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Background We tested the hypothesis that indices of Alzheimer’s disease and related dementia (ADRD) pathologies may explain associations between change in body mass index (BMI) and cognitive decline in old age. Method We used data from 436 older decedents participating in a prospective longitudinal cohort study who had undergone annual cognitive and BMI assessments and postmortem collection of indices of 12 brain pathologies. We identified ADRD brain pathologies associated with BMI range, a previously published metric of change in BMI. We employed sigmoidal mixed-effect models of cognitive decline to examine the associations of change in BMI and cognitive decline with and without terms for ADRD brain pathologies. Results Average age at baseline was 78.6 years, SD = 6.5 years with 64% female. On average, 9 cognitive assessments were obtained with average age at death 88.4 years (SD = 6.2 years). Change in BMI as measured by BMI range was associated with cognitive decline (θ 2 = 0.260). β-Amyloid, hippocampal sclerosis, and substantia nigra neuronal loss were associated with BMI range. β-Amyloid strongly attenuated the association of BMI range with cognitive decline. Hippocampal sclerosis showed only partial attenuation of the association of BMI range and cognitive decline and nigral neuronal loss did not attenuate this association. Conclusion Changes in BMI and cognitive decline in older adults may be affected by similar mechanisms underlying the accumulation of brain pathologies like β-amyloid in aging brains. Elucidating the molecular mechanisms underlying these associations may provide novel targets for developing interventions that maintain brain health and metabolic homeostasis in old age.

Older Black adults face a disproportionate burden of HIV prevalence, but less is known about racial disparities in age-related outcomes in HIV. We assessed the effect of HIV status and race on motor and pulmonary function, as well as how they contribute to mobility disability. Community-based study; Chicago, IL Participants were 363 community-dwelling adults age ≥ 50 years, 48% living with HIV, and 68% Black. Participants with HIV were recruited from a specialty HIV clinic, and participants without HIV (comparable on key demographic, lifestyle, and behavioral characteristics) were recruited from the community. Measures included motor function summarized by 10 motor performance measures, pulmonary function summarized by 3 measures assessed using handheld spirometry, and self-reported mobility disability. In fully adjusted linear models, HIV was associated with better motor (β = 9.35, p

INTRODUCTION: The impact of cardiovascular risk burden on brain pathologies remains unclear. We aimed to examine the association of the Framingham General Cardiovascular Risk Score (FGCRS) with dementia risk, and brain pathologies.METHODS: Within the Rush Memory and Aging Project, 1588 dementia-free participants were assessed on FGCRS at baseline and followed up to 21 years. During the follow-up, 621 participants died and underwent autopsies.RESULTS: The multi-adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) of FGCRS were 1.03 (1.00-1.07) for dementia and 1.04 (1.01-1.07) for Alzheimer's disease (AD) dementia. Further, a higher FGCRS was associated with higher gross chronic cerebral infarctions (odds ratio [OR] 1.08, 95% CI 1.02-1.14), cerebral atherosclerosis (OR 1.10, 95% CI 1.03-1.17), and global AD pathology (OR 1.06, 95% CI 1.01-1.12).CONCLUSIONS: A higher FGCRS is associated with an increased risk of dementia and AD dementia. Both vascular and AD pathologies in the brain may underlie this association.

Background and Purpose: The pathogenesis of cerebral small vessel disease remains incompletely understood. The relationship between circadian rhythm disturbances and histopathologic measures of cerebral small vessel disease has not been studied. We hypothesized that disrupted circadian rest-activity rhythms would be associated with a higher burden of cerebral small vessel disease pathology. Methods: We studied 561 community-dwelling older adults (mean age at death, 91.2, 27.4% male) from the Rush Memory and Aging Project. We used actigraphy to quantify several measures of 24-hour rest-activity rhythmicity, including interdaily stability, intradaily variability, and amplitude, and used ordinal logistic regression models to relate these measures to the severity of cerebral arteriolosclerosis, atherosclerosis, macroinfarcts, and microinfarcts, assessed at autopsy. Results: Lower interdaily stability was associated with a higher burden of arteriolosclerosis, higher intradaily variability was associated with a higher burden of atherosclerosis and subcortical infarcts, and lower amplitude was associated with a higher burden of arteriosclerosis, atherosclerosis and subcortical macroinfarcts. Moreover, the associations between interdaily stability and arteriolosclerosis and intradaily variability and subcortical infarcts were independent of cardiovascular risk factors, sleep fragmentation, and medical comorbidities. Conclusions: Disrupted rest-activity rhythms are associated with a greater burden of cerebral small vessel disease in older adults.

ObjectiveThe associations of Lewy bodies (LBs) with olfactory dysfunction, parkinsonism, and higher odds of dementia were assessed in Black and White community-dwelling elders and racial differences in these associations were tested.MethodsBlack decedents (n = 81) were matched 2-to-1 by age, sex, years of education, and follow-up time in the study with White decedents (n = 154) from 4 longitudinal studies of dementia and aging. Participants underwent uniform clinical examination and cognitive, motor, and olfactory testing. LBs were detected in 7 brain regions by α-synuclein immunohistochemistry and racial differences in their association with olfaction, parkinsonism, and odds of dementia were determined using regression analyses.ResultsThe mean scores of the odor test, global parkinsonism signs, and global cognition were lower in Black than White decedents; the frequency of dementia was similar in both groups. The frequency of LBs was similar in Black and White decedents (∼25%), as was the frequency of LBs in individual brain regions, while the mean LB counts/mm2were similar in all regions except the cingulate cortex, which showed higher mean LB counts in Black decedents. In regression analyses, LBs were associated with impaired olfaction (−2.23, 95% confidence interval [CI] −3.45 to −1.01) and higher odds of dementia (odds ratio 3.0, 95% CI 1.10–8.17) in both racial groups; an association with parkinsonism was stronger in Black than White decedents.ConclusionsThe frequency, distribution, and clinical manifestations of LBs are similar in Black and White elders.

Background There is paucity of data about African American (AA) patients with Parkinson’s disease (PD) and parkinsonism which may precede PD in older adults. Prior studies suggest that there are lower rates of PD in the AA population, with more cognitive impairment in AA with PD. This study aimed to investigate differences in PD, parkinsonism, and cognition between White and AA populations in 3 longitudinal epidemiologic cohort studies of aging. Methods This study examined parkinsonism, PD frequency, and cognition of community-dwelling older individuals in 3 longitudinal epidemiologic cohort studies. Parkinsonism was based on an exam utilizing the modified Unified Parkinson’s Disease Rating Scale performed by a nurse. PD was based on self-report, medications used for treatment of PD, and examination findings. Cognition was assessed using 19 performance-based tests that assess 5 cognitive domains. Results AA participants were less likely to have parkinsonism compared to Whites, even with age and gender differences. Frequency of PD was not significant between groups. AA were more likely to have lower cognitive scores as compared to Whites. AA were less likely to have parkinsonism even with controlling for cognitive differences between groups. Conclusions Parkinsonian signs are present among AA in the community at lower rates than in White individuals. Cognitive profiles of AA and Whites with parkinsonism may be different, suggesting differing contributions of pathology to cognitive decline and parkinsonism between groups. Additional research is needed to understand the progression of parkinsonism to PD, as well as to understanding the cognitive differences in AA with parkinsonism.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10−17), arthritis (GDF5 p = 4 × 10−13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing., Muscle weakness has been associated with morbidity and mortality in older people. Here, the authors have investigated this trait further by performing a genome-wide meta-analysis of grip strength and Mendelian randomization to discover causal relationships between muscle weakness and other diseases.

