Brain morphometric correlates of metabolic variables in HIV: the CHARTER study.

Obesity and other metabolic variables are associated with abnormal brain structural volumes and cognitive dysfunction in HIV-uninfected populations. Since individuals with HIV infection on combined antiretroviral therapy (CART) often have systemic metabolic abnormalities and changes in brain morphology and function, we examined associations among brain volumes and metabolic factors in the multisite CNS HIV AntiRetroviral Therapy Effects Research (CHARTER) cohort, cross-sectional study of 222 HIV-infected individuals. Metabolic variables included body mass index (BMI), total blood cholesterol (C), low- and high-density lipoprotein C (LDL-C and HDL-C), blood pressure, random blood glucose, and diabetes. MRI measured volumes of cerebral white matter, abnormal white matter, cortical and subcortical gray matter, and ventricular and sulcal CSF. Multiple linear regression models allowed us to examine metabolic variables separately and in combination to predict each regional volume. Greater BMI was associated with smaller cortical gray and larger white matter volumes. Higher total cholesterol (C) levels were associated with smaller cortex volumes; higher LDL-C was associated with larger cerebral white matter volumes, while higher HDL-C levels were associated with larger sulci. Higher blood glucose levels and diabetes were associated with more abnormal white matter. Multiple atherogenic metabolic factors contribute to regional brain volumes in HIV-infected, CART-treated patients, reflecting associations similar to those found in HIV-uninfected individuals. These risk factors may accelerate cerebral atherosclerosis and consequent brain alterations and cognitive dysfunction.

Neurocognitive deficits in HIV-infected women and victims of childhood trauma.

The study investigated the behavioral and brain effects of childhood trauma and human immunodeficiency virus (HIV) infection, both separately and in combination, and assessed potential interactions in women who were dually affected. Eighty-three HIV-positive and 47 matched HIV-negative South African women underwent neuromedical, neuropsychiatric, and neurocognitive assessments. Univariate tests of significance assessed if either HIV infection or childhood trauma, or the combination, had a significant effect on neurocognitive performance. The majority of women were Black (96%) and had an average age of 30 years. An analysis of covariance revealed significant HIV effects for the Hopkins Verbal Learning Test (HVLT) learning and delay trials (p < 0.01) and the Halstead Category Test (HCT) (p < 0.05). A significant trauma effect was seen on the HVLT delay trial (p < 0.05). The results provide evidence for neurocognitive dysfunction in memory and executive functions in HIV-infected women and memory disturbances in trauma exposed women.

In vivo evidence of cerebellar atrophy and cerebral white matter loss in Huntington disease.

OBJECTIVE: To investigate the regional pattern of white matter and cerebellar changes, as well as subcortical and cortical changes, in Huntington disease (HD) using morphometric analyses of structural MRI. METHODS: Fifteen individuals with HD and 22 controls were studied; groups were similar in age and education. Primary analyses defined six subcortical regions, the gray and white matter of primary cortical lobes and cerebellum, and abnormal signal in the cerebral white matter. RESULTS: As expected, basal ganglia and cerebral cortical gray matter volumes were significantly smaller in HD. The HD group also demonstrated significant cerebral white matter loss and an increase in the amount of abnormal signal in the white matter; occipital white matter appeared more affected than other cerebral white matter regions. Cortical gray and white matter measures were significantly related to caudate volume. Cerebellar gray and white matter volumes were both smaller in HD. CONCLUSIONS: The cerebellum and the integrity of cerebral white matter may play a more significant role in the symptomatology of HD than previously thought. Furthermore, changes in cortical gray and cerebral white matter were related to caudate atrophy, supporting a similar mechanism of degeneration.

Effects of age on tissues and regions of the cerebrum and cerebellum.

