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Background Subjective cognitive complaint (SCC) is associated with future cognitive decline and may be a marker for clinical intervention in the progression to dementia. Among the viable predictors of SCC, psychological factors are clinically relevant, non-invasive early indicators of older adults at elevated risk. This aim of this study is to determine whether psychological symptoms: dysphoria and apathy precede incident SCC in the dementia pathway.Methods Participants (n = 592) enrolled in the Central Control of Mobility in Aging Study were includes in the analyses, with prevalent cases excluded. Apathy and dysphoria scale scores were derived using confirmatory factor analysis of the Geriatric Depressive Scale. Cox regression analyses was used to determine the association between apathy and dysphoria scores and incident SCC.Results Over a mean follow up of 1.90 years, 44 individuals (9.26%) developed incident SCC. Baseline apathy scale score was significantly associated with 4-fold increased risk of SCC (HR 4.39, 95%CI: 1.32–14.67), adjusted for cognition but not age and dysphoria scale score. Baseline dysphoria scale score was not associated with increased risk of SCC in adjusted analyses.Conclusion In this longitudinal analysis of community dwelling older adults, apathy was associated with an increased risk of SCC, when adjusting for cognition but not dysphoria. Finally, this study highlights apathy as an early risk factor, which may precede SCC in the progression to dementia and consequently, may identify a high risk group for clinical screening and intervention.

The motoric cognitive risk syndrome (MCR) is a syndrome characterized by subjective memory complaints and slow walking speeds that can identify older adults at increased risk for developing Alzheimer’s disease or a related dementia (ADRD). To date, the feasibility of community-based physical activity (PA) programs for improving outcomes in MCR have yet to be examined. To address this knowledge gap, we conducted a translational randomized controlled trial (RCT) comparing 24-weeks of PA to a healthy aging education (HE) control intervention delivered within the infrastructure of an urban senior center in Greater Boston (clincaltrials.gov identifier: NCT03750682). An existing senior center employee was trained to administer the multimodal group-based PA program that included moderate-intensity aerobic walking, strength, flexibility and balance training. A total of 79 older adults attended the senior center for a screening visit, of whom 29 met the MCR criteria and 25 were randomized to PA or HE (mean age: 74.4 ± 7 years; BMI: 32.4 ± 7 kg/m2; 85% female; 3MSE score: 92.4 ± 7; gait speed: 0.52 ± 0.1 m/s; SPPB score 4.8 ± 1.9). Due to the Covid-19 pandemic the study was stopped prematurely. Participants could successfully adhere to the study interventions (overall attendance rate: PA: 69% vs. HE:70% at study termination). Participants also successfully completed baseline and follow-up study assessments that included a computerized cognitive testing battery and objective tests of physical performance and functional exercise capacity. No study-related adverse events occurred. Notable trends for improved cognitive performance, gait speed and 6-min walk distance were exhibited in PA compared to HE. Our study provides important preliminary information to aid the design of larger-scale RCTs of PA that may help to preserve the independence of vulnerable older adults at high risk for ADRD in community-based settings.

BackgroundProgressive difficulty in performing everyday functional activities is a key diagnostic feature of dementia syndromes. However, not much is known about the neural signature of functional decline, particularly during the very early stages of dementia. Early intervention before overt impairment is observed offers the best hope of reducing the burdens of Alzheimer disease (AD) and other dementias. However, to justify early intervention, those at risk need to be detected earlier and more accurately. The decline in complex daily function (CdF) such as managing medications has been reported to precede impairment in basic activities of daily living (eg, eating and dressing). ObjectiveOur goal is to establish the neural signature of decline in CdF during the preclinical dementia period. MethodsGait is central to many CdF and community-based activities. Hence, to elucidate the neural signature of CdF, we validated a novel electroencephalographic approach to measuring gait-related brain activation while participants perform complex gait-based functional tasks. We hypothesize that dementia-related pathology during the preclinical period activates a unique gait-related electroencephalographic (grEEG) pattern that predicts a subsequent decline in CdF. ResultsWe provide preliminary findings showing that older adults reporting CdF limitations can be characterized by a unique gait-related neural signature: weaker sensorimotor and stronger motor control activation. This subsample also had smaller brain volume and white matter hyperintensities in regions affected early by dementia and engaged in less physical exercise. We propose a prospective observational cohort study in cognitively unimpaired older adults with and without subclinical AD (plasma amyloid-β) and vascular (white matter hyperintensities) pathologies. We aim to (1) establish the unique grEEG activation as the neural signature and predictor of decline in CdF during the preclinical dementia period; (2) determine associations between dementia-related pathologies and incidence of the neural signature of CdF; and (3) establish associations between a dementia risk factor, physical inactivity, and the neural signature of CdF. ConclusionsBy establishing the clinical relevance and biological basis of the neural signature of CdF decline, we aim to improve prediction during the preclinical stages of ADs and other dementias. Our approach has important research and translational implications because grEEG protocols are relatively inexpensive and portable, and predicting CdF decline may have real-world benefits. International Registered Report Identifier (IRRID)DERR1-10.2196/56726

