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1.  The Role of Peripheral Inflammatory Markers in Dementia and Alzheimer’s Disease: A Meta-Analysis 
Studies that have investigated the association between markers of inflammation and risk of dementia are conflicting. Therefore, the researchers conducted a systematic review and meta-analysis of observational studies with the hypothesis that an increased level of peripheral proinflammatory markers would be associated with risk of all-cause dementia or Alzheimer’s disease (AD).
The researchers conducted a literature search of observational studies indexed in the PubMed and PsycInfo databases. Selected studies included those with at least one peripheral inflammatory biomarker and its association with risk of all-cause dementia or AD. Random effects models were used to generate pooled hazard ratios (HRs) comparing the top versus bottom quantile of inflammatory marker level. Heterogeneity was assessed using the I 2 statistic.
Seven studies were identified, combining for a total 5,717 participants, 746 cases of all-cause dementia and 565 cases of AD. An increased level of C-reactive protein was associated with a 45% increased risk of all-cause dementia (HR: 1.45; 95% CI: 1.10, 1.91). Similarly, a higher level of interleukin-6 was associated with a 32% increased risk (HR: 1.32; 95% CI: 1.06, 1.64) of all-cause dementia. For AD alone, the association with C-reactive protein was less pronounced (HR: 1.21; 95% CI: 1.03, 1.42) and interleukin-6 was not associated with risk of AD (HR: 1.06; 95% CI: 0.83, 1.35). No significant heterogeneity was found in any of the meta-analyses (I 2 = 0%–40%, p ≥ .16).
An increased peripheral level of inflammatory markers is associated with a modest increase in risk of all-cause dementia. Evidence for an association with risk of AD alone is limited.
PMCID: PMC3693673  PMID: 22982688
Dementia; Alzheimer; Cognitive decline; Inflammation; c-reactive protein; Interleukin-6
2.  The Associations between Serum Brain-Derived Neurotrophic Factor, Potential Confounders, and Cognitive Decline: A Longitudinal Study 
PLoS ONE  2014;9(3):e91339.
Brain-derived neurotrophic factor (BDNF) plays a role in the maintenance and function of neurons. Although persons with Alzheimer’s disease have lower cortical levels of BDNF, evidence regarding the association between circulating BDNF and cognitive function is conflicting. We sought to determine the correlates of BDNF level and whether BDNF level was prospectively associated with cognitive decline in healthy older adults. We measured serum BDNF near baseline in 912 individuals. Cognitive status was assessed repeatedly with the modified Mini-Mental Status Examination and the Digit Symbol Substitution test over the next 10 years. We evaluated the association between BDNF and cognitive decline with longitudinal models. We also assessed the association between BDNF level and demographics, comorbidities and health behaviors. We found an association between serum BDNF and several characteristics that are also associated with dementia (race and depression), suggesting that future studies should control for these potential confounders. We did not find evidence of a longitudinal association between serum BDNF and subsequent cognitive test trajectories in older adults, although we did identify a potential trend toward a cross-sectional association. Our results suggest that serum BDNF may have limited utility as a biomarker of prospective cognitive decline.
PMCID: PMC3966768  PMID: 24670553
3.  Macro- and Microstructural Magnetic Resonance Imaging Indices Associated With Diabetes Among Community-Dwelling Older Adults 
Diabetes Care  2013;36(3):677-682.
To better understand the association between diabetes and cognitive impairment, we evaluated macro- and microstructural brain MRI measures for the total brain and regions of interest (ROIs) in a group of community-dwelling elders with and without diabetes.
MRI measures were obtained on 308 elders (mean age 83.3 years; n = 85 with diabetes) from the Health ABC Healthy Brain Substudy. We performed a series of linear regressions and used standardized β values to estimate the cross-sectional association between diabetes and macrostructural (gray matter volume [GMV] and white matter hyperintensities [WMHs]) and microstructural (mean diffusivity [MD] and fractional anisotropy [FA]) measures for the total brain and ROIs. Models were adjusted for age, race, and sex; GMV values for ROIs were also adjusted for total brain volume (TBV).
In multivariate-adjusted models, diabetes was associated with lower total GMV (P = 0.0006), GMV in the putamen (P = 0.02 for left and right), and TBV (P = 0.04) and greater cerebral atrophy (P = 0.02). There was no association with WMHs. On microstructural measures, diabetes was associated with reduced FA for total white matter (P = 0.006) and greater MD for the hippocampus (P = 0.006 left; P = 0.01 right), dorsolateral prefrontal cortex (P = 0.0007, left; P = 0.002, right), left posterior cingulate (P = 0.02), and right putamen (P = 0.02). Further adjustment for stroke, hypertension, and myocardial infarction produced similar results.
In this cross-sectional study, elders with diabetes compared with those without had greater brain atrophy and early signs of neurodegeneration. Further studies are needed to determine whether these structural changes associated with diabetes predict risk of cognitive decline.
PMCID: PMC3579347  PMID: 23160721
4.  Cardiovascular Health through Young Adulthood and Cognitive Functioning in Midlife 
Annals of neurology  2013;73(2):170-179.
To examine the association between overall cardiovascular health as recently defined by the American Heart Association in young adulthood to middle-age and cognitive function in midlife. Overall ideal cardiovascular health incorporates 7 metrics, including the avoidance of overweight or obesity, a healthful diet, nonsmoking, and physical activity, total cholesterol, blood pressure, and fasting glucose at goal levels.
