D. Mungas

White matter lesions impair frontal lobe function regardless of their location

Objective: To analyze the effect of white matter lesions in different brain regions on regional cortical glucose metabolism, regional cortical atrophy, and cognitive function in a sample with a broad range of cerebrovascular disease and cognitive function. Methods: Subjects (n = 78) were recruited for a study of subcortical ischemic vascular disease (SIVD) and Alzheimer disease (AD) contributions to dementia. A new method was developed to define volumes of interest from high-resolution three-dimensional T1-weighted MR images. Volumetric measures of MRI segmented white matter signal hyperintensities (WMH) in five different brain regions were related to regional PET glucose metabolism (rCMRglc) in cerebral cortex, MRI measures of regional cortical atrophy, and neuropsychological assessment of executive and memory function. Results: WMH was significantly higher in the prefrontal region compared to the other brain regions. In all subjects, higher frontal and parietal WMH were associated with reduced frontal rCMRglc, whereas occipitotemporal WMH was only marginally associated with frontal rCMRglc. These associations were stronger and more widely distributed in nondemented subjects where reduced frontal rCMRglc was correlated with WMH for all regions measured. In contrast, there was no relationship between WMH in any brain region and rCMRglc in either parietal or occipitotemporal regions. WMHs in all brain regions were associated with low executive scores in nondemented subjects. Conclusions: The frontal lobes are most severely affected by SIVD. WMHs are more abundant in the frontal region. Regardless of where in the brain these WMHs are located, they are associated with frontal hypometabolism and executive dysfunction.

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.

Age and education correction of Mini-Mental State Examination for English- and Spanish-speaking elderly

Previous research has shown that the Mini-Mental State Examination (MMS) is biased as a measure of cognitive impairment in minority and low-education patients. The purpose of this study was to (1) develop a statistical correction for effects of age and education and (2) test the efficacy of the statistically adjusted MMS (MMSAdj) as a screening test for dementia using different ethnic groups and education levels. We used a population-base community survey sample (n=590) composed of 46.6% Hispanics and 53.4% non-Hispanics to derive the statistical correction, defined as:MMSAdj = Raw MMS - (0.471 X [Education-12]) + (0.131 X [Age-70]). Ethnicity and language of test administration were not significantly related to MMSAdj in the community survey sample, but the raw MMS was strongly influenced by these factors. We used an independent sample (n=2,983) of patients evaluated through the California Alzheimers Disease Diagnostic and Treatment Centers to test the diagnostic accuracy of the MMS and the MMSAdj across low- and high-education groups and across whites, Hispanics, and blacks. Results showed greater stability of sensitivity and specificity across education levels and ethnic groups for the MMSAdj than for the raw MMS and suggest that the MMSAdj is a preferable measure of cognitive impairment for low- education and minority individuals.

What does fluorodeoxyglucose PET imaging add to a clinical diagnosis of dementia

Background: Few studies have compared the accuracy of [18F]fluorodeoxyglucose (FDG) PET to the accuracy of clinical and pathologic diagnosis in dementia patients. Methods: Forty-four individuals with dementia, cognitive impairment, or normal cognitive function underwent clinical initial evaluation (IE) and PET scanning and were followed up for approximately 4 years until a final evaluation (FE) and 5 years until death and autopsy. Clinical, pathologic, and imaging diagnoses were categorized as Alzheimer disease (AD) or not AD. Results: Sensitivity of the IE for the pathologic diagnosis of AD was 0.76, and specificity was 0.58; PET had values of 0.84 and 0.74, and FE had values of 0.88 and 0.63. Positive predictive values for IE, PET, and FE were 0.70, 0.81, and 0.76. Negative predictive values were 0.65, 0.78, and 0.80. The diagnosis of AD was associated with a 70% probability of detecting AD pathology; with a positive PET scan this increased to 84%, and with a negative PET scan this decreased to 31%. A diagnosis of not AD at IE was associated with a 35% probability of AD pathology, increasing to 70% with a positive PET scan. Conclusions: As a diagnostic tool, PET is superior to a baseline clinical evaluation and similar to an evaluation performed 4 years later. Although the addition of [18F]fluorodeoxyglucose PET to a clinical diagnosis provides useful information that can affect the likelihood of detecting Alzheimer disease pathology, the value of this technique in the current clinical environment with limited therapeutic options is likely to be modest.

