B. Gwen Windham

Drug Burden Index Score and Functional Decline in Older People

BACKGROUND The Drug Burden Index (DBI), a measure of exposure to anticholinergic and sedative medications, has been independently associated with physical and cognitive function in a cross-sectional analysis of community-dwelling older persons participating in the Health, Aging and Body Composition study. Here we evaluate the association between DBI and functional outcomes in Health, Aging and Body Composition study participants over 5 years. METHODS DBI was calculated at years 1 (baseline), 3, and 5, and a measure of the area under the curve for DBI (AUCDB) over the whole study period was devised and calculated. Physical performance was measured using the short physical performance battery, usual gait speed, and grip strength. The association of DBI at each time point and AUCDB with year 6 function was analyzed in data from participants with longitudinal functional measures, controlling for sociodemographics, comorbidities, and baseline function. RESULTS Higher DBI at years 1, 3, and 5 was consistently associated with poorer function at year 6. On multivariate analysis, a 1-unit increase in AUCDB predicted decreases in short physical performance battery score of .08 (P=.01), gait speed of .01 m/s (P=.004), and grip strength of .27 kg (P=.004) at year 6. CONCLUSION Increasing exposure to medication with anticholinergic and sedative effects, measured with DBI, is associated with lower objective physical function over 5 years in community-dwelling older people.

Circulating Brain-Derived Neurotrophic Factor and Indices of Metabolic and Cardiovascular Health: Data from the Baltimore Longitudinal Study of Aging

Background Besides its well-established role in nerve cell survival and adaptive plasticity, brain-derived neurotrophic factor (BDNF) is also involved in energy homeostasis and cardiovascular regulation. Although BDNF is present in the systemic circulation, it is unknown whether plasma BDNF correlates with circulating markers of dysregulated metabolism and an adverse cardiovascular profile. Methodology/Principal Findings To determine whether circulating BDNF correlates with indices of metabolic and cardiovascular health, we measured plasma BDNF levels in 496 middle-age and elderly subjects (mean age ∼70), in the Baltimore Longitudinal Study of Aging. Linear regression analysis revealed that plasma BDNF is associated with risk factors for cardiovascular disease and metabolic syndrome, regardless of age. In females, BDNF was positively correlated with BMI, fat mass, diastolic blood pressure, total cholesterol, and LDL-cholesterol, and inversely correlated with folate. In males, BDNF was positively correlated with diastolic blood pressure, triglycerides, free thiiodo-thyronine (FT3), and bioavailable testosterone, and inversely correlated with sex-hormone binding globulin, and adiponectin. Conclusion/Significance Plasma BDNF significantly correlates with multiple risk factors for metabolic syndrome and cardiovascular dysfunction. Whether BDNF contributes to the pathogenesis of these disorders or functions in adaptive responses to cellular stress (as occurs in the brain) remains to be determined.