ObjectiveTo test the hypothesis that degree of frailty and neuropathologic burden independently contribute to global cognition and odds of dementia.MethodsThis was a secondary analysis of a prospective cohort study of older adults living in Illinois. Participants underwent an annual neuropsychological and clinical evaluation. We included 625 participants (mean age 89.7 ± 6.1 years; 67.5% female) who died and underwent autopsy. We quantified neuropathology using an index measure of 10 neuropathologic features: β-amyloid deposition, hippocampal sclerosis, Lewy bodies, tangle density, TDP-43, cerebral amyloid angiopathy, arteriolosclerosis, atherosclerosis, and gross and chronic cerebral infarcts. Clinical consensus determined dementia status, which we coded as no cognitive impairment, mild cognitive impairment, or dementia. A battery of 19 tests spanning multiple domains quantified global cognition. We operationalized frailty using a 41-item frailty index. We employed regression analyses to model relationships between neuropathology, frailty, and dementia.ResultsBoth frailty and a neuropathology index were independently associated with global cognition and dementia status. These results held after controlling for traditional pathologic measures in a sample of participants with Alzheimer clinical syndrome. Frailty improved the fit of the model for dementia status (χ2[2] 72.64; p < 0.0001) and explained an additional 11%–12% of the variance in the outcomes.ConclusionDementia is a multiply determined condition, to which both general health, as captured by frailty, and neuropathology significantly contribute. This integrative view of dementia and health has implications for prevention and therapy; specifically, future research should evaluate frailty as a means of dementia risk reduction.

Background Mixed-brain pathologies are the most common cause of progressive parkinsonism in older adults. We tested the hypothesis that the impact of individual pathologies associated with progressive parkinsonism differs among older adults. Methods Data were from 1089 decedents who had undergone annual clinical testing and autopsy. Parkinsonism was based on a modified United Parkinson’s Disease Rating Scale. Linear mixed-effects models were employed, to investigate the combinations of 9 pathologies related to progressive parkinsonism. Then we estimated the person-specific contributions of each pathology for progressive parkinsonism. Results The average participant showed 3 pathologies. Parkinson’s disease (PD) and 4 cerebrovascular pathologies (macroinfarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy [CAA]), but not Alzheimer’s disease, TDP-43, hippocampal sclerosis, and microinfarcts, were independently associated with progressive parkinsonism. These pathologies accounted for 13% of additional variance of progressive parkinsonism. Thirty-one different combinations of these 5 pathologies were observed to be associated with progressive parkinsonism observed. On average, PD and CAA accounted, respectively, for 66% and 65% of person-specific progression of parkinsonism, while macroinfarcts, atherosclerosis, and arteriolosclerosis accounted for 41%–48%. Conclusion There is much greater heterogeneity in the comorbidity and relative impact of individual brain pathologies affecting progressive parkinsonism than previously recognized and this may account in part for its phenotypic heterogeneity in older adults.

Study objectives Heart failure has previously been linked to sleep disorders that are often associated with frequent disturbances to human rest/activity patterns. We tested whether fragmentation of sustained rest/activity patterns derived from actigraphic recordings at baseline predicts incident heart failure in community-based elderly individuals. Methods We studied 1099 community-based elderly adults participating in the Rush Memory and Aging Project who had baseline motor activity monitoring up to 11 days and were followed annually for up to 14 years. Fragmentation was assessed using previously validated indexes, derived from the probability of transitions once sustained rest or activity has been established. Heart failure was recorded via a clinical interview during the annual follow-up. Cox proportional hazards models were constructed to examine the relationship between rest fragmentation index and incident heart failure. Covariates grouped in terms of demographics, lifestyle factors and co-morbidities and cardiovascular risk factors/diseases were included. Results Increased rest fragmentation (but not activity fragmentation) was associated with higher risk for incident heart failure. Specifically, a subject with a rest fragmentation at the 90th percentile showed a 57% increased risk of developing incident heart failure compared to a subject at the 10th percentile in this cohort. This effect was equivalent to that of being over a decade older. These observations were consistent after adjusting for all covariates. Conclusion Increased rest fragmentation, a potential surrogate for sleep fragmentation, is independently associated with a higher risk of developing heart failure in community-based elderly adults during up to 14 years of follow-up. Further work is required to examine the specific contributions from daytime napping versus nighttime sleep periods in the elderly, as well as the underlying autonomic and cardio-dynamic pathways that may explain the effects on heart function.

Physical activity relates to reduced dementia risk, but the cellular and molecular mechanisms are unknown. We translated animal andin vitrostudies demonstrating a causal link between physical activity and microglial homeostasis into humans. Decedents from Rush Memory and Aging Project completed actigraphy monitoring (average daily activity) and cognitive evaluation in life, and neuropathological examination at autopsy. Brain tissue was analyzed for microglial activation via immunohistochemistry (anti-human HLA-DP-DQ-DR) and morphology (% Stage I, II, or III), and synaptic protein levels (SNAP-25, synaptophysin, complexin-I, VAMP, syntaxin, synaptotagmin-1). Proportion of morphologically activated microglia (PAM) was estimated in ventromedial caudate, posterior putamen, inferior temporal (IT), and middle frontal gyrus. The 167 decedents averaged 90 years at death, two-thirds were nondemented, and 60% evidenced pathologic Alzheimer's disease (AD). Adjusting for age, sex, education, and motor performances, greater physical activity associated with lower PAM in the ventromedial caudate and IT. Relationships between physical activity and PAM in the ventromedial caudate or IT were particularly prominent in adults evidencing microinfarcts or AD pathology, respectively. Mediational analyses indicated that PAM IT mediated ∼30% of the relationships between (1) physical activity and synaptic protein in IT, and (2) physical activity and global cognition, in separate models. However, the size of the mediation depended on AD pathology ranging from >40% in adults with high AD burden, but SIGNIFICANCE STATEMENTPhysical activity relates to better cognitive aging and reduced risk of neurodegenerative disease, yet the cellular and molecular pathways linking behavior-to-brain in humans are unknown. Animal studies indicate that increasing physical activity leads to decreased microglial activation and corresponding increases in synaptogenesis and neurogenesis. We objectively monitored physical activity (accelerometer-based actigraphy) and cognitive performances in life, and quantified microglial activation and synaptic markers in brain tissue at death in older adults. These are the first data supporting microglial activation as a physiological pathway by which physical activity relates to brain heath in humans. Although more interventional work is needed, we suggest that physical activity may be a modifiable behavior leveraged to reduce pro-inflammatory microglial states in humans.

Importance Progressive parkinsonism is common in older adults without a diagnosis of Parkinson disease and is associated with adverse health outcomes, but its pathologic basis is controversial. Objective To examine if the burden of cerebral white matter hyperintensity (WMH), a common manifestation of cerebrovascular disease pathologies, is associated with the rate of progressive parkinsonism. Design, Setting, and Participants This community-based cohort study included participants recruited in 3 ongoing cohorts that began enrollment in 1994, 1997, and 2004. Prior to death, participants were observed for a mean of 7.5 years, with annual clinical assessments. From 4427 participants enrolled in the 3 cohorts, 2134 died. Postmortem autopsy was performed in 1725 decedents, and 598 also had ex vivo brain magnetic resonance imaging. Participants were excluded if they were missing any of the 9 postmortem pathology indices (n = 22) or repeated parkinsonism assessment (n = 41) or had received a clinical diagnosis of Parkinson disease at any point before or during the study (n = 19). Data were analyzed from April 2020 to August 2021. Exposures WMH burden was assessed using a modified Fazekas rating scale. Main Outcomes and Measures Parkinsonism was assessed annually using 26 items of a modified motor portion of the Unified Parkinson’s Disease Rating Scale. A summary score was developed from the item scores, with higher scores indicating more severe parkinsonism. Results Of 516 included decedents, 364 (70.5%) were female, and the mean (SD) age at death was 90.2 (6.4) years. Higher WMH was associated with faster progressive parkinsonism (estimate, 0.024; SE, 0.008;P = .002). The attenuation of this association was greater when controlling for indices of cerebrovascular disease pathologies than when controlling for neurodegenerative pathologies (cerebrovascular disease: estimate, 0.019; SE, 0.008;P = .02; neurodegenerative: estimate, 0.022; SE, 0.008;P = .003), but both remained significant. Conclusions and Relevance In this cohort study, higher levels of both WMH and indices of cerebrovascular disease pathologies in aging brains were associated with more rapid progressive parkinsonism. Further studies are needed to determine if in vivo brain imaging of older adults for evidence of WMH and aggressive medical treatment of vascular risk factors and diseases can reduce the occurrence or severity of late-life parkinsonism.

