Sexually dimorphic differences in angiogenesis markers predict brain aging trajectories.

Aberrant angiogenesis could contribute to cognitive impairment, representing a therapeutic target for preventing dementia. However, most angiogenesis studies focus on model organisms. To test the relevance of angiogenesis to human cognitive aging, we evaluated associations of circulating blood markers of angiogenesis with brain aging trajectories in two deeply phenotyped human cohorts (n=435, age 74 + 9) with longitudinal cognitive assessments, biospecimens, structural brain imaging, and clinical data. Machine learning and traditional statistics revealed sex dimorphic associations of plasma angiogenic growth factors with brain aging outcomes. Specifically, angiogenesis is associated with higher executive function and less brain atrophy in younger women (not men), a directionality of association that reverses around age 75. Higher levels of basic fibroblast growth factor, known for pleiotropic effects on multiple cell types, predicted favorable cognitive trajectories. This work demonstrates the relevance of angiogenesis to brain aging with important therapeutic implications for vascular cognitive impairment and dementia.

Is staging beneficial for Fowler-Stephens orchiopexy? A systematic review.

PURPOSE: Fowler and Stephens showed that by dividing the spermatic vessels a high intra-abdominal testis could be placed in the scrotum. Testicular atrophy is a potential complication of this technique. We conducted a systematic review to determine whether single or 2-stage Fowler-Stephens orchiopexy results in better testicular viability. MATERIALS AND METHODS: We searched electronic databases, clinical trial registries and gray literature. We included reports describing boys younger than 18 years with a primary outcome of "testicular viability and position." We performed a meta-analysis using random effects models. Heterogeneity was assessed using forest plot and I(2) statistic. RESULTS: We identified 1,807 citations and included 61 articles. Single stage Fowler-Stephens orchiopexy was discussed in 9 articles, a 2-stage procedure in 36 and both approaches in 16. There were no randomized controlled trials, and most studies were cohort or case series. The pooled estimate of success rates was 80% for single stage Fowler-Stephens orchiopexy (95% CI 75 to 86) and 85% for 2-stage Fowler-Stephens orchiopexy (95% CI 81 to 90). The pooled odds ratio of single stage vs 2-stage Fowler-Stephens orchiopexy was 2.0 (95% CI 1.1 to 3.9) favoring the 2-stage procedure. There was no difference in the success rate between laparoscopic and open techniques in either single or 2-stage Fowler-Stephens orchiopexy. There was no evidence of asymmetry on the funnel plot. There were no complications reported with single stage, while ileus, hematoma and infection were the most common complications with 2-stage Fowler-Stephens orchiopexy. CONCLUSIONS: Both techniques have a fairly high success rate but 2-stage Fowler-Stephens orchiopexy appears to carry a higher rate of success than the single stage approach (85% vs 80%, OR 2 in favor of 2-stage). Laparoscopic and open techniques had the same success rate. However, the level of evidence of the studies was low, and a study of a more robust design, such as a randomized controlled trial, should be performed.

Psychological symptoms correlate with reduced hippocampal volume in fragile X premutation carriers.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder occurring in male and occasional female carriers of a premutation expansion (55-200 CGG repeats) of the fragile X mental retardation 1 gene (FMR1). This study assessed the relationship between hippocampal volume and psychological symptoms in carriers, both with and without FXTAS, and controls. Volumetric MRI measures, clinical staging, cognitive testing, molecular analysis, and measures of psychological symptoms were performed for female premutation carriers both with FXTAS (n = 16, age: 57.50 + or - 12.46) and without FXTAS (n = 17, age: 44.94 + or - 11.23), in genetically normal female controls (n = 8, age: 50.63 + or - 11.43), male carriers with FXTAS (n = 34, age: 66.44 + or - 6.77) and without FXTAS (n = 21, age: 52.38 + or - 12.11), and genetically normal male controls (n = 30, age: 57.20 + or - 14.12). We examined the relationship between psychological symptom severity and hippocampal volume, as well as correlations with molecular data. We found a significant negative correlation between total hippocampal volume and anxiety in female carriers, with and without FXTAS. This finding was mainly driven by the significant negative correlation between right hippocampal volume and anxiety. Other anxiety-related subscales also correlated with the right hippocampus in females. In male carriers with and without FXTAS, only paranoid ideation negatively correlated with hippocampal volume. Female premutation carriers demonstrated a negative association between hippocampal volume and the severity of anxiety-related psychological symptoms. Though the presentation of FXTAS symptoms is less common in females, anxiety-related problems are common both prior to and after the onset of FXTAS, and may be related to hippocampal changes.