This analysis of the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a multicenter community-based study with 25 years of follow-up, included 2,932 participants aged 18 to 30 years at baseline (Year 0) who attended follow-up exams at Years 7 and 25. Cardiovascular health metrics were measured at each examination. The Digit Symbol Substitution Test (DSST), modified Stroop Test, and Rey Auditory Verbal Learning Test (RAVLT) were completed at Year 25.
A greater number of ideal cardiovascular metrics in young adulthood and middle-age was independently associated with better cognitive function in midlife (p-trend<0.01, for all). Specifically, each additional ideal metric was associated with 1.32 more symbols on the DSST (95% CI: 0.93 to 1.71), a 0.77-point lower interference score on the Stroop Test (−1.03 to −0.45), and 0.12 more words on the RAVLT (0.04 to 0.20). Participants who had ≥5 ideal metrics at a greater number of the 3 examinations over the 25-year period exhibited better performance on each cognitive test in middle-age (p-trend<0.01, for all).
Ideal cardiovascular health in young adulthood and its maintenance to middle-age is associated with better psychomotor speed, executive function, and verbal memory in midlife.
PMCID: PMC3608821  PMID: 23443990
5.  Normative Data in Women Age 85 and Older: Verbal Fluency, Digit Span, and the CVLT-II Short Form 
The Clinical neuropsychologist  2012;26(1):18-30.
Individuals age 85 years and above (i.e., the oldest old) represent the fastest growing segment of the U.S. population and are at increased risk of developing dementia. This represents an important challenge for the clinical neuropsychologist, as the extant normative data on neuropsychological measures remains relatively limited for this age group. Therefore, the aim of the present study was to characterize the performance effects of age and education in a large, well-characterized sample of women between the ages of 85 and 95 years on the CVLT-II Short Form (Delis et al., 2000), verbal fluency tasks, and the WAIS-III Digit Span Test (Wechsler, 1997). In order to minimize the likelihood that women with an incipient neurodegenerative process were included in the final normative sample, we applied regression-based change scores to identify and exclude women who evidenced a statistically significant decline on a global cognitive screening measure over a 20 year interval. The results of our analysis indicate varying influence of age and education on these measures and we provide tables with descriptive statistics stratified by both age and education. Findings from the present normative study are discussed within the context of “robust” longitudinal normative data.
PMCID: PMC3927723  PMID: 22224509
oldest old; normative data; CVLT
Archives of internal medicine  2011;171(14):1251-1257.
Studies suggest that physically active people have reduced risk of incident cognitive impairment in late life. However, these studies are limited by reliance on subjective self-reports of physical activity, which only moderately correlate to objective measures and often exclude activity not readily quantifiable by frequency and duration. The objective of this study was to investigate the relationship between activity energy expenditure (AEE), an objective measure of total activity, and incidence of cognitive impairment.
We calculated AEE as 90% of total energy expenditure (assessed over two weeks using doubly-labeled water) minus resting metabolic rate (measured using indirect calorimetry) in 197 men and women (mean 74.8 years) who were free of mobility and cognitive impairments at study baseline (1998–2000). Cognitive function was assessed at baseline and 2 or 5 years later using the Modified Mini-Mental State Examination (3MS). Cognitive impairment was defined as a decline of >1.0 SD (9 points) between baseline and follow-up.
After adjustment for baseline 3MS, demographics, fat free mass, sleep duration, self-reported health, and diabetes, older adults in the highest sex-specific tertile of AEE had lower odds of incident cognitive impairment than those in the lowest tertile (OR, 95% CI 0.09, 0.01–0.79). There was also a significant dose response between AEE and incidence of cognitive impairment (p-for-trend over tertiles=0.05).
These findings indicate that greater activity energy expenditure may be protective against cognitive impairment in a dose-response manner. The significance of overall activity in contrast to vigorous or light activity should be determined.
PMCID: PMC3923462  PMID: 21771893
7.  Serum Oxidized LDL Level and Risk of Cognitive Impairment in Older Women 
Neurobiology of aging  2012;34(2):634-635.e2.
We investigated the association between serum level of oxidized low-density lipoprotein (oxLDL) and risk of cognitive impairment (dementia or mild cognitive impairment) among 572 non-demented community-dwelling women from a prospective cohort study of aging. After 5 years of follow-up, 228 (39.9%) developed cognitive impairment; and this did not differ by tertile of baseline oxLDL level (highest compared to lowest tertile 38.2% vs 39.5% OR=0.90; 95% CI: 0.63,1.43). Multivariate adjustment produced similar results (OR: 0.91; 95% CI: 0.60,1.39). These findings suggest that increased levels of serum oxLDL are not associated with a greater risk of incident cognitive impairment in older women.
PMCID: PMC3393809  PMID: 22483339
dementia; Alzheimer’s disease; oxidized LDL; inflammation; oxidative stress
8.  Pulse wave velocity and cognitive decline in elders: The Health, Aging and Body Composition study 
Background and Purpose
Arterial stiffness is a measure of subclinical cardiovascular disease (CVD) and increases with age. This study examines the association between arterial stiffness and cognitive decline in a cohort of older adults.
