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Background and Objectives:Our objective was to determine whether polysomnographic (PSG) sleep parameters are associated with neuroimaging biomarkers of cerebrovascular disease (CVD) related to white matter integrity in older adults with obstructive sleep apnea (OSA).Methods:From the population-based Mayo Clinic Study of Aging, we identified participants without dementia who underwent at least one brain MRI and PSG. We quantified two CVD biomarkers: white matter hyperintensities (WMH) from FLAIR-MRI and fractional anisotropy of the genu of the corpus callosum (genu FA) from diffusion MRI. For this cross-sectional analysis, we fit linear models to assess associations between PSG parameters (N1%, N3% [slow-wave sleep], mean oxyhemoglobin saturation, and log of apnea-hypopnea index [AHI]) and CVD biomarkers (log of WMH and log of genu FA), respectively, while adjusting for age (at MRI), sex, APOε4 status, composite cardiovascular and metabolic conditions (CMC) score, REM stage percentage, sleep duration, and interval between MRI and PSG.Results:We included 140 participants with FLAIR-MRI (of which 103 had additional diffusion MRI). The mean ± s.d. age was 72.7 ± 9.6 years old at MRI with nearly 60% being men. The absolute median (IQR) interval between MRI and PSG was 1.74 (0.9 – 3.2) years. 90.7% were cognitively unimpaired during both assessments. For every 10-point decrease in N3%, there was a 0.058 (95% CI 0.006 to 0.111, p=0.030) increase in the log of WMH and 0.006 decrease (95% CI -0.012 to -0.0002, p=0.042) in the log of genu FA. After matching for age, sex, and N3%, participants with severe OSA had higher WMH (median [IQR] 0.007 [0.005 to 0.015] vs. 0.006 [0.003 to 0.009], p=0.042) and lower genu FA (median [IQR] 0.57 [0.55 to 0.63] vs. 0.63 [0.58 to 0.65], p=0.007), when compared with those with mild/moderate OSA.Discussion:We found that reduced slow-wave sleep and severe OSA were associated with higher burden of white matter abnormalities in predominantly cognitively unimpaired older adults, which may contribute to greater risk of cognitive impairment, dementia, and stroke. Our study supports the association between sleep depth/fragmentation and intermittent hypoxia and CVD biomarkers. Longitudinal studies are required to assess causation.

Background and ObjectivesThe prevalence of midlife cardiovascular conditions and risk factors is higher in men than women. Associations between midlife cardiovascular conditions or risk factors and midlife cognitive decline have been reported, but few studies have assessed sex differences in these associations.MethodsWe included 1,857 participants enrolled in the population-based Mayo Clinic Study of Aging who were 50 to 69 years of age at baseline. Participants were evaluated every 15 months by a coordinator, including neurologic evaluation and neuropsychological testing. The neuropsychological testing used 9 tests to calculate global cognitive and domain-specific (memory, language, executive function, and visuospatial skills) z scores. Nurse abstractors reviewed participant medical records to determine the presence of cardiovascular conditions (coronary heart disease, arrhythmias, congestive heart failure) and risk factors (hypertension, diabetes, dyslipidemia, obesity, ever smoking). Linear mixed-effect models evaluated the association between baseline cardiovascular conditions or risk factors and global and domain-specific cognitive decline. Multivariable models adjusted for demographics, APOE genotype, depression, and other medical conditions. Interactions between sex and each cardiovascular condition or risk factor were examined, and results were stratified by sex.ResultsOverall, 1,465 (78.9%) participants had at least 1 cardiovascular condition or risk factor; the proportion of men was higher than women (767 [83.4%] vs 698 [74.5%], p < 0.0001). Cross-sectionally, coronary heart disease and ever smoking were associated with a lower visuospatial z score in multivariable models. Longitudinally, several cardiovascular conditions and risk factors were associated with declines in global and domain-specific z scores but not visuospatial z scores. Most cardiovascular conditions were more strongly associated with cognition among women: coronary heart disease and other cardiovascular conditions were associated with global cognitive decline only in women (all p < 0.05). In addition, diabetes, dyslipidemia, and coronary heart disease were associated with language z score decline only in women (all p < 0.05). However, congestive heart failure was associated with language z score decline only in men (all p < 0.05).DiscussionMidlife cardiovascular conditions and risk factors are associated with midlife cognitive decline. Moreover, specific cardiovascular conditions and risk factors have stronger associations with cognitive decline in midlife for women than men despite the higher prevalence of those conditions in men.

Background and ObjectivesTo determine the contribution of cerebral amyloid angiopathy (CAA) to Pittsburgh compound B (PiB)–PET tracer retention.MethodsParticipants from the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer's Disease Research Center with antemortem PiB-PET imaging for β-amyloid (Aβ) who later underwent autopsy were included in this study. Pathologic regional leptomeningeal, parenchymal, capillary CAA, and Aβ plaque burden were calculated from one hemisphere. Regional lobar amyloid standardized uptake value ratio (SUVR) on PET was calculated from the same hemisphere sampled at autopsy. Single- and multiple-predictor linear regression models were used to evaluate the relative contributions of pathologically determined regional CAA and Aβ plaques to antemortem PiB-PET SUVR.ResultsForty-one participants (30 male, 11 female) with a mean (SD) age at death of 75.7 (10.6) years were included. Twenty-seven (66%) had high PiB signal with a mean (SD) of 2.3 (1.2) years from time of PET scan to death; 24 (59%) had a pathologic diagnosis of Alzheimer disease. On multivariate analysis, CAA was not associated with PiB-PET SUVR, while plaques remained associated with PiB-PET SUVR in all regions (all p < 0.05). In patients without frequent amyloid plaques, CAA was not associated with PiB-PET in any region.DiscussionWe did not find evidence that pathologically confirmed regional CAA burden contributes significantly to proximal antemortem regional PiB-PET signal, suggesting that amyloid PET imaging for measurement of cortical amyloid burden is unconfounded by CAA on a lobar level. Whether CAA burden contributes to PiB-PET signal in patients with severe CAA phenotypes, such as lobar hemorrhage, requires further investigation.

