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1.  Preventing Loss of Independence through Exercise (PLIÉ): A Pilot Clinical Trial in Older Adults with Dementia 
PLoS ONE  2015;10(2):e0113367.
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.
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.
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.
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 NCT01371214
PMCID: PMC4324943  PMID: 25671576
2.  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.
PMCID: PMC4313561  PMID: 25351110
Aging; Arterial stiffness; Cognitive decline; Dementia; Epidemiology
3.  Depressive symptoms in Chinese Americans with Cognitive Impairment 
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.
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.
Academic subspecialty referral clinic.
Participants included a total of 137 elderly, cognitively impaired and cognitively normal Chinese Americans and 140 Caucasians with and without cognitive impairment.
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).
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.
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.
PMCID: PMC4309267  PMID: 24021225
geriatric depression; dementia; Chinese American
4.  A Clinical Index to Predict Progression from Mild Cognitive Impairment to Dementia Due to Alzheimer's Disease 
PLoS ONE  2014;9(12):e113535.
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.
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).
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.
PMCID: PMC4259326  PMID: 25486250
5.  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.
To determine if older, diabetic women have a greater longitudinal decline in physical performance and if these changes differ by insulin sensitizer use.
Prospective cohort study.
Baltimore, Minneapolis, Portland and the Monongahela valley in Pennsylvania, USA.
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.
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.
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.
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.
PMCID: PMC3827698  PMID: 24219188
elderly; diabetes; insulin sensitizer; physical performance; walk speed
6.  Subclinical Atherosclerotic Calcification and Cognitive Functioning in Middle-Aged Adults: The CARDIA Study 
Atherosclerosis  2013;231(1):10.1016/j.atherosclerosis.2013.08.038.
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.
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).
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).
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.
PMCID: PMC3828555  PMID: 24125414
atherosclerosis; heart disease; calcium score; cognition; subclinical disease; risk factors
7.  Change in Inflammatory Markers and Cognitive Status among Oldest Old Women from the Study of Osteoporotic Fractures 
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.
20-year longitudinal cohort study.
Four clinical sites in the United States.
905 women from the Study of Osteoporotic Fractures (mean age 88.3±2.8 years at cognitive status adjudication).
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.
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.
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.
PMCID: PMC4109652  PMID: 24697580
Dementia; mild cognitive impairment; inflammation; oldest old
8.  A Cognitive Training Program Based on Principles of Brain Plasticity: Results from the Improvement in Memory with Plasticity-based Adaptive Cognitive Training (IMPACT) Study 
To investigate the efficacy of a novel brain plasticity–based computerized cognitive training program in older adults and to evaluate the effect on untrained measures of memory and attention and participant-reported outcomes.
Multisite randomized controlled double-blind trial with two treatment groups.
Communities in northern and southern California and Minnesota.
Community-dwelling adults aged 65 and older (N = 487) without a diagnosis of clinically significant cognitive impairment.
Participants were randomized to receive a broadly-available brain plasticity–based computerized cognitive training program (intervention) or a novelty- and intensity-matched general cognitive stimulation program modeling treatment as usual (active control). Duration of training was 1 hour per day, 5 days per week, for 8 weeks, for a total of 40 hours.
The primary outcome was a composite score calculated from six subtests of the Repeatable Battery for the Assessment of Neuropsychological Status that use the auditory modality (RBANS Auditory Memory/Attention). Secondary measures were derived from performance on the experimental program, standardized neuropsychological assessments of memory and attention, and participant-reported outcomes.
RBANS Auditory Memory/Attention improvement was significantly greater (P = .02) in the experimental group (3.9 points, 95% confidence interval (CI) = 2.7–5.1) than in the control group (1.8 points, 95% CI = 0.6–3.0). Multiple secondary measures of memory and attention showed significantly greater improvements in the experimental group (word list total score, word list delayed recall, digits backwards, letter–number sequencing; P < .05), as did the participant-reported outcome measure (P = .001). No advantage for the experimental group was seen in narrative memory.
The experimental program improved generalized measures of memory and attention more than an active control program.