Objective: Late-life cognitive impairment is heterogeneous. This study examined to what extent varied motor performances are differentially associated with incident Alzheimer’s dementia (AD) and incident mild cognitive impairment (MCI) in older adults.Design: Nested substudy.Setting: Communities across metropolitan Chicago.Participants: African American (N = 580) and European American (N = 580) adults without dementia, propensity-balanced by age (mean = 73.2; SD = 6.0), sex (78.4% women), education (mean = 15.6; SD = 3.3) and number of follow ups.Measurements: Cognitive status was assessed annually and based in part on a composite measure of global cognition including 17 cognitive tests. A global motor score was based on 10 motor performances from which 4 motor domains were computed including hand dexterity, hand strength, gait function, and leg strength.Results: During 7 years of follow-up, 166 of 1,160 (14.3%) developed AD. In a proportional hazards model controlling for age, sex, education, and race, each 1-SD higher baseline global motor score was associated with about a 20% reduction in the risk of AD (hazard ratio: 0.81; 95% CI: 0.68, 0.97). Higher baseline motor function was also associated with decreased risk of incident MCI (hazard ratio: 0.79; 95% CI: 0.68, 0.92). Hand dexterity, hand strength and gait function but not leg strength were associated with incident AD and MCI. When including all four motor domains in the same model, results remained the same for incident MCI, while for incident AD, the association with hand strength remained significant.Conclusion: Diverse motor performances are associated with late-life cognitive impairment. Further work is needed to identify specific motor performances that may differentiate adults at risk for future MCI or AD dementia.

The Rush Alzheimer’s Disease Center (RADC) conducts 5 harmonized prospective clinical-pathologic cohort studies of aging – with 1 study, the Latino Core, focused exclusively on Latinxs, 2 studies consisting of mostly non-Latinx whites, and 2 studies of mostly non-Latinx blacks. This paper contextualizes the Latino Core within the other 4 harmonized RADC cohort studies. The overall aim of the paper is to provide information from the RADC, so that researchers can learn from our participants and procedures to better advance the science of Alzheimer’s disease and related dementias in Latinxs. We describe an annual clinical evaluation that assesses risk factors for Alzheimer’s dementia among older adults without known dementia at enrollment. As all RADC cohort studies offer brain donation as a part of research participation, we discuss our approach to brain donation and subsequent participant decision-making among older Latinxs. We also summarize baseline characteristics of older Latinxs across the 5 RADC cohort studies in relation to the baseline characteristics of non-Latinx blacks and non-Latinx whites. Finally, we outline challenges and considerations as well as potential next steps in cognitive aging research with older Latinxs.

Many outputs from healthy neurophysiological systems including motor activity display nonrandom fluctuations with fractal scaling behavior as characterized by similar temporal fluctuation patterns across a range of time scales. Degraded fractal regulation predicts adverse consequences including Alzheimer's dementia. We examined longitudinal changes in the scaling behavior of motor activity fluctuations during the progression of Alzheimer's disease (AD) in 1068 participants in the Rush Memory and Aging Project. Motor activity of up to 10 days was recorded annually for up to 13 years. Cognitive assessments and clinical diagnoses were administered annually in the same participants. We found that fractal regulation gradually degraded over time (p < 0.0001) even during the stage with no cognitive impairment. The degradation rate was more than doubled after the diagnosis of mild cognitive impairment and more than doubled further after the diagnosis of Alzheimer's dementia (p's ≤ 0.0005). Besides, the longitudinal degradation of fractal regulation significantly correlated with the decline in cognitive performance throughout the progression from no cognitive impairment to mild cognitive impairment, and to AD (p < 0.001). All effects remained the same in subsequent sensitivity analyses that included only 255 decedents with autopsy-confirmed Alzheimer's pathology. These results indicate that the progression of AD accelerates fractal degradation and that fractal degradation may be an integral part of the process of AD.

BACKGROUND: The association of Lewy bodies (LBs) with olfactory dysfunction was investigated in community-dwelling elders without clinical Parkinson’s disease (PD) using the 12-item Brief Smell Identification Test (BSIT), a standard measure of odor identification. METHODS: 280 participants in the Rush Memory and Aging Project completed the BSIT annually. Lewy bodies were detected in 13 brain regions by immunohistochemistry and assigned to the Braak PD stages 1 to 6. RESULTS: Of the 280 participants, 101 (36.1 %) had LBs which were maximal in the olfactory bulb and tract (85.1%) and least in Heschl’s cortex (21.8%). Due to the small number of cases in Braak PD stages 2, 3 and 5, the distribution of LBs in the 6 Braak PD stages was contracted into 3 main LB stages: 1) LBs in olfactory bulbs and dorsal motor nucleus of vagus, 2) further extension of LBs to limbic and other brainstem regions and 3) additional extension of LBs to neocortical areas. MMSE, global cognition and odor test scores were lower and frequency of dementia was higher at the time of the last valid BSIT, in cases with LBs as compared to those without LBs. Linear regression analyses showed that LBs were associated with impaired olfaction. However, on stratification of LBs into 3 stages, only the stage 3 cases were independently associated with impaired olfaction. CONCLUSION: Although LB pathology was detected in olfactory bulbs in the early stage of LB progression (stage 1), the strongest association of LBs with olfactory dysfunction was observed in the late pathological stage (stage 3) when LBs extended to neocortical areas.

Introduction Mobility metrics derived from wearable sensor recordings are associated with parkinsonism in older adults. We examined if these metrics predict incident parkinsonism. Methods Parkinsonism was assessed annually in 683 ambulatory, community-dwelling older adults without parkinsonism at baseline. Four parkinsonian signs were derived from a modified Unified Parkinson's Disease Rating Scale (UPDRS). Parkinsonism was based on the presence of 2 or more signs. Participants wore a sensor on their back while performing a 32 foot walk, standing posture, and Timed Up and Go (TUG) tasks. 12 mobility scores were extracted. Cox proportional hazards models with backward elimination were used to identify combinations of mobility scores independently associated with incident parkinsonism. Results During follow-up of 2.5 years (SD = 1.28), 139 individuals developed parkinsonism (20.4%). In separate models, 6 of 12 mobility scores were individually associated with incident parkinsonism, including: Speed and Regularity (from 32 ft walk), Sway (from standing posture), and 3 scores from TUG subtasks (Posterior sit to stand transition, Range stand to sit transition, and Yaw, a measure of turning efficiency). When all mobility scores were analyzed together in a single model, 2 TUG subtask scores, Range from stand to sit transition (HR, 1.42, 95%CI, 1.09, 1.82) and Yaw from turning (HR, 0.56, 95%CI, 0.42, 0.73) were independently associated with incident parkinsonism. These results were unchanged when controlling for chronic health covariates. Conclusion Mobility metrics derived from a wearable sensor complement conventional gait testing and have potential to enhance risk stratification of older adults who may develop parkinsonism.

