cognition.METHODS: We used a two-choice forced response Choice Reaction Time (CRT) task to probe cognitive processes underlying response selection and execution. Functional magnetic resonance imaging data were acquired from 16 cognitively unimpaired (Level-II) PD participants and 15 well-matched healthy controls (HC). We compared task performance (i.e. reaction time and accuracy) and brain activation of PD participants off dopaminergic medications (PD_OFF) in comparison with HC, and PD_OFF participants with those on dopaminergic medications (PD_ON).RESULTS: PD_OFF and PD_ON groups did not differ from each other, or from the HC group, in reaction time or accuracy. Compared to HC, PD_OFF activated the bilateral putamen less, and this was compensated by higher activation of the anterior insula. No such differences were observed in the PD_ON group, compared to HC. Compared to both HC and PD_OFF, PD_ON participants showed dopamine-related hyperactivation in the frontal cortical regions and hypoactivation in the amygdala.CONCLUSION: Our data provide further evidence that PD_OFF and PD_ON participants engage different cortical and subcortical systems to achieve similar levels of cognitive performance as HC. Crucially, our findings demonstrate dopamine-related dissociation in brain activation between cortical and subcortical regions, and provide novel support for the dopamine overdose hypothesis.

  View details for PubMedID 30040957

• Sex differences in progression to mild cognitive impairment and dementia in Parkinson's disease PARKINSONISM & RELATED DISORDERS Cholerton, B., Johnson, C. O., Fish, B., Quinn, J. F., Chung, K. A., Peterson-Hiller, A. L., Rosenthal, L. S., Dawson, T. M., Albert, M. S., Hu, S., Mata, I. F., Leverenz, J. B., Poston, K. L., Montine, T. J., Zabetian, C. P., Edwards, K. L. 2018; 50: 29–36

  View details for DOI 10.1016/j.parkreldis.2018.02.007

  View details for Web of Science ID 000433273100006

• Motor function impairment in chronic HIV is similar but less severe to that seen in Parkinson's disease Bronte-Stewart, H., Prabhakar, V., Martin, T., Trager, M., Velisar, A., Koop, M., Muller-Oehring, E., Poston, K., Schulte, T. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090804356

• Widespread Cortical Thinning in Parkinson's Disease: Findings from the ENIGMA-Parkinson's Disease Working Group Gutman, B., Bright, J., Rummel, C., Rocha, C. S., Debove, I., Yasuda, C., Guimaraes, R., Bergo, F., D'Abreu, A., Poston, K., Wiest, R., Cendes, F., Thompson, P. M., van der Werf, Y., ENIGMA Parkinson's Dis Working Grp LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090805432

• Domain-specific impact of cerebral white matter hyperintensities on Parkinson's disease cognitive functioning Linortner, P., Hendershott, T., Poston, K. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090802035

• Somatic items on the Beck Depression Inventory-II do not affect self-reported depression severity in Parkinson's disease Ramirez, V., Hendershott, T. R., Faridi, N., Zhu, D., Tian, L., Poston, K. L. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090800073

• Further study of the Montreal Cognitive Assessment's domain-specific metrics could allow for international data comparison and collaboration PARKINSONISM & RELATED DISORDERS Hendershott, T. R., Poston, K. L. 2018; 48: 101

  View details for PubMedID 29221675

• Sex differences in progression to mild cognitive impairment and dementia in Parkinson's disease. Parkinsonism & related disorders Cholerton, B., Johnson, C. O., Fish, B., Quinn, J. F., Chung, K. A., Peterson-Hiller, A. L., Rosenthal, L. S., Dawson, T. M., Albert, M. S., Hu, S., Mata, I. F., Leverenz, J. B., Poston, K. L., Montine, T. J., Zabetian, C. P., Edwards, K. L. 2018

  Abstract

  INTRODUCTION: Identification of factors associated with progression of cognitive symptoms in Parkinson's disease (PD) is important for treatment planning, clinical care, and design of future clinical trials. The current study sought to identify whether prediction of cognitive progression is aided by examining baseline cognitive features, and whether this differs according to stage of cognitive disease.METHODS: Participants with PD in the Pacific Udall Center Clinical Consortium who had longitudinal data available and were nondemented at baseline were included in the study (n = 418). Logistic and Cox regression models were utilized to examine the relationship between cognitive, demographic, and clinical variables with risk and time to progression from no cognitive impairment to mild cognitive impairment (PD-MCI) or dementia (PDD), and from PD-MCI to PDD.RESULTS: Processing speed (OR = 1.05, p = 0.009) and working memory (OR = 1.01, p = 0.03) were associated with conversion to PDD among those with PD-MCI at baseline, over and above demographic variables. Conversely, the primary predictive factor in the transition from no cognitive impairment to PD-MCI or PDD was male sex (OR = 4.47, p = 0.004), and males progressed more rapidly than females (p = 0.01). Further, among females with shorter disease duration, progression was slower than for their male counterparts, and poor baseline performance on semantic verbal fluency was associated with shorter time to cognitive impairment in females but not in males.CONCLUSIONS: This study provides evidence for sex differences in the progression to cognitive impairment in PD, while specific cognitive features become more important indicators of progression with impending conversion to PDD.

