Knopman, David S.

AbstractBackgroundPhysical frailty is associated with increased risk for dementia and other neurologic sequelae. However, the neurobiological changes underlying frailty and frailty risk remain unknown. We examined the association of cerebral white matter structure with current and future frailty.MethodsAtherosclerosis Risk in Communities Study Neurocognitive Study participants who underwent 3T brain MRI were included. Frailty status was classified according to the Fried criteria. Cerebral white matter integrity was defined using white matter hyperintensity (WMH) volume and microstructure, measured using diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD). Multivariable linear regression was used to relate baseline frailty to white matter structure; multivariable logistic regression was used to relate baseline white matter to frailty risk among participants nonfrail at baseline.ResultsIn the cross-sectional analysis (N = 1 754; mean age: 76 years), frailty was associated with greater WMH volume, lower FA, and greater MD. These associations remained consistent after excluding participants with a history of stroke or dementia. Among participants nonfrail at baseline who completed follow-up frailty assessment (N = 1 379; 6.6-year follow-up period), each standard deviation increase in WMH volume was associated with 1.46 higher odds of frailty at follow-up. Composite FA and MD measures were not associated with future frailty; however, secondary analyses found several significant white matter tract-specific associations with frailty risk.ConclusionThe current study demonstrates a robust association of WMH volume with current and future frailty. Although measures of white matter microstructure were altered in frail individuals, these measures were not generally associated with progression from nonfrail to frail status.

Background: Cerebral microbleeds (CMBs) are a common vascular pathology associated with future intracerebral hemorrhage. Plasma biomarkers of amyloid, tau, and neurodegeneration may provide a screening avenue to identify those with CMBs, but evidence is conflicting. Objective: To determine the association between plasma biomarkers (Aβ40, Aβ42, t-tau, p-tau181, p-tau217, neurofilament light chain (NfL)) and CMBs in a population-based study of aging and whether these biomarkers predict higher signal on Aβ-PET imaging in patients with multiple CMBs. Methods: 712 participants from the Mayo Clinic Study of Aging with T2* GRE MRI and plasma biomarkers were included. Biomarkers were analyzed utilizing Simoa (Aβ40, Aβ42, t-tau, NfL) or Meso Scale Discovery (p-tau181, p-tau217) platforms. Cross-sectional associations between CMBs, plasma biomarkers and Aβ-PET were evaluated using hurdle models and multivariable regression models. Results: Among the 188 (26%) individuals with≥1 CMB, a lower plasma Aβ42/Aβ40 ratio was associated with more CMBs after adjusting for covariables (IRR 568.5 95% CI 2.8–116,127). No other biomarkers were associated with risk or number CMBs. In 81 individuals with≥2 CMBs, higher plasma t-tau, p-tau181, and p-tau217 all were associated with higher Aβ-PET signal, with plasma p-tau217 having the strongest predictive value (r2 0.603, AIC –53.0). Conclusion: Lower plasma Aβ42/Aβ40 ratio and higher plasma p-tau217 were associated with brain amyloidosis in individuals with CMBs from the general population. Our results suggest that in individuals with multiple CMBs and/or lobar intracranial hemorrhage that a lower plasma Aβ42/Aβ40 ratio or elevated p-tau217 may indicate underlying cerebral amyloid angiopathy.

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<0.001) were significantly associated with MCI when included simultaneously in the model. We observed similar associations for CVD biomarkers and BAI score with MCI. 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.

