Biomedical subjects

D Carmelli

Publications and source records attributed to D Carmelli.

At least 19 recordsLinked to original sources

PubMed2002

Differential rates of regional brain change in callosal and ventricular size: a 4-year longitudinal MRI study of elderly men.

Brain structure changes in size with normal aging, but the rate at which different structures change is controversial. We used magnetic resonance imaging (MRI) performed twice, 4 years apart, to compare rates of age-related size change of the corpus callosum, which has been inconsistently observed to thin with age, with change in the lateral ventricles, which are well established to enlarge. Subjects were 215 community dwelling, elderly men (70-82 years old at initial MRI), who were participants in a longitudinal study of cardiovascular risk factors. Percent change in size was significant for both the callosal and ventricular measures, but annual rate of ventricular expansion (2.9%) was significantly greater than annual rate of callosal thinning (-0.9%). Callosal regions showed statistically equivalent rates of shrinkage; ventricular dilatation was symmetrical. Neither callosal and ventricular rates of change correlated with each other (r = 0.01), nor did genu and splenium rates of change correlate with each other (r = 0.05). Tests of speeded processing were administered contemporaneously with both MRIs to examine functional ramifications of observed brain changes. Decline in the Mini-Mental State Examination was related to thinning of the splenium, and decline in Stroop test word reading was selectively related to thinning of the callosal body. These longitudinal data support the contentions that differential rates of change occur in different brain regions in normal aging, age-related callosal thinning contributes to functional declines, and rate of change in one region can be independent of rate of change in another region, even within a brain structure.

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PubMed2001

Genetic factors in self-reported snoring and excessive daytime sleepiness: a twin study.

Subjects in this study included 1,560 intact male-male twin pairs (818 monozygotic [MZ], 742 dizygotic [DZ]) of mean age (+/- SD) 74.2 +/- 2.8 yr. The Epworth Sleepiness Scale (ESS) was used to assess daytime sleepiness and standardized questionnaires assessed snoring. Multivariate genetic model fitting was used to estimate the contribution of genetic and nongenetic (environmental) influences to the variation and covariation of obesity with snoring and daytime sleepiness. In this sample, 26% were habitual snorers, 18% reported excessive daytime sleepiness (ESS > or = 11), and 29% were obese (body mass index [BMI] > or = 28). By using structural equation modeling, we estimated that genetic factors accounted for 64% of the variance in obesity, 40% of the variance in daytime sleepiness, and 23% of the variability in self-reports of snoring. We found a significant genetic correlation between obesity and snoring and between obesity and excessive daytime sleepiness (EDS), although for the most part the genetic variance in snoring and sleepiness was nonoverlapping with the genetic variance for obesity. We conclude from these data that self-reported symptoms of snoring and daytime sleepiness in older men have a genetic basis that is largely independent of genes associated with obesity.

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PubMed2001

Genetic regulation of regional microstructure of the corpus callosum in late life.

In order to identify brain structural phenotypes that remain under significant genetic control in late adulthood, we examined the heritability of corpus callosum macrostructure (i.e. size) using MRI and microstructure (e.g. myelin) using diffusion tensor imaging in 15 monozygotic and 18 dizygotic twin pairs of elderly men. The relative proportion of genetic to environmental influences varied considerably by region and structural type and was 5:1 for callosal macrostructure, 3:1 for splenium microstructure, and 1:1 for genu microstructure. This is the first in vivo identification of quantifiable phenotypes of brain white matter microstructure and demonstrates significant and differential genetic regulation in old age, with anterior interhemispheric connecting pathways more susceptible than posterior pathways to environmental influences.

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PubMed2001

Cerebrovascular and brain morphologic correlates of mild cognitive impairment in the National Heart, Lung, and Blood Institute Twin Study.

