Biomedical subjects

Charles DeCarli

Publications and source records attributed to Charles DeCarli.

At least 37 records · Page 2Linked to original sources

PubMed2004

Stroke risk profile predicts white matter hyperintensity volume: the Framingham Study.

BACKGROUND AND PURPOSE: Previous studies of cardiovascular risk factors and white matter hyperintensity (WMH) on brain MRI have been limited by the failure to exclude symptomatic cerebrovascular disease and dementia or by the use of semiquantitative rather than quantitative methods to measure WMH volume (WMHV). We examined the relationship between Framingham Stroke Risk Profile (FSRP) and WMHV measured quantitatively in a stroke and dementia-free subset of the Framingham Offspring Cohort. METHODS: Brain MRI was performed in 1814 members of the Framingham Offspring Cohort. Pixel-based quantitative measures of WMHV corrected for head size were obtained using a semiautomated algorithm. WMHV was not normally distributed and therefore was log-transformed (LWMHV). The FSRP and its component risk factors measured a mean of 7.5 years before MRI were related to both continuous measures of LWMHV and to the presence of large volumes of LWMHV (LWMHV-large). All analyses were adjusted for age and sex. RESULTS: FSRP was strongly associated with LWMHV and LWMHV-large. Age, smoking, history of cardiovascular disease, hypertension, and left ventricular hypertrophy by electrocardiogram were all significantly related to LWMHV or LWMHV-large. CONCLUSIONS: FSRP and several cardiovascular risk factors were related to both WMHV measured continuously and to a categorical designation of large volumes of WMH. These findings provide strong evidence of a vascular basis for WMH.

Adult↗

PubMed2004

Cerebral microbleeds: prevalence and associations with cardiovascular risk factors in the Framingham Study.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMBs) are areas of low signal intensity on gradient echo T2*-weighted magnetic resonance imaging (T2*MRI) corresponding to hemosiderin deposits in the perivascular space. Microangiopathy from atherosclerosis or amyloid angiopathy might lead to the formation of these lesions; therefore, there may be associations between CMBs and cardiovascular risk factors, APOE allele status, and brain morphology. We examined these relationships in the Framingham Study (FHS). METHODS: In 472 subjects from the FHS Offspring and Cohort, we related CMB status to age, sex, systolic blood pressure, total cholesterol and high-density lipoprotein cholesterol (HDL-C) levels, smoking, diabetes, total hemispheric brain volume, white matter hyperintensity volume (WMHV), and APOE allele status. RESULTS: Overall prevalence of CMBs was 4.7%, but CMBs were more prevalent with advanced age and male sex. Blood pressure, brain volume, and WMHV were related to CMBs in crude analysis but not after adjustment for age and sex. There were no significant relationships demonstrated between CMBs and APOE allele status, cholesterol, smoking, or diabetes. CONCLUSIONS: There is a low prevalence of CMBs in the community and a strong relationship with increasing age and male sex. We found no independent relationships with cardiovascular risk factors, APOE status, brain volumes, or WMH.

Age Factors↗

PubMed2004

Genetic variation in white matter hyperintensity volume in the Framingham Study.

BACKGROUND AND PURPOSE: In a previous study of normal elderly male twins, the heritability of quantitative white matter hyperintensity (WMH) volume has been estimated to be high (0.73). We investigated heritability of WMH in a family-based sample of the Framingham Heart Study for sex differences and the impact of age. METHODS: Brain magnetic resonance scans were performed on 2012 individuals in the cohort and offspring of the Framingham study. This report was limited to 1330 stroke-free and dementia-free members (mean age 61.0 years) of the Framingham offspring. Individuals with a history of multiple sclerosis, stroke, dementia, or other neurological condition including traumatic brain injury were excluded from this analysis. WMH volume and total cranial volume (TCV) were quantified using a previously published algorithm. Because of extreme skewing, measures of WMH were log-transformed before analysis. Variance components methods were used to estimate heritability of WMH after adjusting for sex, age, age2, and TCV. RESULTS: In the full dataset, WMH heritability was 0.55 (P<0.0001). Heritability among women was 0.78 (P<0.0001) whereas heritability among men was 0.52 (P<0.0003). Heritability varied as average age increased, with a peak of 0.68 (P<0.0001) in individuals aged 55 or older. CONCLUSIONS: Using a family-based study design comprising generally healthy individuals, this study found high heritability of WMH overall and similar heritability for both men and women. In addition, the heritability of WMH remained high among individuals in whom the prevalence of cerebrovascular brain injury was generally low, suggesting that WMH is also likely to be an excellent genetic marker of brain aging.

