Erica Y. Griffith

White Matter Hyperintensities and Cerebral Amyloidosis Necessary and Sufficient for Clinical Expression of Alzheimer Disease

IMPORTANCE Current hypothetical models emphasize the importance of β-amyloid in Alzheimer disease (AD) pathogenesis, although amyloid alone is not sufficient to account for the dementia syndrome. The impact of small-vessel cerebrovascular disease, visualized as white matter hyperintensities (WMHs) on magnetic resonance imaging scans, may be a key factor that contributes independently to AD presentation. OBJECTIVE To determine the impact of WMHs and Pittsburgh Compound B (PIB) positron-emission tomography-derived amyloid positivity on the clinical expression of AD. DESIGN Baseline PIB-positron-emission tomography values were downloaded from the Alzheimers Disease Neuroimaging Initiative database. Total WMH volume was derived on accompanying structural magnetic resonance imaging data. We examined whether PIB positivity and total WMHs predicted diagnostic classification of patients with AD (n = 20) and control subjects (n = 21). A second analysis determined whether WMHs discriminated between those with and without the clinical diagnosis of AD among those who were classified as PIB positive (n = 28). A third analysis examined whether WMHs, in addition to PIB status, could be used to predict future risk for AD among subjects with mild cognitive impairment (n = 59). SETTING The Alzheimers Disease Neuroimaging Initiative public database. PARTICIPANTS The study involved data from 21 normal control subjects, 59 subjects with mild cognitive impairment, and 20 participants with clinically defined AD from the Alzheimer Diseases Neuroimaging Initiative database. MAIN OUTCOME MEASURES Clinical AD diagnosis and WMH volume. RESULTS Pittsburgh Compound B positivity and increased total WMH volume independently predicted AD diagnosis. Among PIB-positive subjects, those diagnosed as having AD had greater WMH volume than normal control subjects. Among subjects with mild cognitive impairment, both WMH and PIB status at baseline conferred risk for future diagnosis of AD. CONCLUSIONS AND RELEVANCE White matter hyperintensities contribute to the presentation of AD and, in the context of significant amyloid deposition, may provide a second hit necessary for the clinical manifestation of the disease. As risk factors for the development of WMHs are modifiable, these findings suggest intervention and prevention strategies for the clinical syndrome of AD.

Reconsidering harbingers of dementia: progression of parietal lobe white matter hyperintensities predicts Alzheimer's disease incidence

Accumulating evidence implicates small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH) on T2-weighted magnetic resonance imaging, in the pathogenesis and diagnosis of Alzheimers disease (AD). Cross-sectional volumetric measures of WMH, particularly in the parietal lobes, are associated with increased risk of AD. In the present study, we sought to determine whether the longitudinal regional progression of WMH predicts incident AD above-and-beyond traditional radiological markers of neurodegeneration (i.e., hippocampal atrophy and cortical thickness). Three hundred three nondemented older adults (mean age = 79.24 ± 5.29) received high-resolution magnetic resonance imaging at baseline and then again 4.6 years (standard deviation = 1.01) later. Over the follow-up interval 26 participants progressed to AD. Using structural equation modeling, we calculated latent difference scores of parietal and nonparietal WMH, hippocampus volumes, and cortical thickness values in AD-related regions. Within the structural equation modeling framework, we determined whether baseline or change scores or both predicted AD conversion, while controlling for several time-invariant relevant variables. Smaller baseline hippocampus volume, change in hippocampus volume (i.e., atrophy), higher baseline parietal lobe WMH, and increasing parietal lobe WMH volume but not WMH in other regions or measures of cortical thickness, independently predicted progression to AD. The findings provide strong evidence that regionally accumulating WMH predict AD onset in addition to hallmark neurodegenerative changes typically associated with AD.

Cerebral Perfusion is Associated With White Matter Hyperintensities in Older Adults With Heart Failure

Cognitive impairment is common in heart failure (HF) and believed to be the result of cerebral hypoperfusion and subsequent brain changes including white matter hyperintensities (WMHs). The current study examined the association between cerebral blood flow and WMHs in patients with HF and the relationship between WMHs and cognitive impairment. Sixty-nine patients with HF completed the Mini-Mental State Examination (MMSE) and underwent echocardiography, transcranial Doppler sonography for cerebral blood flow velocity of the middle cerebral artery, and brain magnetic resonance imaging. Multivariable hierarchical regression analyses controlling for medical and demographic characteristics as well as intracranial volume showed reduced cerebral blood flow velocity of the middle cerebral artery was associated with greater WMHs (β=-0.34, P=.02). Follow-up regression analyses adjusting for the same medical and demographic factors in addition to cerebral perfusion also revealed marginal significance between increased WMHs and poorer performance on the MMSE (β=-0.26, P=.05). This study suggests that reduced cerebral perfusion is associated with greater WMHs in older adults with HF. These findings support the widely proposed mechanism of cognitive impairment in HF patients and prospective studies are needed to confirm these results.