OBJECTIVE: To evaluate the relative risk (RR) of mild cognitive impairment (MCI) associated with cerebrovascular risk factors and cerebrovascular-related brain changes. DESIGN: Mild cognitive impairment was determined for the subjects of the prospective National Heart, Lung, and Blood Institute Twin Study. Quantitative measures of brain, white matter hyperintensity, cerebral infarction, apolipoprotein E genotype, and psychometric testing were obtained. RESULTS: Subjects with MCI were older (73.5 +/- 3.0 vs 72.1 +/- 2.8 years), consumed less alcohol (3.7 +/- 5.8 vs 7.0 +/- 10.7 drinks per week), had greater white matter hyperintensity volumes (0.56% +/- 0.82% vs 0.25% +/- 0.34% of cranial volume), and had an increased prevalence of apolipoprotein E4 genotype (31.4% vs 19.2%) than normal subjects. White matter hyperintensity and the presence of the apolipoprotein E4 genotype were associated with a significantly increased risk for MCI. When all subjects were included in the analysis, alcohol consumption was associated with a reduced risk for MCI (RR = 0.93, P<.05). When subjects with a history of symptomatic cerebrovascular disease were excluded from the analysis, elevated midlife diastolic blood pressure was associated with an increased risk for MCI (RR = 1.70, P<.05). CONCLUSIONS: Elevated midlife blood pressures, and the resulting increased white matter hyperintensities, increase the risk for MCI in a group of community-dwelling older men to at least the same degree as apolipoprotein E4 genotype. Given the common occurrence of elevations in midlife blood pressure, early and effective treatment may be warranted to prevent late-life brain abnormalities and MCI. Moreover, since many individuals with MCI progress to clinical dementia, longitudinal evaluations of this cohort will be important.

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PubMed2001

Heritability of hippocampal size in elderly twin men: equivalent influence from genes and environment.

Recent studies have established that environmental factors can modify hippocampal structure and enhance function in adult rodents, but the extent to which genes and the environment exert differential contributions to hippocampal structural integrity in humans is unknown. Here, we applied the twin model in a large sample of elderly twin men to examine in late life the balance of environmental and genetic effects on the size of the hippocampus in comparison with other brain structures. This study provides novel evidence that the volume of the hippocampus, as measured on MRI, is subject to substantially less genetic control than are comparison brain regions also measured: temporal horn volume, midsagittal area of the corpus callosum, and intracranial volume (ICV). In particular, about 60% of the temporal horn variance and 80% of the callosal and ICV variance was attributable to genetic influences, whereas only 40% of the hippocampal variance was attributable to genetic influences. These results suggest that environment, whether by itself or in interaction with genes, has the potential of exerting greater and possibly longer control in modifying hippocampal size than other brain regions that are under greater genetic control. Considering the potential of environmental modification of this structure suggested by lower heritability, the hippocampus appears well-suited to support the dynamic processes of encoding and consolidation of new, declarataive memories.

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PubMed2001

A genetic analysis of the Epworth Sleepiness Scale in 1560 World War II male veteran twins in the NAS-NRC Twin Registry.

Responses to the eight-item Epworth Sleepiness Scale (ESS) obtained from 1560 World War II male veteran twin pairs [818 monozygotic (MZ), 742 dizygotic (DZ)] were analysed to determine the extent to which genetic influences are involved in self-reported daytime sleepiness in the elderly. Average ESS score (+/- SD) in this sample was 7.1 +/- 3.9, range 0--24. More than half of the twins (65%--67%) reported a moderate to high chance of falling asleep while lying down to rest; fewer than 3% admitted that this would occur while sitting and talking to someone or while stopped in traffic. Daytime sleepiness was not associated with age but was significantly and positively associated with obesity. The intraclass twin correlation on ESS scores was 0.39 in MZ pairs and 0.21 in DZ pairs (both P < 0.001). Structural equation modeling of the observed variance-covariance matrices for MZ and DZ twins estimated the heritability of ESS to be 38% (95% confidence interval 33%--44%). Environmental influences not shared by twin brothers accounted for the remaining variance in daytime sleepiness. A reasonable interpretation of the heritability of ESS in this healthy cohort of elderly male twins is a genetic susceptibility for disordered breathing during sleep.