PMCID: PMC4169294  PMID: 19220558
clinical trial; cognitive decline; computerized cognitive training; participant-reported outcomes; brain plasticity
9.  Mitochondrial DNA Sequence Variation Associated with Dementia and Cognitive Function in the Elderly 
Mitochondrial dysfunction is a prominent hallmark of Alzheimer's disease (AD). Mitochondrial DNA (mtDNA) damage may be a major cause of abnormal reactive oxidative species production in AD or increased neuronal susceptibility to oxidative injury during aging. The purpose of this study was to assess the influence of mtDNA sequence variation on clinically significant cognitive impairment and dementia risk in the population-based Health, Aging, and Body Composition (Health ABC) Study. We first investigated the role of common mtDNA haplogroups and individual variants on dementia risk and 8-year change on the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) among 1,631 participants of European genetic ancestry. Participants were free of dementia at baseline and incidence was determined in 273 cases from hospital and medication records over 10–12 follow-up years. Participants from haplogroup T had a statistically significant increased risk of developing dementia (OR = 1.86, 95% CI = 1.23, 2.82, p = 0.0008) and haplogroup J participants experienced a statistically significant 8-year decline in 3MS (β = −0.14, 95% CI = −0.27, −0.03, p = 0.0006), both compared with common haplogroup H. The m.15244A>G, p.G166G, CytB variant was associated with a significant decline in DSST score (β = −0.58, 95% CI −0.89, −0.28, p = 0.00019) and the m.14178T>C, p.I166V, ND6 variant was associated with a significant decline in 3MS score (β = −0.87, 95% CI −1.31, −3.86, p = 0.00012). Finally, we sequenced the complete ∼16.5 kb mtDNA from 135 Health ABC participants and identified several highly conserved and potentially functional nonsynonymous variants unique to 22 dementia cases and aggregate sequence variation across the hypervariable 2-3 regions that influences 3MS and DSST scores.
PMCID: PMC4156011  PMID: 22785396
Cognitive function; dementia; DNA sequencing; mitochondria; mtDNA; oxidative phosphorylation
10.  Interleukin-6, Age, and Corpus Callosum Integrity 
PLoS ONE  2014;9(9):e106521.
The contribution of inflammation to deleterious aging outcomes is increasingly recognized; however, little is known about the complex relationship between interleukin-6 (IL-6) and brain structure, or how this association might change with increasing age. We examined the association between IL-6, white matter integrity, and cognition in 151 community dwelling older adults, and tested whether age moderated these associations. Blood levels of IL-6 and vascular risk (e.g., homocysteine), as well as health history information, were collected. Processing speed assessments were administered to assess cognitive functioning, and we employed tract-based spatial statistics to examine whole brain white matter and regions of interest. Given the association between inflammation, vascular risk, and corpus callosum (CC) integrity, fractional anisotropy (FA) of the genu, body, and splenium represented our primary dependent variables. Whole brain analysis revealed an inverse association between IL-6 and CC fractional anisotropy. Subsequent ROI linear regression and ridge regression analyses indicated that the magnitude of this effect increased with age; thus, older individuals with higher IL-6 levels displayed lower white matter integrity. Finally, higher IL-6 levels were related to worse processing speed; this association was moderated by age, and was not fully accounted for by CC volume. This study highlights that at older ages, the association between higher IL-6 levels and lower white matter integrity is more pronounced; furthermore, it underscores the important, albeit burgeoning role of inflammatory processes in cognitive aging trajectories.
PMCID: PMC4154691  PMID: 25188448
11.  Type 2 Diabetes and 10-Year Risk of Dementia and Cognitive Impairment Among Older Mexican Americans 
Diabetes Care  2013;36(9):2600-2606.
Type 2 diabetes has been linked with increased risk of dementia and cognitive impairment among older adults and with premature mortality in young and middle-aged adults. No studies have evaluated the association between diabetes and dementia among Mexican Americans, a population with a high burden of diabetes. We evaluated the association of diabetes with incidence of dementia and cognitive impairment without dementia (CIND) among older Mexican Americans while accounting for competing risk from death.
This study included 1,617 participants 60–98 years of age from the Sacramento Area Latino Study on Aging followed up to 10 years from 1998. We evaluated the association between diabetes and dementia/CIND with competing risk regression models.
