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2.  Personality and resilience to Alzheimer's disease neuropathology: A prospective autopsy study 
Neurobiology of aging  2012;34(4):1045-1050.
Alzheimer's disease (AD) neuropathology is found at autopsy in about 30% of cognitively normal older individuals. We examine whether personality traits are associated with such resilience to clinical dementia in individuals with AD neuropathology. Broad factors and specific facets of personality were assessed up to 28 years (M=11, SD=7) before onset of dementia and up to 30 years (M=15, SD=7) before death in a cohort (N=111) evaluated for AD neuropathology at autopsy. Individuals with higher baseline scores on vulnerability to stress, anxiety, and depression (neuroticism: OR=2.0, 95%CI=1.2-3.5), or lower scores on order and competence (conscientiousness: OR=0.4, 95%CI=0.2-0.9) were less likely to remain asymptomatic in the presence of AD neuropathology. Neuroticism (r=0.26), low agreeableness (r=-0.34), and some facets were also significantly associated with advanced stages of neurofibrillary tangles, but the associations between personality traits and risk of clinical dementia were mostly unchanged by controlling for Braak and CERAD scores. In sum, a resilient personality profile is associated with lower risk or delay of clinical dementia even in persons with AD neuropathology.
PMCID: PMC3541457  PMID: 23040035
Alzheimer's disease; dementia; asymptomatic; personality; neuroticism; depression; conscientiousness; prospective cohort study; autopsy; neurofibrillary tangles; Aβ neuritic plaques; neuropathology
3.  Skeletal Muscle Mitochondrial Energetics Are Associated With Maximal Aerobic Capacity and Walking Speed in Older Adults 
Lower ambulatory performance with aging may be related to a reduced oxidative capacity within skeletal muscle. This study examined the associations between skeletal muscle mitochondrial capacity and efficiency with walking performance in a group of older adults.
Thirty-seven older adults (mean age 78 years; 21 men and 16 women) completed an aerobic capacity (VO2 peak) test and measurement of preferred walking speed over 400 m. Maximal coupled (State 3; St3) mitochondrial respiration was determined by high-resolution respirometry in saponin-permeabilized myofibers obtained from percutanous biopsies of vastus lateralis (n = 22). Maximal phosphorylation capacity (ATPmax) of vastus lateralis was determined in vivo by 31P magnetic resonance spectroscopy (n = 30). Quadriceps contractile volume was determined by magnetic resonance imaging. Mitochondrial efficiency (max ATP production/max O2 consumption) was characterized using ATPmax per St3 respiration (ATPmax/St3).
In vitro St3 respiration was significantly correlated with in vivo ATPmax (r 2 = .47, p = .004). Total oxidative capacity of the quadriceps (St3*quadriceps contractile volume) was a determinant of VO2 peak (r 2 = .33, p = .006). ATPmax (r 2 = .158, p = .03) and VO2 peak (r 2 = .475, p < .0001) were correlated with preferred walking speed. Inclusion of both ATPmax/St3 and VO2 peak in a multiple linear regression model improved the prediction of preferred walking speed (r 2 = .647, p < .0001), suggesting that mitochondrial efficiency is an important determinant for preferred walking speed.
Lower mitochondrial capacity and efficiency were both associated with slower walking speed within a group of older participants with a wide range of function. In addition to aerobic capacity, lower mitochondrial capacity and efficiency likely play roles in slowing gait speed with age.
PMCID: PMC3593613  PMID: 23051977
Muscle; Mitochondria; Aging; Walking speed.
4.  Trajectories of Gait Speed Predict Mortality in Well-Functioning Older Adults: The Health, Aging and Body Composition Study 
Although gait speed slows with age, the rate of slowing varies greatly. To date, little is known about the trajectories of gait speed, their correlates, and their risk for mortality in older adults.
Gait speed during a 20-m walk was measured for a period of 8 years in initially well-functioning men and women aged 70–79 years participating in the Health, Aging and Body Composition study. We described the trajectories of gait speed and examined their correlates using a group-based mixture model. Also risk associated with different gait speed trajectories on all-cause mortality was estimated using a Cox-proportional hazard model.
Of 2,364 participants (mean age, 73.5±2.9 years; 52% women), we identified three gait speed trajectories: slow (n = 637), moderate (n = 1,209), and fast decline (n = 518). Those with fast decline slowed 0.030 m/s per year or 2.4% per year from baseline to the last follow-up visit. Women, blacks, and participants who were obese, had limited knee extensor strength, and had low physical activity were more likely to have fast decline than their counterparts. Participants with fast decline in gait speed had a 90% greater risk of mortality than those with slow decline.
