Alexandra Nicole Trelle

All Publications

• Plasma Aβ42/Aβ40 is sensitive to early cerebral amyloid accumulation and predicts risk of cognitive decline across the Alzheimer's disease spectrum. Alzheimer's & dementia : the journal of the Alzheimer's Association Trelle, A. N., Young, C. B., Vossler, H., Ramos Benitez, J., Cody, K. A., Mendiola, J. H., Swarovski, M. S., Guen, Y. L., Feinstein, I., Butler, R. R., Channappa, D., Romero, A., Park, J., Shahid-Besanti, M., Corso, N. K., Chau, K., Smith, A. N., Skylar-Scott, I., Yutsis, M. V., Fredericks, C. A., Tian, L., Younes, K., Kerchner, G. A., Deutsch, G. K., Davidzon, G. A., Sha, S. J., Henderson, V. W., Longo, F. M., Greicius, M. D., Wyss-Coray, T., Andreasson, K. I., Poston, K. L., Wagner, A. D., Mormino, E. C., Wilson, E. N. 2024

  Abstract

  The availability of amyloid beta (Aβ) targeting therapies for Alzheimer's disease (AD) is increasing the demand for scalable biomarkers that are sensitive to early cerebral Aβ accumulation.We evaluated fully-automated Lumipulse plasma Aβ42/Aβ40 immunoassays for detecting cerebral Aβ in 457 clinically unimpaired (CU) and clinically impaired (CI) Stanford Alzheimer's Disease Research Center (Stanford ADRC) participants and 186 CU in the Stanford Aging and Memory Study (SAMS). Longitudinal change in ADRC plasma Aβ42/Aβ40 and cognition and cross-sectional associations with SAMS memory and tau positron emission tomography (PET) were examined.Plasma Aβ42/Aβ40 exhibited high performance in detecting amyloid positivity defined by PET (area under the curve [AUC]: 0.885, 95% confidence interval [CI]: 0.816-0.955). Once abnomal, plasma Aβ42/Aβ40 remained low and predicted cognitive decline in both CU and CI individuals. Among SAMS CU, plasma Aβ42/Aβ40 was associated with poorer hippocampal-dependent memory and elevated tau accumulation.Lumipulse plasma Aβ42/Aβ40 is a scalable assay for detection of cerebral Aβ and prediction of risk for cognitive decline across the AD continuum.Lumipulse plasma amyloid beta (Aβ)42/Aβ40 exhibited high accuracy in detecting amyloid positivity. Plasma amyloid-positive (Aβ+) individuals exhibited stability of Aβ42/Aβ40 over time. Plasma Aβ42/Aβ40 predicted future cognitive decline across the Alzheimer's disease (AD) spectrum. Plasma Aβ42/Aβ40 was sensitive to memory and tau burden in clinically unimpaired older adults.

  View details for DOI 10.1002/alz.14442

  View details for PubMedID 39713875

• Top-down attention and Alzheimer's pathology impact cortical selectivity during learning, influencing episodic memory in older adults. bioRxiv : the preprint server for biology Sheng, J., Trelle, A. N., Romero, A., Park, J., Tran, T. T., Sha, S. J., Andreasson, K. I., Wilson, E. N., Mormino, E. C., Wagner, A. D. 2024

  Abstract

  Human aging affects the ability to remember new experiences, in part, because of altered neural function during memory formation. One potential contributor to age-related memory decline is diminished neural selectivity -- i.e., a decline in the differential response of cortical regions to preferred vs. non-preferred stimuli during event perception -- yet the factors driving variability in neural selectivity with age remain unclear. We examined the impact of top-down attention and preclinical Alzheimer's disease (AD) pathology on neural selectivity during memory encoding in 156 cognitively unimpaired older participants who underwent fMRI while performing a word-face and word-scene associative memory task. Neural selectivity in face- and place-selective cortical regions was greater during events that were later remembered compared to forgotten. Critically, neural selectivity during learning positively scaled with memory-related variability in top-down attention, whereas selectivity negatively related to early AD pathology, evidenced by elevated plasma pTau181. Path analysis revealed that neural selectivity at encoding mediated the effects of age, top-down attention, and pTau181 on associative memory. Collectively, these data reveal multiple pathways that contribute to memory differences among older adults -- AD-independent reductions in top-down attention and AD-related pathology alter the precision of cortical representations of events during experience, with consequences for remembering.

