Baltimore Longitudinal Study On Aging Research Articles

Longitudinal Variability Analysis on Low-dose Abdominal CT with Deep Learning-based Segmentation.

Metabolic health is increasingly implicated as a risk factor across conditions from cardiology to neurology, and efficiency assessment of body composition is critical to quantitatively characterizing these relationships. 2D low dose single slice computed tomography (CT) provides a high resolution, quantitative tissue map, albeit with a limited field of view. Although numerous potential analyses have been proposed in quantifying image context, there has been no comprehensive study for low-dose single slice CT longitudinal variability with automated segmentation. We studied a total of 1816 slices from 1469 subjects of Baltimore Longitudinal Study on Aging (BLSA) abdominal dataset using supervised deep learning-based segmentation and unsupervised clustering method. 300 out of 1469 subjects that have two year gap in their first two scans were pick out to evaluate longitudinal variability with measurements including intraclass correlation coefficient (ICC) and coefficient of variation (CV) in terms of tissues/organs size and mean intensity. We showed that our segmentation methods are stable in longitudinal settings with Dice ranged from 0.821 to 0.962 for thirteen target abdominal tissues structures. We observed high variability in most organ with ICC<0.5, low variability in the area of muscle, abdominal wall, fat and body mask with average ICC≥0.8. We found that the variability in organ is highly related to the cross-sectional position of the 2D slice. Our efforts pave quantitative exploration and quality control to reduce uncertainties in longitudinal analysis.

NOVEL INSIGHTS INTO GAIT, MOTOR CONTROL, AND THE BRAIN: IMPLICATIONS FOR COGNITIVE AGING

Abstract What can muscles, gait, and brain activity tell us about cognitive decline? Are there certain markers we can track that are early predictors of cognitive status years later? In the current symposia, our goal is to address these questions with recent pilot, longitudinal and cross-sectional studies that measure potential markers of cognitive decline in different older adult cohorts. The first speaker will present findings on changes in skeletal muscle adiposity and 10-year change in global cognition from the Health Aging and Body Composition (Health ABC) study. The second speaker explores cross-national comparisons of gait speed and its association with cognitive function from the Cohort Studies of Memory in an International Consortium (COSMIC). The third speaker investigates changes in brain activity with functional near infra-red spectroscopy (fNIRS) from single to dual-task walking and its relation to changes in several gait quality parameters. The fourth speaker presents pilot work that examines dual-task gait and tapping with fNIRS and compares the dual-task performance and brain activity of older adults who report experiencing subjective cognitive decline to those that do not. The final speaker presents findings from the Baltimore Longitudinal Study on Aging (BLSA) that demonstrate that early markers of slow gait and metabolic dysfunction could identify those at risk of progression to dementia 7 years prior to onset. Taken together, the findings from this symposium present novel markers of changes in cognitive function in older adults and ultimately targets for prevention or slowing of cognitive declines in older adults at risk for dementia.

Contrastive semi-supervised harmonization of single-shell to multi-shell diffusion MRI

Diffusion weighted MRI (DW-MRI) harmonization is necessary for multi-site or multi-acquisition studies. Current statistical methods address the need to harmonize from one site to another, but do not simultaneously consider the use of multiple datasets which are comprised of multiple sites, acquisitions protocols, and age demographics. This work explores deep learning methods which can generalize across these variations through semi-supervised and unsupervised learning while also learning to estimate multi-shell data from single-shell data using the Multi-shell Diffusion MRI Harmonization Challenge (MUSHAC) and Baltimore Longitudinal Study on Aging (BLSA) datasets. We compare disentanglement harmonization models, which seek to encode anatomy and acquisition in separate latent spaces, and a CycleGAN harmonization model, which uses generative adversarial networks (GAN) to perform style transfer between sites, to the baseline preprocessing and to SHORE interpolation. We find that the disentanglement models achieve superior performance in harmonizing all data while at the same transforming the input data to a single target space across several diffusion metrics (fractional anisotropy, mean diffusivity, mean kurtosis, primary eigenvector).