  View details for PubMedID 29478836

• Slower saccadic reading in Parkinson's disease PLOS ONE Jehangir, N., Yu, C., Song, J., Shariati, M., Binder, S., Beyer, J., Santini, V., Poston, K., Liao, Y. 2018; 13 (1): e0191005

  Abstract

  Idiopathic Parkinson's Disease (PD) is characterized by degeneration of dopaminergic and other neurons, leading to motor and non-motor deficits. Abnormal eye movements in PD, including fixations, saccades, and convergence, are well described. However, saccadic reading, which requires serial and alternating saccades and fixations, is not well studied, despite its obvious impact on the quality of life. In this study, we assessed saccadic reading using variations of the King-Devick (KD) test, a rapid single digit number naming test, as a way to assess the ability to make serial left-to-right ocular motor movements necessary for reading. We recruited 42 treated PD patients and 80 age-matched controls and compared their reading times with a variety of measures, including age, duration of disease, Unified Parkinson's Disease Rating Scale (UPDRS), the National Eye Institute 25-Item Visual Functioning Questionnaire 25 (VFQ-25), and Montreal Cognitive assessment (MoCA) test. The subjects performed 4 trials of reading 120 single digit numbers aloud as fast as possible without making errors. In each trial, they read 3 pages (KD1, KD2, and KD3), and each page contained 40 numbers per page in 8 lines with 5 numbers/line. We found that PD patients read about 20% slower than controls on all tests (KD1, 2, and 3 tests) (p < 0.02), and both groups read irregularly spaced numbers slower than regularly spaced numbers. Having lines between numbers to guide reading (KD1 tests) did not impact reading time in both PD and controls, but increased visual crowding as a result of decreased spacing between numbers (KD3 tests) was associated with significantly slower reading times in both PD and control groups. Our study revealed that saccadic reading is slower in PD, but controls and PD patients are both impacted by visuospatial planning challenges posed by increased visual crowding and irregularity of number spacing. Reading time did not correlate with UPDRS or MoCA scores in PD patients but significantly correlated with age, duration of disease, and VFQ-25 scores. The presence of convergence insufficiency did not significantly correlate with reading time in PD patients, although on average there was slower reading time in those with convergence insufficiency by 8 s (p = 0.2613). We propose that a simple reading task using 120 single-digit numbers can be used as a screening tool in the clinical setting to assess functional ocular motor difficulties in Parkinson's disease that can have a profound impact on quality of life.

  View details for PubMedID 29364897

• 7T MRI subthalamic nucleus atlas for use with 3T MRI JOURNAL OF MEDICAL IMAGING Milchenko, M., Norris, S. A., Poston, K., Campbell, M. C., Ushe, M., Perlmutter, J. S., Snyder, A. Z. 2018; 5 (1): 015002

  Abstract

  Deep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces motor symptoms in most patients with Parkinson disease (PD), yet may produce untoward effects. Investigation of DBS effects requires accurate localization of the STN, which can be difficult to identify on magnetic resonance images collected with clinically available 3T scanners. The goal of this study is to develop a high-quality STN atlas that can be applied to standard 3T images. We created a high-definition STN atlas derived from seven older participants imaged at 7T. This atlas was nonlinearly registered to a standard template representing 56 patients with PD imaged at 3T. This process required development of methodology for nonlinear multimodal image registration. We demonstrate mm-scale STN localization accuracy by comparison of our 3T atlas with a publicly available 7T atlas. We also demonstrate less agreement with an earlier histological atlas. STN localization error in the 56 patients imaged at 3T was less than 1 mm on average. Our methodology enables accurate STN localization in individuals imaged at 3T. The STN atlas and underlying 3T average template in MNI space are freely available to the research community. The image registration methodology developed in the course of this work may be generally applicable to other datasets.

  View details for PubMedID 29340288

  View details for PubMedCentralID PMC5757662

• gene therapy trial for Parkinson's disease. JCI insight Niethammer, M., Tang, C. C., LeWitt, P. A., Rezai, A. R., Leehey, M. A., Ojemann, S. G., Flaherty, A. W., Eskandar, E. N., Kostyk, S. K., Sarkar, A., Siddiqui, M. S., Tatter, S. B., Schwalb, J. M., Poston, K. L., Henderson, J. M., Kurlan, R. M., Richard, I. H., Sapan, C. V., Eidelberg, D., During, M. J., Kaplitt, M. G., Feigin, A. 2017; 2 (7)

  Abstract

  BACKGROUND. We report the 12-month clinical and imaging data on the effects of bilateral delivery of the glutamic acid decarboxylase gene into the subthalamic nuclei (STN) of advanced Parkinson's disease (PD) patients. METHODS. 45 PD patients were enrolled in a 6-month double-blind randomized trial of bilateral AAV2-GAD delivery into the STN compared with sham surgery and were followed for 12 months in open-label fashion. Subjects were assessed with clinical outcome measures and (18)F-fluorodeoxyglucose (FDG) PET imaging. RESULTS. Improvements under the blind in Unified Parkinson's Disease Rating Scale (UPDRS) motor scores in the AAV2-GAD group compared with the sham group continued at 12 months [time effect: F(4,138) = 11.55, P < 0.001; group effect: F(1,35) = 5.45, P < 0.03; repeated-measures ANOVA (RMANOVA)]. Daily duration of levodopa-induced dyskinesias significantly declined at 12 months in the AAV2-GAD group (P = 0.03; post-hoc Bonferroni test), while the sham group was unchanged. Analysis of all FDG PET images over 12 months revealed significant metabolic declines (P < 0.001; statistical parametric mapping RMANOVA) in the thalamus, striatum, and prefrontal, anterior cingulate, and orbitofrontal cortices in the AAV2-GAD group compared with the sham group. Across all time points, changes in regional metabolism differed for the two groups in all areas, with significant declines only in the AAV2-GAD group (P < 0.005; post-hoc Bonferroni tests). Furthermore, baseline metabolism in the prefrontal cortex (PFC) correlated with changes in motor UPDRS scores; the higher the baseline PFC metabolism, the better the clinical outcome. CONCLUSION. These findings show that clinical benefits after gene therapy with STN AAV2-GAD in PD patients persist at 12 months. TRIAL REGISTRATION. ClinicalTrials.gov NCT00643890. FUNDING. Neurologix Inc.

