M. W. Weiner

Hippocampal and cortical atrophy predict dementia in subcortical ischemic vascular disease

&NA; Article abstract Background The cause of dementia in subcortical ischemic vascular disease (SIVD) is controversial. Objectives To determine whether cognitive impairment in SIVD 1) correlates with measures of ischemic brain injury or brain atrophy, and/or 2) is due to concomitant AD. Methods Volumetric MRI of the brain was performed in 1) elderly subjects with lacunes (L) and a spectrum of cognitive impairment—normal cognition (NC+L, n = 32), mild cognitive impairment (CI+L, n = 26), and dementia (D+L, n = 29); 2) a comparison group with probable AD (n = 28); and 3) a control group with normal cognition and no lacunes (NC). The authors examined the relationship between the severity of cognitive impairment and 1) volume, number, and location of lacunes; 2) volume of white matter signal hyperintensities (WMSH); and 3) measures of brain atrophy (i.e., hippocampal, cortical gray matter, and CSF volumes). Results Among the three lacune groups, severity of cognitive impairment correlated with atrophy of the hippocampus and cortical gray matter, but not with any lacune measure. Although hippocampal atrophy was the best predictor of severity of cognitive impairment, there was evidence for a second, partially independent, atrophic process associated with ventricular dilation, cortical gray matter atrophy, and increase in WMSH. Eight autopsied SIVD cases showed variable severity of ischemic and neurofibrillary degeneration in the hippocampus, but no significant AD pathology in neocortex. The probable AD group gave evidence of only one atrophic process, reflected in the severity of hippocampal atrophy. Comparison of regional neocortical gray matter volumes showed sparing of the primary motor and visual cortices in the probable AD group, but relatively uniform atrophy in the D+L group. Conclusions Dementia in SIVD, as in AD, correlates best with hippocampal and cortical atrophy, rather than any measure of lacunes. In SIVD, unlike AD, there is evidence for partial independence between these two atrophic processes. Hippocampal atrophy may result from a mixture of ischemic and degenerative pathologies. The cause of diffuse cortical atrophy is not known, but may be partially indexed by the severity of WMSH.

MRI predictors of cognition in subcortical ischemic vascular disease and Alzheimer's disease

Background: Causes of cognitive impairment in subcortical ischemic vascular disease (SIVD) are less well understood than in AD, but have been thought to result from direct effects of subcortical lacunes and white matter lesions, perhaps related to disruption of important cortical–subcortical pathways. Objective: To examine the relation between cognitive abilities and quantitative MRI measures of subcortical cerebrovascular disease and cortical and hippocampal atrophy. Methods: Subjects were 157 participants in a multicenter study of SIVD and AD who included cognitively normal, cognitively impaired, and demented individuals with and without subcortical lacunar infarcts. Dependent variables were neuropsychological tests of global cognitive function, memory, language, and executive function. Independent variables were quantitative MRI measures of volume of lacunar infarcts in specific subcortical structures, volume of white matter lesion (WML), volume of cortical gray matter (cGM), and total hippocampal volume (HV). Multiple regression analyses were used to identify MRI predictors of cognition. Results: Subcortical lacunes were not related to cognitive measures independent of effects of other MRI variables. WML was independently related to selected, timed measures. HV and cGM were strong and independent predictors of cognitive variables, with effects that did not differ in subjects with and without subcortical lacunes. Conclusions: Results suggest that cognitive impairment associated with subcortical ischemic vascular disease is primarily a result of associated hippocampal and cortical changes.

Longitudinal volumetric MRI change and rate of cognitive decline

Objective: To examine how baseline and change of volumetric MRI relate to cognitive decline in older individuals. Background: Memory is associated with hippocampal integrity, whereas executive function has been linked to impaired frontal lobe function. Previous studies have shown that hippocampal and cortical atrophy are more strongly related to cognition than are measures of subcortical cerebrovascular disease (CVD). The authors hypothesized that memory (MEM) decline would be related to change in hippocampal volume (HC), whereas decline in executive function (EXEC) would be related to change of cortical gray matter volume (CGM) and measures of subcortical CVD. Methods: Subjects from a multicenter study (n = 103) included cognitively normal, mildly impaired, and demented cases with and without subcortical lacunes. All had longitudinal cognitive evaluation (mean = 4.8 years) and two or more MRI scans at least one year apart (mean = 3.4 years). MRI measures included HC, CGM, total lacune volume (LAC), and white matter hyperintensity volume (WMH). Random effects modeling of longitudinal data assessed effects of MRI baseline and MRI change on baseline and change of psychometrically matched measures of MEM and EXEC. Results: Change in MEM was related to HC baseline and HC change. Change in EXEC was related to baseline CGM and to change in CGM, HC, and LAC. Results were unchanged when demented cases were excluded. WMH was not associated with change in MEM or EXEC independent of HC, CGM, and LAC. Conclusion: Hippocampal volume was the primary determinant of memory decline, whereas executive function (EXEC) decline was related to multiple brain components. Results support a hypothesis that MEM decline is strongly influenced by Alzheimer disease (AD), whereas EXEC decline may be complexly determined by cerebrovascular disease and AD.