Background and Purpose: Cerebral microbleeds (CMBs) are represented by small areas of hemosiderin deposition, detected on brain magnetic resonance imaging (MRI), and found in ≈23% of the cognitively normal population over age of 60 years. CMBs predict risk of hemorrhagic and ischemic stroke. They correlate with increased cardiovascular mortality. In this article, we sought to determine in a population-based study whether antithrombotic medications correlate with CMBs and, if present, whether the association was direct or mediated by another variable. Methods: The study consisted of 1253 participants from the population-based Mayo Clinic Study of Aging who underwent T2* gradient-recalled echo magnetic resonance imaging. We tested the relationship between antithrombotic medications and CMB presence and location, using multivariable logistic-regression models. Ordinal logistic models tested the relationship between antithrombotics and CMB frequency. Using structural equation models, we assessed the effect of antithrombotic medications on presence/absence of CMBs and count of CMBs in the CMB-positive group, after considering the effects of age, sex, vascular risk factors, amyloid load by positron emission tomography, and apoE. Results: Two hundred ninety-five participants (26.3%) had CMBs. Among 678 participants taking only antiplatelet medications, 185 (27.3%) had CMBs. Among 95 participants taking only an anticoagulant, 43 (45.3%) had CMBs. Among 44 participants taking an anticoagulant and antiplatelet therapy, 21 (48.8%) had CMBs. Anticoagulants correlated with the presence and frequency of CMBs, whereas antiplatelet agents were not. Structural equation models showed that predictors for presence/absence of CMBs included older age at magnetic resonance imaging, male sex, and anticoagulant use. Predictors of CMB count in the CMB-positive group were male sex and amyloid load. Conclusions: Anticoagulant use correlated with presence of CMBs in the general population. Amyloid positron emission tomography correlated with the count of CMBs in the CMB-positive group.

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.

ObjectiveTo assess whether informant-reported apneas during sleep (witnessed apneas) in cognitively unimpaired (CU) elderly persons are associated with higher levels of brain tau.MethodsFrom the population-based Mayo Clinic Study of Aging, we identified 292 CU elderly ≥65 years of age with both AV-1451 tau-PET and Pittsburgh compound B (PiB)-PET scans and whose bed partners and close relatives had completed a questionnaire that assessed whether participants had witnessed apneas during sleep. For this cross-sectional analysis, we selected the entorhinal and inferior temporal cortices as our regions of interest (ROIs) because they are highly susceptible to tau accumulation. PET signal was scaled to the cerebellum crus to calculate standardized uptake value ratio (SUVR). We fit linear models to assess the association between regional tau and witnessed apneas while controlling for age, sex, years of education, body mass index, hypertension, hyperlipidemia, diabetes, reduced sleep, excessive daytime sleepiness, and global PiB.ResultsForty-three participants (14.7%) were found to have witnessed apneas during sleep. The report of witnessed apneas was associated with higher tau-PET SUVR elevation in our ROIs: 0.049 SUVR (95% confidence interval [CI] 0.010–0.087, p = 0.015) in the entorhinal cortex and 0.037 SUVR (95% CI 0.006–0.067, p = 0.019) in the inferior temporal cortex after controlling for confounders.ConclusionWe identified a significant association between witnessed apneas in CU elderly and elevated tau-PET signal in tau-susceptible brain regions. These results suggest a plausible mechanism that could contribute to cognitive impairment and the development of Alzheimer disease. Longitudinal observations are necessary to determine direction of causality.

ObjectiveTo determine whether quantitative polysomnographic REM sleep without atonia (RSWA) distinguishes between cognitive impairment phenotypes.BackgroundNeurodegenerative cognitive impairment in older adults predominantly correlates with tauopathy or synucleinopathy. Accurate antemortem phenotypic diagnosis has important prognostic and treatment implications; additional clinical tools might distinguish between dementia syndromes.MethodsWe quantitatively analyzed RSWA in 61 older adults who underwent polysomnography including 46 with cognitive impairment (20 probable synucleinopathy), 26 probable non-synucleinopathy (15 probable Alzheimer disease, 11 frontotemporal lobar dementia), and 15 age- and sex-matched controls. Submentalis and anterior tibialis RSWA metrics and automated REM atonia index were calculated. Group statistical comparisons and regression were performed, and receiver operating characteristic curves determined diagnostic RSWA thresholds that best distinguished synucleinopathy phenotype.ResultsSubmentalis—but not anterior tibialis RSWA—was greater in synucleinopathy than nonsynucleinopathy; several RSWA diagnostic thresholds distinguished synucleinopathy with excellent specificity including submentalis tonic, 5.6% (area under the curve [AUC] 0.791); submentalis any, 15.0% (AUC 0.871); submentalis phasic, 10.8% (AUC 0.863); and anterior tibialis phasic, 31.4% (AUC 0.694). In the subset of patients without dream enactment behaviors, submentalis RSWA was also greater in patients with synucleinopathy than in those without synucleinopathy. RSWA was detected more frequently by quantitative than qualitative methods (p = 0.0001).ConclusionElevated submentalis RSWA distinguishes probable synucleinopathy from probable nonsynucleinopathy in cognitively impaired older adults, even in the absence of clinical dream enactment symptoms.Classification of evidenceThis study provides Class III evidence that quantitative RSWA analysis is useful for distinguishing cognitive impairment phenotypes. Further studies with pathologic confirmation of dementia diagnoses are needed to confirm the diagnostic utility of RSWA in dementia.

Introduction: Cerebrovascular disease (CVD) and neuropsychiatric symptoms (NPS) are common in older adults and are independently associated with cognitive impairment. In addition, vascular depression (a late-life depression) is hypothesized to be associated with cerebrovascular pathology. Hypothesis: CVD pathology imaging biomarkers (e.g., white matter hyperintensities (WMH), infarctions) are associated with depression and anxiety, and both (depression/anxiety and CVD imaging biomarkers) are independently associated with mild cognitive impairment (MCI). Methods: This cross-sectional study included 1739 Mayo Clinic Study of Aging participants (≥50 years old) without dementia, with comprehensive cognitive evaluations and available data on the Beck Depression Inventory II (BDI), the Beck Anxiety Inventory (BAI) and imaging CVD biomarkers via FLAIR-MRI (i.e., WMH% of total intracranial volume (TIV) and brain infarctions). We used linear and logistic regression models to examine the associations adjusting for age, sex, education, and apolipoprotein E ε4 status. Results: Participants’ mean age (SD) was 71.11 (10.61) years (53.3% males). Higher WMH% TIV burden was significantly associated with higher BDI (b= 0.082, 95%CI: 0.031, 0.133), p=0.002) and BAI scores (b= 0.088, 95%CI: 0.037, 0.140), p=0.001); the presence of infarctions was also associated with a higher BDI score. Both WMH %TIV burden (OR: 1.20 (95%CI:1.05, 1.38), p=0.008) and BDI score (OR: 1.38 (95%CI:1.21, 1.57), p Conclusions: CVD imaging biomarkers and NPS, as measured by BDI and BAI scores, could represent two distinct processes associated with cognitive impairment. Studies are ongoing to further examine these associations and delineate how CVD, NPS, and other pathophysiology processes (e.g., Alzheimer’s disease) interact and are associated with cognitive impairment.