An in vivo study of phosphorus and glucose metabolism in Alzheimer's disease using magnetic resonance spectroscopy and PET.

OBJECTIVES: To study phosphorus and glucose metabolism in whole-brain slices of otherwise healthy patients with dementia of the Alzheimer type (DAT) and healthy controls. DESIGN: We used proton nuclear magnetic resonance imaging phosphorus spectroscopy and positron emission tomography to study in vivo brain phosphorus and glucose metabolism. PATIENTS: Whole-brain slice phosphorus metabolism was studied in nine drug free patients with mild to moderately severe dementia of the Alzheimer type (DAT) and in eight age- and sex-matched healthy controls. Mean ages (+/- SD) of the patients and controls were 60 +/- 10 years and 64 +/- 16 years, respectively. Positron emission tomography was used to study cerebral glucose metabolism in seven of the patients with DAT and seven of the healthy controls. RESULTS: Patients with DAT had significant brain glucose hypometabolism compared with controls, but there was no significant group difference in any phosphorus metabolite concentration or ratio in the same volume of brain tissue. Also, within patients with DAT there was no correlation between any phosphorus metabolite concentration or ratio and either severity of dementia or glucose metabolism. CONCLUSIONS: We suggest glucose metabolism is reduced early in DAT (reflecting decreased basal synaptic functioning) and is unrelated to a rate limitation in glucose delivery, abnormal glucose metabolism, or abnormal coupling between oxidation and phosphorylation. Normal or near-normal levels of phosphorus metabolites are maintained in mild, moderate, and severe DAT. Therefore, altered high-energy phosphate levels are not a consequence of reduced glucose metabolism in DAT, and do not play a major role in the pathophysiology of the disorder, at least in whole-brain sections.

Sex differences in human brain morphometry and metabolism: an in vivo quantitative magnetic resonance imaging and positron emission tomography study on the effect of aging.

BACKGROUND: There are significant age and sex effects in cognitive ability and brain disease. However, sex differences in aging of human brain areas associated with nonreproductive behavior have not been extensively studied. We hypothesized that there would be significant sex differences in aging of brain areas that subserve speech, visuospatial, and memory function. METHODS: We investigated sex differences in the effect of aging on human brain morphometry by means of volumetric magnetic resonance imaging and on regional cerebral metabolism for glucose by positron emission tomography. In the magnetic resonance imaging study, we examined 69 healthy right-handed subjects (34 women and 35 men), divided into young (age range, 20 to 35 years) and old (60 to 85 years) groups. In the positron emission tomography study, we investigated 120 healthy right-handed subjects (65 women and 55 men) aged 21 to 91 years. RESULTS: In the magnetic resonance imaging study, age-related volume loss was significantly greater in men than women in whole brain and frontal and temporal lobes, whereas it was greater in women than men in hippocampus and parietal lobes. In the positron emission tomography study, significant sex differences existed in the effect of age on regional brain metabolism, and asymmetry of metabolism, in the temporal and parietal lobes, Broca's area, thalamus, and hippocampus. CONCLUSIONS: We found significant sex differences in aging of brain areas that are essential to higher cognitive functioning. Thus, our findings may explain some of the age-sex differences in human cognition and response to brain injury and disease.

