Baltimore Longitudinal Study Of Aging Participants Research Articles

MUSCLE UP: WHAT AGING LOOKS LIKE FROM THE INSIDE OUT

Abstract The Longitudinal Studies Section of the Translational Gerontology Branch of the National Institute on Aging Intramural Research Program has the mission and opportunity to examine aging physiology from the cellular to the full body functional level in model systems and human populations. This symposium presents ongoing research that targets pathologic and normative change in muscle with aging and the significance of these changes for understanding the aging process. Data come from the Baltimore Longitudinal Study of Aging (BLSA) and the Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing (GESTALT) study. In nearly 500 BLSA participants aged 50+, Zenobia Moore evaluates the association between multiple epigenetic age metrics and change over 6 years in mid-femur areas of muscle and subcutaneous and intramuscular fat derived from computed tomography. Qu (Teresa) Tian investigates the relationship between skeletal muscle mitochondrial function and risk of MCI or dementia over 3.3 years in 460 initially cognitively normal BLSA participants and PET and blood biomarkers of AD in available subsamples. In 82 men and women from GESTALT, Stefano Donega examines relationships between physical activity, peak oxygen consumption and muscle oxidative capacity using p31 MR spectroscopy and gene expression, transcript usage and splicing events derived from vastus lateralis biopsies. Using volumetric Focused Ion Beam Scanning Electron Microscopy, Lisa Hartnell shares 3D images of muscle samples at the level of the mitochondrial reticulum and sarcomere from young and old healthy and frail GESTALT participants. Together, these findings highlight the value of muscle as a window on aging.

Proteomics identifies immunological drivers of post‐infection brain atrophy and cognitive decline

AbstractBackgroundPrior infections can modify the risk for dementia and neurodegenerative disease, yet the mechanisms by which infections contribute to neurodegeneration remain unclear.MethodWe examined how infection diagnoses documented in the Baltimore Longitudinal Study of Aging (BLSA) are associated with rates of change in brain volumes over time, and how these same infections relate to dementia risk using hospital records from UK Biobank and a Finnish multicohort sample (the Finnish Public Sector study, the Health and Social Support study, and the Still Working study). After determining how infections differentially relate to an immunological plasma proteome (942 proteins) in BLSA participants, we then identified a subset of infection‐related proteins that also predict changes in brain regions vulnerable to infection‐specific atrophy (candidate proteins). In addition to evaluating their associations with longitudinal cognitive performance as well as Alzheimer’s disease and related dementias (ADRD) plasma biomarkers (Aβ42/40, GFAP, NfL, pTau‐181), we also investigated the causal link between candidate proteins and longitudinal brain volume loss using Mendelian randomization. Study design is illustrated in Figure 1.ResultA total of 982 cognitively normal participants (age: 65.4 [SD 14.9]); 55.2% female; 66.9% white) were included in the primary MRI analysis. Of the 15 infections examined, we identified six diagnoses related to accelerated brain volume loss, including influenza, viral, respiratory, and skin/subcutaneous infections, with atrophy commonly observed in the temporal lobe. Each infection linked to brain volume loss in the BLSA was associated with increased risk of dementia in the UK Biobank (n = 495,896), with many also associated with increased risk in the Finnish multicohort sample (n = 273,132). From a set of 260 infection‐related proteins, we identified 35 candidate proteins that also predicted changes in brain regions vulnerable to infection‐specific atrophy (Figure 2A‐F). Many candidate proteins were related to cognitive decline, plasma ADRD biomarkers or mechanistically implicated in longitudinal brain volume loss in Mendelian randomization analyses (Figure 2G‐H; Figure 3A).ConclusionWe demonstrate that infections are linked to accelerated regional brain atrophy and dementia risk. Additionally, we identify molecular mediators by which infections may contribute to neurodegeneration (Figure 3B).

