Stephen Correia

Impaired Awareness, Behavior Disturbance, and Caregiver Burden in Alzheimer Disease

Caregiver burden, the stress experienced as a result of caregiving, is determined by many factors. This study examined the contributions of the patients awareness of memory deficit and behavioral disturbance to caregiver burden in Alzheimer disease. Participants were 41 patients with Alzheimer disease and their caregivers. Dementia severity, functional impairment, awareness of memory deficit, and behavioral disturbance were measured and examined in relation to caregiver burden. Positive correlations were found between caregiver burden and both impaired awareness of memory deficit and behavioral disturbance. Regression analyses demonstrated that both impaired patient awareness of memory deficit and behavioral disturbance contributed to caregiver burden over and above dementia severity and functional impairment. However, when both were entered together into regression equations, only behavioral disturbance contributed to caregiver burden. Of the problem behaviors, measures of disinhibition contributed most to caregiver burden. These data further our understanding of the multiple contributors to caregiver burden. We conclude that both patient awareness of memory deficit and behavioral disturbance impact caregiver burden, with behavioral disturbance making the greater contribution.

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.

Identifying White-Matter Fiber Bundles in DTI Data Using an Automated Proximity-Based Fiber-Clustering Method

We present a method for clustering diffusion tensor imaging (DTI) integral curves into anatomically plausible bundles. An expert rater evaluated the anatomical accuracy of the bundles. We also evaluated the method by applying an experimental cross-subject labeling method to the clustering results. We first employ a sampling and culling strategy for generating DTI integral curves and then constrain the curves so that they terminate in gray matter. We then employ a clustering method based on a proximity measure calculated between every pair of curves. We interactively selected a proximity threshold to achieve visually optimal clustering in models from four DTI datasets. An expert rater then assigned a confidence rating about bundle presence and accuracy for each of 12 target fiber bundles of varying calibers and type in each dataset. We then created a fiber bundle template to cluster and label the fiber bundles automatically in new datasets. According to expert evaluation, the automated proximity-based clustering and labeling algorithm consistently yields anatomically plausible fiber bundles on large and coherent clusters. This work has the potential to provide an automatic and robust way to find and study neural fiber bundles within DTI.

Neuroimaging of White Matter in Aging and Dementia

Clinical neuroscientists have focused increasing attention on white matter connections in the brain and on the effects of aging and disease on these connections. Recent advances in magnetic resonance imaging (MRI) analysis have given researchers new tools for quantifying and visualizing white matter to better relate white matter structure and function. The goals of this article are (a) to acquaint the reader with both established and newer methods for imaging and quantifying white matter anatomy and pathology; and (b) to review recent findings on white matter pathology in aging and dementia. Computer-assisted quantification appears to offer better statistical power than visual rating scales for detecting these relationships. New MR modalities such as diffusion imaging can detect white matter abnormalities not shown with conventional acquisition sequences. These newer techniques hold promise for early detection of disease and for delineating functional connections between brain areas.

Alzheimer disease: time to improve its diagnosis and treatment.

Basic research is bringing a much-needed infusion of optimism and urgency to the clinical diagnosis and treatment of Alzheimer disease. Some of its risk factors may be modifiable, and although current drugs offer only modest benefit, true disease-modifying drugs are on the horizon. This review is aimed at primary care physicians, who are the first clinicians to see patients with Alzheimer disease and are responsible for their ongoing care throughout the course of their dementia. Basic research is bringing a much-needed infusion of optimism and urgency to the clinical diagnosis and treatment of Alzheimer disease. Some of its risk factors may be modifiable, and although current drugs offer only modest benefit, true disease-modifying drugs are on the horizon.

A Novel Interface for Interactive Exploration of DTI Fibers

Visual exploration is essential to the visualization and analysis of densely sampled 3D DTI fibers in biological speciments, due to the high geometric, spatial, and anatomical complexity of fiber tracts. Previous methods for DTI fiber visualization use zooming, color-mapping, selection, and abstraction to deliver the characteristics of the fibers. However, these schemes mainly focus on the optimization of visualization in the 3D space where cluttering and occlusion make grasping even a few thousand fibers difficult. This paper introduces a novel interaction method that augments the 3D visualization with a 2D representation containing a low-dimensional embedding of the DTI fibers. This embedding preserves the relationship between the fibers and removes the visual clutter that is inherent in 3D renderings of the fibers. This new interface allows the user to manipulate the DTI fibers as both 3D curves and 2D embedded points and easily compare or validate his or her results in both domains. The implementation of the framework is GPU based to achieve real-time interaction. The framework was applied to several tasks, and the results show that our method reduces the users workload in recognizing 3D DTI fibers and permits quick and accurate DTI fiber selection.

