Citations

Background: Midlife obesity is associated with dementia in later life, but how the metabolic syndrome (MetS) relates to cognitive change is less understood. We hypothesized that MetS would be more predictive of 6-year cognitive decline than its individual components in a large biethnic cohort (the ARIC study) and that combinations of risk factors would further increase likelihood of change. Methods: The MetS was defined in 1987-89 on 10,687 participants with two cognitive assessments at two time points. In subjects aged 44 to 66, obesity measures included body mass index (BMI) and waist-to-hip ratio (WTHR). The main outcome measure was change in 1990-92 to 96-99 of three cognitive tests: Delayed Word Recall (DWR), Digit Symbol Substitution Test (DSST), and Word Fluency Test (WFT). Linear and logistic regressions were all adjusted for age, combined race-center, sex, education, smoking, drinking, coronary artery disease and prior stroke. Change was measured as the difference divided by the number of years between visits. Results: At baseline, the prevalence of MetS was 22% (mean age 54 years, 27% black, 55% female, and 28% BMI>30 kg/m2). Subjects with MetS performed in the lowest test quintile (adjusted ORs: DWR 1.3 95% CI 1.1-1.4) in 1996-99, and much of this effect size was explained by an elevated WTHR (DWR OR 1.3 CI 1.1-1.5) and diabetes (DWR OR 1.4 CI 1.2-1.7). MetS was not associated with annual cognitive change, and diabetes was the only significant component associated with change (adjusted beta: DWR 0.03 p=.01, DSST 0.2 p<.001, WFT 0.09 p=.01). Conclusion: MetS at ages 44 to 66 was associated with worse cognitive function at follow-up, but not with annual cognitive decline over several years. Elevated WTHR and diabetes explained most of the association of MetS with cognitive function measures, and diabetes with cognitive decline. Until we have a definition of the MetS more based on pathophysiology, the components of the MetS should be the focus of analysis in future studies.

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<.0001) after controlling for age, education, gender, APOE e4 carrier status, coronary artery disease, diabetes, history of clinical stroke, and hypertension. However, atrial fibrillation was not associated with white matter hyperintensity volume, hippocampal volume, Alzheimer’s pattern of FDG hypometabolism or PiB uptake. There was a significant interaction of cortical infarction (p for interaction=0.004) and subcortical infarction (p for interaction =0.015) with atrial fibrillation with regards to odds of mild cognitive impairment (MCI). Using subjects with no atrial fibrillation and no infarction as the reference, the OR (95% confidence intervals [CI]) for MCI was 2.98 (1.66, 5.35;p = 0.0002) among participants with atrial fibrillation and any infarction, 0.69 (0.36, 1.33;p= 0.27) for atrial fibrillation and no infarction, and 1.50 (0.96, 2.32;p = 0.07) for no atrial fibrillation and any infarction. These data highlight that atrial fibrillation is associated with MCI in the presence of infarctions.