ObjectiveTo determine the frequency of high-convexity tight sulci (HCTS) in a population-based sample and whether the presence of HCTS and related features influenced participants' cognitive status and classification within the new Alzheimer-biomarker framework.MethodsWe analyzed 684 participants ≥50 years of age who were enrolled in the prospective population-based Mayo Clinic Study of Aging and underwent structural MRI, amyloid PET imaging, and tau PET imaging. A fully automated machine-learning algorithm that had been developed previously in house was used to detect neuroimaging features of HCTS. On the basis of PET and MRI measures, participants were classified as having normal (A−) or abnormal (A+) amyloid, normal (T−) or abnormal (T+) tau, and normal (N−) or abnormal (N+) neurodegeneration. The neuropsychological battery assessed domain-specific and global cognitive scores. Gait speed also was assessed. Analyses were adjusted for age and sex.ResultsOf 684 participants, 45 (6.6%) were classified with HCTS according to the automated algorithm. Patients with HCTS were older than patients without HCTS (mean [SD] 78.0 [8.3] vs 71.9 [10.8] years; p < 0.001). More were cognitively impaired after age and sex adjustment (27% vs 9%; p = 0.005). Amyloid PET status was similar with and without HCTS, but tau PET standard uptake value ratio (SUVR) was lower for those with HCTS after age and sex adjustment (p < 0.001). Despite a lower tau SUVR, patients with HCTS had lower Alzheimer disease (AD) signature cortical thickness. With the amyloid-tau-neurodegeneration framework, HCTS was overrepresented in the T−(N)+ group, regardless of amyloid status.ConclusionThe HCTS pattern represents a definable subgroup of non-AD pathophysiology (i.e., T−[N]+) that is associated with cognitive impairment. HCTS may confound clinical and biomarker interpretation in AD clinical trials.

ObjectiveTo describe the prevalence of cerebral microbleeds (CMBs) and determine the association between CMBs and β-amyloid burden on PET.MethodsFrom the population-based Mayo Clinic Study of Aging, 1,215 participants (53% male) underwent 3-tesla MRI scans with T2* gradient recalled echo sequences from October 2011 to February 2017. A total of 1,123 participants (92%) underwent 11C-Pittsburgh compound B (PiB)-PET scans. The prevalence of CMBs was derived by adjusting for nonparticipation and standardizing to the Olmsted County, MN, population. The relationship between β-amyloid burden and CMB presence and location was tested using logistic regression models. Ordinal logistic models tested the relationship between CMB frequency and β-amyloid burden.ResultsTwo hundred seventy-four participants (22.6%) had at least one CMB. CMB frequency increased with age by decade (11% aged 60–69 years, 22% 70–79 years, and 39% 80 years and older). After adjusting for age, sex, and hypertension, PiB standardized uptake value ratio (SUVR) was associated with increased odds of a CMB. The association between PiB SUVR and CMBs was location-specific; PiB SUVR was associated with lobar CMBs but not deep CMBs. Age, hypertension, and PiB SUVR were associated with increasing CMB count. CMB density was greatest in parietal and occipital regions; β-amyloid burden correlated with concentration of CMBs in all lobar regions. Among participants with multiple CMBs, greater PiB uptake occurred in the pre- and postcentral gyri superiorly, the superior parietal lobe and precuneus, the angular gyrus, inferior temporal gyrus, and temporal poles.ConclusionsThe prevalence of CMBs increases with age. In this population-based sample, β-amyloid load was associated with lobar but not with deep CMBs.

Background: Atrial fibrillation (AF) is an established risk factor for ischemic stroke, but it can be paroxysmal and may go undiagnosed. An artificial intelligence (AI)-enabled ECG acquired during normal sinus rhythm was recently shown to detect silent AF. The objective of this study was to determine if AI-ECG AF score is associated with presence of cerebral infarcts. Methods: Participants from a population-based study ages 30 to 95 years with T2 fluid attenuation inversion recovery (FLAIR) MRI obtained between October 10, 2011, and November 2, 2017 were considered for inclusion. Participants without ECG were excluded. AI-ECG score was calculated using most recent ECG with normal sinus rhythm at the time of MRI. Presence of infarcts was determined on FLAIR MRI scans. Logistic regression was run to evaluate the relationship between AI-ECG AF score and presence of cerebral infarcts. Similar analyses were performed using history of AF rather than AI-ECG AF score as predictor. Age and sex were included as covariates. We also examined whether a high-threshold AI-ECG score was associated with infarcts. In a prior study, an AI-ECG AF score > 0.5 was associated with a cumulative incidence of AF of 21.5% at 2 years and 52.2% at 10 years. Results: This study included 1,373 individuals. Average age was 69.6 years and 53% of participants were male. There were 136 (10%) individuals with ECG-confirmed AF; 1237 (90%) participants had no AF history. Of participants with AF, 23% (n=31) were on anticoagulation, 47% (n=64) were on antiplatelet and 18% (n=24) were on dual therapy. Only 1.3% (n=16) of patients without AF were on anticoagulation and 47% (n=578) were on antiplatelet therapy. Ischemic infarcts were detected in 214 (15.6%) patients. As a continuous measure AI-ECG was associated with infarcts but not after adjusting for age and sex (p=0.46). AI-ECG AF score > 0.5 was associated with infarcts ( p < 0.001); even after adjusting for age and sex ( p = 0.03). History of AF was also associated with infarcts after adjusting for age and sex ( p = 0.018). Conclusion: AI-ECG AF score and history of AF were associated with presence of cerebral infarcts after adjusting for age and sex. This tool could be useful in select patients with cryptogenic stroke but further investigation would be required.