BackgroundPhysical activity is associated with improved health and function in older adults, yet most older adults are sedentary. Loneliness is associated with decreased physical activity at the cross-section, but longitudinal studies are scarce. We examined longitudinal associations between loneliness and physical activity—and whether they were modified by marital status and network size (the number of children, relatives, and friends a person interacts with at least once a month).MethodsWe analyzed data from 1,931 older adults without dementia at baseline from the Rush Memory and Aging Project with a mean follow-up of 4.8 years (mean age 79.6 ± 7.7, 74.9% women). Loneliness was assessed using the de Jong Gierveld Loneliness Scale. Physical activity was assessed as the frequency with which participants engaged in five categories of activities (e.g., walking, gardening, calisthenics, bicycling, and swimming). Linear mixed effects models examined associations between baseline loneliness and change in physical activity over time after adjusting for demographics, depressive symptoms, global cognition, disability, network size, marital status, social support, and social and cognitive activities. We assessed for effect modification by marital status and network size.ResultsAssociations between loneliness and physical activity differed by marital status. In widowed individuals, baseline loneliness was associated with a 0.06 h/week greater decrease in physical activity per year compared to those who were not lonely (p = 0.005, CI -0.1, 0.02)—which equaled a 150% decrease in physical activity per year. Loneliness did not predict a statistically significant decrease in physical activity in married or unmarried individuals.DiscussionLoneliness is associated with decreased physical activity in widowed older adults and should be considered in the design of interventions to prevent or slow the decline in physical activity and promote healthy aging.

BackgroundThe southern India state of Kerala has among the highest proportion of older adults in its population in the country. An increase in chronic age-related diseases such as dementia is expected in the older Kerala population. Identifying older individuals early in the course of cognitive decline offers the best hope of introducing preventive measures early and planning management. However, the epidemiology and pathogenesis of predementia syndromes at the early stages of cognitive decline in older adults are not well established in India. ObjectiveThe Kerala Einstein Study (KES) is a community-based cohort study that was established in 2008 and is based in the Kozhikode district in Kerala state. KES aims to establish risk factors and brain substrates of motoric cognitive risk syndrome (MCR), a predementia syndrome characterized by the presence of slow gait and subjective cognitive concerns in individuals without dementia or disability. This protocol describes the study design and procedures for this KES project. MethodsKES is proposing to enroll a sample of 1000 adults ≥60 years old from urban and rural areas in the Kozhikode district of Kerala state: 200 recruited in the previous phase of KES and 800 new participants to be recruited in this project. MCR is the cognitive phenotype of primary interest. The associations between previously established risk factors for dementia as well as novel risk factors (apathy and traumatic brain injury) and MCR will be examined in KES. Risk factor profiles for MCR will be compared between urban and rural residents as well as with individuals who meet the criteria for mild cognitive impairment (MCI). Cognitive and physical function, medical history and medications, sociodemographic characteristics, lifestyle patterns, and activities of daily living will be evaluated. Participants will also undergo magnetic resonance imaging and electrocardiogram investigations. Longitudinal follow-up is planned in a subset of participants as a prelude to future longitudinal studies. ResultsKES (2R01AG039330-07) was funded by the US National Institutes of Health in September 2019 and received approval from the Indian Medical Council of Research to start the study in June 2021. We had recruited 433 new participants from urban and rural sites in Kozhikode as of May 2023: 41.1% (178/433) women, 67.7% (293/433) rural residents, and 13.4% (58/433) MCR cases. Enrollment is actively ongoing at all the KES recruitment sites. ConclusionsKES will provide new insights into risk factors and brain substrates associated with MCR in India and will help guide future development of regionally specific preventive interventions for dementia. International Registered Report Identifier (IRRID)DERR1-10.2196/49933

