Karly Cody

All Publications

• Visual read of [F-18]florquinitau PET that includes and extends beyond the mesial temporal lobe is associated with increased plasma pTau217 and cognitive decline in a cohort that is enriched with risk for Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association Rea Reyes, R. E., Cody, K. A., Wilson, R. E., Zetterberg, H., Chin, N. A., Jonaitis, E. M., Bahr, M., Mandel, O., Wintlend, M., Bendlin, B. B., Okonkwo, O. C., Clark, L. R., Zammit, M., Asthana, S., Christian, B. T., Betthauser, T. J., Eisenmenger, L., Langhough, R. E., Johnson, S. C. 2024

  Abstract

  Patterns of signal from tau positron emission tomography (tau-PET) confined to the medial temporal lobe (MTL) or extended into the neocortex may be relevant for Alzheimer's disease (AD) research if they are linked to differential biomarker levels and cognitive decline.Visual assessment of Tau-PET [F-18]florquinitau (FQT) exams from 728 initially non-demented older adults yielded four uptake groups: tau-negative (T-), MTL-only (T+MTL), neocortex-only (T+Neo), or both (T+MTL&Neo). Mixed effects models assessed group differences in retrospective cognitive and plasma pTau217 trajectories.T+MTL&Neo was the most common T+ group (n = 97; 93% A+) and exhibited the sharpest worsening in cognitive and pTau217 trajectories before tau PET.The T+MTL&Neo category represents an intermediate to advanced stage of AD preceded by rising ptau217 and progressive cognitive decline. The pTau217 finding suggests that A+, T+ in MTL or neocortex could represent early AD stages, with a higher likelihood of progressing to more advanced stages.Visual assessments of Tau-PET FQT revealed four distinct uptake groups: tau-negative (T-), MTL-only (T+MTL), neocortex-only (T+Neo), or both (T+MTL&Neo). Amyloid positive participants in the T+MTL and T+MTL&Neo categories showed a retrospectively faster decline in their cognitive trajectories, and a sharper increase in pTau217 levels in plasma, compared to T-. The T+MTL&Neo group displayed sharper trajectories compared with the other Tau positive groups in both their cognitive scores and pTau217 plasma levels. Our results suggest that participants with Tau present in both MTL and neocortex represent an intermediate to advanced stage of AD, whereas participants with signals confined to either MTL or neocortex could represent earlier AD stages.

  View details for DOI 10.1002/alz.14406

  View details for PubMedID 39560002

• Characterizing brain tau and cognitive decline along the amyloid timeline in Alzheimer's disease. Brain : a journal of neurology Cody, K. A., Langhough, R. E., Zammit, M. D., Clark, L., Chin, N., Christian, B. T., Betthauser, T. J., Johnson, S. C. 2024

  Abstract

  Recent longitudinal PET imaging studies have established methods to estimate the age at which amyloid becomes abnormal at the level of the individual. Here we recontextualized amyloid levels into the temporal domain to better understand the downstream Alzheimer's disease processes of tau neurofibrillary tangle (NFT) accumulation and cognitive decline. This cohort study included a total of 601 individuals from the Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center that underwent amyloid and tau PET, longitudinal neuropsychological assessments, and met clinical criteria for three clinical diagnosis groups: cognitively unimpaired (CU; n=537); mild cognitive impairment (MCI; n=48); or dementia (n=16)). Cortical 11C-Pittsburgh compound B (PiB) distribution volume ratio (DVR) and sampled iterative local approximation were used to estimate amyloid positive (A+; global PiB DVR>1.16 equivalent to 17.1 Centiloids) onset age and years of A+ duration at tau PET (i.e., amyloid chronicity). Tau PET burden was quantified using 18F-MK-6240 standardized uptake value ratios (SUVRs; 70-90 min, inferior cerebellar gray matter reference region). Whole-brain and region-specific approaches were used to examine tau PET binding along the amyloid timeline and across the Alzheimer's disease clinical continuum. Voxel-wise 18F-MK-6240 analyses revealed that with each decade of A+, the spatial extent of measurable tau spread (i.e., progressed) from regions associated with early to late NFT tau stages. Regional analyses indicated that tau burden in the entorhinal cortex was detectable, on average, within ten years of A+ onset. Additionally, the entorhinal cortex was the region most sensitive to early amyloid pathology and clinical impairment in this predominantly preclinical sample. Among initially CU (n=472) individuals with longitudinal cognitive follow-up, mixed effects models showed significant linear and non-linear interactions of A+ duration and entorhinal tau on cognitive decline, suggesting a synergistic effect whereby greater A+ duration together with a higher entorhinal tau burden increases the likelihood of cognitive decline beyond their separable effects. Overall, the amyloid time framework enabled a spatiotemporal characterization of tau deposition patterns across the Alzheimer's disease continuum. This approach, which examined cross-sectional tau PET data along the amyloid timeline to make longitudinal disease-course inferences, demonstrated that A+ duration explains a considerable amount of variability in the magnitude and topography of tau spread, which largely recapitulated NFT staging observed in human neuropathological studies. By anchoring disease progression to the onset of amyloid, this study provides a temporal disease context which may help inform disease prognosis and timing windows for anti-amyloid therapies.

  View details for DOI 10.1093/brain/awae116

  View details for PubMedID 38667631

• Longitudinal normative standards for cognitive tests and composites using harmonized data from two Wisconsin AD-risk-enriched cohorts. Alzheimer's & dementia : the journal of the Alzheimer's Association Jonaitis, E. M., Hermann, B. P., Mueller, K. D., Clark, L. R., Du, L., Betthauser, T. J., Cody, K., Gleason, C. E., Christian, B. T., Asthana, S., Chappell, R. J., Chin, N. A., Johnson, S. C., Langhough, R. E. 2024

  Abstract

  Published norms are typically cross-sectional and often are not sensitive to preclinical cognitive changes due to dementia. We developed and validated demographically adjusted cross-sectional and longitudinal normative standards using harmonized outcomes from two Alzheimer's disease (AD) risk-enriched cohorts.Data from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were combined. Quantile regression was used to develop unconditional (cross-sectional) and conditional (longitudinal) normative standards for 18 outcomes using data from cognitively unimpaired participants (N = 1390; mean follow-up = 9.25 years). Validity analyses (N = 2456) examined relationships between percentile scores (centiles), consensus-based cognitive statuses, and AD biomarker levels.Unconditional and conditional centiles were lower in those with consensus-based impairment or biomarker positivity. Similarly, quantitative biomarker levels were higher in those whose centiles suggested decline.This study presents normative standards for cognitive measures sensitive to pre-clinical changes. Future directions will investigate potential clinical applications of longitudinal normative standards.Quantile regression was used to construct longitudinal norms for cognitive tests. Poorer percentile scores were related to concurrent diagnosis and Alzheimer's disease biomarkers. A ShinyApp was built to display test scores and norms and flag low performance.

  View details for DOI 10.1002/alz.13774

  View details for PubMedID 38539269

• Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology. JAMA neurology Ashton, N. J., Brum, W. S., Di Molfetta, G., Benedet, A. L., Arslan, B., Jonaitis, E., Langhough, R. E., Cody, K., Wilson, R., Carlsson, C. M., Vanmechelen, E., Montoliu-Gaya, L., Lantero-Rodriguez, J., Rahmouni, N., Tissot, C., Stevenson, J., Servaes, S., Therriault, J., Pascoal, T., Lleo, A., Alcolea, D., Fortea, J., Rosa-Neto, P., Johnson, S., Jeromin, A., Blennow, K., Zetterberg, H. 2024