2,488 subjects with baseline measure of arterial stiffness (mean age, 74.2 years; 52.3% women) were prospectively followed over 9 years in the Health, Aging and Body Composition study. Arterial stiffness was measured as pulse wave velocity (PWV) and analyzed in tertiles. Cognitive function was assessed using the Modified Mini-Mental State Exam (3MS) at baseline and repeated at years 3, 5, 8 and 10. Lower 3MS scores indicate worse function. We fit linear mixed models to examine longitudinal changes in cognitive function over the 9 years of follow-up and logistic regression models, restricted to 1,331 participants, to examine cognitive impairment defined as a decrease of ≥5 points after 9 years. We adjusted for socio-demographics, Apoe4 and CVD risk factors.
The annual decrease in 3MS scores was 0.30 points at low PWV (95%CI=−0.37;-0.22), 0.46 points at middle PWV (95%CI=−0.54;-0.39) and 0.45 points at high PWV (95%CI=−0.53;-0.38), from fully-adjusted linear mixed models. In fully-adjusted models, the odds of cognitive impairment after 9 years of follow-up was 40% greater for subjects with middle PWV (OR=1.40; 95% CI=1.03; 1.92) and 59% greater for subjects with high PWV (OR=1.59; 95% CI=1.16; 2.18), compared to low PWV.
High arterial stiffness was modestly associated with cognitive decline and impairment. Interventions to prevent arterial stiffness may be effective in delaying cognitive decline.
PMCID: PMC3572783  PMID: 23321445
9.  Adverse Oral Health and Cognitive Decline: The Health, Aging and Body Composition Study 
Periodontal disease has been associated with poorer cross-sectional cognitive function and is correlated with adverse vascular outcomes, but has received little prospective investigation in relation to cognitive decline.
Analysis of a prospective cohort study.
The Health, Aging and Body Composition (Health ABC) Study
Participants and measurements
We examined the prospective association between a range of oral health parameters and cognitive function using data on 1053 participants who were administered the Modified Mini-Mental State Examination (3MS) at year 1 (baseline) and year 3, and had participated in a comprehensive periodontal examination at year 2. We investigated 3MS decline from year 3 to 5 in 947 (89.9%) participants. Covariates included age, sex, education, race, cardiovascular disease/risk and depressive symptoms.
Most indicators of adverse oral health at year 2 were associated with cognitive impairment based on averaged 3MS scores <80 for years 1 and 3, but these associations were substantially confounded by education and race. Higher gingival index, a measure of gingival inflammation, at year 2 remained independently associated with this definition of cognitive impairment and, in fully adjusted analyses, was also an independent predictor of a 5+ point cognitive decline from years 3 to 5.
Periodontitis may be a risk factor for cognitive decline. Gingivitis is reversible and periodontitis to some degree is preventable and controllable when manifest. Therefore, further research is needed to clarify potential underlying mechanisms and oral health interventions that potentially might ameliorate cognitive decline.
PMCID: PMC3578234  PMID: 23405916
cognitive decline; cognitive impairment; periodontitis; periodontal diseases; gingivitis
10.  Leptin, Mild Cognitive Impairment, and Dementia Among Elderly Women 
The association between obesity and dementia has been inconsistent, possibly due to changes in body composition often seen in old age. Leptin may be associated with better cognitive function. However, neuroprotection may be inhibited among obese subjects possibly due to leptin resistance. We sought to determine (i) if leptin is associated with risk of dementia or mild cognitive impairment (MCI) in a cohort of very old women, (ii) if this association is modified by obesity, and (iii) if leptin is a stronger risk factor compared with traditional anthropometric measures.
We studied 579 older women (mean age 82.6 years) from the ongoing prospective cohort Study of Osteoporotic Fractures, who were dementia-free at year-16 examination (our study baseline). Leptin (ng/mL) was measured using year-16 frozen serum, and anthropometric measures were collected during the same visit. Diagnosis of dementia/MCI was determined at year-20 examination.
There was evidence for a multiplicative interaction between log leptin and categorical body mass index (p = .03). Among women with body mass index <25kg/m2 (n = 190), 1SD difference in log leptin (0.91ng/mL) was associated with 32% lower odds of dementia/MCI (OR = .68; 95% CI = .46, .99), after adjustment. The association was not significant among women with body mass index ≥25kg/m2 (n = 377). Traditional anthropometric measures such as weight, height, and body mass index were not associated with dementia/MCI.
In this cohort of very old women, higher serum leptin was prospectively associated with lower odds of dementia/MCI in women with normal body mass index, but not in overweight or obese women. Leptin may be a better predictor of dementia/MCI than traditional anthropometric measures.
PMCID: PMC3598359  PMID: 22859388
Dementia; Elderly; Leptin; Obesity
11.  Ten-Year Trajectory of Potentially Inappropriate Medications in Very Old Women: Importance of Cognitive Status 
Background/ Objectives
Older populations are particularly susceptible to adverse effects from potentially inappropriate medications (PIMs), which can be associated with cognitive impairment. Additionally, many older adults have existing cognitive impairment which can be exacerbated by PIMs. It is not clear which older adults tend to receive PIMs, how this may differ by cognitive status, or how the trajectories of PIM use change over time.
Longitudinal cohort study
Three clinical sites in the United States.