Adult↗

PubMed2004

Managing and analysing data from a large-scale study on Framingham Offspring relating brain structure to cognitive function.

At the Framingham Heart Study under separate research grant funding from the National Institute of Aging, NIH, we are gathering brain structure and cognitive information on the Framingham Offspring, creating one of the largest known data sets to assess changes in brain structure associated with normative ageing and cognitive decline. Subject recruitment, data collection, data management and statistical analysis require a collaborative integrated effort on the part of the Framingham project team. Here we describe this effort, as well as the various brain structure and cognitive function parameters we are now collecting. We are currently performing analyses of data collected through 2002, and we discuss the statistical issues arising relating brain structure parameters to cognitive function.

Aged↗

PubMed2004

Framingham stroke risk profile and lowered cognitive performance.

BACKGROUND AND PURPOSE: The primary objective of this work was to describe the relationships between 10-year risk for stroke and multiple measures of cognitive performance for a large community-based sample of individuals who were free of clinical stroke and dementia at the time of risk assessment. METHODS: Participants were 1011 men and 1164 women from the Framingham Offspring Study. The Framingham Stroke Risk Profile was used to assess 10-year risk of stroke. Using a cross-sectional design, we assessed 10-year risk of stroke, the predictor variable, and cognitive performance, the outcome variable, at examination 7 of the Framingham Offspring Study. Multivariable linear regression models were used to relate 10-year risk of stroke to cognitive tests measuring multiple domains of cognitive functioning. RESULTS: With statistical adjustment for age, education, sex, and other correlates of both stroke and cognitive ability, an inverse association between increments in 10-year risk of stroke and cognitive performance level was observed for tests indexing visual-spatial memory, attention, organization, scanning, and abstract reasoning. CONCLUSIONS: In stroke- and dementia-free individuals, higher 10-year risk for stroke is associated with performance decrements in multiple cognitive domains.

Adult↗

PubMed2004

Regional NAD(P)H:quinone oxidoreductase activity in Alzheimer's disease.

Converging evidence supports the role of oxidative stress in the pathology of Alzheimer's disease (AD). This notion is further supported by recent findings of increased NAD(P)H:quinone oxidodreductase (NQO1) activity, a potent antioxidant system, in association with hippocampal AD pathology. If increased NQO1 activity is truly related to the AD process, however, we would expect to see regional co-localization of NQO1 activity with AD pathology throughout affected brain regions and the absence of NQO1 activity in regions unaffected by AD. We examined this hypothesis by measuring NQO1 enzymatic activity and NQO1 immunohistochemical staining in regions commonly affected by the AD process such as frontal cortex and compared this to regions generally unaffected by the AD process such as occipital cortex, cerebellum, and substantia nigra for a group of AD patients and controls. The ratio of frontal to cerebellar NQO1 enzymatic activity was significantly increased in patients with AD (2.07 +/- 1.90) versus controls (0.60 +/- 0.31; P < 0.03). Moreover, regional immunohistochemical staining revealed specific localization of NQO1 staining to astrocytes and neurites surrounding senile plaques. The extent of immunohistochemical staining also closely correlated with the extent of local AD pathology across the various brain regions examined. Neuronal NQO1 staining seen in frontal cortex of AD patients was absent in frontal cortex of controls, but was found to the same extent in neurons of the substantia nigra of both AD patients and controls. We conclude that NQO1 activity co-localizes closely with AD pathology supporting a presumed role as an antioxidant system upregulated in response to the oxidative stress of the AD process. The antioxidant role for NQO1 is further supported by finding increased neuronal NQO1 activity in substantia nigra neurons of both AD patients and controls as this neuronal population is known to be under constant oxidative stress. While requiring further study, these findings, in conjunction with previous work, suggest that increased NQO1 activity may be neuroprotective, may offer novel insights into the pathophysiology of AD and may also provide possible avenues for future treatment.

