The Influence of Diffusion Weighted Imaging Lesions on Outcomes in Patients with Acute Spontaneous Intracerebral Hemorrhage.

BACKGROUND/OBJECTIVE: Diffusion weighted imaging (DWI) lesions have been well described in patients with acute spontaneous intracerebral hemorrhage (sICH). However, there are limited data on the influence of these lesions on sICH functional outcomes. We conducted a prospective observational cohort study with blinded imaging and outcomes assessment to determine the influence of DWI lesions on long-term outcomes in patients with acute sICH. We hypothesized that DWI lesions are associated with worse modified Rankin Scale (mRS) at 3 months after hospital discharge. METHODS: Consecutive sICH patients meeting study criteria were consented for an magnetic resonance imaging (MRI) scan of the brain and evaluated for remote DWI lesions by neuroradiologists blinded to the patients' hospital course. Blinded mRS outcomes were obtained at 3 months. Logistic regression was used to determine significant factors (p < 0.05) associated with worse functional outcomes defined as an mRS of 4-6. The generalized estimating equation (GEE) approach was used to investigate the effect of DWI lesions on dichotomized mRS (0-3 vs 4-6) longitudinally. RESULTS: DWI lesions were found in 60 of 121 patients (49.6%). The presence of a DWI lesion was associated with increased odds for an mRS of 4-6 at 3 months (OR 5.987, 95% CI 1.409-25.435, p = 0.015) in logistic regression. Using the GEE model, patients with a DWI lesion were less likely to recover over time between 14 days/discharge and 3 months (p = 0.005). CONCLUSIONS: DWI lesions are common in primary sICH, occurring in almost half of our cohort. Our data suggest that DWI lesions are associated with worse mRS at 3 months in good grade sICH and are predictive of impaired recovery after hospital discharge. Further research into the pathophysiologic mechanisms underlying DWI lesions may lead to novel treatment options that may improve outcomes associated with this devastating disease.

Late-life cognitive decline is associated with hippocampal volume, above and beyond its associations with traditional neuropathologic indices.

INTRODUCTION: Reduced hippocampal volume is associated with late-life cognitive decline, but prior studies have not determined whether this association persists after accounting for Alzheimer's disease (AD) and other neuropathologies. METHODS: Participants were 531 deceased older adults from community-based cohort studies of aging who had undergone annual cognitive evaluations. At death, brain tissue underwent neuropathologic examination and magnetic resonance imaging (MRI). Linear mixed models examined whether hippocampal volume measured via MRI accounted for variation in decline rate of global cognition and five cognitive domains, above and beyond neuropathologic indices. RESULTS: Demographics and indices of AD, cerebrovascular disease, Lewy body disease, hippocampal sclerosis, TDP-43, and atherosclerosis accounted for 42.6% of the variation in global cognitive decline. Hippocampal volume accounted for an additional 5.4% of this variation and made similar contributions in four of the five cognitive domains. DISCUSSION: Hippocampal volume is associated with late-life cognitive decline, above and beyond contributions from common neuropathologic indices.

Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional data.