We followed 1,484 community-dwelling women ≥ 75 years of age over 10 years.
At follow-up, we ascertained cognitive status, which was classified as normal, mild cognitive impairment (MCI) or dementia. Beers 2003 criteria and other literature were used to identify PIMs from detailed medication inventory performed at three time points. We also measured anticholinergic load using the Anticholinergic Cognitive Burden scale (ACB), which assigns medications a value from 0 to 3 depending on anticholinergic properties.
At baseline, 23.9% of women were taking at least one PIM and the mean(± SD) ACB score was 1.41(± 1.69). The most frequently reported PIMs were anticholinergics (15.2%), benzodiazepines (8.6%), and antispasmodics (8.0%). Over 10 years, PIM use increased for women with dementia (24.9% to 33.1%; p=0.02), yet remained fairly constant for women with MCI (23.9% to 23.0%; p=0.84) and normal cognitive status (22.2% to 19.8%; p=0.17). Mean ACB score significantly increased (p<0.001) over time for all groups (dementia: 1.28 to 2.05; MCI: 0.98 to 1.66; normal: 0.99 to 1.48).
PIM use and anticholinergic load in a community-dwelling population of older women is high, especially among women who later develop dementia. Future guidelines should limit PIM use and seek safer alternatives.
PMCID: PMC3795413  PMID: 23320787
cognitive function; dementia; potentially inappropriate medication; anticholinergic
12.  Influence of Type 2 Diabetes on Brain Volumes and Changes in Brain Volumes 
Diabetes Care  2012;36(1):90-97.
To study how type 2 diabetes adversely affects brain volumes, changes in volume, and cognitive function.
Regional brain volumes and ischemic lesion volumes in 1,366 women, aged 72–89 years, were measured with structural brain magnetic resonance imaging (MRI). Repeat scans were collected an average of 4.7 years later in 698 women. Cross-sectional differences and changes with time between women with and without diabetes were compared. Relationships that cognitive function test scores had with these measures and diabetes were examined.
The 145 women with diabetes (10.6%) at the first MRI had smaller total brain volumes (0.6% less; P = 0.05) and smaller gray matter volumes (1.5% less; P = 0.01) but not white matter volumes, both overall and within major lobes. They also had larger ischemic lesion volumes (21.8% greater; P = 0.02), both overall and in gray matter (27.5% greater; P = 0.06), in white matter (18.8% greater; P = 0.02), and across major lobes. Overall, women with diabetes had slightly (nonsignificant) greater loss of total brain volumes (3.02 cc; P = 0.11) and significant increases in total ischemic lesion volumes (9.7% more; P = 0.05) with time relative to those without diabetes. Diabetes was associated with lower scores in global cognitive function and its subdomains. These relative deficits were only partially accounted for by brain volumes and risk factors for cognitive deficits.
Diabetes is associated with smaller brain volumes in gray but not white matter and increasing ischemic lesion volumes throughout the brain. These markers are associated with but do not fully account for diabetes-related deficits in cognitive function.
PMCID: PMC3526228  PMID: 22933440
13.  Plasma Beta Amyloid Level and Depression in Older Adults 
Older adults with depression have an increased risk of developing dementia. Low plasma beta-amyloid 42 (Aβ42) and Aβ42/Aβ40 have emerged as promising biomarkers of dementia. The association between depression and plasma Aβ is unclear.
In this longitudinal study of 988 community-dwelling elders from the Health Aging and Body Composition study, depression was assessed with the Center for Epidemiologic Studies-Depression Scale 10-item version. We determined the association between Aβ42 and Aβ42/Aβ40 tertile and depression at baseline and over 9 years. We also stratified the models to determine if apolipoprotein E e4 allele status modified the associations.
Mean baseline age was 74.0 ± 3.0 years, 51 (5.2%) participants had depression, 545 (55.2%) were women, 531 (53.7%) were black, and 286 (30.7%) had one or more apolipoprotein E e4 allele. At baseline, there was no association between Aβ42/Aβ40 or Aβ42 and depression. Over 9 years, 220 (23.5%) participants developed depression. In adjusted Cox proportional hazards models, among those with one or more e4 allele, low Aβ42/Aβ40 was associated with an increased risk of developing depression over time (low 10.8% vs high 3.2%, hazard ratio = 2.38, 95% confidence interval: 1.15–4.92). Among those with no e4 allele, there was no association between Aβ42/Aβ40 and risk of depression over time (13.3% vs 17.5%, hazard ratio = 0.80, 95% confidence interval: 0.52–1.23; p value for interaction = .003).
The association between low plasma Aβ42/Aβ40 and increased risk of incident depression among those with one or more apolipoprotein E e4 allele implies a synergistic relationship similar to that found with dementia. Future work should investigate the interrelationships among plasma Aβ42/Aβ40, depression, and dementia.