Participants free of dementia/CIND at baseline (n = 1,617) were followed annually up to 10 years. There were 677 (41.9%) participants with diabetes, 159 (9.8%) incident dementia/CIND cases, and 361 (22.3%) deaths. Treated and untreated diabetes (hazard ratio 2.12 [95% CI 1.65–2.73] and 2.15 [1.58–2.95]) and dementia/CIND (2.48 [1.75–3.51]) were associated with an increased risk of death. In models adjusted for competing risk of death, those with treated and untreated diabetes had an increased risk of dementia/CIND (2.05 [1.41–2.97] and 1.55 [0.93–2.58]) compared with those without diabetes.
These findings provide evidence that the association between type 2 diabetes and dementia/CIND among Mexican Americans remains strong after accounting for competing risk of mortality. Treatments that modify risk of death among those with diabetes may change future dementia risk.
PMCID: PMC3747945  PMID: 23514732
12.  Neuropsychiatric symptoms in Alzheimer’s disease: Past progress and anticipation of the future 
Neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimer’s first case, Frau Auguste D., presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimer’s Association convened a Research Roundtable on the topic of NPS in AD. A major outcome of the Roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimer’s Research and Treatment (ISTAART). The NPS-PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome specific synthetic reviews and recommendations prepared by NPS-PIA Workgroups on depression, apathy, sleep, agitation, and psychosis.
PMCID: PMC3766403  PMID: 23562430
Neuropsychiatric symptoms; Behavioral and psychological symptoms of dementia; Agitation/aggression; Sleep disorders; Depression; Apathy; Psychosis; Delusions; Hallucinations; Dementia; Alzheimer’s disease; Mild cognitive impairment; Mild Behavioral Impairment
13.  New Insights into the Dementia Epidemic 
The New England journal of medicine  2013;369(24):2275-2277.
PMCID: PMC4130738  PMID: 24283198
14.  Anemia and risk of dementia in older adults 
Neurology  2013;81(6):528-533.
To determine whether anemia is associated with incident dementia in older adults.
We studied 2,552 older adults (mean age 76.1 years; 38.9% black; 51.8% female) participating in the Health, Aging, and Body Composition study and free of dementia at baseline. We defined anemia using WHO criteria (hemoglobin concentration <13 g/dL for men and <12 g/dL for women). Dementia diagnosis was determined by dementia medication use, hospital records, or a change in Modified Mini-Mental State (3MS) score of more than 1.5 SD from mean. Discrete time Cox proportional hazard regression models were used to examine the hazard for developing dementia associated with anemia.
Of 2,552 participants, 392 (15.4%) older adults had anemia at baseline. Over 11 years of follow-up, 455 (17.8%) participants developed dementia. In the unadjusted model, those with baseline anemia had an increased risk of dementia (23% vs 17%, hazard ratio = 1.64; 95% confidence interval 1.30, 2.07) compared to those without anemia. The association remained significant after adjusting for demographics, APOE ε4, baseline 3MS score, comorbidities, and renal function. Additional adjustment for other anemia measures (mean corpuscular volume, red cell distribution width), erythropoietin, and C-reactive protein did not appreciably change the results. There was no interaction by sex and race on risk of developing dementia.
Among older adults, anemia is associated with an increased risk of developing dementia. Findings suggest that further study of anemia as a risk factor for dementia and a target for intervention for cognitive health is warranted.
PMCID: PMC3775683  PMID: 23902706
15.  Depressive Symptoms and Circadian Activity Rhythm Disturbances in Community-Dwelling Older Women 
Aging is associated with changes in circadian rhythms. Current evidence supports a role for circadian rhythms in the pathophysiology of depression. However, little is known about the relationship between depressive symptoms and circadian activity rhythms in older adults. We examined this association in community-dwelling older women.
We performed a cross-sectional analysis of 3,020 women (mean age: 83.55 ± 3.79 years) enrolled in the Study of Osteoporotic Fractures. Depressive symptoms were assessed with the Geriatric Depression Scale categorizing participants as “normal” (0–2; referent group, N = 1,961), “some depressive symptoms” (3–5, N = 704), or “depressed” (≥6, N = 355). Circadian activity rhythm variables were measured using wrist actigraphy.