Introduction: Accelerated cognitive decline is influenced by vascular aging. Arterial stiffness and pressure amplification, measures of vascular aging, are associated with lower cognitive performance though their association with cognitive domains has been understudied. Hypothesis: Arterial stiffness and pressure amplification are associated with lower global and domain-specific cognition among a sample of Caucasian and African American (AA) older adults. Methods: In a cross-sectional study of 4618 members from visit 5 (2011-2013) of ARIC (mean age: 75 years, 41% men, 20% AA), we measured arterial stiffness (carotid-femoral pulse wave velocity (cfPWV)) and pressure amplification (pulse pressure amplification (PPA), central pulse pressure (cPP) and carotid systolic blood pressure (cSBP)) using the Omron VP-1000 Plus device. Race-specific 25th percentile cut points were estimated for each measure. Domain-specific cognitive function was examined using the Delayed Word Recall Test (memory), Digit Symbol Substitution Test (executive function/processing speed), and Word Fluency Test (language). Test-specific z scores were calculated from sample means and standard deviations. A global cognition z score was generated by averaging the test-specific z scores. Linear regression was used to estimate the associations between race-specific 25th percentile dichotomies for arterial stiffness and pressure amplification measures with test-specific and global cognition z scores, adjusted for age, sex, education, ApoE4, heart rate, smoking and body mass index. Results: Among AAs, there was no significant association between measures of arterial stiffness and pressure amplification with either global or the domain-specific measures of cognition. Among Caucasians, all measures of arterial stiffness and pressure amplification were associated with lower global cognitive z scores (cfPWV: Beta (β) =-0.11, 95% Confidence Interval (CI): -0.19, -0.04; PPA: β=-0.11, 95% CI: -0.19, -0.03; cPP: β=-0.11, 95% CI: -0.18, -0.04; cSBP: β=-0.12, 95% CI: -0.20, -0.05). All measures of arterial stiffness and pressure amplification also were associated with lower executive function/processing speed (cfPWV: β=-0.09, 95% CI: -0.16, -0.03; PPA: β=-0.15, 95% CI: -0.22, -0.08; cPP: β=-0.14, 95% CI: -0.21, -0.07; cSBP: β=-0.13, 95% CI: -0.20, -0.07). High cfPWV was associated with lower memory (β=-0.12, 95% CI: -0.20, -0.04); and high cSBP was associated with lower language (β=-0.12, 95% CI: -0.20, -0.04). Conclusions: Arterial stiffness and measures of pressure amplification are inversely associated with global and domain-specific cognition in Caucasian older adults, but not in a smaller sample of AAs. Further study of the role of modifiable components of arterial aging on the preservation of cognition, particularly executive function/psychomotor speed, in older adulthood is warranted.

Background: As a high-flow, low-impedance organ, the brain is sensitive to excessive pressure and flow pulsatility. Increased pulsatility and arterial stiffness are hypothesized to contribute to cerebral microvascular damage linked to cognitive impairment. The association of arterial stiffness with mild cognitive impairment (MCI) and dementia in a biethnic population is not well characterized, and the association of pressure amplification with MCI and dementia is relatively unexplored. Objectives: To quantify the cross-sectional association of arterial stiffness, measured by aortic pulse wave velocity (PWV), and pressure amplification with MCI and dementia in a biethnic population of older adults. Methods: We included 4,945 adults (2,903 females; 1,069 African Americans; mean age 75 years) from the population-based ARIC-NCS. The Omron VP-1000 plus system was used to measure arterial stiffness (carotid-femoral PWV (cfPWV)) and pressure amplification measures (central systolic blood pressure (cSBP), central pulse pressure (cPP), and pulse pressure amplification (PPA)). A neurologist and neuropsychologist classified MCI and dementia using psychometric assessments, medical history, cerebral magnetic resonance imaging, and physical examinations, with adjudication by a third reviewer. We used multinomial logistic regression to evaluate associations of race-specific 25th percentile cut points of PWV and pressure amplification with normal cognition (reference), MCI and dementia. We stratified by race and adjusted for age, sex, and heart rate, ApoE4, education, smoking status, and study center. Results: There were 760 Caucasians with MCI and 110 with dementia, and 201 African Americans with MCI and 47 with dementia. Among Caucasians, those with lower PPA had a higher prevalence of dementia, odds ratio (OR)=1.84 (95% confidence interval (CI): 1.15, 2.97), comparing participants below the 25th percentile to those above it, and those with higher cSBP had a higher prevalence of MCI, OR=1.33 (95% CI: 1.09, 1.63), comparing participants above the 75th percentile to those below it. Also among Caucasians, those with higher cPP had a higher prevalence of MCI, OR=1.25 (95%CI: 1.01, 1.55), and dementia, OR=1.66 (95% CI: 1.00, 2.73), comparing participants above the 75th percentile to those below it. There were no statistically significant associations with cfPWV, among African Americans, and no evidence for effect modification by hypertension or diabetes. Conclusion: Arterial stiffness and components of pressure amplification were associated with MCI and dementia in Caucasians but not in African Americans, possibly due to the limited sample size. Longitudinal characterization of the observed associations is warranted to determine whether these measures are independent predictors of MCI and dementia among Caucasian and African American older adults.