Introduction: Small vessel disease is associated with decreased cognitive function, possibly differential by race. Age-related central arterial stiffening increases pulsatility resulting in hypoperfusion, microvascular damage and remodeling in the brain, potentially impairing cognition. We examined if arterial stiffness and pressure amplification are associated with lacunar infarcts and greater volumes of white matter hyperintensities (WMH) in a sample of Caucasian and African American (AA) older adults. Methods: We analyzed a cross-sectional sample of ARIC participants aged 67-90 years (n=1486) from visit 5 (2011-2013), with brain magnetic resonance imaging (MRI). The Omron VP-1000 Plus was used to measure aortic stiffness (carotid-femoral pulse wave velocity [cfPWV]) and pressure amplification measures (pulse pressure amplification [PPA], central pulse pressure [cPP], and estimated central systolic blood pressure [cSBP]). Aortic stiffness and pressure amplification were dichotomized at race-specific 25th percentile cut points. Brain MRI using 3D-1.5T equipment quantified the presence of lacunar infarcts and volumes of WMH following a standardized protocol. Logistic regression, adjusted for age, sex, education, ApoE4, heart rate, smoking and body mass index, was used to quantify the odds of lacunar infarcts in participants with high vs. low cfPWV, cPP, cSBP, and low vs. high PPA. Linear regression models, additionally adjusted for intracranial volume, estimated the difference in log-transformed volumes of WMH among participants with high vs. low cfPWV, cPP, cSBP, and low vs. high PPA. Probability sampling weights for an MRI were included to allow for generalizability to the full visit 5 cohort. Results: Among the 1486 participants with a brain MRI (mean age: 76, 41% male, 26% AA), measures of aortic stiffness and pressure amplification were associated with lacunar infarcts in Caucasians, but not in AAs. Caucasian participants with a high cfPWV had greater odds of lacunar infarcts (Odds Ratio [OR] =2.02, 95% confidence interval [CI]: 1.23, 2.20). Caucasians with high cSBP had higher odds of lacunar infarcts (OR=1.72, 95% CI: 1.10, 2.69). In Caucasians, high cfPWV was associated with a 21% (95% CI: 6, 38) greater volume of WMH as compared to a low cfPWV; high cSBP was associated with a 28% (95% CI: 14, 45) greater volume of WMH compared to a low cSBP. In AAs, high cfPWV was associated with a 32% (95% CI: 7, 62) greater volume of WMH as compared to low cfPWV. Cerebral microvascular imaging markers did not differ quantitatively with measures of PPA and cPP. Conclusions: Central arterial stiffening and pressure amplification are plausible microvascular contributors to cognitive aging, providing new information on modifiable pathways for previously observed associations between cardiovascular disease risk factors and the rates of cognitive decline and dementia among older adults.

Background: Brain infarcts, white matter hyperintensities (WMH), and brain atrophy appear to contribute to the development of mild cognitive impairment (MCI) and dementia in selected populations, but few prospective studies are available in general populations. Methods: The study included 732 black and white participants, sampled from the original ARIC cohort, who had 3T brain Magnetic Resonance Imaging (MRI) scans, were free of MCI and dementia during 2011-13 (Visit 5), and were evaluated for cognitive impairment during 2016-17 (Visit 6, about 90% complete). We assessed the associations of brain infarcts, WMH, and brain volumes measured on MRI from 2011-2013 with incident MCI and dementia (combined), diagnosed using a computer algorithm based on specified criteria and comprehensive assessment at Visit 6. We used logistic regression, incorporating sampling weights, to evaluate the risk for incident MCI/dementia with adjustment for demographic covariates, major dementia risk factors, and history of cardiovascular diseases. Results: Participants had a median age of 75 (IQR: 71, 79) at Visit 5 (baseline); 62% (453) were female and 33% (242) were African American. There were 156 newly identified cases of MCI or dementia during a median follow-up time of 4.9 (IQR: 3.4, 5.2) years. The presence of any brain infarct was associated with a nonsignificantly higher risk of MCI/dementia (OR: 1.50; 95%CI: 0.87 to 2.58), but the only significant individual association was with cortical infarcts (OR: 1.99; 95%CI: 1.03 to 3.85). WMH volume above the median value was nonsignificantly associated with conversion to MCI/dementia. Smaller Alzheimer’s disease (AD) signature region was an independent predictor for greater risk of MCI/dementia (OR: 1.49; 95%CI: 1.00 to 2.22). A similar but nonsignificant association was observed for total brain volume. Conclusions: Brain infarcts (cortical infarcts) and lower brain volume (AD signature region), measured in community-based older residents, are risk factors for MCI and dementia incidence.