INTRODUCTION: The molecular underpinnings of the dissociation of cognitive performance and neuropathological burden are poorly understood, and there are currently no known genetic or epigenetic determinants of the dissociation. METHODS AND FINDINGS: "Residual cognition" was quantified by regressing out the effects of cerebral pathologies and demographic characteristics on global cognitive performance proximate to death. To identify genes influencing residual cognition, we leveraged neuropathological, genetic, epigenetic, and transcriptional data available for deceased participants of the Religious Orders Study (n = 492) and the Rush Memory and Aging Project (n = 487). Given that our sample size was underpowered to detect genome-wide significance, we applied a multistep approach to identify genes influencing residual cognition, based on our prior observation that independent genetic and epigenetic risk factors can converge on the same locus. In the first step (n = 979), we performed a genome-wide association study with a predefined suggestive p < 10-5, and nine independent loci met this threshold in eight distinct chromosomal regions. Three of the six genes within 100 kb of the lead SNP are expressed in the dorsolateral prefrontal cortex (DLPFC): UNC5C, ENC1, and TMEM106B. In the second step, in the subset of participants with DLPFC DNA methylation data (n = 648), we found that residual cognition was related to differential DNA methylation of UNC5C and ENC1 (false discovery rate < 0.05). In the third step, in the subset of participants with DLPFC RNA sequencing data (n = 469), brain transcription levels of UNC5C and ENC1 were evaluated for their association with residual cognition: RNA levels of both UNC5C (estimated effect = -0.40, 95% CI -0.69 to -0.10, p = 0.0089) and ENC1 (estimated effect = 0.0064, 95% CI 0.0033 to 0.0096, p = 5.7 × 10-5) were associated with residual cognition. In secondary analyses, we explored the mechanism of these associations and found that ENC1 may be related to the previously documented effect of depression on cognitive decline, while UNC5C may alter the composition of presynaptic terminals. Of note, the TMEM106B allele identified in the first step as being associated with better residual cognition is in strong linkage disequilibrium with rs1990622A (r2 = 0.66), a previously identified protective allele for TDP-43 proteinopathy. Limitations include the small sample size for the genetic analysis, which was underpowered to detect genome-wide significance, the evaluation being limited to a single cortical region for epigenetic and transcriptomic data, and the use of categorical measures for certain non-amyloid-plaque, non-neurofibrillary-tangle neuropathologies. CONCLUSIONS: Through a multistep analysis of cognitive, neuropathological, genomic, epigenomic, and transcriptomic data, we identified ENC1 and UNC5C as genes with convergent genetic, epigenetic, and transcriptomic evidence supporting a potential role in the dissociation of cognition and neuropathology in an aging population, and we expanded our understanding of the TMEM106B haplotype that is protective against TDP-43 proteinopathy.

Ex vivo MR volumetry of human brain hemispheres.

PURPOSE: The aims of this work were to (a) develop an approach for ex vivo MR volumetry of human brain hemispheres that does not contaminate the results of histopathological examination, (b) longitudinally assess regional brain volumes postmortem, and (c) investigate the relationship between MR volumetric measurements performed in vivo and ex vivo. METHODS: An approach for ex vivo MR volumetry of human brain hemispheres was developed. Five hemispheres from elderly subjects were imaged ex vivo longitudinally. All datasets were segmented. The longitudinal behavior of volumes measured ex vivo was assessed. The relationship between in vivo and ex vivo volumetric measurements was investigated in seven elderly subjects imaged both antemortem and postmortem. RESULTS: This approach for ex vivo MR volumetry did not contaminate the results of histopathological examination. For a period of 6 months postmortem, within-subject volume variation across time points was substantially smaller than intersubject volume variation. A close linear correspondence was detected between in vivo and ex vivo volumetric measurements. CONCLUSION: Regional brain volumes measured with this approach for ex vivo MR volumetry remain relatively unchanged for a period of 6 months postmortem. Furthermore, the linear relationship between in vivo and ex vivo MR volumetric measurements suggests that this approach captures information linked to antemortem macrostructural brain characteristics.

Associations of brain morphology with cortical proteins of cognitive resilience.

In a recent proteome-wide study, we identified several candidate proteins for drug discovery whose cortical abundance was associated with cognitive resilience to late-life brain pathologies. This study examines the extent to which these proteins are associated with the brain structures of cognitive resilience in decedents from the Religious Orders Study and Memory and Aging Project. Six proteins were associated with brain morphometric characteristics related to higher resilience (i.e., larger anterior and medial temporal lobe volumes), and five were associated with morphometric characteristics related to lower resilience (i.e., enlarged ventricles). Two synaptic proteins, RPH3A and CPLX1, remained inversely associated with the lower resilience signature, after further controlling for 10 neuropathologic indices. These findings suggest preserved brain structure in periventricular regions as a potential mechanism by which RPH3A and CPLX1 are associated with cognitive resilience. Further work is needed to elucidate other mechanisms by which targeting these proteins can circumvent the effects of pathology on individuals at risk for cognitive decline.