Accelerating 2D Abdominal Organ Segmentation with Active Learning.

Abdominal computed tomography CT imaging enables assessment of body habitus and organ health. Quantification of these health factors necessitates semantic segmentation of key structures. Deep learning efforts have shown remarkable success in automating segmentation of abdominal CT, but these methods largely rely on 3D volumes. Current approaches are not applicable when single slice imaging is used to minimize radiation dose. For 2D abdominal organ segmentation, lack of 3D context and variety in acquired image levels are major challenges. Deep learning approaches for 2D abdominal organ segmentation benefit by adding more images with manual annotation, but annotation is resource intensive to acquire given the large quantity and the requirement of expertise. Herein, we designed a gradient based active learning annotation framework by meta-parameterizing and optimizing the exemplars to dynamically select the 'hard cases' to achieve better results with fewer annotated slices to reduce the annotation effort. With the Baltimore Longitudinal Study on Aging (BLSA) cohort, we evaluated the performance with starting from 286 subjects and added 50 more subjects iteratively to 586 subjects in total. We compared the amount of data required to add to achieve the same Dice score between using our proposed method and the random selection in terms of Dice. When achieving 0.97 of the maximum Dice, the random selection needed 4.4 times more data compared with our active learning framework. The proposed framework maximizes the efficacy of manual efforts and accelerates learning.

Assessing Bias in Cognitive Testing for Older Adults with Sensory Impairment: An Analysis of Differential Item Functioning in the Baltimore Longitudinal Study on Aging (BLSA) and the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS).

Vision and hearing impairments affect 55% of people aged 60+ years and are associated with lower cognitive test performance; however, tests rely on vision, hearing, or both. We hypothesized that scores on tests that depend on vision or hearing are different among those with vision or hearing impairments, respectively, controlling for underlying cognition. Leveraging cross-sectional data from the Baltimore Longitudinal Study of Aging (BLSA) and the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), we used item response theory to test for differential item functioning (DIF) by vision impairment (better eye presenting visual acuity worse than 20/40) and hearing impairment (better ear .5-4kHz pure-tone average > 25 decibels). We identified DIF by vision impairment for tests whose administrations do not rely on vision [e.g., Delayed Word Recall both in ARIC-NCS: .50 logit difference between impaired and unimpaired (p=.04) and in BLSA: .62 logits (p=.02)] and DIF by hearing impairment for tests whose administrations do not rely on hearing [Digit Symbol Substitution test in BLSA: 1.25 logits (p=.001) and Incidental Learning test in ARIC-NCS: .35 logits (p=.001)]. However, no individuals had differences between unadjusted and DIF-adjusted measures of greater than the standard error of measurement. DIF by sensory impairment in cognitive tests was independent of administration characteristics, which could indicate that elevated cognitive load among persons with sensory impairment plays a larger role in test performance than previously acknowledged. While these results were unexpected, neither of these samples are nationally representative and each has unique selection factors; thus, replication is critical.

Profiles of Cognitive Change in Preclinical and Prodromal Alzheimer's Disease Using Change-Point Analysis.

Alzheimer's disease (AD) is now understood to have a long preclinical phase in which pathology starts to accumulate in the absence of clinical symptoms. Identifying the temporal stages of accelerated cognitive decline in this phase may help in developing more sensitive neuropsychological tools for early screening of preclinical cognitive decline. Change-point analyses are increasingly used to characterize the temporal stages of accelerated cognitive decline in the preclinical stages of AD. However, statistical comparisons of change-points between specific cognitive measures have not been reported. To characterize and compare the temporal stages of accelerated decline in performance on multiple cognitive tests in a sample of participants from the Baltimore Longitudinal Study on Aging (BLSA) who later developed AD. 165 older adults (baseline age range: 61.1-91.2) from the BLSA developed AD during follow-up. Linear and non-linear mixed models were fit for 11 cognitive measures to determine change-points in rates of decline before AD diagnosis. Bootstrapping was used to compare the timing of change-points across cognitive measures. Change-points followed by accelerated decline ranged from 15.5 years (Standard Error (S.E.) = 1.72) for Card Rotations to 1.9 years (S.E. = 0.68) for the Trail-Making Test Part A before AD diagnosis. Accelerated decline in Card Rotations occurred significantly earlier than all other measures, including learning and memory measures. Results suggest that visuospatial ability, as assessed by Card Rotations, may have the greatest utility as an early predictive tool in identifying preclinical AD.

