Our aim was to test the association of vascular risk factor exposure in midlife with progression of MRI markers of brain aging and measures of cognitive decline.
A total of 1,352 participants without ...dementia from the prospective Framingham Offspring Cohort Study were examined. Multivariable linear and logistic regressions were implemented to study the association of midlife vascular risk factor exposure with longitudinal change in white matter hyperintensity volume (WMHV), total brain volume (TBV), temporal horn volume, logical memory delayed recall, visual reproductions delayed-recall (VR-d), and Trail-Making Test B-A (TrB-A) performance a decade later.
Hypertension in midlife was associated with accelerated WMHV progression (p < 0.001) and worsening executive function (TrB-A score; p = 0.012). Midlife diabetes and smoking were associated with a more rapid increase in temporal horn volume, a surrogate marker of accelerated hippocampal atrophy (p = 0.017 and p = 0.008, respectively). Midlife smoking also predicted a more marked decrease in total brain volume (p = 0.025) and increased risk of extensive change in WMHV (odds ratio = 1.58 95%confidence interval 1.07-2.33, p = 0.021). Obesity in midlife was associated with an increased risk of being in the top quartile of change in executive function (1.39 1.02-1.88, p = 0.035) and increasing waist-to-hip ratio was associated with marked decline in TBV (10.81 1.44-81.01, p = 0.021). Longitudinal changes in brain structure were significantly correlated with decline in memory and executive function.
Midlife hypertension, diabetes, smoking, and obesity were associated with an increased rate of progression of vascular brain injury, global and hippocampal atrophy, and decline in executive function a decade later.
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).
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.
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.
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.
WMH, associated with cognitive decline and cardiovascular risk factors, may represent only the extreme end of a more widespread continuous WM injury process that progresses during aging and is poorly ...understood. We investigated the ability of FLAIR and DTI to characterize the longitudinal course of WMH development.
One hundred nineteen participants (mean age, 74.5 ± 7.4), including cognitively healthy elders and subjects diagnosed with Alzheimer disease and mild cognitive impairment, received a comprehensive clinical evaluation and brain MR imaging, including FLAIR and DTI on 2 dates. The risk for each baseline normal-appearing WM voxel to convert into WMH was modeled as a function of baseline FA (model M1) and both baseline FA and standardized FLAIR (M2). Sensitivity, specificity, accuracy, and AUC for predicting conversion to WMH were compared between models.
Independent of clinical diagnosis, lower baseline FA (P < .001, both models) and higher baseline FLAIR intensity (P < .001, M2) were independently associated with increased risk for conversion from normal WM to WMH. M1 exhibited higher sensitivity but lower specificity, accuracy, and AUC compared with M2.
These findings provide further evidence that WMH result from a continuous process of WM degeneration with time. Stepwise decreases in WM integrity as measured by both DTI and FLAIR were independently associated with stepwise increases in WMH risk, emphasizing that these modalities may provide complementary information for understanding the time course of aging-associated WM degeneration.
Few studies have compared the accuracy of (18)Ffluorodeoxyglucose (FDG) PET to the accuracy of clinical and pathologic diagnosis in dementia patients.
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.
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.
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 (18)Ffluorodeoxyglucose 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.
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The First Key Symposium was held in Stockholm, Sweden, 2–5 September 2003. The aim of the symposium was to integrate clinical and epidemiological perspectives on the topic of Mild Cognitive ...Impairment (MCI). A multidisciplinary, international group of experts discussed the current status and future directions of MCI, with regard to clinical presentation, cognitive and functional assessment, and the role of neuroimaging, biomarkers and genetics. Agreement on new perspectives, as well as recommendations for management and future research were discussed by the international working group. The specific recommendations for the general MCI criteria include the following: (i) the person is neither normal nor demented; (ii) there is evidence of cognitive deterioration shown by either objectively measured decline over time and/or subjective report of decline by self and/or informant in conjunction with objective cognitive deficits; and (iii) activities of daily living are preserved and complex instrumental functions are either intact or minimally impaired.
Higher dietary intake and circulating levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been related to a reduced risk for dementia, but the pathways underlying this ...association remain unclear. We examined the cross-sectional relation of red blood cell (RBC) fatty acid levels to subclinical imaging and cognitive markers of dementia risk in a middle-aged to elderly community-based cohort.
We related RBC DHA and EPA levels in dementia-free Framingham Study participants (n = 1575; 854 women, age 67 ± 9 years) to performance on cognitive tests and to volumetric brain MRI, with serial adjustments for age, sex, and education (model A, primary model), additionally for APOE ε4 and plasma homocysteine (model B), and also for physical activity and body mass index (model C), or for traditional vascular risk factors (model D).