Volumetric brain correlates of gait associated with cognitive decline in community-dwelling older adults.

Objective: To determine the extent to which the regional brain volumes associated with slow gait speed can inform subsequent cognitive decline in older adults from the Rush Memory and Aging Project. Approach: We utilized deformation-based morphometry (DBM) in a whole-brain exploratory approach to identify the regional brain volumes associated with gait speed assessed over a short distance during an in-home assessment. We created deformation scores to summarize the gait-associated regions and entered the scores into a series of longitudinal mixed effects models to determine the extent to which deformation predicted change in cognition over time, controlling for associations between gait and cognition. Results: In 438 older adults (81 ± 7; 76% female), DBM revealed that slower gait speed was associated with smaller volumes across frontal white matter, temporal grey matter, and subcortical areas and larger volumes in the ventricles during the same testing cycle. When a subset was followed over multiple (5 ± 2) years, slower gait speed was also associated with annual declines in global cognition, executive functioning, and memory abilities. Several of the gait-related brain structures were associated with these declines in cognition; however, larger ventricles and smaller medial temporal lobe volumes proved most robust and attenuated the association between slow gait and cognitive decline. Conclusion: Regional brain volumes in the ventricles and temporal lobe associated with both slow gait speed and faster cognitive decline have potential to improve risk stratification for cognitive decline in older adults.

Multi-region brain transcriptomes uncover two subtypes of aging individuals with differences in Alzheimer risk and the impact of APOEε4.

The heterogeneity of the older population suggests the existence of subsets of individuals which share certain brain molecular features and respond differently to risk factors for Alzheimer's disease, but this population structure remains poorly defined. Here, we performed an unsupervised clustering of individuals with multi-region brain transcriptomes to assess whether a broader approach, simultaneously considering data from multiple regions involved in cognition would uncover such subsets. We implemented a canonical correlation-based analysis in a Discovery cohort of 459 participants from two longitudinal studies of cognitive aging that have RNA sequence profiles in three brain regions. 690 additional participants that have data in only one or two of these regions were used in the Replication effort. These clustering analyses identified two meta-clusters, MC-1 and MC-2. The two sets of participants differ primarily in their trajectories of cognitive decline, with MC-2 having a delay of 3 years to the median age of incident dementia. This is due, in part, to a greater impact of tau pathology on neuronal chromatin architecture and to broader brain changes including greater loss of white matter integrity in MC-1. Further evidence of biological differences includes a significantly larger impact of APOEε4 risk on cognitive decline in MC-1. These findings suggest that our proposed population structure captures an aspect of the more distributed molecular state of the aging brain that either enhances the effect of risk factors in MC-1 or of protective effects in MC-2. These observations may inform the design of therapeutic development efforts and of trials as both become increasingly more targeted molecularly. One Sentence Summary: There are two types of aging brains, with one being more vulnerable to APOEε4 and subsequent neuronal dysfunction and cognitive loss.

Inferring protein expression changes from mRNA in Alzheimer's dementia using deep neural networks.

Identifying the molecular systems and proteins that modify the progression of Alzheimer's disease and related dementias (ADRD) is central to drug target selection. However, discordance between mRNA and protein abundance, and the scarcity of proteomic data, has limited our ability to advance candidate targets that are mainly based on gene expression. Therefore, by using a deep neural network that predicts protein abundance from mRNA expression, here we attempt to track the early protein drivers of ADRD. Specifically, by applying the clei2block deep learning model to 1192 brain RNA-seq samples, we identify protein modules and disease-associated expression changes that were not directly observed at the mRNA level. Moreover, pseudo-temporal trajectory inference based on the predicted proteome became more closely correlated with cognitive decline and hippocampal atrophy compared to RNA-based trajectories. This suggests that the predicted changes in protein expression could provide a better molecular representation of ADRD progression. Furthermore, overlaying clinical traits on protein pseudotime trajectory identifies protein modules altered before cognitive impairment. These results demonstrate how our method can be used to identify potential early protein drivers and possible drug targets for treating and/or preventing ADRD.

