Adam M. Brickman

An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus

With continued debate over the functional significance of adult neurogenesis, identifying an in vivo correlate of neurogenesis has become an important goal. Here we rely on the coupling between neurogenesis and angiogenesis and test whether MRI measurements of cerebral blood volume (CBV) provide an imaging correlate of neurogenesis. First, we used an MRI approach to generate CBV maps over time in the hippocampal formation of exercising mice. Among all hippocampal subregions, exercise was found to have a primary effect on dentate gyrus CBV, the only subregion that supports adult neurogenesis. Moreover, exercise-induced increases in dentate gyrus CBV were found to correlate with postmortem measurements of neurogenesis. Second, using similar MRI technologies, we generated CBV maps over time in the hippocampal formation of exercising humans. As in mice, exercise was found to have a primary effect on dentate gyrus CBV, and the CBV changes were found to selectively correlate with cardiopulmonary and cognitive function. Taken together, these findings show that dentate gyrus CBV provides an imaging correlate of exercise-induced neurogenesis and that exercise differentially targets the dentate gyrus, a hippocampal subregion important for memory and implicated in cognitive aging.

Physical Activity, Diet, and Risk of Alzheimer Disease

CONTEXT Both higher adherence to a Mediterranean-type diet and more physical activity have been independently associated with lower Alzheimer disease (AD) risk but their combined association has not been investigated. OBJECTIVE To investigate the combined association of diet and physical activity with AD risk. DESIGN, SETTING, AND PATIENTS Prospective cohort study of 2 cohorts comprising 1880 community-dwelling elders without dementia living in New York, New York, with both diet and physical activity information available. Standardized neurological and neuropsychological measures were administered approximately every 1.5 years from 1992 through 2006. Adherence to a Mediterranean-type diet (scale of 0-9; trichotomized into low, middle, or high; and dichotomized into low or high) and physical activity (sum of weekly participation in various physical activities, weighted by the type of physical activity [light, moderate, vigorous]; trichotomized into no physical activity, some, or much; and dichotomized into low or high), separately and combined, were the main predictors in Cox models. Models were adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, body mass index, smoking status, depression, leisure activities, a comorbidity index, and baseline Clinical Dementia Rating score. MAIN OUTCOME MEASURE Time to incident AD. RESULTS A total of 282 incident AD cases occurred during a mean (SD) of 5.4 (3.3) years of follow-up. When considered simultaneously, both Mediterranean-type diet adherence (compared with low diet score, hazard ratio [HR] for middle diet score was 0.98 [95% confidence interval {CI}, 0.72-1.33]; the HR for high diet score was 0.60 [95% CI, 0.42-0.87]; P = .008 for trend) and physical activity (compared with no physical activity, the HR for some physical activity was 0.75 [95% CI, 0.54-1.04]; the HR for much physical activity was 0.67 [95% CI, 0.47-0.95]; P = .03 for trend) were associated with lower AD risk. Compared with individuals neither adhering to the diet nor participating in physical activity (low diet score and no physical activity; absolute AD risk of 19%), those both adhering to the diet and participating in physical activity (high diet score and high physical activity) had a lower risk of AD (absolute risk, 12%; HR, 0.65 [95% CI, 0.44-0.96]; P = .03 for trend). CONCLUSION In this study, both higher Mediterranean-type diet adherence and higher physical activity were independently associated with reduced risk for AD.

Aging of Cerebral White Matter: A Review of MRI Findings

Cerebral aging is a complex and heterogeneous process that is associated with a high degree of inter‐individual variability. Structural magnetic resonance imaging (MRI) can be used to identify and quantify non‐disease‐related aging of the cerebral white matter.