  View details for DOI 10.1101/2024.12.04.626911

  View details for PubMedID 39713293

  View details for PubMedCentralID PMC11661099

• Clinical Manifestations. Alzheimer's & dementia : the journal of the Alzheimer's Association Taghavi, H. M., Karimpoor, M., van Staalduinen, E., Leventis, S., Young, C. B., Carlson, M. L., Davidzon, G. A., Romero, A., Trelle, A. N., Zaharchuk, G., Vossler, H., Rosenberg, J., Poston, K. L., Wagner, A. D., Henderson, V. W., Georgiadis, M., Mormino, E., Zeineh, M. 2024; 20 Suppl 3: e092936

  Abstract

  Olfactory deficiency can be present in preclinical Alzheimer's (AD) and Parkinson's disease (PD), predicting their subsequent manifestation, including mild cognitive impairment (MCI). Analyzing key regions within the olfactory circuit could reveal important insights into the neuropathological progression. Dysfunction in the olfactory circuit has been shown in the olfactory nerve in limited postmortem studies, including involvement of a key region, the piriform cortex. FDG-positron emission tomography (PET) and fMRI have shown differential and reduced piriform cortex metabolism/activation in AD. Thus, the piriform cortex is a promising candidate in the early identification of neurodegenerative pathology underlying olfaction. We used tau MR-PET to analyze the piriform cortex, in comparison to the adjacent medial temporal lobe.We analyzed 115 subjects: 23 were excluded (incomplete data), leaving 31 amyloid-negative and 25 amyloid-positive healthy controls, 8 MCI, 15 AD, and 13 PD. All subjects underwent MR-PET using tau tracer PI-2620 with a simultaneous coregistered sagittal T1-weighted 3D IR-FSPGR and a simultaneous/recently acquired coronal T2-weighted FSE. Automatic Segmentation of Hippocampal Subfields was performed, including the entorhinal-perirhinal cortices (Fig. 1D-F). Referencing published piriform segmentation guidelines, we manually segmented blind to subject diagnosis the frontal/temporal portions of the piriform cortex (Fig. 1C), including multiple independent quality control checks. As tau distributions appeared non-normal among the five ordinal patient categories (Amyloid-HC, Amyloid+HC, MCI, AD, Normal PD), we used a nonparametric Jonckheere-Terpstra test in Stata to test for ordinal increase in tau uptake across four regions bilaterally (whole hippocampus = CA1-4 + DG + subiculum, entorhinal-perirhinal, amygdala, and piriform).We found an ordinal increase in piriform tau uptake with increasing disease severity (amyloid-negative controls, amyloid-positive controls, MCI and AD) (Figure 2A-D). Amyloid-positive controls showed significantly greater uptake than amyloid-negative controls. Piriform uptake was not elevated in cognitively unimpaired PD compared to Amyloid-HC. Piriform volume was statistically equivalent across groups, except PD had lower volumes (Figure 2E-H). Negative correlations were present between memory performance and piriform uptake (Figure 3).Cross-sectionally, there is an early increase in tau uptake in the piriform cortex in AD but not in PD.