  Abstract

  Importance: Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer disease (AD) pathology, with p-tau217 considered to have the most utility. However, availability of p-tau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests.Objective: To determine the utility of a novel and commercially available immunoassay for plasma p-tau217 to detect AD pathology and evaluate reference ranges for abnormal amyloid beta (Abeta) and longitudinal change across 3 selected cohorts.Design, Setting, and Participants: This cohort study examined data from 3 single-center observational cohorts: cross-sectional and longitudinal data from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (visits October 2017-August 2021) and Wisconsin Registry for Alzheimer's Prevention (WRAP) cohort (visits February 2007-November 2020) and cross-sectional data from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort (baseline visits March 2009-November 2021). Participants included individuals with and without cognitive impairment grouped by amyloid and tau (AT) status using PET or CSF biomarkers. Data were analyzed from February to June 2023.Exposures: Magnetic resonance imaging, Abeta positron emission tomography (PET), tau PET, cerebrospinal fluid (CSF) biomarkers (Abeta42/40 and p-tau immunoassays), and plasma p-tau217 (ALZpath pTau217 assay).Main Outcomes and Measures: Accuracy of plasma p-tau217 in detecting abnormal amyloid and tau pathology, longitudinal p-tau217 change according to baseline pathology status.Results: The study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] and 282 males [35.9%]). High accuracy was observed in identifying elevated Abeta (area under the curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95% CI, 0.84-0.99) across all cohorts. These accuracies were comparable with CSF biomarkers in determining abnormal PET signal. The detection of abnormal Abeta pathology using a 3-range reference yielded reproducible results and reduced confirmatory testing by approximately 80%. Longitudinally, plasma p-tau217 values showed an annual increase only in Abeta-positive individuals, with the highest increase observed in those with tau positivity.Conclusions and Relevance: This study found that a commercially available plasma p-tau217 immunoassay accurately identified biological AD, comparable with results using CSF biomarkers, with reproducible cut-offs across cohorts. It detected longitudinal changes, including at the preclinical stage.

  View details for DOI 10.1001/jamaneurol.2023.5319

  View details for PubMedID 38252443

• Normative Cerebral Hemodynamics in Middle-aged and Older Adults Using 4D Flow MRI: Initial Analysis of Vascular Aging RADIOLOGY Roberts, G. S., Peret, A., Jonaitis, E. M., Koscik, R. L., Hoffman, C. A., Rivera-Rivera, L. A., Cody, K. A., Rowley, H. A., Johnson, S. C., Wieben, O., Johnson, K. M., Eisenmenger, L. B. 2023; 307 (3): e222685

  Abstract

  Background Characterizing cerebrovascular hemodynamics in older adults is important for identifying disease and understanding normal neurovascular aging. Four-dimensional (4D) flow MRI allows for a comprehensive assessment of cerebral hemodynamics in a single acquisition. Purpose To establish reference intracranial blood flow and pulsatility index values in a large cross-sectional sample of middle-aged (45-65 years) and older (>65 years) adults and characterize the effect of age and sex on blood flow and pulsatility. Materials and Methods In this retrospective study, patients aged 45-93 years (cognitively unimpaired) underwent cranial 4D flow MRI between March 2010 and March 2020. Blood flow rates and pulsatility indexes from 13 major arteries and four venous sinuses and total cerebral blood flow were collected. Intraobserver and interobserver reproducibility of flow and pulsatility measures was assessed in 30 patients. Descriptive statistics (mean ± SD) of blood flow and pulsatility were tabulated for the entire group and by age and sex. Multiple linear regression and linear mixed-effects models were used to assess the effect of age and sex on total cerebral blood flow and vessel-specific flow and pulsatility, respectively. Results There were 759 patients (mean age, 65 years ± 8 [SD]; 506 female patients) analyzed. For intra- and interobserver reproducibility, median intraclass correlation coefficients were greater than 0.90 for flow and pulsatility measures across all vessels. Regression coefficients β ± standard error from multiple linear regression showed a 4 mL/min decrease in total cerebral blood flow each year (age β = -3.94 mL/min per year ± 0.44; P < .001). Mixed effects showed a 1 mL/min average annual decrease in blood flow (age β = -0.95 mL/min per year ± 0.16; P < .001) and 0.01 arbitrary unit (au) average annual increase in pulsatility over all vessels (age β = 0.011 au per year ± 0.001; P < .001). No evidence of sex differences was observed for flow (β = -1.60 mL/min per male patient ± 1.77; P = .37), but pulsatility was higher in female patients (sex β = -0.018 au per male patient ± 0.008; P = .02). Conclusion Normal reference values for blood flow and pulsatility obtained using four-dimensional flow MRI showed correlations with age. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Steinman in this issue.

  View details for DOI 10.1148/radiol.222685

  View details for Web of Science ID 001001897600012

  View details for PubMedID 36943077

  View details for PubMedCentralID PMC10140641

• Plasma phosphorylated tau 217 in preclinical Alzheimer's disease BRAIN COMMUNICATIONS Jonaitis, E. M., Janelidze, S., Cody, K. A., Langhough, R., Du, L., Chin, N. A., Mattsson-Carlgren, N., Hogan, K. J., Christian, B. T., Betthauser, T. J., Hansson, O., Johnson, S. C. 2023; 5 (2): fcad057

  Abstract

  An accurate blood test for Alzheimer's disease that is sensitive to preclinical proteinopathy and cognitive decline has clear implications for early detection and secondary prevention. We assessed the performance of plasma phosphorylated tau 217 ( pTa u 217 ) against brain PET markers of amyloid [ [ 11 C ] -labelled Pittsburgh compound B (PiB)] and tau ( [ 18 F ] MK-6240) and its utility for predicting longitudinal cognition. Samples were analysed from a subset of participants with up to 8 years follow-up in the Wisconsin Registry for Alzheimer's Prevention (WRAP; 2001-present; plasma 2011-present), a longitudinal cohort study of adults from midlife, enriched for parental history of Alzheimer's disease. Participants were a convenience sample who volunteered for at least one PiB scan, had usable banked plasma and were cognitively unimpaired at first plasma collection. Study personnel who interacted with participants or samples were blind to amyloid status. We used mixed effects models and receiver-operator characteristic curves to assess concordance between plasma pTa u 217 and PET biomarkers of Alzheimer's disease and mixed effects models to understand the ability of plasma pTa u 217 to predict longitudinal performance on WRAP's preclinical Alzheimer's cognitive composite (PACC-3). The primary analysis included 165 people (108 women; mean age = 62.9 ± 6.06; 160 still enrolled; 2 deceased; 3 discontinued). Plasma pTa u 217 was strongly related to PET-based estimates of concurrent brain amyloid ( β ^ = 0.83 (0.75, 0.90), P < 0.001). Concordance was high between plasma pTa u 217 and both amyloid PET (area under the curve = 0.91, specificity = 0.80, sensitivity = 0.85, positive predictive value = 0.58, negative predictive value = 0.94) and tau PET (area under the curve = 0.95, specificity = 1, sensitivity = 0.85, positive predictive value = 1, negative predictive value = 0.98). Higher baseline pTa u 217 levels were associated with worse cognitive trajectories ( β ^ p T a u × a g e = -0.07 (-0.09, -0.06), P < 0.001). In a convenience sample of unimpaired adults, plasma pTa u 217 levels correlate well with concurrent brain Alzheimer's disease pathophysiology and with prospective cognitive performance. These data indicate that this marker can detect disease before clinical signs and thus may disambiguate presymptomatic Alzheimer's disease from normal cognitive ageing.

  View details for DOI 10.1093/braincomms/fcad057

  View details for Web of Science ID 000961967800001

  View details for PubMedID 37013174

  View details for PubMedCentralID PMC10066514

• Associations between self-reported sleep patterns and health, cognition and amyloid measures: results from the Wisconsin Registry for Alzheimer's Prevention BRAIN COMMUNICATIONS Du, L., Langhough, R., Hermann, B. P., Jonaitis, E., Betthauser, T. J., Cody, K., Mueller, K., Zuelsdorff, M., Chin, N., Ennis, G. E., Bendlin, B. B., Gleason, C. E., Christian, B. T., Plante, D. T., Chappell, R., Johnson, S. C. 2023; 5 (2): fcad039