Walking energetics and white matter hyperintensities: findings from the Baltimore Longitudinal Study of Aging (BLSA)

AbstractBackgroundWhite matter hyperintensities (WMH) increase with advancing age and may contribute to the development of Alzheimer’s Disease. Energy utilization, as defined by walking efficiency, worsens with advancing age and is a prognostic marker of physical and cognitive function in older adults. While both WMH and energy utilization have been associated with cognition and Alzheimer’s‐related pathology, the links between WMH and walking energy utilization are unexplored. The purpose of this study was to examine the cross‐sectional association between walking energy utilization and WMH in cognitively normal middle‐to‐late aged men and women.MethodThe study included 708 BLSA participants who completed standardized slow‐ and peak‐pace walking assessments with indirect calorimetry (VO2 ml/kg/min) and underwent brain magnetic resonance imaging. Energy utilization was defined as the ratio of slow‐to‐peak walking energy capacity (the cost‐ratio), which describes the percentage of peak walking capacity required for the standardized slow walking task; a higher percentage indicates worse energy utilization. T2‐weighted scans and FLAIR images based on a validated support vector machine classifier approach were used to quantify total WMH volumes, which were log‐transformed to normalize the distribution. Sample characteristics were summarized using means and standard deviations. Linear regression was used to examine the association between WMH and the cost‐ratio adjusted for total white matter volume, age, sex, race, lean mass, fat mass, education, height, and comorbid conditions.ResultIn this sample of cognitively normal adults (56% women, mean age 66.7±15.3 years) the average cost‐ratio was 71.6±12.2% (range 34.3‐98.7) and mean log10(WHH) was 3.01±0.80 (range 0.08‐4.68). After covariate adjustment, a higher cost‐ratio was associated with greater total WMH (B = 0.008; SE = 0.002; p<.001; Table 1). Aside from age and total white matter volume, which track closely with WMH, the cost‐ratio was most strongly associated with WMH in our model (Table 1).ConclusionIn a large sample of community‐dwelling middle‐to‐late aged adults, walking energy utilization was associated with WMH volumes, suggesting that a combination of higher energy cost of walking and lower peak walking energy capacity is associated with adverse brain health in mid‐to‐late life. Longitudinal research is needed to elucidate the directionality and temporality of the observed association.

Identification of Clinically Relevant Brain Endothelial Cell Biomarkers in Plasma.

Proteins expressed by brain endothelial cells (BECs), the primary cell type of the blood-brain barrier, may serve as sensitive plasma biomarkers for neurological and neurovascular conditions, including cerebral small vessel disease. Using data from the BLSA (Baltimore Longitudinal Study of Aging; n=886; 2009-2020), BEC-enriched proteins were identified among 7268 plasma proteins (measured with SomaScanv4.1) using an automated annotation algorithm that filtered endothelial cell transcripts followed by cross-referencing with BEC-specific transcripts reported in single-cell RNA-sequencing studies. To identify BEC-enriched proteins in plasma most relevant to the maintenance of neurological and neurovascular health, we selected proteins significantly associated with 3T magnetic resonance imaging-defined white matter lesion volumes. We then examined how these candidate BEC biomarkers related to white matter lesion volumes, cerebral microhemorrhages, and lacunar infarcts in the ARIC study (Atherosclerosis Risk in Communities; US multisite; 1990-2017). Finally, we determined whether these candidate BEC biomarkers, when measured during midlife, were related to dementia risk over a 25-year follow-up period. Of the 28 proteins identified as BEC-enriched, 4 were significantly associated with white matter lesion volumes (CDH5 [cadherin 5], CD93 [cluster of differentiation 93], ICAM2 [intracellular adhesion molecule 2], GP1BB [glycoprotein 1b platelet subunit beta]), while another approached significance (RSPO3 [R-Spondin 3]). A composite score based on 3 of these BEC proteins accounted for 11% of variation in white matter lesion volumes in BLSA participants. We replicated the associations between the BEC composite score, CDH5, and RSPO3 with white matter lesion volumes in ARIC, and further demonstrated that the BEC composite score and RSPO3 were associated with the presence of ≥1 cerebral microhemorrhages. We also showed that the BEC composite score, CDH5, and RSPO3 were associated with 25-year dementia risk. In addition to identifying BEC proteins in plasma that relate to cerebral small vessel disease and dementia risk, we developed a composite score of plasma BEC proteins that may be used to estimate blood-brain barrier integrity and risk for adverse neurovascular outcomes.

Plant Protein but Not Animal Protein Consumption Is Associated with Frailty through Plasma Metabolites.