Age-associated changes in human CD4+ T cells point to mitochondrial dysfunction consequent to impaired autophagy.

To gain understanding on the mechanisms that drive immunosenescence in humans, we examined CD4+ T cells obtained from younger (20-39 years-old) and older (70+ years-old) healthy participants of the Baltimore Longitudinal Study on Aging (BLSA). We found that mitochondrial proteins involved in the electron transport chain were overrepresented in cells from older participants, with prevalent dysregulation of oxidative phosphorylation and energy metabolism molecular pathways. Surprisingly, gene transcripts coding for mitochondrial proteins pertaining to oxidative phosphorylation and electron transport chain pathways were underrepresented in older individuals. Paralleling the observed decrease in gene expression, mitochondrial respiration was impaired in CD4+ T cells from older subjects. Though mitochondrial number in both naïve and memory cells visualized with electron microcopy was similar in older versus younger participants, there were a significantly higher number of autophagosomes, many of them containing undegraded mitochondria, in older individuals. The presence of mitochondria inside the accumulated autophagic compartments in CD4+ T cells from older individuals was confirmed by immunofluorescence. These findings suggest that older age is associated with persistence of dysfunctional mitochondria in CD4+ T lymphocytes caused by defective mitochondrial turnover by autophagy, which may trigger chronic inflammation and contribute to the impairment of immune defense in older persons.

The Relationship Between Brain–Heart Autonomic Signaling and Aging: A Gender-Specific Longitudinal Perspective from the Baltimore Longitudinal Study on Aging

<h3>Background</h3> Low heart rate variability (HRV) has been previously associated with adverse cardiovascular outcomes in high-risk populations or subjects with previously documented cardiovascular conditions. Information about HRV in healthy subjects is, however, scant. Moreover, gender effects of HRV in healthy subjects have not being well described. The objective of this study was to evaluate aging-related changes of the autonomic nervous system as measured by HRV in a cohort of healthy subjects. <h3>Methods</h3> We evaluated 368 subjects from the Baltimore Longitudinal Study on Aging (BLSA) who had 2 or more Holter studies with time-domain variables lasting 24 hours. The study population is a series of healthy volunteers of different ages, starting at 20 years old, followed indefinitively with a series of evaluations over time. The data were analyzed using linear mixed effects that account for unbalanced unequally spaced observations using SAS® 9.2 software, which is characteristic of the BLSA cohort. The number of pairs of successive NNs that differ by >50 ms (pNN50), the standard deviation of NN intervals (SDNN), and the standard deviation of the average NN intervals (SDANN) were used to measure HRV. <h3>Results</h3> Average age of participants in this study is 65.3 years (range 20–97 years). We found a statistically significant difference on HRV variables and gender, with women having lower HRV values than men (pNN50 –5.416%, <i>P</i> = .002; SDNN –18.974 ms, <i>P</i> = .0001; SDANN –12.945 ms, <i>P</i> = .0001). When each variable was analyzed by gender, our study did not show a significant longitudinal association between aging and changes in HRV, but it did show a significant cross-sectional association. This association is characterized by lower HRV variables measurements in later ages of life compared to earlier ones. <h3>Conclusions</h3> Our study shows that changes in HRV are gender dependent, with women having lower HRV than men at any given age. We also found that HRV variable measurements are lower in advanced ages compared to younger ones.