  Abstract

  Previous studies suggest associations between self-reported sleep problems and poorer health, cognition, Alzheimer's disease pathology and dementia-related outcomes. It is important to develop a deeper understanding of the relationship between these complications and sleep disturbance, a modifiable risk factor, in late midlife, a time when Alzheimer's disease pathology may be accruing. The objectives of this study included application of unsupervised machine learning procedures to identify distinct subgroups of persons with problematic sleep and the association of these subgroups with concurrent measures of mental and physical health, cognition and PET-identified amyloid. Dementia-free participants from the Wisconsin Registry for Alzheimer's Prevention (n = 619) completed sleep questionnaires including the Insomnia Severity Index, Epworth Sleepiness Scale and Medical Outcomes Study Sleep Scale. K-means clustering analysis identified discrete sleep problem groups who were then compared across concurrent health outcomes (e.g. depression, self-rated health and insulin resistance), cognitive composite indices including episodic memory and executive function and, in a subset, Pittsburgh Compound B PET imaging to assess amyloid burden. Significant omnibus tests (P < 0.05) were followed with pairwise comparisons. Mean (SD) sample baseline sleep assessment age was 62.6 (6.7). Cluster analysis identified three groups: healthy sleepers [n = 262 (42.3%)], intermediate sleepers [n = 229 (37.0%)] and poor sleepers [n = 128 (20.7%)]. All omnibus tests comparing demographics and health measures across sleep groups were significant except for age, sex and apolipoprotein E e4 carriers; the poor sleepers group was worse than one or both of the other groups on all other measures, including measures of depression, self-reported health and memory complaints. The poor sleepers group had higher average body mass index, waist-hip ratio and homeostatic model assessment of insulin resistance. After adjusting for covariates, the poor sleepers group also performed worse on all concurrent cognitive composites except working memory. There were no differences between sleep groups on PET-based measures of amyloid. Sensitivity analyses indicated that while different clustering approaches resulted in different group assignments for some (predominantly the intermediate group), between-group patterns in outcomes were consistent. In conclusion, distinct sleep characteristics groups were identified with a sizable minority (20.7%) exhibiting poor sleep characteristics, and this group also exhibited the poorest concurrent mental and physical health and cognition, indicating substantial multi-morbidity; sleep group was not associated with amyloid PET estimates. Precision-based management of sleep and related factors may provide an opportunity for early intervention that could serve to delay or prevent clinical impairment.

  View details for DOI 10.1093/braincomms/fcad039

  View details for Web of Science ID 000946665900003

  View details for PubMedID 36910417

  View details for PubMedCentralID PMC9999364

• Prediction of Longitudinal Cognitive Decline in Preclinical Alzheimer Disease Using Plasma Biomarkers JAMA NEUROLOGY Mattsson-Carlgren, N., Salvado, G., Ashton, N. J., Tideman, P., Stomrud, E., Zetterberg, H., Ossenkoppele, R., Betthauser, T. J., Cody, K., Jonaitis, E. M., Langhough, R., Palmqvist, S., Blennow, K., Janelidze, S., Johnson, S. C., Hansson, O. 2023; 80 (4): 360-369

  Abstract

  Alzheimer disease (AD) pathology starts with a prolonged phase of β-amyloid (Aβ) accumulation without symptoms. The duration of this phase differs greatly among individuals. While this disease phase has high relevance for clinical trial designs, it is currently unclear how to best predict the onset of clinical progression.To evaluate combinations of different plasma biomarkers for predicting cognitive decline in Aβ-positive cognitively unimpaired (CU) individuals.This prospective population-based prognostic study evaluated data from 2 prospective longitudinal cohort studies (the Swedish BioFINDER-1 and the Wisconsin Registry for Alzheimer Prevention [WRAP]), with data collected from February 8, 2010, to October 21, 2020, for the BioFINDER-1 cohort and from August 11, 2011, to June 27, 2021, for the WRAP cohort. Participants were CU individuals recruited from memory clinics who had brain Aβ pathology defined by cerebrospinal fluid (CSF) Aβ42/40 in the BioFINDER-1 study and by Pittsburgh Compound B (PiB) positron emission tomography (PET) in the WRAP study. A total of 564 eligible Aβ-positive and Aβ-negative CU participants with available relevant data from the BioFINDER-1 and WRAP cohorts were included in the study; of those, 171 Aβ-positive participants were included in the main analyses.Baseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, and neurofilament light measured in plasma; CSF biomarkers in the BioFINDER-1 cohort, and PiB PET uptake in the WRAP cohort.The primary outcome was longitudinal measures of cognition (using the Mini-Mental State Examination [MMSE] and the modified Preclinical Alzheimer Cognitive Composite [mPACC]) over a median of 6 years (range, 2-10 years). The secondary outcome was conversion to AD dementia. Baseline biomarkers were used in linear regression models to predict rates of longitudinal cognitive change (calculated separately). Models were adjusted for age, sex, years of education, apolipoprotein E ε4 allele status, and baseline cognition. Multivariable models were compared based on model R2 coefficients and corrected Akaike information criterion.Among 171 Aβ-positive CU participants included in the main analyses, 119 (mean [SD] age, 73.0 [5.4] years; 60.5% female) were from the BioFINDER-1 study, and 52 (mean [SD] age, 64.4 [4.6] years; 65.4% female) were from the WRAP study. In the BioFINDER-1 cohort, plasma P-tau217 was the best marker to predict cognitive decline in the mPACC (model R2 = 0.41) and the MMSE (model R2 = 0.34) and was superior to the covariates-only models (mPACC: R2 = 0.23; MMSE: R2 = 0.04; P < .001 for both comparisons). Results were validated in the WRAP cohort; for example, plasma P-tau217 was associated with mPACC slopes (R2 = 0.13 vs 0.01 in the covariates-only model; P = .01) and MMSE slopes (R2 = 0.29 vs 0.24 in the covariates-only model; P = .046). Sparse models were identified with plasma P-tau217 as a predictor of cognitive decline. Power calculations for enrichment in hypothetical clinical trials revealed large relative reductions in sample sizes when using plasma P-tau217 to enrich for CU individuals likely to experience cognitive decline over time.In this study, plasma P-tau217 predicted cognitive decline in patients with preclinical AD. These findings suggest that plasma P-tau217 may be used as a complement to CSF or PET for participant selection in clinical trials of novel disease-modifying treatments.

  View details for DOI 10.1001/jamaneurol.2022.5272

  View details for Web of Science ID 000937076100002

  View details for PubMedID 36745413

  View details for PubMedCentralID PMC10087054

• Age at natural menopause impacts cerebrovascular reactivity and brain structure AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Moir, M., Corkery, A. T., Senese, K. A., Miller, K. B., Pearson, A. G., Loggie, N. A., Howery, A. J., Gaynor-Metzinger, S. A., Cody, K. A., Eisenmenger, L. B., Johnson, S. C., Barnes, J. N. 2023; 324 (2): R207-R215

  Abstract

  Menopause is associated with adverse changes in vascular health coinciding with an increased risk of stroke and vascular cognitive impairment. However, there is significant variation in the age at menopause. The present study examined how the age at natural menopause impacts cerebrovascular reactivity and structural biomarkers of brain aging. Thirty-five healthy postmenopausal women were classified as early-onset menopause (Early; n = 19, age at menopause: 47 ± 2 yr) or later-onset menopause (Late; n = 16, age at menopause: 55 ± 2 yr). Middle cerebral artery blood velocity (MCAv), mean arterial blood pressure (MAP), and end-tidal carbon dioxide (ETCO2) were recorded during a stepped hypercapnia protocol. Reactivity was calculated as the slope of the relationship between ETCO2 and each variable of interest. Brain volumes and white matter hyperintensities (WMHs) were obtained with 3T MRI. Resting MAP was greater in the Early group (99 ± 9 mmHg) compared with the Late group (90 ± 12 mmHg; P = 0.02). Cerebrovascular reactivity, assessed using MCAv, was blunted in the Early group (1.87 ± 0.92 cm/s/mmHg) compared with the Late group (2.37 ± 0.75 cm/s/mmHg; P = 0.02). Total brain volume did not differ between groups (Early: 1.08 ± 0.07 L vs. Late: 1.07 ± 0.06 L; P = 0.66), but the Early group demonstrated greater WMH fraction compared with the Late group (Early: 0.36 ± 0.14% vs. Late: 0.25 ± 0.14%; P = 0.02). These results suggest that age at natural menopause impacts cerebrovascular function and WMH burden in healthy postmenopausal women.

