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1.  Association Between Cerebellar Gray Matter Volumes, Gait Speed, and Information-Processing Ability in Older Adults Enrolled in the Health ABC Study 
Background.
The cerebellum plays an important role in mobility and cognition. However, it is unclear which regions of the cerebellum are associated with gait speed and information-processing ability in older adults without overt brain damage.
Methods.
Cross-sectional associations between cerebellar gray matter volumes (GMV), gait speed, and information-processing ability were explored in 231 community-dwelling adults (mean age: 83 years, 48% black, 58% female). We measured gait speed on an automated walkway and information-processing ability on the Digit Symbol Substitution test (DSST). Total and regional cerebellar GMV was measured on 3T-magnetic resonance imaging. Lobar GMV of the cerebellum, obtained by an automated parcellation process, were aggregated based on the cognitive (lobules VI, VII, VIII and crus I, II), sensorimotor (lobules II, IV, V), and vestibular (lobules IX and X) functions ascribed to the cerebellar regions.
Results.
Larger cerebellar GMV correlated with faster gait speed and superior DSST scores (both p < .001) independent of age, gender, atrophy, and small vessel disease. After adjusting for age, gender, and atrophy, larger cognitive cerebellar GMV correlated with both faster gait speed (p = .04) and higher DSST scores (p < .001), larger sensorimotor cerebellar GMV correlated significantly with DSST alone (p = .02), and the vestibular cerebellar GMV with neither. The association between cognitive cerebellar GMV and gait speed was no longer significant after adjusting for DSST score in the linear regression models.
Conclusions.
The relationship between gait speed and cerebellar GMV is influenced by information-processing ability, and this relationship is stronger in subregions ascribed to cognitive than vestibular or sensorimotor functions.
doi:10.1093/gerona/glt151
PMCID: PMC4095927  PMID: 24170673
Gait; Brain aging; Cognition; Imaging.
2.  Traumatic brain injury and risk of dementia in older veterans 
Neurology  2014;83(4):312-319.
Objectives:
Traumatic brain injury (TBI) is common in military personnel, and there is growing concern about the long-term effects of TBI on the brain; however, few studies have examined the association between TBI and risk of dementia in veterans.
Methods:
We performed a retrospective cohort study of 188,764 US veterans aged 55 years or older who had at least one inpatient or outpatient visit during both the baseline (2000–2003) and follow-up (2003–2012) periods and did not have a dementia diagnosis at baseline. TBI and dementia diagnoses were determined using ICD-9 codes in electronic medical records. Fine-Gray proportional hazards models were used to determine whether TBI was associated with greater risk of incident dementia, accounting for the competing risk of death and adjusting for demographics, medical comorbidities, and psychiatric disorders.
Results:
Veterans were a mean age of 68 years at baseline. During the 9-year follow-up period, 16% of those with TBI developed dementia compared with 10% of those without TBI (adjusted hazard ratio, 1.57; 95% confidence interval: 1.35–1.83). There was evidence of an additive association between TBI and other conditions on risk of dementia.
Conclusions:
TBI in older veterans was associated with a 60% increase in the risk of developing dementia over 9 years after accounting for competing risks and potential confounders. Our results suggest that TBI in older veterans may predispose toward development of symptomatic dementia and raise concern about the potential long-term consequences of TBI in younger veterans and civilians.
doi:10.1212/WNL.0000000000000616
PMCID: PMC4115602  PMID: 24966406
3.  Pathways Linking Regional Hyperintensities in the Brain and Slower Gait 
NeuroImage  2014;99:7-13.
Importance
Cerebral white matter hyperintensities (WMHs) are involved in the evolution of impaired mobility and executive functions. Executive functions and mobility are also associated. Thus, WMHs may impair mobility directly, by disrupting mobility-related circuits, or indirectly, by disrupting circuits responsible for executive functions. Understanding the mechanisms underlying impaired mobility in late life will increase our capacity to develop effective interventions.
Objective
To identify regional WMHs most related to slower gait and to examine whether these regional WMHs directly impact mobility, or indirectly by executive functions.
Design
Cross-sectional study. Twenty-one WMH variables (i.e., total WMH volume and WMHs in 20 tracts), gait speed, global cognition (Modified Mini-Mental State Examination; 3MS), and executive functions and processing speed (Digit-Symbol Substitution Test; DSST) were assessed. A L1–L2 regularized regression (i.e., Elastic Net model) identified the WMH variables most related to slower gait. Multivariable linear regression models quantified the association between these WMH variables and gait speed. Formal tests of mediation were also conducted.
Setting
Community-based sample.
Participants
253 adults (mean age: 83 years, 58% women, 41% black).
Main Outcome Measure
Gait speed.
Results
In older adults with average gait speed of 0.91 m/sec, total WMH volume, WMHs located in right anterior thalamic radiation (ATRR) and frontal corpus callosum (CCF) were most associated with slower gait. There was a >10% slower gait for each standard deviation of WMH in CCF, ATRR or total brain (standardized beta in m/sec [p value]: −0.11 [p=0.046], −0.15 [p=0.007] and −0.14 [p=0.010], respectively). These associations were substantially and significantly attenuated after adjustment for DSST. This effect was stronger for WMH in CCF than for ATRR or total WMH (standardized beta in m/sec [p value]: −0.07 [p=0.190], −0.12 [p=0.024] and −0.10 [p=0.049], respectively). Adjustment for 3MS did not change these associations. The mediation analyses also found that DSST significantly mediated the associations between WMHs and gait speed. Our models were adjusted for age, sex, BMI, quadriceps strength, years of education, standing height, and prevalent hypertension.