Aged↗

PubMed2003

Cerebrospinal fluid tau and beta-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses?

BACKGROUND: Tau and beta-amyloid (Abeta) are proposed diagnostic biomarkers for Alzheimer disease (AD). Previous studies report their relationship to clinical diagnoses of AD and other dementias. To understand their value as predictors of disease-specific pathology, levels determined during life must be correlated with definitive diagnoses in mixed dementia groups and cognitively normal subjects. OBJECTIVES: To correlate antemortem cerebrospinal fluid (CSF) tau and Abeta levels with definitive dementia diagnosis in a diverse group of patients; to calculate statistics for CSF tau and Abeta. DESIGN: Prospective study. SETTING: Ten clinics experienced in the diagnosis of neurodegenerative dementias. Patients One hundred six patients with dementia and 4 cognitively normal subjects with a definitive diagnosis, and 69 clinically diagnosed cognitively normal subjects. MAIN OUTCOME MEASURES: Correlation of CSF tau and Abeta with final diagnosis. RESULTS: Mean tau level was 612 pg/mL for the 74 patients with AD, 272 pg/mL for 10 patients with frontal dementia, 282 pg/mL for 3 patients with dementia with Lewy bodies, and 140 pg/mL for 73 cognitively normal control subjects. Tau was less than 334 pg/mL for 20 patients with AD. Abeta42 was reduced in patients with AD (61 fmol/mL) compared with patients with frontal dementia (133 fmol/mL) and control subjects (109 fmol/mL), but not compared with patients with dementia with Lewy bodies (14 fmol/mL) or prion disease (60 fmol/mL). CONCLUSIONS: Elevated CSF tau levels are associated with AD pathology and can help discriminate AD from other dementing disorders. However, some patients with AD have a level less than the mean +/- 2 SDs of the cognitively normal cohort.

Adult↗

PubMed2003

Total cerebral volume is reduced in patients with localization-related epilepsy and a history of complex febrile seizures.

CONTEXT: Febrile seizures may lead to later epilepsy. They have been associated with hippocampal atrophy but their effect on total cerebral volume is unknown. OBJECTIVE: To compare total cerebral volume in patients with mesial temporal lobe epilepsy with and without a history of complex febrile seizures (CFS). DESIGN: Survey. SETTING: Epilepsy monitoring center. SUBJECTS: Forty patients with localization-related epilepsy and temporal lobe onset determined by video electroencephalogram and 20 controls. INTERVENTION: Magnetic resonance imaging measurement of cerebral volume. MAIN OUTCOME MEASURE: Total cerebral volume. RESULTS: Patients with a history of CFS had significantly reduced total cerebral volume compared with patients without CFS. In addition, male patients with CFS had significantly lower total cerebral volume than male normal controls. There was no significant difference between patients without CFS, or all patients, and controls. CONCLUSION: Complex febrile seizures may have a global effect on brain development.

Adult↗

PubMed2003

Mild cognitive impairment: prevalence, prognosis, aetiology, and treatment.

Mild cognitive impairment (MCI) is a recently described syndrome that is currently thought of as a transition phase between healthy cognitive ageing and dementia. Although this notion seems to be reasonable, the general nature of the term MCI--including its many definitions--makes accurate accounting of the prevalence, prognosis, and potential benefit from treatment somewhat difficult. The differences in cognitive profile and clinical progression among individuals with MCI are generally recognised. However, recent evidence also suggests that the aetiological heterogeneity among individuals with MCI could be greater than previously reported. For example, cerebrovascular disease seems to be underestimated as a potential cause of MCI. In this review, I attempt to recognise workable definitions of MCI to discuss the prevalence, pathophysiology, prognosis, and possibilities for treatment of this disorder.

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PubMed2003

Vascular cognitive impairment.