  View details for DOI 10.1002/alz.092936

  View details for PubMedID 39750218

• Developing Topics. Alzheimer's & dementia : the journal of the Alzheimer's Association Winer, J. R., Plastini, M. J., Romero, A., Wilson, E. N., Young, C. B., Trelle, A. N., Henderson, V. W., Wagner, A. D., Poston, K. L., Mormino, E. 2024; 20 Suppl 8: e095792

  Abstract

  α-Synuclein is the hallmark pathology of Parkinson's disease and dementia with Lewy bodies, described together as Lewy body disease (LBD). α-Synuclein is also commonly observed in the context of Alzheimer's disease (AD). Here we investigate the frequency of α-synuclein positivity in an AD research cohort and clinically unimpaired individuals (CU), as well as associations with demographics and AD biomarkers.We assessed α-synuclein status (αSyn±) in 69 clinically diagnosed AD (38 mild cognitive impairment and 31 dementia) and 277 CU using a cerebrospinal fluid α-synuclein seeding aggregation assay. 91 LBD spectrum participants were included for comparison. Aβ status and tau levels were measured with cerebrospinal fluid Aβ42/40 and pTau181 using the Lumipulse G assay. Memory performance was examined in CU individuals enrolled in the Stanford Aging and Memory Study (SAMS, N = 164/277).As expected, αSyn+ was highest in LBD (81%). 16% of AD and 9% of CU were αSyn+. Among αSyn+ CU, 45% were Aβ+ compared to 31% in αSyn- CU. In a logistic regression that included only participants with AD, α-synuclein positivity was associated with male sex, clinical impairment (dementia versus mild cognitive impairment), and higher pTau181 (Figure 1A). In CU, α-synuclein positivity was associated with older age (Figure 1B). Among CU from SAMS, the αSyn+ group showed cross-sectional memory reductions that were similar to the A+/T+ CU group (Figure 2).α-Synuclein status may be an important independent predictor of clinical impairment among individuals on the AD spectrum, as well as subtle memory changes in in aging.

  View details for DOI 10.1002/alz.095792

  View details for PubMedID 39783243

• Public Health. Alzheimer's & dementia : the journal of the Alzheimer's Association Lu, O., Mormino, E., He, Z., Carr, V. A., Trelle, A. N., Young, C. B., Romero, A., Vossler, H., Park, J., Skylar-Scott, I. A. 2024; 20 Suppl 7: e084160

  Abstract

  It is increasingly clear that delaying the onset of Alzheimer's disease (AD) dementia by several years can meaningfully lower its prevalence. The goal of the present study is to examine the relationship between lifestyle activities and cognition function as well as cerebrospinal fluid (CSF) biomarkers of AD to determine whether these activities can serve as protective factors for AD resistance and resilience.173 cognitively normal older individuals (mean ± SD, 69 ± 6.4 years) were recruited to the Stanford Aging and Memory Study (SAMS) and completed the Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire regarding current social, cognitive, and physical activity (Table 1). They also underwent APOE genetic testing and a detailed neuropsychological evaluation. The following cognitive domains were evaluated after conversion to z-scores: global cognition (cognitive composite), executive function, working memory, attention, episodic memory, visuospatial function, and language (see Table 2 for definitions). 127 participants completed lumbar punctures, and levels of Aβ-40, Aβ-42, p-tau181, and total tau were measured in the CSF. Cross-sectional regression models included age, sex, years of education, and APOE status as co-variates. Benjamini-Hochberg corrections for multiple hypotheses were completed.There was a significant association between social activity (frequency/week) and global cognition (β = 0.20, p = 0.03), executive function (β = 0.15, p<0.05), and working memory (β = 0.26, p = 0.01) but not episodic memory, visuospatial function, or language function. There was also a significant association with attention prior to correction for multiple hypotheses (β = 0.17, p = 0.04) but not afterward (Table 2). Additionally, there was a significant association between cognitive activity (hours/week) and global cognition (β = 0.19, p = 0.03) as well as executive function (β = 0.25, p = 0.007) but not with other cognitive domains tested (Table 3). There was no association between light or moderate caloric expenditure and cognitive measures. There was also no significant relationship between CSF biomarkers and levels of social, cognitive, and physical activity.In a well-characterized cohort of cognitively normal older adults, higher levels of social and cognitive activity were associated with higher cognitive scores on tasks of executive function but not episodic memory. The mechanism mediating this relationship appears to be independent of both Aβ and tau burden.