Correlates of D-dimer in older persons

D-dimer is a marker of active fibrinolysis. Understanding how age-related factors affect D-dimer levels may help the interpretation of high D-dimer levels in older individuals. 776 Baltimore Longitudinal Study on Aging (BLSA) participants (mean age 68.4+/-13.9 yrs) were divided into three groups according to baseline D-dimer levels >200 ng/mL; 100-200 ng/mL and <100 ng/mL. D-dimer level increased with age (p<0.0001). Using polychotomous logistic regression models, we found that age, cholesterol, triglycerides, creatinine, erythrocyte sedimentation rate, hemoglobin and body mass index were independently associated with D-dimer level. Rising levels of D-dimer with age can be explained in part by the high prevalence of pro-inflammatory conditions and increasing burden of lipid abnormalities, anemia and obesity. These factors compromise the specificity of D-dimer levels as a diagnostic aid to thrombosis in older individuals.

Longitudinal Paths to the Metabolic Syndrome: Can the Incidence of the Metabolic Syndrome Be Predicted? The Baltimore Longitudinal Study of Aging

To determine the predictors of incidence of metabolic syndrome (MetS) (Adult Treatment Panel III criteria) and to determine if longitudinal changes in specific MetS components differ by age or gender in participants who developed versus those who did not develop MetS. A total of 506 men and 461 women (baseline age 52.4 +/- 17.5 years) from the Baltimore Longitudinal Study on Aging (BLSA) were followed longitudinally (at least two study visits), and censored when they developed the MetS or reported use of antihypertensive or lipid-lowering medications. After a follow-up period of 6 years, the incidence of the MetS was 25.5% in men and 14.8% in women. As many as 66% of men and 73% of women with one or two altered MetS components at baseline did not develop the MetS. Predictors of developing MetS were higher baseline abdominal obesity or triglycerides and lower high-density lipoprotein cholesterol (area under receiver-operated curve [AUC] = 0.84 in men, 0.88 in women). Addition of the rate of changes in MetS components over time slightly improved predictive accuracy (AUC = 0.94 in men, 0.92 in women). Men were more likely than women to have the MetS without obesity, whereas women were more likely than men to have the MetS without an altered glucose metabolism. The patterns of MetS components and the longitudinal changes that lead to the MetS are different in men and women. Interestingly, components with the highest prevalence prior to MetS development, such as elevated blood pressure, are not necessarily the stronger risk factors.

Rates of Depression in Individuals With Pathologic But Not Clinical Alzheimer Disease are Lower Than Those in Individuals Without the Disease: Findings From the Baltimore Longitudinal Study on Aging (BLSA)

The prevalence of major depression is increased in Alzheimer disease (AD), but currently the basis of this association remains unclear. The present study examined rates of depression in 4 groups of participants with postmortem examination from the Baltimore Longitudinal Study of Aging: (1) cognitively normal controls with no Alzheimer pathology, (2) cognitively normal individuals with Alzheimer pathology, (3) individuals with mild cognitive impairment plus Alzheimer pathology, (4) individuals with clinical diagnoses of dementia plus Alzheimer pathology. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. Individuals with Alzheimer pathology but no cognitive decline before death had significantly lower rates of depression than cognitively normal controls with no Alzheimer pathology and individuals with Alzheimer pathology plus clinical diagnoses of dementia. These findings suggest that depression is a risk factor for AD in the presence of AD pathology, but depression is not a risk factor for AD pathology.