  View details for DOI 10.1172/jci.insight.90133

  View details for PubMedID 28405611

• Domain-specific accuracy of the Montreal Cognitive Assessment subsections in Parkinson's disease. Parkinsonism & related disorders Hendershott, T. R., Zhu, D., Llanes, S., Poston, K. L. 2017

  Abstract

  The Montreal Cognitive Assessment (MoCA) is among the most widely adopted screening tools for cognitive impairment because it includes tests in multiple domains and is available in 55 languages. The MoCA is often the only formal cognitive assessment available when comprehensive neuropsychological testing is not practical, such as rural clinical settings or large retrospective and multi-lingual research settings. However, the MoCA domain-specific subsections have never been formally assessed for sensitivity or specificity. Therefore, in Parkinson's disease, we examined whether the subsections of the MoCA could identify cognitive impairment within specific cognitive domains.We administered a comprehensive neuropsychological battery to 85 Parkinson's disease participants, who were then categorized as with or without cognitive impairment, with respect to global cognition and in five cognitive domains. We then assessed the domain-specific categorization of the MoCA subsections compared to the full neuropsychology battery.All MoCA subsections predicted impairment in their respective cognitive domain. However, the executive subsection showed the highest sensitivity and specificity (89.3% and 82.5%, respectively), followed by visuospatial (93.3% and 45.7%, respectively) and memory (84.6% and 56.5%, respectively).The MoCA is a useful screening tool for PD global cognitive and executive functions. The MoCA is also highly sensitive to visuospatial and memory impairment, but with limited specificity and accuracy these subsections should be interpreted with caution.

  View details for DOI 10.1016/j.parkreldis.2017.02.008

  View details for PubMedID 28215728

  View details for PubMedCentralID PMC5400012

• Distinct alterations in Parkinson's medication-state and disease-state connectivity NEUROIMAGE-CLINICAL Ng, B., Varoquaux, G., Poline, J., Thirion, B., Greicius, M. D., Poston, K. L. 2017; 16: 575–85

  Abstract

  Altered brain connectivity has been described in people with Parkinson's disease and in response to dopaminergic medications. However, it is unclear whether dopaminergic medications primarily 'normalize' disease related connectivity changes or if they induce unique alterations in brain connectivity. Further, it is unclear how these disease- and medication-associated changes in brain connectivity relate differently to specific motor manifestations of disease, such as bradykinesia/rigidity and tremor. In this study, we applied a novel covariance projection approach in combination with a bootstrapped permutation test to resting state functional MRI data from 57 Parkinson's disease and 20 healthy control participants to determine the Parkinson's medication-state and disease-state connectivity changes associated with different motor manifestations of disease. First, we identified brain connections that best classified Parkinson's disease ON versus OFF dopamine and Parkinson's disease versus healthy controls, achieving 96.9 ± 5.9% and 72.7 ± 12.4% classification accuracy, respectively. Second, we investigated the connections that significantly contribute to the classifications. We found that the connections greater in Parkinson's disease OFF compared to ON dopamine are primarily between motor (cerebellum and putamen) and posterior cortical regions, such as the posterior cingulate cortex. By contrast, connections that are greater in ON compared to OFF dopamine are between the right and left medial prefrontal cortex. We also identified the connections that are greater in healthy control compared to Parkinson's disease and found the most significant connections are associated with primary motor regions, such as the striatum and the supplementary motor area. Notably, these are different connections than those identified in Parkinson's disease OFF compared to ON. Third, we determined which of the Parkinson's medication-state and disease-state connections are associated with the severity of different motor symptoms. We found two connections correlate with both bradykinesia/rigidity severity and tremor severity, whereas four connections correlate with only bradykinesia/rigidity severity, and five connections correlate with only tremor severity. Connections that correlate with only tremor severity are anchored by the cerebellum and the supplemental motor area, but only those connections that include the supplemental motor area predict dopaminergic improvement in tremor. Our results suggest that dopaminergic medications do not simply 'normalize' abnormal brain connectivity associated with Parkinson's disease, but rather dopamine drives distinct connectivity changes, only some of which are associated with improved motor symptoms. In addition, the dissociation between of connections related to severity of bradykinesia/rigidity versus tremor highlights the distinct abnormalities in brain circuitry underlying these specific motor symptoms.

  View details for PubMedID 28971008

• Abnormal eye movement behavior during reading in Parkinson's disease PARKINSONISM & RELATED DISORDERS Yu, C. Y., Lee, T., Shariati, A., Santini, V., Poston, K., Liao, Y. 2016; 32: 130–32

  Abstract

  Reading difficulties are common in Parkinson's disease (PD) but not well studied. We report a case of reading difficulties in a 40-year-old man with 6-year history of PD on dopamine replacement therapy.We performed detailed neuro-ophthalmic examination and assessment of reading with and without infrared oculography.Clinical examination revealed visual acuity of 20/20, no evidence of vision loss, and normal eye movement and ocular alignment with normal saccades, pursuit, and normal convergence. During King-Devick test, a rapid number reading task performed on a book, patient had normal number reading speed. More detailed study of number and word reading using infrared oculography revealed that while this patient had normal speed and eye movement behavior during number reading, he had dramatic slowing and eye movement abnormality during word reading. The slower reading speed during word reading was due to increased number of progressive saccades, smaller saccade amplitudes, increased number of regressive saccades, and longer fixation durations.This case nicely illustrated the importance of comprehensive neuro-ophthalmic evaluations in Parkinson's disease and shows that reading difficulties can arise even when there is good visual acuity, ocular motor abilities necessary to read, and accommodation. In this case, reading difficulty was due to higher order ocular motor planning or cognitive abilities involved in word reading since the patient had no difficulty with ocular motor planning while reading numbers. These findings may have important implications towards our understanding of PD and can serve to spark further research in this important area.