Objective:To estimate the prevalence of elevated brain amyloid and reduced cortical thickness (as a marker for neurodegeneration) in a defined population.Methods:Mayo Clinic Study of Aging participants underwent MRI to assess a composite Alzheimer disease (AD) signature cortical thickness measure and PET to assess brain amyloid accumulation. Participants were characterized as having elevated amyloid (A+/A−), reduced cortical thickness (N+/N−), and A+N+, A+N−, A−N+, or A−N−. The prevalence of AD biomarkers was derived by adjusting for nonparticipation and standardizing to the Olmsted County, Minnesota, population.Results:Among 1,646 participants without dementia (mean age 70.8 years; 53.2% men), the prevalence (95% confidence interval) of amyloidosis was 21.1% (19.1%–23.2%): women, 24.3%; men, 17.5%. The prevalence of reduced cortical thickness was 28.9% (26.4%–31.5%): women, 27.9%; men, 30.2%. The prevalence estimates of biomarker categories were as follows: A−N−: 61.4%; A+N−: 9.7%; A−N+: 17.4%; and A+N+: 11.5%, and varied by sex and by APOE ε4 carrier status. In men, prevalence estimates were as follows: A−N−: 62.6%; A+N−: 7.3%; A−N+: 19.9%; and A+N+: 10.2%. In women, prevalence estimates were as follows: A−N−: 60.4%; A+N−: 11.7%; A−N+: 15.3%; and A+N+: 12.6%. In ε4 carriers, prevalence estimates were as follows: A−N−: 54.6%; A+N−: 16.6%; A−N+: 12.4%; and A+N+: 16.4%. In non-ε4 carriers, prevalence estimates were as follows: A−N−: 63.3%; A+N−: 6.9%; A−N+: 19.9%; and A+N+: 10.0%.Conclusions:These prevalence estimates are important for understanding age-related trends in amyloid positivity and AD signature cortical thickness in the population, and for potentially projecting the future burden of biomarkers in elderly persons.

Background: Although white matter hyperintensities (WMH) have been viewed as a marker of vascular disease, pathology studies have found an association of WMH with Alzheimer’s disease (AD) pathologies. Our objective was to investigate the topographic patterns of WMH associated with AD biomarkers. Methods: From the population-based Mayo Clinic Study of aging, 434 non-demented participants with FLAIR-MRI, tau-PET and PiB-PET scans were identified. A subset had microbleeds on T2* GRE scans. We ran SPM12 based voxel-wise multiple regression analyses to detect WMH regions associated with AD biomarkers (global amyloid from PiB-PET and meta-ROI tau uptake from tau-PET) adjusting for age, sex, and hypertension. For amyloid associations, we additionally adjusted for tau and vice versa. Results: Topographic patterns of WMH associated with amyloid after both voxel and cluster level corrections primarily included periventricular WMH (frontal and parietal lobes). Masks with lenient threshold (greater detection sensitivity) and strict thresholds (greater detection specificity) are shown in the figure. (A) and (B) show the areas of positive associations between PIB ratio and WMHs adjusted by age, sex, education, hypertension and Tau meta ROI. The sensitive mask (A) was thresholded at FDR p Conclusion: Amyloid but not tau load on PET was associated with WMH topographically. The WMH regions associated with amyloid were associated with CMBs suggesting that cerebral amyloid angiopathy may be contributing to the relationship between amyloid and WMH.

Background: Non-traumatic convexal subarachnoid hemorrhages (cSAH) in the elderly can be a manifestation of cerebral amyloid angiopathy (CAA) and predict future intracerebral hemorrhage risk. The frequency of cSAH in the elderly population is unknown. Our objective was to determine the frequency of convexal subarachnoid hemorrhage in a population-based study among individuals who underwent amyloid PET imaging. Methods: Between 11/29/2004 and 3/11/2017 there were 1,687 participants ages 50-years and older in the population-based Mayo Clinic Study of Aging (MCSA) with Pittsburgh compound B (PiB) PET imaging. All intracerebral hemorrhages among participants were identified utilizing the Rochester Epidemiology Project’s records linkage system, and records and images were reviewed to identify those with both symptomatic and asymptomatic convexal subarachnoid hemorrhage. Neuroimaging characteristics, demographics, medications, and ApoE genotype were recorded. Results: Four (0.23%) cSAHs were identified among the individuals who underwent PiB PET imaging. Three were women and median age was 73 (range: 67-84). cSAH occurred in the following locations: right frontal (3), and right parieto-occipital (1). Two went on to develop a lobar intracerebral hemorrhage at a median of 4.75 years after cSAH. Coexisting cerebral microbleeds were identified in one case. The APOE allele combinations of the four participants were: 3/3, 3/3, 2/2, and 2/3. On PiB PET imaging, the median SUVR was 1.81 (range: 1.38-2.34). Conclusion: cSAH is a relatively rare manifestation of CAA occurring in less than 1% of the general population, but may represent a subset with a high risk of future intracerebral hemorrhage. Half of the participants with cSAH had an APOE e2 allele.

Introduction: Cerebral microbleed (CMB) location may predict underlying pathology. Deep CMBs are more associated with hypertensive vascular disease, while lobar CMBs are more associated with cerebral amyloid angiopathy (CAA). The objective of this study was to determine the neuroimaging pathology associated with CMBs. Methods: We analyzed 1,831 nondemented ARIC participants (mean age=76.3 ±5.3 years, 40% male, 27% black) with 3T MRI scans at the fifth exam (2011-13). We fit multinomial logistic regression models to assess the effect of brain volumes (AD signature region atrophy, total gray matter, frontal, and log 2 -transformed white matter hyperintensities (WMH) volume), infarct frequencies (lacunar, non-lacunar, and total), and APOE (number of ε4 alleles) on CMB location (no, any deep, or lobar only CMBs). Models were weighted for the sample selection scheme and adjusted for age, male, education, hypertension, ever smoking status, diabetes, race-site membership, and estimated intracranial volume (brain volume models only). Results: The frequency of CMBs was 24.1%. A larger WMH volume, greater total infarct frequency, and smaller total grey volume increased the relative risks (RR) of both deep and lobar CMBs compared to no CMBs; increasing the WMH volume also increased the RR of deep to lobar CMBs. Additional lacunar infarcts increased the RR of deep compared to no CMBs, whereas AD signature region atrophy and APOE ε4 homozygosity increased the RR of lobar CMBs. Conclusion: CMBs are a common vascular pathology in the elderly. Deep CMB presence is associated with MRI features of hypertensive small vessel disease, while lobar CMB presence is associated with MRI features of CAA and Alzheimer’s disease.