In age-adjusted and Study of Osteoporotic Fractures site–adjusted models, greater levels of depressive symptoms were associated with decreased amplitude (height; df = 3,014, t = −11.31, p for linear trend <0.001), pseudo F-statistic (robustness; df =3,014, t =−8.07, p for linear trend <0.001), and mesor (mean modeled activity; df = 3014, t = −10.36, p for linear trend <0.001) of circadian activity rhythms. Greater levels of depressive symptoms were also associated with increased odds of being in the lowest quartile for amplitude (df =1, χ2 =9240, p for linear trend <0.001), pseudo F-statistic (df =1, χ2 =49.73, p for linear trend <0.001), and mesor (df =1, χ2 =81.12, p for linear trend <0.001). These associations remained significant in multivariate models. Post-hoc analyses comparing mean amplitude, mesor, and pseudo F-statistic values pair-wise between depression-level groups revealed significant differences between women with “some depressive symptoms” and the “normal” group.
These data suggest a graded association between greater levels of depressive symptoms and more desynchronization of circadian activity rhythms in community-dwelling older women. This association was observed even for women endorsing subthreshold levels of depressive symptoms.
PMCID: PMC4109690  PMID: 23567424
Depression; circadian rhythms; activity rhythms; actigraphy; older women; subthreshold depression
16.  The Demographic and Medical Correlates of Plasma Aβ40 and Aβ42 
Plasma amyloid beta-42 (Aβ42) and Aβ42/Aβ40 are increasingly recognized as biomarkers for dementia, with low levels indicating increased risk. Little is known about the demographic and medical correlates of plasma Aβ40 or Aβ42. In 997 community-dwelling, non-demented older adults from the Health, Aging and Body Composition Study, we determined the cross-sectional association between a wide range of demographic and medical variables with Aβ40 and Aβ42. In multivariate stepwise linear regression models, Aβ40 was significantly associated with race (β=−14.70, F=22.01, p<0.0001), age (β=1.34, F=6.39, p=0.01), creatinine (β=52.91, F=151.77, p<0.0001), and serum brain-derived neurotrophic factor (BDNF) (β=−0.0004, F=7.34, p=0.007); Aβ42 was significantly associated with race (β=−3.72, F=30.83, p<0.0001), sex (β=1.39, F=4.32, p=0.04), education (β=1.50, F=4.78, p=0.03), Apolipoprotein E (APOE) e4 allele status (β=−2.82, F=16.57, p<0.0001), and creatinine (β=9.32, F=120.09, p<0.0001). These correlates should be considered as potential confounders in future studies investigating plasma Aβ as a biomarker of dementia. Understanding fully how these correlates mediate or modify the association between plasma Aβ and dementia will be a fundamental step in determining the biological pathways through which plasma Aβ40 and Aβ42 are associated with dementia, and in determining their full potential as biomarkers.
PMCID: PMC3473156  PMID: 22732677
Plasma amyloid beta; dementia; cognitive decline; biomarker; epidemiology
Hypertension  2013;63(1):181-187.
Reduced Heart Rate Variability is a strong predictor of cardiovascular risk factors, cardiovascular events and mortality; and thus may be associated with cognitive neurodegeneration. Yet this has been relatively unexplored, particularly in minority populations with high cardiovascular burden. We used data from the Sacramento Area Latino Study on Aging to examine the cross-sectional association of reduced heart rate variability with cognitive function among elderly Mexican Americans. A total of 869 participants (mean age of 75 years; 59% females) had their 6-minute heart rate variability measured using an ECG monitor and respiration pacer in response to deep breathing. We used the Mean Circular Resultant, known as R bar, as a measure of heart rate variability and categorized it into quartiles (Q1 to Q4 of R bar: reduced to high heart rate variability). Cognitive function was assessed using the Modified Mini Mental State Exam, a 100-point test of global cognitive function and the Spanish and English Verbal Learning Test, a 15-point test of verbal memory recall. In fully-adjusted linear regression models, participants in quartile 1 had a 4-point lower Modified Mini Mental State Exam score (p<0.01), those in quartile 2 had 2-point lower score (p=0.04), and those in quartile 3 had 1-point lower score (p=0.35), as compared to those in the highest quartile of R bar. Reduced R bar was not associated with verbal memory. Our results suggest that reduced heart rate variability is associated with worse performance on the test of global cognitive function, above and beyond traditional cardiovascular risk factors.