There is evidence that the association of protein intake and frailty may depend on the source of dietary protein. The mechanism underlying this association is not clear. In this study, we explore circulating metabolites as mediators of the relationship between dietary protein and of frailty in participants of the Baltimore Longitudinal Study of Aging (BLSA). Cross-sectional analyses in 735 BLSA participants of associations between plant and animal protein intake and frailty. Usual protein intake from plant and animal sources were estimated with a Food Frequency Questionnaire (FFQ) and frailty was assessed with a 44-item Frailty Index (FI). Compared with the lowest quartile, higher quartiles of plant, but not animal, protein were associated with lower FI. Twenty-five plasma metabolites were associated with plant protein intake; of these, fifteen, including phosphatidylcholines, cholesterol esters, sphingomyelins, and indole metabolites, mediated the association between plant protein intake and FI. The protective association between plant protein consumption and FI is mediated by lower abundance of lipid metabolites and higher abundance of tryptophan-related metabolites.

Association of protein-based indices with brain volume and cognition in the Baltimore Longitudinal Study of Aging (BLSA) (P12-6.007)

<h3>Objective:</h3> Determine whether proteomic indicators of peripheral (non-neurologic) health are associated with change in cognition and brain volume. <h3>Background:</h3> Numerous peripheral diseases have been associated with brain health. Changes in the plasma proteome related to physical health and disease status likely contribute to cognitive and structural brain changes. Plasma proteomic changes may therefore be leveraged to study the link between peripheral health and brain health. <h3>Design/Methods:</h3> We used plasma samples from participants of the Baltimore Longitudinal Study of Aging (BLSA) to assess 7000+ proteins using SomaScan assay. Brain health was assessed using in BLSA participants with concurrent 3T brain MR imaging to assess total brain volume (TBV). Using SomaLogic’s SomaSignal Test (SST) algorithm, we generated protein-based measures of cardiovascular risk, kidney disease, resting energy rate, body composition, and other health indicators. Linear mixed effects models were used to examine the relationship between SST protein-based health indicators and longitudinal change in TBV and memory. <h3>Results:</h3> The analysis included 1220 participants (mean age: 68.1 [14.3 SD]; 99% cognitively normal). We evaluated 14 unique protein-based health indices (SSTs). None were associated with longitudinal brain volume loss. At baseline, the protein-based indicator of liver fat was associated with better memory. Protein-based indicators of lower V02 max and kidney disease risk were associated with longitudinal declines in memory. <h3>Conclusions:</h3> Protein-based health indicators can be used to understand how facets of peripheral health and disease risk influence brain health in cognitively healthy older adults. Our findings implicate cardiovascular, pulmonary, and kidney health in brain structure or function. <b>Disclosure:</b> Ms. Daya has nothing to disclose. Dr. Dark has nothing to disclose. Dr. Duggan has nothing to disclose. Dr. Peng has nothing to disclose. An immediate family member of Dr. Moore has received personal compensation for serving as an employee of Gilead. Dr. Tanaka has nothing to disclose. Dr. Candia has nothing to disclose. The institution of Keenan Walker has received research support from NIH.

THE BALTIMORE LONGITUDINAL STUDY OF AGING: READY TO SHARE

Abstract Beginning January 2023, the new National Institutes of Health (NIH) Data Sharing Policy for NIH-funded and conducted research is scheduled to go into effect. In anticipation of this requirement, scientists and staff of the Baltimore Longitudinal Study of Aging (BLSA) launched a comprehensive effort to create a user friendly well-documented accessible database scheduled for a “soft” release just in time for GSA. The BLSA, established in 1958 to study normative aging, continues to advance knowledge and understanding of aging mechanisms and their impact on and response to disease processes. During a 3-day clinic visit, the 1200+ BLSA participants undergo comprehensive evaluation covering the full range of physical functional and cognitive performance capacity as well as extensive imaging studies, biological sample collection and clinical examination. In this symposium, Dr. Griswold will introduce the data sharing platform and demonstrate its facility. Dr. Simonsick will elaborate on development of a fitness percentile-based approach to define exceptional aging and the factors associated with maintaining exceptional status. Dr. Moore will provide findings on life-course physical activity and CT derived muscle parameters and homeostatic regulation in later life. Dr. Tian will share her ongoing work aimed at identifying metabolomic signatures of brain atrophy and Alzheimer’s disease risk. Dr. Tanaka will report on her work analyzing the metabolomic profile of different dietary patterns and their association with frailty. Our Discussant, Dr. Ferrucci will briefly share future directions for the BLSA and then invite attendees to comment on the BLSA data sharing platform and scientific priorities.

Quality Specific Associations of Carbohydrate Consumption and Frailty Index.