PMCID: PMC3598362  PMID: 22499763
Depression; Epidemiology; Plasma beta amyloid
14.  Dementia in the oldest old: a multi-factorial and growing public health issue 
The population of oldest old, or people aged 85 and older, is growing rapidly. A better understanding of dementia in this population is thus of increasing national and global importance. In this review, we describe the major epidemiological studies, prevalence, clinical presentation, neuropathological and imaging features, risk factors, and treatment of dementia in the oldest old. Prevalence estimates for dementia among those aged 85+ ranges from 18 to 38%. The most common clinical syndromes are Alzheimer's dementia, vascular dementia, and mixed dementia from multiple etiologies. The rate of progression appears to be slower than in the younger old. Single neuropathological entities such as Alzheimer's dementia and Lewy body pathology appear to have declining relevance to cognitive decline, while mixed pathology with Alzheimer's disease, vascular disease (especially cortical microinfarcts), and hippocampal sclerosis appear to have increasing relevance. Neuroimaging data are sparse. Risk factors for dementia in the oldest old include a low level of education, poor mid-life general health, low level of physical activity, depression, and delirium, whereas apolipoprotein E genotype, late-life hypertension, hyperlipidemia, and elevated peripheral inflammatory markers appear to have less relevance. Treatment approaches require further study, but the oldest old may be more prone to negative side effects compared with younger patients and targeted therapies may be less efficacious since single pathologies are less frequent. We also highlight the limitations and challenges of research in this area, including the difficulty of defining functional decline, a necessary component for a dementia diagnosis, the lack of normative neuropsychological data, and other shortcomings inherent in existing diagnostic criteria. In summary, our understanding of dementia in the oldest old has advanced dramatically in recent years, but more research is needed, particularly among varied racial, ethnic, and socioeconomic groups, and with respect to biomarkers such as neuroimaging, modifiable risk factors, and therapy.
PMCID: PMC3706944  PMID: 23809176
15.  A variant of sparse partial least squares for variable selection and data exploration 
When data are sparse and/or predictors multicollinear, current implementation of sparse partial least squares (SPLS) does not give estimates for non-selected predictors nor provide a measure of inference. In response, an approach termed “all-possible” SPLS is proposed, which fits a SPLS model for all tuning parameter values across a set grid. Noted is the percentage of time a given predictor is chosen, as well as the average non-zero parameter estimate. Using a “large” number of multicollinear predictors, simulation confirmed variables not associated with the outcome were least likely to be chosen as sparsity increased across the grid of tuning parameters, while the opposite was true for those strongly associated. Lastly, variables with a weak association were chosen more often than those with no association, but less often than those with a strong relationship to the outcome. Similarly, predictors most strongly related to the outcome had the largest average parameter estimate magnitude, followed by those with a weak relationship, followed by those with no relationship. Across two independent studies regarding the relationship between volumetric MRI measures and a cognitive test score, this method confirmed a priori hypotheses about which brain regions would be selected most often and have the largest average parameter estimates. In conclusion, the percentage of time a predictor is chosen is a useful measure for ordering the strength of the relationship between the independent and dependent variables, serving as a form of inference. The average parameter estimates give further insight regarding the direction and strength of association. As a result, all-possible SPLS gives more information than the dichotomous output of traditional SPLS, making it useful when undertaking data exploration and hypothesis generation for a large number of potential predictors.
PMCID: PMC3939647  PMID: 24624079
high-dimensional; multicollinearity; over-fitting; SPLS; inference; tuning parameters; network; MRI
16.  Hearing Loss and Cognitive Decline Among Older Adults 
JAMA internal medicine  2013;173(4):10.1001/jamainternmed.2013.1868.
Whether hearing loss is independently associated with accelerated cognitive decline in older adults is unknown.
We studied 1984 older adults (mean age 77.4 years) enrolled in the HealthABC study, a prospective observational study begun in 1997–98. Our baseline cohort consisted of participants without prevalent cognitive impairment (Modified Mini-Mental State [3MS] scores ≥ 80) who underwent audiometric testing in Year 5. Participants were followed for 6 years. Hearing was defined at baseline using a pure-tone average (PTA) of thresholds at 0.5 – 4 kHz in the better-hearing ear. Cognitive testing was performed in Years 5, 8, 10, and 11 and consisted of the 3MS (measuring global function) and the Digit Symbol Substitution test (DSS, measuring executive function). Incident cognitive impairment was defined as a 3MS score < 80 or a decline in 3MS > 5 points from baseline. Mixed-effects regression and Cox models were adjusted for demographic and cardiovascular risk factors.
Individuals with baseline hearing loss (PTA > 25 dB, n = 1162) had rates of decline in 3MS and DSS scores that were 41% and 32% greater, respectively, than those in normal hearing individuals (3MS: −0.65 points/year [95% CI: −0.73 – −0.56] vs. −0.46 points/year [95% CI: −0.55 – −0.36], p=.004; DSS: −0.83 points/year [95% CI: −0.94 – −0.73] vs. −0.63 points/year [95% CI: −0.75 – −0.51], p=.015). Compared to those with normal hearing, individuals with hearing loss had a 24% (Hazard ratio: 1.24 [95% CI: 1.05 – 1.48]) increased risk of incident cognitive impairment. Rates of cognitive decline and the risk of incident cognitive impairment were linearly associated with the severity of an individual’s baseline hearing loss.
Hearing loss is independently associated with accelerated cognitive decline and incident cognitive impairment in community-dwelling older adults. Further studies investigating the mechanistic basis of this association and whether hearing rehabilitative interventions could affect cognitive decline are needed.