Abstract Metabolic acidosis is associated with impaired physical function in patients with chronic kidney disease (CKD) and older adults. However, whether acidosis is associated with gait abnormalities has received little attention. In a cohort of 323 community-dwelling adults ≥ 65 years old who underwent quantitative gait analysis, we examined associations of serum bicarbonate with eight individual gait variables. After multivariable adjustment, participants in the lowest bicarbonate tertile (

Identification of novel, non-invasive, non-cognitive based markers of Alzheimer’s disease (AD) and related dementias are a global priority. Growing evidence suggests that Alzheimer’s pathology manifests in sensory association areas well before appearing in neural regions involved in higher-order cognitive functions, such as memory. Previous investigations have not comprehensively examined the interplay of sensory, cognitive, and motor dysfunction with relation to AD progression. The ability to successfully integrate multisensory information across multiple sensory modalities is a vital aspect of everyday functioning and mobility. Our research suggests that multisensory integration, specifically visual-somatosensory integration (VSI), could be used as a novel marker for preclinical AD given previously reported associations with important motor (balance, gait, and falls) and cognitive (attention) outcomes in aging. While the adverse effect of dementia and cognitive impairment on the relationship between multisensory functioning and motor outcomes has been highlighted, the underlying functional and neuroanatomical networks are still unknown. In what follows we detail the protocol for our study, named The VSI Study, which is strategically designed to determine whether preclinical AD is associated with neural disruptions in subcortical and cortical areas that concurrently modulate multisensory, cognitive, and motor functions resulting in mobility decline. In this longitudinal observational study, a total of 208 community-dwelling older adults with and without preclinical AD will be recruited and monitored yearly. Our experimental design affords assessment of multisensory integration as a new behavioral marker for preclinical AD; identification of functional neural networks involved in the intersection of sensory, motor, and cognitive functioning; and determination of the impact of early AD on future mobility declines, including incident falls. Results of The VSI Study will guide future development of innovative multisensory-based interventions aimed at preventing disability and optimizing independence in pathological aging.

A close inter-relationship between mobility and cognition is reported in older adults, with improvements in gait performance noticeable after cognitive remediation in frail individuals. The aim of this study was to evaluate the efficacy of computerized cognitive training (CCT) on mobility in healthy, independently living older adults, and to determine whether CCT is associated with changes in neural activation for mobility-related brain processes. Using a randomized single-blind control design, sixty-three non-demented adults age 60 y and older (mean age = 67 y; 76% female, mean Montreal Cognitive Assessment [MoCA] score = 27) were recruited from a local Senior Activity Center. Participants were randomly assigned to either a 2-month CCT program (8 weeks, 3x/week, 40 min/session) or a wait-list control group. Primary outcome was self-selected gait speed during single- and dual-task walking. Secondary outcome was executive function on Trail Making Test (TMT), Part B. Neural activity was assessed via electroencephalography/event-related potentials (EEG/ERPs) targeting lower-limb performance. Results from a linear mixed effect model, adjusted for baseline MoCA score, age, gender, and study completion revealed that compared to controls, CCT improved gait speed during the dual-task (p = 0.008) but not during the single-task walking condition (p = 0.057). CCT also improved executive function (p = 0.024). Further, shorter foot reaction time responses (p = 0.019) were found with enhanced neural activation over sensorimotor areas, with shorter ERP latencies during the P2 component (p = 0.008) and enhanced motor responses (p = 0.009) also evident in the CCT group after the intervention. Overall, the electrophysiological findings suggest possible neural adaptations that could explain improvements in mobility and executive functions associated with CCT in healthy older adults.