Background: The quality of carbohydrate consumed may influence the risk of frailty. In this study, we tested the hypothesis that indices of carbohydrate intake are associated with trajectories of frailty in participants of the Baltimore Longitudinal Study of Aging (BLSA). Methods: Cross sectional and longitudinal analyses were conducted in 1024 BLSA participants to examine the association between usual intake of carbohydrate and frailty index. Seven measures of carbohydrate consumption were estimated using data derived from Food Frequency Questionnaires (FFQs) and examined in association with a 43-item Frailty Index (FI). Results: In cross-sectional analyses, there was a significant, positive association between higher tertiles of total carbohydrate, glycemic load, and non-whole grains and FI. Conversely, higher tertiles of fiber-to-carbohydrate ratio was associated with lower FI. These differences persisted over the follow-up period of up to 13.8 years. Women in the highest tertile of the fiber-to-carbohydrate ratio showed a less steep increase in FI over time. Conclusions: Carbohydrate intake was positively associated with increased frailty risk in the BLSA participants, whereas a higher fiber-to-carbohydrate ratio was related to reduced risk for frailty.

Abstract 13280: Proteomic Indicators of Cardiovascular Health Relate to Brain Volume and Dementia Risk

Introduction: Several studies demonstrate that cardiovascular (CV) health - even among individuals without overt CV disease - is associated with brain function and may influence Alzheimer’s disease (AD) and dementia progression. Using a proteomic score to quantify the full spectrum of CV health, the current study examined the association of protein-based indicators of CV risk and CV-related mortality with brain structure and dementia risk among older adults. Methods: The SomaScan platform was used for plasma proteomic phenotyping in the Baltimore Longitudinal Study of Aging (BLSA) (n=984) and the Atherosclerosis Risk in Communities (ARIC) study (n=7901). SomaSignal Test measures of risk for CV events, and heart failure-related mortality were derived from the proteome. Concurrent with blood-draw for proteomic assessments, BLSA participants received 3T brain MRI scans, which quantified AD-relevant brain atrophy (SPARE-AD) and total brain volume (TBV). Following protein measurement at Visit 3, ARIC participants were followed for 20+ years, during which time incident dementia was assessed. We used demographic-, intracranial volume, and APOE ε4-adjusted linear regression and Cox models to relate proteomic indicators of CV health to brain volume and dementia risk, respectively. Results: Protein-based risk for CV events and heart-failure mortality were each associated with greater brain atrophy in regions vulnerable to AD and lower total brain volume ( Figure 1 ). Higher risk scores for CV events and both preserved and reduced ejection fraction heart failure mortality were associated with incident dementia (HR per z-score increase (95% CI): 1.26 (1.20-1.33), 1.18 (1.12-1.23) and 1.27 (1.22-1.32), respectively, all p &lt; 0.001). Conclusions: Proteomic indicators of risk for CV disease/mortality are associated with neurodegeneration and future dementia risk. Proteomic indicators of CV health may aid in monitoring and prediction of neurodegenerative disease.

Motor and Sensory Function as Predictors of MCI and Dementia in the Baltimore Longitudinal Study of Aging (BLSA)

Motor and sensory impairments are linked with dementia risk, but whether there is a joint effect of deficits in motor and sensory function is unknown. We analyzed 649 BLSA participants (aged 72±11 years; 55% women; 68% white) who had concurrent baseline 6-meter usual gait speed and sensory function (vision, hearing) between 2012-2019. Mild cognitive impairment (MCI) and dementia were adjudicated during an average follow-up of 3 years. We examined the association between baseline gait speed, z-scored sensory function, and a gait*sensory interaction with risk of MCI/dementia using Cox proportional hazard models, adjusted for demographics and chronic conditions. Each .01 m/s faster baseline gait was associated with a reduced risk (HR:0.98 (0.96-0.99)) of MCI/dementia, and each 1 SD higher in hearing and vision z-score was associated with an increased risk (HR:1.84 (1.1-3.1)) increased risk. The was no significant interaction, suggesting motor and sensory impairments may be independently associated with MCI/dementia risk.