Conclusion
The impact, direct or indirect, of WMHs on gait speed depended on their location and was mediated by executive function. Thus, multi-faceted interventions targeting executive control functions as well as motor functions, such as balance and strength training, are candidates to the maintenance of mobility across the lifespan.
doi:10.1016/j.neuroimage.2014.05.017
PMCID: PMC4508128  PMID: 24841418 CAMSID: cams4627
White Matter Hyperintensities; Mobility; Cognitive Function; Executive Function; Gait Speed; Mediation
4.  Older Adults With Limited Literacy Are at Increased Risk for Likely Dementia 
Background.
Low literacy is common among the elderly and possibly more reflective of educational attainment than years of school completed. We examined the association between literacy and risk of likely dementia in older adults.
Methods.
Participants were 2,458 black and white elders (aged 71–82) from the Health, Aging and Body Composition study, who completed the Rapid Estimate of Adult Literacy in Medicine and were followed for 8 years. Participants were free of dementia at baseline; incidence of likely dementia was defined by hospital records, prescription for dementia medication, or decline in Modified Mini-Mental State Examination score. We conducted Cox proportional hazard models to evaluate the association between literacy and incidence of likely dementia. Demographics, education, income, comorbidities, lifestyle variables, and apolipoprotein E (APOE) ε4 status were included in adjusted analyses.
Results.
Twenty-three percent of participants had limited literacy (<9th-grade level). Limited literacy, as opposed to adequate literacy (≥9th-grade level), was associated with greater incidence of likely dementia (25.5% vs17.0%; unadjusted hazard ratio [HR] = 1.75, 95% confidence interval 1.44–2.13); this association remained significant after adjustment. There was a trend for an interaction between literacy and APOE ε4 status (p = .07); the association between limited literacy and greater incidence of likely dementia was strong among ε4 noncarriers (unadjusted HR = 1.85) but nonsignificant among ε4 carriers (unadjusted HR = 1.25).
Conclusions.
Limited literacy is an important risk factor for likely dementia, especially among APOE ε4-negative older adults, and may prove fruitful to target in interventions aimed at reducing dementia risk.
doi:10.1093/gerona/glt176
PMCID: PMC4067115  PMID: 24158765
Cognitive aging; Risk factors; Epidemiology.
5.  Race-related Differences in Depression Onset and Recovery in Older Persons Over Time: The Health, Aging, and Body Composition Study 
Objectives
To evaluate race-related differences in depression onset and recovery in older persons, overall and by sex, and examine race-related differences in mortality according to depression.
Design
Prospective cohort study.
Setting
General community in pre-designated zip code areas in Memphis, Tennessee, and Pittsburgh, Pennsylvania.
Participants
3,075 persons age 70-79 at baseline in the Health, Aging, and Body Composition study.
Measurements
Depression was assessed at 8 time points over 10 years using the 10-item Center for Epidemiologic Studies – Depression (CES-D) scale; scores of <8 and ≥8 denoted nondepressed and depressed, respectively. We created variables for transitions across each 18-month time interval, namely, from nondepressed or depressed to nondepressed, depressed, or death, and determined the association between race and the average likelihood of these transitions over time.
Results
A higher percentage of blacks than whites were depressed at nearly all time points. Adjusting for demographics, common chronic conditions, and body mass index, blacks had a higher likelihood of experiencing depression onset than whites (odds ratio, 1.22; 95% confidence interval, 1.03-1.43); among men, blacks were more likely to experience depression onset than whites (odds ratio, 1.44; 95% confidence interval, 1.24-2.89). Blacks also had a higher likelihood of transitioning from nondepressed to death (odds ratio, 1.79; 95% confidence interval, 1.30-2.46). Overall and in sex-stratified analyses, race was not associated with recovery from depression or with the transition from depression to death.
Conclusion
Our findings highlight race differences in depression in older persons and encourage further research on the course of depression in older blacks.
doi:10.1016/j.jagp.2013.09.001
PMCID: PMC3984378  PMID: 24125816
Aging; Depression; Depressive symptoms; Race differences; Epidemiology; Prospective studies
6.  Dementia Prevention: optimizing the use of observational data for personal, clinical, and public health decision-making 
Worldwide, over 35 million people suffer from Alzheimer’s disease and related dementias. This number is expected to triple over the next 40 years. How can we improve the evidence supporting strategies to reduce the rate of dementia in future generations? The risk of dementia is likely influenced by modifiable factors such as exercise, cognitive activity, and the clinical management of diabetes and hypertension. However, the quality of evidence is limited and it remains unclear whether specific interventions to reduce these modifiable risk factors can, in turn, reduce the risk of dementia. Although randomized controlled trials are the gold-standard for causality, the majority of evidence for long-term dementia prevention derives from, and will likely continue to derive from, observational studies. Although observational research has some unavoidable limitations, its utility for dementia prevention might be improved by, for example, better distinction between confirmatory and exploratory research, higher reporting standards, investment in effectiveness research enabled by increased data-pooling, and standardized exposure and outcome measures. Informed decision-making by the general public on low-risk health choices that could have broad potential benefits could be enabled by internet-based tools and decision-aids to communicate the evidence, its quality, and the estimated magnitude of effect.
PMCID: PMC4487813  PMID: 26146610
Alzheimer’s; primary prevention; non-randomized studies; low-risk; communication
7.  Dysphoria and Anhedonia as Risk factors for Disability or Death in Older Persons: Implications for the Assessment of Geriatric Depression 
Objectives
Either dysphoria (sadness) or anhedonia (loss of interest in usually pleasurable activities) is required for a diagnosis of major depression. While major depression is a known risk factor for disability in older persons, few studies have examined the relationship between the 2 core symptoms of major depression and disability or mortality. Our objective was to examine the relationship between these two core symptoms and time to disability or death
Design
Longitudinal cohort study
Setting and Participants
We used the nationally representative Health and Retirement Study to examine this relationship in 11,353 persons over the age of 62 (mean = 74) followed for up to 13 years.
