Altered cerebellar and caudate gray-matter volumes and structural covariance networks preceding dual cognitive and mobility impairments in older people.

INTRODUCTION: The neuroanatomical changes driving both cognitive and mobility impairments, an emerging preclinical dementia syndrome, are not fully understood. We examined gray-matter volumes (GMVs) and structural covariance networks (SCNs) abnormalities in community-based older people preceding the conversion to physio-cognitive decline syndrome (PCDS). METHODS: Voxel-wise brain GMV and established SCNs were compared between PCDS and non-PCDS converters. RESULTS: The study included 343 individuals (60.2 ± 6.9 years, 49.6% men) with intact cognitive and mobility functions. Over an average 5.6-year follow-up, 116 transitioned to PCDS. Identified regions with abnormal GMVs in PCDS converters were over cerebellum and caudate, which served as seeds for SCNs establishment. Significant differences in cerebellum-based (to right frontal pole and left middle frontal gyrus) and caudate-based SCNs (to right caudate putamen, right planum temporale, left precentral gyrus, right postcentral gyrus, and left parietal operculum) between converters and nonconverters were observed. DISCUSSION: This study reveals early neuroanatomic changes, emphasizing the cerebellum's role, in dual cognitive and mobility impairments. HIGHLIGHTS: Neuroanatomic precursors of dual cognitive and mobility impairments are identified. Cerebellar GMV reductions and increased right caudate GMV precede the onset of PCDS. Altered cerebellum- and caudate-based SCNs drive PCDS transformation. This research establishes a foundation for understanding PCDS as a specific dementia syndrome.

Dual cognitive and mobility impairments and future dementia - Setting a research agenda.

Dual cognitive and mobility impairments are associated with an increased risk of dementia. Recent studies examining temporal trajectories of mobility and cognitive function in aging found that dual decline is associated with higher dementia risk than memory decline or gait decline only. Although initial data show that individuals with dual decline or impairment have excessive cardiovascular and metabolic risk factors, the causes of dual decline or what underlies dual decline with a high risk of dementia remain largely unknown. In December 2021, the National Institute on Aging Intramural and Extramural Programs jointly organized a workshop on Biology Underlying Moving and Thinking to explore the hypothesis that older persons with dual decline may develop dementia through a specific pathophysiological pathway. The working group discussed assessment methods for dual decline and possible mechanisms connecting dual decline with dementia risk and pinpointed the most critical questions to be addressed from a translational perspective.

Shared plasma metabolomic profiles of cognitive and mobility decline predict future dementia.

Experiencing decline in both cognition and mobility is associated with a substantially higher dementia risk than cognitive decline only. Metabolites associated with both cognitive and mobility declines may be early predictors of dementia and reveal specific pathways to dementia. We analyzed data from 2450 participants initially free of dementia who had 613 metabolites measured in plasma in 1998-1999 (mean age = 75.2 ± 2.9 years old, 37.8% Black, 50% women) from the Health, Aging and Body Composition study. Dementia diagnosis was determined by race-specific decline in 3MS scores, medication use, and hospital records through 2014. Cognition and mobility were repeatedly measured using 3MS and a 20-m walking test up to 10 years, respectively. We examined metabolite associations with changes in 3MS (n = 2046) and gait speed (n = 2019) using multivariable linear regression adjusted for age, sex, race, and baseline performance and examined metabolite associations with dementia risk using Cox regression. During a mean follow-up of 9.3 years, 534 (21.8%) participants developed dementia. On average, 3MS declined 0.47/year and gait declined 0.04 m/sec/year. After covariate adjustment, 75 metabolites were associated with cognitive decline, and 111 metabolites were associated with gait decline (FDR-adjusted p < 0.05). Twenty-six metabolites were associated with both cognitive and gait declines. Eighteen of 26 metabolites were associated with dementia risk (p < 0.05), notably amino acids, glycerophospholipids (lysoPCs, PCs, PEs), and sphingolipids. Results remained similar after adjusting for cardiovascular disease or apolipoprotein E ɛ4 carrier status. During aging, metabolomic profiles of cognitive decline and mobility decline show distinct and shared signatures. Shared metabolomic profiles suggest that inflammation and deficits in mitochondria and the urea cycle in addition to the central nervous system may play key roles in both cognitive and mobility declines and predict dementia. Future studies are warranted to investigate longitudinal metabolite changes and metabolomic markers with dementia pathologies.

Muscle mitochondrial energetics predicts mobility decline in well-functioning older adults: The baltimore longitudinal study of aging.