Personality Associations With Amyloid and Tau: Results From the Baltimore Longitudinal Study of Aging and Meta-analysis

BackgroundHigher neuroticism and lower conscientiousness are risk factors for Alzheimer’s disease and related dementias, but the underlying neuropathological correlates remain unclear. Our aim was to examine whether personality traits are associated with amyloid and tau neuropathology in a new sample and meta-analyses. MethodsParticipants from the BLSA (Baltimore Longitudinal Study of Aging) completed the Revised NEO Personality Inventory and underwent amyloid (11C-labeled Pittsburgh compound B) and tau (18F-flortaucipir) positron emission tomography. ResultsAmong cognitively normal BLSA participants, neuroticism was associated with higher cortical amyloid burden (odds ratio 1.68, 95% CI 1.20–2.34), and conscientiousness was associated with lower cortical amyloid burden (odds ratio 0.61, 95% CI 0.44–0.86). These associations remained significant after accounting for age, sex, education, depressive symptoms, hippocampal volume, and APOE ε4. Similar associations were found with tau in the entorhinal cortex. Random-effects meta-analyses of 12 studies found that higher neuroticism (N = 3015, r = 0.07, p = .008) and lower conscientiousness (N = 2990, r = −0.11, p < .001) were associated with more amyloid deposition. Meta-analyses of 8 studies found that higher neuroticism (N = 2231, r = 0.15, p < .001) and lower conscientiousness (N = 2206, r = −0.14, p < .001) were associated with more tau pathology. The associations were moderated by cognitive status, with stronger effects in cognitively normal compared with heterogeneous samples, suggesting that the associations between personality and proteopathies are not phenomena that emerge with neuropsychiatric clinical symptoms. ConclusionsBy aggregating results across samples, this study advances knowledge on the association between personality and neuropathology. Neuroticism and conscientiousness may contribute to resistance against amyloid and tau neuropathology.

Association of Extracellular Vesicle Biomarkers With Alzheimer Disease in the Baltimore Longitudinal Study of Aging

Blood biomarkers able to diagnose Alzheimer disease (AD) at the preclinical stage would enable trial enrollment when the disease is potentially reversible. Plasma neuronal-enriched extracellular vesicles (nEVs) of patients with AD were reported to exhibit elevated levels of phosphorylated (p) tau, Aβ42, and phosphorylated insulin receptor substrate 1 (IRS-1). To validate nEV biomarkers as AD predictors. This case-control study included longitudinal plasma samples from cognitively normal participants in the Baltimore Longitudinal Study of Aging (BLSA) cohort who developed AD up to January 2015 and age- and sex-matched controls who remained cognitively normal over a similar length of follow-up. Repeated samples were blindly analyzed over 1 year from participants with clinical AD and controls from the Johns Hopkins Alzheimer Disease Research Center (JHADRC). Data were collected from September 2016 to January 2018. Analyses were conducted in March 2019. Neuronal-enriched extracellular vesicles were immunoprecipitated; tau, Aβ42, and IRS-1 biomarkers were quantified by immunoassays; and nEV concentration and diameter were determined by nanoparticle tracking analysis. Levels and longitudinal trajectories of nEV biomarkers between participants with future AD and control participants were compared. Overall, 887 longitudinal plasma samples from 128 BLSA participants who eventually developed AD and 222 age and sex-matched controls who remained cognitively normal were analyzed. Participants were followed up (from earliest sample to AD symptom onset) for a mean (SD) of 3.5 (2.31) years (range, 0-9.73 years). Overall, 161 participants were included in the training set, and 80 were in the test set. Participants in the BLSA cohort with future AD (mean [SD] age, 79.09 [7.02] years; 68 women [53.13%]) had longitudinally higher p-tau181, p-tau231, pSer312-IRS-1, pY-IRS-1, and nEV diameter than controls (mean [SD] age, 76.2 [7.36] years; 110 women [50.45%]) but had similar Aβ42, total tau, TSG101, and nEV concentration. In the training BLSA set, a model combining preclinical longitudinal data achieved 89.6% area under curve (AUC), 81.8% sensitivity, and 85.8% specificity for predicting AD. The model was validated in the test BLSA set (80% AUC, 55.6% sensitivity, 88.7% specificity). Preclinical levels of nEV biomarkers were associated with cognitive performance. In addition, 128 repeated samples over 1 year from 64 JHADRC participants with clinical AD and controls were analyzed. In the JHADRC cohort (35 participants with AD: mean [SD] age, 74.03 [8.73] years; 18 women [51.43%] and 29 controls: mean [SD] age, 72.14 [7.86] years; 23 women [79.31%]), nEV biomarkers achieved discrimination with 98.9% AUC, 100% sensitivity, and 94.7% specificity in the training set and 76.7% AUC, 91.7% sensitivity, and 60% specificity in the test set. We validated nEV biomarker candidates and further demonstrated that their preclinical longitudinal trajectories can predict AD diagnosis. These findings motivate further development of nEV biomarkers toward a clinical blood test for AD.