  View details for DOI 10.1152/ajpregu.00228.2022

  View details for Web of Science ID 000972747500007

  View details for PubMedID 36622085

  View details for PubMedCentralID PMC9886341

• Optimal combinations of CSF biomarkers for predicting cognitive decline and clinical conversion in cognitively unimpaired participants and mild cognitive impairment patients: A multi-cohort study ALZHEIMERS & DEMENTIA Salvado, G., Larsson, V., Cody, K. A., Cullen, N. C., Jonaitis, E. M., Stomrud, E., Kollmorgen, G., Wild, N., Palmqvist, S., Janelidze, S., Mattsson-Carlgren, N., Zetterberg, H., Blennow, K., Johnson, S. C., Ossenkoppele, R., Hansson, O. 2023; 19 (7): 2943-2955

  Abstract

  Our objective was determining the optimal combinations of cerebrospinal fluid (CSF) biomarkers for predicting disease progression in Alzheimer's disease (AD) and other neurodegenerative diseases.We included 1,983 participants from three different cohorts with longitudinal cognitive and clinical data, and baseline CSF levels of Aβ42, Aβ40, phosphorylated tau at threonine-181 (p-tau), neurofilament light (NfL), neurogranin, α-synuclein, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), glial fibrillary acidic protein (GFAP), YKL-40, S100b, and interleukin 6 (IL-6) (Elecsys NeuroToolKit).Change of modified Preclinical Alzheimer's Cognitive Composite (mPACC) in cognitively unimpaired (CU) was best predicted by p-tau/Aβ42 alone (R2 ≥ 0.31) or together with NfL (R2  = 0.25), while p-tau/Aβ42 (R2 ≥ 0.19) was sufficient to accurately predict change of the Mini-Mental State Examination (MMSE) in mild cognitive impairment (MCI) patients. P-tau/Aβ42 (AUC ≥ 0.87) and p-tau/Aβ42 together with NfL (AUC ≥ 0.75) were the best predictors of conversion to AD and all-cause dementia, respectively.P-tau/Aβ42 is sufficient for predicting progression in AD, with very high accuracy. Adding NfL improves the prediction of all-cause dementia conversion and cognitive decline.

  View details for DOI 10.1002/alz.12907

  View details for Web of Science ID 000917893900001

  View details for PubMedID 36648169

  View details for PubMedCentralID PMC10350470

• Harnessing cognitive trajectory clusterings to examine subclinical decline risk factors. Brain communications Du, L., Hermann, B. P., Jonaitis, E. M., Cody, K. A., Rivera-Rivera, L., Rowley, H., Field, A., Eisenmenger, L., Christian, B. T., Betthauser, T. J., Larget, B., Chappell, R., Janelidze, S., Hansson, O., Johnson, S. C., Langhough, R. 2023; 5 (6): fcad333

  Abstract

  Cognitive decline in Alzheimer's disease and other dementias typically begins long before clinical impairment. Identifying people experiencing subclinical decline may facilitate earlier intervention. This study developed cognitive trajectory clusters using longitudinally based random slope and change point parameter estimates from a Preclinical Alzheimer's disease Cognitive Composite and examined how baseline and most recently available clinical/health-related characteristics, cognitive statuses and biomarkers for Alzheimer's disease and vascular disease varied across these cognitive clusters. Data were drawn from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal cohort study of adults from late midlife, enriched for a parental history of Alzheimer's disease and without dementia at baseline. Participants who were cognitively unimpaired at the baseline visit with ≥3 cognitive visits were included in trajectory modelling (n = 1068). The following biomarker data were available for subsets: positron emission tomography amyloid (amyloid: n = 367; [11C]Pittsburgh compound B (PiB): global PiB distribution volume ratio); positron emission tomography tau (tau: n = 321; [18F]MK-6240: primary regions of interest meta-temporal composite); MRI neurodegeneration (neurodegeneration: n = 581; hippocampal volume and global brain atrophy); T2 fluid-attenuated inversion recovery MRI white matter ischaemic lesion volumes (vascular: white matter hyperintensities; n = 419); and plasma pTau217 (n = 165). Posterior median estimate person-level change points, slopes' pre- and post-change point and estimated outcome (intercepts) at change point for cognitive composite were extracted from Bayesian Bent-Line Regression modelling and used to characterize cognitive trajectory groups (K-means clustering). A common method was used to identify amyloid/tau/neurodegeneration/vascular biomarker thresholds. We compared demographics, last visit cognitive status, health-related factors and amyloid/tau/neurodegeneration/vascular biomarkers across the cognitive groups using ANOVA, Kruskal-Wallis, chi2, and Fisher's exact tests. Mean (standard deviation) baseline and last cognitive assessment ages were 58.4 (6.4) and 66.6 (6.6) years, respectively. Cluster analysis identified three cognitive trajectory groups representing steep, n = 77 (7.2%); intermediate, n = 446 (41.8%); and minimal, n = 545 (51.0%) cognitive decline. The steep decline group was older, had more females, APOE e4 carriers and mild cognitive impairment/dementia at last visit; it also showed worse self-reported general health-related and vascular risk factors and higher amyloid, tau, neurodegeneration and white matter hyperintensity positive proportions at last visit. Subtle cognitive decline was consistently evident in the steep decline group and was associated with generally worse health. In addition, cognitive trajectory groups differed on aetiology-informative biomarkers and risk factors, suggesting an intimate link between preclinical cognitive patterns and amyloid/tau/neurodegeneration/vascular biomarker differences in late middle-aged adults. The result explains some of the heterogeneity in cognitive performance within cognitively unimpaired late middle-aged adults.

  View details for DOI 10.1093/braincomms/fcad333

  View details for PubMedID 38107504

• Differential roles of A beta 42/40, p-tau231 and p-tau217 for Alzheimer's trial selection and disease monitoring NATURE MEDICINE Ashton, N. J., Janelidze, S., Mattsson-Carlgren, N., Binette, A., Strandberg, O., Brum, W. S., Karikari, T. K., Gonzalez-Ortiz, F., Di Molfetta, G., Meda, F. J., Jonaitis, E. M., Koscik, R., Cody, K., Betthauser, T. J., Li, Y., Vanmechelen, E., Palmqvist, S., Stomrud, E., Bateman, R. J., Zetterberg, H., Johnson, S. C., Blennow, K., Hansson, O. 2022; 28 (12): 2555-+

  Abstract

  Blood biomarkers indicative of Alzheimer's disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio were more changed at lower thresholds of amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent changes over 4-6 years in both preclinical and symptomatic stages of the disease, with no such changes observed in p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein or neurofilament light. Only longitudinal increases of p-tau217 were also associated with clinical deterioration and brain atrophy in preclinical AD. The selective longitudinal increase of p-tau217 and its associations with cognitive decline and atrophy was confirmed in an independent cohort (Wisconsin Registry for Alzheimer's Prevention). These findings support the differential association of plasma biomarkers with disease development and strongly highlight p-tau217 as a surrogate marker of disease progression in preclinical and prodromal AD, with impact for the development of new disease-modifying treatments.

  View details for DOI 10.1038/s41591-022-02074-w

  View details for Web of Science ID 000925199900006

  View details for PubMedID 36456833

  View details for PubMedCentralID PMC9800279

• Sympathoexcitatory Responses to Isometric Handgrip Exercise Are Associated With White Matter Hyperintensities in Middle-Aged and Older Adults FRONTIERS IN AGING NEUROSCIENCE Pearson, A. G., Miller, K. B., Corkery, A. T., Eisenmann, N. A., Howery, A. J., Cody, K. A., Chin, N. A., Johnson, S. C., Barnes, J. N. 2022; 14: 888470