  View details for DOI 10.1002/alz.084160

  View details for PubMedID 39784972

• 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

• 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

• 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

• Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment. Cell Piehl, N., van Olst, L., Ramakrishnan, A., Teregulova, V., Simonton, B., Zhang, Z., Tapp, E., Channappa, D., Oh, H., Losada, P. M., Rutledge, J., Trelle, A. N., Mormino, E. C., Elahi, F., Galasko, D. R., Henderson, V. W., Wagner, A. D., Wyss-Coray, T., Gate, D. 2022

  Abstract

  Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with aging or neurodegenerative disease. Here, we performed single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years old. We uncovered an upregulation of lipid transport genes in monocytes with age. We then compared this cohort with 14 cognitively impaired subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred concomitantly with altered cytokine signaling to CD8 Tcells. Clonal CD8T effector memory cells upregulated C-X-C motif chemokine receptor 6 (CXCR6) in cognitively impaired subjects. The CXCR6 ligand, C-X-C motif chemokine ligand 16 (CXCL16), was elevated in the CSF of cognitively impaired subjects, suggesting CXCL16-CXCR6 signaling as a mechanism for antigen-specific Tcell entry into the brain. Cumulatively, these results reveal cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.

  View details for DOI 10.1016/j.cell.2022.11.019

  View details for PubMedID 36516855

• 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

• Medial temporal lobe structure, mnemonic and perceptual discrimination in healthy older adults and those at risk for mild cognitive impairment. Neurobiology of aging Gellersen, H. M., Trelle, A. N., Farrar, B. G., Coughlan, G., Korkki, S. M., Henson, R. N., Simons, J. S. 2022; 122: 88-106

  Abstract

  Cognitive tests sensitive to the integrity of the medial temporal lobe (MTL), such as mnemonic discrimination of perceptually similar stimuli, may be useful early markers of risk for cognitive decline in older populations. Perceptual discrimination of stimuli with overlapping features also relies on MTL but remains relatively unexplored in this context. We assessed mnemonic discrimination in two test formats (Forced Choice, Yes/No) and perceptual discrimination of objects and scenes in 111 community-dwelling older adults at different risk status for cognitive impairment based on neuropsychological screening. We also investigated associations between performance and MTL sub-region volume and thickness. The at-risk group exhibited reduced entorhinal thickness and impaired perceptual and mnemonic discrimination. Perceptual discrimination impairment partially explained group differences in mnemonic discrimination and correlated with entorhinal thickness. Executive dysfunction accounted for Yes/No deficits in at-risk adults, demonstrating the importance of test format for the interpretation of memory decline. These results suggest that perceptual discrimination tasks may be useful tools for detecting incipient cognitive impairment related to reduced MTL integrity in nonclinical populations.

  View details for DOI 10.1016/j.neurobiolaging.2022.11.004

  View details for PubMedID 36516558

• Thalamic nuclei atrophy at high and heterogenous rates during cognitively unimpaired human aging. NeuroImage Choi, E. Y., Tian, L., Su, J. H., Radovan, M. T., Tourdias, T., Tran, T. T., Trelle, A. N., Mormino, E., Wagner, A. D., Rutt, B. K. 2022: 119584