Diabetes in Midlife and Cognitive Change Over 20 Years: A Cohort Study

Context Data are limited on the relationship of midlife glycemic control and long-term cognitive impairment. Contribution This prospective longitudinal study involved 13351 adults living in 4 U.S. communities. Diabetes status was defined at baseline, and cognitive function was assessed at baseline and periodically during the 20-year follow-up. Caution The relationship between improvement in glucose control over time and cognitive decline could not be examined. Implication Diabetes and prediabetes in midlife were associated with a greater risk for cognitive decline over 20 years. Longer-duration diabetes had a stronger association with cognitive decline. The Editors The prevalence of diabetes has increased substantially over the past several decades to approximately 10%, and 21 million adults are affected in the United States (1). Type 2 diabetes is an established risk factor for heart disease, stroke, hypertension, blindness, and kidney disease (24). The association of diabetes with dementia risk is well-established (57), but the association of diabetes with cognitive decline is less well-characterized. Because cognitive decline is a precursor to dementia, strong risk factors for decline can help identify persons who may benefit from early intervention. The effects of diabetes and early hyperglycemic states assessed in midlife on long-term cognitive decline are relatively uncharacterized (6). Previous studies have been limited by short follow-up and a lack of rigorous adjustment for potential confounding variables, and most were limited to white persons and were done in elderly populations, where associations tend to be weaker (8, 9). Hemoglobin A1c (HbA1c) level is a measure of the average circulating glucose level in the blood over the preceding 2 to 3 months. It is the standard measure used in the clinical management of diabetes, and its use is now recommended for diagnosis of diabetes and identification of persons at risk for the condition (10). Studies have shown cross-sectional associations between HbA1c level and cognitive scores in persons with diabetes (11, 12). However, there is little evidence prospectively linking better glycemic control to slower cognitive decline, and few studies have examined whether chronic hyperglycemia below the threshold for a diagnosis of diabetes (prediabetes) is associated with long-term cognitive impairment (1315). Our objective was to examine the association of diabetes assessed in middle age with subsequent 20-year cognitive decline in a community-based population of black and white adults. We also examined the associations of prediabetes and glycemic control in the setting of diabetes with 20-year cognitive decline. An inherent challenge to accurately quantifying the long-term risk factor associations in observational studies is that participants who are ill are less likely to return for study visits. In this study, we used methods to account for this attrition, which is important in quantifying the long-term associations of diabetes with cognitive decline. Methods Study Population The ARIC (Atherosclerosis Risk in Communities) study is a community-based, prospective cohort study of 15792 middle-aged adults from 4 U.S. communities: Washington County, Maryland; Forsyth County, North Carolina; and suburbs of Minneapolis, Minnesota, and Jackson, Mississippi. The field centers in all 4 communities selected participants by probability sampling; the Mississippi field center recruited only black persons, the Forsyth County site recruited black and white persons, and the racial distribution in the other locations resulted in a small percentage of nonwhite participants. Participants were seen at 4 visits approximately 3 years apart beginning in 1987 to 1989, and a fifth visit took place in 2011 to 2013. Cognitive function was evaluated at visit 2 (1990 to 1992), at visit 4 (1996 to 1998), and as part of the ARIC-NCS (ARIC Neurocognitive Study) at visit 5 (2011 to 2013). Detailed information about the ARIC study can be found elsewhere (16). Baseline for the present analysis was visit 2, the first visit at which cognitive data were collected. Of the 14348 participants who attended visit 2, we excluded participants who were neither white nor black and the small number of black persons in the Minnesota and Washington County cohorts (n= 91), those missing results from 1 or more cognitive function tests at baseline (n= 217), and those missing variables of interest (n= 689), resulting in a final sample size of 13351 participants at baseline (93% of the visit 2 sample). A flow diagram of the study population and the pattern of visit attendance is provided in Figure 1 . Figure 1. Study flow diagram. Assessment of Cognitive Function We used 3 neuropsychological tests to assess cognitive function: the delayed word recall test (DWRT) (17), the digit symbol substitution test (DSST) of the Wechsler Adult Intelligence Scale-Revised (18), and the word fluency test (WFT) (19). Protocols for the tests were standardized, and trained examiners administered the tests in a fixed order during 1 session in a quiet room. The DWRT is a test of verbal learning and recent memory. Participants were asked to learn 10 common nouns by using each in a sentence. Two exposures to each word were given. After a 5-minute filled delay, participants had 60 seconds to recall the words. The score was equal to the number of words recalled. The DSST is a test of executive function and processing speed. In this 90-second test, participants were asked to use a key to translate numbers to symbols. The score was equal to the count of numbers correctly translated to symbols, with possible scores ranging from 0 to 93. The WFT is a test of executive function and language. Participants were given 60 seconds for each of the letters F, A, and S and were asked to generate as many words as possible beginning with each letter, excluding proper nouns. The score was equal to the total number of words generated for each letter. To facilitate comparison across cognitive tests, Zscores standardized to visit 2 were calculated for each test by subtracting the participants test score at each visit from the mean score at visit 2 and dividing by the SD of the visit 2 scores. A composite global cognitive Zscore was calculated by averaging the Zscores of the 3 tests and was then standardized to visit 2 by using the mean and SD of the global Zscores at visit 2. Thus, a Zscore of 1 would describe cognitive performance that is 1 SD below the mean score at visit 2. Composite global scores derived in this manner have been used in analyses of cognitive change in the ARIC study (20, 21) and elsewhere (2224). Assessment of Diabetes We defined diabetes as self-reported physician diagnosis or diabetes medication use or HbA1c level of 6.5% or greater. HbA1c Measurement We measured HbA1c level in stored whole-blood samples by using high-performance liquid chromatography methods standardized to the Diabetes Control and Complications Trial assay (Tosoh A1c 2.2 Plus and G7 analyzers) (25). For analyses of the association between HbA1c level and cognitive decline, HbA1c level was categorized by using standard clinical cut points (<5.7%, 5.7% to 6.4%, and 6.5% in persons without a history of diabetes and <7.0% and 7.0% in those with a history of diabetes) (10). Covariates All covariates used in the regression models were assessed at visit 2 except education, race, and sex, which were assessed at visit 1. We evaluated the following covariates as confounders: age; age squared; sex; racefield center (white persons from Minnesota, white persons from Washington County, white persons from Forsyth County, black persons from Forsyth County, and black persons from Mississippi); education (less than high school; high school, high school equivalent, or vocational school; or college, graduate, or professional school); cigarette smoking status (current, former, or never); alcohol consumption (current, former, or never); body mass index (kg/m2); hypertension, defined as use of blood pressurelowering medication, systolic blood pressure greater than 140 mm Hg, or diastolic blood pressure greater than 90 mm Hg (yes or no); history of coronary heart disease (yes or no, with persons who were unsure of their history classified as no); history of stroke (yes or no); and apolipoprotein E 4 genotype (0, 1, or 2 alleles). We also included interaction terms between each of these variables and time to allow for different rates of decline by these covariates. In sensitivity analyses, we treated cigarette smoking status, alcohol consumption, body mass index, hypertension, history of coronary heart disease, and history of stroke as time-varying and updated values at each study visit. We also adjusted for total cholesterol level and lipid-lowering medication use. Statistical Analysis We used linear models to estimate associations between diabetes and cognitive decline and fit them with generalized estimating equations to account for the within-person correlations of test scores arising from the repeated measures across time. We used unstructured correlation matrices and robust variance estimates. Time since baseline was modeled by using a linear spline with a knot at 6 years (the mean duration between visits 2 and 4). The spline term allowed for a nonlinear association between time and cognitive decline, more appropriately fit the study design than a quadratic term, and was supported by diagnostic Lowess smoothers. The primary coefficients of interest were the interactions between diabetes and the time spline terms, which address the hypothesis of greater decline among participants with diabetes after adjustment for age and the other covariates. To examine the role of stroke in mediating the association between diabetes and cognitive decline, we censored participant values at the time of stroke, thus excluding any poststroke cognitive information from our analyses. To test the robustness