Relation between stage of disease and neurobehavioral measures in children with symptomatic HIV disease.

OBJECTIVE: To study the relationships between stage of HIV disease, reflected by CD4+ lymphocyte percentages and p24 antigen levels, and HIV-associated central nervous system (CNS) abnormalities, measured by computed tomography (CT) brain-scan ratings and neurobehavioral tests. DESIGN: Consecutive case series. SETTING: Government medical research center. PATIENTS: Eighty-six previously untreated children with symptomatic HIV-1 disease. RESULTS: CD4% measures correlated significantly with overall CT brain-scan severity ratings (r = -0.45; P < 0.001) as well as with its component parts (cortical atrophy, white matter abnormalities, and intracerebral calcifications); they were of comparable magnitude for vertically and transfusion-infected children. CD4% measures were also associated with the general level of cognitive function (r = 0.32; P < 0.005). Furthermore, patients with detectable serum p24 antigen levels (n = 39) had CT brain scans that were more abnormal than patients with undetectable p24 levels (n = 20; CT abnormality ratings of 21.3 versus 35.9; P < 0.02); similar differences were found for the cortical atrophy and calcification ratings. p24 levels also correlated with the overall CT brain-scan severity rating (r = 0.34; P < 0.01). CONCLUSIONS: Degree of CT brain-scan abnormality and level of cognitive dysfunction were significantly associated with the stage of HIV-1 disease, as reflected by either CD4 leukocyte measures or elevations of p24 antigen. The relation between the CT brain-scan lesions and markers of HIV disease (both CD4 and p24) suggest that these CNS abnormalities are most likely associated with HIV-1 infection, and further support the hypothesis that the interaction between systemic disease progression and CNS manifestations is continuous rather than discrete.

Brain atrophy in hypertension. A volumetric magnetic resonance imaging study.

To determine whether hypertension, the predominant risk factor for stroke and vascular dementia, is associated with brain atrophy, magnetic resonance imaging (MRI) scans were performed to quantify brain volumes and cerebrospinal fluid spaces. Eighteen otherwise healthy, cognitively normal older hypertensive men (mean +/- SD age, 69 +/- 8 years, duration of hypertension 10-35 years) and 17 age-matched healthy, normotensive male control subjects were studied in a cross-sectional design. Axial proton-density image slices were analyzed using region-of-interest and segmentation analyses. The hypertensive subjects had significantly larger mean volumes of the right and left lateral ventricles (p less than 0.05, both absolute volume and volume normalized to intracranial volume) and a significantly smaller normalized mean left hemisphere brain volume (p less than 0.05) with a trend toward significance for a smaller normalized mean right hemisphere volume (p less than 0.09). Four hypertensive subjects and one healthy control subject were found to have severe periventricular hyperintensities on T2-weighted MRI images. When data for these subjects were removed from the analyses, the normalized lateral ventricle volumes remained significantly larger in the hypertensive group. Lateral ventricle enlargement was not related to age or use of diuretics in the hypertensive group nor to duration of hypertension between 10 and 24 years. Our findings suggest that long-standing hypertension results in structural changes in the brain. Longitudinal studies will determine whether MRI-associated changes are progressive and if such changes identify hypertensive subjects at increased risk for clinically apparent brain dysfunction.

Volumetric magnetic resonance imaging in men with dementia of the Alzheimer type: correlations with disease severity.