Frequency and Underlying Pathology of Pure Vascular Cognitive Impairment.

Importance: It is not clear how common pure vascular cognitive impairment (VCI) is in the absence of Alzheimer disease (AD) and/or other neurodegenerative pathologies. Objective: To identify participants without AD and other neurodegenerative pathologies and determine the extent to which cerebrovascular disease pathologies were associated with cognitive impairment. Design, Setting, and Participants: This clinical pathological study included participants from 2 ongoing community-based cohorts that began enrollment in 1994 and 1997. Prior to death, participants were observed for a mean (SD) of 8.4 (5.3) years with annual assessments. From 2096 participants who died, 1799 (85.8%) underwent autopsy and 1767 had complete postmortem pathological examination data at the time of data analyses. To identify participants without neurodegenerative pathologies, we categorized them in 3 subgroups. A vascular subgroup was composed of participants without significant levels of neurodegenerative brain pathologies. A neurodegenerative subgroup was composed of participants without significant levels of cerebrovascular disease pathologies. A mixed subgroup was composed of the rest of the participants. Data were analyzed from May 2021 to July 2022. Exposures: Brain pathology indices obtained by postmortem pathological assessments. Main Outcomes and Measures: The primary outcome was cognitive impairment defined by presence of mild cognitive impairment or dementia. The secondary outcome was cognition assessed by 19 neuropsychological tests. Results: Of 1767 included participants, 1189 (67.3%) were women, and the mean (SD) age at death was 89.4 (6.6) years. In the vascular subgroup (n = 369), cognitive impairment was present in 156 participants (42.3%) and was associated with cerebrovascular disease pathologies (macroinfarcts: odds ratio [OR], 2.05; 95% CI, 1.49-2.82; P < .001; arteriolosclerosis in basal ganglia: OR, 1.35; 95% CI, 1.04-1.76; P = .03) but not AD or other neurodegenerative pathologies, an indication of pure VCI. In mixed-effects models including all the pathologies, only macroinfarcts were associated with a faster cognitive decline rate (estimate, -0.019; SE, 0.005; P < .001) in the vascular subgroup. Further analyses identified macroinfarcts in the frontal white matter to be associated with faster cognitive decline rate when macroinfarcts of cortical and subcortical brain regions were examined in a single model. Conclusions and Relevance: In this study, pure VCI was not rare. Macroinfarcts, specifically in frontal white matter, were the main cerebrovascular disease pathologies associated with cognitive decline in pure VCI.

Dividing attention during the Timed Up and Go enhances associations of several subtask performances with MCI and cognition.

We tested the hypothesis that dividing attention would strengthen the ability to detect mild cognitive impairment (MCI) and specific cognitive abilities from Timed Up and Go (TUG) performance in the community setting. While wearing a belt-worn sensor, 757 dementia-free older adults completed TUG during two conditions, with and without a concurrent verbal serial subtraction task. We segmented TUG into its four subtasks (i.e., walking, turning, and two postural transitions), and extracted 18 measures that were summarized into nine validated sensor metrics. Participants also underwent a detailed cognitive assessment during the same visit. We then employed a series of regression models to determine the combinations of subtask sensor metrics most strongly associated with MCI and specific cognitive abilities for each condition. We also compared subtask performances with and without dividing attention to determine whether the costs of divided attention were associated with cognition. While slower TUG walking and turning were associated with higher odds of MCI under normal conditions, these and other subtask associations became more strongly linked to MCI when TUG was performed under divided attention. Walking and turns were also most strongly associated with executive function and attention, particularly under divided attention. These differential associations with cognition were mirrored by performance costs. However, since several TUG subtasks were more strongly associated with MCI and cognitive abilities when performed under divided attention, future work is needed to determine how instrumented dual-task TUG testing can more accurately estimate risk for late-life cognitive impairment in older adults.