Distinct MRI atrophy patterns in autopsy-proven Alzheimer's disease and frontotemporal lobar degeneration.

To better define the anatomic distinctions between Alzheimers disease (AD) and frontotemporal lobar degeneration (FTLD), we retrospectively applied voxel-based morphometry to the earliest magnetic resonance imaging scans of autopsy-proven AD (N = 11), FTLD (N = 18), and controls (N = 40). Compared with controls, AD patients showed gray matter reductions in posterior temporoparietal and occipital cortex; FTLD patients showed atrophy in medial prefrontal and medial temporal cortex, insula, hippocampus, and amygdala; and patients with both disorders showed atrophy in dorsolateral and orbital prefrontal cortex and lateral temporal cortex (P FWE-corr < .05). Compared with FTLD, AD patients had decreased gray matter in posterior parietal and occipital cortex, whereas FTLD patients had selective atrophy in anterior cingulate, frontal insula, subcallosal gyrus, and striatum (P < .001, uncorrected). These findings suggest that AD and FTLD are anatomically distinct, with degeneration of a posterior parietal network in AD and degeneration of a paralimbic fronto-insular-striatal network in FTLD.

Reduced brain N-acetylaspartate suggests neuronal loss in cognitively impaired human immunodeficiency virus-seropositive individuals : in vivo 1H magnetic resonance spectroscopic imaging

We used magnetic resonance imaging (MRI) and water-suppressed proton magnetic resonance spectroscopic imaging to study the effects of human immunodeficiency virus (HIV) infection on the brains of 10 individuals with cognitive impairment due to HIV and seven normal controls. 1H spectra from nine 2.5-ml volumes in the centrum semiovale and the mesial cortex showed significantly reduced N-acetylaspartate (NAA) relative to choline and creatine in the cognitively impaired HIV-infected subjects. This reduction was due to a nonlocalized decrease of NAA in these patients, only two of whom had moderate atrophy and white matter signal hyperintensities on MRI. Since NAA is a putative neuronal marker, the findings suggest neuronal damage in early stages of HIV infection that is not evident on standard MRI and are consistent with the neuropathologically known neuronal loss.

Measurement of hippocampal subfields and age-related changes with high resolution MRI at 4T.

Histological studies suggest that hippocampal subfields are differently affected by aging and Alzheimer’s disease (AD). The aims of this study were: (1) To test if hippocampal subfields can be identified and marked using anatomical landmarks on high resolution MR images obtained on a 4T magnet. (2) To test if age-specific volume changes of subfields can be detected. Forty-two healthy controls (21–85 years) and three AD subjects (76–86 years) were studied with a high resolution T2 weighted fast spin echo sequence. The entorhinal cortex (ERC), subiculum, CA1, CA2 and CA3/4 and dentate were marked. A significant correlation between age and CA1 (r = −0.51, p = 0.0002) which was most pronounced in the seventh decade of life was found in healthy controls. In AD subjects, CA1 and subiculum were smaller than in age-matched controls. These preliminary findings suggest that measurement of hippocampal subfields may be helpful to distinguish between normal aging and AD.

Changes of hippocampal N-acetyl aspartate and volume in Alzheimer's disease A proton MR spectroscopic imaging and MRI study

Hippocampal atrophy detected by MRI is a prominent feature of early Alzheimers disease (AD), but it is likely that MRI underestimates the degree of hippocampal neuron loss, because reactive gliosis attenuates atrophy. We tested the hypothesis that hippocampal N-acetyl aspartate (NAA; a neuronal marker) and volume used together provide greater discrimination between AD and normal elderly than does either measure alone. We used proton MR spectroscopic imaging (1H MRSI) and tissue segmented and volumetric MR images to measure atrophy-corrected hippocampal NAA and volumes in 12 AD patients (mild to moderate severity) and 17 control subjects of comparable age. In AD, atrophy-corrected NAA from the hippocampal region was reduced by 15.5% on the right and 16.2% on the left (both p<0.003), and hippocampal volumes were smaller by 20.1% (p<0.003) on the right and 21.8% (p <0.001) on the left when compared with control subjects. The NAA reductions and volume losses made independent contributions to the discrimination of AD patients from control subjects. When used separately, neither hippocampal NAA nor volume achieved to classify correctly AD patients better than 80%. When used together, however, the two measures correctly classified 90% of AD patients and 94% of control subjects. In conclusion, hippocampal NAA measured by 1H MRSI combined with quantitative measurements of hippocampal atrophy by MRI may improve diagnosis of AD.

Region and tissue differences of metabolites in normally aged brain using multislice 1H magnetic resonance spectroscopic imaging.

