Jordan Muraskin

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.

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.

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.

Reduction in cerebral blood flow in areas appearing as white matter hyperintensities on magnetic resonance imaging

The purpose of this study was to examine cerebral blood flow (CBF) as measured by arterial spin labeling (ASL) in tissue classified as white matter hyperintensities (WMH), normal appearing white matter, and grey matter. Seventeen healthy older adults received structural and ASL MRI. Cerebral blood flow was derived for three tissue types: WMH, normal appearing white matter, and grey matter. Cerebral blood flow was lower in WMH areas relative to normal appearing white matter, which in turn, was lower than grey matter. Regions with consistently lower CBF across individuals were more likely to appear as WMH. Results are consistent with an emerging literature linking diminished regional perfusion with the risk of developing WMH.

Brain Tissue Volume Changes Following Weight Gain in Adults with Anorexia Nervosa

OBJECTIVE To measure brain volume deficits among underweight patients with anorexia nervosa (AN) compared to control participants and evaluate the reversibility of these deficits with short-term weight restoration. METHOD Brain volume changes in gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) were examined in 32 adult women with AN and compared to 21, age and body mass index-range matched control women. RESULTS Patients with AN had a significant increase in GM (p = .006, η(2) = 0.14) and WM volume (p = .001, η(2) = 0.19) following weight restoration. Patients on average had lower levels of GM at low weight (647.63 ± 62.07 ml) compared to controls (679.93 ± 53.31 ml), which increased with weight restoration (662.64 ± 69.71 ml), but did not fully normalize. DISCUSSION This study suggests that underweight adult patients with AN have reduced GM and WM volumes that increase with short-term weight restoration.

Simultaneous EEG-fMRI Reveals Temporal Evolution of Coupling between Supramodal Cortical Attention Networks and the Brainstem

Cortical and subcortical networks have been identified that are commonly associated with attention and task engagement, along with theories regarding their functional interaction. However, a link between these systems has not yet been demonstrated in healthy humans, primarily because of data acquisition and analysis limitations. We recorded simultaneous EEG–fMRI while subjects performed auditory and visual oddball tasks and used these data to investigate the BOLD correlates of single-trial EEG variability at latencies spanning the trial. We focused on variability along task-relevant dimensions in the EEG for identical stimuli and then combined auditory and visual data at the subject level to spatially and temporally localize brain regions involved in endogenous attentional modulations. Specifically, we found that anterior cingulate cortex (ACC) correlates strongly with both early and late EEG components, whereas brainstem, right middle frontal gyrus (rMFG), and right orbitofrontal cortex (rOFC) correlate significantly only with late components. By orthogonalizing with respect to event-related activity, we found that variability in insula and temporoparietal junction is reflected in reaction time variability, rOFC and brainstem correlate with residual EEG variability, and ACC and rMFG are significantly correlated with both. To investigate interactions between these correlates of temporally specific EEG variability, we performed dynamic causal modeling (DCM) on the fMRI data. We found strong evidence for reciprocal effective connections between the brainstem and cortical regions. Our results support the adaptive gain theory of locus ceruleus–norepinephrine (LC–NE) function and the proposed functional relationship between the LC–NE system, right-hemisphere ventral attention network, and P300 EEG response.

Quantitative approaches for assessment of white matter hyperintensities in elderly populations

White matter hyperintensities (WMH) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI), including fluid attenuated inverse recovery sequences. Total and regional WMH burden (i.e., volume or severity) has been associated with myriad cognitive, neurological, and psychiatric conditions among older adults. In the current report, we illustrate two approaches to quantify periventricular, deep, and total WMH and examine their reliability and criterion validity among 28 elderly patients enrolled in a depression treatment trial. The first approach, an operator-driven quantitative approach, involves visual inspection of individual MRI scans and manual labeling using a three-step series of procedures. The second approach, a fully automated quantitative approach, uses a processing stream that involves image segmentation, voxel intensity thresholding, and seed growing to label WMH and calculate their volume automatically. There was good agreement in WMH quantification between the two approaches (Cronbachs alpha values from 0.835 to 0.968). Further, severity of WMH was significantly associated with worse depression and increased age, and these associations did not differ significantly between the two quantification approaches. We provide evidence for good reliability and criterion validity for two approaches for WMH volume determination. The operator-driven approach may be better suited for smaller studies with highly trained raters, whereas the fully automated quantitative approach may be more appropriate for larger, high-throughput studies.