Contribution of Vascular Risk Factors to the Progression in Alzheimer Disease

BACKGROUND Vascular factors including medical history (heart disease, stroke, diabetes, and hypertension), smoking, and prediagnosis blood lipid measurements (cholesterol: total, high-density lipoprotein, low-density lipoprotein [LDL-C], and triglyceride concentrations) may be predictors for progression of Alzheimer disease (AD). OBJECTIVE To determine whether prediagnosis vascular risk factors are associated with progression of AD. DESIGN Inception cohort followed up longitudinally for a mean of 3.5 (up to 10.2) years. SETTING Washington Heights/Inwood Columbia Aging Project, New York, New York. Patients One hundred fifty-six patients with incident AD (mean age at diagnosis, 83 years). Main Outcome Measure Change in a composite score of cognitive ability from diagnosis onward. RESULTS In generalized estimating equation models (adjusted for age, race/ethnicity, and years of education), higher cholesterol (total cholesterol and LDL-C) concentrations and history of diabetes were associated with faster cognitive decline. Each 10-U increase in cholesterol and LDL-C was associated with a 0.10-SD decrease in cognitive score per year of follow-up (P < .001 for total cholesterol; P = .001 for LDL-C). High-density lipoprotein cholesterol and triglyceride concentrations were not associated with rate of decline. A history of diabetes was associated with an additional 0.05-SD decrease in cognitive score per year (P = .05). History of heart disease and stroke were associated with cognitive decline only in carriers of the apolipoprotein E epsilon4 (APOE-epsilon4) gene. In a final generalized estimating equation model that included high-density lipoprotein cholesterol and LDL-C concentrations and history of diabetes, only higher LDL-C was independently associated with faster cognitive decline. CONCLUSION Higher prediagnosis total cholesterol and LDL-C concentrations and history of diabetes were associated with faster cognitive decline in patients with incident AD, which provides further evidence for the role of vascular risk factors in the course of AD.

Regional variability of imaging biomarkers in autosomal dominant Alzheimer’s disease

Significance Beta-amyloid plaque accumulation, glucose hypometabolism, and neuronal atrophy are hallmarks of Alzheimer’s disease. However, the regional ordering of these biomarkers prior to dementia remains untested. In a cohort with Alzheimer’s disease mutations, we performed an integrated whole-brain analysis of three major imaging techniques: amyloid PET, [18F]fluro-deoxyglucose PET, and structural MRI. We found that most gray-matter structures with amyloid plaques later have hypometabolism followed by atrophy. Critically, however, not all regions lose metabolic function, and not all regions atrophy, even when there is significant amyloid deposition. These regional disparities have important implications for clinical trials of disease-modifying therapies. Major imaging biomarkers of Alzheimer’s disease include amyloid deposition [imaged with [11C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [18F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer’s disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer’s disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease.

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.

Brain Morphology in Older African Americans, Caribbean Hispanics, and Whites From Northern Manhattan

BACKGROUND Aging is accompanied by a decrease in brain volume and by an increase in cerebrovascular disease. OBJECTIVE To examine the effects of age, sex, race/ethnicity, and vascular disease history on measures of brain morphology, including relative brain volume, ventricular volume, hippocampus and entorhinal cortex volumes, and white matter hyperintensity (WMH) burden, in a large community-based cohort of racially/ethnically diverse older adults without dementia. DESIGN The associations of age, sex, race/ethnicity, and self-reported vascular disease history with brain morphology were examined in a cross-sectional study using multiple linear regression analyses. Sex x race/ethnicity interactions were also considered. SETTING The Washington Heights-Inwood Columbia Aging Project, a community-based epidemiological study of older adults from 3 racial/ethnic groups (white, Hispanic, and African American) from northern Manhattan. PARTICIPANTS Beginning in 2003, high-resolution quantitative magnetic resonance (MR) images were acquired in 769 participants without dementia. MAIN OUTCOME MEASURES Relative brain volume (total brain volume/intracranial volume), ventricular volume, and hippocampus and entorhinal cortex volumes were derived manually on high-resolution MR images. White matter hyperintensities were quantified semiautomatically on fluid-attenuated inversion recovery-T2-weighted MR images. RESULTS Older age was associated with decreased relative brain volume and with increased ventricular and WMH volumes. Hispanic and African American participants had larger relative brain volumes and more severe WMH burden than white participants, but the associations of these variables with age were similar across racial/ethnic groups. Compared with men, women had larger relative brain volumes. Vascular disease was associated with smaller relative brain volume and with higher WMH burden, particularly among African Americans. CONCLUSIONS Older age and vascular disease, particularly among African Americans, are associated with increased brain atrophy and WMH burden. African American and Hispanic subjects have larger relative brain volumes and more WMH than white subjects. Racial/ethnic group differences in WMH severity seem to be partially attributable to differences in vascular disease. Future work will focus on the determinants and cognitive correlates of these differences.