BACKGROUND: Muscle mitochondrial dysfunction is associated with poor mobility in aging. Whether mitochondrial dysfunction predicts subsequent mobility decline is unknown. METHODS: We examined 380 cognitively normal participants aged 60 and older (53%women, 22%Black) who were well-functioning (gait speed ≥ 1.0 m/s) and free of Parkinson's disease and stroke at baseline and had data on baseline skeletal muscle oxidative capacity and one or more mobility assessments during an average 2.5 years. Muscle oxidative capacity was measured by phosphorus magnetic resonance spectroscopy as the post-exercise recovery rate of phosphocreatine (kPCr ). Mobility was measured by four walking tests. Associations of baseline kPCr with mobility changes were examined using linear mixed-effects models, adjusted for covariates. In a subset, we examined whether changes in muscle strength and mass affected these associations by adjusting for longitudinal muscle strength, lean mass, and fat mass. RESULTS: Lower baseline kPCr was associated with greater decline in all four mobility measures (ß, p-value: (0.036, 0.020) 6-m usual gait speed; (0.029, 0.038) 2.5-min usual gait speed; (0.034, 0.011) 6-m rapid gait speed; (-0.042, <0.001) 400-m time). In the subset, further adjustment for longitudinal muscle strength, lean mass, and fat mass attenuated longitudinal associations with changes in mobility (Δß reduced 26-63%). CONCLUSION: Among initially well-functioning older adults, worse muscle mitochondrial function predicts mobility decline, and part of this longitudinal association is explained by decline in muscle strength and mass. Our findings suggest that worse mitochondrial function contributes to mobility decline with aging. These findings need to be verified in studies correlating longitudinal changes in mitochondrial function, muscle, and mobility performance.

Longitudinal Study on Sustained Attention to Response Task (SART): Clustering Approach for Mobility and Cognitive Decline.

The Sustained Attention to Response Task (SART) is a computer-based go/no-go task to measure neurocognitive function in older adults. However, simplified average features of this complex dataset lead to loss of primary information and fail to express associations between test performance and clinically meaningful outcomes. Here, we combine a novel method to visualise individual trial (raw) information obtained from the SART test in a large population-based study of ageing in Ireland and an automatic clustering technique. We employed a thresholding method, based on the individual trial number of mistakes, to identify poorer SART performances and a fuzzy clusters algorithm to partition the dataset into 3 subgroups, based on the evolution of SART performance after 4 years. Raw SART data were available for 3468 participants aged 50 years and over at baseline. The previously reported SART visualisation-derived feature 'bad performance', indicating the number of SART trials with at least 4 mistakes, and its evolution over time, combined with the fuzzy c-mean (FCM) algorithm, individuated 3 clusters corresponding to 3 degrees of physiological dysregulation. The biggest cluster (94% of the cohort) was constituted by healthy participants, a smaller cluster (5% of the cohort) by participants who showed improvement in cognitive and psychological status, and the smallest cluster (1% of the cohort) by participants whose mobility and cognitive functions dramatically declined after 4 years. We were able to identify in a cohort of relatively high-functioning community-dwelling adults a very small group of participants who showed clinically significant decline. The selected smallest subset manifested not only mobility deterioration, but also cognitive decline, the latter being usually hard to detect in population-based studies. The employed techniques could identify at-risk participants with more specificity than current methods, and help clinicians better identify and manage the small proportion of community-dwelling older adults who are at significant risk of functional decline and loss of independence.

Depression and Functional Mobility Decline in Long Term Care Home Residents with Dementia: a Prospective Cohort Study.

OBJECTIVE: Assess the association between depression among new long-term care residents (<3 months stay) with dementia and functional mobility decline. METHODS: A multi-site prospective cohort study was carried out among 26 participants diagnosed with dementia. Functional mobility was measured by Timed-Up-and-Go (TUG) and 2-Minute walk test (2MWT) at baseline, and 60-day post-baseline while participants received usual care. Linear mixed models were applied to examine the association between depression and functional mobility decline. RESULTS: Residents experienced a statistically significant decline in functional mobility in as soon as 60 days. Each additional year of age was associated with a 2% increase in TUG. The interaction between depression and time spent in LTC was statistically significant. Age and time living in LTC were significantly associated with functional mobility decline in new residents with dementia. DISCUSSION: Further work determining why residents with dementia experience decline in functional mobility at an accelerated rate is needed.

SART and Individual Trial Mistake Thresholds: Predictive Model for Mobility Decline.