Echo‐planar imaging with prospective slice‐by‐slice motion correction using active markers

Head motion is a fundamental problem in functional magnetic resonance imaging and is often a limiting factor in its clinical implementation. This work presents a rigid‐body motion correction strategy for echo‐planar imaging sequences that uses micro radiofrequency coil “active markers” for real‐time, slice‐by‐slice prospective correction. Before the acquisition of each echo‐planar imaging‐slice, a short tracking pulse‐sequence measures the positions of three active markers integrated into a headband worn by the subject; the rigid‐body transformation that realigns these markers to their initial positions is then fed back to dynamically update the scan‐plane, maintaining it at a fixed orientation relative to the head. Using this method, prospectively‐corrected echo‐planar imaging time series are acquired on volunteers performing in‐plane and through‐plane head motions, with results demonstrating increased image stability over conventional retrospective image‐realignment. The benefit of this improved image stability is assessed in a blood oxygenation level dependent functional magnetic resonance imaging application. Finally, a non‐rigid‐body distortion‐correction algorithm is introduced to reduce the remaining signal variation. Magn Reson Med, 2011.

Combined prospective and retrospective correction to reduce motion-induced image misalignment and geometric distortions in EPI.

Despite rigid‐body realignment to compensate for head motion during an echo‐planar imaging time‐series scan, nonrigid image deformations remain due to changes in the effective shim within the brain as the head moves through the B0 field. The current work presents a combined prospective/retrospective solution to reduce both rigid and nonrigid components of this motion‐related image misalignment. Prospective rigid‐body correction, where the scan‐plane orientation is dynamically updated to track with the subjects head, is performed using an active marker setup. Retrospective distortion correction is then applied to unwarp the remaining nonrigid image deformations caused by motion‐induced field changes. Distortion correction relative to a reference time‐frame does not require any additional field mapping scans or models, but rather uses the phase information from the echo‐planar imaging time‐series itself. This combined method is applied to compensate echo‐planar imaging scans of volunteers performing in‐plane and through‐plane head motions, resulting in increased image stability beyond what either prospective or retrospective rigid‐body correction alone can achieve. The combined method is also assessed in a blood oxygen level dependent functional MRI task, resulting in improved Z‐score statistics. Magn Reson Med, 2013.

Caffeine, cognitive functioning, and white matter lesions in the elderly: establishing causality from epidemiological evidence

The present study examines the epidemiological evidence for a causal relationship between caffeine consumption and cognitive deterioration in the elderly. Using a population of 641 elderly persons, we examined cognitive functioning, caffeine consumption, magnetic resonance imaging volumetrics, and other factors known to affect cognitive performance. Our findings demonstrate the association between caffeine consumption and lower cognitive change over time to be statistically significant for women only, taking into account multiple confounders, to be dose-dependent and temporarily related (caffeine consumption precedes cognitive change). Mean log transformed white matter lesion/cranial volume ratios were found to be significantly lower in women consuming more than 3 units of caffeine per day after adjustment for age (-1.23 SD=0.06) than in women consuming 2-3 units (-1.04 SD=0.04) or one unit or less (-1.04 SD=0.07, -35% in cm3 compared to low drinkers). This observation is coherent with biological assumptions that caffeine through adenosine is linked to amyloid accumulation and subsequently white matter lesion formation. The significant relationship observed between caffeine intake in women and lower cognitive decline is highly likely to be a true causal relationship and not a spurious association.