Psychological, physical, and sensory correlates of fear of falling and consequent activity restriction in the elderly: the InCHIANTI study.

Deshpande N, Metter EJ, Bandinelli S, Lauretani F, Windham BG, Ferrucci L: Psychological, physical, and sensory correlates of fear of falling and consequent activity restriction in the elderly: the InCHIANTI study. Am J Phys Med Rehabil 2008;87:354–362. Objective:To identify psychological, physical, and sensory function parameters that are specifically associated with fear of falling (FF) and fear-induced activity restriction in a population-based sample of older adults. Design:FF, fear-induced activity restriction, cognition, depression, personal mastery, chair-stand performance, standing balance, lower-limb and grip strength, visual acuity and contrast sensitivity, and vibrotactile sensitivity were evaluated in the population-based, older cohort (n = 926, age ≥ 65) enrolled in the InCHIANTI study. Results:Nearly 50% participants reported FF. Of these, 65% reported some activity restriction. Personal mastery (P < 0.001) and chair-standing performance (P = 0.001) were independently associated with FF. In those who did not have depression, personal mastery, standing balance, lower-limb strength, and visual contrast sensitivity were associated with activity restriction (P < 0.001–0.011). In those who were depressed, total FF was the major factor strongly associated with activity restriction (P < 0.001), with marginal but significant associations for cognition (P = 0.027) and standing balance (P = 0.015). Conclusion:Psychological and physical factors are independently associated with FF. Presence of depression possibly modulates which factors, in addition to fear of falling, affect fear-induced activity restriction. A longitudinal study is warranted to substantiate causal relationships.

Influence of Leptin, Adiponectin, and Resistin on the Association Between Abdominal Adiposity and Arterial Stiffness

BACKGROUND Adiposity is associated with arterial stiffness, and both adiposity and arterial stiffness independently predict morbidity and mortality. Because adipocytes account for most adipokine production, the objectives of this study were to examine the influence of adipokines such as leptin, adiponectin, and resistin on the relationship between abdominal adiposity and arterial stiffness. METHODS This is a cross-sectional analysis of data from the Baltimore Longitudinal Study of Aging (BLSA). Adiposity was measured as kilograms of abdominal adipose tissue using dual-energy X-ray absorptiometry (DXA). Arterial stiffness was assessed as carotid-femoral pulse wave velocity (PWV). Leptin, adiponectin, and resistin were assayed in fasting serum samples. The influence of adipokines on the relationship between adiposity and arterial stiffness by adipokines was examined using standard mediation pathway analysis. RESULTS Among 749 participants ages 26-96 years (mean age 67, 52% men, 27% black), abdominal adiposity was positively associated with PWV (relative ratio (RR) = 1.04, P = 0.02), after adjusting for potential confounders but was attenuated and no longer significant after adjusting for leptin (RR = 0.99, P = 0.77). The relationship between adiposity and PWV was not substantially influenced by adiponectin (RR = 1.03, P = 0.06) or resistin (RR = 1.05, P = 0.010). Leptin (RR = 1.02, P < 0.001), resistin (RR = 0.92, P < 0.0001), and adiponectin (RR = 0.97, P = 0.004), but not abdominal adiposity (RR = 1.00, P = 0.94), retained significant associations with PWV when adjusting for each other and confounders. CONCLUSIONS Our findings are consistent with the hypothesis that leptin explains, in part, the observed relationship between abdominal adiposity and arterial stiffness. Adiponectin, leptin, and resistin are independent correlates of PWV.