Introduction: Cortical superficial siderosis (cSS) refers to deposition of blood breakdown products along the cerebral cortex, causing characteristic staining patterns seen with iron-sensitive MRI techniques. Cortical superficial siderosis is a relatively rare disorder, but has been linked to cerebral amyloid angiopathy and Alzheimer’s disease. The objective of this study was to determine the frequency and natural history of cSS in the general elderly population. Methods: MRI scans from the Mayo Clinic Study of Aging (MCSA), an ongoing population-based study of elderly residents in Olmsted County, Minnesota, were reviewed by neuroradiologists. Participants with cSS were identified based on linear pattern of hypointensity on gradient recalled echo imaging consistent with cSS. Exclusion criteria were: 1) MRI findings not consistent with cSS or 2) alternative explanation for MRI findings (such as aneurysmal subarachnoid hemorrhage, intracranial surgery, or trauma). Additional data abstracted included extent of cSS, presence of cerebral microbleeds, and clinical outcome. Results: Eleven out of 1,441 participants had MRI scans showing cSS (0.8%). When stratified by age, the frequency was 0.4% in those 50 to 70 years old and 1.1% in those over 70 years old. Six participants had only focal involvement of cSS (restricted to three or fewer sulci) and five had disseminated involvement (affecting more than three sulci). Microbleeds were seen in four of five (80%) participants with disseminated cSS, but none with focal cSS. Five participants (2 focal, 3 disseminated cSS) had follow up MRI scans, with an average follow up of 25 months. There was no further hemorrhage in those with focal cSS. However, all three participants with disseminated cSS experienced additional hemorrhage: one with new microbleeds, one with new microbleeds and lobar hemorrhage, and one with sulcal subarachnoid hemorrhage and lobar hemorrhage. Conclusion: Although rare, cSS may be encountered in the general elderly population. Extent of involvement of cSS and concomitant microbleeds may be important risk factors for progression of disease and intracerebral hemorrhage. The clinical significance of focal cSS occurring in the absence of microbleeds requires further investigation.

Objective: To determine antemortem MRI findings associated with microinfarcts at autopsy. Methods: Patients with microinfarcts (n = 22) and patients without microinfarcts (n = 44) who underwent antemortem MRI were identified from a dementia clinic–based, population–based, and community clinic–based autopsy cohort. The microinfarct and no-microinfarct groups were matched on age at MRI, age at death, sex, APOE status, Mini-Mental State Examination score, and pathologic diagnosis of Alzheimer disease. Brain infarcts were assessed on fluid-attenuated inversion recovery (FLAIR) MRI. White matter hyperintensities on FLAIR MRI and hippocampal volumes on T1-weighted MRI were quantified using automated methods. A subset of subjects with microinfarcts (n = 15) and a matched group of subjects without microinfarcts (n = 15) had serial T1-weighted MRIs and were included in an analysis of global and regional brain atrophy rates using automated methods. Results: The presence of cortical ( p = 0.03) and subcortical ( p = 0.02) infarcts on antemortem MRI was associated with presence of microinfarcts at autopsy. Higher numbers of cortical ( p = 0.05) and subcortical ( p = 0.03) infarcts on antemortem MRI were also associated with presence of microinfarcts. Presence of microinfarcts was not associated with white matter hyperintensities and cross-sectional hippocampal volume on antemortem MRI. Whole-brain and regional precuneus, motor, and somatosensory atrophy rates were higher in subjects with microinfarcts compared to subjects without microinfarcts. Conclusions: Microinfarcts increase brain atrophy rates independent of Alzheimer disease pathology. Association between microinfarct pathology and macroinfarcts on MRI suggests either common risk factors or a shared pathophysiology and potentially common preventive targets.

Objective: To test the hypotheses predicted in a hypothetical model of Alzheimer disease (AD) biomarkers that rates of β-amyloid (Aβ) accumulation on PET imaging are not related to hippocampal neurodegeneration whereas rates of neurodegenerative brain atrophy depend on the presence of both amyloid and neurodegeneration in a population-based sample. Methods: A total of 252 cognitively normal (CN) participants from the Mayo Clinic Study of Aging had 2 or more serial visits with both amyloid PET and MRI. Subjects were classified into 4 groups based on baseline positive/negative amyloid PET (A+ or A−) and baseline hippocampal volume (N+ or N−). We compared rates of amyloid accumulation and rates of brain atrophy among the 4 groups. Results: At baseline, 148 (59%) were amyloid negative and neurodegeneration negative (A−N−), 29 (12%) amyloid negative and neurodegeneration positive (A−N+), 56 (22%) amyloid positive and neurodegeneration negative (A+N−), and 19 (8%) amyloid positive and neurodegeneration positive (A+N+). High rates of Aβ accumulation were found in those with abnormal amyloid at baseline and were not influenced by hippocampal neurodegeneration at baseline. In contrast, rates of brain atrophy were greatest in A+N+. Conclusions: We describe a 2-feature biomarker approach to classifying elderly CN subjects that is complementary to the National Institute on Aging–Alzheimer9s Association preclinical staging criteria. Our results support 2 key concepts in a model of the temporal evolution of AD biomarkers. First, the rate of Aβ accumulation is not influenced by neurodegeneration and thus may be a biologically independent process. Second, Aβ pathophysiology increases or catalyzes neurodegeneration.