Enhanced ICBM diffusion tensor template of the human brain.

Development of a diffusion tensor (DT) template that is representative of the micro-architecture of the human brain is crucial for comparisons of neuronal structural integrity and brain connectivity across populations, as well as for the generation of a detailed white matter atlas. Furthermore, a DT template in ICBM space may simplify consolidation of information from DT, anatomical and functional MRI studies. The previously developed "IIT DT brain template" was produced in ICBM-152 space, based on a large number of subjects from a limited age-range, using data with minimal image artifacts, and non-linear registration. That template was characterized by higher image sharpness, provided the ability to distinguish smaller white matter fiber structures, and contained fewer image artifacts, than several previously published DT templates. However, low-dimensional registration was used in the development of that template, which led to a mismatch of DT information across subjects, eventually manifested as loss of local diffusion information and errors in the final tensors. Also, low-dimensional registration led to a mismatch of the anatomy in the IIT and ICBM-152 templates. In this work, a significantly improved DT brain template in ICBM-152 space was developed, using high-dimensional non-linear registration and the raw data collected for the purposes of the IIT template. The accuracy of inter-subject DT matching was significantly increased compared to that achieved for the development of the IIT template. Consequently, the new template contained DT information that was more representative of single-subject human brain data, and was characterized by higher image sharpness than the IIT template. Furthermore, a bootstrap approach demonstrated that the variance of tensor characteristics was lower in the new template. Additionally, compared to the IIT template, brain anatomy in the new template more accurately matched ICBM-152 space. Finally, spatial normalization of a number of DT datasets through registration to the new and existing IIT templates was improved when using the new template.

Automatic Quantification of Tandem Walking Using a Wearable Device: New Insights Into Dynamic Balance and Mobility in Older Adults.

BACKGROUND: Wearable sensors are increasingly employed to quantify diverse aspects of mobility. We developed novel tandem walking (TW) metrics, validated these measures using data from community-dwelling older adults, and evaluated their association with mobility disability and measures of gait and postural control. METHODS: Six hundred ninety-three community-dwelling older adults (age: 78.69 ± 7.12 years) wore a 3D accelerometer on their lower back while performing 3 tasks: TW, usual-walking, and quiet standing. Six new measures of TW were extracted from the sensor data along with the clinician's conventional assessment of TW missteps (ie, trip other loss of balance in which recovery occurred to prevent a fall) and duration. Principal component analysis transformed the 6 new TW measures into 2 summary TW composite factors. Logistic regression models evaluated whether these TW factors were independently associated with mobility disability. RESULTS: Both TW factors were moderately related to the TW conventional measures (r < 0.454, p < .001) and were mildly correlated with usual-walking (r < 0.195, p < .001) and standing, postural control (r < 0.119, p < .001). The TW frequency composite factor (p = .008), but not TW complexity composite factor (p = .246), was independently associated with mobility disability in a model controlling for age, sex, body mass index, race, conventional measures of TW, and other measures of gait and postural control. CONCLUSIONS: Sensor-derived TW metrics expand the characterization of gait and postural control and suggest that they reflect a relatively independent domain of mobility. Further work is needed to determine if these metrics improve risk stratification for other adverse outcomes (eg, falls and incident disability) in older adults.

Motor function is the primary driver of the associations of sarcopenia and physical frailty with adverse health outcomes in community-dwelling older adults.

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.

Physical activity, brain tissue microstructure, and cognition in older adults.