The Sustained Attention to Response Task (SART) has been used to measure neurocognitive functions in older adults. However, simplified average features of this complex dataset may result in loss of primary information and fail to express associations between test performance and clinically meaningful outcomes. Here, we describe a new method to visualise individual trial (raw) information obtained from the SART test, vis-à-vis age, and groups based on mobility status in a large population-based study of ageing in Ireland. A thresholding method, based on the individual trial number of mistakes, was employed to better visualise poorer SART performances, and was statistically validated with binary logistic regression models to predict mobility and cognitive decline after 4 years. Raw SART data were available for 4864 participants aged 50 years and over at baseline. The novel visualisation-derived feature bad performance, indicating the number of SART trials with at least 4 mistakes, was the most significant predictor of mobility decline expressed by the transition from Timed Up-and-Go (TUG) < 12 to TUG ≥ 12 s (OR = 1.29; 95% CI 1.14-1.46; p < 0.001), and the only significant predictor of new falls (OR = 1.11; 95% CI 1.03-1.21; p = 0.011), in models adjusted for multiple covariates. However, no SART-related variables resulted significant for the risk of cognitive decline, expressed by a decrease of ≥2 points in the Mini-Mental State Examination (MMSE) score. This novel multimodal visualisation could help clinicians easily develop clinical hypotheses. A threshold approach to the evaluation of SART performance in older adults may better identify subjects at higher risk of future mobility decline.

Pittsburgh Fatigability Scale: One-Page Predictor of Mobility Decline in Mobility-Intact Older Adults.

OBJECTIVES: To evaluate the Pittsburgh Fatigability Scale (PFS) as a predictor of performance and functional decline in mobility-intact older adults. DESIGN: Longitudinal analysis of Baltimore Longitudinal Study of Aging data. SETTING: National Institute on Aging, Clinical Research Unit, Baltimore, Maryland. PARTICIPANTS: Mobility-intact men (46.8%) and women aged 60 to 89 with concurrent PFS administration and performance and functional assessment and follow-up assessment within 1 to 4 years (N=579). MEASUREMENTS: The PFS is a self-administered, 1-page assessment of expected physical and mental fatigue with a score ranging from 0 (no) to 5 (extreme) associated with performing 10 activities. Analyses examined associations between each dimension scored continuously (0-50), categorically (0-5), and dichotomously and change in and likelihood of clinically meaningful decline in usual and fast gait speed, chair stand pace, and reported walking ability. Covariates included age, age2 , sex, race, visit status, baseline function, and follow-up time. We defined meaningful decline as 0.05 m/s per year for usual gait speed, 0.07 m/s per year for fast gait speed, 0.02 chair stands/s per year and 1 point or more for walking ability index. RESULTS: Over a mean 2.2 years, 20.5% to 37.7% of participants experienced meaningful decline across assessments. Independent of covariates, higher PFS physical and mental scores were most consistently associated with greater decline in usual gait speed, chair stand pace, and reported walking ability regardless of scoring approach. For example, higher physical fatigability was associated with twice the likelihood of meaningful decline in gait speed as lower physical fatigability (p=.001). PFS scores were superior to fatigue symptoms such as tiredness and energy level in predicting performance decline, which showed no association. CONCLUSION: Routine self-administered perceived fatigability assessment may help identify older persons vulnerable to accelerated mobility decline. J Am Geriatr Soc 66:2092-2096, 2018.

Fatigued, but Not Frail: Perceived Fatigability as a Marker of Impending Decline in Mobility-Intact Older Adults.

OBJECTIVES: To evaluate perceived fatigability as a predictor of meaningful functional decline in non-mobility-limited older adults. DESIGN: Longitudinal analysis of data from the Baltimore Longitudinal Study of Aging (BLSA). SETTING: National Institute on Aging, Clinical Research Unit, Baltimore, Maryland. PARTICIPANTS: Men and women aged 60 to 89 participating in the BLSA with concurrent perceived fatigability and functional assessments and follow-up functional assessment within 1 to 3 years (N = 540). MEASUREMENTS: Perceived fatigability was ascertained using the Borg rating of perceived exertion (RPE) after 5 minutes of treadmill walking at 1.5 miles per hour. Functional assessments included usual and fast gait speed, the Health, Aging and Body Composition physical performance battery (HABC PPB) and reported walking ability. Reported tiredness and energy level were examined as complementary predictors. Covariates included age, age squared, race, follow-up time, and baseline function. Meaningful decline was defined as 0.05 m/s per year for usual gait speed, 0.07 m/s per year for fast gait speed, 0.12 points/year for HABC PPB, and 1 point for walking ability index. RESULTS: Over a mean 2.1 years, 20-31% of participants declined across functional assessments. Fatigability was associated with a 13-19% greater likelihood of meaningful decline in all measures (P = .002- .02) per 1-unit RPE increase. After considering tiredness and energy level separately, findings were essentially unchanged, and neither was associated with gait speed or physical performance decline. In contrast, each separately predicted decline in reported walking ability independent of fatigability (P = .03 and P < .001, respectively). CONCLUSION: Routine assessment of fatigability may help identify older persons vulnerable to greater-than-expected functional decline.