Objectives: We determined whether head trauma was associated with amyloid deposition and neurodegeneration among individuals who were cognitively normal (CN) or had mild cognitive impairment (MCI). Methods: Participants included 448 CN individuals and 141 individuals with MCI from the Mayo Clinic Study of Aging who underwent Pittsburgh compound B (PiB)-PET, fluorodeoxyglucose-PET, and MRI. Head trauma was defined as a self-reported brain injury with at least momentary loss of consciousness or memory. Regression models examined whether head trauma was associated with each neuroimaging variable (assessed as continuous and dichotomous measures) in both CN and MCI participants, controlling for age and sex. Results: Among 448 CN individuals, 74 (17%) self-reported a head trauma. There was no difference in any neuroimaging measure between CN subjects with and without head trauma. Of 141 participants with MCI, 25 (18%) self-reported a head trauma. MCI participants with a head trauma had higher amyloid levels (by an average 0.36 standardized uptake value ratio units, p = 0.002). Conclusions: Among individuals with MCI, but not CN individuals, self-reported head trauma with at least momentary loss of consciousness or memory was associated with greater amyloid deposition, suggesting that head trauma may be associated with Alzheimer disease–related neuropathology. Differences between CN individuals and individuals with MCI raise questions about the relevance of head injury–PET abnormality findings in those with MCI.

Objective: To estimate the incidence of and to characterize cognitive and imaging findings associated with incident amyloid PET positivity. Methods: Cognitively normal (CN) participants in the Mayo Clinic Study of Aging who had 2 or more serial imaging assessments, which included amyloid PET, FDG-PET, and MRI at each time point, were eligible for analysis (n = 207). Twelve subjects with Alzheimer disease dementia were included for comparison. Results: Of the 123 CN participants who were amyloid-negative at baseline, 26 met criteria for incident amyloid PET positivity. Compared to the 69 subjects who remained stable amyloid-negative, on average these 26 did not differ on any imaging, demographic, or cognitive variables except amyloid PET (by definition) and task-free functional connectivity, which at baseline was greater in the incident amyloid-positive group. Eleven of the 26 incident amyloid-positive subjects had abnormal hippocampal volume, FDG-PET, or both at baseline. Conclusions: The incidence of amyloid PET positivity is approximately 13% per year among CN participants over age 70 sampled from a population-based cohort. In 15/26 (58%), incident amyloid positivity occurred prior to abnormalities in FDG-PET and hippocampal volume. However, 11/26 (42%) incident amyloid-positive subjects had evidence of neurodegeneration prior to incident amyloid positivity. These 11 could be subjects with combinations of preexisting non-Alzheimer pathophysiologies and tau-mediated neurodegeneration who newly entered the amyloid pathway. Our findings suggest that both “amyloid-first” and “neurodegeneration-first” biomarker profile pathways to preclinical AD exist.

ObjectiveTo determine structural MRI and digital microscopic characteristics of REM sleep behavior disorder in individuals with low-, intermediate-, and high-likelihood dementia with Lewy bodies (DLB) at autopsy.MethodsPatients with autopsy-confirmed low-, intermediate-, and high-likelihood DLB, according to the probability statement recommended by the third report of the DLB Consortium, and antemortem MRI, were identified (n = 75). The clinical history was assessed for presence (n = 35) and absence (n = 40) of probable REM sleep behavior disorder (pRBD), and patients' antemortem MRIs were compared using voxel-based morphometry. Pathologic burdens of phospho-tau, β-amyloid, and α-synuclein were measured in regions associated with early neuropathologic involvement, the hippocampus and amygdala.ResultspRBD was present in 21 patients (60%) with high-likelihood, 12 patients (34%) with intermediate-likelihood, and 2 patients (6%) with low-likelihood DLB. Patients with pRBD were younger, more likely to be male (p ≤ 0.001), and had a more frequent neuropathologic diagnosis of diffuse (neocortical) Lewy body disease. In the hippocampus and amygdala, phospho-tau and β-amyloid burden were lower in patients with pRBD compared with those without pRBD (p < 0.01). α-Synuclein burden did not differ in the hippocampus, but trended in the amygdala. Patients without pRBD had greater atrophy of temporoparietal cortices, hippocampus, and amygdala (p < 0.001) than those with pRBD; atrophy of the hippocampus (p = 0.005) and amygdala (p = 0.02) were associated with greater phospho-tau burdens in these regions.ConclusionPresence of pRBD is associated with a higher likelihood of DLB and less severe Alzheimer-related pathology in the medial temporal lobes, whereas absence of pRBD is characterized by Alzheimer-like atrophy patterns on MRI and increased phospho-tau burden.

Objective: To investigate MRI and proton magnetic resonance spectroscopy (MRS) predictors of mild cognitive impairment (MCI) in cognitively normal older adults. Methods: Subjects were cognitively normal older adults (n = 1,156) who participated in the population-based Mayo Clinic Study of Aging MRI/MRS study from August 2005 to December 2010 and had at least one annual clinical follow-up. Single-voxel MRS was performed from the posterior cingulate gyri, and hippocampal volumes and white matter hyperintensity volumes were quantified using automated methods. Brain infarcts were assessed on MRI. Cox proportional hazards regression, with age as the time scale, was used to assess the effect of MRI and MRS markers on the risk of progression from cognitively normal to MCI. Linear mixed-effects models were used to assess the effect of MRI and MRS markers on cognitive decline. Results: After a median follow-up of 2.8 years, 214 participants had progressed to MCI or dementia (estimated incidence rate = 6.1% per year; 95% confidence interval = 5.3%–7.0%). In univariable modeling, hippocampal volume, white matter hyperintensity volume, and N -acetylaspartate/ myo -inositol were significant predictors of MCI in cognitively normal older adults. In multivariable modeling, only decreased hippocampal volume and N -acetylaspartate/ myo -inositol were independent predictors of MCI. These MRI/MRS predictors of MCI as well as infarcts were associated with cognitive decline ( p Conclusion: Quantitative MRI and MRS markers predict progression to MCI and cognitive decline in cognitively normal older adults. MRS may contribute to the assessment of preclinical dementia pathologies by capturing neurodegenerative changes that are not detected by hippocampal volumetry.