Long-term Blood Pressure Fluctuation and Cerebrovascular Disease in an Elderly Cohort

BACKGROUND The importance of subclinical cerebrovascular disease in the elderly is increasingly recognized, but its determinants have not been fully explicated. Elevated blood pressure (BP) and fluctuation in BP may lead to cerebrovascular disease through ischemic changes and compromised cerebral autoregulation. OBJECTIVE To determine the association of BP and long-term fluctuation in BP with cerebrovascular disease. DESIGN A community-based epidemiological study of older adults from northern Manhattan. SETTING The Washington Heights-Inwood Columbia Aging Project. PARTICIPANTS A total of 686 nondemented older adults who had BP measurements during 3 study visits at 24-month intervals and underwent structural magnetic resonance imaging (corresponding temporally with the third assessment). We derived the mean (SD) of the mean BP for each participant during the 3 intervals and divided the participants into 4 groups defined as below or above the group median (<or=96.48 or >96.48 mm Hg) and further subdivided them as below or above the median SD (<or=7.21 or >7.21 mm Hg). This scheme yielded 4 groups representing the full range of BPs and fluctuations in BP. MAIN OUTCOME MEASURES Differences in white matter hyperintensity (WMH) volume and presence of brain infarctions across groups. RESULTS White matter hyperintensity volume increased across the 4 groups in a linear manner, with the lowest WMH volume in the lowest mean/lowest SD group and the highest WMH volume in the highest mean/highest SD group (F(3,610) = 3.52, P = .02). Frequency of infarction also increased monotonically across groups (from 22% to 41%, P for trend = .004). CONCLUSIONS Compared with individuals with low BP and low fluctuations in BP, the risk of cerebrovascular disease increased with higher BP and BP fluctuations. Given that cerebrovascular disease is associated with disability, these findings suggest that interventions should focus on long-term fluctuating BP and elevated BP.

Obesity Is Associated With Reduced White Matter Integrity in Otherwise Healthy Adults

Existing work demonstrates that obesity is independently associated with cognitive dysfunction and macrostructural brain changes; however, little is known about the association between obesity and white matter (WM) integrity. We explore this relationship in a large cohort of otherwise healthy subjects. The present study classified 103 adult participants from the Brain Resource International Database between 21 and 86 years of age without history of neurological, medical, or psychiatric illness according to BMI (normal weight, overweight, obese) and subjected them to diffusion tensor imaging (DTI). Resulting fractional anisotropy (FA) indexes for the corpus callosum and fornix were examined in relation to BMI and age in a multiple regression framework. Results indicated that increasing BMI was independently associated with lower FA in the genu, splenium, and fornix, and a BMI × age interaction emerged for FA in the splenium and body of the corpus callosum. When categorized, obese persons demonstrated lower FA than normal and overweight persons for all WM indexes, but no FA differences emerged between overweight and normal persons. Results indicate both a direct association between obesity and reduced WM tract integrity and an interaction between obesity and aging processes on certain WM tracts in otherwise healthy adults. While such findings suggest a possible role for adiposity in WM dysfunction and associated cognitive deficits, prospective studies are needed to clarify the nature of these relationships and elucidate underlying mechanisms.

Emotional Processing Deficits in Individuals With Unilateral Brain Damage

This article presents a review of the neural mechanisms underlying emotional processing deficits (EPDs) in individuals with unilateral brain damage. First, key theoretical issues pertaining to the neuropsychology of emotion are presented. These include parameters of emotional processing, the componential approach, emotional domains, and hypotheses regarding hemispheric specialization for emotion. Second, the literature on hemispheric asymmetries for emotion is reviewed in terms of processing mode (perception and expression) and communication channel (facial, prosodic-intonational, and lexical-verbal). Studies involving normal adults and individuals with right- or left-sided brain damage are reviewed. Third, recent findings identifying the role of the right hemisphere in emotional processing are described. The article is concluded by aligning these new data with findings from the general literature, providing added support for the right-hemisphere emotion hypothesis.