MRI subcortical hyperintensities in old and very old depressed outpatients: The important role of age in late-life depression

OBJECTIVE There is increasing evidence that cerebrovascular factors play a key role in the etiology of late-life depression. This study examined the severity of subcortical hyperintensities (SH) and the relationship between SH and depression characteristics in two samples of elderly depressed outpatients differing in age. METHODS The samples consisted of 59 subjects age 60 and over, (69+/-5.6 years), who participated in a trial of sertraline, and 111 subjects age 75 and over, (79+/-4.1 years), who participated in a trial of citalopram. RESULTS The citalopram group was significantly older than the sertraline group and had more severe SH (72% vs. 42% high ratings). The High SH group was significantly older than the Low SH group in the sertraline study but there was no difference in age in the SH groups in the citalopram sample. There was no relationship between SH severity and baseline depression or age of onset. However, age strongly correlated with later age of onset. There was no relationship between SH severity and cardiovascular risk factors or treatment response in the sertraline sample. CONCLUSION Age is a major factor for the development of SH and late-life depression. There may not be an association between SH and depression severity, cardiovascular risk factors, or treatment response in geriatric depressed outpatients. The etiologic factors and clinical course of late-life depression requires further study.

Effect of APOE genotype on microvascular basement membrane in Alzheimer's disease

APOE4 homozygosity has been associated with an increased risk of sporadic Alzheimers disease through a mechanism, which has yet to be defined. Recent evidence has suggested that microvascular basement membrane injury may be a critical factor in the pathogenesis of AD-related dementia. In previous studies, we have shown that the synaptic organizing protein agrin can be found in neurons, and is a major component of the brain microvascular basement membrane. Here, we compare the basement membrane surface area of cortical microvasculature in AD brains by staining with an anti-agrin antibody. Quantitative morphometric analysis was used to determine the mean basement area (micro(2)) of prefrontal cortical microvessels. An average of 10 capillaries was measured in each of 35 cases of AD genotyped for APOE status. APOE4,4 homozygotes had smaller capillary basement membrane areas (17.4 micro(2))+/-6.2) than APOE3,3 homozygotes (26.9 micro(2)+/-6.5), p<0.001. The capillary basement membrane areas (CBMA) of heterozygotes APOE3,4 did not differ significantly from APOE3,3 or APOE4,4. Braak stage did not contribute significantly to CBMA. However, a preliminary analysis suggests an interaction between APOE4,4 and Braak V-VI producing smaller CBMA, a finding which needs to be confirmed with a larger sample. These data support the hypothesis that APOE4,4 is associated with thinning of the microvascular basement membrane in Alzheimers disease.

Spontaneous lobar haemorrhage in CADASIL

CADASIL is an autosomal dominant form of arteriopathy, primarily affecting cerebral vessels, and predominantly caused by point mutations in the Notch3 gene on the short arm of chromosome 19.1 Affected individuals develop subcortical strokes and cognitive deficits in their 50s and 60s.2 Brain magnetic resonance imaging (MRI) shows large areas of leukoencephalopathy and multiple subcortical lacunar infarcts. Small arteries and capillaries are characterised histologically by a non-atherosclerotic, non-amyloid angiopathy with accumulation of granular osmiophilic material (GOM) within the smooth muscle cell basement membranes and extracellular matrix.3 While CADASIL is considered a primarily ischaemic form of vascular dementia, microhaemorrhages have recently been reported in 31% of symptomatic Notch3 mutation carriers, suggesting that structural fragility of the arterial walls may lead to leaking of haem products.4 Lobar haemorrhage in the absence of other risk factors for haemorrhage has previously been reported in one patient with CADASIL.5 Here we report a second case. A 56 year old man who had been diagnosed with multiple sclerosis six years earlier was admitted to the hospital with an acute change in mental state. He had collapsed at home and was …

Relationship of plasma cytokines and clinical biomarkers to memory performance in HIV.

Chronic systemic immune activation and inflammatory processes have been linked to brain dysfunction in medically stable HIV-infected people. We investigated the association between verbal memory performance and plasma concentrations of 13 cytokines measured using multiplexed bead array immunoassay in 74 HIV-seropositive individuals and 50 HIV-seronegative controls. Memory performance was positively related to levels of IL-8 and IFN-γ, and negatively related to IL-10 and IL-18 and to hepatitis C infection. Memory performance was not significantly related to HIV disease markers. The results indicate the importance of systemic immune and inflammatory markers to neurocognitive function in chronic and stable HIV disease.