Cystatin-C as a Marker of Cognitive Function in Elders: Findings from the Health ABC Study

We determined whether serum cystatin C, a novel measure of kidney function that colocalizes with brain β‐amyloid, is associated with cognition among 3,030 elders. Those with high cystatin C (n = 445; 15%) had worse baseline scores on Modified Mini‐Mental State Examination or Digit Symbol Substitution Test (p ≤ 0.02) compared with those with intermediate/low level and 7 years greater decline (p ≤ 0.04). Incident cognitive impairment (decline ≥1.0 standard deviation) was greatest among those with high cystatin C (Modified Mini‐Mental State Examination: 38 vs 25%; adjusted odds ratio, 1.92; 95% confidence interval, 1.37–2.69; Digit Symbol Substitution: 38 vs 26%; odds ratio, 1.54; 95% confidence interval, 1.10–2.15). Ann Neurol 2008

Magnitude of Underascertainment of Impaired Kidney Function in Older Adults with Normal Serum Creatinine

OBJECTIVES: To estimate in a community‐dwelling elderly population the magnitude of renal function misclassification, occurring when persons with normal serum creatinine have reduced glomerular filtration rate (GFR), and to describe the participant characteristics related to misclassification.

The Relationship between Heart Rate Variability and Adiposity Differs for Central and Overall Adiposity

While frank obesity is associated with reduced HRV, indicative of poorer autonomic nervous system (ANS) function, the association between body mass index (BMI) and HRV is less clear. We hypothesized that effects of adiposity on ANS are mostly mediated by visceral fat and less by subcutaneous fat; therefore, centrally distributed adipose tissue, that is, waist circumference (WC), should be more strongly associated with HRV than overall adiposity (BMI). To examine this hypothesis, we used data collected in a subset of the Baltimore Longitudinal Study of Aging to compare strength of association between HRV and WC to that of HRV and BMI. Time domain HRV variables SDNN (standard deviation of successive differences in normal-to-normal (N-N) intervals) and RMSSD (root mean square of successive differences in N-N intervals) were calculated from 24-hour Holter recordings in 159 participants (29–96 years). Increasing WC was associated with decreasing SDNN and RMSSD in younger but not older participants (P value for WC-by-age interaction = 0.003). BMI was not associated with either SDNN or RMSSD at any age. In conclusion, central adiposity may contribute to sympathetic and parasympathetic ANS declines early in life.

Physiological Complexity Underlying Heart Rate Dynamics and Frailty Status in Community-Dwelling Older Women

OBJECTIVES: To assess whether less physiological complexity underlying regulation of heart rate dynamics, as indicated by lower approximate entropy for heart rate (ApEnHR), is associated with frailty. For supporting validity, relationships between frailty and traditional linear indices of heart rate variability (HRV) were also assessed.

Impact of Differential Attrition on the Association of Education with Cognitive Change Over 20 Years of Follow-up The ARIC Neurocognitive Study

Studies of long-term cognitive change should account for the potential effects of education on the outcome, since some studies have demonstrated an association of education with dementia risk. Evaluating cognitive change is more ideal than evaluating cognitive performance at a single time point, because it should be less susceptible to confounding. In this analysis of 14,020 persons from a US cohort study, the Atherosclerosis Risk in Communities (ARIC) Study, we measured change in performance on 3 cognitive tests over a 20-year period, from ages 48-67 years (1990-1992) through ages 70-89 years (2011-2013). Generalized estimating equations were used to evaluate the association between education and cognitive change in unweighted adjusted models, in models incorporating inverse probability of attrition weighting, and in models using cognitive scores imputed from the Telephone Interview for Cognitive Status for participants not examined in person. Education did not have a strong relationship with change in cognitive test performance, although the rate of decline was somewhat slower among persons with lower levels of education. Methods used to account for selective dropout only marginally changed these observed associations. Future studies of risk factors for cognitive impairment should focus on cognitive change, when possible, to allow for reduction of confounding by social or cultural factors.