P2‐340: LASTING CONSEQUENCES OF CONCUSSION: BRAIN FINDINGS FROM THE BALTIMORE LONGITUDINAL STUDY OF AGING

While recent studies have reported alterations in the structure and function of the brain following a concussive event, few have examined the long-term impact of concussions on the aging brain. Here, we examine these long-term effects, 20+ years after the incident. We used neuroimaging and neuropsychological data from 51 participants (mean age at neuroimaging baseline=65.1, SD=11.23) in the Baltimore Longitudinal Study of Aging (BLSA) who reported a concussion in their medical history an average of 22 years prior to first visit, and compared them to 150 age, sex, and race matched BLSA participants with no history of concussion. Participants underwent structural magnetic resonance imaging (MRI) over a mean of 5.17 years (SD=6.14) and diffusion tensor imaging (DTI) over a mean of 2.92 years (SD=2.22) to measure brain structure, as well as 15O-water Positron Emission Tomography (PET) over a mean of 5.33 years (SD=2.19) to measure brain function. A battery of neuropsychological tests was also administered over a mean of 11.62 years (SD=7.41). Structural MRI changes indicating brain atrophy were seen in temporal lobe white matter and hippocampus at first visit, and in the occipital pole during longitudinal follow-up. Structural differences in white matter integrity using DTI were seen with increased radial and axial diffusivity in the fornix/stria terminalis, and internal capsule at first visit, and in fractional anisotropy in the corona radiata during longitudinal follow-up. Functional differences were seen in 15O-PET resting cerebral blood flow at first visit and longitudinal follow-up in regions including the frontal, temporal, and parietal cortices. No significant differences in neuropsychological performance were seen between groups, but within the concussion group itself, there was a correlation between age at concussive event and visuospatial performance, with concussion sustained at older ages associated with lower performance levels at first visit. These findings indicate that a single concussion can produce subtle, long-lasting structural and functional changes to brain. As many of these regions are susceptible to age-related neuropathologic changes, these findings also suggest that individuals with a history of concussion may be more vulnerable to further dysfunction in these brain regions with advancing age.

Association Between Accelerated Multimorbidity and Age-Related Cognitive Decline in Older Baltimore Longitudinal Study of Aging Participants without Dementia.

To explore the association between rate of physical health deterioration, operationalized as rising multimorbidity overtime, and longitudinal decline in cognitive function in older adults without dementia. Longitudinal (Baltimore Longitudinal Study of Aging (BLSA)). Community. BLSA participants aged 65 and older followed for an average of 3 years and free of dementia or mild cognitive impairment (MCI) at baseline and follow-up (N = 756). Standardized neurocognitive tests evaluating mental status, memory, executive function, processing speed, and verbal fluency were administered. Multimorbidity was assessed at each visit as number of diagnosed chronic diseases from a predefined list. Faster accumulation of chronic diseases was defined as upper quartile of rate of change in number of diseases over time (≥0.25 diseases/year). Faster accumulation of chronic diseases was significantly associated with greater rate of decline on the Category (P = .01) and Letter (P = .01) Fluency Tests. Similar trends were also found for the Trail-Making Test Parts A (P = .08) and B (P = .07); no association was found with rate of change in visual and verbal memory. Although further investigations are required to validate the results and fully understand the underlying mechanisms, these findings suggest that accelerated deterioration of physical health is associated with accelerated decline with aging in specific cognitive domains in older adults without dementia.

Association Between Visuospatial Ability and Vestibular Function in the Baltimore Longitudinal Study of Aging.