  View details for PubMedID 27592009

• Effects of Dopaminergic Medication on Working Memory in Patients with Parkinson's Disease with and without Mild Cognitive Impairment Sherman, E., Zhang, K., Everling, D., Marshall, A., YorkWilliams, S., Menon, V., Poston, K. LIPPINCOTT WILLIAMS & WILKINS. 2016

  View details for Web of Science ID 000411328602468

• The effects of dopamine on digit span in Parkinson's disease. Journal of clinical movement disorders Warden, C., Hwang, J., Marshall, A., Fenesy, M., Poston, K. L. 2016; 3: 5-?

  Abstract

  Parkinson's disease patients are at an elevated risk of developing cognitive impairment. Although cognitive impairment is one of the strongest predictors of quality of life, dopaminergic anti-parkinsonian medications are designed to target motor symptoms. However, there is substantial evidence that dopamine also impacts cognition, in particular working memory. It is therefore critical for movement disorders physicians to understand the potential dopaminergic effects on working memory when prescribing these medications. Verbal digit span tasks offer a potentially straightforward and quick assessment of baseline working memory. Moreover, Digit Span Backward was recently validated as a screening tool for mild cognitive impairment in Parkinson's disease when participants were medicated. Research indicates that the interaction between dopamine and working memory follows an Inverted-U shaped curve, but the effect of dopamine on Digit Span has not been well studied. Our study seeks to: (1) determine the validity of verbal Digit Spans for detecting cognitive impairment in Parkinson's disease patients both ON and OFF medications; and (2) ascertain the effects of dopaminergic medications on verbal Digit Span.We recruited 64 Parkinson's disease patients and 22 age-and education-matched controls. Parkinson's patients completed Digit Span Backward and Digit Span Forward ON and OFF medications, while healthy controls completed them once. All participants were categorized by cognitive diagnosis using level-II consensus criteria.Digit Span Backward successfully identified mild cognitive impairment in Parkinson's disease, both ON and OFF medications. Combining patients with and without cognitive impairment, we found that dopamine significantly improved performance on Digit Span Backward, but not Forward. In a secondary analysis, we found this dopaminergic improvement was restricted to the Low baseline working memory group; the High baseline working memory group was unaffected.This study provides evidence for Digit Span Backward as a screening tool for working memory impairment in Parkinson's disease and for its utility in measuring baseline working memory. Moreover, it reveals a partial beneficial effect of dopamine on Digit Span in Parkinson's disease patients.

  View details for DOI 10.1186/s40734-016-0033-z

  View details for PubMedID 26955482

  View details for PubMedCentralID PMC4780147

• Do CSF Biomarkers Predict Progression to Cognitive Impairment in Parkinson's disease patients? A Systematic Review. Neuropsychology review Leaver, K., Poston, K. L. 2015; 25 (4): 411-423

  Abstract

  Many patients with Parkinson's disease (PD) will develop cognitive impairment. Cross-sectional studies have shown that certain protein levels are altered in the cerebrospinal fluid (CSF) of PD patients with dementia and are thought to represent potential biomarkers of underlying pathogenesis. Recent studies suggest that CSF biomarker levels may be predictive of future risk of cognitive decline in non-demented PD patients. However, the strength of this evidence and difference between specific CSF biomarkers is not well delineated. We therefore performed a systematic review to assess if levels of specific CSF protein biomarkers are predictive of progression to cognitive impairment. Nine articles were identified that met inclusion criteria for the review. Findings from the review suggest a convergence of evidence that a low baseline Aβ42 in the CSF of non-demented PD patients predicts development of cognitive impairment over time. Conversely, there is limited evidence that CSF levels of tau, either total tau or phosphorylated tau, is a useful predictive biomarker. There are mixed results for other CSF biomarkers such as α-synuclein, Neurofilament light chain, and Heart fatty acid-binding protein. Overall the results of this review show that certain CSF biomarkers have better predictive ability to identify PD patients who are at risk for developing cognitive impairment. Given the interest in developing disease-modifying therapies, identifying this group will be important for clinical trials as initiation of therapy prior to the onset of cognitive decline is likely to be more efficacious.

  View details for DOI 10.1007/s11065-015-9307-8

  View details for PubMedID 26626621

  View details for PubMedCentralID PMC5152566

• Task-rest modulation of basal ganglia connectivity in mild to moderate Parkinson's disease. Brain imaging and behavior Müller-Oehring, E. M., Sullivan, E. V., Pfefferbaum, A., Huang, N. C., Poston, K. L., Bronte-Stewart, H. M., Schulte, T. 2015; 9 (3): 619-638

  Abstract

  Parkinson's disease (PD) is associated with abnormal synchronization in basal ganglia-thalamo-cortical loops. We tested whether early PD patients without demonstrable cognitive impairment exhibit abnormal modulation of functional connectivity at rest, while engaged in a task, or both. PD and healthy controls underwent two functional MRI scans: a resting-state scan and a Stroop Match-to-Sample task scan. Rest-task modulation of basal ganglia (BG) connectivity was tested using seed-to-voxel connectivity analysis with task and rest time series as conditions. Despite substantial overlap of BG-cortical connectivity patterns in both groups, connectivity differences between groups had clinical and behavioral correlates. During rest, stronger putamen-medial parietal and pallidum-occipital connectivity in PD than controls was associated with worse task performance and more severe PD symptoms suggesting that abnormalities in resting-state connectivity denote neural network dedifferentiation. During the executive task, PD patients showed weaker BG-cortical connectivity than controls, i.e., between caudate-supramarginal gyrus and pallidum-inferior prefrontal regions, that was related to more severe PD symptoms and worse task performance. Yet, task processing also evoked stronger striatal-cortical connectivity, specifically between caudate-prefrontal, caudate-precuneus, and putamen-motor/premotor regions in PD relative to controls, which was related to less severe PD symptoms and better performance on the Stroop task. Thus, stronger task-evoked striatal connectivity in PD demonstrated compensatory neural network enhancement to meet task demands and improve performance levels. fMRI-based network analysis revealed that despite resting-state BG network compromise in PD, BG connectivity to prefrontal, premotor, and precuneus regions can be adequately invoked during executive control demands enabling near normal task performance.