Despite being well-functioning at baseline, a quarter of older adults experienced fast decline in gait speed, which was associated with an increased risk of mortality.
PMCID: PMC3593620  PMID: 23051974
Gait speed; Older adults; Mortality.
5.  Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke: Systematic review and meta-analysis of 14 015 stroke cases and pooled analysis of primary biomarker data from up to 60 883 individuals 
Background At the APOE gene, encoding apolipoprotein E, genotypes of the ε2/ε3/ε4 alleles associated with higher LDL-cholesterol (LDL-C) levels are also associated with higher coronary risk. However, the association of APOE genotype with other cardiovascular biomarkers and risk of ischaemic stroke is less clear. We evaluated the association of APOE genotype with risk of ischaemic stroke and assessed whether the observed effect was consistent with the effects of APOE genotype on LDL-C or other lipids and biomarkers of cardiovascular risk.
Methods We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke. We pooled 41 studies (with a total of 9027 cases and 61 730 controls) using a Bayesian meta-analysis to calculate the odds ratios (ORs) for ischaemic stroke with APOE genotype. To better evaluate potential mechanisms for any observed effect, we also conducted a pooled analysis of primary data using 16 studies (up to 60 883 individuals) of European ancestry. We evaluated the association of APOE genotype with lipids, other circulating biomarkers of cardiovascular risk and carotid intima-media thickness (C-IMT).
Results The ORs for association of APOE genotypes with ischaemic stroke were: 1.09 (95% credible intervals (CrI): 0.84–1.43) for ε2/ε2; 0.85 (95% CrI: 0.78–0.92) for ε2/ε3; 1.05 (95% CrI: 0.89–1.24) for ε2/ε4; 1.05 (95% CrI: 0.99–1.12) for ε3/ε4; and 1.12 (95% CrI: 0.94–1.33) for ε4/ε4 using the ε3/ε3 genotype as the reference group. A regression analysis that investigated the effect of LDL-C (using APOE as the instrument) on ischaemic stroke showed a positive dose-response association with an OR of 1.33 (95% CrI: 1.17, 1.52) per 1 mmol/l increase in LDL-C. In the separate pooled analysis, APOE genotype was linearly and positively associated with levels of LDL-C (P-trend: 2 × 10−152), apolipoprotein B (P-trend: 8.7 × 10−06) and C-IMT (P-trend: 0.001), and negatively and linearly associated with apolipoprotein E (P-trend: 6 × 10−26) and HDL-C (P-trend: 1.6 × 10−12). Associations with lipoprotein(a), C-reactive protein and triglycerides were non-linear.
Conclusions In people of European ancestry, APOE genotype showed a positive dose-response association with LDL-C, C-IMT and ischaemic stroke. However, the association of APOE ε2/ε2 genotype with ischaemic stroke requires further investigation. This cross-domain concordance supports a causal role of LDL-C on ischaemic stroke.
PMCID: PMC3619955  PMID: 23569189
Stroke; lipids; apolipoprotein E; cardiovascular disease; systematic review; meta-analysis; biomarkers
6.  Apolipoprotein E Epsilon 4 Allele Interacts with Sex and Cognitive Status to Influence All-Cause and Cause-Specific Mortality Among US Older Adults 
Apolipoprotein E ε4 (ApoE4 carrier) status, sex and cognitive impairment may interact to affect all-cause and cause-specific mortality risk.
To confirm associations of ApoE4 carrier status, sex and time-dependent cognitive status with mortality risk, and investigate these associations' joint effects in a cohort of community-dwelling US adults.
Design & Setting
Data from the Baltimore Longitudinal Study of Aging were used.
Of n=3,047 (First-visit Age:17–98y, 60.1% men), we selected a sample with complete genetic data and with ≥1 visit at age≥50y (n=1,461).
Time-to-death from all, cardiovascular or non-cardiovascular causes.
Survival probability was lower for ApoE4 carriers, particularly at oldest ages. Cox proportional hazards model for all-cause mortality yielded a hazard ratio (HR) for ApoE4 carrier vs. non-carriers of 1.31,95%CI:1.02–1.68. This association was also found for cardiovascular mortality. Time-dependent all-cause dementia (HR=1.73, 95%CI:1.33–2.26) and mild cognitive impairment (HR=1.95,95%CI:1.42–2.67) increased all-cause mortality risk, associations also detected for non-cardiovascular mortality. When individuals were free of cognitive impairment, a dose-response relationship with ε4 alleles was found for all-cause mortality (HR=1.40,95%CI:0.94–2.07 for 1 ε4, and HR=2.61; 95%CI:1.12–6.07 for 2 ε4). After Alzheimer's Disease-type (AD) dementia onset, carrying only 1 ε4 allele increased all-cause mortality risk by ~77% compared to non-carriers. ApoE4 carrier status increased all-cause mortality risk in men and interacted with time-dependent AD to increase the risk of this outcome (RERI=2.15; 95% CI:1.22–3.07).