To determine the association of conventional cardiovascular risk factors, markers of platelet activation, and thrombogenic blood-borne microvesicles with white matter hyperintensity (WMH) load and progression in recently menopausal women.Women (n = 95) enrolled in the Mayo Clinic Kronos Early Estrogen Prevention Study underwent MRI at baseline and at 18, 36, and 48 months after randomization to hormone treatments. Conventional cardiovascular risk factors, carotid intima-medial thickness, coronary arterial calcification, plasma lipids, markers of platelet activation, and thrombogenic microvesicles were measured at baseline. WMH volumes were calculated using a semiautomated segmentation algorithm based on fluid-attenuated inversion recovery MRI. Correlations of those parameters with baseline WMH and longitudinal change in WMH were adjusted for age, months past menopause, and APOE ε4 status in linear regression analysis.At baseline, WMH were present in all women. The WMH to white matter volume fraction at baseline was 0.88% (0.69%, 1.16%). WMH volume increased by 122.1 mm(3) (95% confidence interval: -164.3, 539.5) at 36 months (p = 0.003) and 155.4 mm(3) (95% confidence interval: -92.13, 599.4) at 48 months (p0.001). These increases correlated with numbers of platelet-derived and total thrombogenic microvesicles at baseline (p = 0.03).Associations of platelet-derived, thrombogenic microvesicles at baseline and increases in WMH suggest that in vivo platelet activation may contribute to a cascade of events leading to development of WMH in recently menopausal women.

Objectives: Secondary prevention trials in subjects with preclinical Alzheimer disease may require documentation of brain amyloidosis. The identification of inexpensive and noninvasive screening variables that can identify individuals who have significant amyloid accumulation would reduce screening costs. Methods: A total of 483 cognitively normal (CN) individuals, aged 70–92 years, from the population-based Mayo Clinic Study of Aging, underwent Pittsburgh compound B (PiB)–PET imaging. Logistic regression determined whether age, sex, APOE genotype, family history, or cognitive performance was associated with odds of a PiB retention ratio >1.4 and >1.5. Area under the receiver operating characteristic curve (AUROC) evaluated the discrimination between PiB-positive and -negative subjects. For each characteristic, we determined the number needed to screen in each age group (70–79 and 80–89) to identify 100 participants with PiB >1.4 or >1.5. Results: A total of 211 (44%) individuals had PiB >1.4 and 151 (31%) >1.5. In univariate and multivariate models, discrimination was modest (AUROC ∼0.6–0.7). Multivariately, age and APOE best predicted odds of PiB >1.4 and >1.5. Subjective memory complaints were similar to cognitive test performance in predicting PiB >1.5. Indicators of PiB positivity varied with age. Screening APOE e4 carriers alone reduced the number needed to screen to enroll 100 subjects with PIB >1.5 by 48% in persons aged 70–79 and 33% in those aged 80–89. Conclusions: Age and APOE genotype are useful predictors of the likelihood of significant amyloid accumulation, but discrimination is modest. Nonetheless, these results suggest that inexpensive and noninvasive measures could significantly reduce the number of CN individuals needed to screen to enroll a given number of amyloid-positive subjects.

To determine the association between the focal atrophy measures on antemortem MRI and postmortem neuropathologic classification of dementia with Lewy bodies (DLB) using the Third Report of the DLB Consortium criteria.We retrospectively identified 56 subjects who underwent antemortem MRI and had Lewy body (LB) pathology at autopsy. Subjects were pathologically classified as high (n = 25), intermediate (n = 22), and low likelihood DLB (n = 9) according to the Third Report of the DLB Consortium criteria. We included 2 additional pathologic comparison groups without LBs: one with low likelihood Alzheimer disease (AD) (control; n = 27) and one with high likelihood AD (n = 33). The associations between MRI-based volumetric measurements and the pathologic classification of DLB were tested with analysis of covariance by adjusting for age, sex, and MRI-to-death interval.Antemortem hippocampal and amygdalar volumes increased from low to intermediate to high likelihood DLB (p0.001, trend test). Smaller hippocampal and amygdalar volumes were associated with higher Braak neurofibrillary tangle stage (p0.001). Antemortem dorsal mesopontine gray matter (GM) atrophy was found in those with high likelihood DLB compared with normal control subjects (p = 0.004) and those with AD (p = 0.01). Dorsal mesopontine GM volume decreased from low to intermediate to high likelihood DLB (p = 0.01, trend test).Antemortem hippocampal and amygdalar volumes increase and dorsal mesopontine GM volumes decrease in patients with low to high likelihood DLB according to the Third Report of the DLB Consortium criteria. Patients with high likelihood DLB typically have normal hippocampal volumes but have atrophy in the dorsal mesopontine GM nuclei.

Objective: To investigate age-related default mode network (DMN) connectivity in a large cognitively normal elderly cohort and in patients with Alzheimer disease (AD) compared with age-, gender-, and education-matched controls. Methods: We analyzed task-free–fMRI data with both independent component analysis and seed-based analysis to identify anterior and posterior DMNs. We investigated age-related changes in connectivity in a sample of 341 cognitively normal subjects. We then compared 28 patients with AD with 56 cognitively normal noncarriers of the APOE ϵ4 allele matched for age, education, and gender. Results: The anterior DMN shows age-associated increases and decreases in fontal lobe connectivity, whereas the posterior DMN shows mainly age-associated declines in connectivity throughout. Relative to matched cognitively normal controls, subjects with AD display an accelerated pattern of the age-associated changes described above, except that the declines in frontal lobe connectivity did not reach statistical significance. These changes survive atrophy correction and are correlated with cognitive performance. Conclusions: The results of this study indicate that the DMN abnormalities observed in patients with AD represent an accelerated aging pattern of connectivity compared with matched controls.

Objective: To compare the annual change in MRI and CSF biomarkers in cognitively normal (CN), amnestic mild cognitive impairment (aMCI), and Alzheimer disease (AD). Comparisons were based on intergroup discrimination, correlation with concurrent cognitive/functional changes, relationships to APOE genotype, and sample sizes for clinical trials.Methods: We used data from the Alzheimer's Disease Neuroimaging Initiative study consisting of CN, aMCI, and AD cohorts with both baseline and 12-month follow-up CSF and MRI. The annual change in CSF (total-tau [t-tau], Aβ1-42) and MRI (change in ventricular volume) was obtained in 312 subjects (92 CN, 149 aMCI, 71 AD).Results: There was no significant average annual change in either CSF biomarker in any clinical group except t-tau in CN; moreover, the annual change did not differ by clinical group in pairwise comparisons. In contrast, annual increase in ventricular volume increased in the following order, AD > aMCI > CN, and differences were significant between all clinical groups in pairwise comparisons. Ventricular volume increase correlated with concurrent worsening on cognitive/functional indices in aMCI and AD whereas evidence of a similar correlation with change in CSF measures was unclear. The annual changes in MRI differed by APOE ε4 status overall and among aMCI while annual changes in CSF biomarkers did not. Estimated sample sizes for clinical trials are notably less for MRI than the CSF or clinical measures.Conclusions: Unlike the CSF biomarkers evaluated, changes in serial structural MRI are correlated with concurrent change on general cognitive and functional indices in impaired subjects, track with clinical disease stage, and are influenced by APOE genotype.