PMCID: PMC3869227  PMID: 23337978
17.  Depressive Symptoms in Oldest-Old Women: Risk of Mild Cognitive Impairment and Dementia 
Increasing evidence suggests that depression is a risk factor for cognitive impairment, but it is unclear if this is true among the oldest old. We determined whether elevated depressive symptoms predicted five-year incident mild cognitive impairment (MCI) or dementia, and neuropsychological test performance among oldest-old women.
Three study sites
302 women ≥85 years (mean, 87 ±2)
Depressive symptoms were measured with the 15-item Geriatric Depression Scale (GDS); scores ≥6 indicated elevated symptoms. Five years later, participants completed neuropsychological testing and clinical cognitive status was adjudicated.
In analyses of MCI vs. normal cognition, 70% of women with GDS ≥6 at baseline developed MCI vs. 37% with GDS <6. After adjustment for age, education, alcohol and benzodiazepine use, and study site, GDS ≥6 remained independently associated with much greater likelihood of developing MCI (multivariable odds ratio (MOR) = 3.71, 95% confidence interval (CI) 1.30, 10.59). In analyses of dementia vs. normal cognition, 65% of women with GDS ≥6 developed dementia compared to 37% of those with GDS <6 (MOR = 3.15, 95% CI 1.03, 9.65). Only 19% of women with GDS ≥6 had normal cognitive status five years later, compared to 46% of those with GDS <6 (MOR = 0.28, 95% CI 0.11, 0.73). Women with elevated depressive symptoms had worse scores on tests of global cognition and working memory.
Elevated depressive symptoms are an important risk factor for cognitive disorders and lower cognitive performance among women living to their ninth and tenth decades.
PMCID: PMC3326212  PMID: 22015706
oldest-old; women; depression; mild cognitive impairment; dementia
18.  Body Mass and White Matter Integrity: The Influence of Vascular and Inflammatory Markers 
PLoS ONE  2013;8(10):e77741.
High adiposity is deleteriously associated with brain health, and may disproportionately affect white matter integrity; however, limited information exists regarding the mechanisms underlying the association between body mass (BMI) and white matter integrity. The present study evaluated whether vascular and inflammatory markers influence the relationship between BMI and white matter in healthy aging. We conducted a cross-sectional evaluation of white matter integrity, BMI, and vascular/inflammatory factors in a cohort of 138 healthy older adults (mean age: 71.3 years). Participants underwent diffusion tensor imaging, provided blood samples, and participated in a health evaluation. Vascular risk factors and vascular/inflammatory blood markers were assessed. The primary outcome measure was fractional anisotropy (FA) of the genu, body, and splenium (corpus callosum); exploratory measures included additional white matter regions, based on significant associations with BMI. Regression analyses indicated that higher BMI was associated with lower FA in the corpus callosum, cingulate, and fornix (p<.001). Vascular and inflammatory factors influenced the association between BMI and FA. Specifically, BMI was independently associated with the genu [β=-.21; B=-.0024; 95% CI, -.0048 to -.0000; p=.05] and cingulate fibers [β=-.39; B=-.0035; 95% CI,-.0056 to -.0015; p<.001], even after controlling for vascular/inflammatory risk factors and blood markers. In contrast, BMI was no longer significantly associated with the fornix and middle/posterior regions of the corpus callosum after controlling for these markers. Results partially support a vascular/inflammatory hypothesis, but also suggest a more complex relationship between BMI and white matter characterized by potentially different neuroanatomic vulnerability.
PMCID: PMC3797689  PMID: 24147070
19.  Association Between Serum 25(OH) Vitamin D and the Risk of Cognitive Decline in Older Women 
Results of prospective studies examining the association between 25 hydroxyvitamin D (25[OH]D) levels and cognitive decline have been inconsistent. We tested the hypothesis that lower 25(OH)D levels are associated with a greater likelihood of cognitive impairment and risk of cognitive decline.
The study is a cross-sectional and longitudinal analysis of a prospective cohort of 6,257 community-dwelling elderly women followed for 4 years. Global cognitive function was measured by the Modified Mini-Mental State Examination and executive function was measured by Trail Making Test Part B (Trails B). Cognitive impairment at baseline was defined as a score >1.5 SD below the sample mean; cognitive decline was defined as decline from baseline to follow-up >1 SD from mean change in score.
Women with very low vitamin D levels had an increased odds of global cognitive impairment at baseline: odds ratio (95% confidence interval), 1.60 (1.05–2.42) for women with 25(OH)D <10 ng/mL (25 nmol/L) compared with those with 25(OH)D levels ≥30 ng/mL (75 nmol/L). Compared with women with baseline 25(OH)D level ≥30 ng/mL (75 nmol/L), women with lower levels had an increased risk of global cognitive decline: odds ratio (95% confidence interval), 1.58(1.12–2.22) for women with levels <10 ng/mL (25 nmol/L), and 1.31 (1.04–1.64) for those with levels 10–19.9 ng/mL (25–49 nmol/L). Levels of 25(OH)D were not associated with executive cognitive function.
Low 25(OH)D levels among older women were associated with a higher odds of global cognitive impairment and a higher risk of global cognitive decline.
PMCID: PMC3437964  PMID: 22454371
Vitamin D; Cognitive decline; Executive function; Cohort studies; Risk factors in epidemiology
20.  20-Year Depressive Trajectories among Older Women 
Archives of general psychiatry  2012;69(10):1073-1079.