Measurements
Dysphoria and anhedonia were assessed with the Short Form Composite International Diagnostic Interview. Our outcome measure was time to either death or increased disability, defined as the new need for help in a basic activity of daily living. We adjusted for a validated disability risk index and other confounders.
Results
Compared to subjects without either dysphoria or anhedonia, the risk for disability or death was not elevated in elders with dysphoria without anhedonia (adjusted HR = 1.11, 95%CI = 0.91–1.36). The risk was elevated in those with anhedonia without dysphoria (HR = 1.30, 95%CI = 1.06–1.60) and those with both anhedonia and dysphoria (HR = 1.28, 95%CI = 1.13–1.46).
Conclusion
Our results highlight the need for clinicians to learn whether patients have lost interest in usually pleasurable activities, even if they deny sadness.
doi:10.1016/j.jagp.2012.12.001
PMCID: PMC3766414  PMID: 23602308
Depression; anhedonia; activities of daily living; quality of life; health status
8.  Depressive Symptoms among Dementia Caregivers: The Role of Mediating Factors 
Objectives
To compare depressive symptoms between caregivers to persons with dementia and other illnesses, and determine whether caregiver role captivity and care recipient disruptive behaviors mediate this association.
Design
Prospective cohort study of older women in four U.S. communities followed from 1999 to 2009.
Setting
Home-based interviews.
Participants
345 caregiving participants from the Caregiver-Study of Osteoporotic Fractures.
Measurements
Caregiver status based on self-report of performing one or more instrumental or basic activities of daily living for care recipient. Depressive symptoms measured using the 20-item Center for Epidemiologic Studies Depression Scale. Scores of 16 or greater represented high depressive symptoms. Caregiver role captivity and care recipient problematic behaviors measured using validated instruments.
Results
Approximately one-third of the caregivers cared for a person with dementia. High depressive symptoms were more common among dementia caregivers (22.8% vs. 11.2%, p <0.001), (unadjusted odds ratio [OR] 2.12, 95% CI 1.20-3.74). This association was completely mediated by caregiver role captivity and care recipient problematic behaviors. In adjusted results, high depressive symptoms was associated with middle and highest tertiles of role captivity (adjusted odds ratios [AOR] 5.01, 95% CI 2.31-11.05 and 9.41, 95% CI 3.95-22.40 for the middle and highest tertiles, respectively) and care recipient problematic behaviors (AOR 2.52 95% CI 1.02-6.19 and 5.26, 95% CI 2.00-13.8 for each tertile, respectively).
Conclusions
Older caregivers to persons with dementia are at increased risk of high depressive symptoms. Targeting problematic behaviors among dementia patients and addressing aspects of dementia care that result in role captivity may ameliorate caregiver depression.
doi:10.1016/j.jagp.2012.08.010
PMCID: PMC3710308  PMID: 23567432
caregiver burden; dementia; depression
9.  Long-term Cumulative Depressive Symptom Burden and Risk of Cognitive Decline and Dementia Among Very Old Women 
Background.
Depressive symptoms and cognitive outcomes are strongly interrelated. Despite that rates of depressive symptoms fluctuate during late life, little is known about the impact of long-term cumulative depressive symptom burden on cognitive decline and dementia in older adults. This study examines the association of nearly 20 years of cumulative depressive symptoms with cognitive outcomes in a cohort of older women.
Methods.
We assessed depressive symptoms in 7,240 women using the Geriatric Depression scale (GDS) at serial visits. We used a Poisson model with random slopes to estimate GDS trajectories for each participant from baseline to death or end of follow-up, and then characterized depressive symptom burden by quartile of the area under the curve. We assessed cognitive outcomes using repeated measures of the Mini-Mental State Examination (MMSE) and Trails B score over 20 years, Year-20 neuropsychological test battery, and adjudicated dementia and mild cognitive impairment (MCI).
Results.
Adjusting for potential confounders, compared with women in the lowest quartile of cumulative depressive symptoms burden, women in the highest quartile had 21% more MMSE errors over time (95% CI = 17%, 26%), 20% worse Trails B score over time (95% CI = 17%, 23%), worse scores on most of the Year-20 cognitive tests, and a twofold greater likelihood of developing dementia or MCI (95% CI = 1.48, 3.11).
Conclusions.
Long-term cumulative depressive symptom burden was associated with cognitive decline and risk of dementia or MCI. Older adults with a history of depression should be closely monitored for recurrent episodes or unresolved depressive symptoms as well as any cognitive deficits.
doi:10.1093/gerona/glt139
PMCID: PMC3991142  PMID: 24097423
Depression; Cognition; Alzheimer’s.
10.  Higher Step Length Variability Indicates Lower Grey Matter Integrity of Selected Regions in Older Adults 
Gait & posture  2014;40(1):225-230.
Step length variability (SLV) increases with age in those without overt neurologic disease, is higher in neurologic patients, is associated with falls, and predicts dementia. Whether higher SLV in older adults without neurologic disease indicates presence of neurologic abnormalities is unknown. Our objective was to identify whether SLV in older adults without overt disease is associated with findings from multimodal neuroimaging. A well-characterized cohort of 265 adults (79–90 years) was concurrently assessed by gait mat, magnetic resonance imaging with diffusion tensor, and neurological exam. Linear regression models adjusted for gait speed, demographic, health, and functional covariates assessed associations of MRI measures (grey matter volume, white matter hyperintensity volume, mean diffusivity, fractional anisotropy) with SLV. Regional distribution of associations was assessed by sparse partial least squares analyses. Higher SLV (mean: 8.4, SD: 3.3) was significantly associated with older age, slower gait speed, and poorer executive function and also with lower grey matter integrity measured by mean diffusivity (standardized beta=0.16; p=0.02). Associations between SLV and grey matter integrity were strongest for the hippocampus and anterior cingulate gyrus (both β=0.18) as compared to other regions. Associations of SLV with other neuroimaging markers were not significant. Lower integrity of normal-appearing grey matter may underlie higher SLV in older adults. Our results highlighted the hippocampus and anterior cingulate gyrus, regions involved in memory and executive function. These findings support previous research indicating a role for cognitive function in motor control. Higher SLV may indicate focal neuropathology in those without diagnosed neurologic disease.
doi:10.1016/j.gaitpost.2014.03.192
PMCID: PMC4071448  PMID: 24792638
gait disorders; diffusion tensor imaging; aging; brain
11.  Chronicity of PTSD and Risk of Disability in Older Persons 
JAMA psychiatry  2014;71(5):540-546.