Normal volunteers, aged 30 to 99 years, were studied with MRI. Age was related to estimated volumes of: gray matter, white matter, and CSF of the cerebrum and cerebellum; gray matter, white matter, white matter abnormality, and CSF within each cerebral lobe; and gray matter of eight subcortical structures. The results were: 1) Age-related losses in the hippocampus were significantly accelerated relative to gray matter losses elsewhere in the brain. 2) Among the cerebral lobes, the frontal lobes were disproportionately affected by cortical volume loss and increased white matter abnormality. 3) Loss of cerebral and cerebellar white matter occurred later than, but was ultimately greater than, loss of gray matter. It is estimated that between the ages of 30 and 90 volume loss averages 14% in the cerebral cortex, 35% in the hippocampus, and 26% in the cerebral white matter. Separate analyses were conducted in which genetic risk associated with the Apolipoprotein E epsilon4 allele was either overrepresented or underrepresented among elderly participants. Accelerated loss of hippocampal volume was observed with both analyses and thus does not appear to be due to the presence of at-risk subjects. MR signal alterations in the tissues of older individuals pose challenges to the validity of current methods of tissue segmentation, and should be considered in the interpretation of the results.

Brain dysmorphology in individuals with severe prenatal alcohol exposure.

Our previous studies revealed abnormalities on structural MRI (sMRI) in small groups of children exposed to alcohol prenatally. Microcephaly, disproportionately reduced basal ganglia volume, and abnormalities of the cerebellar vermis and corpus callosum were demonstrated. The present study used sMRI to examine in detail the regional pattern of brain hypoplasia resulting from prenatal exposure to alcohol using a higher resolution imaging protocol and larger sample sizes than reported previously. Fourteen participants (mean 11.4 years; eight females, six males) with fetal alcohol syndrome (FAS) and 12 participants (mean 14.8 years; four females, eight males) with prenatal exposure to alcohol (PEA) but without the facial features of FAS were compared to a group of 41 control participants (mean 12.8 years, 20 females, 21 males). Findings of significant microcephaly and disproportionately reduced basal ganglia volumes in the FAS group were confirmed. Novel findings were that in FAS participants, white matter volumes were more affected than gray matter volumes in the cerebrum, and parietal lobes were more affected than temporal and occipital lobes. Among subcortical structures, in contrast to the disproportionate effects on caudate nucleus, the hippocampus was relatively preserved in FAS participants. Differences between the PEA group and controls were generally non-significant; however, among a few of the structures most affected in FAS participants, there was some evidence for volume reduction in PEA participants as well, specifically in basal ganglia and the parietal lobe. There were no group differences in cerebral volume asymmetries. Severe prenatal alcohol exposure appears to produce a specific pattern of brain hypoplasia.

Does an increase in sulcal or ventricular fluid predict where brain tissue is lost?

Quantitative volumes of cerebrospinal fluid (CSF) and brain tissue were measured on magnetic resonance images (MRIs) of 287 individuals from 5 diagnostic groups: Alzheimer's disease (AD), chronic alcoholics (ALC), individuals positive for human immunodeficiency virus (HIV), schizophrenia subjects (SZ), and normal comparison subjects (NC) older than 50 years of age. Within each group, mean volumes were calculated for ventricular CSF, cortical (sulcal) CSF, cortical gray matter, total white matter, basal ganglia gray matter, and thalamic gray matter. Correlations of CSF measures with brain tissue measures were determined, and multiple regression analyses were performed to try and predict volume of gray matter or white matter region from volume of CSF compartment. Results indicated the following: 1. Enlarged cortical fluid volume significantly predicts cortical gray matter deficits for subjects with AD and those who are ALC and SZ but not for subjects with HIV or NC. 2. Enlarged cortical fluid volume also significantly predicts white matter deficits in all five groups. 3. Enlarged ventricular fluid volume significantly predicts basal ganglia deficits in AD, HIV, and NC but not in SZ or ALC. 4. Enlarged ventricular volume has no predictive value for thalamic volume for any of the groups. This study supports the clinical practice of predicting brain tissue volume loss from CSF enlargement but not for all brain regions in all diagnoses.