Quantitative measurements of regional and tissue specific concentrations of brain metabolites were measured in elderly subjects using multislice proton magnetic resonance spectroscopic imaging (1H MRSI). Selective k‐space extrapolation and an inversion‐recovery sequence were used to minimize lipid contamination and linear regression was used to account for partial volume problems. The technique was applied to measure the concentrations of N‐acetyl aspartate (NAA), and creatine (Cr)‐ and choline (Cho)‐containing compounds in cortical gray and white matter, and white matter lesions of the frontal and the parietal lobe in 40 normal elderly subjects (22 females and 18 males, 56–89 years old, mean age 74 ± 8). NAA was about 15% lower in cortical gray matter and 23% lower in white matter lesions when compared to normal white matter. Cr was 11% higher in cortical gray matter than in white matter, and also about 15% higher in the parietal cortex than in the frontal cortex. Cho was 28% lower in cortical gray matter than in white matter. Furthermore, NAA and Cr changes correlated with age. In conclusion, regional and tissue differences of brain metabolites must be considered in addition to age‐related changes when interpreting 1H MRSI data. Magn Reson Med 45:899–907, 2001.

Elevated subcortical choline metabolites in cognitively and clinically asymptomatic HIV patients

Objective: To determine whether the concentrations of the neuronal marker N-acetylaspartate (NAA) and the choline-containing metabolites (Cho) are altered in the subcortical brain of HIV+ patients who are cognitively normal and clinically asymptomatic, and to determine whether these alterations are greater in the presence of cognitive impairments and clinical symptoms. Background: Pathologic studies suggest that subcortical gray matter carries a heavy HIV load, and neuropsychological test results are consistent with involvement of subcortical and frontostriatal brain systems in HIV disease. Noninvasive proton magnetic resonance spectroscopy (1H MRS) suggests neuronal preservation and macrophage infiltration in the subcortical brain of clinically symptomatic and cognitively impaired HIV+ individuals. Improved 1H MRS methods may allow the early detection of metabolite alterations in the subcortical brain of asymptomatic HIV+ individuals. Methods: Two-dimensional 1H MRS imaging was performed on 30 HIV− control subjects and 70 HIV+ patients with varying severities of systemic disease and neuropsychological impairments, but without cerebral opportunistic infections. Results: Subcortical Cho was elevated in HIV+ patients compared with control subjects regardless of the presence or absence of cognitive impairment or clinical symptoms. Subcortical NAA was lower than control NAA only in severely cognitively impaired HIV+ subjects. Subcortical NAA correlated with performance on a variety of neuropsychological tests but not with Centers for Disease Control clinical stage, whereas high-thalamic Cho was associated with low CD4 lymphocyte counts. Conclusions: 1H MRS imaging detects higher Cho in subcortical brain early in HIV disease, when individuals are clinically and neuropsychologically asymptomatic, whereas lower NAA is only found in subcortical brain in individuals with severe neuropsychological impairments. Quantitative 1H MRS imaging may play a role in the objective assessment of the presence, magnitude, and progression of brain involvement in HIV infection.

Effects of heavy drinking, binge drinking, and family history of alcoholism on regional brain metabolites.

BACKGROUND The main goals are to investigate the effects of chronic active heavy drinking on N-acetylaspartate (NAA) and other metabolites throughout the brain and to determine whether they are affected by family history (FH) of alcoholism and long-term drinking pattern. METHODS Forty-six chronic heavy drinkers (HD) and 52 light drinkers (LD) were recruited from the community and compared on measures of regional brain structure using magnetic resonance imaging and measures of common brain metabolites in gray matter (GM) and white matter (WM) of the major lobes, subcortical nuclei, brainstem, and cerebellum using short-echo time magnetic resonance spectroscopic imaging. Regional atrophy-corrected levels of NAA, myoinositol (mI), creatine, and choline-containing metabolites were compared as a function of group, FH of alcoholism, and bingeing. RESULTS Frontal WM NAA was lower in FH-negative HD than FH-positive HD and tended to be lower in women than men. Creatine-containing metabolites in parietal GM were higher in HD than LD. FH-negative compared with FH-positive HD also had more mI in the brainstem and tended to have lower NAA and more mI in frontal GM. Although parietal GM NAA was not significantly lower in HD than LD, it was lower in non-binge drinkers than bingers. Frontal WM NAA was lower in HD than LD, with the difference driven by a small number of women, FH-negative HD, and older age. Lower frontal WM NAA in HD was associated with lower executive and working memory functions and with lower P3b amplitudes at frontal electrodes. CONCLUSIONS Community-dwelling HD who are not in alcoholism treatment have brain metabolite changes that are associated with lower brain function and are likely of behavioral significance. Age, FH, and binge drinking modulate brain metabolite abnormalities. Metabolite changes in active HD are less pronounced and present with a different spatial and metabolite pattern than reported in abstinent alcoholics.