  Abstract

  The thalamus is a central integration structure in the brain, receiving and distributing information among the cerebral cortex, subcortical structures, and the peripheral nervous system. Prior studies clearly show that the thalamus atrophies in cognitively unimpaired aging. However, the thalamus is comprised of multiple nuclei involved in a wide range of functions, and the age-related atrophy of individual thalamic nuclei remains unknown. Using a recently developed automated method of identifying thalamic nuclei (3T or 7T MRI with white-matter-nulled MPRAGE contrast and THOMAS segmentation) and a cross-sectional design, we evaluated the age-related atrophy rate for 10 thalamic nuclei (AV, CM, VA, VLA, VLP, VPL, pulvinar, LGN, MGN, MD) and an epithalamic nucleus (habenula). We also used T1-weighted images with the FreeSurfer SAMSEG segmentation method to identify and measure age-related atrophy for 11 extra-thalamic structures (cerebral cortex, cerebral white matter, cerebellar cortex, cerebellar white matter, amygdala, hippocampus, caudate, putamen, nucleus accumbens, pallidum, and lateral ventricle). In 198 cognitively unimpaired participants with ages spanning 20-88 years, we found that the whole thalamus atrophied at a rate of 0.45% per year, and that thalamic nuclei had widely varying age-related atrophy rates, ranging from 0.06% to 1.18% per year. A functional grouping analysis revealed that the thalamic nuclei involved in cognitive (AV, MD; 0.53% atrophy per year), visual (LGN, pulvinar; 0.62% atrophy per year), and auditory/vestibular (MGN; 0.64% atrophy per year) functions atrophied at significantly higher rates than those involved in motor (VA, VLA, VLP, and CM; 0.37% atrophy per year) and somatosensory (VPL; 0.32% atrophy per year) functions. A proximity-to-CSF analysis showed that the group of thalamic nuclei situated immediately adjacent to CSF atrophied at a significantly greater atrophy rate (0.59% atrophy per year) than that of the group of nuclei located farther from CSF (0.36% atrophy per year), supporting a growing hypothesis that CSF-mediated factors contribute to neurodegeneration. We did not find any significant hemispheric differences in these rates of change for thalamic nuclei. Only the CM thalamic nucleus showed a sex-specific difference in atrophy rates, atrophying at a greater rate in male versus female participants. Roughly half of the thalamic nuclei showed greater atrophy than all extra-thalamic structures examined (0% to 0.54% per year). These results show the value of white-matter-nulled MPRAGE imaging and THOMAS segmentation for measuring distinct thalamic nuclei and for characterizing the high and heterogeneous atrophy rates of the thalamus and its nuclei across the adult lifespan. Collectively, these methods and results advance our understanding of the role of thalamic substructures in neurocognitive and disease-related changes that occur with aging.

  View details for DOI 10.1016/j.neuroimage.2022.119584

  View details for PubMedID 36007822

• Executive function and high ambiguity perceptual discrimination contribute to individual differences in mnemonic discrimination in older adults. Cognition Gellersen, H. M., Trelle, A. N., Henson, R. N., Simons, J. S. 2021; 209: 104556

  Abstract

  Mnemonic discrimination deficits, or impaired ability to discriminate between similar events in memory, is a hallmark of cognitive aging, characterised by a stark age-related increase in false recognition. While individual differences in mnemonic discrimination have gained attention due to potential relevance for early detection of Alzheimer's disease, our understanding of the component processes that contribute to variability in task performance across older adults remains limited. The present investigation explores the roles of representational quality, indexed by perceptual discrimination of objects and scenes with overlapping features, and strategic retrieval ability, indexed by standardised tests of executive function, to mnemonic discrimination in a large cohort of older adults (N=124). We took an individual differences approach and characterised the contributions of these factors to performance under Forced Choice (FC) and Yes/No (YN) recognition memory formats, which place different demands on strategic retrieval. Performance in both test formats declined with age. Accounting for age, individual differences in FC memory performance were best explained by perceptual discrimination score, whereas YN memory performance was best explained by executive functions. A linear mixed model and dominance analyses confirmed the relatively greater importance of perceptual discrimination over executive functioning for FC performance, while the opposite was true for YN. These findings highlight parallels between perceptual and mnemonic discrimination in aging, the importance of considering demands on executive functions in the context of mnemonic discrimination, and the relevance of test format for modulating the impact of these factors on performance in older adults.

