Dan Mungas

Extent and distribution of white matter hyperintensities in normal aging, MCI, and AD

Objective: To analyze the extent and spatial distribution of white matter hyperintensities (WMH) in brain regions from cognitively normal older individuals (CN) and patients with mild cognitive impairment (MCI) and Alzheimer disease (AD). Methods: We studied 26 mild AD, 28 MCI, and 33 CN. MRI analysis included quantification of WMH volume, nonlinear mapping onto a common anatomic image, and spatial localization of each WMH voxel to create an anatomically precise frequency distribution map. Areas of greatest frequency of WMH from the WMH composite map were used to identify 10 anatomic regions involving periventricular areas and the corpus callosum (CC) for group comparisons. Results: Total WMH volumes were associated with age, extent of concurrent vascular risk factors, and diagnosis. After correcting for age, total WMH volumes remained significantly associated with diagnosis and extent of vascular risk. Regional WMH analyses revealed significant differences in WMH across regions that also differed significantly according to diagnosis. In post-hoc analyses, significant differences were seen between CN and AD in posterior periventricular regions and the splenium of the CC. MCI subjects had intermediate values at all regions. Repeated measures analysis including vascular risk factors in the model found a significant relationship between periventricular WMH and vascular risk that differed by region, but regional differences according to diagnosis remained significant and there was no interaction between diagnosis and vascular risk. Conclusions: Differences in white matter hyperintensities (WMH) associated with increasing cognitive impairment appear related to both extent and spatial location. Multiple regression analysis of regional WMH, vascular risk factors, and diagnosis suggest that these spatial differences may result from the additive effects of vascular and degenerative injury. Posterior periventricular and corpus callosum extension of WMH associated with mild cognitive impairment and Alzheimer disease indicate involvement of strategic white matter bundles that may contribute to the cognitive deficits seen with these syndromes.

Prevalence of dementia in older latinos: the influence of type 2 diabetes mellitus, stroke, and genetic factors

OBJECTIVES: To estimate dementia prevalence in older Mexican Americans, determine the distribution of dementia by etiology, and evaluate the contribution of type 2 diabetes mellitus, stroke, and apolipoprotein E (ApoE) genotype to dementia.

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.

Progression of Mild Cognitive Impairment to Dementia in Clinic- vs Community-Based Cohorts

BACKGROUND Mild cognitive impairment is increasingly recognized as an important public health problem associated with increased risk of developing dementia. Annual conversion rates, however, vary across different studies with clinic samples showing higher rates of conversion than community-based samples. OBJECTIVES To establish whether the rates of conversion from mild cognitive impairment to dementia differed according to recruitment source and, if so, to investigate factors that might explain this discrepancy. DESIGN Rates and predictors of conversion were examined in a prospective longitudinal study at a single center. SETTING Among the participants, 46% were recruited from a clinical setting and 54% were recruited directly through community outreach. PARTICIPANTS One hundred eleven individuals with mild cognitive impairment were followed up longitudinally for an average of 2.4 years (range, 0.5-4.0 years). MAIN OUTCOME MEASURES Conversion from mild cognitive impairment to dementia. RESULTS During the follow-up period, 28 individuals progressed to dementia with a mean (SD) time to conversion of 2.19 (0.72) years. The clinic sample had an annual conversion rate of 13%, whereas the community sample had an annual conversion rate of 3%. In a Cox proportional hazards model, clinic recruitment source alone was associated with an increased hazard of incident dementia (hazard ratio = 3.50; 95% confidence interval, 1.31-9.18; P = .01). When other variables were added to the model, only baseline functional impairment as measured by the Clinical Dementia Rating Scale (and no demographic, cognitive, or neuroimaging variables or mild cognitive impairment subtype) accounted for the differences in conversion rates across the 2 cohorts. CONCLUSIONS These findings add to the growing literature to suggest that the degree of functional impairment at baseline is an important predictor of conversion to dementia and may help explain differences in findings between epidemiological and clinic-based studies.

Neuropathological basis of magnetic resonance images in aging and dementia

Magnetic resonance (MR) imaging is used widely for assessment of patients with cognitive impairment, but the pathological correlates are unclear, especially when multiple pathologies are present.