Importance
Little is known about the association of posttraumatic stress disorder (PTSD) with disability in late life. Most studies of late-life psychiatric disorders and function have focused on depression and generalized anxiety disorder (GAD).
Objective
To determine the association between PTSD and disability among older adults, and investigate if association differs by chronicity of PTSD.
Design
The Collaborative Psychiatric Epidemiology Surveys (CPES 2001-2003) includes three aggregated, nationally representative studies (National Comorbidity Survey Replication, National Survey of American Life, and National Latino and Asian American Study or NLAAS) totaling 20,013 participants 18 years and older. Analyses used weights and complex design-corrected statistical tests to infer generalizability to US population.
Setting
Continental US; additionally Alaska and Hawaii for NLAAS.
Participants
We studied 3,287 CPES participants aged 55 years and older (mean (SD) age=66 (8.7) years, 60% female).
Main Outcome Measures
Disability was defined by 5 domains (out of role, self-care, mobility, cognition, and social) using the WHO-DAS.
Results
3.7% of older adults had a history of PTSD defined by DSM-IV criteria. Of these, approximately half had persistent PTSD in later life (age of onset < 55 years as well as a recent diagnosis) (1.8%). Examining three PTSD groups, frequency of any disability was 79.7% for persistent PTSD, 69.6% for pre-late-life (age of onset < 55 years and age at last diagnosis < 55 years), and 36.9% for no PTSD (P <.001). In logistic regression analyses, adjusting for demographics, smoking, individual medical conditions, depression, GAD, and substance use disorders, respondents with persistent PTSD were three times more likely to have any disability than respondents with no PTSD (odds ratio [OR], 3.18; 95% CI, 1.32-7.64). Global disability results were non-significant for pre-late-life relative to no PTSD (OR, 1.99; 95% CI, 0.97-4.08). In addition, the results suggest that persistent PTSD relative to no PTSD has a strong association with all individual domains.
Conclusions and Relevance
Disability in older Americans is strongly associated with PTSD, particularly PTSD that persists into later life. These findings suggest that monitoring and treatment of PTSD is important over the long term.
doi:10.1001/jamapsychiatry.2014.5
PMCID: PMC4119004  PMID: 24647756
12.  Prospective Study of Endogenous Circulating Estradiol and Risk of Stroke in Older Women 
Archives of neurology  2010;67(2):195-201.
Objective
To test the hypothesis that circulating endogenous estradiol is associated with stroke risk in older postmenopausal women. Stroke incidence increases after menopause, when endogenous estrogen levels fall, yet exogenous estrogen increases strokes in older postmenopausal women. The relation between endogenous estrogen and stroke is unclear.
Design
Prospective case-control study.
Setting
Study of Osteoporotic Fractures.
Patients or Other Participants
Women at least age 65 years (99% follow-up) who were not taking estrogen at baseline.
Main Outcome Measures
Free estradiol index (FEI) was calculated by dividing total estradiol by sex hormone–binding globulin concentrations measured in banked baseline serum. Using logistic regression, odds ratios were estimated for a first-ever atherothrombotic stroke associated with endogenous FEI in 196 women who had a subsequent validated stroke (median follow-up, 8 years) compared with 219 randomly selected women who did not. Potential mediators were assessed in multivariable models.
Results
The age-adjusted odds of atherothrombotic stroke increased with increasing FEI quartiles (Ptrend=.007). Women in the highest FEI quartile had an age-adjusted 2.31-fold (odds ratio, 2.31; 95% confidence interval, 1.28–4.17) higher odds than women in the lowest quartile. Women with greater central adiposity had a suggestively stronger association (P =.08). Atherogenic dyslipidemia, type 2 diabetes mellitus, and C-reactive protein level were potential mediators of this relation.
Conclusions
Endogenous estradiol level is an indicator of stroke risk in older postmenopausal women, especially in those with greater central adiposity. Potential mediators, including atherogenic dyslipidemia, insulin resistance, and inflammation, might underlie this association. Whether estradiol, independent of atherogenic adiposity, influences such mediators and stroke risk needs to be determined. Estrogen-altering agents might be harmful or beneficial depending on endogenous estradiol levels, especially in women with greater central adiposity.
doi:10.1001/archneurol.2009.322
PMCID: PMC4406483  PMID: 20142527
13.  Cardiorespiratory fitness and cognitive function in middle age 
Neurology  2014;82(15):1339-1346.
Objective:
To investigate whether greater cardiorespiratory fitness (CRF) is associated with better cognitive function 25 years later.
Methods:
We studied 2,747 participants in the community-based Coronary Artery Risk Development in Young Adults Study of black and white men and women aged 18 to 30 years at recruitment in 1985–1986 (baseline year 0). Symptom-limited maximal treadmill test durations at years 0 and 20 provided measures of CRF. Cognitive tests at year 25 measured verbal memory (Rey Auditory Verbal Learning Test [RAVLT]), psychomotor speed (Digit Symbol Substitution Test [DSST]), and executive function (Stroop Test).