  View details for DOI 10.1007/s11682-014-9317-9

  View details for PubMedID 25280970

  View details for PubMedCentralID PMC4385510

• Task-rest modulation of basal ganglia connectivity in mild to moderate Parkinson's disease BRAIN IMAGING AND BEHAVIOR Mueller-Oehring, E. M., Sullivan, E. V., Pfefferbaum, A., Huang, N. C., Poston, K. L., Bronte-Stewart, H. M., Schulte, T. 2015; 9 (3): 619-638

  Abstract

  Parkinson's disease (PD) is associated with abnormal synchronization in basal ganglia-thalamo-cortical loops. We tested whether early PD patients without demonstrable cognitive impairment exhibit abnormal modulation of functional connectivity at rest, while engaged in a task, or both. PD and healthy controls underwent two functional MRI scans: a resting-state scan and a Stroop Match-to-Sample task scan. Rest-task modulation of basal ganglia (BG) connectivity was tested using seed-to-voxel connectivity analysis with task and rest time series as conditions. Despite substantial overlap of BG-cortical connectivity patterns in both groups, connectivity differences between groups had clinical and behavioral correlates. During rest, stronger putamen-medial parietal and pallidum-occipital connectivity in PD than controls was associated with worse task performance and more severe PD symptoms suggesting that abnormalities in resting-state connectivity denote neural network dedifferentiation. During the executive task, PD patients showed weaker BG-cortical connectivity than controls, i.e., between caudate-supramarginal gyrus and pallidum-inferior prefrontal regions, that was related to more severe PD symptoms and worse task performance. Yet, task processing also evoked stronger striatal-cortical connectivity, specifically between caudate-prefrontal, caudate-precuneus, and putamen-motor/premotor regions in PD relative to controls, which was related to less severe PD symptoms and better performance on the Stroop task. Thus, stronger task-evoked striatal connectivity in PD demonstrated compensatory neural network enhancement to meet task demands and improve performance levels. fMRI-based network analysis revealed that despite resting-state BG network compromise in PD, BG connectivity to prefrontal, premotor, and precuneus regions can be adequately invoked during executive control demands enabling near normal task performance.

  View details for DOI 10.1007/s11682-014-9317-9

  View details for Web of Science ID 000361604300021

  View details for PubMedCentralID PMC4385510

• Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double-blind, randomized, controlled trial. Annals of neurology Warren Olanow, C., Bartus, R. T., Baumann, T. L., Factor, S., Boulis, N., Stacy, M., Turner, D. A., Marks, W., Larson, P., Starr, P. A., Jankovic, J., Simpson, R., Watts, R., Guthrie, B., Poston, K., Henderson, J. M., Stern, M., Baltuch, G., Goetz, C. G., Herzog, C., Kordower, J. H., Alterman, R., Lozano, A. M., Lang, A. E. 2015; 78 (2): 248-57

  Abstract

  A 12-month double-blind sham-surgery-controlled trial assessing adeno-associated virus type 2 (AAV2)-neurturin injected into the putamen bilaterally failed to meet its primary endpoint, but showed positive results for the primary endpoint in the subgroup of subjects followed for 18 months and for several secondary endpoints. Analysis of postmortem tissue suggested impaired axonal transport of neurturin from putamen to substantia nigra. In the present study, we tested the safety and efficacy of AAV2-neurturin delivered to putamen and substantia nigra.We performed a 15- to 24-month, multicenter, double-blind trial in patients with advanced Parkinson disease (PD) who were randomly assigned to receive bilateral AAV2-neurturin injected bilaterally into the substantia nigra (2.0 × 10(11) vector genomes) and putamen (1.0 × 10(12) vector genomes) or sham surgery. The primary endpoint was change from baseline to final visit performed at the time the last enrolled subject completed the 15-month evaluation in the motor subscore of the Unified Parkinson's Disease Rating Scale in the practically defined off state.Fifty-one patients were enrolled in the trial. There was no significant difference between groups in the primary endpoint (change from baseline: AAV2-neurturin, -7.0 ± 9.92; sham, -5.2 ± 10.01; p = 0.515) or in most secondary endpoints. Two subjects had cerebral hemorrhages with transient symptoms. No clinically meaningful adverse events were attributed to AAV2-neurturin.AAV2-neurturin delivery to the putamen and substantia nigra bilaterally in PD was not superior to sham surgery. The procedure was well tolerated, and there were no clinically significant adverse events related to AAV2-neurturin. Ann Neurol 2015;78:248-257.

  View details for DOI 10.1002/ana.24436

  View details for PubMedID 26061140

• A disease-specific metabolic brain network associated with corticobasal degeneration BRAIN Niethammer, M., Tang, C. C., Feigin, A., Allen, P. J., Heinen, L., Hellwig, S., Amtage, F., Hanspal, E., Vonsattel, J. P., Poston, K. L., Meyer, P. T., Leenders, K. L., Eidelberg, D. 2014; 137: 3036-3046