Cognition assessment using the NIH Toolbox

Vision is a sensation that is created from complex processes and provides us with a representation of the world around us. There are many important aspects of vision, but visual acuity was judged to be the most appropriate vision assessment for the NIH Toolbox for Assessment of Neurological and Behavioral Function, both because of its central role in visual health and because acuity testing is common and relatively inexpensive to implement broadly. The impact of visual impairments on health-related quality of life also was viewed as important to assess, in order to gain a broad view of ones visual function. To test visual acuity, an easy-to-use software program was developed, based on the protocol used by the E-ETDRS. Children younger than 7 years were administered a version with only the letters H, O, T, and V. Reliability and validity of the Toolbox visual acuity test were very good. A 53-item vision-targeted, health-related quality of life survey was also developed.

Cognitive impact of subcortical vascular and Alzheimer's disease pathology

To assess the interactions among three types of pathology (ie, cerebrovascular disease, hippocampal sclerosis [HS], and Alzheimers disease [AD]), cognitive status, and apolipoprotein E genotype.

Longitudinal MRI and cognitive change in healthy elderly

Cross-sectional studies of normal aging indicate an association between memory and hippocampal volume, and between executive functioning and subcortical-frontal circuits. Much less is known, however, about the relationship between longitudinal MRI changes and cognitive decline. The authors hypothesized that longitudinal change in memory would be best predicted by change in hippocampal volumes, whereas change in executive functioning would be best predicted by cortical atrophy and progression of MRI markers of cerebrovascular disease. For this study, 50 healthy elderly subjects underwent structural MRI and cognitive testing at baseline and again at follow-up, with a mean follow-up interval of 45 months. Volumetric MRI measures were hippocampus, cortical gray matter, white matter signal hyperintensity (WMSH), and lacunae. Neuropsychological measures were psychometrically robust composite scores of episodic memory (MEM) and executive functioning (EXEC). Hierarchical multiple regression indicated that a decrease in hippocampus was associated with a decline in MEM, whereas decreased cortical gray matter and increased WMSH were independently associated with a decline in EXEC. Results suggest that in normal aging, cognitive functioning declines as cortical gray matter and hippocampus decrease, and WMSH increases. The association between WMSH and EXEC further highlights the cognitive sequealae associated with cerebrovascular disease in normal elderly.

Relation of cognitive status and abnormal behaviors in Alzheimer's disease.

Some studies suggest that abnormal behaviors are associated with increasing cognitive loss in Alzheimers disease (AD). Other studies do not show this association. We examined the relation of cognitive loss, represented by Folstein Mini‐Mental State Examination (MMSE) score, with abnormal behaviors in 680 patients with probable AD. Six behaviors were examined: agitation / anger, personality change, wandering, hallucinations / delusions, insomnia, and depression. All but depression were associated with declining MMSE score. The number of abnormal behaviors present in each patient was also related to declining MMSE score. Several other associations were also found: hallucinations / delusions were associated with age and race; agitation / anger was related to male gender; and wandering was associated with increased age. Although these data support the general notion that five of the six abnormal behaviors studied are more likely to occur with increasing cognitive loss, the correlations are small and it is suggested that other as yet unproven factors may play an as large or greater role than MMSE score in predicting such behaviors.

Correlates of hippocampal neuron number in Alzheimer's disease and ischemic vascular dementia

The cornu ammonis 1 region of the hippocampus (CA1) sector of hippocampus is vulnerable to both Alzheimers disease (AD)‐type neurofibrillary degeneration and anoxia–ischemia. The objective of this article is to compare number and size of neurons in CA1 in AD versus ischemic vascular dementia. Unbiased stereological methods were used to estimate the number and volume of neurons in 28 autopsy‐derived brain samples. For each case, the entire hippocampus from one cerebral hemisphere was sliced into 5mm slabs (5–7 slabs/case), cut into 50μm sections, and stained with gallocyanine. Using the optical dissector, we systematically sampled the number and size of neurons throughout the extent of CA1 and CA2. The total number of neurons was significantly less in AD compared with ischemic vascular dementia (p < 0.02), but there was no significant difference in neuron size. The greatest loss of neurons was observed in two cases with combined AD and hippocampal sclerosis. Regardless of causative diagnosis, the number of CA1 neurons correlates with magnetic resonance imaging–derived hippocampal volume (r = 0.72; p < 0.001) and memory score (r = 0.62; p < 0.01). We conclude that although CA1 neuron loss is more consistently observed in AD than ischemic vascular dementia, severity of loss shows the expected correlation with structure and function across causative subtype. Reductions in magnetic resonance imaging–derived hippocampal volume reflect loss, rather than shrinkage, of CA1 neurons. Ann Neurol 2005;57:896–903