PMCID: PMC4045649  PMID: 24144650
Aging; autonomic function; cognition; epidemiology; heart rate variability
18.  Association Between Hypoglycemia and Dementia in a Biracial Cohort of Older Adults With Diabetes Mellitus 
JAMA internal medicine  2013;173(14):1300-1306.
Hypoglycemia commonly occurs in patients with diabetes mellitus (DM) and may negatively influence cognitive performance. Cognitive impairment in turn can compromise DM management and lead to hypoglycemia.
To prospectively evaluate the association between hypoglycemia and dementia in a biracial cohort of older adults with DM.
Prospective population-based study.
We studied 783 older adults with DM (mean age, 74.0 years; 47.0% of black race/ethnicity; and 47.6% female) who were participating in the prospective population-based Health, Aging, and Body Composition Study beginning in 1997 and who had baseline Modified Mini-Mental State Examination scores of 80 or higher.
Dementia diagnosis was determined during the follow-up period from hospital records indicating an admission associated with dementia or the use of prescribed dementia medications. Hypoglycemic events were determined during the follow-up period by hospital records.
During the 12-year follow-up period, 61 participants (7.8%) had a reported hypoglycemic event, and 148 (18.9%) developed dementia. Those who experienced a hypoglycemic event had a 2-fold increased risk for developing dementia compared with those who did not have a hypoglycemic event (34.4% vs 17.6%, P < .001; multivariate-adjusted hazard ratio, 2.1; 95% CI, 1.0–4.4). Similarly, older adults with DM who developed dementia had a greater risk for having a subsequent hypoglycemic event compared with participants who did not develop dementia (14.2% vs 6.3%, P < .001; multivariate-adjusted hazard ratio, 3.1; 95% CI, 1.5–6.6). Further adjustment for stroke, hypertension, myocardial infarction, and cognitive change scores produced similar results.
Among older adults with DM, there seems to be a bidirectional association between hypoglycemia and dementia.
PMCID: PMC4041621  PMID: 23753199
19.  Retinopathy and Cognitive Impairment in Adults With CKD 
Retinal microvascular abnormalities have been associated with cognitive impairment, possibly serving as a marker of cerebral small vessel disease. This relationship has not been evaluated among persons with chronic kidney disease (CKD), a condition associated with increased risk of both retinal pathology and cognitive impairment.
Study Design
Cross-sectional study
Setting & Participants
588 participants ≥ 52 years old with CKD in the Chronic Renal Insufficiency Cohort (CRIC) Study
Retinopathy graded using the Early Treatment Diabetic Retinopathy Study severity scale and diameters of retinal vessels.
Neuropsychological battery of six cognitive tests
Logistic regression models were used to evaluate the association of retinopathy, individual retinopathy features, and retinal vessel diameters with cognitive impairment (≤1 SD from the mean), and linear regression models were used to compare cognitive test scores across levels of retinopathy adjusting for age, race, sex, education, and medical comorbidities.
The mean age of the cohort was 65.3 +/− 5.6 (SD) years; 51.9% were non-White, and 52.6% were male. The prevalence of retinopathy was 30.1% and 14.3% for cognitive impairment. Compared to those without retinopathy, participants with retinopathy had increased likelihood of cognitive impairment on executive function (35.1% vs. 11.5%; OR, 3.4; 95% CI, 2.0-6.0), attention (26.7% vs. 7.3%; OR, 3.0; 95% CI, 1.8-4.9), and naming (26.0% vs. 10.0%; OR, 2.1; 95% CI, 1.2-3.4) after multivariable adjustment. Increased level of retinopathy was also associated with lower cognitive performance on executive function and attention. Microaneurysms were associated with cognitive impairment on some domains, but there were no significant associations with other retinal measures after multivariable adjustment.
Unknown temporal relationship between retinopathy and impairment.
In adults with CKD, retinopathy is associated with poor performance on several cognitive domains including executive function and attention. Evaluation of retinal microvascular abnormalities may be a promising tool for identifying patients with CKD who are at increased risk of cognitive impairment.
PMCID: PMC4030670  PMID: 23206534
20.  Mitochondrial DNA sequence associations with dementia and amyloid-β in elderly African Americans 
Neurobiology of aging  2013;35(2):442.e1-442.e8.