Cerebrovascular disease is the second most common cause of acquired cognitive impairment and dementia and contributes to cognitive decline in the neurodegenerative dementias. The current narrow definitions of vascular dementia should be broadened to recognise the important part cerebrovascular disease plays in several cognitive disorders, including the hereditary vascular dementias, multi-infarct dementia, post-stroke dementia, subcortical ischaemic vascular disease and dementia, mild cognitive impairment, and degenerative dementias (including Alzheimer's disease, frontotemporal dementia, and dementia with Lewy bodies). Here we review the current state of scientific knowledge on the subject of vascular brain burden. Important non-cognitive features include depression, apathy, and psychosis. We propose use of the term vascular cognitive impairment, which is characterised by a specific cognitive profile involving preserved memory with impairments in attentional and executive functioning. Diagnostic criteria have been proposed for some subtypes of vascular cognitive impairment, and there is a pressing need to validate and further refine these. Clinical trials in vascular cognitive impairment are in their infancy but support the value of therapeutic interventions for symptomatic treatment.

Cerebrovascular Disorders↗

PubMed2003

Prevention of white-matter lesions through control of cerebrovascular risk factors.

Multiple epidemiological and brain imaging studies show a strong association between elevations in systolic blood pressure and lesions of cerebral white matter. The association between white-matter lesions and systolic blood pressure persists even if individuals are receiving treatment, suggesting that these individuals may be undertreated. In addition, these studies suggest that lesions of cerebral white matter may serve as markers for atherosclerotic vascular disease. Treatment strategies, therefore, should focus on early and aggressive management of elevated blood pressure, but definitions of elevated blood pressure may need to be revised downward to achieve best results.

Aged↗

PubMed2003

The role of cerebrovascular disease in dementia.

BACKGROUND: Improvements in health care over the last 50 years have lengthened average life expectancy significantly, resulting in considerable growth of the population over 65 years of age. With increased age, however, comes an increased risk for Alzheimer's disease (AD), and the prevalence of AD is predicted to reach epidemic proportions by the later half of the 21st century. The prevalence of cerebrovascular disease also increases with age, and recent evidence suggests that cerebrovascular risk factors such as hypertension and hypercholesterolemia also increase an individual's risk for AD, suggesting a potential interaction between these two very common disorders. The potential impact of cerebrovascular disease on general cognitive health is not yet well understood, but is now being actively explored and clarified. REVIEW SUMMARY: Cerebrovascular disease may manifest itself in many ways, and this review begins by discussing the possible spectrum of brain injury associated with common cerebrovascular risk factors. The prominent role of brain imaging to detect clinically silent cerebrovascular disease is recognized and reviewed. The neuropsychological consequences of cerebrovascular disease across the cognitive spectrum is also reviewed, including potential mechanisms by which cerebrovascular disease may interact with AD to increase the expression or hasten the progression of dementia. CONCLUSIONS: Cerebrovascular risk factors, common to the elderly, lead to pernicious brain injury and subtle cognitive impairment that most probably places the individual at greater lifetime risk for dementia. The cause of dementia among individuals with cerebrovascular disease, however, remains AD. Recognition of the potential role of cerebrovascular disease as an independent risk factor for AD offers the possibility of primary prevention through treatment of well-recognized risk factors and deserves further study. In the meantime, clinicians presented with an individual suffering from a slowly progressive dementia and findings of clinically silent cerebrovascular brain injury should recognize the potential role of cerebrovascular disease in the dementia process but not ignore the likely overwhelming effects of AD and treat appropriately.

Age Factors↗

PubMed2003

Hippocampal volume is associated with memory but not monmemory cognitive performance in patients with mild cognitive impairment.

Mild cognitive impairment (MCI) appears to be a transitional stage in the development of Alzheimer's disease (AD). Patients with MCI show impaired memory performance and hippocampal atrophy relative to normal elderly controls. Prior studies indicate that the degree of hippocampal atrophy in MCI patients predicts conversion to AD. In contrast to patients with MCI who have deficits primarily in memory, AD patients have clinically evident impairments in both memory and nonmemory cognitive domains. One explanation for the observation that a smaller hippocampal volume predicts conversion to AD might be that hippocampal atrophy is associated with early impairment in nonmemory cognitive areas as well as memory. A link between hippocampal volume and nonmemory function could occur if hippocampal atrophy was correlated with AD pathology in other brain regions. We therefore sought to determine the relationship of hippocampal volume with performance on memory and nonmemory tasks in patients with MCI. Although we found a significant correlation between hippocampal volume and memory performance, we did not find a significant correlation between hippocampal volume and nonmemory performance. We conclude that the relationship between hippocampal volume and risk of AD is likely tied to reduced memory performance and not associated with impairment in nonmemory cognitive domains.