To investigate the relationship between vestibular loss associated with aging and age-related decline in visuospatial function. Cross-sectional analysis within a prospective cohort study. Baltimore Longitudinal Study of Aging (BLSA). Community-dwelling BLSA participants with a mean age of 72 (range 26-91) (N = 183). Vestibular function was measured using vestibular-evoked myogenic potentials. Visuospatial cognitive tests included Card Rotations, Purdue Pegboard, Benton Visual Retention Test, and Trail-Making Test Parts A and B. Tests of executive function, memory, and attention were also considered. Participants underwent vestibular and cognitive function testing. In multiple linear regression analyses, poorer vestibular function was associated with poorer performance on Card Rotations (P = .001), Purdue Pegboard (P = .005), Benton Visual Retention Test (P = 0.008), and Trail-Making Test Part B (P = .04). Performance on tests of executive function and verbal memory were not significantly associated with vestibular function. Exploratory factor analyses in a subgroup of participants who underwent all cognitive tests identified three latent cognitive abilities: visuospatial ability, verbal memory, and working memory and attention. Vestibular loss was significantly associated with lower visuospatial and working memory and attention factor scores. Significant consistent associations between vestibular function and tests of visuospatial ability were observed in a sample of community-dwelling adults. Impairment in visuospatial skills is often one of the first signs of dementia and Alzheimer's disease. Further longitudinal studies are needed to evaluate whether the relationship between vestibular function and visuospatial ability is causal.

The Pittsburgh Fatigability scale for older adults: development and validation.

To describe the development of the Pittsburgh Fatigability Scale (PFS) and establish its reliability and concurrent and convergent validity against performance measures. Cross-sectional. University of Pittsburgh, Pittsburgh, Pennsylvania. Scale development sample: 1,013 individuals aged 60 and older from two registries; validation sample: 483 adults aged 60 and older from the Baltimore Longitudinal Study of Aging (BLSA). The scale development sample and BLSA participants self-administered an initial 26-item perceived fatigability scale. BLSA participants also completed measures of performance fatigability (perceived exertion from a standard treadmill task and performance deterioration from a fast-paced long-distance corridor walk), a 6-m usual-paced corridor walk, and five timed chair stands. Principal components analysis with varimax rotation reduced the 26-item scale to the 10-item PFS. The PFS showed strong internal consistency (Cronbach's alpha 0.88) and excellent test-retest reliability (intraclass correlation 0.86). In the validation sample, PFS scores, adjusted for age, sex, and race, were greater for those with high performance fatigability, slow gait speed, worse physical function, and lower fitness, with differences between high and low fatigability ranging from 3.2 to 5.1 points (P < .001). The 10-item PFS physical fatigability score is a valid and reliable measure of perceived fatigability in older adults and can serve as an adjunct to performance-based fatigability measures for identifying older adults at risk of mobility limitation in clinical and research settings.

Apolipoprotein E ε4 allele interacts with sex and cognitive status to influence all-cause and cause-specific mortality in U.S. older adults.

To confirm associations of apolipoprotein E (ApoE) ε4 carrier status, sex, and time-dependent cognitive status with mortality risk and to investigate these joint effects of these associations in a cohort of community-dwelling U.S. adults. Prospective cohort study. The Baltimore Longitudinal Study of Aging (BLSA). Of 3,047 BLSA participants aged 17 to 98 at first visit (60.1% male), 1,704 with complete ApoE genotype data were included, of whom 1,461 aged 50 and older with one or more visits were eligible. Time to death from all, cardiovascular, and noncardiovascular causes. Probability of survival was lower for ApoE ε4 carriers, particularly those who were older. A Cox proportional hazards model for all-cause mortality yielded a hazard ratio (HR) for ApoE ε4 carrier versus noncarriers of 1.31 (95% confidence interval (CI)=1.02-1.68). This association was also found for cardiovascular mortality. Time-dependent all-cause dementia (HR=1.73, 95% CI= 1.33-2.26) and mild cognitive impairment (HR=1.95, 95% CI=1.42-2.67) increased all-cause mortality risk, associations that were also detected for noncardiovascular mortality. When individuals were free of cognitive impairment, a dose-response relationship with ε4 alleles was found for all-cause mortality (HR=1.40, 95% CI=0.94-2.07 for 1 ε4; HR=2.61, 95% CI=1.12-6.07 for 2 ε4). After onset of Alzheimer's disease (AD), carrying only one ε4 allele resulted in an approximately 77% greater all-cause mortality risk than in noncarriers. ApoE ε4 carrier status increased all-cause mortality risk in men and interacted with time-dependent AD to increase the risk of this outcome (relative excess risk due to interaction=2.15, 95% CI=1.22-3.07). ApoE ε4 carrier status was found to increase all-cause and cardiovascular mortality risks and interacted with sex and time-dependent AD status to affect all-cause mortality.