Mitochondrial dysfunction occurs early in the course of several neurodegenerative diseases, and is potentially related to increased oxidative damage and amyloid-β (Aβ) formation in Alzheimer’s disease. The goals of this study were to assess mtDNA sequence associations with dementia risk, 10-year cognitive change, and markers of oxidative stress and Aβ among 1089 African-Americans in the population-based Health, Aging, and Body Composition Study. Participants were free of dementia at baseline, and incidence was determined in 187 (18%) cases over 10 to 12 follow-up years. Haplogroup L1 participants were at increased risk for developing dementia (odds ratio = 1.88, 95% confidence interval = 1.23–2.88, p = 0.004), lower plasma Aβ42 levels (p = 0.03), and greater 10-year decline on the Digit Symbol Substitution Test (p = 0.04) when compared with common haplogroup L3. The p.V193I, ND2 substitution was associated with significantly higher Aβ42 levels (p = 0.0012), and this association was present in haplogroup L3 (p = 0.018) but not L1 (p = 0.90) participants. All associations were independent of potential confounders, including APOEε4 status and nuclear genetic ancestry. Identification of mtDNA sequence variation associated with dementia risk and cognitive decline may contribute to the development of new treatment targets and diagnostic tests that identify responders to interventions targeting mitochondria.
PMCID: PMC4019378  PMID: 24140124
Dementia; Mitochondria; mtDNA; Amyloid-β; Oxidative stress
21.  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
22.  A Genome-Wide Association Study of Depressive Symptoms 
Hek, Karin | Demirkan, Ayse | Lahti, Jari | Terracciano, Antonio | Teumer, Alexander | Cornelis, Marilyn C. | Amin, Najaf | Bakshis, Erin | Baumert, Jens | Ding, Jingzhong | Liu, Yongmei | Marciante, Kristin | Meirelles, Osorio | Nalls, Michael A. | Sun, Yan V. | Vogelzangs, Nicole | Yu, Lei | Bandinelli, Stefania | Benjamin, Emelia J. | Bennett, David A. | Boomsma, Dorret | Cannas, Alessandra | Coker, Laura H. | de Geus, Eco | De Jager, Philip L. | Diez-Roux, Ana V. | Purcell, Shaun | Hu, Frank B. | Rimma, Eric B. | Hunter, David J. | Jensen, Majken K. | Curhan, Gary | Rice, Kenneth | Penman, Alan D. | Rotter, Jerome I. | Sotoodehnia, Nona | Emeny, Rebecca | Eriksson, Johan G. | Evans, Denis A. | Ferrucci, Luigi | Fornage, Myriam | Gudnason, Vilmundur | Hofman, Albert | Illig, Thomas | Kardia, Sharon | Kelly-Hayes, Margaret | Koenen, Karestan | Kraft, Peter | Kuningas, Maris | Massaro, Joseph M. | Melzer, David | Mulas, Antonella | Mulder, Cornelis L. | Murray, Anna | Oostra, Ben A. | Palotie, Aarno | Penninx, Brenda | Petersmann, Astrid | Pilling, Luke C. | Psaty, Bruce | Rawal, Rajesh | Reiman, Eric M. | Schulz, Andrea | Shulman, Joshua M. | Singleton, Andrew B. | Smith, Albert V. | Sutin, Angelina R. | Uitterlinden, André G. | Völzke, Henry | Widen, Elisabeth | Yaffe, Kristine | Zonderman, Alan B. | Cucca, Francesco | Harris, Tamara | Ladwig, Karl-Heinz | Llewellyn, David J. | Räikkönen, Katri | Tanaka, Toshiko | van Duijn, Cornelia M. | Grabe, Hans J. | Launer, Lenore J. | Lunetta, Kathryn L. | Mosley, Thomas H. | Newman, Anne B. | Tiemeier, Henning | Murabito, Joanne
Biological psychiatry  2013;73(7):10.1016/j.biopsych.2012.09.033.
Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.
In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p < 1 × 10−5) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies.
The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05 × 10−7). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19 × 10−3). This 5q21 region reached genome-wide significance (p = 4.78 × 10−8) in the overall meta-analysis combining discovery and replication studies (n = 51,258).
The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.
PMCID: PMC3845085  PMID: 23290196
Center for Epidemiologic Studies Depression Scale; CHARGE consortium; depression; depressive symptoms; genetics; genome-wide association study; meta-analysis
23.  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
24.  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
25.  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

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