Epigenetic clocks are calculated by combining DNA methylation states across select CpG sites to estimate biologic age, and have been noted as the most successful markers of biologic aging to date. Yet, limited research has considered epigenetic clocks calculated in brain tissue. We used DNA methylation states in dorsolateral prefrontal cortex specimens from 721 older participants of the Religious Orders Study and Rush Memory and Aging Project, to calculate DNA methylation age using four established epigenetic clocks: Hannum, Horvath, PhenoAge, GrimAge, and a new Cortical clock. The four established clocks were trained in blood samples (Hannum, PhenoAge, GrimAge) or using 51 human tissue and cell types (Horvath); the recent Cortical clock is the first trained in postmortem cortical tissue. Participants were recruited beginning in 1994 (Religious Orders Study) and 1997 (Memory and Aging Project), and followed annually with questionnaires and clinical evaluations; brain specimens were obtained for 80-90% of participants. Mean age at death was 88.0 (SD 6.7) years. We used linear regression, logistic regression, and linear mixed models, to examine relations of epigenetic clock ages to neuropathologic and clinical aging phenotypes, controlling for chronologic age, sex, education, and depressive symptomatology. Hannum, Horvath, PhenoAge and Cortical clock ages were related to pathologic diagnosis of Alzheimer's disease (AD), as well as to Aβ load (a hallmark pathology of Alzheimer's disease). However, associations were substantially stronger for the Cortical than other clocks; for example, each standard deviation (SD) increase in Hannum, Horvath, and PhenoAge clock age was related to approximately 30% greater likelihood of pathologic AD (all p < 0.05), while each SD increase in Cortical age was related to 90% greater likelihood of pathologic AD (odds ratio = 1.91, 95% confidence interval 1.38, 2.62). Moreover, Cortical age was significantly related to other AD pathology (eg, mean tau tangle density, p = 0.003), and to odds of neocortical Lewy body pathology (for each SD increase in Cortical age, odds ratio = 2.00, 95% confidence 1.27, 3.17), although no clocks were related to cerebrovascular neuropathology. Cortical age was the only epigenetic clock significantly associated with the clinical phenotypes examined, from dementia to cognitive decline (5 specific cognitive systems, and a global cognitive measure averaging 17 tasks) to Parkinsonian signs. Overall, our findings provide evidence of the critical necessity for bespoke clocks of brain aging for advancing research to understand, and eventually prevent, neurodegenerative diseases of aging.

Background Disrupted nighttime sleep has been associated with heart failure (HF). However, the relationship between daytime napping, an important aspect of sleep behavior commonly seen in older adults, and HF remains unclear. We sought to investigate the association of objectively assessed daytime napping and risk of incident HF during follow‐up. Methods and Results We studied 1140 older adults (age, 80.7±7.4 [SD] years; female sex, 867 [76.1%]) in the Rush Memory and Aging Project who had no HF at baseline and were followed annually for up to 14 years. Motor activity (ie, actigraphy) was recorded for ≈10 days at baseline. We assessed daytime napping episodes between 9 am and 7 pm objectively from actigraphy using a previously published algorithm for sleep detection. Cox proportional hazards models examined associations of daily napping duration and frequency with incident HF. Eighty‐six participants developed incident HF, and the mean onset time was 5.7 years (SD, 3.4; range, 1–14). Participants who napped longer than 44.4 minutes (ie, the median daily napping duration) showed a 1.73‐fold higher risk of developing incident HF than participants who napped 1.7 times/day (ie, the median daily napping frequency) showed a 2.20‐fold increase compared with participants who napped Conclusions Longer and more frequent objective napping predicted elevated future risk of developing incident HF. Future studies are needed to establish underlying mechanisms.

OBJECTIVE: We examined whether sarcopenia is associated with the occurrence of late-life cognitive impairment. METHODS: Nondemented older adults (N = 1175) underwent annual testing with 17 cognitive tests summarized as a global cognitive score. A composite sarcopenia score was constructed based on muscle mass measured with bioelectrical impedance and muscle function based on grip strength. Cox proportional hazard models were employed to examine associations of sarcopenia with incident Alzheimer's dementia (AD) and incident mild cognitive impairment (MCI). Linear mixed-effect models determined the association of sarcopenia with cognitive decline. All models controlled for age, sex, education, race, and height squared. RESULTS: Average follow-up was 5.6 years. More severe sarcopenia at baseline was associated with a higher risk of incident AD (hazard ratio [HR], 1.50 [95% confidence interval 1.20–1.86]; p < 0.001) and of MCI (1.21 [1.01–1.45]; 0.04) and a faster rate of cognitive decline (estimate =0.013; p = 0.01). Analyses of the individual components of sarcopenia showed that muscle function was associated with incident AD, incident MCI, and cognitive decline with and without a term for lean muscle mass in the model. In contrast, lean muscle mass was not associated with incident cognitive impairment or cognitive decline when a term for muscle function was included in the model. CONCLUSIONS: Poor muscle function, but not reduced lean muscle mass, drives the association of sarcopenia with late-life cognitive impairment. Further work is needed to identify features of muscle structure, which may increase the specificity of sarcopenia for identifying older adults at risk for late-life cognitive impairment.

Motor resilience proteins may be a high value therapeutic target that offset the negative effects of pathologies on motor function. This study sought to identify cortical proteins associated with motor decline unexplained by brain pathologies that provide motor resilience. We studied 1226 older decedents with annual motor testing, postmortem brain pathologies and quantified 226 proteotypic peptides in prefrontal cortex. Twenty peptides remained associated with motor decline in models controlling for ten brain pathologies (FDR

Background: Patients with Parkinson's disease (PD) and progressive supranuclear palsy Richardson's syndrome (PSP-RS) often show overlapping clinical features, leading to misdiagnoses. The objective of this study was to investigate the feasibility and utility of using multi-modal MRI datasets for an automatic differentiation of PD patients, PSP-RS patients, and healthy control (HC) subjects.Material and Methods: T1-weighted, T2-weighted, and diffusion-tensor (DTI) MRI datasets from 45 PD patients, 20 PSP-RS patients, and 38 HC subjects were available for this study. Using an atlas-based approach, regional values of brain morphology (T1-weighted), brain iron metabolism (T2-weighted), and microstructural integrity (DTI) were measured and employed for feature selection and subsequent classification using combinations of various established machine learning methods.Results: The optimal machine learning model using regional morphology features only achieved a classification accuracy of 65% (67/103 correct classifications) differentiating PD patients, PSP-RS patients, and HC subjects. The optimal machine learning model using only quantitative T2 values performed slightly better and achieved an accuracy of 75.7% (78/103). The optimal classifier using DTI features alone performed considerably better with 95.1% accuracy (98/103). The optimal multi-modal classifier using all features also achieved an accuracy of 95.1% but required more features and achieved a slightly lower F1-score compared to the optimal model using DTI features alone.Conclusion: Machine learning models using multi-modal MRI perform significantly better than uni-modal machine learning models using morphological parameters based on T1-weighted MRI datasets alone or brain iron metabolism markers based on T2-weighted MRI datasets alone. However, machine learnig models using regional brain microstructural integrity metrics computed from DTI datasets perform similar to the optimal multi-modal machine learning model. Thus, given the results from this study cohort, it appears that morphology and brain iron metabolism markers may not provide additional value for classification compared to using DTI metrics alone.

Background and Purpose: The general cardiovascular Framingham risk score (FRS) identifies adults at increased risk for stroke. We tested the hypothesis that baseline FRS is associated with the presence of postmortem cerebrovascular disease (CVD) pathologies. Methods: We studied the brains of 1672 older decedents with baseline FRS and measured CVD pathologies including macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy. We employed a series of logistic regressions to examine the association of baseline FRS with each of the 5 CVD pathologies. Results: Average age at baseline was 80.5±7.0 years and average age at death was 89.2±6.7 years. A higher baseline FRS was associated with higher odds of macroinfarcts (odds ratio, 1.10 [95% CI, 1.07–1.13], P P =0.009), atherosclerosis (odds ratio, 1.07 [95% CI, 1.04–1.11], P P =0.005). C statistics for these models ranged from 0.537 to 0.595 indicating low accuracy for predicting CVD pathologies. FRS was not associated with the presence of cerebral amyloid angiopathy. Conclusions: A higher FRS score in older adults is associated with higher odds of some, but not all, CVD pathologies, with low discrimination at the individual level. Further work is needed to develop a more robust risk score to identify adults at risk for accumulating CVD pathologies.