Objective: To investigate the relationship between baseline MRI and CSF biomarkers and subsequent change in continuous measures of cognitive and functional abilities in cognitively normal (CN) subjects and patients with amnestic mild cognitive impairment (aMCI) and Alzheimer disease (AD) and to examine the ability of these biomarkers to predict time to conversion from aMCI to AD. Methods: Data from the Alzheimer9s Disease Neuroimaging Initiative, which consists of CN, aMCI, and AD cohorts with both CSF and MRI, were used. Baseline CSF (t-tau, Aβ 1–42 , and p-tau 181P ) and MRI scans were obtained in 399 subjects (109 CN, 192 aMCI, 98 AD). Structural Abnormality Index (STAND) scores, which reflect the degree of AD-like features in MRI, were computed for each subject. Results: Change on continuous measures of cognitive and functional performance was modeled as average Clinical Dementia Rating–sum of boxes and Mini-Mental State Examination scores over a 2-year period. STAND was a better predictor of subsequent cognitive/functional change than CSF biomarkers. Single-predictor Cox proportional hazard models for time to conversion from aMCI to AD showed that STAND and log (t-tau/Aβ 1–42 ) were both predictive of future conversion. The age-adjusted hazard ratio for an interquartile change (95% confidence interval) of STAND was 2.6 (1.7, 4.2) and log (t-tau/Aβ 1–42 ) was 2.0 (1.1, 3.4). Both MRI and CSF provided information about future cognitive change even after adjusting for baseline cognitive performance. Conclusions: MRI and CSF provide complimentary predictive information about time to conversion from amnestic mild cognitive impairment to Alzheimer disease and combination of the 2 provides better prediction than either source alone. However, we found that MRI was a slightly better predictor of future clinical/functional decline than the CSF biomarkers tested.

Objective: To determine the anatomic correlate of prosopagnosia in subjects with semantic dementia. Methods: We identified all subjects who had been evaluated by an experienced behavioral neurologist, met criteria for semantic dementia, and had completed a volumetric head MRI scan. In all subjects, historical records were reviewed and subjects in which the presence (n = 15) or absence (n = 12) of prosopagnosia was specifically ascertained by the neurologist were identified. Voxel-based morphometry was used to assess patterns of gray matter atrophy in subjects with and without prosopagnosia compared to a group of age and gender-matched normal controls, and compared to each other. Results: Compared to controls, both groups showed prominent temporal lobe volume loss. Those with prosopagnosia showed bilateral loss but with greater involvement of the right temporal lobe, while those without prosopagnosia showed predominantly left anterior temporal lobe loss. On direct comparison, subjects with prosopagnosia showed greater loss predominantly in the right amygdala, hippocampus, fusiform gyrus, and anterior temporal pole than those without prosopagnosia. No regions were involved to a greater degree in those without prosopagnosia, compared to those with prosopagnosia. Conclusions: Prosopagnosia appears to be associated with volume loss of the right temporal lobe, particularly medial temporal lobe, fusiform gyrus, and anterior temporal pole, although in semantic dementia it is occurring in the context of bilateral temporal lobe volume loss.

Background: Neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau proteins, are one of the pathologic hallmarks of Alzheimer disease (AD). We aimed to determine whether patterns of gray matter atrophy from antemortem MRI correlate with Braak staging of NFT pathology. Methods: Eighty-three subjects with Braak stage III through VI, a pathologic diagnosis of low- to high-probability AD, and MRI within 4 years of death were identified. Voxel-based morphometry assessed gray matter atrophy in each Braak stage compared with 20 pathologic control subjects (Braak stages 0 through II). Results: In pairwise comparisons with Braak stages 0 through II, a graded response was observed across Braak stages V and VI, with more severe and widespread loss identified at Braak stage VI. No regions of loss were identified in Braak stage III or IV compared with Braak stages 0 through II. The lack of findings in Braak stages III and IV could be because Braak stage is based on the presence of any NFT pathology regardless of severity. Actual NFT burden may vary by Braak stage. Therefore, tau burden was assessed in subjects with Braak stages 0 through IV. Those with high tau burden showed greater gray matter loss in medial and lateral temporal lobes than those with low tau burden. Conclusions: Patterns of gray matter loss are associated with neurofibrillary tangle (NFT) pathology, specifically with NFT burden at Braak stages III and IV and with Braak stage itself at higher stages. This validates three-dimensional patterns of atrophy on MRI as an approximate in vivo surrogate indicator of the full brain topographic representation of the neurodegenerative aspect of Alzheimer disease pathology.

The objective of this study was to investigate the cross-sectional associations of atrial fibrillation with neuroimaging measures of cerebrovascular disease and Alzheimer’s disease-related pathology, and their interaction with cognitive impairment. MRI scans of non-demented individuals (n=1044) from the population-based Mayo Clinic Study of Aging were analyzed for infarctions, total grey matter, hippocampal and white matter hyperintensity volumes. A subset of 496 individuals underwent FDG and C-11 Pittsburgh compound B (PiB) PET scans. We assessed the associations of atrial fibrillation with i) categorical MRI measures (cortical and subcortical infarctions) using multivariable logistic regression models, and with ii) continuous MRI measures ( hippocampal, total grey matter, and white matter hyperintensity volumes) and FDG-PET and PiB-PET measures using multivariable linear regression models, and adjusting for confounders. Among participants who underwent MRI (median age, 77.8, 51.6% male), 13.5% had atrial fibrillation. Presence of atrial fibrillation was associated with subcortical infarctions (odds ratio [OR], 1.83; p=0.002), cortical infarctions (OR, 1.91; p=0.03), total grey matter volume (Beta [β], -.025, p

Dementia affects a staggering proportion of individuals, imposing a huge cost to our society. There are currently no disease-modifying treatments for dementia, making lifestyle factors that influence dementia risk of utmost importance. One such lifestyle factor that has shown promise in delaying dementia onset is engagement in cognitively stimulating activities, such as reading, writing, and playing games.1,2 However, the mechanisms by which these activities exert protective effects remain unclear (figure).