Volumetric MRI predicts rate of cognitive decline related to AD and cerebrovascular disease

ObjectiveTo examine volumetric MRI correlates of longitudinal cognitive decline in normal aging, AD, and subcortical cerebrovascular brain injury (SCVBI). BackgroundPrevious cross-sectional studies examining the relationship between cognitive impairment and dementia have shown that hippocampal and cortical gray matter atrophy are the most important predictors of cognitive impairment, even in cases with SCVBI. The authors hypothesized that hippocampal and cortical gray matter volume also would best predict rate of cognitive decline in cases with and without SCVBI. Methods Subjects were recruited for a multicenter study of contributions to dementia of AD and SCVBI. The sample (n = 120) included cognitively normal, cognitively impaired, and demented cases with and without lacunes identified by MRI. Cases with cortical strokes were excluded. Average length of follow-up was 3.0 years. Measures of hippocampal volume, volume of cortical gray matter, presence of subcortical lacunes, and volume of white matter hyperintensity were derived from MRI. Random effects modeling of longitudinal data was used to assess effects of baseline MRI variables on longitudinal change in a measure of global cognitive ability. Results Cortical gray matter atrophy predicted cognitive decline regardless of whether lacunes were present. Hippocampal atrophy predicted decline only in those without lacunes. Neither lacunes nor white matter hyperintensity independently predicted decline. ConclusionsResults suggest that cortical atrophy is an index of disease severity in both AD and subcortical cerebrovascular brain injury and consequently predicts faster progression. Hippocampal volume may index disease severity and predict progression in AD. The absence of this effect in cases with lacunes suggests that this group is etiologically heterogeneous and is not composed simply of cases of AD with incidental stroke.

Atrophy rates of entorhinal cortex in AD and normal aging

Objectives: To explore the atrophy rate of entorhinal cortex (ERC) in AD and normal aging and assess the value of rate measurement of ERC atrophy for classifying subjects with AD from cognitively normal (CN) control subjects. Methods: Twenty-one AD patients and 23 CN subjects had MRI scans and clinical evaluations twice within 1.8 ± 0.6 years. ERC volumes were manually measured on volumetric T1-weighted MR images. Results: Patients with AD had a greater annual percentage volume change of ERC than CN subjects on both sides (left: 6.8 ± 4.3%/year for AD vs 1.4 ± 2.5%/year for CN [F1,42 = 25.6, p < 0.001]; right: 6.3 ± 3.3%/year for AD vs 1.4 ± 2.3%/year for CN [F1,42 = 25.6, p < 0.001]). Furthermore, increased ERC atrophy rate was correlated (r = −0.56, p = 0.01) with decreased memory performance in AD. CN subjects had on average annual ERC atrophy rates greater than zero (p < 0.01). Baseline volume of ERC predicted atrophy rate of ERC (left: r = −0.53, p < 0.01; right: r = −0.42, p < 0.05) in CN subjects but not in AD subjects. Using ERC baseline volumes alone resulted in 77% overall correct classification (p < 0.01) between AD and CN subjects, with 76% sensitivity and 78% specificity and an area under receiver operator characteristic (ROC) curve of 0.83. Adding annual atrophy rate of ERC to the model accounted for most of the variance (p < 0.01), diminishing contributions from baseline volume and yielding 82% overall classification, with 76% sensitivity and 86% specificity and an area under the ROC curve of 0.93. Conclusion: ERC volume loss over time may be a better indicator for AD than cross-sectional measurements.