Hippocampal volume varies with educational attainment across the life-span

Socioeconomic disparities—and particularly differences in educational attainment—are associated with remarkable differences in cognition and behavior across the life-span. Decreased educational attainment has been linked to increased exposure to life stressors, which in turn have been associated with structural differences in the hippocampus and the amygdala. However, the degree to which educational attainment is directly associated with anatomical differences in these structures remains unclear. Recent studies in children have found socioeconomic differences in regional brain volume in the hippocampus and amygdala across childhood and adolescence. Here we expand on this work, by investigating whether disparities in hippocampal and amygdala volume persist across the life-span. In a sample of 275 individuals from the BRAINnet Foundation database ranging in age from 17 to 87, we found that socioeconomic status (SES), as operationalized by years of educational attainment, moderates the effect of age on hippocampal volume. Specifically, hippocampal volume tended to markedly decrease with age among less educated individuals, whereas age-related reductions in hippocampal volume were less pronounced among more highly educated individuals. No such effects were found for amygdala volume. Possible mechanisms by which education may buffer age-related effects on hippocampal volume are discussed.

White matter predictors of cognitive functioning in older adults

Few studies have applied multiple imaging modalities to examine cognitive correlates of white matter. We examined the utility of T2-weighted magnetic resonance imaging (MRI) -derived white matter hyperintensities (WMH) and diffusion tensor imaging-derived fractional anisotropy (FA) to predict cognitive functioning among older adults. Quantitative MRI and neuropsychological evaluations were performed in 112 older participants from an ongoing study of the genetics of Alzheimers disease (AD) in African Americans. Regional WMH volumes and FA were measured in multiple regions of interest. We examined the association of regional WMH and an FA summary score with cognitive test performance. Differences in WMH and FA were compared across diagnostic groups (i.e., normal controls, mild cognitive impairment, and probable AD). Increased WMH volume in frontal lobes was associated with poorer delayed memory performance. FA did not emerge as a significant predictor of cognition. White matter hyperintensity volume in the frontal and parietal lobes was increased in MCI participants and more so in AD patients relative to controls. These results highlight the importance of regionally distributed small vessel cerebrovascular disease in memory performance and AD among African American older adults. White matter microstructural changes, quantified with diffusion tensor imaging, appear to play a lesser role in our sample.

The right insula contributes to memory awareness in cognitively diverse older adults.

Unawareness of memory loss is a challenging characteristic of Alzheimers disease (AD) and other age-related neurodegenerative conditions at their earliest stages, adversely affecting important outcomes such as patient decision making and safety. The basis of this metacognitive disturbance has been elusive; however it is almost certainly determined in part by compromise to brain regions critical for self-assessment. The subjectivity of traditional measurements of self-awareness in dementia has likely limited the rigor with which its neuroanatomic correlates can be established. Here we objectively measure memory awareness (metamemory) using a Feeling of Knowing (FOK) task in a group of cognitively diverse older adults, including 14 with mild AD and 20 cognitively healthy older adults. Performance on the metamemory task was examined in relation to the structural integrity of 14 bilateral neuroanatomic regions hypothesized to support self-awareness. Less accurate metamemory was associated only with reduced right insular volume (r=.41, p=.019). Implications of the current findings for models of metacognitive aging are discussed, with attention to the role of the insula in the conscious detection of errors.

Poorer physical fitness is associated with reduced structural brain integrity in heart failure

OBJECTIVE Physical fitness is an important correlate of structural and functional integrity of the brain in healthy adults. In heart failure (HF) patients, poor physical fitness may contribute to cognitive dysfunction and we examined the unique contribution of physical fitness to brain structural integrity among patients with HF. METHODS Sixty-nine HF patients performed the Modified Mini Mental State examination (3MS) and underwent brain magnetic resonance imaging. All participants completed the 2-minute step test (2MST), a brief measure of physical fitness. We examined the associations between cognitive performance, physical fitness, and three indices of global brain integrity: total cortical gray matter volume, total white matter volume, and whole brain cortical thickness. RESULTS Regression analyses adjusting for demographic characteristics, medical variables (e.g., left ventricular ejection fraction), and intracranial volume revealed reduced performance on the 2MST were associated with decreased gray matter volume and thinner cortex (p<.05). Follow up analyses showed that reduced gray matter volume and decreased cortical thickness were associated with poorer 3MS scores (p<.05). CONCLUSIONS Poor physical fitness is common in HF and associated with reduced structural brain integrity. Prospective studies are needed to elucidate underlying mechanisms for the influence of physical fitness on brain health in HF.