Introduction Physical activity (PA) is associated with better cognitive and brain health. However, it remains unclear whether PA relates to accumulation of disease pathology (“resistance”) or indirectly moderates adverse effects of pathology on cognition (“cognitive resilience”). Methods Five hundred thirteen Rush Memory and Aging Project (MAP) decedents completed longitudinal actigraphy monitoring, cognitive testing, and neuropathological examination. Cross‐sectional models tested the relationship between average PA and pathology, and the moderating effect of baseline PA on the association between pathology and cognition. Longitudinal models examined whether changes in PA moderated associations between pathology and cognition. Results PA was negatively associated with Lewy body disease (LBD), but positively associated with Alzheimer's disease (AD) burdens. Baseline PA attenuated the association between cerebrovascular pathology and cognition, whereas longitudinal change in PA attenuated associations between AD, cerebral amyloid angiopathy, TAR DNA‐binding protein 43, and atherosclerosis on cognitive decline. Discussion Whereas PA relates to “cognitive resilience” against cerebrovascular disease, AD, and other neuropathologies, “resistance” effects were limited.

The inflammatory hypothesis posits that sustained neuroinflammation is sufficient to induce neurodegeneration and the development of Alzheimer’s disease (AD) and Alzheimer’s dementia. One potential source of inflammation is the intestine which harbors pro-inflammatory microorganisms capable of promoting neuroinflammation. Systemic inflammation is robustly associated with neuroinflammation as well as low levels of brain derived neurotrophic factor (BDNF) in the systemic circulation and brain. Thus, in this pilot study, we tested the hypothesis that intestinal barrier dysfunction precedes risk of death, incident AD dementia and MCI, cognitive impairment and neuropathology. Serum BDNF was associated with changes in global cognition, working memory, and perceptual speed but not risk of death, incident AD dementia, incident MCI, or neuropathology. Neither of the markers of intestinal barrier integrity examined, including lipopolysaccharide binding protein (LBP) nor intestinal fatty acid binding protein (IFABP), were associated with risk of death, incident AD dementia, incident mild cognitive impairment (MCI), change in cognition (global or domains), or neuropathology. Taken together, the data in this pilot study suggest that intestinal barrier dysfunction does not precede diagnosis of AD or MCI, changes in cognition, or brain pathology. However, since MCI and AD are related to global cognition, the findings with BDNF and the contiguous cognitive measures suggest low power with the trichotomous cognitive status measures. Future studies with larger sample sizes are necessary to further investigate the results from this pilot study.

Background Mobility disability and parkinsonism are associated with decreased survival in older adults. This study examined the transition from no motor impairment to mobility disability and parkinsonism and their associations with death. Methods 867 community-dwelling older adults without mobility disability or parkinsonism at baseline were examined annually. Mobility disability was based on annual measured gait speed. Parkinsonism was based on the annual assessment of 26 items from the motor portion of the Unified Parkinson’s Disease Rating Scale. A multistate Cox model simultaneously examined the incidences of mobility disability and parkinsonism and their associations with death. Results Average age at baseline was 75 years old and 318 (37%) died during 10 years of follow-up. Mobility disability was almost 2-fold more common than parkinsonism. Some participants developed mobility disability alone (42%), or parkinsonism alone (5%), while many developed both (41%). Individuals with mobility disability or parkinsonism alone had an increased risk of death, but their risk was less than the risk in individuals with both impairments. The risk of death did not depend on the order in which impairments occurred. Conclusion The varied patterns of transitions from no motor impairment to motor impairment highlights the heterogeneity of late-life motor impairment and its contribution to survival. Further studies are needed to elucidate the underlying biology of these different transitions and how they might impact survival.

Summary Background Circadian disturbances are commonly seen in people with Alzheimer's disease and have been reported in individuals without symptoms of dementia but with Alzheimer's pathology. We aimed to assess the temporal relationship between circadian disturbances and Alzheimer's progression. Methods We did a prospective cohort study of 1401 healthy older adults (aged >59 years) enrolled in the Rush Memory and Aging Project (Rush University Medical Center, Chicago, IL, USA) who had been followed up for up to 15 years. Participants underwent annual assessments of cognition (with a battery of 21 cognitive performance tests) and motor activities (with actigraphy). Four measures were extracted from actigraphy to quantify daily and circadian rhythmicity, which were amplitude of 24-h activity rhythm, acrophase (representing peak activity time), interdaily stability of 24-h activity rhythm, and intradaily variability for hourly fragmentation of activity rhythm. We used Cox proportional hazards models and logistic regressions to assess whether circadian disturbances predict an increased risk of incident Alzheimer's dementia and conversion of mild cognitive impairment to Alzheimer's dementia. We used linear mixed-effects models to investigate how circadian rhythms changed longitudinally and how the change integrated to Alzheimer's progression. Findings Participants had a median age of 81·8 (IQR 76·3–85·7) years. Risk of developing Alzheimer's dementia was increased with lower amplitude (1 SD decrease, hazard ratio [HR] 1·39, 95% CI 1·19–1·62) and higher intradaily variability (1 SD increase, 1·22, 1·04–1·43). In participants with mild cognitive impairment, increased risk of Alzheimer's dementia was predicted by lower amplitude (1 SD decrease, HR 1·46, 95% CI 1·24–1·72), higher intradaily variability (1 SD increase, 1·36, 1·15–1·60), and lower interdaily stability (1 SD decrease, 1·21, 1·02–1·44). A faster transition to Alzheimer's dementia in participants with mild cognitive impairment was predicted by lower amplitude (1 SD decrease, odds ratio [OR] 2·08, 95% CI 1·53–2·93), increased intradaily variability (1 SD increase, 1·97, 1·43–2·79), and decreased interdaily stability (1 SD decrease, 1·35, 1·01–1·84). Circadian amplitude, acrophase, and interdaily stability progressively decreased over time, and intradaily variability progressively increased over time. Alzheimer's progression accelerated these aging effects by doubling or more than doubling the annual changes in these measures after the diagnosis of mild cognitive impairment, and further doubled them after the diagnosis of Alzheimer's dementia. The longitudinal change of global cognition positively correlated with the longitudinal changes in amplitude and interdaily stability and negatively correlated with the longitudinal change in intradaily variability. Interpretation Our results indicate a link between circadian dysregulation and Alzheimer's progression, implying either a bidirectional relation or shared common underlying pathophysiological mechanisms. Funding National Institutes of Health, and the BrightFocus Foundation.

Background: Vascular mechanisms may contribute to the accumulation of AD pathology. Objective: We examined whether the burden of vascular risk factors proximate to death is associated with amyloid-β and tau levels or modified their known association. Methods: We examined the brains of 1, 585 participants from two longitudinal community-based studies of older adults. Amyloid-β and tau were quantified by postmortem examination. The burden of vascular risk factors was summarized by calculating the Framingham general cardiovascular risk score (FRS) proximate to death. Using linear regressions, we examined the association of the FRS with the amyloid-β and tau levels and examined if the FRS modified the association of the amyloid-β with tau. Results: On average, participants were nearly 90 years old and two-thirds were women. The FRS was not associated with amyloid-β (Spearman r = –0.00, p = 0.918) or tau (r = 0.01, p = 0.701). However, the FRS as a whole (estimate = –0.022, SE = 0.008, p = 0.009), and specifically the systolic blood pressure (SBP) component (estimate = –0.033, SE = 0.012, p = 0.009), modified the association of the amyloid-β with tau. Further analysis showed that the association between amyloid-β and tau was stronger at lower levels of SBP. Conclusion: Late-life vascular risk scores were not related to postmortem levels of amyloid-β or tau. However, lower levels of vascular risk scores and SBP were associated with a stronger association between amyloid-β and tau. These data suggest that vascular risk factors may modify the relation of AD pathology markers to one another.