Higher atrophy rate of entorhinal cortex than hippocampus in AD

Objectives: To determine if atrophy rates were higher for entorhinal cortex (ERC) than for hippocampus in Alzheimer disease (AD), to determine the relationship between hippocampal atrophy rate and memory impairment, and to compare atrophy rates of ERC and hippocampus in differentiating between patients with AD and cognitively normal (CN) controls. Methods: Twenty patients with AD and 25 CN subjects had MRI scans and clinical evaluations twice approximately 1.9 years apart. ERC volumes were measured manually and hippocampal volumes were measured semiautomatically on volumetric T1-weighted MR images. Results: In AD, the atrophy rate of ERC (7.1 ± 3.2%/year) was higher (p < 0.02) than that of hippocampus (5.9 ± 2.4%/year). Furthermore, memory deficit in mild AD, measured with the Delayed List Verbal Recall test, correlated significantly with atrophy rates of both ERC (r = −0.61) and hippocampus (r = −0.59). Atrophy rates of ERC and hippocampus were comparable in differentiating between AD and CN. Using atrophy rates of ERC or hippocampus to detect a 20% treatment effect with 90% power (p < 0.05) would require about 100 completed patients per arm in a 2-year study. Conclusion: The finding in AD that the atrophy rate in the entorhinal cortex is higher than in the hippocampus is consistent with the view that AD pathology begins in the entorhinal cortex.

Preliminary evidence that estrogen protects against age-related hippocampal atrophy

Few studies have examined gender differences in hippocampal volumes, and the potential effect of estrogen on these measures has not been well studied. We used MRI to measure hippocampal volumes in elderly Mexican American men and women subjects in order to determine if there were gender differences and if estrogen replacement therapy (ERT) had an effect on hippocampal volume in postmenopausal women. MRI measures of hippocampal volumes (normalized to intracranial volume) were compared in 59 women and 38 men. Further comparisons were made between men subjects, women subjects taking ERT, and women subjects not taking ERT. There were no significant effects of gender on normalized hippocampal volumes. However, women subjects taking ERT had larger right hippocampal volumes than women subjects not taking ERT and larger anterior hippocampal volumes than men subjects and women subjects not taking ERT. These findings suggest a neuroprotective effect of estrogen.

Brain atrophy associated with baseline and longitudinal measures of cognition

The overall goal was to identify patterns of brain atrophy associated with cognitive impairment and future cognitive decline in non-demented elders. Seventy-one participants were studied with structural MRI and neuropsychological testing at baseline and 1-year follow-up. Deformation-based morphometry was used to examine the relationship between regional baseline brain tissue volume with baseline and longitudinal measures of delayed verbal memory, semantic memory, and executive function. Smaller right hippocampal and entorhinal cortex (ERC) volumes at baseline were associated with worse delayed verbal memory performance at baseline while smaller left ERC volume was associated with greater longitudinal decline. Smaller left superior temporal cortex at baseline was associated with worse semantic memory at baseline, while smaller left temporal white and gray matter volumes were associated with greater semantic memory decline. Increased CSF and smaller frontal lobe volumes were associated with impaired executive function at baseline and greater longitudinal executive decline. These findings suggest that baseline volumes of prefrontal and temporal regions may underlie continuing cognitive decline due to aging, pathology, or both in non-demented elderly individuals.

Memory failure has different mechanisms in subcortical stroke and Alzheimer's disease

Patients with extensive subcortical cerebrovascular disease may have impaired memory, often despite the absence of medial temporal or diencephalic strokes. In this group, episodic memory failure may arise from frontal lobe dysfunction based on disruption of frontosubcortical loops caused by lacunae. We tested this idea by studying cognitively impaired subcortical stroke (CIS) patients and Alzheimers disease (AD) patients with [18F]‐fluorodeoxyglucose positron emission tomography using a continuous verbal memory task during the period of tracer uptake. Patients were matched on severity of cognitive impairment and overall memory task performance. As hypothesized, we found a double dissociation in the relations between metabolism and memory in these groups, such that memory in CIS (but not in AD) correlates with prefrontal lobe metabolism, whereas in AD (but not in CIS), memory correlates with left hippocampal and temporal lobe metabolism. Analysis of memory subscores showed that CIS patients made more errors on short‐delay trials, which is consistent with working memory failure. It seems that different pathogenic mechanisms underlie episodic memory failure in subcortical cerebrovascular disease and AD. Ann Neurol 2000;48:275–284