White Matter Hyperintensities and Cognition: Testing the Reserve Hypothesis

OBJECTIVE: White matter hyperintensities (WMH), visualized on T2-weighted MRI, are thought to reflect small-vessel vascular disease. Much like other markers of brain disease, the association between WMH and cognition is imperfect. The concept of reserve may account for this imperfect relationship. The purpose of this study was to test the reserve hypothesis in the association between WMH severity and cognition. We hypothesized that individuals with higher amounts of reserve would be able to tolerate greater amounts of pathology than those with lower reserve. METHODS: Neurologically healthy older adults (n=717) from a community-based study received structural MRI, neuropsychological assessment, and evaluation of reserve. WMH volume was quantified algorithmically. We derived latent constructs representing four neuropsychological domains, a measure of cognitive reserve, and a measure of brain reserve. Measures of cognitive and brain reserve consisted of psychosocial (e.g., education) and anthropometric (e.g., craniometry) variables, respectively. RESULTS: Increased WMH volume was associated with poorer cognition and higher cognitive and brain reserve were associated with better cognition. Controlling for speed/executive function or for language function, those with higher estimates of cognitive reserve had significantly greater degrees of WMH volume, particularly among women. Controlling for cognitive functioning across all domains, individuals with higher estimates of brain reserve had significantly greater WMH volume. CONCLUSIONS: For any given level of cognitive function, those with higher reserve had more pathology in the form of WMH, suggesting that they are better able to cope with pathology than those with lower reserve. Both brain reserve and cognitive reserve appear to mitigate the impact of pathology on cognition

Regional white matter hyperintensity volume, not hippocampal atrophy, predicts incident Alzheimer disease in the community

Background: New-onset Alzheimer disease (AD) is often attributed to degenerative changes in the hippocampus. However, the contribution of regionally distributed small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMHs) on magnetic resonance imaging, remains unclear. Objective: To determine whether regional WMHs and hippocampal volume predict incident AD in an epidemiological study. Design: A longitudinal community-based epidemiological study of older adults from northern Manhattan, New York. Setting: The Washington Heights/Inwood Columbia Aging Project. Participants: Between 2005 and 2007, 717 participants without dementia received magnetic resonance imaging scans. A mean (SD) of 40.28 (9.77) months later, 503 returned for follow-up clinical examination and 46 met criteria for incident dementia (45 with AD). Regional WMHs and relative hippocampal volumes were derived. Three Cox proportional hazards models were run to predict incident dementia, controlling for relevant variables. The first included all WMH measurements; the second included relative hippocampal volume; and the third combined the 2 measurements. Main Outcome: Measure Incident AD. Results: White matter hyperintensity volume in the parietal lobe predicted time to incident dementia (hazard ratio [HR] = 1.194; P = .03). Relative hippocampal volume did not predict incident dementia when considered alone (HR = 0.419; P = .77) or with the WMH measures included in the model (HR = 0.302; P = .70). Including hippocampal volume in the model did not notably alter the predictive utility of parietal lobe WMHs (HR = 1.197; P = .049). Conclusions: The findings highlight the regional specificity of the association of WMHs with AD. It is not clear whether parietal WMHs solely represent a marker for cerebrovascular burden or point to distinct injury compared with other regions. Future work should elucidate pathogenic mechanisms linking WMHs and AD pathology

White matter hyperintensities and cognition: Testing the reserve hypothesis

Objective: White matter hyperintensities (WMH), visualized on T2-weighted MRI, are thought to reflect small-vessel vascular disease. Much like other markers of brain disease, the association between WMH and cognition is imperfect. The concept of reserve may account for this imperfect relationship. The purpose of this study was to test the reserve hypothesis in the association between WMH severity and cognition. We hypothesized that individuals with higher amounts of reserve would be able to tolerate greater amounts of pathology than those with lower reserve. Methods: Neurologically healthy older adults (n = 717) from a community-based study received structural MRI, neuropsychological assessment, and evaluation of reserve. WMH volume was quantified algorithmically. We derived latent constructs representing four neuropsychological domains, a measure of cognitive reserve, and a measure of brain reserve. Measures of cognitive and brain reserve consisted of psychosocial (e.g., education) and anthropometric (e.g., craniometry) variables, respectively. Results: Increased WMH volume was associated with poorer cognition and higher cognitive and brain reserve were associated with better cognition. Controlling for speed/executive function or for language function, those with higher estimates of cognitive reserve had significantly greater degrees of WMH volume, particularly among women. Controlling for cognitive functioning across all domains, individuals with higher estimates of brain reserve had significantly greater WMH volume. Conclusions: For any given level of cognitive function, those with higher reserve had more pathology in the form of WMH, suggesting that they are better able to cope with pathology than those with lower reserve. Both brain reserve and cognitive reserve appear to mitigate the impact of pathology on cognition

Implementing new health interventions in developing countries: why do we lose a decade or more?

BACKGROUND: It is unclear how long it takes for health interventions to transition from research and development (R&D) to being used against diseases prevalent in resource-poor countries. We undertook an analysis of the time required to begin implementation of four vaccines and three malaria interventions. We evaluated five milestones for each intervention, and assessed if the milestones were associated with beginning implementation. METHODS: The authors screened WHO databases to determine the number of years between first regulatory approval of interventions, and countries beginning implementation. Descriptive analyses of temporal patterns and statistical analyses using logistic regression and Cox proportional hazard models were used to evaluate associations between five milestones and the beginning of implementation for each intervention. The milestones were: (A) presence of a coordinating group focused on the intervention; (B) availability of an intervention tailored to developing country health systems; (C) international financing commitment, and; (D) initial and (E) comprehensive WHO recommendations. Countries were categorized by World Bank income criteria. RESULTS: Five years after regulatory approval, no low-income countries (LICs) had begun implementing any of the vaccines, increasing to an average of only 4% of LICs after 10 years. Each malaria intervention was used by an average of 7% of LICs after five years and 37% after 10 years. Four of the interventions had similar implementation rates to HepB, while one was slower and one was faster than HepB. A financing commitment and initial WHO recommendation appeared to be temporally associated with the beginning of implementation. The initial recommendation from WHO was the only milestone associated in all statistical analyses with countries beginning implementation (relative rate = 1.97, P > 0.001). CONCLUSIONS: Although possible that four milestones were not associated with countries beginning implementation, we propose an alternative interpretation; that the milestones were not realized early enough in each intervention's development to shorten the time to beginning implementation. We discuss a framework built upon existing literature for consideration during the development of future interventions. Identifying critical milestones and their timing relative to R&D, promises to help new interventions realize their intended public health impact more rapidly