Results:
Per minute of baseline CRF, the RAVLT was 0.12 words recalled higher (standard error [SE] = 0.03, p < 0.0001), the DSST was 0.92 digits higher (SE = 0.13, p < 0.0001), and the Stroop Test score was 0.52 lower (better performance, SE = 0.11, p < 0.0001), after accounting for race, sex, age, education, and clinical center. Compared with the lowest quartile of CRF, each cognitive test was 21% to 34% of an SD better in the highest CRF quartile. Further adjustment for lifestyle and clinical measures attenuated coefficients for RAVLT and DSST slightly, while the coefficient predicting the Stroop Test lost more than half its value (p = 0.07). Analysis in the subset of 1,957 participants who also completed the year-20 treadmill test showed that 20-year change in CRF was positively associated only with DSST (p < 0.001).
Conclusions:
Better verbal memory and faster psychomotor speed at ages 43 to 55 years were clearly associated with better CRF 25 years earlier.
doi:10.1212/WNL.0000000000000310
PMCID: PMC4001190  PMID: 24696506
14.  Effects of traumatic brain injury and posttraumatic stress disorder on Alzheimer’s disease in veterans, using the Alzheimer’s Disease Neuroimaging Initiative 
Both traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are common problems resulting from military service, and both have been associated with increased risk of cognitive decline and dementia resulting from Alzheimer’s disease (AD) or other causes. This study aims to use imaging techniques and biomarker analysis to determine whether traumatic brain injury (TBI) and/or PTSD resulting from combat or other traumas increase the risk for AD and decrease cognitive reserve in Veteran subjects, after accounting for age. Using military and Department of Veterans Affairs records, 65 Vietnam War veterans with a history of moderate or severe TBI with or without PTSD, 65 with ongoing PTSD without TBI, and 65 control subjects are being enrolled in this study at 19 sites. The study aims to select subject groups that are comparable in age, gender, ethnicity, and education. Subjects with mild cognitive impairment (MCI) or dementia are being excluded. However, a new study just beginning, and similar in size, will study subjects with TBI, subjects with PTSD, and control subjects with MCI. Baseline measurements of cognition, function, blood, and cerebrospinal fluid bio-markers; magnetic resonance images (structural, diffusion tensor, and resting state blood-level oxygen dependent (BOLD) functional magnetic resonance imaging); and amyloid positron emission tomographic (PET) images with florbetapir are being obtained. One-year follow-up measurements will be collected for most of the baseline procedures, with the exception of the lumbar puncture, the PET imaging, and apolipoprotein E genotyping. To date, 19 subjects with TBI only, 46 with PTSD only, and 15 with TBI and PTSD have been recruited and referred to 13 clinics to undergo the study protocol. It is expected that cohorts will be fully recruited by October 2014. This study is a first step toward the design and statistical powering of an AD prevention trial using at-risk veterans as subjects, and provides the basis for a larger, more comprehensive study of dementia risk factors in veterans.
doi:10.1016/j.jalz.2014.04.005
PMCID: PMC4392759  PMID: 24924673
Traumatic brain injury; Posttraumatic stress disorder; Alzheimer’s disease; Veterans; Neuroimaging
15.  Long-term Cognitive and Functional Effects of Potentially Inappropriate Medications in Older Women 
Background.
The use of potentially inappropriate medications in older adults can lead to known adverse drug events, but long-term effects are less clear. We therefore conducted a prospective cohort study of older women to determine whether PIM use is associated with risk of functional impairment or low cognitive performance.
Methods.
We followed up 1,429 community-dwelling women (≥75 years) for a period of 5 years at four clinical sites in the United States. The primary predictor at baseline was PIM use based on 2003 Beers Criteria. We also assessed anticholinergic load using the Anticholinergic Cognitive Burden scale. Outcomes included scores on a battery of six cognitive tests at follow-up and having one or more incident impairments in instrumental activities of daily living. Regression models were adjusted for baseline age, race, education, smoking, physical activity, a modified Charlson Comorbidity Index, and cognitive score.
Results.
The mean ± SD age of women at baseline was 83.2 ± 3.3. In multivariate models, baseline PIM use and higher ACB scores were significantly associated with poorer performance in category fluency (PIM: p = .01; ACB: p = .02) and immediate (PIM: p = .04; ACB: p = .03) and delayed recall (PIM: p = .04). Both PIM use (odds ratio [OR]: 1.36 [1.05–1.75]) and higher ACB scores (OR: 1.11 [1.04–1.19]) were also strongly associated with incident functional impairment.
Conclusions.
The results provide suggestive evidence that PIM use and increased anticholinergic load may be associated with risk of functional impairment and low cognitive performance. More cautious selection of medications in older adults may reduce these potential risks.
doi:10.1093/gerona/glt192
PMCID: PMC3968824  PMID: 24293516
Dementia; Cognitive aging; Medication; Epidemiology; Physical function.
16.  Relationship Between 25-Hydroxyvitamin D and Cognitive Function in Older Adults: The Health ABC Study 
Objectives
To examine the relationship between 25-hydroxyvitamin D (25(OH)D) levels and cognitive performance over time in older adults in the Health, Aging, and Body Composition (Health ABC) study.
Design
Prospective cohort study
Setting
Community-dwelling participants in Pittsburgh, PA, and Memphis, TN
Participants
2,777 well-functioning adults aged 70–79 at baseline with serum 25(OH)D measured at the 12 month follow-up visit and cognitive function measured at baseline and 4-year follow-up visit.
Measurements
Vitamin D status was categorized as 25(OH)D levels <20 ng/mL, 20 - <30 ng/mL, or ≥ 30ng/mL. Cognition was measured using the Modified Mini-Mental State Exam (3MS) and Digit Symbol Substitution Test (DSST). Linear regression models adjusting for multiple covariates, including age, education, sex, race, site, season, physical activity, and comorbidities were used in the analysis.