Changes in gait, especially decreased gait velocity, may be a harbinger of cognitive decline in aging. Motoric cognitive risk syndrome (MCR), a pre-dementia syndrome combining slow gait and cognitive complaints, is a powerful clinical tool used to identify older adults at a high risk of developing dementia. The mean prevalence of MCR worldwide, including in a Korean cohort, was around 10%. The reported risk factors for incident MCR include older age, low education, cardiovascular disease, obesity, physical inactivity, and depression. In addition to dementia, MCR is also a risk factor for other age-related adverse conditions such as falls, disability, frailty, and mortality. The use of MCR has advantages over other pre-dementia syndromes in being much simpler to implement and requires fewer resources. Identification of mechanisms responsible for MCR may help in developing interventions to reduce the growing burden of dementia and disability worldwide.

OBJECTIVES/GOALS: Motoric cognitive risk (MCR) is a pre-dementia syndrome characterized by slow gait and subjective cognitive complaints. In the Atherosclerosis Risk in Communities (ARIC) study, we aim to (1) identify plasma proteins and protein modules associated with MCR and (2) compare the proteomic signature of MCR to that of mild cognitive impairment (MCI). METHODS/STUDY POPULATION: Nondemented ARIC participants were classified by MCR status (yes/no) according to a memory questionnaire and 4-meter walk. MCI status (yes/no) was classified by expert diagnosis using standardized criteria. We measured 4,877 proteins in plasma collected at ARIC Visit 5 (late-life) and Visit 2 (midlife) utilizing the SomaScan4 proteomic assay. Multivariable logistic regression”adjusted for demographic variables, kidney function, cardiovascular risk factors, and APOE4 status”related each protein to MCR at late-life. An FDR corrected P RESULTS/ANTICIPATED RESULTS: Proteome-wide association study among 4076 ARIC participants (mean age=75; 58% women, 17% Black, 4% MCR+, 21% MCI+; MCR+ and MCI+ groups overlapped) at late-life identified 26 MCR-associated proteins involved in metabolism, vascular/visceral smooth muscle, and extracellular matrix organization. At an uncorrected P DISCUSSION/SIGNIFICANCE: This proteomic characterization of MCR identifies novel plasma proteins and networks, both distinct from and overlapping with those of MCI, thus highlighting the partially divergent mechanisms underlying these pre-dementia syndromes. These findings may be leveraged toward dementia prognostication and targeted therapeutic approaches.

Background: Inflammation may play a role in Motoric Cognitive Risk (MCR) syndrome, a pre-dementia syndrome comprised of slow gait and cognitive complaints. Our objective was to examine associations of inflammatory biomarkers with MCR. Methods: We examined association of interleukin-6 (IL-6) and C-reactive protein (CRP) with prevalent MCR using logistic regression in 3,101 older adults (52% female) from five cohorts (National Center for Geriatrics & Gerontology Study of Geriatric Syndromes [NCGG-SGS], Central Control of Mobility in Aging [CCMA], Tasmanian Study of Cognition and Gait [TASCOG], LonGenity, and Einstein Aging Study [EAS]). Associations were reported as odds ratios adjusted for sex, age, education, depressive symptoms, body mass index, and vascular diseases (aOR) with 95% confidence intervals (CI). Meta-analysis and analyses stratified by vascular disease were also done. Results: Although associations between higher (worse) CRP and IL-6 tertiles and MCR were only seen in three out of the five cohorts (EAS, TASCOG, and LonGenity), when a pooled meta-analysis was performed, a robust association was demonstrated. In meta-analysis, highest tertiles of IL-6 (aOR 1.57, 95%CI 1.01- 2.44) and CRP (aOR 1.65, 95%CI 1.09–2.48) was associated with MCR versus lowest tertiles in the pooled sample. Higher CRP was associated with MCR among those with vascular disease in TASCOG and LonGenity cohorts, and among those without vascular disease in EAS. Conclusions: IL-6 and CRP levels are associated with MCR in older adults, and this association varies by presence of vascular disease.