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PubMed2000

Biobehavioral characteristics of nondemented older adults with subclinical brain atrophy.

OBJECTIVE: To characterize the risk factors and neuropsychological performance of two subgroups of community-dwelling, white elderly men free of severe cognitive impairment (n = 383; mean age, 72.9 +/- 3.0 years) who differ on volumetric measurements of total brain parenchyma and white matter hyperintensity (WMH) volumes. METHODS: Group comparisons were made of cerebrovascular disease risk factors measured at the time of imaging and at three prior examinations extending over 25 years of adult life. Measures of verbal memory and speed psychomotor processing at the time of imaging and 10 years before imaging were also available. RESULTS: Compared with those in the "nonatrophy" group, individuals in the subgroup with "atrophy" (defined by low total brain volume and high WMH volume) were older, reported a higher level of depressive symptomatology, experienced a steeper decline in diastolic blood pressure (DBP) and a steeper increase in pulse pressure, were less physically active, had smoked for more years, and had a higher prevalence of several cardiovascular disease indicators, including an ankle/arm systolic blood pressure ratio less than 0.9, and hypertension. After multivariate analysis, the 25-year decline in DBP, the number of years smoked, and an ankle/arm index of less than 0.9 remained significant discriminators of the two groups. Lower levels of speeded performance at the time of imaging and a steeper 10-year decline in cognitive performance on selected tests were also observed in the atrophic group. CONCLUSION: Community-dwelling older adults with volumetric brain measurements associated with accelerated aging are distinguishable on the basis of several health-related characteristics. These individuals also perform less well on certain tasks involving executive functioning.

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PubMed2000

Contribution of genetic and environmental influences to ankle-brachial blood pressure index in the NHLBI Twin Study. National Heart, Lung, and Blood Institute.

The ankle-brachial index (ABI) is widely used in the clinical diagnosis of peripheral arterial disease. The contributions of genetic and environmental influences to normal and abnormal ABI values are unknown. In this study, the authors used available data on 94 monozygotic pairs and 90 dizygotic pairs of elderly, White, male twins examined in 1995-1997 to investigate the contributions of genetic and environmental influences to normative ABI values. Within-twin-pair correlations for normative ABI values were statistically significant, and the correlation in monozygotic twin pairs was significantly greater than that in dizygotic pairs. Structural equation modeling of the variance-covariance matrices of monozygotic and dizygotic twins indicated that 48% of the observed variability in ABI values could be attributed to additive genetic effects. In contrast, concordance rates for low ABI values (ABI< or =0.9) for both monozygotic and dizygotic twins were significantly greater than would be expected by chance alone, but within-pair monozygotic similarity was not significantly greater than dizygotic similarity. A matched-cotwin analysis in 21 pairs that were discordant for low ABI values found that twins with low ABI values were physically less active and more likely to be persistent smokers than their normal-control brothers. These findings reinforce the role of individual health practices (e.g., physical activity, smoking) in the manifestation of peripheral arterial disease among subjects matched for age, genetics, and early shared environment.

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PubMed2000

Ten-year follow-up for male twins divided into high- or low-risk groups for ischemic heart disease based on risk factors measured 25 years previously.