Results
Sixty-eight percent of participants had 25(OH)D levels<30 ng/mL. Lower 25(OH)D levels were associated with lower baseline cognitive scores on the 3MS (adjusted means (95% CI): 89.9 (89.4–90.4), 90.8 (90.4–91.3), and 90.6 (90.2–91.1) for <20, 20-<30, and ≥30ng/mL, respectively; p trend =0.02) and the DSST (35.2 (34.5–36.0), 35.9 (35.2–36.6), and 37.0 (36.3–37.8), p trend =0.01). Participants with low 25(OH)D levels had greater declines in 3MS scores over 4 years than those with higher levels (LS mean change (95% CI): −1.0 (−1.5 to −0.6), −0.8 (−1.2 to −0.3), and −0.2 (−0.7 to 0.2) for <20, 20-<30, and ≥30ng/mL, respectively; p=0.05). There was no significant difference in DSST decline by 25(OH)D level.
Conclusion
Low 25(OH)D levels were associated with worse global cognitive function and greater decline over time as measured by the 3MS. Intervention trials are needed to determine if vitamin D supplementation can reduce cognitive decline.
doi:10.1111/jgs.12765
PMCID: PMC3989387  PMID: 24635412
Vitamin D; cognition; cognitive function; memory
17.  Contribution of Alzheimer disease to mortality in the United States 
Neurology  2014;82(12):1045-1050.
Objective:
To assess the burden of mortality attributable to Alzheimer disease (AD) dementia in the United States.
Methods:
Data came from 2,566 persons aged 65 years and older (mean 78.1 years) without dementia at baseline from 2 cohort studies of aging with identical annual diagnostic assessments of dementia. Because both studies require organ donation, ascertainment of mortality was complete and dates of death accurate. Mortality hazard ratios (HRs) after incident AD dementia were estimated per 10-year age strata from proportional hazards models. Population attributable risk percentage was derived to estimate excess mortality after a diagnosis of AD dementia. The number of excess deaths attributable to AD dementia in the United States was then estimated.
Results:
Over an average of 8 years, 559 participants (21.8%) without dementia at baseline developed AD dementia and 1,090 (42.4%) died. Median time from AD dementia diagnosis to death was 3.8 years. The mortality HR for AD dementia was 4.30 (confidence interval = 3.33, 5.58) for ages 75–84 years and 2.77 (confidence interval = 2.37, 3.23) for ages 85 years and older (too few deaths after AD dementia in ages 65–74 were available to estimate HR). Population attributable risk percentage was 37.0% for ages 75–84 and 35.8% for ages 85 and older. An estimated 503,400 deaths in Americans aged 75 years and older were attributable to AD dementia in 2010.
Conclusions:
A larger number of deaths are attributable to AD dementia in the United States each year than the number (<84,000 in 2010) reported on death certificates.
doi:10.1212/WNL.0000000000000240
PMCID: PMC3962992  PMID: 24598707
18.  Effect of Exercise and Cognitive Activity on Self-Reported Sleep Quality in Community-Dwelling Older Adults with Cognitive Complaints: A Randomized Controlled Trial 
Objectives
To compare the effects of different types of physical and mental activity on self-reported sleep quality over 12 weeks in older adults with cognitive and sleep complaints.
Design
Randomized controlled trial.
Setting
General community.
Participants
Seventy-two inactive community-dwelling older adults with self-reported sleep and cognitive problems (mean age 73.3±6.1; 60% women).
Intervention
Random allocation to four arms using a two-by-two factorial design: aerobic+cognitive training, aerobic+educational DVD, stretching+cognitive training, and stretching+educational DVD arms (60 min/d, 3 d/wk for physical and mental activity for 12 weeks).
Measurements
Change in sleep quality using seven questions from the Sleep Disorders Questionnaire on the 2005–06 National Health and Nutrition Examination Survey (range 0–28, with higher scores reflecting worse sleep quality). Analyses used intention-to-treat methods.
Results
Sleep quality scores did not differ at baseline, but there was a significant difference between the study arms in change in sleep quality over time (p<.005). Mean sleep quality scores improved significantly more in the stretching+educational DVD arm (5.1 points) than in the stretching+cognitive training (1.2 points), aerobic+educational DVD (1.1 points), or aerobic+cognitive training (0.25 points) arm (all p<.05, corrected for multiple comparisons). Differences between arms were strongest for waking at night (p=.02) and taking sleep medications (p=.004).
Conclusion
Self-reported sleep quality improved significantly more with low-intensity physical and mental activities than with moderate- or high-intensity activities in older adults with self-reported cognitive and sleep difficulties. Future longer-term studies with objective sleep measures are needed to corroborate these results.
doi:10.1111/jgs.13158
PMCID: PMC4356237  PMID: 25516028
physical activity; cognition; sleep; aging; intervention
19.  Preventing Loss of Independence through Exercise (PLIÉ): A Pilot Clinical Trial in Older Adults with Dementia 
PLoS ONE  2015;10(2):e0113367.
Background
Current dementia medications have small effect sizes, many adverse effects and do not change the disease course. Therefore, it is critically important to study alternative treatment strategies. The goal of this study was to pilot-test a novel, integrative group exercise program for individuals with mild-to-moderate dementia called Preventing Loss of Independence through Exercise (PLIÉ), which focuses on training procedural memory for basic functional movements (e.g., sit-to-stand) while increasing mindful body awareness and facilitating social connection.
Methods
We performed a 36-week cross-over pilot clinical trial to compare PLIÉ with usual care (UC) at an adult day program for individuals with dementia in San Francisco, CA. Assessments of physical performance, cognitive function, physical function, dementia-related behaviors, quality of life and caregiver burden were performed by blinded assessors at baseline, 18 weeks (cross-over) and 36 weeks. Our primary outcomes were effect sizes based on between-group comparisons of change from baseline to 18 weeks; secondary outcomes were within-group comparisons of change before and after cross-over.