We found that ApoE4 carrier status increased all-cause and cardiovascular mortality risks, while interacting with sex and time-dependent AD status to affect all-cause mortality.
PMCID: PMC3628727  PMID: 23581910
Apolipoprotein E genotype; dementia; mild cognitive impairment; mortality; cardiovascular disease
7.  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
8.  Genome-Wide Association Study Identifies Novel Loci Associated With Concentrations of Four Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway: Results from the CHARGE Consortium 
Palmitic acid(16:0), stearic acid(18:0), palmitoleic acid(16:1n-7), and oleic acid(18:1n-9) are major saturated and mono-unsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis (DNL) and are the main saturated and mono-unsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes and coronary heart disease.
Methods and Results
Genome-wide association studies were conducted in 5 population-based cohorts comprising 8,961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these four fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of one or more of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0(P=2.7×10-11) and lower 18:0(P=2.2×10-18). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7(P=6.6×10-13) and 18:1n-9(P=2.2×10-32), and lower 18:0(P =1.3×10-20). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0(P=2.8×10-9). GCKR(glucokinase regulator, P =9.8×10-10) and HIF1AN(factor inhibiting hypoxia-inducible factor-1, P=5.7×10-9) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1(polycystic kidney disease 2-like 1, P=5.7×10-15) and a locus on chromosome 2(not near known genes) were associated with lower 16:1n-7(P=4.1×10-8).
Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of four fatty acids in the DNL pathway. These results expand our knowledge of genetic factors relevant to DNL and fatty acid biology.
PMCID: PMC3891054  PMID: 23362303
epidemiology; fatty acids; genome-wide association study
9.  The Walking Impairment Questionnaire Stair-Climbing Score predicts mortality in men and women with peripheral arterial disease 
Journal of vascular surgery  2012;55(6):1662-73.e2.
The Walking Impairment Questionnaire (WIQ) measures self-reported walking distance, walking speed, and stair-climbing ability in men and women with lower extremity peripheral arterial disease (PAD). We determined whether poorer WIQ scores are associated with higher all-cause and cardiovascular disease (CVD) mortality in individuals with and without PAD.
1048 men and women with and without PAD were identified from Chicago-area medical centers. Participants completed the WIQ at baseline and were followed for a median of 4.5 years. Cox proportional hazards models were used to relate baseline WIQ scores with mortality, adjusting for age, sex, race, the ankle brachial index (ABI), comorbidities, and other covariates.
461 participants (44.0%) died during follow-up, including 158 deaths from cardiovascular disease. PAD participants in the lowest baseline quartile of the WIQ stair-climbing scores had higher all-cause mortality (HR = 1.70 [95% Confidence Interval (CI) 1.08-2.66, p=0.02] and higher CVD mortality (HR = 3.11 [95% CI 1.30 – 7.47, p=0.01]) compared to those with the highest baseline WIQ stair climbing score. Among PAD participants there were no significant associations of lower baseline WIQ distance or speed scores with rates of all-cause mortality (p for trend = 0.20 and 0.07, respectively) or CVD mortality (p for trend = 0.51 and p for trend = 0.33, respectively). Among non-PAD participants there were no significant associations of lower baseline WIQ stair climbing, distance, or speed score with rates of all-cause mortality (p for trend = 0.94, 0.69, and 0.26, respectively) or CVD mortality (p for trend = 0.28, 0.68, and 0.78, respectively).
Among participants with PAD, lower WIQ stair climbing scores are associated with higher all-cause and CVD mortality, independently of the ABI and other covariates.
PMCID: PMC3963605  PMID: 22608041
10.  Association of Plasma Selenium Concentrations with Total IGF-1 Among Older Community-Dwelling Adults: the InCHIANTI Study 
Background and Aims
Insulin-like growth factor (IGF-1) stimulates cell proliferation and inhibits cell apoptosis. Recent studies underline its importance as anabolic hormone and nutritional marker in older individuals. IGF-1 synthesis and bioactivity are modulated by nutritional factors including selenium intake. However, whether circulating IGF-1 levels are positively influenced by plasma selenium, one of the most important human antioxidants, is still unknown.