OBJECTIVE: To test whether postmortem MRI captures brain tissue characteristics that mediate the association between physical activity and cognition in older adults. METHODS: Participants (N = 318) were older adults from the Rush Memory and Aging Project who wore a device to quantify physical activity and also underwent detailed cognitive and motor testing. Following death, cerebral hemispheres underwent MRI to quantify the transverse relaxation rate R2, a metric related to tissue microstructure. For analyses, we reduced the dimensionality of the R2 maps from approximately 500,000 voxels to 30 components using spatial independent component analysis (ICA). Via path analysis, we examined whether these R2 components attenuated the association between physical activity and cognition, controlling for motor abilities and indices of common brain pathologies. RESULTS: Two of the 30 R2 components were associated with both total daily physical activity and global cognition assessed proximate to death. We visualized these components by highlighting the clusters of voxels whose R2 values contributed most strongly to each. One of these spatial signatures spanned periventricular white matter and hippocampus, while the other encompassed white matter of the occipital lobe. These two R2 components partially mediated the association between physical activity and cognition, accounting for 12.7% of the relationship (p = .01). This mediation remained evident after controlling for motor abilities and neurodegenerative and vascular brain pathologies. CONCLUSION: The association between physically activity and cognition in older adults is partially accounted for by MRI-based signatures of brain tissue microstructure. Further studies are needed to elucidate the molecular mechanisms underlying this pathway.

Quantitative mobility measures complement the MDS-UPDRS for characterization of Parkinson's disease heterogeneity.

INTRODUCTION: Emerging 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). METHODS: We evaluated 176 PD subjects (mean age 65, 65% male, 66% H&Y stage 2) during routine clinic visits using the motor MDS-UPDRS and a 10-min motor protocol with a body-fixed sensor (DynaPort MT, McRoberts BV), including the 32-ft walk, Timed Up and Go (TUG), and standing posture with eyes closed. 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. RESULTS: Quantitative mobility measures from gait, TUG transitions, turning, and posture were significantly associated with motor MDS-UPDRS (7 of 12 measures, p < 0.05) and motor subtype (6 of 12 measures, p < 0.05). Compared with motor MDS-UPDRS, several quantitative mobility measures accounted for a 1.5- or 1.9-fold increased variance in either cognition or physical functioning disability, respectively. Among minimally-impaired subjects in the bottom quartile of motor MDS-UPDRS, including subjects with normal gait exam, the measures captured substantial residual motor heterogeneity. CONCLUSION: Clinic-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.

Total Daily Physical Activity and the Risk of Parkinsonism in Community-Dwelling Older Adults.

BACKGROUND: Physical activity is a modifiable risk factor associated with health benefits. We hypothesized that a more active lifestyle in older adults is associated with a reduced risk of incident parkinsonism and a slower rate of its progression. METHODS: Total daily physical activity was recorded with an activity monitor in 889 community-dwelling older adults participating in the Rush Memory and Aging Project. Four parkinsonian signs were assessed with a modified motor portion of the Unified Parkinson's Disease Rating Scale and summarized as a categorical measure and continuous global parkinsonian score. We used Cox models to determine whether physical activity was associated with incident parkinsonism and linear mixed-effects models to examine if physical activity was associated with the rate of progressive parkinsonism. RESULTS: During an average follow-up of 4 years, 233 of 682 (34%) participants, without parkinsonism, developed incident parkinsonism. In Cox models controlling for age, sex, and education, a higher level of physical activity was associated with a reduced risk of developing parkinsonism (hazard ratio = 0.79; 95% CI = 0.70-0.88, p < .001). This association was not attenuated when controlling for cognition, depressive symptoms, Apolipoprotein E ℇ4 allele, and chronic health conditions. In a linear mixed-effects model including all participants (N = 889) which controlled for age, sex, and education, a 1 SD total daily physical activity was associated with a 20% slower rate of progression of parkinsonism. CONCLUSION: Older adults with a more active lifestyle have a reduced risk for parkinsonism and a slower rate of its progression.

Total daily physical activity, brain pathologies, and parkinsonism in older adults.