IC-P2-091: Integration of MRI measures of atrophy and protein aggregation with CSF biomarkers of AD pathology in individuals with mild cognitive impairment

sis and prognosis. This study was based on two large neuroimaging studies of normal aging and AD: the Baltimore Longitudinal Study of Aging (BLSA) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We investigated longitudinal progression of AD-like patterns of atrophy, determined from ADNI, in the BLSA cohort of cognitively normal (CN) elderly and of MCI. Methods: A high-dimensional pattern classifier was trained on 66 CN and 56 AD ADNI patients, and was subsequently applied to 109 CN and 15 MCI individuals from the BLSA study over a period of 9 years. The longitudinal progression of AD-like patterns of atrophy was determined for different age brackets. Results: 98.7% of all BLSA participants that remained CN were correctly classified as CN, thereby crossvalidating the accuracy of ADNI-derived classification on datasets from a different study. CN subjects of ages above 80 progressively displayed AD-like patterns of brain atrophy. The rates of change of classificationderived abnormality scores of CN’s were fairly well clustered around 0, except a small subgroup of them (especially older subjects), generally indicating lack of progression of CN towards AD-like phenotypes. In contrast, rates of change of individuals that developed MCI were more variable and positive, indicating gradual progression of many, but not all, to AD-like structure. Moreover, cognitive scores of CN and MCI that were determined to have AD-like classification scores were significantly lower than their counterparts classified as normal-like. Conclusions: A biomarker of structural abnormality distinguishing CN from AD was derived using sophisticated high-dimensional pattern classification, and was tested on longitudinal MRI scans from cognitively normal elderly and of MCI individuals. Although most CN’s that remain cognitively stable display normal and stable patterns of atrophy, individuals that develop MCI show steady increases in AD-like atrophy patterns. Structural abnormality scores and their rates of change define subgroups of CN and MCI individuals whose cognitive scores differ significantly, further indicating the clinical relevance of this structural biomarker.

Number of Teeth and Mortality Risk in the Baltimore Longitudinal Study of Aging

Findings from several studies suggested an association between oral health and several health outcomes including cardiovascular disease, aspiration pneumonia, malnutrition, poor quality of life, and mortality. Using data from the Baltimore Longitudinal Study of Aging (BLSA), we tested the hypothesis that number of teeth is indicative of mortality risk independent of other confounders. Dentists conducted a standardized oral examination that included tooth count, tooth with coronal and cervical caries count, and gingival and periodontal index. Blood tests used in the analysis included fasting glucose, oral glucose tolerance test, serum low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol, triglycerides, and white blood cell counts. Physical activity, skin fold thickness, body mass index and chronic diseases were also evaluated. Of the 500 BLSA participants evaluated, 198 died an average of 130 (+/-75) months postdental evaluation, and 302 survivors were followed for a mean of 185 (+/-90) months. Based on multivariate Cox regression models, being edentulous or having than 20 teeth was independently associated with mortality. The results of this study support the notion that number of teeth is a significant and independent risk indicator for early mortality. These findings suggest that the improvement of oral health may have a positive impact on general health and may delay mortality.

Visual memory predicts Alzheimer's disease more than a decade before diagnosis.

Recent studies have suggested that AD may reflect a chronic process that begins many years before the clinical expression of dementia. The current study examines premorbid Benton Visual Retention Test (BVRT) and Wechsler Adult Intelligence Scale-vocabulary (WAIS-voc) test scores in order to determine whether long-term deficits in these tests can predict the development of AD decades later in the Baltimore Longitudinal Study of Aging (BLSA). Participants are volunteers from the BLSA, a multidisciplinary study of normal aging conducted by the National Institute on Aging. A total of 1,425 BLSA participants who were older than 60 years were included in the analyses. Cox proportional hazards models were used to estimate the relative risk of developing AD associated with BVRT and WAIS-voc scores at different time periods up to 20 years before the diagnosis of AD. The relative risks for 6 or more BVRT errors vs less than 6 errors at 1 to 3, 3 to 5, 5 to 10, and 10 to 15 years before the diagnosis of AD were 5.69, 2.11, 1.76, and 1.83 (p < 0.05). The relative risk for 15 or more years before diagnosis was not significant (p > 0.10). WAIS-voc scores were not significantly associated with the risk of AD in any time period. A greater number of errors on the BVRT is associated with an increased risk of AD up to 15 years later. Poor visual memory performance may represent an early expression of AD years before diagnosis. This result suggests the need to continue to revise views on the natural history of AD and the possibility of an increased window of opportunity for preventive treatment before definitive diagnosis.