Selenium and total IGF-1 were measured in 951 men and women ≥65 years from the InCHIANTI study, Tuscany, Italy.
Means (SD) of plasma selenium and total IGF-1 were 0.95 (0.15) µmol/L and 113.4 (31.2) ng/mL, respectively. After adjustment for age and sex, selenium levels were positively associated with total IGF-1 (ß ± SE: 43.76±11.2, p=0.0001).After further adjustment for total energy and alcohol intake, serum alanine amino transferase (ALT), congestive heart failure, selenium remained significantly associated with IGF-1 (β ± SE: 36.7 ± 12.2, p=0.003). The association was still significant when IL-6 was introduced in the model (β ± SE: 40.1 ± 12.0, p=0.0008).
We found an independent, positive and significant association between selenium and IGF-1 serum levels in community dwelling older adults.
PMCID: PMC3963695  PMID: 20416996
aging; total IGF-1; selenium
11.  Alzheimer risk variant CLU and brain function during aging 
Biological psychiatry  2012;73(5):399-405.
We examined the effect of the novel Alzheimer's disease (AD) risk variant rs11136000 single nucleotide polymorphism (SNP) in the clusterin gene (CLU) on longitudinal changes in resting state regional cerebral blood flow (rCBF) during normal aging and investigated its influence on cognitive decline in pre-symptomatic stages of disease progression.
Subjects were participants in the Baltimore Longitudinal Study of Aging. A subset of 88 cognitively normal older individuals had longitudinal 15O-water PET measurements of rCBF at baseline and up to 8 annual follow-up visits. We also analyzed trajectories of cognitive decline among CLU risk carriers and non-carriers both in individuals who remained cognitively normal (N=599) as well as in those who subsequently converted to mild cognitive impairment (MCI) or AD (N=95).
Cognitively normal carriers of the CLU risk allele show significant and dose-dependent longitudinal increases in resting state rCBF in brain regions intrinsic to memory processes. There were no differences in trajectories of memory performance between CLU risk carriers and non-carriers who remained cognitively normal. However, in cognitively normal individuals who eventually convert to MCI or AD, CLU risk carriers show faster rates of decline in memory performance relative to non-carriers in the pre-symptomatic stages of disease progression.
The AD risk variant CLU influences longitudinal changes in brain function in asymptomatic individuals and is associated with faster cognitive decline in pre-symptomatic stages of disease progression. These results suggest mechanisms underlying the role of CLU in AD and may be important in monitoring disease progression in at-risk elderly.
PMCID: PMC3488132  PMID: 22795969
Clusterin; single nucleotide polymorphism; Alzheimer's disease; 15O-water PET; cerebral blood flow; memory
12.  The Effect of CR1 on Brain Amyloid Burden during Aging and its Modification by APOE Genotype 
Biological psychiatry  2012;73(5):422-428.
The rs3818361 single nucleotide polymorphism in CR1 is associated with increased risk of Alzheimer's disease (AD). Although this novel variant is associated with a small effect size and, is unlikely to be useful as a predictor of AD risk, it may provide insights into AD pathogenesis. We examined the association between rs3818361 and brain amyloid deposition in non-demented older individuals.
We used 11C-Pittsburgh Compound-B (PiB) PET to quantify brain amyloid burden in 57 non-demented older individuals (mean age 78.5 years) in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging. In a replication study, we analyzed 11C-PiB PET data from 22 cognitively normal older individuals (mean age 77.1 years) in the Alzheimer's disease neuroimaging initiative (ADNI) dataset.
Risk allele carriers of rs3818361 have lower brain amyloid burden relative to non-carriers. There is a strikingly greater variability in brain amyloid deposition in the non-carrier group relative to risk carriers, an effect explained partly by APOE genotype. In non-carriers of the CR1 risk allele, APOE ε4 individuals showed significantly higher brain amyloid burden relative to APOE ε4 non-carriers. We also independently replicate our observation of lower brain amyloid burden in risk allele carriers of rs3818361 in the ADNI sample.
Our findings suggest complex mechanisms underlying the interaction of CR1, APOE and brain amyloid pathways in AD. Our results are relevant to treatments targeting brain Aβ in non-demented individuals at risk for AD and suggest that clinical outcomes of such treatments may be influenced by complex gene-gene interactions.