  Abstract

  Vascular dysfunction may occur prior to declines in cognitive function and accumulation of neuropathology. White matter hyperintensities (WMH) develop due to cerebral ischemia and elevated blood pressure in midlife. The purpose of this study was to evaluate associations between cardiovascular and cerebrovascular responses to sympathoexcitatory stimuli and WMH burden in cognitively unimpaired middle-aged and older adults. Sixty-eight adults (age = 63 ± 4y, men = 20, women = 48) participated in this study. Participants completed isometric handgrip exercise (IHG) exercise at 40% of maximal voluntary contraction until fatigue followed by a 90s period of post-exercise ischemia. Heart rate (HR), mean arterial pressure (MAP), middle cerebral artery blood velocity (MCAv), and end-tidal CO2 were continuously measured throughout the protocol. Cerebrovascular resistance index (CVRi) was calculated as MAP/MCAv. WMH lesion volume and intracranial volume (ICV) were measured using a FLAIR and T1 scan on a 3T MRI scanner, respectively. WMH fraction was calculated as (WMH lesion volume/ICV)*100 and cubic root transformed. Multiple linear regressions were used to determine the association between cardiovascular and cerebrovascular responses to IHG exercise and post-exercise ischemia and WMH fraction. Multiple linear regression models were adjusted for age, sex, apolipoprotein ε4 status, and total work performed during IHG exercise. During IHG exercise, there were significant increases from baseline in HR (25 ± 12%), MAP (27 ± 11%), MCAv (5 ± 10%), and CVRi (22 ± 17%; P < 0.001 for all). During post-exercise ischemia, HR (8 ± 7%), MAP (22 ± 9%), and CVRi (23 ± 16%) remained elevated (P < 0.001) while MCAv (0 ± 10%) was not different compared to baseline. There was an inverse association between the percent change in HR (r = -0.42, P = 0.002), MAP (r = -0.41, P = 0.002), and CVRi (r = -0.31, P = 0.045), but not MCAv (r = 0.19, P = 0.971) in response to IHG exercise and WMH fraction. There were no associations between responses to post-exercise ischemia and WMH fraction. Lower sympathoexcitatory responses to IHG exercise are associated with greater WMH burden in middle-aged to older adults. These findings suggest that individuals who demonstrate smaller increases in HR, MAP, and CVRi in response to sympathoexcitatory stress have greater WMH burden.

  View details for DOI 10.3389/fnagi.2022.888470

  View details for Web of Science ID 000832694400001

  View details for PubMedID 35898329

  View details for PubMedCentralID PMC9309556

• Trajectory of clinical symptoms in relation to amyloid chronicity ALZHEIMER'S & DEMENTIA: DIAGNOSIS, ASSESSMENT & DISEASE MONITORING Birdsill, A. C., Koscik, R. L., Cody, K. A., Jonaitis, E. M., Cadman, R. V., Erickson, C. M., Chin, N. A., Przybelski, R. J., Carlsson, C. M., Asthana, S., Christian, B. T., Eisenmenger, L. B., Betthauser, T. J., Johnson, S. C. 2022; 14 (1): e12360

  Abstract

  While it is generally appreciated that amyloid precedes symptomatic Alzheimer's disease (AD) by decades, a greater understanding of this timeline may increase prognostic accuracy, planning, and care of persons who are on the AD continuum.We examined trajectories of Clinical Dementia Rating-Sum of Boxes (CDR-SB) relative to estimated years of amyloid positivity (A+) in n = 123 participants who were all A+ based on [C-11]Pittsburgh compound B positron emission tomography.The average amyloid chronicity at CDR-SB of 2.5 was 20.1 years. The average trajectory of CDR-SB accelerated after 10 years of elevated amyloid and varied greatly between 10 and 30 years. Exploratory analyses suggested that older age and higher volume of white matter hyperintensities shortened the interval between amyloid onset and cognitive impairment.The recontextualization of amyloid burden into the time domain will facilitate studies of disease progression, the influence of co-pathology, and factors that hasten or slow cognitive impairment.

  View details for DOI 10.1002/dad2.12360

  View details for Web of Science ID 000914865700099

  View details for PubMedID 36187195

  View details for PubMedCentralID PMC9489232

• Associations of the Lifestyle for Brain Health index with longitudinal cognition and brain amyloid beta in clinically unimpaired older adults: Findings from the Wisconsin Registry for Alzheimer's Prevention ALZHEIMER'S & DEMENTIA: DIAGNOSIS, ASSESSMENT & DISEASE MONITORING Cody, K. A., Koscik, R. L., Erickson, C. M., Berman, S. E., Jonaitis, E. M., Williams, V. J., Mueller, K. D., Christian, B. T., Chin, N. A., Clark, L. R., Betthauser, T. J., Johnson, S. C. 2022; 14 (1): e12351

  Abstract

  Modifiable health and lifestyle factors increase risk of dementia, but whether modifiable factors, when measured in late-midlife, impact the emergence or progression of Alzheimer's disease (AD) pathophysiologic or cognitive changes remains unresolved.In initially cognitively unimpaired, late middle-aged participants (N = 1215; baseline age, M [standard deviation] = 59.3 [6.7] years) from the Wisconsin Registry for Alzheimer's Prevention (WRAP), we investigated the influence of the Lifestyle for Brain Health (LIBRA) index, a lifestyle-based dementia risk score, on AD-related cognitive trajectories and amyloid beta (Aβ) plaque accumulation.Overall, lower baseline LIBRA, denoting healthier lifestyle and lower dementia risk, was related to better overall cognitive performance, but did not moderate apolipoprotein E ε4 or Aβ-related longitudinal cognitive trajectories. LIBRA was not significantly associated with Aβ accumulation or estimated age of Aβ onset.In WRAP, late-midlife LIBRA scores were related to overall cognitive performance, but not AD-related cognitive decline or Aβ accumulation in the preclinical timeframe.The Lifestyle for Brain Health (LIBRA) index was associated with cognitive performance in late-midlife.LIBRA did not moderate apolipoprotein E ε4 or amyloid-related cognitive decline.LIBRA was not associated with the onset or accumulation of amyloid plaques.

  View details for DOI 10.1002/dad2.12351

  View details for Web of Science ID 000914865700088

  View details for PubMedID 36110432

  View details for PubMedCentralID PMC9464997

• White matter microstructure associations to amyloid burden in adults with Down syndrome NEUROIMAGE-CLINICAL Bazydlo, A. M., Zammit, M. D., Wu, M., Lao, P. J., Dean, D. C., Johnson, S. C., Tudorascu, D. L., Cohen, A., Cody, K. A., Ances, B., Laymon, C. M., Klunk, W. E., Zaman, S., Handen, B. L., Hartley, S. L., Alexander, A. L., Christian, B. T. 2022; 33: 102908

  Abstract

  Individuals with Down syndrome (DS) are at an increased risk of developing Alzheimer's Disease (AD). One of the early underlying mechanisms in AD pathology is the accumulation of amyloid protein plaques, which are deposited in extracellular gray matter and signify the first stage in the cascade of neurodegenerative events. AD-related neurodegeneration is also evidenced as microstructural changes in white matter. In this work, we explored the correlation of white matter microstructure with amyloid load to assess amyloid-related neurodegeneration in a cohort of adults with DS.In this study of 96 adults with DS, the relation of white matter microstructure using diffusion tensor imaging (DTI) and amyloid plaque burden using [11C]PiB PET were examined. The amyloid load (AβL) derived from [11C]PiB was used as a global measure of amyloid burden. AβL and DTI measures were compared using tract-based spatial statistics (TBSS) and corrected for imaging site and chronological age.TBSS of the DTI maps showed widespread age-by-amyloid interaction with both fractional anisotropy (FA) and mean diffusivity (MD). Further, diffuse negative association of FA and positive association of MD with amyloid were observed.These findings are consistent with the white matter microstructural changes associated with AD disease progression in late onset AD in non-DS populations.