  Abstract

  Corticobasal degeneration is an uncommon parkinsonian variant condition that is diagnosed mainly on clinical examination. To facilitate the differential diagnosis of this disorder, we used metabolic brain imaging to characterize a specific network that can be used to discriminate corticobasal degeneration from other atypical parkinsonian syndromes. Ten non-demented patients (eight females/two males; age 73.9 ± 5.7 years) underwent metabolic brain imaging with (18)F-fluorodeoxyglucose positron emission tomography for atypical parkinsonism. These individuals were diagnosed clinically with probable corticobasal degeneration. This diagnosis was confirmed in the three subjects who additionally underwent post-mortem examination. Ten age-matched healthy subjects (five females/five males; age 71.7 ± 6.7 years) served as controls for the imaging studies. Spatial covariance analysis was applied to scan data from the combined group to identify a significant corticobasal degeneration-related metabolic pattern that discriminated (P < 0.001) the patients from the healthy control group. This pattern was characterized by bilateral, asymmetric metabolic reductions involving frontal and parietal cortex, thalamus, and caudate nucleus. These pattern-related changes were greater in magnitude in the cerebral hemisphere opposite the more clinically affected body side. The presence of this corticobasal degeneration-related metabolic topography was confirmed in two independent testing sets of patient and control scans, with elevated pattern expression (P < 0.001) in both disease groups relative to corresponding normal values. We next determined whether prospectively computed expression values for this pattern accurately discriminated corticobasal degeneration from multiple system atrophy and progressive supranuclear palsy (the two most common atypical parkinsonian syndromes) on a single case basis. Based upon this measure, corticobasal degeneration was successfully distinguished from multiple system atrophy (P < 0.001) but not progressive supranuclear palsy, presumably because of the overlap (∼ 24%) that existed between the corticobasal degeneration- and the progressive supranuclear palsy-related metabolic topographies. Nonetheless, excellent discrimination between these disease entities was achieved by computing hemispheric asymmetry scores for the corticobasal degeneration-related pattern on a prospective single scan basis. Indeed, a logistic algorithm based on the asymmetry scores combined with separately computed expression values for a previously validated progressive supranuclear palsy-related pattern provided excellent specificity (corticobasal degeneration: 92.7%; progressive supranuclear palsy: 94.1%) in classifying 58 testing subjects. In conclusion, corticobasal degeneration is associated with a reproducible disease-related metabolic covariance pattern that may help to distinguish this disorder from other atypical parkinsonian syndromes.

  View details for DOI 10.1093/brain/awu256

  View details for Web of Science ID 000346760900025

  View details for PubMedID 25208922

  View details for PubMedCentralID PMC4208467

• What light have resting state fMRI studies shed on cognition and mood in Parkinson's disease? Journal of clinical movement disorders YorkWilliams, S., Poston, K. L. 2014; 1: 4-?

  Abstract

  Much remains unknown about non-motor symptoms of Parkinson's disease (PD), which have variable occurrence, progression, and severity among patients. The existing suite of neuroimaging tools has yielded insight that cannot be garnered by traditional methods such as behavioral and post-mortem assessment. They provide information on brain activity and structure that is invaluable to understanding abnormalities associated with neurodegeneration in PD. Among these tools, functional magnetic resonance imaging (fMRI) is often favored for its safety and spatial resolution. Resting state fMRI research capitalizes on the wealth of information that the brain offers when a person is not performing a motor or cognitive task. It is also a good means to study impaired and heterogeneous populations, such as people with PD. The present article reviews research that applies resting state fMRI to the ongoing hunt for biomarkers of PD non-motor symptoms. Thus far, research in this subfield has focused on two of the most common and significant non-motor symptoms: cognitive impairment and depression. These studies support resting state fMRI as a valid and practical tool for the study of these symptoms, but discrepancies among findings highlight the importance of further research with standardized procedures.

  View details for DOI 10.1186/2054-7072-1-4

  View details for PubMedID 26788330

  View details for PubMedCentralID PMC4677732

• Functional brain networks and abnormal connectivity in the movement disorders NEUROIMAGE Poston, K. L., Eidelberg, D. 2012; 62 (4): 2261-2270

  Abstract

  Clinical manifestations of movement disorders, such as Parkinson's disease (PD) and dystonia, arise from neurophysiological changes within the cortico-striato-pallidothalamocortical (CSPTC) and cerebello-thalamo-cortical (CbTC) circuits. Neuroimaging techniques that probe connectivity within these circuits can be used to understand how these disorders develop as well as identify potential targets for medical and surgical therapies. Indeed, network analysis of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has identified abnormal metabolic networks associated with the cardinal motor symptoms of PD, such as akinesia and tremor, as well as PD-related cognitive dysfunction. More recent task-based and resting state functional magnetic resonance imaging studies have reproduced several of the altered connectivity patterns identified in these abnormal PD-related networks. A similar network analysis approach in dystonia revealed abnormal disease related metabolic patterns in both manifesting and non-manifesting carriers of dystonia mutations. Other multimodal imaging approaches using magnetic resonance diffusion tensor imaging in patients with primary genetic dystonia suggest abnormal connectivity within the CbTC circuits mediate the clinical manifestations of this inherited neurodevelopmental disorder. Ongoing developments in functional imaging and future studies in early patients are likely to enhance our understanding of these movement disorders and guide novel targets for future therapies.

  View details for DOI 10.1016/j.neuroimage.2011.12.021

  View details for Web of Science ID 000308265200010

  View details for PubMedID 22206967

  View details for PubMedCentralID PMC3489159

• Network correlates of disease severity in multiple system atrophy NEUROLOGY Poston, K. L., Tang, C. C., Eckert, T., Dhawan, V., Frucht, S., Vonsattel, J., Fahn, S., Eidelberg, D. 2012; 78 (16): 1237-1244

  Abstract

  Multiple system atrophy (MSA), the most common of the atypical parkinsonian disorders, is characterized by the presence of an abnormal spatial covariance pattern in resting state metabolic brain images from patients with this disease. Nonetheless, the potential utility of this pattern as a MSA biomarker is contingent upon its specificity for this disorder and its relationship to clinical disability in individual patients.We used [(18)F]fluorodeoxyglucose PET to study 33 patients with MSA, 20 age- and severity-matched patients with idiopathic Parkinson disease (PD), and 15 healthy volunteers. For each subject, we computed the expression of the previously characterized metabolic covariance patterns for MSA and PD (termed MSARP and PDRP, respectively) on a prospective single-case basis. The resulting network values for the individual patients were correlated with clinical motor ratings and disease duration.In the MSA group, disease-related pattern (MSARP) values were elevated relative to the control and PD groups (p < 0.001 for both comparisons). In this group, MSARP values correlated with clinical ratings of motor disability (r = 0.57, p = 0.0008) and with disease duration (r = -0.376, p = 0.03). By contrast, MSARP expression in the PD group did not differ from control values (p = 1.0). In this group, motor ratings correlated with PDRP (r = 0.60, p = 0.006) but not with MSARP values (p = 0.88).MSA is associated with elevated expression of a specific disease-related metabolic pattern. Moreover, differences in the expression of this pattern in patients with MSA correlate with clinical disability. The findings suggest that the MSARP may be a useful biomarker in trials of new therapies for this disorder.