Despite the high occurrence of depressive symptoms in older adults, especially women, little is known about the long-term course of late-life depressive symptoms.
To characterize the natural course of depressive symptoms among elderly women followed for nearly 20 years, going from young old to oldest old.
Using a latent class growth-curve analysis, we analyzed women enrolled in an ongoing prospective cohort study (1988–2009).
Clinic sites in Baltimore, MD, Minneapolis, MN, the Monongahela Valley near Pittsburgh, PA, and Portland, OR.
We studied 7240 community-dwelling women age 65 years or older.
Main Outcome Measure
The Geriatric Depression Scale (GDS) short form (range: 0–15) was used to assess depressive symptoms repeatedly over follow-up.
We identified four latent classes over 20 years, comprising an expected 28% of women with minimal depressive symptoms, 54% with persistently low symptoms, 15% with increasing symptoms, and 3% with persistently high symptoms. In an adjusted model for latent class membership, odds ratios (ORs) for belonging in the increasing and persistently high depressive symptom classes, respectively, compared with minimal symptom group were substantially and significantly (P < .05) elevated for baseline smoking (ORs, 4.69 and 7.97), physical inactivity (ORs, 2.11 and 2.78), small social network (ORs, 3.24 and 6.75), physical impairment (ORs, 8.11 and 16.43), myocardial infarction (ORs, 2.09 and 2.41), diabetes (ORs, 2.98 and 3.03), and obesity (ORs, 1.86 and 2.90).
Over 20 years, approximately 20% of older women experienced persistently high or increasing depressive symptoms. In addition, these women had more comorbidities, physical impairment, and negative lifestyle factors at baseline. These associations support the need for intervention and prevention strategies to reduce depressive symptoms into oldest-old years.
PMCID: PMC3646479  PMID: 23026957
21.  Patterns of Focal Gray Matter Atrophy Are Associated With Bradykinesia and Gait Disturbances in Older Adults 
Identify the neuroimaging correlates of parkinsonian signs in older adults living in the community.
Magnetic resonance imaging was obtained in 307 adults (82.9 years, 55% women, 39% blacks) concurrently with the Unified Parkinson Disease Rating scale—motor part. Magnetic resonance imaging measures included volume of whole-brain white matter hyperintensities and of gray matter for primary sensorimotor, supplementary motor, medial temporal areas, cerebellum, prefronto-parietal cortex, and basal ganglia.
About 25% of the participants had bradykinesia, 26% had gait disturbances, and 12% had tremor. Compared with those without, adults with any one of these signs were older, walked more slowly, had worse scores on tests of cognition, mood and processing speed, and higher white matter hyperintensities volume (all p ≤ .002). Gray matter volume of primary sensorimotor area was associated with bradykinesia (standardized odds ratio [95% confidence interval]: 0.46 [0.31, 0.68], p < .0001), and gray matter volume of medial temporal area was associated with gait disturbances (0.56 [0.42, 0.83], p < .0001), independent of white matter hyperintensities volume and age. Further adjustment for measures of muscle strength, cardiovascular health factors, cognition, processing speed, and mood or for gait speed did not substantially change these results.
Atrophy within primary sensorimotor and medial temporal areas might be important for development of bradykinesia and of gait disturbances in community-dwelling elderly adults. The pathways underlying these associations may not include changes in white matter hyperintensities volume, cognition, information processing speed, mood, or gait speed.
PMCID: PMC3436092  PMID: 22367436
Bradykinesia; Gait disturbances; Brain MRI
22.  Diabetes, glucose control and 9 year cognitive decline among non-demented older adults 
Archives of neurology  2012;69(9):1170-1175.
While several studies report an association between prevalent diabetes mellitus (DM) and cognitive impairment, less is known about incident DM in late life and cognitive decline. Glycemic control among elders with DM may also be associated with cognitive function, but findings are inconsistent.
To determine if prevalent and incident DM increases risk of cognitive decline, and if, among elders with DM, poor glucose control is related to worse cognitive performance.
Prospective cohort study.
Health Aging and Body Composition Study at two community clinics.
A total of 3,069 elders (mean age 74.2 years; 42% black; 52% female).
Main Outcome Measures
Participants completed the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and selected intervals over 10 years. DM status was determined at baseline and during follow-up visits. Glycosylated hemoglobin A1c (HbA1c) was measured at year 1 (baseline), 4, 6, and 10 from fasting whole blood.
At baseline 717 (23.4%) participants had prevalent DM and 2352 (76.6%) were without diabetes, 159 of whom developed incident DM during follow-up. Participants with prevalent DM had lower baseline test scores than participants without DM (3MS: 88.8 vs. 90.9; DSST: 32.5 vs 36.3, respectively; |t|=6.09, p=0.001 for both tests). Results from mixed-effects models showed a similar pattern for 9-year decline (3MS: −6.0 vs. −4.5 point decline; |t|=2.66, p=0.008; DSST: −7.9 vs. −5.7, point decline; |t|=3.69, p=0.001, respectively). Participants with incident DM tended to have baseline and 9-year decline scores between the other two groups but were not statistically different from the group without diabetes. Multivariate adjustment for demographics and medical co-morbidities produced similar results. Among participants with prevalent DM, HbA1c level was associated with lower average mean cognitive scores (3MS p for overall=0.003; DSST p for overall=0.04), even after multivariate adjustment.