Background: Distinct domains of gait such as pace and rhythm are linked to an increased risk for cognitive decline, falls, and dementia in aging. The brain substrates supporting these domains and underlying diseases, however, remain relatively unknown. The current study aimed to identify patterns of gray matter volume (GMV) associated with pace and rhythm, and whether these patterns vary as a function of vascular and non-vascular comorbidities. Methods: A cross-sectional sample of 297 older adults (M Age = 72.5 years ± 7.2 years, 43% women) without dementia was drawn from the Tasmanian Study of Cognition and Gait (TASCOG). Factor analyses were used to reduce eight quantitative gait variables into two domains. The “pace” domain was primarily composed of gait speed, stride length, and double support time. The “rhythm” domain was composed of swing time, stance time, and cadence. Multivariate covariance-based analyses adjusted for age, sex, education, total intracranial volume, and presence of mild cognitive impairment identified gray matter volume (GMV) patterns associated with pace and rhythm, as well as participant-specific expression (or factor) scores for each pattern. Results: Pace was positively associated with GMV in the right superior temporal sulcus, bilateral supplementary motor areas (SMA), and bilateral cerebellar regions. Rhythm was positively associated with GMV in bilateral SMA, prefrontal, cingulate, and paracingulate cortices. The GMV pattern associated with pace was less expressed in participants with any vascular disease; this association was also found independently with hypertension, diabetes, and myocardial infarction. Conclusion: Both pace and rhythm domains of gait were associated with the volume of brain structures that have been linked to controlled and automatic aspects of gait control, as well as with structures involved in multisensory integration. Only the brain structures associated with pace, however, were associated with vascular disease.

Introduction One of the known risk factors for fall incidents is the use of specific medications, fall-risk-increasing drugs (FRIDs). However, to date, there is uncertainty related to the effectiveness of deprescribing as a single intervention in falls prevention. Thus, a comprehensive update of the literature focusing on all settings in which older people receive healthcare and all deprescribing interventions is warranted to enhance the current knowledge.Methods and analysis This systematic review protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A systematic search was performed in Cochrane Central Register of Controlled Trials, MEDLINE, Embase and PsycINFO (2 November 2020). We will also search in trial registers. We will include randomised controlled trials, in which any deprescribing intervention is compared with usual care and reports falls as an outcome. Both title and abstract screening and full-text screening will be done by two reviewers. The Cochrane Collaboration revised tool of Risk of Bias will be applied to perform risk of bias assessment. We will categorise the results separately for every setting. If a group of sufficiently comparable studies will be identified, we will perform a meta-analysis applying random effects model. We will investigate heterogeneity using a combination of visual inspection of the forest plot along with consideration of the χ2 test and the I2 statistic results. We have prespecified several subgroup and sensitivity analyses.Ethics and dissemination Ethics approval is not applicable for this study since no original data will be collected. The results will be disseminated through peer-reviewed publication and conference presentations. Furthermore, this systematic review will inform the recommendations of working group of polypharmacy and FRIDs of the anticipated World’s Falls Guidelines.PROSPERO registration number CRD42020218231.

Since the beginning of 2020, COVID-19 infections have increased exponentially, overwhelming health-care services globally. Survivors of this infection have significant disabilities due to the debilitating weakness and compromised lung function. Unfortunately, rehabilitation services are scarce due to diversion of rehabilitation clinicians to emergency medical care. This manual aims to bridge this gap by providing a self-directed home care and graduated exercise program which does not require any special equipment. The exercises were carefully selected based on research by the authors on self-directed home exercises in frail, elderly patients.

BackgroundEmerging evidence suggests that there is significant variability in the progression of frailty in aging. We aimed to identify latent subpopulations of frailty trajectories, and examine their clinical and biological correlates.MethodsWe characterized frailty using a 41-item cumulative deficit score at baseline and annual visits up to 12 years in 681 older adults (55% women, mean age 74·6 years). Clinical risk profile and walking while talking performance as a clinical marker of trajectories were examined. Mortality risk associated with trajectories was evaluated using Cox regression adjusted for established survival predictors, and reported as hazard ratios (HR). Proteome-wide analysis was done.FindingsLatent class modeling identified 4 distinct frailty trajectories: relatively stable (34·4%) as well as mild (36·1%), moderate (24·1%) and severely frail (5·4%). Four distinct classes of frailty trajectories were also shown in an independent sample of 515 older adults (60% women, 68% White, 26% Black). The stable group took a median of 31 months to accumulate one additional deficit compared to 20 months in the severely frail group. The worst trajectories were associated with modifiable risk factors such as low education, living alone, obesity, and physical inactivity as well as slower walking while talking speed. In the pooled sample, mild (HR 2·33, 95% CI 1·30-4·18), moderate (HR 2·49, 95% CI 1·33-4·66), and severely frail trajectories (HR 5·28, 95% CI 2·68-10·41) had higher mortality compared to the stable group. Proteomic analysis showed 11 proteins in lipid metabolism and growth factor pathways associated with frailty trajectories.ConclusionFrailty shows both stable and accelerated patterns in aging, which can be distinguished clinically and biologically.