Early involvement of small inhibitory cortical interneurons in Alzheimer’s disease

Work on acute models of cortical injury has revealed a population of small GABAergic interneurons that are induced to increase their low constitutive expression of neuronal nitric oxide (NO) synthase (nNOS). In some cases, this activation may play a role in NO-mediated degeneration of pyramidal neurons. In this report, we explore the anatomy of various classes of cortical nNOS (+) (nitrergic) neurons, with emphasis on small interneurons, in the medial temporal lobe of subjects with Alzheimer's disease (AD) from two well-characterized cohorts, the Baltimore Longitudinal Study on Aging (BLSA) and the Religious Order Study (ROS). We find that small calbindin (+) cortical interneurons are induced to high levels of NADPHd/nNOS reactivity early in AD and abound in areas with emerging neurofibrillary pathology, that is, in entorhinal cortex in the beginning of the limbic stage of Braak, in hippocampal CA1 in the mature limbic stage and in temporal neocortex in the late limbic stage. This pattern was robust and significant in the younger of the two AD cohorts studied (BLSA), but persisted as a trend in the older cohort (ROS). In optimally prepared material, we find a significant correlation between numbers of these interneurons and markers of neuronal cell death, for example, caspase-3 activation. Our results show that small cortical inhibitory interneurons represent an extensive signaling system that is induced to higher levels of NADPHd/nNOS expression early in the paralimbic-limbic-neocortical sequence of AD progression. We propose that nNOS/NO signaling initiated in these interneurons can serve as a marker of early cortical injury in AD. The specific role played by inhibitory interneurons and NO in the elaboration of specific neuropathologies associated with AD, that is, Abeta and neurofibrillary deposits and cell death deserves further exploration in experimental animal models.

Serum Erythropoietin and Aging: A Longitudinal Analysis

To determine the changes in serum erythropoietin with age in patients with and without anemia and to assess the importance of certain comorbidities on changes in erythropoietin level and the development of anemia. Clinical history, hematological parameters, and serum erythropoietin levels were examined at 1- to 2-year intervals for 8 to 30 years. Baltimore Longitudinal Study on Aging (BLSA), National Institute on Aging. One hundred forty-three BLSA participants. Complete blood count and serum chemistries were performed at the time of each visit, and archived serum samples were used for erythropoietin level. Although all subjects were healthy and without anemia at the time of initial evaluation, some developed chronic illness-most notably hypertension and diabetes mellitus. Erythropoietin levels rose significantly for the group as a whole, and the slope of the rise was found to be greater for those who did not have associated diabetes mellitus or hypertension. During the subsequent years, subjects who developed anemia but did not have hypertension or diabetes mellitus had the greatest slope in erythropoietin rise over time, whereas those with hypertension or diabetes mellitus and anemia had the lowest erythropoietin slope. The increase in serum erythropoietin with aging may be compensation for subclinical blood loss, increased red blood cell turnover, or increased erythropoietin resistance of red cell precursors. It is suspected that, with very advanced age, or in those with compromised renal function (e.g., diabetes mellitus or hypertension), the compensatory mechanism becomes inadequate and anemia results.

Serum Erythropoietin and Aging: A Longitudinal Analysis.

There are conflicting data regarding expected changes in serum erythropoietin (EPO) with advancing age, primarily because prior reports have been based upon cross-sectional analyses of diverse populations. To examine changes in serum EPO with age, we reviewed the clinical history, hematological parameters and serum EPO levels of 143 participants in the Baltimore Longitudinal Study on Aging (BLSA) who were studied at 1 – 2 year intervals for eight to thirty years. None had anemia at the time of the first visit (by WHO criteria: <12g/dL for women; or <13 g/dL for men) but it developed in 10 (7%) over the period of evaluation. An additional 20 individuals (14%) had a fall in hemoglobin of 1.5 g/dL or more, sustained over at least two visits, and for the purpose of this analysis were also considered anemic. EPO levels rose significantly with age for the group as a whole, and the slope of the rise was found to be greater for those who did not have associated diabetes or hypertension. Subjects who developed anemia but did not have hypertension or diabetes had the greatest slope in EPO rise over time. In contrast, those who had, or developed hypertension or diabetes during the period of follow-up within the BLSA, had significantly higher initial EPO levels and a reduced EPO slope over time. The increase in serum EPO with aging may be compensating for increased RBC turnover or increased EPO resistance of red cell precursors. We suspect that with very advanced age, or in those with compromised renal function (e.g., diabetes or hypertension), the compensatory mechanism becomes inadequate. [Display omitted] [Display omitted]

Ciliary neurotrophic factor (CNTF) genotype and body composition.