PURPOSE: To undertake medical follow-up in white males in the National Heart, Lung, and Blood Institute (NHLBI) twin study, previously divided on the basis of cardiovascular disease risk factors. METHODS: Tree structured survival analysis (TSSA) used at a mean age of 63 years to classify twins into high and low risk subgroups for ischemic heart disease (IHD) found that subjects at a mean age of 48 years were at highest risk with high systolic blood pressures and low high density lipoprotein cholesterol levels. Low risk subjects had lower blood pressures, better pulmonary function tests, and a negative family history for IHD or low post load plasma glucose levels. Medical record review was performed ten years later at the 4th Examination of the NHLBI twin cohort conducted in 1995-1997. RESULTS: The percentage of men in the NHLBI twin study who died nearly tripled (from 9.3% to 25.8%) in the ten-year period between the ages of 63 and 73 years. Deaths have tended to remain higher in DZ than MZ twins (27.8% versus 23.7%). At Exam 4, the relative risk of IHD (fatal or non-fatal) was 5.24 times higher for those in the high risk group than those in the low risk class (95% confidence limit 2.72-10.07, p < 0.0001 and 5.86 for any cardiovascular disease (95% confidence limit 3.03-11.33). The proportion of deaths from IHD in subjects with a high risk profile at entry was 51.7%, and 70.0% had died from all cardiovascular related disease. CONCLUSION: The present results indicate TSSA remained effective in classifying subjects into subgroups with greater risk of morbidity and mortality related to cardiovascular disease after ten additional years.

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PubMed2000

Segregation analysis of drinking problem in elderly men and their first-degree relatives from the Western Collaborative Group Study.

PURPOSE: The purpose of this study is to determine the mode of inheritance of alcohol-related drinking problems. METHODS: Family history was collected by interview from 493 elderly male participants (probands) in a follow-up cardiovascular exam of healthy white men living in the San Francisco Bay Area and Los Angeles. Segregation analysis was used to test for the presence of a major gene effect underlying the liability to develop an alcohol-related drinking problem. RESULTS: The results showed that the liability to drinking problem is due, in part, to a single major gene with no residual effects from shared familial influences. CONCLUSIONS: These results suggest that at least one major gene is involved in the genetic predisposition to develop drinking problem in late adulthood.

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PubMed2000

Longitudinal changes in the contribution of genetic and environmental influences to symptoms of depression in older male twins.

Genetically informative longitudinal data on self-reported symptoms of depression allow for an investigation of the causes of stability and change in depression symptoms throughout adult life. In this report, the authors investigated the relative contribution of genetic and environmental influences to symptoms of depression in 83 monozygotic and 84 dizygotic male twin pairs from the National Heart, Lung, and Blood Institute (NHLBI) Twin Study. Participants first completed the Center for Epidemiologic Studies-Depression (CES-D) scale in 1985-1986 and again during 1995-1997. Mean age of twins at baseline was 63 years, range 59 to 70. From cross-sectional genetic analyses we estimated the heritability of CES-D to be 25% (95% confidence interval [CI], 11%-39%) at baseline and 55% (95% CI, 40%-71%) at follow-up. Fitting longitudinal genetic models to the two-wave data, we found that stability of symptoms over the 10-year follow-up was due primarily to continuity of genetic influences.

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PubMed2000

Relationship of 30-year changes in obesity to sleep-disordered breathing in the Western Collaborative Group Study.

OBJECTIVE: Obesity is an important etiologic factor in sleep-disordered breathing (SDB), but the extent to which changes in obesity across adult life contribute independently to SDB in old age has not been studied. In this study, we examined the association between changes in obesity from midlife to late adulthood and overnight recording of respiration during sleep. RESEARCH METHODS AND PROCEDURES: Subjects in this study are from the Western Collaborative Group Study, a longitudinal cardiovascular epidemiological study that began in 1960 through 1961. Overnight sleep recordings were obtained from 281 male participants in the 1995 through 1996 follow-up of the Western Collaborative Group Study. Subjects were 75 to 91 years old when assessed for SDB as indexed by the respiratory disturbance index and an oxygen desaturation index (O2DI). Long-term changes in anthropometrics were evaluated and examined in relation to SDB severity. RESULTS: Over the 30 years of follow-up, body mass index and waist circumference increased significantly for this sample and were associated with SDB severity as indexed by respiratory disturbance index and O2DI. Waist circumference at baseline and gain in waist circumference over the 30 years of follow-up (both p = 0.01) were significantly and independently associated with SDB severity as assessed by O2DI. However, percentage of variance as accounted for by waist circumference was modest. DISCUSSION: This study supports the hypothesis that gain in waist circumference over adult life is significantly associated with SDB severity in older men.