Abstract Introduction Cognitive impairment is the hallmark of Alzheimer's disease (AD) and related dementias. However, motor decline has been recently described as a prodromal state that can help to detect at‐risk individuals. Similarly, sensory changes, sleep and behavior disturbances, and frailty have been associated with higher risk of developing dementia. These clinical findings, together with the recognition that AD pathology precedes the diagnosis by many years, raises the possibility that non‐cognitive changes may be early and non‐invasive markers for AD or, even more provocatively, that treating non‐cognitive aspects may help to prevent or treat AD and related dementias. Methods A subcommittee of the Canadian Consensus Conference on Diagnosis and Treatment of Dementia reviewed areas of emerging evidence for non‐cognitive markers of dementia. We examined the literature for five non‐cognitive domains associated with future dementia: motor, sensory (hearing, vision, olfaction), neuro‐behavioral, frailty, and sleep. The Grading of Recommendations Assessment, Development, and Evaluation system was used to assign the strength of the evidence and quality of the recommendations. We provide recommendations to primary care clinics and to specialized memory clinics, answering the following main questions: (1) What are the non‐cognitive and functional changes associated with risk of developing dementia? and (2) What is the evidence that sensory, motor, behavioral, sleep, and frailty markers can serve as potential predictors of dementia? Results Evidence supported that gait speed, dual‐task gait speed, grip strength, frailty, neuropsychiatric symptoms, sleep measures, and hearing loss are predictors of dementia. There was insufficient evidence for recommending assessing olfactory and vision impairments as a predictor of dementia. Conclusions Non‐cognitive markers can assist in identifying people at risk for cognitive decline or dementia. These non‐cognitive markers may represent prodromal symptoms and several of them are potentially amenable to treatment that might delay the onset of cognitive decline.

Cardiovascular risk factors are implicated in cerebrovascular disease, resulting in cognitive impairment. This study investigated the relationship between objective cardiac markers and cerebral changes in older Indian adults with and without dementia. Dementia patients with major electrocardiographic (EKG) abnormalities were 8.19 times more likely to have evidence of stroke on magnetic resonance imaging (MRI) compared with patients with no EKG abnormalities (p < .05). The relationship between major EKG abnormalities and stroke on MRI was not significant for patients without dementia. Objective cardiac markers may identify MRI cerebrovascular lesions in patients with dementia, and thus guide neuroimaging allocation in resource-poor areas.

(1) Background: one out of every four adults over the age of 65 are living with diabetes, and this alarming rate continues to increase with age. Diabetes in older adults is associated with many adverse health outcomes, including sensory and motor impairments. The objective of this exploratory study was to determine whether diabetes influences the interplay between multisensory integration processes and mobility in aging. (2) Methods: in this cross-sectional observational study, we recruited 339 non-demented older adults (76.59 ± 6.21 years; 52% female, 18% with diabetes). Participants completed a simple reaction time test in response to visual, somatosensory, and combined visual-somatosensory stimulation. Magnitude of visual-somatosensory integration was computed and served as the independent variable. (3) Results: logistic regression revealed that presence of diabetes was inversely associated with the magnitude of visual-somatosensory integration (β = −3.21; p < 0.01). Further, mediation models revealed that presence of diabetes negatively influenced the relationship of visual–somatosensory integration magnitude with balance (95% CI −0.16, −0.01) and gait (95% CI −0.09, −0.01). Participants with diabetes and taking insulin (n = 14) failed to integrate sensory information entirely; (4) conclusions: taken together, results from this exploration provide compelling evidence to support the adverse effect of diabetes on both multisensory and motor functioning in older adults.