  View details for DOI 10.1016/j.cognition.2020.104556

  View details for PubMedID 33450438

• Association of CSF Biomarkers with Hippocampal-dependent Memory in Preclinical Alzheimer Disease. Neurology Trelle, A. N., Carr, V. A., Wilson, E. N., Swarovski, M. S., Hunt, M. P., Toueg, T. N., Tran, T. T., Channappa, D. n., Corso, N. K., Thieu, M. K., Jayakumar, M. n., Nadiadwala, A. n., Guo, W. n., Tanner, N. J., Bernstein, J. D., Litovsky, C. P., Guerin, S. A., Khazenzon, A. M., Harrison, M. B., Rutt, B. K., Deutsch, G. K., Chin, F. T., Davidzon, G. A., Hall, J. N., Sha, S. J., Fredericks, C. A., Andreasson, K. I., Kerchner, G. A., Wagner, A. D., Mormino, E. C. 2021

  Abstract

  To determine if memory tasks with demonstrated sensitivity to hippocampal function can detect variance related to preclinical Alzheimer's disease (AD) biomarkers, we examined associations between performance in three memory tasks and CSF Aβ42/Aβ40 and p-tau181 in cognitively unimpaired older adults (CU).CU enrolled in the Stanford Aging and Memory Study (N=153; age 68.78 ± 5.81 yrs; 94 female) completed a lumbar puncture and memory assessments. CSF Aβ42, Aβ40, and phosopho-tau181 (p-tau181) were measured with the automated Lumipulse G system in a single-batch analysis. Episodic memory was assayed using a standardized delayed recall composite, paired associate (word-picture) cued recall, and a mnemonic discrimination task that involves discrimination between studied 'target' objects, novel 'foil' objects, and perceptually similar 'lure' objects. Analyses examined cross-sectional relationships between memory performance, age, and CSF measures, controlling for sex and education.Age and lower Aβ42/Aβ40 were independently associated with elevated p-tau181. Age, Aβ42/Aβ40, and p-tau181 were each associated with a) poorer associative memory and b) diminished improvement in mnemonic discrimination performance across levels of decreased task difficulty (i.e., target-lure similarity). P-tau mediated the effect of Aβ42/Aβ40 on memory. Relationships between CSF proteins and delayed recall were similar but non-significant. CSF Aβ42 was not significantly associated with p-tau181 or memory.Tests designed to tax hippocampal function are sensitive to subtle individual differences in memory among CU, and correlate with early AD-associated biomarker changes in CSF. These tests may offer utility for identifying cognitively unimpaired older adults with preclinical AD pathology.

  View details for DOI 10.1212/WNL.0000000000011477

  View details for PubMedID 33408146

• Hippocampal and cortical mechanisms at retrieval explain variability in episodic remembering in older adults. eLife Trelle, A. N., Carr, V. A., Guerin, S. A., Thieu, M. K., Jayakumar, M. n., Guo, W. n., Nadiadwala, A. n., Corso, N. K., Hunt, M. P., Litovsky, C. P., Tanner, N. J., Deutsch, G. K., Bernstein, J. D., Harrison, M. B., Khazenzon, A. M., Jiang, J. n., Sha, S. J., Fredericks, C. A., Rutt, B. K., Mormino, E. C., Kerchner, G. A., Wagner, A. D. 2020; 9

  Abstract

  Age-related episodic memory decline is characterized by striking heterogeneity across individuals. Hippocampal pattern completion is a fundamental process supporting episodic memory. Yet, the degree to which this mechanism is impaired with age, and contributes to variability in episodic memory, remains unclear. We combine univariate and multivariate analyses of fMRI data from a large cohort of cognitively normal older adults (N=100) to measure hippocampal activity and cortical reinstatement during retrieval of trial-unique associations. Trial-wise analyses revealed that (a) hippocampal activity scaled with reinstatement strength, (b) cortical reinstatement partially mediated the relationship between hippocampal activity and associative retrieval, (c) older age weakened cortical reinstatement and its relationship to memory behaviour. Moreover, individual differences in the strength of hippocampal activity and cortical reinstatement explained unique variance in performance across multiple assays of episodic memory. These results indicate that fMRI indices of hippocampal pattern completion explain within- and across-individual memory variability in older adults.