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PubMed2000

A genetic analysis of smoking behavior in family members of older adult males.

AIMS: To conduct a genetic study of smoking behavior in 493 three-generation families. DESIGN: Complex segregation analysis and maximum likelihood statistics were used to describe the familial clustering of ever-smoking under several transmission models. SETTING: The Western Collaborative Group Study, an ageing and health study currently in its 39th year of follow-up. PARTICIPANTS: Probands were male participants who were of mean age 71.6 years at the time of the family history interview in 1986-88. MEASUREMENTS: Data were collected via an interview that focused on the family smoking history of participants. Smoking histories of all first-degree relatives were obtained from probands. FINDINGS: Evidence for genetic transmission was indicated by rejection of both the environmental and sporadic models in favor of a Mendelian genetic model with residual familial effects from spouses and both parents. CONCLUSIONS: The best-fitting model was that of a dominant major gene with low estimated frequency and residual familial correlations. This is the first study to date to model the familial transmission of ever-smoking in three-generation families.

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PubMed2000

The contribution of genetic influences to measures of lower-extremity function in older male twins.

Tests of balance, gait, and endurance were administered to 95 monozygotic (MZ) and 92 dizygotic (DZ), white male twins aged 68 to 79 years who had been born in the United States. Within-twin-pair correlations were calculated for each individual task and for an overall summary performance score. These were subjected to structural equation modeling to determine the contributions of genetic and environmental influences to individual differences in performance scores. MZ intraclass correlations were significant and greater than DZ correlations for the 8-foot walk and the repeated chair stands task, but not for the standing balance task. The heritability of the lower-extremity summary score was 57%, of which 39% was due to additive genetic effects and 18% due to nonadditive effects. In addition, we found that genetic influences contributed primarily to twin similarity in the poorest quartile of performance, whereas shared environmental influences contributed to twin similarity in the best quartile.

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PubMed2000

The joint effect of apolipoprotein E epsilon4 and MRI findings on lower-extremity function and decline in cognitive function.

BACKGROUND: Cognitive decline and poor physical function are risk factors for disability in old age and may occur more often in subjects with the apolipoprotein E epsilon4 (ApoE-epsilon4) allele. The objective of this study was to investigate the joint effect of ApoE-epsilon4 and structural changes detected on MRI brain scans on cognitive decline and lower-extremity function. METHODS: Brain MRI (1.5 T), neuropsychological tests, and lower-extremity physical function tests were administered to World War II male veteran twins ages 69 to 80. Quantification of MRI scans used a previously published algorithm to segment brain images into total cerebral brain (TCB), cerebrospinal fluid (CSF), and white-matter hyperintensity (WMH) volumes. A short battery of physical performance tests was used to assess lower-extremity function. Ten-year changes in performance on the Mini-Mental State Exam (MMSE), the Benton Visual Retention Test (BVRT), and the Digit Symbol Substitution (DSS) test were used to assess cognitive decline. RESULTS: For the sample as a whole, the comparison of subjects by median split of total cerebral brain volume found that those with brain volumes below the median performed worse on tests of gait and balance (p < .01) and experienced greater cognitive decline on the MMSE and BVRT cognitive test batteries (both p < .01). In addition, subjects with WMH volumes above the median had poor performance on the standing balance tasks and experienced greater decline on the DSS test (p < .01). Stratified analyses revealed that the joint effect of radiological findings and the ApoE-epsilon4 allele on cognitive decline and lower-extremity function was often greater than that expected from the separate effects combined. CONCLUSIONS: We conclude that radiological findings in conjunction with ApoE-epsilon4 may single out a group at higher risk for dementia. We speculate that the observed interaction effect may be due to increased susceptibility to brain injury or impaired repair mechanisms in subjects with ApoE-epsilon4.

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PubMed2000

Stability and change in genetic and environmental influences on hand-grip strength in older male twins.