Exogenous ciliary neurotrophic factor (CNTF) administration causes significant weight loss in both humans and animal models, but the effects of endogenous CNTF and the CNTF null allele on body composition are not fully understood. A recent study in a European cohort demonstrated a significantly higher body weight and body mass index (BMI) in older males homozygous for the CNTF null allele (A/A genotype). We sought to replicate these findings in three cohorts: the Baltimore Longitudinal Study on Aging (BLSA) consisting of 422 adult men and women (19-90 years); the Study of Osteoporotic Risk in Men (STORM) consisting of 333 older men (50-84 years); and a third sample obtained by combining older males aged 59-73 years from the BLSA and STORM cohorts (n=286). In contrast to the European study, we were unable to detect a significant association between CNTF genotype and body weight in the BLSA (P=0.49), the STORM (P=0.28), or the combined samples (P=0.72). There was also no significant association observed between CNTF genotype and BMI in the BLSA (P=0.59), the STORM (P=0.34) or the combined (P=0.56) samples. In addition, we were unable to detect a significant association between CNTF genotype and total body fat (P=0.95) or fat-free mass (P=0.86) in the BLSA cohort. Our results do not support an effect of the CNTF null allele on body composition, contrary to previous findings.

Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease.

The preceding article in this series1 reviewed evidence as to why age-associated changes in the central arterial system are risky with respect to vascular disease. In a similar vane, the focus of this article is on the potential link between age-associated changes in the heart and clinical cardiac disease outcomes. Left ventricular hypertrophy, heart failure, and atrial fibrillation increase dramatically with age (Figure 1). The prevalence of left ventricular hypertrophy (LVH) also increases with rising blood pressure and body mass index, a measure of obesity.2–4 Whether identified by electrocardiography or echocardiography, left ventricular hypertrophy has been shown to be associated with increased risk for coronary heart disease, sudden death, stroke, and overall cardiovascular disease.4,5 Figure 1. A, Prevalence of echocardiographic left ventricular hypertrophy (LVH) in women according to baseline age and systolic blood pressure. B, Prevalence of echocardiographic LVH in men according to baseline age and systolic blood pressure. Both A and B are reprinted from Levy D, Anderson KM, Savage DD, et al. Echocardiographically detected left ventricular hypertrophy: prevalence and risk factors: the Framingham Heart Study. Ann Intern Med . 1988;108:7–13. C, Prevalence of heart failure by age in Framingham Heart Study men (light bars) and women (dark bars). Reprinted from Ho KK, Pinsky JL, Kannel WB, et al. The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol 1993;22:6A–13A. D, Prevalence of AF by age in subjects from the Framingham Heart Study. Reprinted from Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke . 1991;22:983–988. It has been increasingly appreciated that the development of heart failure with apparently preserved systolic function, as evidenced by a “normal” ejection fraction, occurs in about one-third to one-half of older patients with heart failure.6–9 In a …

Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a "set up" for vascular disease.

