Vemuri, Prashanthi

AbstractTau deposition is a key biological feature of Alzheimer’s disease that is closely related to cognitive impairment. However, it remains poorly understood why certain individuals may be more susceptible to tau deposition while others are more resistant. The recent availability of in vivo assessment of tau burden through positron emission tomography provides an opportunity to test the hypothesis that common genetic variants may influence tau deposition. We performed a genome-wide association study of tau-positron emission tomography on a sample of 754 individuals over age 50 (mean age 72.4 years, 54.6% men, 87.6% cognitively unimpaired) from the population-based Mayo Clinic Study of Aging. Linear regression was performed to test nucleotide polymorphism associations with AV-1451 (18F-flortaucipir) tau-positron emission tomography burden in an Alzheimer’s-signature composite region of interest, using an additive genetic model and covarying for age, sex and genetic principal components. Genome-wide significant associations with higher tau were identified for rs76752255 (P = 9.91 × 10−9, β = 0.20) in the tau phosphorylation regulatory gene PPP2R2B (protein phosphatase 2 regulatory subunit B) and for rs117402302 (P = 4.00 × 10−8, β = 0.19) near IGF2BP3 (insulin-like growth factor 2 mRNA-binding protein 3). The PPP2R2B association remained genome-wide significant after additionally covarying for global amyloid burden and cerebrovascular disease risk, while the IGF2BP3 association was partially attenuated after accounting for amyloid load. In addition to these discoveries, three single nucleotide polymorphisms within MAPT (microtubule-associated protein tau) displayed nominal associations with tau-positron emission tomography burden, and the association of the APOE (apolipoprotein E) ɛ4 allele with tau-positron emission tomography was marginally nonsignificant (P = 0.06, β = 0.07). No associations with tau-positron emission tomography burden were identified for other single nucleotide polymorphisms associated with Alzheimer’s disease clinical diagnosis in prior large case–control studies. Our findings nominate PPP2R2B and IGF2BP3 as novel potential influences on tau pathology which warrant further functional characterization. Our data are also supportive of previous literature on the associations of MAPT genetic variation with tau, and more broadly supports the inference that tau accumulation may have a genetic architecture distinct from known Alzheimer’s susceptibility genes, which may have implications for improved risk stratification and therapeutic targeting.

Objective: High plasma ceramide levels and ratios are associated with poor outcomes in individuals with cardiovascular disease; less is known about their relation to cerebral small vessel disease. We examined whether high plasma ceramide levels or ratios were associated with cerebral microbleeds (CMBs) and lacunes and whether associations differ by sex. Approach and Results: We included 548 participants enrolled in the MCSA (Mayo Clinic Study of Aging) with concurrent plasma ceramide assays and magnetic resonance imaging. CMBs were quantified on T2* magnetic resonance imaging and lacunes on T2 fluid-attenuated inversion recovery magnetic resonance imaging. Fasting plasma ceramides were assayed using liquid chromatography-electrospray ionization tandem mass spectrometry. We used logistic regression models adjusting for age, sex, hypertension, and diabetes mellitus to examine the relationship between ceramides and presence of a lacune; hurdle models were used for presence and number of CMBs. Each SD increase in the log ceramide C16:0/24:0 ratio was associated with greater odds of a CMB (odds ratio, 1.28 [95% CI, 1.01–1.64]). There was an interaction between sex and the ceramide C16:0/24:0 ratio ( P =0.049). The association between this ratio and presence of a CMB was stronger for women (odds ratio, 1.87 [95% CI, 1.20–3.00]) than men (odds ratio, 1.09 [95% CI, 0.80–1.46]). Several ceramides and all ceramide ratios were associated with number of CMBs. We did not find associations between plasma ceramides and lacunes. Conclusions: In a population-based sample, the plasma ceramide C16:0/24:0 ratio was associated with CMBs and was stronger for women. Plasma ceramides are differentially associated with cerebral small vessel pathologies.