  View details for DOI 10.7554/eLife.55335

  View details for PubMedID 32469308

• 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

• Neural evidence for age-related differences in representational quality and strategic retrieval processes. Neurobiology of aging Trelle, A. N., Henson, R. N., Simons, J. S. 2019; 84: 50–60

  Abstract

  Mounting behavioral evidence suggests that declines in both representational quality and controlled retrieval processes contribute to episodic memory decline with age. The present study sought neural evidence for age-related change in these factors by measuring neural differentiation during encoding of paired associates and changes in regional blood oxygenation level-dependent activity and functional connectivity during retrieval conditions that placed low (intact pairs) and high (recombined pairs) demands on controlled retrieval processes. Pattern similarity analysis revealed age-related declines in the differentiation of stimulus representations at encoding, manifesting as both reduced pattern similarity between closely related events and increased pattern similarity between distinct events. During retrieval, both groups increased recruitment of areas within the core recollection network when endorsing studied pairs, including the hippocampus and angular gyrus. In contrast, only younger adults increased recruitment of, and hippocampal connectivity with, lateral prefrontal regions during correct rejections of recombined pairs. These results provide evidence for age-related changes in representational quality and in the neural mechanisms supporting memory retrieval under conditions of high, but not low, control demand.

  View details for DOI 10.1016/j.neurobiolaging.2019.07.012

  View details for PubMedID 31491595

• Dissociable contributions of thalamic nuclei to recognition memory: novel evidence from a case of medial dorsal thalamic damage LEARNING & MEMORY Newsome, R. N., Trelle, A. N., Fidalgo, C., Hong, B., Smith, V. M., Jacob, A., Ryan, J. D., Rosenbaum, R., Cowell, R. A., Barense, M. D. 2018; 25 (1): 31–44

  Abstract

  The thalamic nuclei are thought to play a critical role in recognition memory. Specifically, the anterior thalamic nuclei and medial dorsal nuclei may serve as critical output structures in distinct hippocampal and perirhinal cortex systems, respectively. Existing evidence indicates that damage to the anterior thalamic nuclei leads to impairments in hippocampal-dependent tasks. However, evidence for the opposite pattern following medial dorsal nuclei damage has not yet been identified. In the present study, we investigated recognition memory in NC, a patient with relatively selective medial dorsal nuclei damage, using two object recognition tests with similar foils: a yes/no (YN) test that requires the hippocampus, and a forced choice corresponding test (FCC) that is supported by perirhinal cortex. NC performed normally in the YN test, but was impaired in the FCC test. Critically, FCC performance was impaired only when the study-test delay period was filled with interference. We interpret these results in the context of the representational-hierarchical model, which predicts that memory deficits following damage to the perirhinal system arise due to increased vulnerability to interference. These data provide the first evidence for selective deficits in a task that relies on perirhinal output following damage to the medial dorsal nuclei, providing critical evidence for dissociable thalamic contributions to recognition memory.

  View details for DOI 10.1101/lm.045484.117

  View details for Web of Science ID 000423996900004

  View details for PubMedID 29246979

  View details for PubMedCentralID PMC5733467

• Declines in Representational Quality and Strategic Retrieval Processes Contribute to Age-Related Increases in False Recognition JOURNAL OF EXPERIMENTAL PSYCHOLOGY-LEARNING MEMORY AND COGNITION Trelle, A. N., Henson, R. N., Green, D. E., Simons, J. S. 2017; 43 (12): 1883–97

  Abstract

  In a Yes/No object recognition memory test with similar lures, older adults typically exhibit elevated rates of false recognition. However, the contributions of impaired retrieval, relative to reduced availability of target details, are difficult to disentangle using such a test. The present investigation sought to decouple these factors by comparing performance on a Yes/No (YN) test to that on a Forced Choice (FC) test, which minimizes demands on strategic retrieval processes, enabling a more direct measure of the availability of object details. Older adults exhibited increased lure false recognition across test formats (Experiment 1), suggesting a decline in the availability of object details contributes to deficits in performance. Manipulating interference by varying the number of objects studied selectively enhanced performance in the FC test, resulting in matched performance across groups, whereas age differences in YN performance persisted (Experiment 2), indicating an additional contribution of impaired strategic retrieval. Consistent with differential sensitivity of test format to strategic retrieval and the quality of stimulus representations among older adults, variability in the quality of object representations, measured using a perceptual discrimination task, was selectively related to FC performance. In contrast, variability in memory control processes, as measured with tests of recall and executive function, was related to performance across test formats. These results suggest that both declines in the availability of object details and impaired retrieval of object details contribute to elevated rates of lure false recognition with age, and highlight the utility of test format for dissociating these factors in memory-impaired populations. (PsycINFO Database Record