OBJECTIVE: We examined the association of physical activity, postmortem brain pathologies, and parkinsonism proximate to death in older adults. METHODS: We 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. RESULTS: Mean 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, p<0.001). The association of more physical activity with less severe parkinsonism persisted after adding terms for ten brain pathologies (Estimate, -0.283, S.E., 0.052, p<0.001). The associations of brain pathologies with more severe parkinsonism did not vary with the level of physical activity. CONCLUSION: The 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.

Contribution of TDP and hippocampal sclerosis to hippocampal volume loss in older-old persons.

OBJECTIVE: To investigate the contribution of Alzheimer disease (AD) vs non-AD neuropathologies to hippocampal atrophy. METHODS: The Religious Orders Study and Rush Memory and Aging Project are clinicopathologic cohort studies of aging. The current study included 547 participants who had undergone brain autopsy and postmortem hippocampal volume measurement by November 1, 2018. Hippocampal volume was measured with postmortem MRI via a 3D region of interest applied to the hippocampal formation. Neuropathologies were measured via uniform structured evaluations. Linear regression analyses estimated the proportion of variance of hippocampal volume attributable to AD and non-AD neuropathologies. RESULTS: The average age at death was 90 years, and the average hippocampal volume was 2.1 mL. AD, transactive response DNA-binding protein 43 (TDP), hippocampal sclerosis (HS), and atherosclerosis were associated with hippocampal volume. After demographics and total hemisphere volume were controlled for, 7.0% of the variance (95% bootstrapped confidence interval [CI] 4.3%-10.5%) of hippocampal volume was attributable to AD pathology. TDP/HS explained an additional 4.5% (95% CI 2.2%-7.6%). Among individuals with Alzheimer dementia (n = 232), 3.1% (95% CI 0.6%-7.7%) of the variance was attributable to AD pathology, and TDP/HS explained an additional 6.1% (95% CI 2.2%-11.6%). Among those without Alzheimer dementia (n = 307), 3.2% (95% CI 0.9%-7.3%) of the variance was attributable to AD pathology, and TDP/HS explained an additional 1.1%, which did not reach statistical significance. Lewy bodies and vascular diseases had modest contribution to the variance of hippocampal volume. CONCLUSIONS: Both AD and TDP/HS contribute to hippocampal volume loss in older-old persons, with TDP/HS more strongly associated with hippocampal volume than AD in Alzheimer dementia.

Different Combinations of Mobility Metrics Derived From a Wearable Sensor Are Associated With Distinct Health Outcomes in Older Adults.

BACKGROUND: Gait speed is a robust nonspecific predictor of health outcomes. We examined if combinations of gait speed and other mobility metrics are associated with specific health outcomes. METHODS: A sensor (triaxial accelerometer and gyroscope) placed on the lower back, measured mobility in the homes of 1,249 older adults (77% female; 80.0, SD = 7.72 years). Twelve gait scores were extracted from five performances, including (a) walking, (b) transition from sit to stand, (c) transition from stand to sit, (d) turning, and (e) standing posture. Using separate Cox proportional hazards models, we examined which metrics were associated with time to mortality, incident activities of daily living disability, mobility disability, mild cognitive impairment, and Alzheimer's disease dementia. We used a single integrated analytic framework to determine which gait scores survived to predict each outcome. RESULTS: During 3.6 years of follow-up, 10 of the 12 gait scores predicted one or more of the five health outcomes. In further analyses, different combinations of 2-3 gait scores survived backward elimination and were associated with the five outcomes. Sway was one of the three scores that predicted activities of daily living disability but was not included in the final models for other outcomes. Gait speed was included along with other metrics in the final models predicting mortality and activities of daily living disability but not for other outcomes. CONCLUSIONS: When analyzing multiple mobility metrics together, different combinations of mobility metrics are related to specific adverse health outcomes. Digital technology enhances our understanding of impaired mobility and may provide mobility biomarkers that predict distinct health outcomes.