Our population is aging; in the United States today there are 35 million people 65 years of age or older. That number will double by the year 2030 (Figure 1). Although epidemiological studies have discovered that lipid levels, diabetes, sedentary lifestyle, and genetic factors are risk factors for coronary disease, hypertension, congestive heart failure, and stroke, the quintessential cardiovascular diseases within our society, advancing age unequivocally confers the major risk. The incidence and prevalence of these diseases increase steeply with advancing age (Figure 2). Not only does clinically overt cardiovascular disease increase dramatically with aging, but so do subclinical or occult diseases, such as silent coronary atherosclerosis. Figure 3 (top) shows that a substantial percentage of older, community-dwelling, otherwise healthy volunteers have evidence of inducible ischemia during combined thallium/ECG treadmill stress testing, and their prognosis is poor compared with their counterparts without subclinical coronary disease (Figure 3, bottom). Figure 1. The demographic imperative. Numbers of persons 65 years of age or older (light bars) and 85 years of age or older in the United States from 1900 through 2030. Data taken from the US Census Bureau data with projections for 2030. Figure 2. A, Prevalence of hypertension, defined as systolic blood pressure ≥140, diastolic blood pressure ≥90, or current use of medication for purposes of treating high blood pressure. Data are based on National Health and Nutrition Examination Survey III (1988–1991) (Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population: results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension . 1995;25:305–313). B, Incidence of atherothrombotic stroke (per 1000 subjects per year) by age in men (light bars) and women (dark bars) from the Framingham Heart Study. Data from Wolf PA. Lewis A. Conner lecture: contributions of epidemiology to the …

The relationship between aerobic exercise capacity and circulating IGF-1 levels in healthy men and women.

To determine whether aerobic capacity is associated independently with insulin-like growth factor-I (IGF-1) levels in healthy community-dwelling men and women. The Baltimore Longitudinal Study on Aging (BLSA). A cross-sectional analysis of data from the population-based cohort of the Baltimore Longitudinal Study of Aging (BLSA). We studied 181 men and 92 women aged 20 to 93 years, volunteers in the Baltimore Longitudinal Study on Aging (BLSA). Subjects were free of endocrine, renal, hepatic, gastrointestinal, or cardiac diseases, and they were taking no medications known to interfere with the growth hormone-IGF-1 axis. All subjects underwent a single measurement of serum IGF-1 in the fasting state, as well as peak VO2 determinations during maximal treadmill exercise testing performed within one visit of the IGF-1 determination. Dual energy X-ray absorptiometry (DEXA) scans were performed in a subset of 171 subjects (64 women and 107 men) for determination of fat free mass (FFM). In the pooled group of women and men, univariate regression analysis revealed that age was correlated strongly with decreasing IGF-1 levels (r = -0.53, P < .001) and with peak VO2r = -0.56, P < .001). IGF-1 levels were also significantly correlated with peak VO2 (r = 0.29, P < .001). There were no significant gender-related differences in these relationships. On multivariate analysis, age (beta = -0.54, P < .001), but not peak VO2 (P = -0.01, P = .840), remained strongly associated with IGF-1 levels. After adjustment of peak VO2 for FFM in subjects with DEXA scans, results were similar. These findings indicate that although both peak aerobic capacity and circulating IGF-1 levels decline with age, aerobic capacity is not independently related to circulating IGF-1 in healthy men and women across the adult life span.

End tidal CO2 is an independent determinant of systolic blood pressure in women.

Recent studies have shown that high resting end tidal CO2 (PECO2) is a marker for blood pressure sensitivity to high sodium intake by normotensive humans. The present study investigated the association of resting PECO2 with resting blood pressure in participants in the Baltimore Longitudinal Study on Aging (BLSA). PECO2 of 314 healthy participants (153 men and 161 women, aged 21-79 years) was measured by a respiratory gas monitor during 25 min of seated rest, and blood pressure every 5 min by an automated oscillometric system. The independent associations of PECO2 and other variables with systolic (SBP) and diastolic (DBP) blood pressure were analysed via multiple regression. Sex differences in age-associated changes in PECO2 and in the role of pulmonary capacity in the PECO2 -blood pressure relationships were also studied. Resting PECO2 was an independent predictor of SBP in women (beta = 0.215; P<0.0015; overall r2 = 0.27; P<0.0001), and accounted for more than 10% of the variance in SBP in women over age 50 years. No such associations of PECO2 with SBP of men, or with DBP of men or women, were observed. PECO2 was lower in younger women (36.0+/-0.9 mm Hg) than in younger men (40.4+/-2.0), but higher in older women (37.1+/-0.5) than in older men (35.5+/-0.4). PECO2 is an independent determinant of resting SBP in women, especially those aged 50 years or more. The origin of individual differences in resting PECO2 and its possible role in the development of chronic hypertension remain to be clarified.