  View details for DOI 10.1037/xlm0000412

  View details for Web of Science ID 000417904300004

  View details for PubMedID 28530412

  View details for PubMedCentralID PMC5729965

• Identifying Age-Invariant and Age-Limited Mechanisms for Enhanced Memory Performance: Insights From Self-Referential Processing in Younger and Older Adults PSYCHOLOGY AND AGING Trelle, A. N., Henson, R. N., Simons, J. S. 2015; 30 (2): 324–33

  Abstract

  Self-referential processing has been identified as a possible tool for supporting effective encoding processes in the elderly population. However, the importance of self-reference per se, relative to the increase in meaningful elaboration normally associated with self-reference instructions, remains unclear. The present study sought to explore this issue further by examining self-referential encoding strategies that inherently involve more extensive stimulus elaboration: episodic autobiographical memory (AM) retrieval and semantic AM retrieval. These were compared with an analogous task involving retrieval of general semantic knowledge, as well as traditional binary self-referential and semantic encoding judgments. We found that both AM retrieval and general semantic retrieval at encoding resulted in substantial enhancements to recall and recognition memory of concrete nouns relative to binary encoding judgments across both age groups. Furthermore, older adults exhibited larger benefits from this additional elaboration than did younger adults, leading to elimination of age-related deficits in recognition memory. However, younger adults showed an additional boost to subsequent memory following episodic, relative to semantic, AM retrieval during free recall that was not exhibited by older adults. This may be because of greater demands on frontally mediated control processes and cognitive resources associated with the use of this strategy. Taken together, the results suggest that the mnemonic benefits associated with self-referential processing vary substantially depending on the specific nature of the encoding strategy, and suggest that, under certain conditions, semantic processing and self-referential processing are equally effective in mitigating age-related deficits in memory performance.

  View details for DOI 10.1037/a0039116

  View details for Web of Science ID 000355839900012

  View details for PubMedID 25961877

• Decoding the Role of the Angular Gyrus in the Subjective Experience of Recollection JOURNAL OF NEUROSCIENCE Trelle, A. 2014; 34 (43): 14167–69

  View details for DOI 10.1523/JNEUROSCI.3215-14.2014

  View details for Web of Science ID 000343658100002

  View details for PubMedID 25339731

  View details for PubMedCentralID PMC6608389

• Hyper-Binding Across Time: Age Differences in the Effect of Temporal Proximity on Paired-Associate Learning JOURNAL OF EXPERIMENTAL PSYCHOLOGY-LEARNING MEMORY AND COGNITION Campbell, K. L., Trelle, A., Hasher, L. 2014; 40 (1): 293–99

  Abstract

  Older adults show hyper- (or excessive) binding effects for simultaneously and sequentially presented distraction. Here, we addressed the potential role of hyper-binding in paired-associate learning. Older and younger adults learned a list of word pairs and then received an associative recognition task in which rearranged pairs were formed from items that had originally occurred either close together or far apart in the study list. Across 3 experiments, older adults made more false alarms to near re-pairings than to far re-pairings. Younger adults, on the other hand, showed no difference in false alarms to the 2 types of rearranged pairs. These findings may be tied to the greater tendency of older adults to maintain access to recently attended information, inadvertently forming broader associations across time, than is the case for younger adults.

  View details for DOI 10.1037/a0034109

  View details for Web of Science ID 000329049600021

  View details for PubMedID 23937237