Participants with RBC DHA levels in the lowest quartile (Q1) when compared to others (Q2-4) had lower total brain and greater white matter hyperintensity volumes (for model A: β ± SE = -0.49 ± 0.19; p = 0.009, and 0.12 ± 0.06; p = 0.049, respectively) with persistence of the association with total brain volume in multivariable analyses. Participants with lower DHA and ω-3 index (RBC DHA+EPA) levels (Q1 vs. Q2-4) also had lower scores on tests of visual memory (β ± SE = -0.47 ± 0.18; p = 0.008), executive function (β ± SE = -0.07 ± 0.03; p = 0.004), and abstract thinking (β ± SE = -0.52 ± 0.18; p = 0.004) in model A, the results remaining significant in all models.
Lower RBC DHA levels are associated with smaller brain volumes and a "vascular" pattern of cognitive impairment even in persons free of clinical dementia.
We test the hypothesis that endothelial cells adopt an inflammatory phenotype in functionally intact aged human subjects with radiographic evidence of white matter hyperintensity (WMH) suggestive of ...small cerebrovascular disease. Components of all three complement effector pathways and regulatory proteins were quantified in extracts of plasma endothelial-derived exosomes (EDE) of 11 subjects (age 70-82) with and 15 without evidence of WMH on MRI. Group differences and associations with plasma markers of immune activation (IL6, ICAM1), cognition and neuroimaging were calculated via regression modelling. EDE complement factors within the alternative and classical pathways were found to be higher and regulatory proteins lower in subjects with WMH. EDE levels of some complement components demonstrated significant associations with cognitive slowing and elevated systolic blood pressure. The inhibitor of the membrane attack complex, CD46, showed a significant positive association with cerebral grey matter volume. Plasma inflammatory markers, IL6 and ICAM1, were positively associated with EDE levels of several complement components. These findings provide the first in vivo evidence of the association of endothelial cell inflammation with white matter disease, age-associated cognitive changes, and brain degeneration in functionally normal older individuals. Future endothelial biomarker development may permit recognition of early or preclinical stages of vascular contributions to cognitive impairment and dementia.
Objective
To assess the interactions among three types of pathology (ie, cerebrovascular disease, hippocampal sclerosis HS, and Alzheimer's disease AD), cognitive status, and apolipoprotein E ...genotype.
Methods
We report clinicopathological correlations from 79 autopsy cases derived from a prospective longitudinal study of subcortical ischemic vascular disease and AD.
Results
Thirty percent of the cases had significant cerebrovascular parenchymal pathology scores (CVDPS), 54% had significant AD pathology, and 18% had HS. In an ordinal logistic regression analysis that included interaction terms to assess the effects of each pathological variable when the other variables are interpolated to zero, each of the three pathology variables contributed independently to cognitive status: Braak and Braak stage odds ratio (OR) = 2.84 (95% confidence interval, 1.81–4.45), HS score OR = 2.43 (95% confidence interval, 1.01–5.85), and CVDPS OR = 1.02 (95% confidence interval, 1.00–1.04). Only Braak and Braak stage contributed to a global neuropsychological measure of cognitive impairment. Apolipoprotein E4 genotype was associated with Braak and Braak stage (OR, 1.31 95% confidence interval, 1.03–1.68), but not CVDPS or HS scores.
Interpretation
In this convenience sample enriched for subcortical ischemic vascular disease, HS was a common unsuspected neuropathological finding. Apolipoprotein E4 genotype was associated with cerebral amyloid angiopathy, but not HS or arteriosclerosis. When Braak and Braak stage was interpolated to zero, both CVDPS and HS contributed to cognitive impairment. However, advancing stages of AD pathology overwhelmed the effects of CVDPS and HS, to become the major determinant of dementia. Ann Neurol 2006;60:677–687
To investigate the interrelations of serum vitamin B12 markers with brain volumes, cerebral infarcts, and performance in different cognitive domains in a biracial population sample cross-sectionally.
...In 121 community-dwelling participants of the Chicago Health and Aging Project, serum markers of vitamin B12 status were related to summary measures of neuropsychological tests of 5 cognitive domains and brain MRI measures obtained on average 4.6 years later among 121 older adults.
Concentrations of all vitamin B12-related markers, but not serum vitamin B12 itself, were associated with global cognitive function and with total brain volume. Methylmalonate levels were associated with poorer episodic memory and perceptual speed, and cystathionine and 2-methylcitrate with poorer episodic and semantic memory. Homocysteine concentrations were associated with decreased total brain volume. The homocysteine-global cognition effect was modified and no longer statistically significant with adjustment for white matter volume or cerebral infarcts. The methylmalonate-global cognition effect was modified and no longer significant with adjustment for total brain volume.
Methylmalonate, a specific marker of B12 deficiency, may affect cognition by reducing total brain volume whereas the effect of homocysteine (nonspecific to vitamin B12 deficiency) on cognitive performance may be mediated through increased white matter hyperintensity and cerebral infarcts. Vitamin B12 status may affect the brain through multiple mechanisms.
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