Association of the Pro12Ala variant in the peroxisome proliferator-activated receptor-gamma2 gene with obesity in two Caucasian populations.

The nuclear receptor, peroxisome proliferatora c t ivated receptor( P PA R ), is an important regulator of adipocyte differentiation and a modulator of intracellular insulin-signaling events (1). PPA R mRNA expression in both skeletal muscle and adipose tissue in vitro is induced by insulin (2,3). In skeletal muscle of obese subjects, PPA R mRNA is elevated in direct relation to BMI and fasting insulinemia (2); reports are mixed as to whether expression is increased in adipose tissue of obese subjects (3–5). In one report, activators of PPA R were shown to increase adiposity in a rodent model (6), while in another (7) they were found to increase the number of adipocytes, but not the mass of adipose tissue. Clinically, most studies have not found that PPA R –activating thiazolidinediones cause weight gain when administered to humans for treatment of diabetes (1). Alternate use of promoters and differential splicing of the human PPARgene results in two isoforms: PPAR1 and PPAR2. PPAR2 contains 28 additional amino acids at its NH2 terminus (1,8). PPAR1 and PPAR2 both are expressed in adipose tissue (1,3–5), and there appears to be no difference in the abilities of the two isoforms to participate in ligand-induced initiation of transcription of target genes or in ligand-induced adipocyte differentiation (9). Interestingly, however, it was demonstrated recently that P PA R could activate transcription in a ligand-independent fashion and that insulin potentiated this activity (9). F u r t hermore, the 2 isoform is much more potent at doing so than is the 1 isoform (9), suggesting a possible distinct role for PPA R 2 in obesity, insulin resistance, and diabetes. R e c e n t l y, we reported a naturally occurring variant in the human PPA R 2 gene that predicts substitution at amino acid 12 of alanine for the proline that is present in both normal human and mouse PPA R 2 sequences (10). This amino acid position is within the domain of PPA R 2 that enhances ligand-independent activation, as described by Werman et al. (9). Because the substitution of alanine for proline is nonconservative and could cause a significant change in protein structure, we hypothesize that it may alter the function of P PA R 2 such that individuals with this variant may be at an increased genetic risk for obesity and/or insulin resistance. To test this hypothesis, we genotyped and performed association studies of the Pro12Ala PPA R 2 variant in two independently recruited cohorts of unrelated, nondiabetic, adult Caucasian subjects from the Baltimore metropolitan area. One cohort of 517 subjects, with a distribution of being lean-to-moderately obese (mean BMI 26.5 kg/m, range 18.6–43.2 kg/m), is from the Baltimore Longitudinal Study on Aging (BLSA) and has been recruited continuously since 1958. The other cohort is of 169 very obese subjects (mean BMI 36.5 kg/m, range 24.2–76.8 kg/m), recruited prospectively from August 1994 through June 1996 from the Johns Hopkins University We i g h t Management Center (JHU-WMC). Subjects with diabetes by history or with fasting glucose ≥7.1 mmol/l (126 mg/dl) were excluded to avoid the well-known confounding effects of diabetes and its treatment on the obesity-related traits that were studied. All protocols were approved by the Institutional Review Board of the Johns Hopkins University, and informed written consent was obtained from all subjects. Genomic DNA was obtained from peripheral blood using standard methods, and the Pro12Ala PPA R 2 variant was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. This PCR-RFLP analysis, previously described (10), uses a mutagenic PCR primer to introduce a B s t UI site only when a C → G substitution at nucleotide 34 of the PPA R 2 gene is present. Genotyping was repeated for all Ala 2 homozygotes, several Pro12Ala heterozygotes chosen randomly, and several Pro 2