Background This study tested the hypothesis that sarcopenia and its constituent components, reduced lean muscle mass and impaired motor function, are associated with reduced survival and increased risk of incident disabilities. Methods 1466 community-dwelling older adults underwent assessment of muscle mass with bioelectrical impedance analysis (BIA), grip strength, gait speed and other components of physical frailty and annual self-report assessments of disability. We used Cox proportional hazards models that controlled for age, sex, race, education and height to examine the associations of a continuous sarcopenia metric with the hazard of death and incident disabilities. Results Mean baseline age was about 80 years old and follow-up was 5.5 years. In a proportional hazards model controlling for age, sex, race, education and baseline sarcopenia, each 1-SD higher score on a continuous sarcopenia scale was associated with lower hazards of death (HR 0.70, 95%CI [0.62, 0.78]), incident IADL (HR 0.80,95%CI [0.70, 0.93]), incident ADL disability (HR 0.80 95%CI [71, 91]) and incident mobility disability (HR 0.81, 95%CI [0.70, 0.93]). Further analyses suggest that grip strength and gait speed rather than muscle mass drive the associations with all four adverse health outcomes. Similar findings were observed when controlling for additional measures used to assess physical frailty including BMI, fatigue and physical activity. Conclusions Motor function is the primary driver of the associations of sarcopenia and physical frailty with diverse adverse health outcomes. Further work is needed to identify other facets of muscle structure and motor function which together can identify adults at risk for specific adverse health outcomes.

Age‐related bone loss is common in older adults. However, the association of low bone mass with incident disability and mortality is not well established. A sample of 738 participants in the Rush Memory and Aging Project (MAP) was evaluated at baseline for bone mineral density (BMD) using quantitative ultrasound at the calcaneus. An annual interview assessed basic activities of daily living (BADL), instrumental activities of daily living (IADL), mobility disability, and history of hip fracture. The associations between baseline BMD and risk of death; incident BADL, IADL, and mobility disability; and hip fracture were investigated using Cox hazard models, adjusting for age, sex, education, race, and body mass index (BMI). The robustness of our findings was evaluated by adjusting for confounding factors and health conditions including joint pain, musculoskeletal medications, smoking status, motor function, global cognition, falls, cardiovascular events, and diabetes. Participants were on average (mean ± SD) 80.9 ± 7.0 years old, 72% female, and 3.8% black, with a baseline BMI of 27.3 ± 5.4 kg/m2, and a baseline of BMD of 0.44 ± 0.14 g/cm2. In models adjusted for age, sex, education, race, and BMI, lower BMD was associated with a higher rate of death (hazard ratio [HR] 1.20; 95% confidence interval [CI], 1.08–1.33), incident BADL disability (HR 1.20; 95% CI, 1.05–1.37), and hip fracture (HR 2.57; 95% CI, 1.72–3.82), but not of IADL disability (HR 1.00; 95% CI, 0.85–1.17) or mobility disability (HR 1.13; 95% CI, 0.97–1.32). The association between BMD and mortality was not significant in fully adjusted models, but the BMD and BADL associations remained significant in models adjusting for both demographic variables and BMD‐modifying health conditions. BMD is associated with incident disability in older adults. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

IntroductionEmerging technologies show promise for enhanced characterization of Parkinson’s Disease (PD) motor manifestations. We evaluated quantitative mobility measures from a wearable device compared to the conventional motor assessment, the Movement Disorders Society-Unified PD Rating Scale part III (motor MDS-UPDRS).MethodsWe evaluated 176 subjects with PD (mean age 65, 65% male, 66% H&Y stage 2) at the time of routine clinic visits using the motor MDS-UPDRS and a structured 10-minute motor protocol, which included a 32-ft walk, Timed Up and Go (TUG), and standing posture with eyes closed, while wearing a body-fixed sensor (DynaPort MT, McRoberts BV). Regression models examined 12 quantitative mobility measures for associations with (i) motor MDS-UPDRS, (ii) motor subtype (tremor dominant vs. postural instability/gait difficulty), (iii) Montreal Cognitive Assessment (MoCA), and (iv) physical functioning disability (PROMIS-29). All analyses included age, gender, and disease duration as covariates. Models iii-iv were secondarily adjusted for motor MDS-UPDRS.ResultsQuantitative mobility measures from gait, TUG transitions, turning, and posture were significantly associated with motor MDS-UPDRS (7 of 12 measures, p< 0.05) and subtype (6 of 12 measures, p< 0.05). Compared with motor MDS-UPDRS, several quantitative mobility measures accounted for ∼1.5-fold increased variance in either cognition or physical functioning disability. Among minimally-impaired subjects within the bottom quartile of motor MDS-UPDRS, including subjects with normal gait exam, the measures captured substantial residual motor heterogeneity.ConclusionClinic-based quantitative mobility assessments using a wearable sensor captured features of motor performance beyond those obtained with the motor MDS-UPDRS and may offer enhanced characterization of disease heterogeneity.

Type 2 diabetes (T2D) is associated with motor impairments and a higher dementia risk. The relationships of motor decline with cognitive decline in T2D older adults has rarely been studied. Using data from the Israel Diabetes and Cognitive Decline study (N = 892), we examined associations of decline in motor function with cognitive decline over a 54-month period.Motor function measures were strength (handgrip) and gait speed (time to walk 3 m). Participants completed a neuropsychologic battery of 13 tests transformed into z-scores, summarized into 4 cognitive domains: episodic memory, attention/working memory, executive functions, and language/semantic categorization. The average of the 4 domains' z-scores defined global cognition. Motor and cognitive functions were assessed in 18-months intervals. A random coefficients model delineated longitudinal relationships of cognitive decline with baseline and change from baseline in motor function, adjusting for sociodemographic, cardiovascular, and T2D-related covariates.Slower baseline gait speed levels were significantly associated with more rapid decline in global cognition (P = .004), language/semantic categorization (P = .006) and episodic memory (P = .029). Greater decline over time in gait speed was associated with an accelerated rate of decline in global cognition (P = .050), attention/working memory (P = .047) and language/semantic categorization (P.001). Baseline strength levels were not associated with cognitive decline but the rate of declining strength was associated with an accelerated decline in executive functions (P = .025) and language/semantic categorization (P = .006).In T2D older adults, the rate of decline in motor function, beyond baseline levels, was associated with accelerated cognitive decline, suggesting that cognitive and motor decline share common neuropathologic mechanisms in T2D.

ObjectiveTo examine the associations of physical activity, Alzheimer disease (AD), and other brain pathologies and cognition in older adults.MethodsWe studied 454 brain autopsies from decedents in a clinical-pathologic cohort study. Nineteen cognitive tests were summarized in a global cognitive score. Total daily physical activity summarized continuous multiday recordings of activity during everyday living in the community setting. A global motor ability score summarized 10 supervised motor performance tests. A series of regression analyses were used to examine associations of physical activity, AD, and other brain pathologies with global cognition proximate to death controlling for age, sex, education, and motor abilities.ResultsHigher levels of total daily activity (estimate 0.148, 95% confidence interval 0.053–0.244, SE 0.049, p = 0.003) and better motor abilities (estimate 0.283, 95% confidence interval, 0.175–0.390, SE 0.055, p < 0.001) were independently associated with better cognition. These independent associations remained significant when terms for AD and other pathologies were added as well as in sensitivity analyses excluding cases with poor cognition or dementia. Adding interaction terms, the associations of total daily activity and motor abilities with cognition did not vary in individuals with and without dementia. The associations of AD and other pathologies with cognition did not vary with the levels of total daily activity or motor abilities.ConclusionsPhysical activity in older adults may provide cognitive reserve to maintain function independent of the accumulation of diverse brain pathologies. Further studies are needed to identify the molecular mechanisms underlying this potential reserve and to ensure the causal effects of physical activity.