  View details for DOI 10.1212/WNL.0b013e318250d7fd

  View details for Web of Science ID 000302933200010

  View details for PubMedID 22491861

  View details for PubMedCentralID PMC3324319

• Dopaminergic Modulation of Basal Ganglia Connectivity in Parkinson's Disease Poston, K. L., Shire, W., Joseph, R., Menon, V., Greicius, M. WILEY-BLACKWELL. 2012: S109

  View details for Web of Science ID 000312938700431

• AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial LANCET NEUROLOGY LeWitt, P. A., Rezai, A. R., Leehey, M. A., Ojemann, S. G., Flaherty, A. W., Eskandar, E. N., Kostyk, S. K., Thomas, K., Sarkar, A., Siddiqui, M. S., Tatter, S. B., Schwalb, J. M., Poston, K. L., Henderson, J. M., Kurlan, R. M., Richard, I. H., Van Meter, L., Sapan, C. V., During, M. J., Kaplitt, M. G., Feigin, A. 2011; 10 (4): 309-319

  Abstract

  Gene transfer of glutamic acid decarboxylase (GAD) and other methods that modulate production of GABA in the subthalamic nucleus improve basal ganglia function in parkinsonism in animal models. We aimed to assess the effect of bilateral delivery of AAV2-GAD in the subthalamic nucleus compared with sham surgery in patients with advanced Parkinson's disease.Patients aged 30-75 years who had progressive levodopa-responsive Parkinson's disease and an overnight off-medication unified Parkinson's disease rating scale (UPDRS) motor score of 25 or more were enrolled into this double-blind, phase 2, randomised controlled trial, which took place at seven centres in the USA between Nov 17, 2008, and May 11, 2010. Infusion failure or catheter tip location beyond a predefined target zone led to exclusion of patients before unmasking for the efficacy analysis. The primary outcome measure was the 6-month change from baseline in double-blind assessment of off-medication UPDRS motor scores. This trial is registered with ClinicalTrials.gov, NCT00643890.Of 66 patients assessed for eligibility, 23 were randomly assigned to sham surgery and 22 to AAV2-GAD infusions; of those, 21 and 16, respectively, were analysed. At the 6-month endpoint, UPDRS score for the AAV2-GAD group decreased by 8·1 points (SD 1·7, 23·1%; p<0·0001) and by 4·7 points in the sham group (1·5, 12·7%; p=0·003). The AAV2-GAD group showed a significantly greater improvement from baseline in UPDRS scores compared with the sham group over the 6-month course of the study (RMANOVA, p=0·04). One serious adverse event occurred within 6 months of surgery; this case of bowel obstruction occurred in the AAV2-GAD group, was not attributed to treatment or the surgical procedure, and fully resolved. Other adverse events were mild or moderate, likely related to surgery and resolved; the most common were headache (seven patients in the AAV2-GAD group vs two in the sham group) and nausea (six vs two).The efficacy and safety of bilateral infusion of AAV2-GAD in the subthalamic nucleus supports its further development for Parkinson's disease and shows the promise for gene therapy for neurological disorders.Neurologix.

  View details for DOI 10.1016/S1474-4422(11)70039-4

  View details for Web of Science ID 000289185000014

  View details for PubMedID 21419704

• Accurate differential diagnosis of parkinsonism by pattern analysis of metabolic imaging data Tang, C., Dhawan, V., Poston, K., Feigin, A., Eidelberg, D. SOC NUCLEAR MEDICINE INC. 2010

  View details for Web of Science ID 000447387101350

• Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) with Myoclonus MOVEMENT DISORDERS Poston, K. L., McGovern, R. A., Goldman, J. S., Caccappolo, E., Mazzoni, P. 2010; 25 (4): 514-516

  View details for DOI 10.1002/mds.22929

  View details for Web of Science ID 000276337400027

  View details for PubMedID 20063436

• Abnormalities in Metabolic Network Activity Precede the Onset of Motor Symptoms in Parkinson's Disease JOURNAL OF NEUROSCIENCE Tang, C. C., Poston, K. L., Dhawan, V., Eidelberg, D. 2010; 30 (3): 1049-1056

  Abstract

  Imaging studies show that Parkinson's disease (PD) alters the activity of motor- and cognition-related metabolic brain networks. However, it is not known whether the network changes appear at or before symptom onset. In this study, we examined 15 hemiparkinsonian patients who underwent serial metabolic imaging with [(18)F]-fluorodeoxyglucose (FDG) PET at baseline and again 2.1 +/- 0.6 (mean +/- SD) and 3.9 +/- 0.7 years later. We assessed longitudinal changes in network activity in each cerebral hemisphere, focusing specifically on the "presymptomatic" hemisphere--ipsilateral to the initially involved body side. At the network level, the activity of the PD motor-related pattern (PDRP) increased symmetrically in both hemispheres over time (p < 0.001), with significant bilateral elevations at each of the three time points. Hemispheric expression of the PD cognition-related pattern likewise increased symmetrically (p < 0.001), although significant elevations were not evident on either side until 4 years. At the regional level, putamen metabolism contralateral to the initially affected body side was elevated at all three time points, without longitudinal change. In contrast, in the initially presymptomatic hemisphere, putamen metabolic activity increased steadily over time, reaching abnormal levels only at 4 years. Metabolic activity in the contralateral precuneus fell to subnormal levels by the final time point. These findings suggest that abnormal PDRP activity antecedes the appearance of motor signs by approximately 2 years. The timing and laterality of symptom onset relates to focal asymmetric metabolic changes at the putamenal node of this network.