  View details for DOI 10.1016/j.nicl.2021.102908

  View details for Web of Science ID 000731343200001

  View details for PubMedID 34902714

  View details for PubMedCentralID PMC8672096

• White matter microstructure associations with episodic memory in adults with Down syndrome: a tract-based spatial statistics study JOURNAL OF NEURODEVELOPMENTAL DISORDERS Bazydlo, A., Zammit, M., Wu, M., Dean, D., Johnson, S., Tudorascu, D., Cohen, A., Cody, K., Ances, B., Laymon, C., Klunk, W., Zaman, S., Handen, B., Alexander, A., Christian, B., Hartley, S. 2021; 13 (1): 17

  Abstract

  Nearly all persons with Down syndrome will show pathology of Alzheimer's disease in their 40s. There is a critical need for studies to identify early biomarkers of these various pathological changes of Alzheimer's disease in the Down syndrome population and understand the relationship of these biomarkers to cognitive symptoms in order to inform clinical trials. Although Alzheimer's disease is often considered a disease of gray matter, white matter degeneration has been documented during the preclinical stage of Alzheimer's disease. The current study examined the association between diffusion tensor imaging (DTI) measures of white matter microstructure and episodic memory performance in 52 adults with Down syndrome.Seventy (N = 70) participants (M = 40.13, SD = 7.77 years) received baseline scans as part of the Neurodegeneration in Aging Down Syndrome (NiAD) study at two imaging facilities (36 at the University of Wisconsin-Madison [UW-Madison] and 34 at the University of Pittsburgh Medical Center [UPMC]). All participants had genetically confirmed trisomy 21. Fifty-two (N = 52) participants remained after QC. The DTI measures, fractional anisotropy (FA) and mean diffusivity (MD), were calculated for each participant. A combined measure of episodic memory was generated by summing the z-scores of (1) Free and Cued Recall test and (2) Rivermead Behavioural Memory Test for Children Picture Recognition. The DTI data were projected onto a population-derived FA skeleton and tract-based spatial statistics analysis was conducted using the FSL tool PALM to calculate Pearson's r values between FA and MD with episodic memory.A positive correlation of episodic memory with FA and a negative correlation of episodic memory and MD in the major association white matter tracts were observed. Results were significant (p < 0.05) after correction for chronological age, imaging site, and premorbid cognitive ability.These findings suggest that white matter degeneration may be implicated in early episodic memory declines prior to the onset of dementia in adults with Down syndrome. Further, our findings suggest a coupling of episodic memory and white matter microstructure independent of chronological age.

  View details for DOI 10.1186/s11689-021-09366-1

  View details for Web of Science ID 000641796500001

  View details for PubMedID 33879062

  View details for PubMedCentralID PMC8059162

• Prescription Medications and Co-Morbidities in Late Middle-Age are Associated with Greater Cognitive Declines: Results from WRAP. Frontiers in aging Du, L., Koscik, R. L., Chin, N. A., Bratzke, L. C., Cody, K., Erickson, C. M., Jonaitis, E., Mueller, K. D., Hermann, B. P., Johnson, S. C. 2021; 2: 759695

  Abstract

  The present study investigated: 1) sex differences in polypharmacy, comorbidities, self-rated current health (SRH), and cognitive performance, 2) associations between comorbidities, polypharmacy, SRH, and objective measures of health, and 3) associations of these factors with longitudinal cognitive performance. Analyses included 1039 eligible Wisconsin Registry for Alzheimer's Prevention (WRAP) participants who were cognitively unimpaired at baseline and had ≥2 visits with cognitive composites, self-reported health history, and concurrent medication records. Repeated measures correlation (rmcorr) examined the associations between medications, co-morbidities, SRH, and objective measures of health (including LIfestyle for BRAin Health Index (LIBRA), and depression). Linear mixed-effect models examined associations between medications, co-morbidities, and cognitive change over time using a preclinical Alzheimer's cognitive composite (PACC3) and cognitive domain z-scores (executive function, working memory, immediate learning, and delayed recall). In secondary analyses, we also examined whether the number of medications interacted with co-morbidities and whether they modified age-related cognitive trajectories. The number of prescribed medications was associated with worse SRH and a higher number of self-reported co-morbidities. More prescribed medications were associated with a faster decline in executive function, and more comorbidities were associated with faster PACC3 decline. Those with a non-elevated number of co-morbidities and medications performed an average of 0.26 SD higher (better) in executive function and an average of 0.18 SD higher on PACC3 than those elevated on both. Associations between medications, co-morbidities, and executive function, and PACC3 suggest that persons with more co-morbidities and medications may be at increased risk of reaching clinical levels of impairment earlier than healthier, less medicated peers.

  View details for DOI 10.3389/fragi.2021.759695

  View details for PubMedID 35822000

• Cerebrovascular stiffness and flow dynamics in the presence of amyloid and tau biomarkers ALZHEIMER'S & DEMENTIA: DIAGNOSIS, ASSESSMENT & DISEASE MONITORING Rivera-Rivera, L. A., Eisenmenger, L., Cody, K. A., Reher, T., Betthauser, T., Cadman, R., Rowley, H. A., Carlsson, C. M., Chin, N. A., Johnson, S. C., Johnson, K. M. 2021; 13 (1): e12253

  Abstract

  This work investigated the relationship between cerebrovascular disease (CVD) markers and Alzheimer's disease (AD) biomarkers of amyloid beta deposition, and neurofibrillary tau tangles in subjects spanning the AD clinical spectrum.A total of 136 subjects participated in this study. Four groups were established based on AD biomarker positivity from positron emission tomography (amyloid [A] and tau [T]) and clinical diagnosis (cognitively normal [CN] and impaired [IM]). CVD markers were derived from structural and quantitative magnetic resonance imaging data.Transcapillary pulse wave delay was significantly longer in controls compared to AT biomarker-confirmed groups (A+/T-/CN P < .001, A+/T+/CN P < .001, A+/T+/IM P = .003). Intracranial low-frequency oscillations were diminished in AT biomarker-confirmed groups both CN and impaired (A+/T-/CN P = .039, A+/T+/CN P = .007, A+/T+/IM P = .011). A significantly higher presence of microhemorrhages was measured in A+/T+/CN compared to controls (P = .006).Cerebrovascular markers indicate increased vessel stiffness and reduced vasomotion in AT biomarker-positive subjects during preclinical AD.

  View details for DOI 10.1002/dad2.12253

  View details for Web of Science ID 000736650000001

  View details for PubMedID 35005194

  View details for PubMedCentralID PMC8719432

• Association of sleep with cognition and beta amyloid accumulation in adults with Down syndrome NEUROBIOLOGY OF AGING Cody, K. A., Piro-Gambetti, B., Zammit, M. D., Christian, B. T., Handen, B. L., Klunk, W. E., Zaman, S., Johnson, S. C., Plante, D. T., Hartley, S. L. 2020; 93: 44-51

  Abstract

  Adults with Down syndrome have an increased risk for both disordered sleep and Alzheimer's disease (AD). In the general population, disrupted sleep has been linked to beta amyloid accumulation, an early pathophysiologic feature of AD. In this study, the association among sleep, beta amyloid, and measures of AD-related cognitive decline was examined in 47 non-demented adults with Down syndrome (aged 26-56 years). Sleep was measured using actigraphy over 7 nights. Pittsburgh Compound B positron emission tomography was used to assess global and striatal beta amyloid burden. Participants had the following clinical AD status: 7 (15%) mild cognitive impairment and 40 (85%) cognitively unaffected. Average length of night-time awakenings was significantly positively associated with striatal beta amyloid and decreased cognitive performance in executive functioning and motor planning and coordination. Findings suggest that disrupted sleep is associated with beta amyloid accumulation and cognitive features of preclinical AD in Down syndrome. Early identification and treatment of sleep problems could be a lifestyle intervention that may delay beta amyloid accumulation and cognitive decline in this AD vulnerable group.

  View details for DOI 10.1016/j.neurobiolaging.2020.04.018

  View details for Web of Science ID 000540453200006

  View details for PubMedID 32447011

  View details for PubMedCentralID PMC7380565

• Assessment of vascular stiffness in the internal carotid artery proximal to the carotid canal in Alzheimer's disease using pulse wave velocity from low rank reconstructed 4D flow MRI JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Rivera-Rivera, L. A., Cody, K. A., Eisenmenger, L., Cary, P., Rowley, H. A., Carlsson, C. M., Johnson, S. C., Johnson, K. M. 2021; 41 (2): 298-311

  Abstract

  Clinical evidence shows vascular factors may co-occur and complicate the expression of Alzheimer's disease (AD); yet, the pathologic mechanisms and involvement of different compartments of the vascular network are not well understood. Diseases such as arteriosclerosis diminish vascular compliance and will lead to arterial stiffness, a well-established risk factor for cardiovascular morbidity. Arterial stiffness can be assessed using pulse wave velocity (PWV); however, this is usually done from carotid-to-femoral artery ratios. To probe the brain vasculature, intracranial PWV measures would be ideal. In this study, high temporal resolution 4D flow MRI was used to assess transcranial PWV in 160 subjects including AD, mild cognitive impairment (MCI), healthy controls, and healthy subjects with apolipoprotein ɛ4 positivity (APOE4+) and parental history of AD dementia (FH+). High temporal resolution imaging was achieved by high temporal binning of retrospectively gated data using a local-low rank approach. Significantly higher transcranial PWV in AD dementia and MCI subjects was found when compared to old-age-matched controls (AD vs. old-age-matched controls: P <0.001, AD vs. MCI: P = 0.029, MCI vs. old-age-matched controls P = 0.013). Furthermore, vascular changes were found in clinically healthy middle-age adults with APOE4+ and FH+ indicating significantly higher transcranial PWV compared to controls (P <0.001).