PMCID: PMC3535537  PMID: 23022416
CR1; APOE; single nucleotide polymorphism; Alzheimer's disease; amyloid; 11C-PiB PET
13.  Sensitivity Analysis for Nonignorable Missingness and Outcome Misclassification from Proxy Reports 
Epidemiology (Cambridge, Mass.)  2013;24(2):215-223.
Researchers often recruit proxy respondents, such as relatives or caregivers, for epidemiologic studies of older adults when study participants are unable to provide self-reports (e.g., due to illness or cognitive impairment). In most studies involving proxy-reported outcomes, proxies are recruited only to report on behalf of participants who have missing self-reported outcomes; thus, either a proxy report or participant self-report, but not both, is available for each participant. When outcomes are binary and investigators conceptualize participant self-reports as gold standard measures, substituting proxy reports in place of missing participant self-reports in statistical analysis can introduce misclassification error and lead to biased parameter estimates. However, excluding observations from participants with missing self-reported outcomes may also lead to bias. We propose a pattern-mixture model that uses error-prone proxy reports to reduce selection bias from missing outcomes, and we describe a sensitivity analysis to address bias from differential outcome misclassification. We perform model estimation with high-dimensional (e.g., continuous) covariates using propensity-score stratification and multiple imputation. We apply the methods to the Second Cohort of the Baltimore Hip Studies, a study of elderly hip-fracture patients, to assess the relation between type of surgical treatment and perceived physical recovery. Simulation studies show that the proposed methods perform well. We provide SAS programs in the eAppendix to enhance the methods’ accessibility.
PMCID: PMC3566762  PMID: 23348065
14.  Relationship between vitamin D status and left ventricular geometry in a healthy population: results from the Baltimore Longitudinal Study of Aging 
Journal of internal medicine  2012;273(3):253-262.
The effects of vitamin D on the heart have been studied in patients with cardiac disease, but not in healthy persons. We investigated the relation between vitamin D status and left ventricular (LV) structure and function in community-dwelling subjects without heart disease.
The relationship between concentrations of 25-hydroxyvitamin D [25(OH)D], a marker of vitamin D reserve, and LV transthoracic echocardiography measures was analysed in 711 participants in the Baltimore Longitudinal Study of Aging who were without cardiac disease.
Mean 25(OH)D in the study population was 32.3±11.4 ng/mL; only 15.5% of subjects had moderate or severe vitamin D deficiency [25(OH)D <20 ng/mL]. Adjusting for age, body mass index, cardiovascular disease risk factors, physical activity, calcium and parathyroid hormone, 25(OH)D was positively correlated with LV thickness (β 0.095, SE 0.039, P<0.05) and LV mass index (β 7.5, SE 2.6, P<0.01). A significant non-linear relation between 25(OH)D and LV concentric remodelling was observed. LV remodelling was more likely in participants with 25(OH)D levels <30 ng/mL [odds ratio (OR) 1.24; 95% confidence interval (CI) 0.83–1.85] or ≥38 ng/mL (OR 1.73; 95% CI 1.13–2.65), compared with those with 30–37 ng/mL 25(OH)D. Consistently, LV relative wall thickness was significantly lower (P for trend=0.05), and LV diastolic internal diameter index (P for trend<0.05) and end-diastolic volume index (P for trend<0.05) were significantly higher in subjects with 30–37 ng/mL 25(OH)D compared to the rest of the study population. There was a significant interaction between 25(OH)D and hypertension on the risk of LV hypertrophy (P<0.05).
In a population-based sample of predominantly vitamin D-sufficient subjects without heart disease, LV geometry was most favourable at intermediate 25(OH)D concentrations.
PMCID: PMC3568460  PMID: 23061475
heart; left ventricular mass; left ventricular remodeling; population; vitamin D
15.  The Trajectory of Depressive Symptoms Across the Adult Lifespan 
JAMA psychiatry (Chicago, Ill.)  2013;70(8):803-811.
Long-term longitudinal studies are needed to delineate the trajectory of depressive symptoms across adulthood and to individuate factors that may contribute to increases in depressive symptoms in older adulthood.
(1) To estimate the trajectory of depressive symptoms across the adult lifespan, (2) to test whether this trajectory varies by demographic factors (sex, ethnicity, education) and antidepressant medication use, and (3) to test whether disease burden, functional limitations, and proximity to death explain the increase in depressive symptoms in old age.
Longitudinal study
2,320 participants (47% female; mean age at baseline=58.10 years, SD=17.05; range 19–95 years) from the Baltimore Longitudinal Study of Aging
Main Outcome Measure
Estimated trajectory of depressive symptoms modeled from 10,982 assessments (M assessments per participant=4.73, SD=3.63, range=1–21) of the Center for Epidemiological Studies Depression scale and three subscales (depressed affect, somatic complaints, and interpersonal problems).