Among well-functioning older adults, DM and poor glucose control among those with DM are associated with worse cognitive function and greater decline. This suggests severity of DM may contribute to accelerated cognitive aging.
PMCID: PMC3752423  PMID: 22710333
23.  Dysthymia and Depression Increase Risk of Dementia and Mortality among Older Veterans 
To determine if less severe depression spectrum diagnoses such as dysthymia, as well as depression, are associated with risk of developing dementia and mortality in a “real world” setting.
Retrospective cohort study conducted using the Department of Veterans Affairs (VA) National Patient Care Database (1997-2007).
VA medical centers in the United States.
A total of 281,540 veterans 55 years and older without dementia at study baseline (1997-2000).
Depression status and incident dementia were ascertained from ICD-9 codes during study baseline (1997-2000) and follow-up (2001-2007), respectively. Mortality was ascertained by time of death dates in the VA Vital Status File.
Ten percent of veterans had baseline diagnosis of depression and nearly 1% had dysthymia. The unadjusted incidence of dementia was 11.2% in veterans with depression, 10.2% with dysthymia and 6.4% with neither. After adjusting for demographics and comorbidities, patients diagnosed with dysthymia or depression were twice as likely to develop incident dementia compared to those with no dysthymia/depression (adjusted dysthymia hazard ratio [HR]: 1.96, 95% confidence interval [CI]: 1.71-2.25; and depression HR: 2.18, 95% CI: 2.08-2.28). Dysthymia and depression also were associated with increased risk of death (31.6% dysthymia and 32.9% depression vs 28.5% neither; adjusted dysthymia HR: 1.41, 95% CI: 1.31-1.53; and depression HR: 1.47, 95% CI: 1.43-1.51).
Findings suggest that older adults with dysthymia or depression need to be monitored closely for adverse outcomes. Future studies should determine whether treatment of depression spectrum disorders may reduce risk of these outcomes.
PMCID: PMC3229643  PMID: 21597358
Dysthymia; Depression; Dementia; Mortality
24.  Neuroimaging differences between older adults with maintained versus declining cognition over a 10-year period 
NeuroImage  2012;62(1):307-313.
Maintaining cognitive function protects older adults from developing functional decline. This study aims to identify the neuroimaging correlates of maintenance of higher global cognition as measured by the Modified Mini Mental State Test (3MS) score.
Repeated 3MS measures from 1997–98 through 2006–07 and magnetic resonance imaging with diffusion tensor in 2006–07 were obtained in a biracial cohort of 258 adults free from dementia (mean age 82.9 years, 56% women, 42% blacks). Participants were classified as having shown either maintenance (3MS slope>0) or decline (3MS slopeb1 SD below the mean) of cognition using linear mixed models. Measures of interest were white matter hyperintensity volume (WMHv) from total brain, volume of the gray matter (GMv) and microstructure (mean diffusivity, MD) for total brain and for brain areas known to be related to memory and executive control function: medial temporal area (hippocampus, parahippocampus and entorhinal cortex), cingulate cortex, dorsolateral prefrontal and posterior parietal cortex.
Differences between cognitive maintainers (n=153) and non-maintainers (n=107) were significant for GMv of the medial temporal area (35.8%, p=0.004) and lower MD of the cingulate cortex (37.9%, p=0.008), but not for other neuroimaging markers. In multivariable regression models adjusted for age, race, WMHv and GMV from the total brain and vascular conditions, each standard deviation of GMv of the medial temporal area and each standard deviation of MD of the cingulate cortex were associated with a nearly 4 times greater probability (odds ratio [standard deviation]: 3.80 [1.16, 12.44]) and a 34% lower probability (0.66, [0.46, 0.97]) of maintaining cognitive function, respectively. In these models neither WMHv nor GMv from total brain were significantly associated with probability of maintaining cognitive function.
Preserving the volume of the medial temporal area and the microstructure of the cingulate cortex may contribute to maintaining cognitive function late in life.
PMCID: PMC3690545  PMID: 22542701
25.  Low Use of Mental Health Services among Older Americans with Mood and Anxiety Disorders 
It is unclear why late-life mood and anxiety disorders are highly undertreated, despite being common in older adults. Thus, this study determined the prevalence and key factors associated with non-use of mental health services among older community-dwelling adults with mood and anxiety disorders.
The study examined 348 participants aged 55 years and older who met criteria for prevalent DSM-IV mood and anxiety disorders from the National Comorbidity Survey Replication (NCS-R), a population-based probability sample. Analyses included frequency measures and logistic regression using weights and complex design-corrected statistical tests. Key factors associated with not using mental health services were determined in a final multivariable model using a systematic approach accounting for a comprehensive list of potential predictors.
Approximately 70% of older adults with prevalent mood and anxiety disorders did not use services. Those who were from minority race/ethnic groups, not comfortable with discussing personal problems, who were married or cohabitating, and middle versus high income status had increased odds of not using mental health services. In addition, respondents with mild versus serious disorders, no chronic pain complaints, and low versus high perceived cognitive impairment had greater odds of non-use.
The results support improving perception of need and comfort to seek help, as well as increased screening and other prevention efforts, in order to combat the very high number of mood and anxiety disorders that go untreated in older Americans.
PMCID: PMC3726310  PMID: 22227762

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