Aged↗

PubMed2002

Heritability of lobar brain volumes in twins supports genetic models of cerebral laterality and handedness.

Although the left and right human cerebral hemispheres differ both functionally and anatomically, little is known about the environmental or genetic factors that govern central nervous system asymmetry. Nevertheless, cerebral asymmetry is strongly correlated with handedness, and handedness does have a significant genetic component. To explore the relative contribution of environmental and genetic influences on cerebral asymmetry, we examined the volumes of left and right cerebral cortex in a large cohort of aging identical and fraternal twins and explored their relationship to handedness. Cerebral lobar volumes had a major genetic component, indicating that genes play a large role in changes in brain volume that occur with aging. Shared environment, which likely represents in utero events, had about twice the effect on the left hemisphere as on the right, consistent with less genetic control over the left hemisphere. To test the major genetic models of handedness and cerebral asymmetry, twin pairs were divided into those with two right handers and those with at least one left hander (nonright handers). Genetic factors contributed twice the influence to left and right cerebral hemispheric volumes in right-handed twin pairs, suggesting a large decrement in genetic control of cerebral volumes in the nonright-handed twin pairs. This loss of genetic determination of the left and right cerebral hemispheres in the nonright-handed twin pairs is consistent with models postulating a right-hand/left-hemisphere-biasing genetic influence, a "right-shift" genotype that is lost in nonright handers, resulting in decreased cerebral asymmetry.

Aged↗

PubMed2002

Quantitative genetic modeling of regional brain volumes and cognitive performance in older male twins.

As part of an ongoing longitudinal twin study, data from both MRI brain scanning and from neuropsychological testing were obtained from 139 male-male twin pairs (72 monozygotic [MZ] and 67 dizygotic [DZ]), 69-80 years old at the time of examination. For descriptive purposes, we examined the MZ and DZ intraclass correlations (ICC) of four lobar brain volumes (frontal, temporal, parietal, and occipital), two cerebrospinal fluid (CSF) volumes (lateral ventricle and temporal horn of the lateral ventricles), and two measures of cognitive functioning (verbal memory and executive function). We found that for lobar brain and CSF space volumes, the MZ ICC were significantly greater than zero (r=0.37-0.77) and greater than the corresponding DZ correlations (r=0.02-0.49). Similarly, within-pair correlations for the two neuropsychological factors were statistically significant and significantly larger in MZ twin pairs than in DZ pairs, suggesting the presence of genetic variance. Bivariate genetic analysis revealed that while close to 60% of individual differences in neuropsychological performance were due to genetic influences, less than 50% of genetic effects were in common with those influencing brain volumes. These data may shed light on the genetic liability for brain diseases that affect the elderly.

Aged↗

PubMed2002

Radial width of the temporal horn: a sensitive measure in Alzheimer disease.