Both the linear (γ10=.52, p<.01) and quadratic (γ20=.43, p<.01) terms were significant, which indicated that depressive symptoms were highest in young adulthood, decreased across middle adulthood, and increased again in older adulthood. The subscales followed a similar pattern. Women reported more depressed affect at younger ages, but an interaction with age suggested that this gap disappeared in old age. Accounting for comorbidity, functional limitations, and impending death slightly reduced, but did not eliminate, the uptick in depressive symptoms in old age.
Symptoms of depression follow a U-shaped pattern across adulthood. Older adults experience an increase in distress that is not due solely to declines in physical health or approaching death.
PMCID: PMC3740038  PMID: 23760442
16.  Superficial Femoral Artery Plaque and Functional Performance in Peripheral Arterial Disease 
JACC. Cardiovascular imaging  2011;4(7):730-739.
We studied associations of magnetic resonance imaging measurements of plaque area and relative percent lumen reduction in the proximal superficial femoral artery with functional performance among participants with peripheral arterial disease.
The clinical significance of directly imaged plaque characteristics in lower extremity arteries is not well established.
A total of 454 participants with an ankle brachial index <1.00 underwent magnetic resonance cross-sectional imaging of the proximal superficial femoral artery and completed a 6-min walk test, measurement of 4-m walking velocity at usual and fastest pace, and measurement of physical activity with a vertical accelerometer.
Adjusting for age, sex, race, body mass index, smoking, statin use, comorbidities, and other covariates, higher mean plaque area (1st quintile [least plaque]: 394 m, 2nd quintile: 360 m, 3rd quintile: 359 m, 4th quintile: 329 m, 5th quintile [greatest plaque]: 311 m; p trend <0.001) and smaller mean percent lumen area (1st quintile [greatest plaque]: 319 m, 2nd quintile: 330 m, 3rd quintile: 364 m, 4th quintile: 350 m, 5th quintile: 390 m; p trend <0.001) were associated with shorter distance achieved in the 6-min walk test. Greater mean plaque area was also associated with slower usual-paced walking velocity (p trend = 0.006) and slower fastest-paced 4-m walking velocity (p trend = 0.003). Associations of mean plaque area and mean lumen area with 6-min walk distance remained statistically significant even after additional adjustment for the ankle brachial index and leg symptoms.
Among participants with peripheral arterial disease, greater plaque burden and smaller lumen area in the proximal superficial femoral artery are associated independently with poorer functional performance, even after adjusting for the ankle brachial index and leg symptoms.
PMCID: PMC3906625  PMID: 21757163
atherosclerotic plaque intermittent claudication; peripheral arterial disease; physical functioning
17.  The Relationship between Mean Corpuscular Volume and Cognitive Performance in Older Adults 
To examine the relationship between erythrocyte mean corpuscular volume (MCV) and cognitive performance over time.
Sample from the Baltimore Longitudinal Study of Aging (BLSA)
The sample consisted of 827 participants from the Baltimore Longitudinal Study of Aging (BLSA; M age = 67; range = 50 – 96).
MCV and several other blood indices were measured including hemoglobin, iron, ferritin, vitamin B12, folate, white blood cell count, albumin and erythrocyte sedimentation rate. Cognitive performance was examined using neuropsychological measures of visual memory, verbal memory, language, attention, executive function and global mental status.
High MCV levels were significantly associated with lower global mental status even after adjusting for potential confounders. High MCV levels were also significantly associated with accelerated rates of decline on tasks of global mental status, long delay memory, and attention even after adjusting for potential confounders.
Our findings confirm a previous observation that larger erythrocytes in older adults are associated with poorer cognitive function. The relationship between MCV and cognition does not appear to be explained by anemia and inflammation. Further research is needed to clarify the mechanisms behind this association.
PMCID: PMC3555566  PMID: 23301873
18.  UNC13A influences survival in Italian ALS patients: a population-based study 
Neurobiology of aging  2012;34(1):357.e1-357.e5.