Abstract Clinical trials with anti-tau drugs will need to target individuals at risk of accumulating tau. Our objective was to identify variables available in a research setting that predict future rates of tau PET accumulation separately among individuals who were either cognitively unimpaired or cognitively impaired. All 337 participants had: a baseline study visit with MRI, amyloid PET, and tau PET exams, at least one follow-up tau PET exam; and met clinical criteria for membership in one of two clinical diagnostic groups: cognitively unimpaired (n = 203); or cognitively impaired (n = 134, a combined group of participants with either mild cognitive impairment or dementia with Alzheimer’s clinical syndrome). Our primary analyses were in these two clinical groups; however, we also evaluated subgroups dividing the unimpaired group by normal/abnormal amyloid PET and the impaired group by clinical phenotype (mild cognitive impairment, amnestic dementia, and non-amnestic dementia). Linear mixed effects models were used to estimate associations between age, sex, education, APOE genotype, amyloid and tau PET standardized uptake value ratio (SUVR), cognitive performance, cortical thickness, and white matter hyperintensity volume at baseline, and the rate of subsequent tau PET accumulation. Log-transformed tau PET SUVR was used as the response and rates were summarized as annual per cent change. A temporal lobe tau PET meta-region of interest was used. In the cognitively unimpaired group, only higher baseline amyloid PET was a significant independent predictor of higher tau accumulation rates (P < 0.001). Higher rates of tau accumulation were associated with faster rates of cognitive decline in the cognitively unimpaired subgroup with abnormal amyloid PET (P = 0.03), but among the subgroup with normal amyloid PET. In the cognitively impaired group, younger age (P = 0.02), higher baseline amyloid PET (P = 0.05), APOE ε4 (P = 0.05), and better cognitive performance (P = 0.05) were significant independent predictors of higher tau accumulation rates. Among impaired individuals, faster cognitive decline was associated with faster rates of tau accumulation (P = 0.01). While we examined many possible predictor variables, our results indicate that screening of unimpaired individuals for potential inclusion in anti-tau trials may be straightforward because the only independent predictor of high tau rates was amyloidosis. In cognitively impaired individuals, imaging and clinical variables consistent with early onset Alzheimer’s disease phenotype were associated with higher rates of tau PET accumulation suggesting this may be a highly advantageous group in which to conduct proof-of-concept clinical trials that target tau-related mechanisms. The nature of the dementia phenotype (amnestic versus non-amnestic) did not affect this conclusion.

Abstract Introduction Sleepiness has been associated with functional and cognitive decline, and may present with excessive daytime sleepiness (EDS) and/or increased sleep duration. We investigated whether sleepiness and changes in sleep patterns are associated with FDG-PET levels in wake-promoting regions. Methods From the Mayo Clinic Study of Aging cohort, we identified 373 cognitively-unimpaired middle-aged and older adults (mean +/- s.d. 66.1 +/- 13.2 yo) who underwent FDG-PET. EDS was defined as ESS score >=10. Changes in sleep patterns (sleeping more, less, or no change) were assessed using question #16 of the Beck Depression Inventory-2. We used probabilistic maps to create regions of interest (ROIs): the locus coeruleus (LC), posterior lateral hypothalamus (PLH), and the basal forebrain divided in 1) medial septum/diagonal band of Broca (MS/DB) and 2) nucleus basalis of Meynert (nbM). FDG-PET levels were referenced to the pons (SUVR). In this cross-sectional analysis, we fit linear models to assess the association between EDS and changes in sleeping patterns with FDG SUVR in in each ROI, while controlling for age, sex, education, BMI, witnessed apneas, and cardiovascular risk factors. Results 10.5% had EDS, 15% reported sleeping more and 21% reported sleeping less than usual. 30.7% of participants with EDS reported sleeping more, 25.6% less, and 43.5% the same. EDS was associated with an elevation in FDG-PET SUVR in the MS/DB region (.035 [95% CI .008; .063], p=.012), while sleeping more was associated with a decrease in FDG-PET SUVR in the same region (-.027 [95%CI -.052; -.002], p=.036). Sleeping less was associated with an increase in FDG-PET SUVR in the PLH (.021 [95% CI .005; .03], p=.019). No associations were found in other ROIs. Conclusion Our results suggest that sleepiness and changes in sleep patterns in cognitively-unimpaired middle-aged and older adults were associated with measurable metabolic changes in areas of the brain involved in sleep and wakefulness. Further research should clarify whether these findings could represent different phenotypes of sleepiness with potential diagnostic and prognostic implications. Support NIA/NIH

AbstractIntroductionWe examined differences in cortical thickness in empirically derived mild cognitive impairment (MCI) subtypes in the Mayo Clinic Study of Aging.MethodsWe compared cortical thickness of four incident MCI subtypes (n = 192) to 1257 cognitive unimpaired individuals.ResultsThe subtle cognitive impairment cluster had atrophy in the entorhinal and parahippocampal cortex. The amnestic, dysnomic, and dysexecutive clusters also demonstrated entorhinal cortex atrophy as well as thinning in temporal, parietal, and frontal isocortex in somewhat different patterns.DiscussionWe found patterns of atrophy in each of the incident MCI clusters that corresponded to their patterns of cognitive impairment. The identification of MCI subtypes based on cognitive and structural features may allow for more efficient trial and study designs. Given individuals in the subtle cognitive impairment cluster have less structural changes and cognitive decline and may represent the earliest group, this could be a unique group to target with early interventions.