Regional cerebral volume loss associated with verbal learning and memory in dementia of the Alzheimer type.

Twenty-seven research participants with dementia of the Alzheimer type were studied with the California Verbal Learning Test (D. C. Delis, J. H. Kramer, E. Kaplan, & B. A. Ober, 1987) and standardized volume measures of the mesial temporal cortical gray matter, neocortical gray matter, thalamus, and caudate nuclei, from magnetic resonance imaging. A pattern of atrophic brain changes in the mesial temporal lobes (MTL) and the thalamus, with relatively less severe atrophy in the neocortical gray matter, was associated with poorer learning of the word list. Similar patterns of brain atrophy were observed for measures of delayed recall and recognition hits. However, for delayed recall, neither contribution was statistically significant, and for recognition hits, MTL was only at the trend level for significance. These results provide evidence that the verbal memory deficit of Alzheimer's disease (AD) is associated not only with the mesial temporal limbic cortex, thought to be the site of earliest and most severe pathology in AD, but also with damage in the thalamus.

Progressive cerebral volume loss in human immunodeficiency virus infection: a longitudinal volumetric magnetic resonance imaging study. HIV Neurobehavioral Research Center Group.

OBJECTIVE: To compare rates and anatomical patterns of brain atrophy during 3 stages of human immunodeficiency virus (HIV) disease. DESIGN: Comparisons of multiple serial brain magnetic resonance images in men without HIV infection and HIV-infected men in Centers for Disease Control and Prevention (CDC, Atlanta, Ga) stages A, B, and C. SETTING: Longitudinal cohort study of the San Diego HIV Neurobehavioral Research Center, San Diego, Calif. PARTICIPANTS: Eighty-six HIV-1-positive (HIV-positive) and 23 HIV-negative men who were similar in age and risk group. The number of HIV-positive men in each CDC stage was as follows: A, 33; B, 19; C, 34. All HIV-positive men were free of clinically detectable opportunistic neurologic illness. MAIN OUTCOME MEASURES: Regional volumes of serial magnetic resonance images converted to standardized slope estimates of change in regional volumes of interest. RESULTS: Medically asymptomatic men (CDC stage A) and medically symptomatic men (CDC stage C) had more rapid loss of cortical tissues than did HIV-negative men as manifested by higher slopes (Tukey honestly significant difference test, P=.02 and P=.001, respectively) for cortical fluid volume. Accelerated ventricular volume enlargement occurred only in men with CDC stage C disease. Reduction in the volume of white matter was accelerated in participants with CDC stage C disease compared with participants with CDC stage A disease. Of the gray matter regions, only the caudate nucleus sustained accelerated volume loss during CDC stage C disease. Participants whose systemic disease progressed to a higher CDC stage had significantly accelerated ventricular volume increases and caudate atrophy. Rates of cortical and subcortical fluid volume increases and reductions in the volumes of white matter and the caudate nucleus were significantly related to the rate of decline in the CD4+ lymphocyte count. CONCLUSIONS: In the absence of cerebral opportunistic disease, HIV infection causes progressive atrophy within the gray and white matter in the brain. These changes were most severe in the most advanced stage of disease but were evident even in medically asymptomatic HIV-positive persons. Within the gray matter, the caudate nucleus exhibited progressive volume loss linked to disease stage and the rate of decline of the CD4+ cell count. Structural brain changes can begin in the early stages of HIV infection and accelerate during advanced illness.

Association of dementia severity with cortical gray matter and abnormal white matter volumes in dementia of the Alzheimer type.