Results
Twelve individuals enrolled (7 PLIÉ, 5 UC) and 2 withdrew (1 PLIÉ, 18 weeks; 1 UC, 36 weeks). Participants were 82% women (mean age, 84 ± 4 years); caregivers were 82% daughters (mean age, 56 ± 13 years). Effect sizes were not statistically significant but suggested potentially clinically meaningful (≥0.25 SDs) improvement with PLIÉ versus UC for physical performance (Cohen’s D: 0.34 SDs), cognitive function (0.76 SDs) and quality of life (0.83 SDs) as well as for caregiver measures of participant’s quality of life (0.33 SDs) and caregiver burden (0.49 SDs). Results were similar when within-group comparisons were made before and after cross-over.
Conclusions
PLIÉ is a novel, integrative exercise program that shows promise for improving physical function, cognitive function, quality of life and caregiver burden in individuals with mild-to-moderate dementia. Larger randomized, controlled trials are warranted.
Trial Registration
ClinicalTrials.gov NCT01371214
doi:10.1371/journal.pone.0113367
PMCID: PMC4324943  PMID: 25671576
20.  Arterial stiffness and cognitive function in the elderly 
Journal of Alzheimer's disease : JAD  2014;42(0 4):S503-S514.
Cognitive decline and dementia are a major cause of disability and mortality among older adults. Cross-sectional evidence from observational studies suggests that greater arterial stiffness is associated with worse cognitive performance. These associations have been observed on measures of global cognition and across multiple domains of cognition. Epidemiologic evidence on the association between arterial stiffness and rate of cognitive decline has been less definitive, and very few studies have investigated the risk of developing dementia. This review summarizes the current research on arterial stiffness and cognition, issues around measurement and the effect that potential intervention might have on the course of cognitive aging. The evidence on pharmacological and non-pharmacological (exercise, nutrition, etc) interventions in older adults with arterial stiffness is promising. Yet there are no studies or trials that directly evaluate how interventions of arterial stiffness reduce or prevent cognitive impairment and risk of developing dementia. More research is needed to elucidate the causal link between arterial stiffness and cognitive decline and dementia, and to identify whether potential interventions to prevent or reduce arterial stiffness may benefit cognitive health of the elderly.
doi:10.3233/JAD-141563
PMCID: PMC4313561  PMID: 25351110
Aging; Arterial stiffness; Cognitive decline; Dementia; Epidemiology
21.  Depressive symptoms in Chinese Americans with Cognitive Impairment 
Objectives
To assess the prevalence of geriatric depression in Chinese American patients with cognitive impairment and to compare the prevalence to that of cognitively normal elderly Chinese Americans and Caucasians.
Design
We compared rates of depressive symptomatology in elderly Chinese Americans to a matched group of Caucasians, with and without dementia, and assessed rates of treatment for depression across all groups.
Setting
Academic subspecialty referral clinic.
Participants
Participants included a total of 137 elderly, cognitively impaired and cognitively normal Chinese Americans and 140 Caucasians with and without cognitive impairment.
Measurements
Demographic (e.g. age, education, race, language ability), cognitive (MMSE score), medical (e.g. cardiovascular morbidity) and functional (Clinical Dementia Rating Scale) risk factors were assessed for association with depressive symptomatology as measured by the Geriatric Depression Scale (GDS).
Results
Depression (GDS score ≥ 6 out of 15) was significantly more common in cognitively impaired Chinese Americans (35%) versus cognitively impaired Caucasians (15%, χ2 = 33.8, p<0.05), and Chinese Americans were less likely to be on treatment for depression (12%) than Caucasians (37%, χ2 = 41, p<0.05). Cognitive and functional impairment, age and education were all independent predictors of GDS score. Rates of depression were not significantly different in cognitively normal Chinese American (6%) and Caucasian (0%) groups.
Conclusions
These findings indicate that elderly Chinese Americans with cognitive impairment are at significantly increased risk for unrecognized depression and that education, and/or other cultural factors associated with education may contribute to this risk.
doi:10.1016/j.jagp.2012.10.029
PMCID: PMC4309267  PMID: 24021225
geriatric depression; dementia; Chinese American
22.  A Clinical Index to Predict Progression from Mild Cognitive Impairment to Dementia Due to Alzheimer's Disease 
PLoS ONE  2014;9(12):e113535.
Background
Mild cognitive impairment is often a precursor to dementia due to Alzheimer's disease, but many patients with mild cognitive impairment never develop dementia. New diagnostic criteria may lead to more patients receiving a diagnosis of mild cognitive impairment.
Objective
To develop a prediction index for the 3-year risk of progression from mild cognitive impairment to dementia relying only on information that can be readily obtained in most clinical settings.
Design and Participants
382 participants diagnosed with amnestic mild cognitive impairment enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI), a multi-site, longitudinal, observational study.
Main Predictors Measures
Demographics, comorbid conditions, caregiver report of participant symptoms and function, and participant performance on individual items from basic neuropsychological scales.
Main Outcome Measure
Progression to probable Alzheimer's disease.
Key Results
Subjects had a mean (SD) age of 75 (7) years and 43% progressed to probable Alzheimer's disease within 3 years. Important independent predictors of progression included being female, resisting help, becoming upset when separated from caregiver, difficulty shopping alone, forgetting appointments, number of words recalled from a 10-word list, orientation and difficulty drawing a clock. The final point score could range from 0 to 16 (mean [SD]: 4.2 [2.9]). The optimism-corrected Harrell's c-statistic was 0.71(95% CI: 0.68–0.75). Fourteen percent of subjects with low risk scores (0–2 points, n = 124) converted to probable Alzheimer's disease over 3 years, compared to 51% of those with moderate risk scores (3–8 points, n = 223) and 91% of those with high risk scores (9–16 points, n = 35).
Conclusions
An index using factors that can be obtained in most clinical settings can predict progression from amnestic mild cognitive impairment to probable Alzheimer's disease and may help clinicians differentiate between mild cognitive impairment patients at low vs. high risk of progression.
doi:10.1371/journal.pone.0113535
PMCID: PMC4259326  PMID: 25486250
23.  Changes in Physical Performance in Older Women by Diabetes Presence and Treatment 
Journal of the American Geriatrics Society  2013;61(11):10.1111/jgs.12502.