AbstractObjectiveTo examine the association of baseline elevated brain amyloid and neurodegeneration with changes in activities of daily living in participants without dementia (ND; i.e., cognitively unimpaired and participants with mild cognitive impairment) at baseline in the population‐based Mayo Clinic Study of Aging.MethodsWe included 1747 ND participants with 11C‐PiB PET and MR imaging in the study, with data on activities of daily living (as assessed by the Functional Activities Questionnaire (FAQ) and the Clinical Dementia Rating scale Sum of Boxes for functional domains (CDR‐SOB (functional)), with a median (range) of 4.3 (0.0–12.7) years of follow‐up. Abnormal (elevated; A+) 11C‐PiB‐PET retention ratio was defined as standardized uptake value ratio ≥ 1.48, and abnormal (reduced) AD signature cortical thickness as ≤ 2.68 mm (neurodegeneration; N+). Associations were examined with mixed effects models, adjusting for age, sex, education, apolipoprotein E ε4 allele carrier status, and global cognitive z‐score.ResultsMean age (SD) was 71.4 years (10.1), 46.7% were females, 195 (11.2%) had A+N‐, 442 (25.3%) had A‐N+, and 339 (19.4%) had A+N+ biomarkers. The A+N+ group had the largest annualized change in the FAQ score from baseline (difference in annual change A+N+ vs. A‐N‐; ß (SE): 0.80 (0.07)); associations were substantially attenuated when a time‐varying global cognitive composite was included in the model (A+N+ vs. A‐N‐; ß (SE): 0.31 (0.05)). CDR‐SOB (functional) findings partly agreed with FAQ score findings.InterpretationThe longitudinal increase in functional limitations is greater for individuals with abnormal neuroimaging biomarkers, especially for those with both elevated brain amyloid and neurodegeneration.

ObjectiveTo investigate β‐amyloid and tau depositions using Pittsburgh compound B (PiB) positron emission tomography (PET) and AV1451 tau PET imaging in aging multiple sclerosis (MS) patients.MethodsPatients with MS (n = 16) and controls (n = 80) matched for age, sex, andAPOEε4 status from the population‐based Mayo Clinic Study of Aging who underwent PiB PET imaging were studied. Of these individuals, 12 patients with MS and 60 matching controls also underwent AV1451 tau PET. Cortical PiB and AV1451 standard uptake value ratios (SUVrs) from the entire cortex and previously determined Alzheimer disease (AD) signature regions in the same population were calculated for group comparisons and testing for associations with age.ResultsAD signature PiB SUVr (odds ratio [OR] [95% confidence interval (CI)] = 0.52 [0.27–0.98],p= 0.044), total cortical PiB SUVr (OR [95% CI] = 0.52 [0.28–0.99],p= 0.048), and the frequency of abnormal PiB SUVrs (OR [95% CI] = 0.10 [0.01–0.90],p= 0.040) were lower in MS than controls. Although AD‐signature and total cortical AV1451 SUVrs were not different between the groups, the frequency of abnormal AV1451 SUVrs was higher (OR [95% CI] = 10.65 [1.10–103.35],p= 0.041) in MS than controls. The association of AD signature PiB SUVr with age was steeper in the controls compared to patients with MS (estimate [95% CI] = −0.14 [−0.023 to −0.006],p= 0.002). Similarly, the association of total cortical PiB SUVr with age was steeper in the controls compared to patients with MS (estimate [95% CI] = −0.13 [−0.021 to −0.005],p= 0.002). There was no difference in the association of AV1451 SUVr findings with age between the MS patients and controls.InterpretationAlthough both β‐amyloid and tau are biomarkers of cognitive aging and AD, cortical β‐amyloid deposition was lower in MS than age‐matched controls, suggesting that some aspect of MS pathobiology retards the accumulation of β‐amyloid but not the accumulation of tau.ANN NEUROL 2020;87:556–567