While the growth hormone/insulin-like growth factor-1 (GH/IGF-1) pathway plays essential roles in growth and development, diminished signaling via this pathway in model organisms extends lifespan and health-span. In humans, circulating IGF-1 and IGF-binding proteins 3 and 1 (IGFBP-3 and 1), surrogate measures of GH/IGF-1 system activity, have not been consistently associated with morbidity and mortality. In a prospective cohort of independently-living older adults (n = 840, mean age 76.1 ± 6.8 years, 54.5% female, median follow-up 6.9 years), we evaluated the age- and sex-adjusted hazards for all-cause mortality and incident age-related diseases, including cardiovascular disease, diabetes, cancer, and multiple-domain cognitive impairment (MDCI), as predicted by baseline total serum IGF-1, IGF-1/IGFBP-3 molar ratio, IGFBP-3, and IGFBP-1 levels. All-cause mortality was positively associated with IGF-1/IGFBP-3 molar ratio (HR 1.28, 95% CI 1.05–1.57) and negatively with IGFBP-3 (HR 0.82, 95% CI 0.680–0.998). High serum IGF-1 predicted greater risk for MDCI (HR 1.56, 95% CI 1.08–2.26) and composite incident morbidity (HR 1.242, 95% CI 1.004–1.538), whereas high IGFBP-1 predicted lower risk for diabetes (HR 0.50, 95% CI 0.29–0.88). In conclusion, higher IGF-1 levels and bioavailability predicted mortality and morbidity risk, supporting the hypothesis that diminished GH/IGF-1 signaling may contribute to human longevity and health-span.

Background: The ability to integrate information across sensory modalities is an integral aspect of mobility. Yet, the association between visual-somatosensory (VS) integration and gait performance has not been well-established in aging.Methods: A total of 333 healthy older adults (mean age 76.53 ± 6.22; 53% female) participated in a visual-somatosensory simple reaction time task and underwent quantitative gait assessment using an instrumented walkway. Magnitude of VS integration was assessed using probability models, and then categorized into four integration classifications (superior, good, poor, or deficient). Associations of VS integration with three independent gait factors (Pace, Rhythm, and Variability derived by factor analysis method) were tested at cross-section using linear regression analyses. Given overlaps in neural circuitry necessary for both multisensory integration and goal-directed locomotion, we hypothesized that VS integration would be significantly associated with pace but not rhythm which is a more automatic process controlled mainly through brainstem and spinal networks.Results: In keeping with our hypothesis, magnitude of VS integration was a strong predictor of pace (β = 0.12, p < 0.05) but not rhythm (β = −0.01, p = 0.83) in fully-adjusted models. While there was a trend for the association of magnitude of VS integration with variability (β = −0.11, p = 0.051), post-hoc testing of individual gait variables that loaded highest on the variability factor revealed that stride length variability (β = −0.13, p = 0.03) and not swing time variability (β = −0.08, p = 0.15) was significantly associated with magnitude of VS integration. Of the cohort, 29% had superior, 26% had good, 29% had poor, and 16% had deficient VS integration effects.Conclusions: Worse VS integration in aging is associated with worse spatial but not temporal aspects of gait performance.

Over the last few decades, considerable evidence shows that greater levels of aerobic exercise and cardiovascular fitness benefit cognitive performance. However, the degree to which free-living activity in community settings is related to cognitive performance remains unclear, particularly in older adults vulnerable to disability. Also, it is unknown whether the manner in which daily physical activity (PA) and sedentary time are accumulated throughout the day is associated with cognition. Cross-sectional associations between accelerometer-characterized PA and sedentary patterns and cognitive performance were examined in 1,274 mobility-limited older adults. Percent time spent in various bout lengths of PA (≥1, ≥2, and ≥5 min) and sedentary (≥1, ≥30, and ≥60 min) was defined as the number of minutes registered divided by total wear time × 100. Percent time was then tertiled for each bout length. Multiple linear regression models were used to estimate the associations between accelerometer bout variables and separate cognitive domains that included processing speed (Digit Symbol Coding; DSC), immediate and delayed recall (Hopkins Verbal Learning Test; HVLT), information processing and selective attention (Flanker), working memory (n-back), reaction time (switch and non-switch reaction time), and a composite score that averaged results from all cognitive tests. After adjusting for demographics, behavioral factors, and morbid conditions, more time spent in PA was associated with higher DSC for all bout lengths (p < 0.03 for all). Higher PA was associated with higher HVLT and global cognition scores but only for longer bout lengths (p < 0.05 for all). The association was largely driven by participants who spent the lowest amount of time performing activity while awake (p < 0.04). An inverse linear relationship was observed between total sedentary time and DSC (p = 0.02), but not for other measures of cognition. These results suggest that, while higher PA was associated with higher cognitive performance, PA’s association with memory was sensitive to bout duration. The time, but not the manner, spent in sedentary behaviors showed a minor association with executive function. Further research is warranted to characterize longitudinal changes in daily activity and sedentary patterns as potential biophysical markers of cognitive status in older adults.