Background: Few data are available on associations of antiphospholipid (aPL) antibodies with cognitive and motor decline in aging, and cerebrovascular disease on in vivo neuroimaging and postmortem neuropathology. Methods: This longitudinal, clinical-pathologic study (aPL antibodies, brain infarcts, and cognitive and motor decline in aging), was derived from 2 ongoing community-based cohort studies. A panel of 3 aPL antibodies was assayed in serum from 956 older individuals (mean age = 81.1 years; 72% women). Serum was also tested in a subset for markers of inflammation (C-reactive protein [CRP]) and blood-brain barrier breakdown (matrix metalloproteinases, MMPs). Annual clinical evaluations documented cognitive (17 neuropsychological tests) and motor function including parkinsonism. Cerebrovascular disease data were derived from in vivo neuroimaging and postmortem neuropathologic evaluations (699 individuals). We examined associations of aPL with cognitive and motor decline, other serum markers, neuroimaging, and neuropathology. Results: Of 956 individuals, 197 (20.6%) had aPL positivity, defined as positivity on any of the assays, at the time of first measurement. During a mean follow-up of 6.6 years (SD 4), overall aPL positivity was not associated with change in global cognition (estimate = –0.005, SE 0.011; p = 0.622) or parkinsonian signs (estimate = –0.003, SE 0.017; p = 0.860). aPL were not associated with serum CRP or MMPs (both p > 0.268). aPL were not associated with in vivo brain magnetic resonance imaging white matter hyperintensities or infarcts (both p > 0.376). Among those autopsied, aPL were not associated with pathologically confirmed brain infarcts, or cerebral atherosclerosis or arteriolosclerosis (all p≥ 0.447). Conclusions: In older individuals followed longitudinally, aPL do not relate to cognitive or motor decline, inflammation, or cerebrovascular disease on in vivo neuroimaging or postmortem neuropathology.

BACKGROUND: In old age, motor impairments including parkinsonian signs are common, but treatment is lacking for many older adults. In this study, we examined the association of a diet specifically developed to promote brain health, called MIND (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay), to the incidence and progression of parkinsonism in older adults. METHODS: A total of 706 Memory and Aging Project participants aged 59 −97 years and without parkinsonism at baseline were assessed annually for the presence of four parkinsonian signs using a 26-item modified version of the United Parkinson’s Disease Rating Scale. Incident parkinsonism was defined as the first occurrence over 4.6 years of follow-up of two or more parkinsonian signs. The progression of parkinsonism was assessed by change in a global parkinsonian score (range: 0–100). MIND, Mediterranean, and DASH diet pattern scores were computed based on a validated food frequency questionnaire including 144 food items. We employed Cox-Proportional Hazard models and linear mixed models, to examine the associations of baseline diet scores with incident parkinsonism and the annual rate of change in global parkinsonian score, respectively. RESULTS: In models adjusted for age, sex, smoking, total energy intake, BMI and depressive symptoms, higher MIND diet scores were associated with a decreased risk of parkinsonism [(HR=0.89, 95% CI 0.83–0.96)]; and a slower rate of parkinsonism progression [(β= −0.008; SE=0.0037; p=0.04)]. The Mediterranean diet was marginally associated with reduced parkinsonism progression (β= −0.002; SE=0.0014; p=0.06). The DASH diet, by contrast, was not associated with either outcome. CONCLUSION: The MIND diet created for brain health may be a associated with decreased risk and slower progression of parkinsonism in older adults.

Objective Previous gene expression analysis identified a network of coexpressed genes that is associated with β-amyloid neuropathology and cognitive decline in older adults. The current work targeted influential genes in this network with quantitative proteomics to identify potential novel therapeutic targets. Methods Data came from 834 community-based older persons who were followed annually, died, and underwent brain autopsy. Uniform structured postmortem evaluations assessed the burden of β-amyloid and other common age-related neuropathologies. Selected reaction monitoring quantified cortical protein abundance of 12 genes prioritized from a molecular network of aging human brain that is implicated in Alzheimer's dementia. Regression and linear mixed models examined the protein associations with β-amyloid load and other neuropathological indices as well as cognitive decline over multiple years preceding death. Results Average age at death was 88.6 years. Overall, 349 participants (41.9%) had Alzheimer's dementia at death. A higher level of PLXNB1 abundance was associated with more β-amyloid load (p = 1.0 × 10-7 ) and higher PHFtau tangle density (p = 2.3 × 10-7 ), and the association of PLXNB1 with cognitive decline is mediated by these known Alzheimer's disease pathologies. On the other hand, higher IGFBP5, HSPB2, and AK4 and lower ITPK1 levels were associated with faster cognitive decline, and, unlike PLXNB1, these associations were not fully explained by common neuropathological indices, suggesting novel mechanisms leading to cognitive decline. Interpretation Using targeted proteomics, this work identified cortical proteins involved in Alzheimer's dementia and begins to dissect two different molecular pathways: one affecting β-amyloid deposition and another affecting resilience without a known pathological footprint. Ann Neurol 2018;83:78-88.

Background The Religious Orders Study and Rush Memory and Aging Project are both ongoing longitudinal clinical-pathologic cohort studies of aging and Alzheimer's disease (AD). Objectives To summarize progress over the past five years and its implications for understanding neurodegenerative diseases. Methods Participants in both studies are older adults who enroll without dementia and agree to detailed longitudinal clinical evaluations and organ donation. The last review summarized findings through the end of 2011. Here we summarize progress and study findings over the past five years and discuss new directions for how these studies can inform on aging and AD in the future. Results We summarize 1) findings on the relation of neurobiology to clinical AD; 2) neurobiologic pathways linking risk factors to clinical AD; 3) non-cognitive AD phenotypes including motor function and decision making; 4) the development of a novel drug discovery platform. Conclusion Complexity at multiple levels needs to be understood and overcome to develop effective treatments and preventions for cognitive decline and AD dementia.

Introduction Healthy physiological systems exhibit fractal regulation (FR), generating similar fluctuation patterns in physiological outputs across different time scales. FR in motor activity is degraded in dementia, and the degradation correlates to cognitive decline. We tested whether degraded FR predicts Alzheimer's dementia. Methods FR in motor activity was assessed in 1097 nondemented older adults at baseline. Cognition was assessed annually for up to 11 years. Results Participants with an FR metric at the 10th percentile in this cohort had a 1.8-fold Alzheimer's disease risk (equivalent to the effect of being ∼5.2 years older) and 1.3-fold risk for mild cognitive impairment (equivalent to the effect of being ∼3.0 years older) than those at the 90th percentile. Consistently, degraded FR predicted faster cognitive decline. These associations were independent of physical activity, sleep fragmentation, and stability of daily activity rhythms. Discussion FR may be a useful tool for predicting Alzheimer's dementia.

Background Chemotherapy for early breast cancer is associated with a small risk of developing myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). The aim of this study was to determine the risk of developing AML or MDS after modern adjuvant chemotherapy in older breast cancer patients and to further define the risk of individual chemotherapy regimens. Methods Patients diagnosed with stage I to III breast cancer from 2003 to 2009 were identified in the Surveillance, Epidemiology, and End Results-Medicare and Texas Cancer Registry-Medicare linked databases. The development of AML/MDS, chemotherapy use, and comorbidities were identified with International Classification of Diseases, Ninth Revision and Healthcare Common Procedure Coding System codes. Analyses included descriptive statistics, cumulative incidences, and Cox proportional hazards models to estimate the hazard of AML/MDS after adjustments for clinically relevant covariates. Results In all, 92,110 patients were included; after a median follow-up of 85 months, the overall rates per 1000 person-years were 0.65 for AML and 1.56 for MDS. Patients who received an anthracycline (A) or anthracycline and taxane (A+T) regimen were more likely to develop AML (hazard ratio [HR] for A, 1.70; 95% confidence interval [CI], 1.16-2.50; HR for A+T, 1.68; 95% CI, 1.22-2.30) or MDS (HR for A, 2.18; 95% CI, 1.70-2.80; HR for A+T, 1.62; 95% CI, 1.29-2.03) than patients who did not receive chemotherapy. Patients using docetaxel and cyclophosphamide (TC) were not at increased risk for AML or MDS. Conclusions Adjuvant chemotherapy is associated with a small but significant increase in the risk of AML and MDS, especially with regimens that include A. Longer follow-up is needed to confirm that risk is not increased with the recently adopted TC regimen. Cancer 2018;124:899-906. © 2017 American Cancer Society.