Using magnetic resonance imaging (MRI), we measured the volumes of various brain structures and cerebrospinal fluid (CSF) in 19 men with dementia of the Alzheimer type (DAT) and 18 healthy age-matched control men. The mean (+/- S.D) Mini-Mental State exam score (MMSE) of the DAT men was 16 +/- 7; 9 were mildly (MMSE > 20), 5 moderately (MMSE 10-20), and 5 severely (MMSE < 10) demented. Brain and CSF volumes were normalized as a percent of the traced intracranial volume to control for the relation of volumes of cerebral structures to head size, and analyzed statistically. The whole group of DAT subjects had significantly smaller mean cerebral brain matter and temporal lobe volumes (p < 0.05), and significantly larger mean ventricular and temporal lobe peripheral CSF volumes than did controls. Mean volumes of the subcortical nuclei did not differ significantly between groups, and mean volume of temporal lobe brain matter decreased significantly more than whole brain, suggesting regional loss of brain matter in DAT. Mildly demented DAT patients had significantly smaller mean cerebral brain matter and temporal lobe volumes and significantly larger volumes of lateral ventricles, and of temporal lobe peripheral CSF, than did controls. Neuropsychological measures of disease severity in DAT patients were significantly (p < 0.05) and appropriately correlated to volumes of cerebral brain matter and right lateral ventricle. These results suggest that in DAT: (i) significant brain atrophy is present early in the disease process, (ii) brain atrophy correlates with severity of cognitive impairment, and (iii) there is greater involvement of the telencephalic association system than whole brain, and there is relative sparing of the caudate, lenticular and thalamic nuclei.

NAD(P)H:quinone oxidoreductase activity is increased in hippocampal pyramidal neurons of patients with Aalzheimer's disease.

NAD(P)H:quinone oxidoreductase (QR) catalyzes the two-electron reduction of quinones, preventing their participation in redox cycling and subsequent generation of reactive oxygen species. Pretreatment of neuroblastoma cells with compounds, such as tert-butylhydroquinone and dimethyl fumarate, that increase QR expression protect cells from oxidative stress-induced cell death by glutamate, H(2)O(2,) and dopamine. The potential neuroprotective role of QR as well as the evidence for oxidative stress-induced neuronal cell death in Alzheimer's disease (AD) led us to examine the expression pattern of QR from AD and control patients. Histochemical staining of hippocampal sections from AD patients revealed QR activity in pyramidal neurons. The presence of QR protein in these neurons also was confirmed by immunoreactivity. In control patients, hippocampal pyramidal neurons were negative for both QR enzymatic activity and QR immunoreactivity. In addition, the QR positive neurons of AD patients were selectively located in areas where neuronal populations exhibited tau immunostaining. Our data demonstrate that QR is up-regulated in hippocampal pyramidal neurons of AD patients. We hypothesize that this is part of a neuroprotective system up-regulated in response to the AD process. Understanding this system may lead to further insights into the pathogenesis and potential new avenues of treatment for AD.

Correlation between computed tomographic brain scan abnormalities and neuropsychological function in children with symptomatic human immunodeficiency virus disease.

OBJECTIVE: To evaluate the clinical significance of computed tomographic brain scan abnormalities observed in children with symptomatic human immunodeficiency virus disease. PATIENTS: Eighty-seven previously untreated children with symptomatic human immunodeficiency virus type 1 disease. METHODS: General levels of cognitive functioning, obtained from age-appropriate intelligence tests, and social-emotional behavior were correlated with computed tomographic brain scan abnormality ratings. RESULTS: A significant relation between computed tomographic brain scan abnormalities and cognitive dysfunction as well as aberrant behavior was found, which appeared stronger in (younger) vertically infected children compared with transfusion-infected patients. Calcifications, independent from the degree of brain atrophy, were associated with significantly greater delays in neurocognitive development. CONCLUSION: Computed tomographic brain scan abnormalities, even when mild, were of clinical significance, suggesting that human immunodeficiency virus-associated central nervous system compromise is a continuous process and that scans may be helpful at baseline in defining patients at risk and for monitoring them during therapy.

Age-related differences in volumes of subcortical nuclei, brain matter, and cerebrospinal fluid in healthy men as measured with magnetic resonance imaging.