Abstract Background Cognitive function is essential to effective self‐management of heart failure (HF). Alzheimer's disease and Alzheimer's disease‐related dementias (AD/ADRD) can coexist with HF, but its exact prevalence and impact on health care utilization and death are not well defined. Methods Residents from 7 southeast Minnesota counties with a first‐ever diagnosis code for HF between January 1, 2013 and December 31, 2018 were identified. Clinically diagnosed AD/ADRD was ascertained using the Centers for Medicare and Medicaid (CMS) Chronic Conditions Data Warehouse algorithm. Patients were followed through March 31, 2020. Cox and Andersen‐Gill models were used to examine associations between AD/ADRD (before and after HF) and death and hospitalizations, respectively. Results Among 6336 patients with HF (mean age [SD] 75 years [14], 48% female), 644 (10%) carried a diagnosis of AD/ADRD at index HF diagnosis. The 3‐year cumulative incidence of AD/ADRD after HF diagnosis was 17%. During follow‐up (mean [SD] 3.2 [1.9] years), 2618 deaths and 15,475 hospitalizations occurred. After adjustment, patients with AD/ADRD before HF had nearly a 2.7 times increased risk of death, but no increased risk of hospitalization compared to those without AD/ADRD. When AD/ADRD was diagnosed after the index HF date, patients experienced a 3.7 times increased risk of death and a 73% increased risk of hospitalization compared to those who remain free of AD/ADRD. Conclusions In a large, community cohort of patients with incident HF, the burden of AD/ADRD is quite high as more than one‐fourth of patients with HF received a diagnosis of AD/ADRD either before or after HF diagnosis. AD/ADRD markedly increases the risk of adverse outcomes in HF underscoring the need for future studies focused on holistic approaches to improve outcomes.

AbstractBackgroundHospitalization in older age is associated with accelerated cognitive decline, typically preceded by neuropathologic changes. We assess the association between indication for hospitalization and brain neurodegeneration.MethodsIncluded were participants from the Mayo Clinic Study of Aging, a population-based longitudinal study, with ≥1 brain imaging available in those older than 60 years of age between 2004 and 2017. Primary analyses used linear mixed-effects models to assess association of hospitalization with changes in longitudinal trajectory of cortical thinning, amyloid accumulation, and white matter hyperintensities (WMH). Additional analyses were performed with imaging outcomes dichotomized (normal vs abnormal) using Cox proportional hazards regression.ResultsOf 2 480 participants, 1 966 had no hospitalization and 514 had ≥1 admission. Hospitalization was associated with accelerated cortical thinning (annual slope change −0.003 mm [95% confidence interval (CI) −0.005 to −0.001], p = .002), but not amyloid accumulation (0.003 [95% CI −0.001 to 0.006], p = .107), or WMH increase (0.011 cm3 [95% CI −0.001 to 0.023], p = .062). Interaction analyses assessing whether trajectory changes are dependent on admission type (medical vs surgical) found interactions for all outcomes. While surgical hospitalizations were not, medical hospitalizations were associated with accelerated cortical thinning (−0.004 mm [95% CI −0.008 to −0.001, p = .014); amyloid accumulation (0.010, [95% CI 0.002 to 0.017, p = .011), and WMH increase (0.035 cm3 [95% CI 0.012 to 0.058, p = .006). Hospitalization was not associated with developing abnormal cortical thinning (p = .407), amyloid accumulation (p = .596), or WMH/infarctions score (p = .565).ConclusionsMedical hospitalizations were associated with accelerated cortical thinning, amyloid accumulation, and WMH increases. These changes were modest and did not translate to increased risk for crossing the abnormality threshold.