Introduction Patients with Parkinson's disease (PD) frequently experience disrupted sleep, and several sleep abnormalities are associated with an increased risk of incident PD. However, there are few data concerning the relationship between objectively quantified sleep disruption and the cardinal histopathological features of PD, especially in individuals without clinical PD. Methods We studied 269 older adults without PD who had participated in the Rush Memory and Aging Project and undergone uniform structured neuropathologic evaluations upon death. Sleep fragmentation was measured using actigraphy. Logistic regression models examined the associations of sleep fragmentation proximate to death with the burden of Lewy body pathology and substantia nigra neuron loss. Results Greater sleep fragmentation was associated with the presence of Lewy body pathology (odds ratio 1.40; 95% confidence interval 1.05-1.86; P = .02) and substantia nigra neuron loss (odds ratio 1.43; 95% confidence interval 1.10-1.88; P = .008) and a higher odds of a pathological diagnosis of PD (odds ratio 2.04; 95% confidence interval 1.34-3.16; P = .0009). These associations were independent of motor features of parkinsonism, demographic characteristics, and a wide range of medical co-morbidities. Conclusions Sleep fragmentation is associated with PD pathology in older adults without PD. These results suggest that sleep fragmentation may be a marker of or risk factor for PD pathology in older adults without PD. © 2017 International Parkinson and Movement Disorder Society

Objective: To test the hypothesis that Lewy body pathology (LBs) is present in the spinal cord of older community-dwelling adults without a clinical diagnosis of Parkinson's disease (PD). Methods: We studied 162 prospective autopsies from older adults with PD (N=6) and without PD (N=156). We documented the presence of LBs in cerebrum and brainstem structures from each of the 6 regions used for Braak PD staging and 4 spinal cord levels (C5/6, T7, L4/5 and S4/5). Parkinsonism proximate to death was based on a previously validated measure present if 2 or more of the 4 signs of parkinsonism were present based on a modified version of the Unified Parkinson's Disease Rating Scale (UPDRS). Results: Fifty-three of 156 individuals without PD (34%) had LBs in a least one site within the CNS. About half of cases with LBs in the cerebrum or brainstem, (25/53, 47%) also had spinal LBs. Almost 90% (22/25 88%) of cases with spinal LBs had LBs in the cerebrum (Braak stages 4-6) and about 10% (3/25, 12%) had only brainstem LBs (Braak stages 1-3). Four of 6 cases with PD showed LBs in cerebrum, brainstem and spinal cord. Individuals with LBs in the spinal cord were more likely to have clinical parkinsonism proximate to death compared to individuals with LBs in brainstem and cerebrum alone (52% vs 32%; Chi-Square х2 = 5.368, df = 1, p = 0.0.021) and more severe nigral neuronal loss (48%% vs 11%; Chi-Square х2 = 9.049, df = 1, p = 0.003). These findings were unchanged when we included cases with a history of PD. Conclusion: Older community-dwelling adults without a clinical diagnosis of PD have evidence of LBs throughout the CNS including the spinal cord which is associated with parkinsonism and more severe nigral neuronal loss. This article is protected by copyright. All rights reserved.

A method for capturing gait signatures in neurological conditions that allows comparison of human gait with animal models would be of great value in translational research. However, the velocity dependence of gait parameters and differences between quadruped and biped gait have made this comparison challenging. Here we present an approach that accounts for changes in velocity during walking and allows for translation across species. In mice, we represented spatial and temporal gait parameters as a function of velocity and established regression models that reproducibly capture the signatures of these relationships during walking. In experimental parkinsonism models, regression curves representing these relationships shifted from baseline, implicating changes in gait signatures, but with marked differences between models. Gait parameters in healthy human subjects followed similar strict velocity dependent relationships which were altered in Parkinson’s patients in ways that resemble some but not all mouse models. This novel approach is suitable to quantify qualitative walking abnormalities related to CNS circuit dysfunction across species, identify appropriate animal models, and it provides important translational opportunities.

Alterations of the transverse relaxation rate, R 2 , measured using MRI, are observed in older persons with Alzheimer’s (AD) dementia. However, the spatial pattern of these alterations and the degree to which they reflect the accumulation of common age-related neuropathologies are unknown. In this study, we characterized the profile of R 2 alterations in post-mortem brains of persons with clinical diagnosis of AD dementia and investigated how the profile differs after accounting for neuropathologic indices of AD, cerebral infarcts, Lewy body disease, hippocampal sclerosis and transactive response DNA-binding protein 43. Data came from 567 post-mortem brains donated by participants in two cohort studies of aging and dementia. R 2 was quantified using fast spin echo imaging. Voxelwise linear regression examined R 2 alterations between subjects diagnosed with AD dementia at death and those with no cognitive impairment. Voxels showing significant R 2 alterations were clustered into regions of interest (ROIs). Three R 2 profiles were compared, which were adjusted for (1) demographics only; (2) demographics and AD pathology; (3) demographics, AD pathology and other common neuropathologies. R 2 alterations were observed throughout the hemisphere, most commonly in white matter. Of the distinct ROIs identified, the largest region encompassed large portions of white matter in all lobes. This ROI became smaller in size but remained largely intact after adjusting for AD and other neuropathologic indices. Further, R 2 alterations identify AD dementia with improved accuracy, above and beyond demographics and neuropathologic indices (p 2 alterations in AD dementia are not solely reflective of common age-related neuropathologies, suggesting that other mechanisms are at work.

ObjectiveWe examined the association of physical activity, postmortem brain pathologies, and parkinsonism proximate to death in older adults.MethodsWe studied the brains of 447 older decedents participating in a clinical-autopsy cohort study. We deployed a wrist worn activity monitor to record total daily physical activity during everyday living in the community-setting. Parkinsonism was assessed with 26 items of a modified motor portion of Unified Parkinson's Disease Rating Scale (UPDRS). We used linear regression models, controlling for age and sex, to examine the association of physical activity with parkinsonism with and without indices of Alzheimer's disease and related disorders (ADRD) pathologies. In separate models, we added interaction terms to examine if physical activity modified the associations of brain pathologies with parkinsonism.ResultsMean age at death was 90.9 (SD, 6.2), mean severity of parkinsonism was 14.1 (SD, 9.2, Range 0-59.4), and 350 (77%) had evidence of more than one ADRD pathologies. Higher total daily physical activity was associated with less severe parkinsonism (Estimate, -0.315, S.E., 0.052, pConclusionThe association of higher physical activity with less severe parkinsonism may be independent of the presence of ADRD brain pathologies. Further work is needed to identify mechanisms through which physical activity may maintain motor function in older adults.

Poor sleep in older adults is associated with aging of the brain’s resident innate immune cells and impaired cognition., Sleep disruption is associated with cognitive decline and dementia in older adults; however, the underlying mechanisms are unclear. In rodents, sleep disruption causes microglial activation, inhibition of which improves cognition. However, data from humans are lacking. We studied participants in two cohort studies of older persons—the Rush Memory and Aging Project and the Religious Orders Study. We assessed sleep fragmentation by actigraphy and related this to cognitive function, to neocortical microglial marker gene expression measured by RNA sequencing, and to the neocortical density of microglia assessed by immunohistochemistry. Greater sleep fragmentation was associated with higher neocortical expression of genes characteristic of aged microglia, and a higher proportion of morphologically activated microglia, independent of chronological age- and dementia-related neuropathologies. Furthermore, these were, in turn, associated with worse cognition. This suggests that sleep fragmentation is accompanied by accelerated microglial aging and activation, which may partially underlie its association with cognitive impairment.