OBJECTIVE: To examine associations between dementia severity and quantitative magnetic resonance imaging measures of cortical gray matter volume and abnormal white matter volume in 52 patients diagnosed with probable Alzheimer disease. DESIGN: Analysis of the relationship between magnetic resonance imaging volume measures and dementia severity using multiple regression and Pearson correlations. SETTING: Alzheimer's Disease Research Center, University of California, San Diego. PARTICIPANTS: Twenty-three men and 29 women with probable Alzheimer disease (average age, 71.7 years; average education, 13.3 years). MAIN OUTCOME MEASURES: The Mattis Dementia Rating Scale (MDRS) and the Mini-Mental State Examination. RESULTS: Using simultaneous multiple regression, magnetic resonance imaging volumetric measures of cortical gray matter and abnormal white matter were independently associated with dementia severity measured by either the MDRS or the Mini-Mental State Examination. Cortical gray matter volume and abnormal white matter volume also made independent contributions to performance in 4 of 5 cognitive domains assessed by the MDRS. Regional analysis indicated that limbic cortical gray matter volume and nonlimbic cortical gray matter volume were also correlated with the MDRS score; however, in the regression analysis the individual gray matter measures were not independently associated with MDRS performance. A similar analysis revealed statistically independent relationships of limbic gray matter volume and abnormal white matter volume, but not nonlimbic cortical gray matter volume, to Mini-Mental State Examination performance. CONCLUSIONS: Quantitative magnetic resonance methods provided strong evidence that cortical gray matter volume, which may reflect atrophy, and abnormal white matter volume are independently related to dementia severity in probable Alzheimer disease: lower gray matter and higher abnormal white matter volumes are associated with more severe dementia.

The relationship of quantitative brain magnetic resonance imaging measures to neuropathologic indexes of human immunodeficiency virus infection.

OBJECTIVE: To directly examine the relationship between magnetic resonance imaging (MRI) abnormalities and neuropathologic changes in the brains of patients with the acquired immunodeficiency syndrome. DESIGN: A total of 17 brains from patients with acquired immunodeficiency syndrome for which postmortem MRI scans were available were used in this study. Volumes of cortical gray matter, deep gray matter, and abnormal white matter were estimated from the MRIs of the left hemispheres of the formalin-fixed brains from patients with acquired immunodeficiency syndrome using quantitative morphometric techniques. Quantitative estimates of human immunodeficiency virus, gliosis, and neocortical synaptic and dendritic density were obtained from the corresponding right hemispheres. Quantification of human immunodeficiency virus and gliosis was performed on all 17 specimens, while quantification of synaptic and dendritic density was performed on 10 of the 17 specimens. SETTING: All specimens were obtained from patients with the acquired immunodeficiency syndrome who underwent autopsy between 1990 and 1992 at the University of California-San Diego Medical Center and the San Diego (Calif) Department of Veterans Affairs Hospital. RESULTS: No association was found between MRI volumes and gliosis, a nonspecific marker of central nervous system damage. Significant and regionally specific relationships were obtained, however, between the severity of central nervous system human immunodeficiency virus infection and the MRI volume estimates of gray matter and abnormal white matter. In addition, a significant association was observed between cortical gray matter volumes and cortical synaptic density. CONCLUSION: These findings indicate that the quantitative morphometric analysis of MRIs in patients may provide sensitive in vivo markers of neuropathologic changes associated with human immunodeficiency virus infection of the brain.

Cerebral structure on MRI, Part I: Localization of age-related changes.

In this report, earlier findings of age-related changes in brain morphology on magnetic resonance (MR) images are extended to include measurements of individual cerebral grey matter structures and an index of white matter degeneration. Volumes of caudate, lenticular, and diencephalic structures are estimated, as are grey matter volumes in eight separate cortical regions. Results suggest that between 30 and 79 years significant decreases occur in the volume of the caudate nucleus, in anterior diencephalic structures, and in the grey matter of most cortical regions. The data suggest that the volumes of the thalamus and the anterior cingulate cortex may be unchanged. Among those cortical regions found to be affected in aging, some evidence is present for greater change in association cortices and mesial temporal lobe structures. There are also dramatic age-related changes in the white matter, manifest as lengthened T2 values on MR images.