  View details for DOI 10.1177/0271678X20910302

  View details for Web of Science ID 000523834200001

  View details for PubMedID 32169012

  View details for PubMedCentralID PMC8370001

• Amyloid accumulation in Down syndrome measured with amyloid load ALZHEIMER'S & DEMENTIA: DIAGNOSIS, ASSESSMENT & DISEASE MONITORING Zammit, M. D., Laymon, C. M., Betthauser, T. J., Cody, K. A., Tudorascu, D. L., Minhas, D. S., Sabbagh, M. N., Johnson, S. C., Zaman, S. H., Mathis, C. A., Klunk, W. E., Handen, B. L., Cohen, A. D., Christian, B. T. 2020; 12 (1): e12020

  Abstract

  Individuals with Down syndrome (DS) show enhanced amyloid beta (Aβ) deposition in the brain. A new positron emission tomography (PET) index of amyloid load (AβL ) was recently developed as an alternative to standardized uptake value ratios (SUVrs) to quantify Aβ burden with high sensitivity for detecting and tracking Aβ change.1.AβL was calculated in a DS cohort (N = 169, mean age ± SD = 39.6 ± 8.7 years) using [C-11]Pittsburgh compound B (PiB) PET imaging. DS-specific PiB templates were created for Aβ carrying capacity (K) and non-specific binding (NS).The highest values of Aβ carrying capacity were found in the striatum and precuneus. Longitudinal changes in AβL displayed less variability when compared to SUVrs.These results highlight the utility of AβL for characterizing Aβ deposition in DS. Rates of Aβ accumulation in DS were found to be similar to that observed in late-onset Alzheimer's disease (AD; ≈3% to 4% per year), suggesting that AD progression in DS is of earlier onset but not accelerated.

  View details for DOI 10.1002/dad2.12020

  View details for Web of Science ID 000707203600020

  View details for PubMedID 32435686

  View details for PubMedCentralID PMC7233422

• Intracranial vascular flow oscillations in Alzheimer's disease from 4D flow MRI NEUROIMAGE-CLINICAL Rivera-Rivera, L. A., Cody, K. A., Rutkowski, D., Cary, P., Eisenmenger, L., Rowley, H. A., Carlsson, C. M., Johnson, S. C., Johnson, K. M. 2020; 28: 102379

  Abstract

  Recent modeling and experimental evidence suggests clearance of soluble metabolites from the brain can be driven by low frequency flow oscillations (LFOs) through the intramural periarterial drainage (IPAD) pathway. This study investigates the use of 4D flow MRI to derive LFOs from arterial and venous measures of blood flow. 3D radial 4D flow MRI data were acquired on a 3.0 T scanner and reconstructed using a low-rank constraint to produce time resolved measurements of blood flow. Physical phantom experiments were performed to validate the time resolved 4D flow against a standard 2D phase contrast (PC) approach. To evaluate the ability of 4D flow to distinguish physiologic flow changes from noise, healthy volunteers were scanned during a breath-hold (BH) maneuver and compared against 2D PC measures. Finally, flow measures were performed in intracranial arteries and veins of 112 participants including subjects diagnosed with Alzheimer's disease (AD) clinical syndrome (n = 23), and healthy controls (n = 89) on whom apolipoprotein ɛ4 positivity (APOE4+) and parental history of AD dementia (FH+) was known. To assess LFOs, flow range, standard deviation, demeaned temporal flow changes, and power spectral density were quantified from the time series. Group differences were assessed using ANOVA followed by Tukey-Kramer method for pairwise comparison for adjusted means (P < 0.05). Significantly lower LFOs as measured from flow variation range and standard deviations were observed in the arteries of AD subjects when compared to age-matched controls (P = 0.005, P = 0.011). Results suggest altered vascular function in AD subjects. 4D flow based spontaneous LFO measures might hold potential for longitudinal studies aimed at predicting cognitive trajectories in AD and study disease mechanisms.

  View details for DOI 10.1016/j.nicl.2020.102379

  View details for Web of Science ID 000600619100022

  View details for PubMedID 32871386

  View details for PubMedCentralID PMC7476069

• Amyloid duration is associated with preclinical cognitive decline and tau PET ALZHEIMER'S & DEMENTIA: DIAGNOSIS, ASSESSMENT & DISEASE MONITORING Koscik, R. L., Betthauser, T. J., Jonaitis, E. M., Allison, S. L., Clark, L. R., Hermann, B. P., Cody, K. A., Engle, J. W., Barnhart, T. E., Stone, C. K., Chin, N. A., Carlsson, C. M., Asthana, S., Christian, B. T., Johnson, S. C. 2020; 12 (1): e12007

  Abstract

  This study applies a novel algorithm to longitudinal amyloid positron emission tomography (PET) imaging to identify age-heterogeneous amyloid trajectory groups, estimate the age and duration (chronicity) of amyloid positivity, and investigate chronicity in relation to cognitive decline and tau burden.Cognitively unimpaired participants (n = 257) underwent one to four amyloid PET scans (Pittsburgh Compound B, PiB). Group-based trajectory modeling was applied to participants with longitudinal scans (n = 171) to identify and model amyloid trajectory groups, which were combined with Bayes theorem to estimate age and chronicity of amyloid positivity. Relationships between chronicity, cognition, clinical progression, and tau PET (MK-6240) were investigated using regression models.Chronicity explained more heterogeneity in amyloid burden than age and binary amyloid status. Chronicity was associated with faster cognitive decline, increased risk of abnormal cognition, and higher entorhinal tau.Amyloid chronicity provides unique information about cognitive decline and neurofibrillary tangle development and may be useful to investigate preclinical Alzheimer's disease.

  View details for DOI 10.1002/dad2.12007

  View details for Web of Science ID 000707203600008

  View details for PubMedID 32211502

  View details for PubMedCentralID PMC7085284

• Amyloid and tau imaging biomarkers explain cognitive decline from late middle-age BRAIN Betthauser, T. J., Koscik, R. L., Jonaitis, E. M., Allison, S. L., Cody, K. A., Erickson, C. M., Rowley, H. A., Stone, C. K., Mueller, K. D., Clark, L. R., Carlsson, C. M., Chin, N. A., Asthana, S., Christian, B. T., Johnson, S. C. 2020; 143: 320-335

  Abstract

  This study investigated differences in retrospective cognitive trajectories between amyloid and tau PET biomarker stratified groups in initially cognitively unimpaired participants sampled from the Wisconsin Registry for Alzheimer's Prevention. One hundred and sixty-seven initially unimpaired individuals (baseline age 59 ± 6 years; 115 females) were stratified by elevated amyloid-β and tau status based on 11C-Pittsburgh compound B (PiB) and 18F-MK-6240 PET imaging. Mixed effects models were used to determine if longitudinal cognitive trajectories based on a composite of cognitive tests including memory and executive function differed between biomarker groups. Secondary analyses investigated group differences for a variety of cross-sectional health and cognitive tests, and associations between 18F-MK-6240, 11C-PiB, and age. A significant group × age interaction was observed with post hoc comparisons indicating that the group with both elevated amyloid and tau pathophysiology were declining approximately three times faster in retrospective cognition compared to those with just one or no elevated biomarkers. This result was robust against various thresholds and medial temporal lobe regions defining elevated tau. Participants were relatively healthy and mostly did not differ between biomarker groups in health factors at the beginning or end of study, or most cognitive measures at study entry. Analyses investigating association between age, MK-6240 and PiB indicated weak associations between age and 18F-MK-6240 in tangle-associated regions, which were negligible after adjusting for 11C-PiB. Strong associations, particularly in entorhinal cortex, hippocampus and amygdala, were observed between 18F-MK-6240 and global 11C-PiB in regions associated with Braak neurofibrillary tangle stages I-VI. These results suggest that the combination of pathological amyloid and tau is detrimental to cognitive decline in preclinical Alzheimer's disease during late middle-age. Within the Alzheimer's disease continuum, middle-age health factors likely do not greatly influence preclinical cognitive decline. Future studies in a larger preclinical sample are needed to determine if and to what extent individual contributions of amyloid and tau affect cognitive decline. 18F-MK-6240 shows promise as a sensitive biomarker for detecting neurofibrillary tangles in preclinical Alzheimer's disease.