ABSTRACT Background and Objective Patients with dementia with Lewy bodies (DLB) may have overlapping Alzheimer's disease pathology. We investigated the longitudinal rate of tau accumulation and its association with neurodegeneration and clinical disease progression in DLB. Methods Consecutive patients with probable DLB (n = 22) from the Mayo Clinic Alzheimer's Disease Research Center and age‐matched and sex‐matched cognitively unimpaired controls (CU; n = 22) with serial magnetic resonance imaging and flortaucipir positron emission tomography scans within an average of 1.6 years were included. Regional annualized rates of flortaucipir uptake standardized uptake value ratios (SUVr) were calculated. Regional annualized rates of cortical volume change were measured with the Tensor Based Morphometry–Syn algorithm. Results The annual increase of flortaucipir SUVr was greater in the middle and superior occipital, fusiform, and inferior parietal cortices in DLB (mean: 0.017, 0.019, 0.019, and 0.015, respectively) compared with the CU (mean: −0.006, −0.009, −0.003, and − 0.005, respectively; P < 0.05). In patients with DLB (but not the CU), a longitudinal increase in flortaucipir SUVr was associated with longitudinal cortical atrophy rates in the lateral occipital and inferior temporoparietal cortices, hippocampus, and the temporal pole as well as a concurrent decline on Mini‐Mental State Examination and Clinical Dementia Rating–Sum of Boxes in the lateral occipital and the fusiform cortices. Conclusions Tau accumulation was faster in DLB compared with the CU, with increased accumulation rates in the lateral occipital and temporoparietal cortices. These increased rates of tau accumulation were associated with neurodegeneration and faster disease progression in DLB. Tau may be a potential treatment target in a subset of patients with DLB. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Abstract Introduction : Plasma glial fibrillary acidic protein (GFAP) may be associated with amyloid burden, neurodegeneration, and stroke but its specificity for Alzheimer's disease (AD) in the general population is unclear. We examined associations of plasma GFAP with amyloid and tau positron emission tomography (PET), cortical thickness, white matter hyperintensities (WMH), and cerebral microbleeds (CMBs). Methods : The study included 200 individuals from the Mayo Clinic Study of Aging who underwent amyloid and tau PET and magnetic resonance imaging and had plasma GFAP concurrently assayed; multiple linear regression and hurdle model analyses were used to investigate associations controlling for age and sex. Results : GFAP was associated with amyloid and tau PET in multivariable models. After adjusting for amyloid, the association with tau PET was no longer significant. GFAP was associated with cortical thickness, WMH, and lobar CMBs only among those who were amyloid‐positive. Discussion : This cross‐sectional analysis demonstrates the utility of GFAP as a plasma biomarker for AD‐related pathologies.

AbstractIntroductionSlower mobility is associated with mild cognitive impairment (MCI) and dementia. We examined the interaction of endurance with gait speed on prevalent MCI and dementia.MethodsCross‐sectional multinomial regression in the ARIC cohort (n = 2844 participants; 71 to 94 years; 44% men; 18% Black persons) with cognitive status (normal/MCI/dementia), 4 m gait speed, and endurance (2 minute walk [2MW]).ResultsFaster gait speed (up to but not above 1 m/s) and better 2MW were separately associated with lower dementia risk. Good performance in both (2MW = 200 m, gait speed = 1.2 m/s) was associated with 99% lower dementia (Relative Prevalence Ratio [RPR] = 0.01 [95% CI: 0.0 to 0.06]) and 73% lower MCI, RPR = 0.27 (0.15 to 0.48) compared to poor performance in both (2MW = 100 m, gait speed = 0.8 m/s). Models incorporating a gait speed‐by‐2MW interaction term outperformed gait speed‐only models (P < .001).DiscussionGait speed relationships with dementia diminish at faster gait speeds. Combining endurance with gait speed may yield more sensitive markers of MCI and dementia than gait speed alone.