Frailty is a complex aging phenotype associated with increased vulnerability to disability and death. Understanding the biological antecedents of frailty may provide clues to healthy aging. The genome-wide association study hotspot, 9p21-23 region, is a risk locus for a number of age-related complex disorders associated with frailty. Hence, we conducted an association study to examine whether variations in 9p21-23 locus plays a role in the pathogenesis of frailty in 637 community-dwelling Ashkenazi Jewish adults aged 65 and older enrolled in the LonGenity study. The strongest association with frailty (adjusted for age and gender) was found with the SNP rs518054 (odds ratio: 1.635, 95% CI = 1.241–2.154; p-value: 4.81 × 10−04) intergenic and located between LOC105375977 and C9orf146. The prevalence of four SNPs (rs1324192, rs7019262, rs518054, and rs571221) risk alleles haplotype in this region was significantly higher (compared with other haplotypes) in frail older adults compared with non-frail older adults (29.7 vs. 20.8%, p = 0.0005, respectively). Functional analyses using in silico approaches placed rs518054 in the CTCF binding site as well as DNase hypersensitive region. Furthermore, rs518054 was found to be in an enhancer site of NFIB gene located downstream. NFIB is a transcription factor that promotes cell differentiation during development, has antiapoptotic effect, maintains stem cell populations in adult tissues, and also acts as epigenetic regulators. Our study found novel association of SNPs in the regulatory region in the 9p21-23 region with the frailty phenotype; signifying the importance of this locus in aging.

Background: Gait disorders, a highly prevalent condition in older adults, are associated with several adverse health consequences. Gait analysis allows qualitative and quantitative assessments of gait that improves the understanding of mechanisms of gait disorders and the choice of interventions. This manuscript aims (1) to give consensus guidance for clinical and spatiotemporal gait analysis based on the recorded footfalls in older adults aged 65 years and over, and (2) to provide reference values for spatiotemporal gait parameters based on the recorded footfalls in healthy older adults free of cognitive impairment and multi-morbidities.Methods: International experts working in a network of two different consortiums (i.e., Biomathics and Canadian Gait Consortium) participated in this initiative. First, they identified items of standardized information following the usual procedure of formulation of consensus findings. Second, they merged databases including spatiotemporal gait assessments with GAITRite® system and clinical information from the “Gait, cOgnitiOn & Decline” (GOOD) initiative and the Generation 100 (Gen 100) study. Only healthy—free of cognitive impairment and multi-morbidities (i.e., ≤ 3 therapeutics taken daily)—participants aged 65 and older were selected. Age, sex, body mass index, mean values, and coefficients of variation (CoV) of gait parameters were used for the analyses.Results: Standardized systematic assessment of three categories of items, which were demographics and clinical information, and gait characteristics (clinical and spatiotemporal gait analysis based on the recorded footfalls), were selected for the proposed guidelines. Two complementary sets of items were distinguished: a minimal data set and a full data set. In addition, a total of 954 participants (mean age 72.8 ± 4.8 years, 45.8% women) were recruited to establish the reference values. Performance of spatiotemporal gait parameters based on the recorded footfalls declined with increasing age (mean values and CoV) and demonstrated sex differences (mean values).Conclusions: Based on an international multicenter collaboration, we propose consensus guidelines for gait assessment and spatiotemporal gait analysis based on the recorded footfalls, and reference values for healthy older adults.