Introduction: Several studies report late-life physical activity (PA) to be associated with less brain atrophy. Associations of PA and subclinical brain markers evaluated at older ages may be subject to reverse causality due to comorbidity, age-related changes in lifestyle, or incipient cognitive impairment. Therefore, we aimed to compare late-life cross-sectional estimates of PA and ROI brain volumes to those using prospective PA measures from mid- to late-life. Methods: Participants (n=1549, mean age: 75, 39% male, 20% Black) with repeat assessments of PA from visit 1 (1987-1989) and a brain magnetic resonance imaging (MRI) in 2011-2013 were included. Total volume of PA in metabolic equivalent-min/week was estimated using the Baecke Physical Activity Questionnaire and classified as no, low, middle or high at each visit. Based on visit 1 and 3 (1993-1995) PA assessments, a subset of participants (n=663) were further categorized as habitually inactive or having habitually low, middle, or high PA in mid-life. Brain MRI using 3D-1.5T equipment quantified ROI volumes following a standardized protocol. Weighted linear regression adjusted for intracranial volume, demographics, select cardiovascular risk factors and ApoE4 estimated the standardized difference in ROI volumes. Results: Compared to no PA, high PA was associated with larger ROI brain volumes cross-sectionally in late-life (Table). High mid-life PA was only modestly associated with larger frontal cortical and deep gray matter volumes in late-life (Table). Habitually high PA in mid-life was not associated with less atrophy across brain regions in late-life. Conclusions: Our results do not support a causal interpretation of the cross-sectional associations between PA and brain volumes reported in late-life. Drawing on long-term population-based data, this study provides novel information on the associations of PA across life epochs with brain health, which can inform translational and intervention efforts to reduce age-related cognitive impairment.

Background: Midlife vascular risk factors (MVRF) are associated with incident dementia. Similarly, amyloid β(Aβ) and neurodegeneration (e.g.brain volumes), as parts of the Alzheimer’s Disease (AD) ATN framework, are associated with cognition. Whether vascular and AD-associated factors contribute to dementia independently or interact synergistically to reduce cognitive ability is not well understood. Methods: Recruited from 3 U.S. communities, ARIC-PET participants were followed from 1987-89 (45-64 yo) through 2016-17 (74-94 yo). Cognition was evaluated in 2011-13 (ages 69-88), and twice more, every 2-3 years. In 2011-13, nondemented ARIC-PET participants had a brain MRI, with measurement of white matter hyperintensities (WMH) and brain volumes, with florbetapir (Aβ) PET scans in 2012-14; global cortical standardized uptake value ratio (SUVR) was log-transformed and standardized. Dementia was classified by expert review, as well as phone and medical record surveillance. The relative contributions of vascular risk (MVRF, WMH volume) and AD pathology (elevated Aβ SUVR, smaller AD signature region volumes) to incident dementia were evaluated with Cox proportional hazards regression. Results: In 298 individuals, 36 developed dementia. In models with key MVRF, demographics, and Aβ SUVR, hypertension and Aβ each independently predicted dementia risk (per SD of Aβ SUVR: HR 2.57, 95% CI 1.72-3.84; hypertension: HR 2.57, 95% CI 1.16-5.67), but didn’t interact on dementia risk. WMH (per SD: HR 1.51, 95% CI 1.03-2.20) and Aβ SUVR (per SD: HR 2.52, 95% CI 1.83-3.47) each contributed to incident dementia but WMH lost significance when MVRF were added to the model. Smaller AD signature regions were associated with incident dementia, independent of Aβ SUVR, and remained significant after adjustment for MVRF (HR per SD 2.18, 95% CI 1.18-4.01). Conclusions: Midlife hypertension and late-life Aβ independently contribute to dementia risk, but don’t synergize on a multiplicative scale. Neurodegeneration (e.g.smaller AD signature region volume) is also associated with incident dementia, independent of Aβ and MVRF. Multiple pathways leading to dementia should be considered when evaluating risk factors and interventions to reduce the burden of dementia.