Objectives
To determine if older, diabetic women have a greater longitudinal decline in physical performance and if these changes differ by insulin sensitizer use.
Design
Prospective cohort study.
Setting
Baltimore, Minneapolis, Portland and the Monongahela valley in Pennsylvania, USA.
Participants
2864 community-dwelling women (mean age 78.5±3.6 years) enrolled in the Study of Osteoporotic Fractures in 1997–1998 and re-studied 4.9 ± 0.6 years later.
Measurements
Women were categorized as having no diabetes (n=2680) or having diabetes (n=184). The prescription medication inventory was used to determine use of insulin sensitizers (metformin/thiazolidinedione). The outcomes were longitudinal changes in physical performance measures, including grip strength, usual walk speed, and rapid walk speed.
Results
Estimates from fully adjusted models showed that diabetic women had greater declines in usual walk speed (−0.16 m/s [95%CI −0.19, −0.14]) and rapid walk speed (−0.21 m/s [95%CI −0.24, −0.17]) compared to non-diabetic women (usual: −0.11 m/s [95%CI −0.12, −0.11], rapid: −0.15 m/s [95% CI −0.16, −0.14]), p<0.01 for both comparisons. Diabetic women on insulin sensitizers had an attenuated decline in the loss of usual walk speed compared to those not on insulin sensitizers, p<0.05. Declines in grip strength did not differ significantly by diabetes status or insulin sensitizer use.
Conclusion
Older women with diabetes have a greater decline in walk speed, but not grip strength compared to older women without diabetes. Clinical studies in older adults to determine whether diabetes treatments like insulin sensitizers can prevent the loss in walk speed and mobility are needed.
doi:10.1111/jgs.12502
PMCID: PMC3827698  PMID: 24219188
elderly; diabetes; insulin sensitizer; physical performance; walk speed
24.  Subclinical Atherosclerotic Calcification and Cognitive Functioning in Middle-Aged Adults: The CARDIA Study 
Atherosclerosis  2013;231(1):10.1016/j.atherosclerosis.2013.08.038.
Objective
Cardiovascular risk factors in middle-age are associated with cognitive impairment and dementia in older age. Less is known about the burden of calcified subclinical atherosclerosis and cognition, especially in midlife. We examined the association of coronary artery and abdominal aortic calcified plaque (CAC and AAC, respectively) with cognitive functioning in middle-aged adults.
Methods
This cross-sectional study included 2,510 black and white adults (age: 43–55 years) without heart disease or stroke who completed a year 25 follow-up exam (2010–11) as part of the Coronary Artery Risk Development in Young Adults Study. CAC and AAC were measured with non-contrast computed tomography. Cognition was assessed with the Digit Symbol Substitution Test (DSST) (psychomotor speed), Stroop Test (executive function), and Rey Auditory Verbal Learning Test (RAVLT) (verbal memory).
Results
A greater amount of CAC and AAC was associated with worse performance on each test of cognitive function after adjustment for age, sex, race, education, and study center. Associations were attenuated, but remained significant for the DSST and RAVLT following additional adjustment for vascular risk factors, including adiposity, smoking, alcohol use, dyslipidemia, hypertension, and diabetes. Compared to participants without CAC or AAC, those with both CAC and AAC, but not CAC or AAC alone was associated with lower DSST scores (p<0.05).
Conclusions
In this community-based sample, greater subclinical atherosclerotic calcification was associated with worse psychomotor speed and memory in midlife. These findings underscore the importance of a life course approach to the study of cognitive impairment with aging.
doi:10.1016/j.atherosclerosis.2013.08.038
PMCID: PMC3828555  PMID: 24125414
atherosclerosis; heart disease; calcium score; cognition; subclinical disease; risk factors
25.  Change in Inflammatory Markers and Cognitive Status among Oldest Old Women from the Study of Osteoporotic Fractures 
OBJECTIVES
To determine the association between interleukin-6 (IL-6), IL-6 soluble receptor (sR) and tumor necrosis factor soluble receptor-1 (STNF-R1) and cognitive status among oldest old women.
DESIGN
20-year longitudinal cohort study.
SETTING
Four clinical sites in the United States.
PARTICIPANTS
905 women from the Study of Osteoporotic Fractures (mean age 88.3±2.8 years at cognitive status adjudication).
MEASUREMENTS
At Year 20, cognitive status was adjudicated as normal, mild cognitive impairment (MCI), or dementia. Inflammatory markers were measured from blood serum at Years 10 and 16 in a random sample of women.
RESULTS
Over 10 years, 199 (22.0%) developed MCI, and 145 (16.0%) dementia. There were no significant associations between IL-6 or STNF-R1 and cognitive status. High IL-6 sR (≥37401.36pg/ml, high tertile) at Year 16 was significantly associated with decreased risk for dementia (OR=0.54; 95% CI: 0.30, 0.97), compared to women with lower levels (<37401.36 pg/ml, lower two tertiles). Women with high IL-6 sR at both time points (OR=0.39; 95% CI: 0.17, 0.89) or who transitioned to a high level (OR=0.35; 95% CI: 0.14, 0.88) had reduced risk of dementia.
CONCLUSION
In this cohort of white, high functioning oldest old women, a consistently high or an increasing level of IL-6 sR is associated with reduced risk of dementia. Compared to other studies of younger old adults, this suggests the effect of inflammation on dementia may differ in younger old and oldest old. Understanding these differences will be crucial in interpreting results from ongoing clinical trials and in targeting therapeutic strategies to the oldest old.
doi:10.1111/jgs.12739
PMCID: PMC4109652  PMID: 24697580
Dementia; mild cognitive impairment; inflammation; oldest old

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