BACKGROUND AND PURPOSE: Atrophy in the medial temporal lobe (MTL) structures depicted with brain imaging is one of the most accurate markers of Alzheimer disease (AD), but practical considerations have thus far limited their routine clinical use. The aim of this study was to explore the validity of a CT- and MR-based measure of MTL atrophy that would be feasible for routine clinical use. METHODS: We acquired brain CT scans in the temporal lobe plane with thin sections in 42 patients with AD and in 29 control patients without dementia. We also acquired MR images (according to a 3D magnetization-prepared rapid gradient-echo protocol) in 28 patients with AD and in 28 control subjects without dementia. The radial width of the temporal horn (rWTH) of the lateral ventricle was measured with a precision caliper at the tip of the horn on CT scans or high-quality MR images. The validity of the rWTH variable was assessed by test-retest and interrater reliability, convergent and discriminant validity compared with progressively distant brain regions, and known-group validity (accuracy of the separation of patients with AD from control subjects). Convergent and discriminant validity compared with volumetric measures was tested in the patients who underwent MR imaging. RESULTS: Intraclass correlation coefficients for inter- and intrarater reliability were between 0.94 and 0.98. On CT scans, Pearson's correlation of the rWTH with the transverse width of the temporal horn was between 0.60 and 0.79; with Jobst's minimum thickness of the MTL, between 0.63 and 0.78 (interuncal distance approximately 0.50); and with an index of frontal atrophy, between 0.35 and 0.42. On MR images, the correlation with volumetric MR measures was 0.80 in the temporal horn, 0.74 in the hippocampus, 0.68 in the temporal lobe, 0.58 in the entorhinal cortex, and 0.49 in the frontal lobe. On CT scans (cutoff value for AD, >5.3 mm; age range of subjects, 50-90 y), the rWTH measure was a sensitive marker for AD in 39 of 42 patients with AD (sensitivity, 93%) and was a specific marker in 28 of the 29 control patients (specificity, 97%). On MR images (cutoff 3.6-6.7 mm; age range of subject, 50-90 y), the rWTH was a sensitive marker for AD in 21 of 28 patients with AD (sensitivity, 75%) and was a specific marker in 26 of 28 control subjects (specificity, 93%). The accuracy of other linear CT-based measures of MTL atrophy and linear and volumetric MR-based measures was lower. With specificity set to 95%, sensitivity ranged from 57% to 74% for CT-based measures and from 52% to 74% for MR-based measures. CONCLUSION: The rWTH is an accurate marker of AD that could be used in routine clinical settings.

Aged↗

PubMedDate not supplied

Brain MRI hippocampal volume and prediction of clinical status in a mild cognitive impairment trial.

Mild Cognitive Impairment (MCI) is considered a transitional stage in the pathogenesis of Alzheimer's disease; however, not all MCI patients progress to clinically defined AD or decline at identical rates. Hippocampal atrophy, as measured by Magnetic Resonance Imaging (MRI), may be a marker for hippocampal pathology in patients with MCI and predict a more rapid deterioration to clinical AD. In this study, we used MRI data from an ongoing MCI clinical trial to determine whether MRI hippocampal volume at baseline was associated with cognitive and functional performance in MCI subjects and whether it predicted those individuals who were more likely to develop AD. We performed correlational analyses between the MRI hippocampal volumes at study entry and the subjects' concurrent performance on neuropsychological measures and clinical ratings. Larger hippocampal volume was associated with better performance on tests of memory, general cognition, and overall clinical ratings. Further analyses suggested that a smaller baseline hippocampal volume may be associated with a higher risk of developing clinical AD. As the trial is still ongoing, these results require confirmation once the trial is completed. In summary, these data suggest that MRI hippocampal volume may be a useful correlate of disease severity in MCI subjects and a prognostic indicator of subsequent AD.

Aged↗

PubMedDate not supplied

A bivariate genetic analysis of cerebral white matter hyperintensities and cognitive performance in elderly male twins.

White matter hyperintensities (WMHs) are frequently observed on MRI scans of elderly nondemented people and have been associated in the past with cognitive impairment and physical dysfunction. Individual differences in the prevalence and severity of WMHs have been documented and more recently we reported on the significant contribution of genetic influences to this variability. The objective of the present study was to further investigate, in the context of a behavioral genetic paradigm, the nature of the association between WMHs and cognitive and physical function. MRI brain scans and a battery of neuropsychological and physical function tests were given to 142 male-male twin pairs [72 monozygotic (MZ) and 70 dizygotic (DZ)], participants in the 4th exam of the NHLBI Twin Study. Biometric genetic modeling was used to estimate the genetic and/or environmental covariation between WMHs and cognitive and physical summary scores. The phenotypic association between WMHs and cognitive function in this sample of twins was modest but statistically significant. Genetic analyses of cognitive and physical function summary scores found that 55% to 70% of the observed variability was due to genetic influences. A further decomposition of the phenotypic association between WMHs and cognitive function found that 70% to 100% of the phenotypic covariation was due to common genetic effects. Similar results explained the association between WMHs and performance on two physical function tests. We conclude from these analyses that common genetic influences explain to a large extent previously observed phenotypic associations between large amounts of WMHs and poor cognitive and physical function in the elderly.

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