  View details for DOI 10.1093/brain/awz378

  View details for Web of Science ID 000522638800032

  View details for PubMedID 31886494

  View details for PubMedCentralID PMC6935717

• Leisure Activity, Brain beta-amyloid, and Episodic Memory in Adults with Down Syndrome DEVELOPMENTAL NEUROBIOLOGY Mihaila, I., Handen, B. L., Christian, B. T., Lao, P. J., Cody, K. A., Klunk, W. E., Tudorascu, D. L., Cohen, A. D., Okonkwo, O. C., Hartley, S. L. 2019; 79 (7): 738-749

  Abstract

  The present study provided an investigation of associations between leisure activity and early Alzheimer's disease neuropathology (i.e., brain β-amyloid) and episodic memory in a sample of 65 adults with Down syndrome (aged 30-53 years), at baseline and follow-up, approximately three years apart. Findings indicated that leisure activity at baseline was not associated with brain β-amyloid at baseline or change in brain β-amyloid from baseline to follow-up. Greater cognitively stimulating leisure activity at baseline was associated with better episodic memory at baseline, and greater social leisure activity at baseline was associated with less decline in episodic memory from baseline to follow-up. High (as opposed to low) levels of social and overall leisure activity at baseline moderated the association between increase in brain β-amyloid and decline in episodic memory, from baseline to follow-up. Findings suggest that cognitively stimulating and social leisure activity could protect against the effect of Alzheimer's disease neuropathology on episodic memory in adults with Down syndrome.

  View details for DOI 10.1002/dneu.22677

  View details for Web of Science ID 000487144700011

  View details for PubMedID 30912871

  View details for PubMedCentralID PMC7063586

• Amyloid Load in the Down syndrome population measured with [C-11]PiB PET Zammit, M., Laymon, C., Cody, K., Cohen, A., Tudorascu, D., Johnson, S., Betthauser, T., Barnhart, T., Murali, D., Stone, C., Minhas, D., Klunk, W., Handen, B., Christian, B. SOC NUCLEAR MEDICINE INC. 2019

  View details for Web of Science ID 000473116800250

• Imaging neurodegeneration in Down syndrome: brain templates for amyloid burden and tissue segmentation Lao, P. J., Handen, B. L., Betthauser, T. J., Cody, K. A., Cohen, A. D., Tudorascu, D. L., Stone, C. K., Price, J. C., Johnson, S. C., Klunk, W. E., Christian, B. T. SPRINGER. 2019: 345-353

  Abstract

  The focus of Alzheimer's disease (AD) neuroimaging research has shifted towards an investigation of the earliest stages of AD pathogenesis, which manifests in every young adult with Down syndrome (DS; trisomy 21) resulting from a deterministic genetic predisposition to amyloid precursor protein overproduction. Due to morphological differences in brain structure in the DS population, special consideration must be given to processing pipelines and the use of normative atlases developed for the non-DS population. Further, the use of typical MRI to MRI template spatial normalization is less desirable in this cohort due to a greater presence of motion artefacts in MRI images. The diffuse nature of PiB uptake and comparatively lower spatial resolution of the PET image permits the purposing of this modality as a template for spatial normalization, which can substantially improve the robustness of this procedure in the cases of MRI images with motion. The aim of this work was to establish standardized methods for spatial normalization and tissue type segmentation using DS specific templates in order to perform voxel-wise analyses. A total of 72 adults with DS underwent [11C]PiB PET to assess brain amyloid burden and volumetric MRI imaging. A DS specific PiB template for spatial normalization and a set of DS specific prior probability templates were created with two-pass methods. With implementation of this DS specific PiB template, no participants were excluded due to poor spatial normalization, thus maximizing the sample size for PiB analyses in standardized space. In addition, difference images between prior probability templates created from the general population and the DS population reflected known morphological differences, particularly in the frontal cortex. In conclusion, DS specific templates that account for unique challenges improve spatial normalization and tissue type segmentation, and provide a framework for reliable voxel-wise analysis of AD biomarkers in this atypical population.

  View details for DOI 10.1007/s11682-018-9888-y

  View details for Web of Science ID 000466183200006

  View details for PubMedID 29752653

  View details for PubMedCentralID PMC6230506

• In Vivo Characterization and Quantification of Neurofibrillary Tau PET Radioligand F-18-MK-6240 in Humans from Alzheimer Disease Dementia to Young Controls JOURNAL OF NUCLEAR MEDICINE Betthauser, T. J., Cody, K. A., Zammit, M. D., Murali, D., Converse, A. K., Barnhart, T. E., Stone, C. K., Rowley, H. A., Johnson, S. C., Christian, B. T. 2019; 60 (1): 93-99

  Abstract

  Tau PET imaging has potential for elucidating changes in the deposition of neuropathological tau aggregates that are occurring during the progression of Alzheimer disease (AD). This work investigates in vivo kinetics, quantification strategies, and imaging characteristics of a novel tau PET radioligand 18F-MK-6240 in humans. Methods: Fifty-one individuals ranging from cognitively normal young controls to persons with dementia underwent T1-weighted MRI as well as 11C-PiB and 18F-MK-6240 PET imaging. PET data were coregistered to the MRI, and time-activity curves were extracted from regions of interest to assess 18F-MK-6240 kinetics. The pons and inferior cerebellum were investigated as potential reference regions. Reference tissue methods (Logan graphical analysis [LGA] and multilinear reference tissue method [MRTM2]) were investigated for quantification of 18F-MK-6240 distribution volume ratios (DVRs) in a subset of 19 participants. Stability of DVR methods was evaluated using truncated scan durations. SUV ratio (SUVR) estimates were compared with DVR estimates to determine the optimal timing window for SUVR analysis. Parametric SUVR images were used to identify regions of potential off-target binding and to compare binding patterns with neurofibrillary tau staging established in neuropathology literature. Results: SUVs in the pons and the inferior cerebellum indicated consistent clearance across all 51 subjects. LGA and MRTM2 DVR estimates were similar, with LGA slightly underestimating DVR compared with MRTM2. DVR estimates remained stable when truncating the scan duration to 60 min. SUVR determined 70-90 min after injection of 18F-MK-6240 indicated linearity near unity when compared with DVR estimates and minimized potential spill-in from uptake outside the brain. 18F-MK-6240 binding patterns in target regions were consistent with neuropathological neurofibrillary tau staging. Off-target binding regions included the ethmoid sinus, clivus, meninges, substantia nigra, but not the basal ganglia or choroid plexus. Conclusion:18F-MK-6240 is a promising PET radioligand for in vivo imaging of neurofibrillary tau aggregates in AD with minimal off-target binding in the human brain.

  View details for DOI 10.2967/jnumed.118.209650

  View details for Web of Science ID 000454687800020

  View details for PubMedID 29777006

  View details for PubMedCentralID PMC6354223

• [F-18]MK-6240 PET quantification and image feature characterization from controls to Alzheimer's disease Betthauser, T., Cody, K., Zammit, M., DeFilippo, A., Murali, D., Barnhart, T., Stone, C., Rowley, H., Johnson, S., Christian, B. SOC NUCLEAR MEDICINE INC. 2018

  View details for Web of Science ID 000467489900083

• Fitness, Independent Of Physical Activity Is Associated With Cerebral Blood Flow In Older Adults At-risk For Alzheimer's Disease Dougherty, R. J., Boots, E. A., Cody, K. A., Schultz, S. A., Edwards, D. F., Johnson, S. C., Einerson, J., Okonkwo, O. C., Cook, D. B. LIPPINCOTT WILLIAMS & WILKINS. 2017: 824-825

  View details for DOI 10.1249/01.mss.0000519213.54254.e2

  View details for Web of Science ID 000415216000027