Magnetic resonance imaging was used to determine the volumes of brain, subcortical gray matter nuclei, and the ventricular and sulcal cerebrospinal fluid in 27 healthy men. Subjects were divided into young (less than 35 years, n = 10) and old (greater than 60 years, n = 17) groups. Volumes were normalized as percent intracranial volume. Older subjects had significantly less brain mass and significantly larger ventricular and peripheral cerebrospinal fluid volumes than the younger men. The caudate and lenticular nuclei were significantly smaller in older than younger men. This significant difference remained when their volumes were expressed as a ratio of cerebral brain matter volume. This cross-sectional study demonstrates age-related atrophy and concurrent dilation of cerebrospinal fluid spaces in healthy subjects. Of brain regions affected, the caudate and lenticular nuclei are significantly more affected by healthy aging than is cerebral brain matter; this may account for some of the motor abnormalities in aging.

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.

White matter hyperintensities in dementia of Alzheimer's type and in healthy subjects without cerebrovascular risk factors. A magnetic resonance imaging study.

T2-weighted (0.5 T) magnetic resonance images were used to study the prevalence of subcortical white matter hyperintensities (WMHIs) in 22 patients with dementia of Alzheimer's type (DAT), 20 age-matched older healthy control subjects, and 10 younger healthy control subjects. Exclusionary criteria for all groups included cerebrovascular risk factors. All subjects had Hachinski Ischemic Index scores of less than 2 and computed tomographic scans showing no infarct. The WMHIs were classified as periventricular WMHIs or deep WMHIs and graded 0 through 3 (0 indicated absent, and 3, severe). For the group with DAT and older control subjects, periventricular WMHIs and deep WMHIs were graded 2 or 3 in fewer than 17% and 27% of subjects, respectively, whereas in the younger control subjects, all ratings were grade 1 or less. Serum cholesterol and systolic blood pressure values, although within the normal range, were elevated significantly in older control subjects when compared with those in younger control subjects. No significant differences in WMHI ratings, blood pressure, cholesterol, or triglyceride levels were found between patients with DAT and age-matched control subjects. Systolic blood pressure levels correlated with the severity of periventricular WMHIs only in older control subjects. Age correlated with periventricular WMHIs and deep WMHIs within both the older control subjects and the patients with DAT. There was no significant correlation between WMHIs and the severity of dementia in the group with DAT. These results suggest that, in subjects screened for cerebrovascular risk factors, WMHIs are rare and occur with identical frequency in patients with DAT as in age-matched healthy control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Postoperative changes in cerebral metabolism in temporal lobe epilepsy.

BACKGROUND: Fludeoxyglucose F 18 positron emission tomography ((18)F-FDG-PET) can detect focal metabolic abnormalities ipsilateral to the seizure focus in 80% of patients with temporal lobe epilepsy (TLE). Regions outside the epileptogenic zone can also be affected. We hypothesized that these remote regions might show altered metabolism, tending to return toward normal values, after surgery. DESIGN: Interictal preoperative and postoperative (18)F-FDG-PET metabolism were compared in patients with refractory TLE. Based on pathological findings, disease was classified in the following 3 groups: mesial temporal sclerosis, mass lesions, and no pathological diagnosis. Quantitative PET data analysis was performed using the region-of-interest template previously described. Global normalization was used to adjust for the effect of antiepileptic medication changes. Data were analyzed by Wilcoxon signed rank test and analysis of variance. SETTING: The Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health. PATIENTS: Twenty-two patients with refractory TLE. RESULTS: Preoperatively, in all groups, cerebral metabolic rate for glucose was decreased ipsilateral to the resection site in inferior lateral temporal, inferior mesial temporal, and inferior frontal areas and thalamus. Postoperatively, in all groups, cerebral metabolic rate for glucose increased in ipsilateral inferior frontal area and thalamus. In the mesial temporal sclerosis group, we found a statistically significant increase in the contralateral thalamus. CONCLUSION: Temporal lobe epilepsy is associated with extensive preoperative decreased metabolism in inferior lateral temporal, inferior mesial temporal, and inferior frontal areas and thalamus. Postoperatively, we found increased IF and thalamic metabolism. Seizures may have a reversible effect on brain areas connected with, but remote from, the epileptogenic cortex. Arch Neurol. 2000;57:1447-1452

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.