Hypertension is highly prevalent in the elderly population and microinfarcts are the most common vascular brain pathology identified in older adults at autopsy. We investigated the associations between systolic and diastolic blood pressures measured antemortem and the presence of microinfarcts at autopsy. Study subjects (n=302; age range=71-95) were participants in the population-based Mayo Clinic Study of Aging autopsy study, who had blood pressure measurements recorded during life. We investigated both cross-sectional systolic and diastolic blood pressure measurements at the baseline visit and the change in blood pressure (slope). Presence and location (subcortical or cortical) of chronic microinfarcts was abstracted from the autopsy reports. Of the 302 study subjects, 47 (16%) had cerebral microinfarcts, and, of those, 18 (38%) had subcortical microinfarcts and 29 (62%) had only cortical microinfarcts. The baseline blood pressures were not different between subjects with no microinfarcts, subcortical microinfarcts, and only cortical microinfarcts. In a logistic regression model including time between last blood pressure measurement and death, a greater decline in systolic [OR= 1.06 (1.01, 1.11); p=0.02]) and greater decline in diastolic [OR= 1.11 (1.02, 1.20); p=0.01] blood pressures were predictors of the presence of subcortical microinfarcts at autopsy. However, these variables were not associated with the presence of cortical microinfarcts. In conclusion, microinfarcts are common in the older adult population, and most of them are located in the cortex. A greater decline in both systolic and diastolic blood pressures and their association with subcortical microinfarcts, but not with cortical microinfarcts, may have implications for aggressive lowering of blood pressure in the elderly population.

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.

Abstract Dementia with Lewy bodies (DLB) is neuropathologically defined by the presence of α-synuclein aggregates, but many DLB cases show concurrent Alzheimer’s disease pathology in the form of amyloid-β plaques and tau neurofibrillary tangles. The first objective of this study was to investigate the effect of Alzheimer’s disease co-pathology on functional network changes within the default mode network (DMN) in DLB. Second, we studied how the distribution of tau pathology measured with PET relates to functional connectivity in DLB. Twenty-seven DLB, 26 Alzheimer’s disease and 99 cognitively unimpaired participants (balanced on age and sex to the DLB group) underwent tau-PET with AV-1451 (flortaucipir), amyloid-β-PET with Pittsburgh compound-B (PiB) and resting-state functional MRI scans. The resing-state functional MRI data were used to assess functional connectivity within the posterior DMN. This was then correlated with overall cortical flortaucipir PET and PiB PET standardized uptake value ratio (SUVr). The strength of interregional functional connectivity was assessed using the Schaefer atlas. Tau-PET covariance was measured as the correlation in flortaucipir SUVr between any two regions across participants. The association between region-to-region functional connectivity and tau-PET covariance was assessed using linear regression. Additionally, we identified the region with highest and the region with lowest tau SUVrs (tau hot- and cold spots) and tested whether tau SUVr in all other brain regions was associated with the strength of functional connectivity to these tau hot and cold spots. A reduction in posterior DMN connectivity correlated with overall higher cortical tau- (r = −0.39, P = 0.04) and amyloid-PET uptake (r = −0.41, P = 0.03) in the DLB group, i.e. patients with DLB who have more concurrent Alzheimer’s disease pathology showed a more severe loss of DMN connectivity. Higher functional connectivity between regions was associated with higher tau covariance in cognitively unimpaired, Alzheimer’s disease and DLB. Furthermore, higher functional connectivity of a target region to the tau hotspot (i.e. inferior/medial temporal cortex) was related to higher flortaucipir SUVrs in the target region, whereas higher functional connectivity to the tau cold spot (i.e. sensory-motor cortex) was related to lower flortaucipir SUVr in the target region. Our findings suggest that a higher burden of Alzheimer’s disease co-pathology in patients with DLB is associated with more Alzheimer’s disease-like changes in functional connectivity. Furthermore, we found an association between the brain’s functional network architecture and the distribution of tau pathology that has recently been described in Alzheimer’s disease. We show that this relationship also exists in patients with DLB, indicating that similar mechanisms of connectivity-dependent occurrence of tau pathology might be at work in both diseases.