The common variant rs12608932, located within an intron of UNC13A gene on chromosome 19p13.3, has been suggested to influence susceptibility to ALS, as well as survival, in patients of north European descent. To examine this possibility further, we evaluated the association of rs12608932 with susceptibility and survival in a population-based cohort of 500 Italian ALS patients and 1,457 Italian control samples. Although rs12608932 was not associated to ALS susceptibility in our series (p=0.124), it was significantly associated with survival under the recessive model (median survival for AA/AC genotypes = 3.5 years [IQR 2.2–6.4]; CC = 2.5 years [IQR 1.6–4.2]; p=0.017). Furthermore, rs12608932 genotype remained an independent prognostic factor in Cox multivariable analysis adjusting for other factors known to influence survival (p=0.023). Overall, minor allele carrier status of rs12608932 was strongly associated with an ~1-year reduction of survival in ALS patients, making it a significant determinant of phenotype variation. The identification of UNC13A as a modifier of prognosis among sporadic ALS patients potentially provides a new therapeutic target aimed at slowing disease progression.
PMCID: PMC3483408  PMID: 22921269
19.  Determinants and clinical significance of plasma oxidized LDLs in older individuals. A 9 years follow-up study 
Atherosclerosis  2012;226(1):201-207.
Oxidized LDLs (ox.LDLs) uptake by macrophages inside the arterial wall is a crucial step in atherosclerotic disease, and some studies suggest that high ox.LDLs plasma levels might be associated with cardiovascular disease (CVD). However, whether high ox.LDLs continue to be a CVD risk factors in older persons is unknown. We investigated the clinical correlates of plasma ox.LDLs, and their role in predicting long-term CVD/cardiac mortality in 1025 older community-dwelling individuals (mean age:75.5±7.4yrs; females:55%) from the InCHIANTI study. Kaplan-Meier curves were fitted to explore the relationship between tertiles of ox.LDLs (ox.LDL/LDL-C ratio) and time to CVD/cardiac death. Hazard Ratios (HR) were estimated by Cox regression analysis.
At multivariate analysis, ox.LDLs were independently associated with LDL-C, triglycerides, and HDL-C (adjusted r2:0.42; P=0.001). The ox.LDL/LDL-C ratio (the extent of LDLs oxidation) was independently correlated with HDL-C, triglycerides, and beta-carotene (adjusted r2:0.15, P=0.001). Among 1025 individuals, 392 died after 9 years, 166 from CVD. The HR for CVD/cardiac mortality was not significantly different across tertiles of ox.LDLs or ox.LDL/LDL-C ratio, both in the whole sample and in individuals with prevalent CVD.
We conclude that in an elderly population LDL-C, triglycerides, and HDL-C are the most important determinants of ox.LDLs levels, indirectly suggesting an association between small dense LDLs and LDLs oxidation. No association emerged between higher ox.LDLs levels and 9-years CVD/cardiac mortality, suggesting that in advanced age the prognostic information added by ox.LDLs on CVD/cardiac mortality might be negligible.
PMCID: PMC3529836  PMID: 23141584
Oxidized LDL; Mortality; Cardiovascular Disease; Aging
20.  Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD 
Human genetics  2012;132(1):79-90.
Accelerated lung function decline is a key COPD phenotype; however its genetic control remains largely unknown.
We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European-American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry.
Measurements and Main Results
Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status.
We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.
PMCID: PMC3536920  PMID: 22986903
COPD; lung function decline; GWAS; genome wide association; genes; polymorphisms
21.  Searching for an Operational Definition of Frailty: A Delphi Method Based Consensus Statement. The Frailty Operative Definition-Consensus Conference Project 
There is no consensus regarding the definition of frailty for clinical uses.
A modified Delphi process was used to attempt to achieve consensus definition. Experts were selected from different fields and organized into five Focus Groups. A questionnaire was developed and sent to experts in the area of frailty. Responses and comments were analyzed using a pre-established strategy. Statements with an agreement more than or equal to 80% were accepted.
Overall, 44% of the statements regarding the concept of frailty and 18% of the statements regarding diagnostic criteria were accepted. There was consensus on the value of screening for frailty and about the identification of six domains of frailty for inclusion in a clinical definition, but no agreement was reached concerning a specific set of clinical/laboratory biomarkers useful for diagnosis.
There is agreement on the usefulness of defining frailty in clinical settings as well as on its main dimensions. However, additional research is needed before an operative definition of frailty can be established.
PMCID: PMC3598366  PMID: 22511289
Frailty; Consensus definition; Older people; Biomarkers
22.  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
23.  Carotid Atherosclerosis and Prospective Risk of Dementia 
Background and Purpose
Though vascular risk factors have been implicated in the development of all-cause dementia and Alzheimer’s disease (AD), few studies have examined the association between subclinical atherosclerosis and prospective risk of dementia.