Soluble amyloid beta levels are elevated in the white matter of Alzheimer’s patients, independent of cortical plaque severity

Alzheimer’s disease (AD) is the most common neurodegenerative disease and the leading cause of dementia. In addition to grey matter pathology, white matter changes are now recognized as an important pathological feature in the emergence of the disease. Despite growing recognition of the importance of white matter abnormalities in the pathogenesis of AD, the causes of white matter degeneration are still unknown. While multiple studies propose Wallerian-like degeneration as the source of white matter change, others suggest that primary white matter pathology may be due, at least in part, to other mechanisms, including local effects of toxic Aβ peptides. In the current study, we investigated levels of soluble amyloid-beta (Aβ) in white matter of AD patients (n=12) compared with controls (n=10). Fresh frozen white matter samples were obtained from anterior (Brodmann area 9) and posterior (Brodmann area 1, 2 and 3) areas of post-mortem AD and control brains. ELISA was used to examine levels of soluble Aβ -42 and Aβ -40. Total cortical neuritic plaque severity rating was derived from individual ratings in the following areas of cortex: mid-frontal, superior temporal, pre-central, inferior parietal, hippocampus (CA1), subiculum, entorhinal cortex, transentorhinal cortex, inferior temporal, amygdala and basal forebrain. Compared with controls, AD samples had higher white matter levels of both soluble Aβ -42 and Aβ -40. While no regional white matter differences were found in Aβ -40, Aβ -42 levels were higher in anterior regions than in posterior regions across both groups. After statistically controlling for total cortical neuritic plaque severity, differences in both soluble Aβ -42 and Aβ -40 between the groups remained, suggesting that white matter Aβ peptides accumulate independent of overall grey matter fibrillar amyloid pathology and are not simply a reflection of overall amyloid burden. These results shed light on one potential mechanism through which white matter degeneration may occur in AD. Given that white matter degeneration may be an early marker of disease, preceding grey matter atrophy, understanding the mechanisms and risk factors that may lead to white matter loss could help to identify those at high risk and to intervene earlier in the pathogenic process.

Is residual memory variance a valid method for quantifying cognitive reserve? A longitudinal application

Cognitive reserve describes the mismatch between brain integrity and cognitive performance. Older adults with high cognitive reserve are more resilient to age-related brain pathology. Traditionally, cognitive reserve is indexed indirectly via static proxy variables (e.g., years of education). More recently, cross-sectional studies have suggested that reserve can be expressed as residual variance in episodic memory performance that remains after accounting for demographic factors and brain pathology (whole brain, hippocampal, and white matter hyperintensity volumes). The present study extends these methods to a longitudinal framework in a community-based cohort of 244 older adults who underwent two comprehensive neuropsychological and structural magnetic resonance imaging sessions over 4.6 years. On average, residual memory variance decreased over time, consistent with the idea that cognitive reserve is depleted over time. Individual differences in change in residual memory variance predicted incident dementia, independent of baseline residual memory variance. Multiple-group latent difference score models revealed tighter coupling between brain and language changes among individuals with decreasing residual memory variance. These results suggest that changes in residual memory variance may capture a dynamic aspect of cognitive reserve and could be a useful way to summarize individual cognitive responses to brain changes. Change in residual memory variance among initially non-demented older adults was a better predictor of incident dementia than residual memory variance measured at one time-point.

Structural MRI Predictors of Late-Life Cognition Differ Across African Americans, Hispanics, and Whites

BACKGROUND Structural magnetic resonance imaging (MRI) provides key biomarkers to predict onset and track progression of Alzheimers disease (AD). However, most published reports of relationships between MRI variables and cognition in older adults include racially, ethnically, and socioeconomically homogenous samples. Racial/ethnic differences in MRI variables and cognitive performance, as well as health, socioeconomic status and psychological factors, raise the possibility that brain-behavior relationships may be stronger or weaker in different groups. The current study tested whether MRI predictors of cognition differ in African Americans and Hispanics, compared with non-Hispanic Whites. METHODS Participants were 638 non-demented older adults (29% non-Hispanic White, 36% African American, 35% Hispanic) in the Washington Heights-Inwood Columbia Aging Project. Composite scores of memory, language, speed/executive functioning, and visuospatial function were derived from a neuropsychological battery. Hippocampal volume, regional cortical thickness, infarcts, and white matter hyperintensity (WMH) volumes were quantified with FreeSurfer and in-house developed procedures. Multiple-group regression analysis, in which each cognitive composite score was regressed onto MRI variables, demographics, and cardiovascular health, tested which paths differed across groups. RESULTS Larger WMH volume was associated with worse language and speed/executive functioning among African Americans, but not among non-Hispanic Whites. Larger hippocampal volume was more strongly associated with better memory among non-Hispanic Whites compared with Hispanics. Cortical thickness and infarcts were similarly associated with cognition across groups. CONCLUSION The main finding of this study was that certain MRI predictors of cognition differed across racial/ethnic groups. These results highlight the critical need for more diverse samples in the study of cognitive aging, as the type and relation of neurobiological substrates of cognitive functioning may be different for different groups.