  View details for DOI 10.1523/JNEUROSCI.4188-09.2010

  View details for Web of Science ID 000273779200026

  View details for PubMedID 20089913

  View details for PubMedCentralID PMC2866050

• FDG PET in the Evaluation of Parkinson's Disease. PET clinics 2010; 5 (1): 55–64

  Abstract

  Network analysis of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is an innovative approach for the study of in movement disorders, such as Parkinson's disease (PD). Spatial covariance analysis of imaging data acquired from PD patients has revealed characteristic regional patterns associated with the motor and cognitive features of disease. Quantification of pattern expression in individual patients can be used for diagnosis, assessment of disease severity, and evaluation of novel medical and surgical therapies. Identification of disease-specific patterns in other parkinsonian syndromes, such as multiple system atrophy and progressive supranuclear palsy, has improved diagnostic accuracy in patients with difficult to diagnose parkinsonism. Further developments of these techniques are likely to enhance the role of functional imaging in investigating underlying abnormalities and potential new therapies in these neurodegenerative diseases.

  View details for DOI 10.1016/j.cpet.2009.12.004

  View details for PubMedID 20689674

  View details for PubMedCentralID PMC2913894

• Action tremor of the legs in essential tremor: Prevalence, clinical correlates, and comparison with age-matched controls PARKINSONISM & RELATED DISORDERS Poston, K. L., Rios, E., Louis, E. D. 2009; 15 (8): 602-605

  Abstract

  The hallmark feature of essential tremor (ET) is action tremor of the arms. Leg tremor may also occur yet it has not been the central focus of previous studies. Its prevalence has only rarely been reported, its clinical correlates have yet to be explored. Our aims were to report the prevalence and analyze the clinical correlates of leg action tremor in patients with ET and, given the propensity for normal elderly individuals to manifest mild limb tremors, compare the prevalence with that in age-matched controls. Kinetic leg tremor rated > or =1 occurred in 28/63 (44.4%) ET cases and in only 9/63 (14.3%) controls (p<0.001); moderate leg tremor occurred in 14.3% of cases. Leg tremor severity modestly correlated with disease duration (r=0.31, p=0.02). However, the severity and laterality of leg tremor did not correlate with those of arm tremor. The pathophysiological implications of this finding deserve further exploration.

  View details for DOI 10.1016/j.parkreldis.2008.11.006

  View details for Web of Science ID 000270122500011

  View details for PubMedID 19103506

  View details for PubMedCentralID PMC2728140

• Network biomarkers for the diagnosis and treatment of movement disorders NEUROBIOLOGY OF DISEASE Poston, K. L., Eidelberg, D. 2009; 35 (2): 141-147

  Abstract

  Functional brain networks provide a set of useful biomarkers for the assessment of movement disorders such as Parkinson's disease (PD). Spatial covariance analysis of imaging data from PD patients has led to the identification of abnormal metabolic patterns associated with the motor and cognitive features of this disease. Measurements of pattern expression have been used for diagnosis, assessment of rates of disease progression, and objective evaluation of the efficacy of therapeutic interventions. For instance, the recent identification of new disease-specific patterns for Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) has improved diagnostic accuracy in patients with parkinsonian syndromes. Further, disease-related networks have been found to be modulated by novel treatment strategies such as gene therapy. Finally, the application of network analysis to the study of inherited movement disorders such as Huntington's disease can aid in the assessment of disease-modifying therapies in pre-symptomatic gene mutation carriers.

  View details for DOI 10.1016/j.nbd.2008.09.026

  View details for Web of Science ID 000268078300004

  View details for PubMedID 19013242

• Movement disorder emergencies 16th Symposium on the Treatment of Parkinsons Disease Poston, K. L., Frucht, S. J. SPRINGER HEIDELBERG. 2008: 2–13

  Abstract

  Movement disorder emergencies include any movement disorder which evolves over hours to days, in which failure to appropriately diagnose and manage can result in patient morbidity or mortality. It is crucial that doctors recognize these emergencies with accuracy and speed by obtaining the proper history and by being familiar with the phenomenology of frequently encountered movements. These disorders will be discussed based on the most common associated involuntary movement, either parkinsonism, dystonia, chorea, tics or myoclonus, and, when available, review the workup and treatment options based on the current literature.

  View details for DOI 10.1007/s00415-008-4002-9

  View details for Web of Science ID 000259034000002

  View details for PubMedID 18821080

• Zydis selegilline in the management of Parkinson's disease EXPERT OPINION ON PHARMACOTHERAPY Poston, K. L., Waters, C. 2007; 8 (15): 2615-2624

  Abstract

  Selegiline, a selective monoamine oxidase-B inhibitor, has been used for decades in the treatment of Parkinson's disease. The recent development of an orally disintegrating dosage form using Zydis technology allows pregastric drug absorption and, thus, greatly improving the pharmacodynamic and pharmacokinetic drug profiles. This new formulation provides higher drug bioavailability and a substantially reduced concentration of active metabolites. As an adjunct to levodopa, Zydis selegiline is shown to be a safe and effective therapy in patients with motor fluctuations and wearing off. This review outlines the advantages of a Zydis formulation in Parkinson's disease and the evidence supporting the use of Zydis selegiline for motor fluctuations.

  View details for DOI 10.1517/14656566.8.15.2615

  View details for Web of Science ID 000250426000014

  View details for PubMedID 17931095