Brain growth and cognitive improvement in children with human immunodeficiency virus-induced encephalopathy after 6 months of continuous infusion zidovudine therapy.

The ventricular area at the level of the foramen of Monro was measured from axial x-ray computed tomography (CT) scans obtained prior to and 6 months after the initiation of continuous infusion of zidovudine (ZDV) in eight children with human immunodeficiency virus-induced encephalopathy. Evidence of moderate to severe central atrophy was present on initial CT scans (p less than 0.05). Ventricular area and ventricular brain area ratio (VBR) decreased after ZDV therapy in seven of eight children (mean decrease of 21.5 and 20%, respectively, p less than 0.05). The degree of decrease in VBR correlated with reductions in cerebrospinal fluid (CSF) protein concentration (r = 0.93, p less than 0.01), but not lymphocyte T4 or T8 counts. Intelligence quotients (IQs) improved in all seven children tested (mean improvement of 17.7%, p less than 0.01) and correlated significantly with reductions in CSF protein concentration (r = -0.85, p = 0.003). The magnitude of IQ changes was not significantly correlated with the magnitude of changes in ventricular area. We conclude that the cognitive improvement of HIV encephalopathy seen after 6 months of continuous infusion of ZDV is accompanied by reduction in brain atrophy and decreased CSF protein, suggesting an ameliorating effect of ZDV on the pathogenesis of AIDS encephalopathy in children.

Free light chains in multiple sclerosis and infections of the CNS.

The intrathecal humoral immune response was analyzed in 83 patients with MS and 35 patients with acute CNS infections. CSF free kappa chains and CSF free lambda chains were quantified by radioimmunoassay; CSF IgG and albumin were measured by electroimmunodiffusion. The MS patients were characterized by higher levels of free kappa chains; free kappa:free lambda chain ratio; free kappa chain:albumin ratio; and IgG:albumin ratio. There were no differences in the level of free lambda chains or absolute concentration of IgG. A significant correlation was observed between free kappa chains and total IgG in MS and between free lambda chains and total IgG in infections, suggesting that the immune response was predominantly IgG-kappa in MS and IgG-lambda in infections.

Longitudinal changes in lateral ventricular volume in patients with dementia of the Alzheimer type.

We determined the rates of lateral ventricular enlargement and decline in cognitive performance for 11 men and nine women with dementia of the Alzheimer type (DAT), and compared these rates with the same measures obtained for age-matched healthy controls (nine men and eight women). DAT patients, as a group, had only mild cognitive impairment at initial evaluation, and each patient was followed from 9 months to over 7 years with yearly evaluations. Six DAT patients had isolated memory impairment as their only cognitive deficit early in the course of the disease. The rate of total lateral ventricle enlargement (cm3/yr) was significantly different between DAT and healthy controls, and was more specific and sensitive to the diagnosis of DAT than comparison of cross-sectional volumes at final evaluation. The rate of total lateral ventricular enlargement did not differ significantly by patient sex, ventricular size at initial evaluation, age, or degree of cognitive impairment as measured by Mini Mental State Examination scores. However, in the six DAT patients initially found to have isolated memory impairment, the rate of ventricular enlargement during the period of isolated memory impairment was significantly less than the rate of ventricular enlargement after the onset of nonmemory cognitive impairment. The diagnostic power of total lateral ventricular measures made from two CTs separated by 1 year and obtained early in the course of the illness, however, was only 0.33. We conclude that the total lateral ventricular enlargement accompanying DAT is due to continuous, pathologic cell loss, significantly greater than cell loss due to the healthy aging process.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.