Participants from the Baltimore Longitudinal Study of Aging (n=364, aged 60–95, median age=73, 60% male, 82% white) underwent initial carotid atherosclerosis assessment and were subsequently assessed for dementia and AD annually for up to 14 years (median=7.0). Cox proportional hazards models predicting (a) all-cause dementia and (b) AD were adjusted for age, sex, race, education, blood pressure, cholesterol, cardiovascular disease, diabetes, and smoking.
Sixty participants developed dementia, with 53 diagnosed as Alzheimer’s disease. Raw rates of future dementia and AD among individuals initially (a) in the upper quintile of carotid intimal medial thickness (IMT) or (b) with bilateral carotid plaque were generally double the rates of individuals with IMT in the lower quintiles or no plaque at baseline. Adjusted proportional hazards models revealed a >2.5-fold increased risk of dementia and AD among individuals in the upper quintile of carotid IMT, and a nearly 2.0-fold increased risk of dementia among individuals with bilateral plaque.
Multiple measures of carotid atherosclerosis are associated with prospective risk of dementia. Individuals in the upper quintile of carotid IMT or bilateral carotid plaque were at greatest risk. These findings underscore the possibility that early intervention to reduce atherosclerosis may help delay or prevent onset of dementia and AD.
PMCID: PMC3508298  PMID: 23103489
atherosclerosis; intimal medial thickness; dementia; Alzheimer’s disease
24.  Correspondence between in vivo 11C-PiB PET amyloid imaging and post-mortem, region-matched assessment of plaques 
Acta neuropathologica  2012;124(6):823-831.
The definitive Alzheimer’s disease diagnosis requires post-mortem confirmation of neuropathological hallmarks – amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). The advent of radiotracers for amyloid imaging presents an opportunity to investigate amyloid deposition in vivo. The 11C-Pittsburgh Compound-B (PiB) PET ligand remains the most widely studied to date; however, regional variations in 11C-PiB binding and the extent of agreement with neuropathological assessment have not been thoroughly investigated. We examined the correspondence among quantitative immunohistological assessments of Aβ and NFTs, regional 11C-PiB load, and brain atrophy (MRI) in six older Baltimore Longitudinal Study of Aging participants who came to autopsy (imaging-autopsy interval range 0.2–2.4 years). The total number of Aβ plaques (6E10) and NFTs (PHF1) in paraffin sections from hippocampus, orbito-frontal cortex, anterior and posterior cingulate gyrus, precuneus and cerebellum were quantified using a technique guided by unbiased stereological principles. We report a general agreement between the regional measures of amyloid obtained via stereological assessment and imaging, with significant relationships evident for the anterior (r=0.87; p=0.02) and posterior (r=0.93; p=0.007) cingulate gyri, and the precuneus (r=0.98; p=0.001). Moreover, higher Aβ count in the hippocampus was associated with lower hippocampal volume (r= −0.86; p=0.03). No associations were observed between 11C-PiB load and NFT count for any of the regions examined (p>0.2 in all regions) or between regional NFT count and corresponding brain volumes. The strong associations of PiB retention with region-matched, quantitative analyses of Aβ in post-mortem tissue offer support for the validity of 11C-PiB-PET imaging as a method for evaluation of plaque burden in vivo.
PMCID: PMC3566238  PMID: 22864813
plaques; tangles; stereology; PiB; Alzheimer; neuroimaging
25.  Associations of Openness and Conscientiousness With Walking Speed Decline: Findings From the Health, Aging, and Body Composition Study 
The objective of this study was to explore the associations between openness to experience and conscientiousness, two dimensions of the five-factor model of personality, and usual gait speed and gait speed decline.
Baseline analyses were conducted on 907 men and women aged 71–82 years participating in the Cognitive Vitality substudy of the Health, Aging, and Body Composition study. The longitudinal analytic sample consisted of 740 participants who had walking speed assessed 3 years later.
At baseline, gait speed averaged 1.2 m/s, and an average decline of 5% over the 3-year follow-up period was observed. Higher conscientiousness was associated with faster initial walking speed and less decline in walking speed over the study period, independent of sociodemographic characteristics. Lifestyle factors and disease status appear to play a role in the baseline but not the longitudinal association between conscientiousness and gait speed. Openness was not associated with either initial or decline in gait speed.
These findings extend the body of evidence suggesting a protective association between conscientiousness and physical function to performance-based assessment of gait speed. Future studies are needed to confirm these associations and to explore mechanisms that underlie the conscientiousness mobility connection in aging adults.
PMCID: PMC3478724  PMID: 22451484
Chronic conditions; Conscientiousness; Lifestyle factors; Openness to experience; Walking speed

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