The aim of this study was to investigate aging-related changes in the contribution of genetic and environmental influences to hand-grip strength in late adulthood. Subjects in this study are 152 intact twin pairs (77 monozygotic and 75 dizygotic pairs) from the National Heart, Lung, and Blood Institute Twin Study assessed repeatedly for hand-grip strength at mean ages of 63 and 73 yr. Structural equation genetic modeling was used to investigate stability and change in the genetic and environmental components of variance of hand-grip strength in late adulthood. Average decline in strength over the 10 yr of follow-up was -1.05+/-6.8 (SD) kg and was highly significant (P = 0.003). The test-retest correlation between baseline and follow-up grip strength was 0.62 (P<0.001). Bivariate genetic modeling found significant genetic and shared environmental stability in hand-grip strength over the 10 yr of follow-up, with genetic and shared environmental influences accounting for 35 and 48%, respectively, of the test-retest phenotypic correlation. We conclude from these results that stability in hand-grip strength in late adulthood is due primarily to continuity of genetic and familial influences.

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PubMed1999

Midlife cardiovascular risk factors and brain morphology in identical older male twins.

OBJECTIVE: Structural changes in the human brain have been reported to a greater extent in subjects with cardiovascular risk factors. We conducted a matched co-twin analysis of elderly monozygotic twins from the National Heart, Lung, and Blood Institute Twin Study to examine the association between midlife cardiovascular risk factors and MRI-based measures of brain atrophy. METHODS: Brain MRIs (1.5-T) were obtained from 74 monozygotic, white, male, World War II veteran twins born in the United States from 1917 to 1927 and age 68 to 79 at the time of the brain scan. A semiautomated algorithm was used to segment brain images into total brain, CSF, and white matter hyperintensity volumes. Cardiovascular risk factors, medical history variables, and health practices were available from data collected over 25 years of adult life. RESULTS: Independent of shared genetic or familial influences, within-pair differences in midlife glucose levels, high-density lipoprotein cholesterol, and systolic blood pressure were significantly associated with differences in white matter hyperintensities. Within-pair differences in coronary heart disease history and in current consumption of alcohol and level of physical activity were significantly associated with differences in brain parenchyma. In addition, within-pair differences in white matter hyperintensity volumes were significantly associated with differences in performance on cognitive and physical function tests and self-reports of depression symptoms. CONCLUSION: Independent of age effects and shared genetic or familial influences, midlife cardiovascular risk factors and lifetime health practices were predictive of structural brain changes in old age.

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PubMed1999

Differential genetic influence for components of memory in aging adult twins.

OBJECTIVE: To investigate the relative proportion of genetic and environmental contributions to verbal memory in community-dwelling World War II veteran twins. DESIGN: The California Verbal Learning Test (CVLT) was administered to 94 monozygotic (MZ) and 89 dizygotic (DZ) elderly male twin pair participants in the fourth examination of the National Heart, Lung, and Blood Institute Twin Study. SETTING: Subjects voluntarily participated on an outpatient basis at a research or medical center facility in 1 of 4 sites in the United States. PARTICIPANTS: Subjects had a mean age of 71.8 years (SD, 2.9 years), a mean educational level of 13.6 years (SD, 2.8 years), and no history of stroke and/or a Mini-Mental State Examination score of 23 or greater. MAIN OUTCOME MEASURES: Twin pair similarity in performance on 4 factor analytically derived components of the CVLT measuring verbal learning and memory, response discrimination, learning strategy, and recognition memory. RESULTS: The MZ intraclass correlation was significantly larger than the DZ correlation for verbal learning and memory (I<.001) but not for the other 3 components of memory. Using maximum likelihood methods, the best-fitting genetic model indicated that verbal learning and memory has a substantial genetic component (56% of total variance), whereas response discrimination has a much smaller, although still detectable, genetic component (24% of total variance). There is no evidence of genetic influence on learning strategy or recognition memory. CONCLUSION: Differential contribution of genetic and environmental influences to specific components of memory suggest that, in this group of elderly male twin pairs, some components may be more amenable to intervention than others.

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