Showing papers by "George Bartzokis published in 2014"

Research Article The EADC-ADNI Harmonized Protocol for manual hippocampal segmentation on magnetic resonance: Evidence of validity

Abstract: Background: An international Delphi panel has defined a harmonized protocol (HarP) for themanual segmentation of the hippocampus on MR. The aim of this study is to study the concurrentvalidity of the HarP toward local protocols, and its major sources of variance.Methods: Fourteen tracers segmented 10 Alzheimer’s Disease Neuroimaging Initiative (ADNI)cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on theHarP through a standard web-platform and resegmented following the HarP. The five most accuratetracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 Tand3T.Results: Theagreementamongtracerswasrelativelylowwiththelocalprotocols(absoluteleft/rightICC0.44/0.43)andmuchhigherwiththeHarP(absoluteleft/rightICC0.88/0.89).Onthelargersetof15cases,theHarPagreementwithin(left/rightICCrange:0.94/0.95to0.99/0.99)andamongtracers(left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates(3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variancedue to atrophy (33.5%, P ,.001), and physiological variability (49.2%, P ,.001).Conclusions: The HarP has high measurement stability compared with local segmentation proto-cols, and good reproducibility within and among human tracers. Hippocampi segmented with theHarP can be used as a reference for the qualification of human tracers and automated segmentationalgorithms. 2014 The Alzheimer’s Association. All rights reserved.

Multisystem component phenotypes of bipolar disorder for genetic investigations of extended pedigrees.

Abstract: Importance Genetic factors contribute to risk for bipolar disorder (BP), but its pathogenesis remains poorly understood. A focus on measuring multisystem quantitative traits that may be components of BP psychopathology may enable genetic dissection of this complex disorder, and investigation of extended pedigrees from genetically isolated populations may facilitate the detection of specific genetic variants that affect BP as well as its component phenotypes. Objective To identify quantitative neurocognitive, temperament-related, and neuroanatomical phenotypes that appear heritable and associated with severe BP (bipolar I disorder [BP-I]) and therefore suitable for genetic linkage and association studies aimed at identifying variants contributing to BP-I risk. Design, Setting, and Participants Multigenerational pedigree study in 2 closely related, genetically isolated populations: the Central Valley of Costa Rica and Antioquia, Colombia. A total of 738 individuals, all from Central Valley of Costa Rica and Antioquia pedigrees, participated; among them, 181 have BP-I. Main Outcomes and Measures Familial aggregation (heritability) and association with BP-I of 169 quantitative neurocognitive, temperament, magnetic resonance imaging, and diffusion tensor imaging phenotypes. Results Of 169 phenotypes investigated, 119 (70%) were significantly heritable and 51 (30%) were associated with BP-I. About one-quarter of the phenotypes, including measures from each phenotype domain, were both heritable and associated with BP-I. Neuroimaging phenotypes, particularly cortical thickness in prefrontal and temporal regions and volume of the corpus callosum, represented the most promising candidate traits for genetic mapping related to BP based on strong heritability and association with disease. Analyses of phenotypic and genetic covariation identified substantial correlations among the traits, at least some of which share a common underlying genetic architecture. Conclusions and Relevance To our knowledge, this is the most extensive investigation of BP-relevant component phenotypes to date. Our results identify brain and behavioral quantitative traits that appear to be genetically influenced and show a pattern of BP-I association within families that is consistent with expectations from case-control studies. Together, these phenotypes provide a basis for identifying loci contributing to BP-I risk and for genetic dissection of the disorder.

The Early Longitudinal Course of Cognitive Deficits in Schizophrenia

Abstract: Cognitive impairment is a core feature of schizophrenia. However, the longitudinal course and pattern of this impairment, and its relationship to functional outcome is not fully understood. Among the likely factors in the persistence of cognitive deficits in schizophrenia are brain tissue changes over time, which in turn appear to be related to antipsychotic medication adherence. Cognitive deficits are viewed as a core feature of schizophrenia primarily because cognitive deficits clearly exist before the onset of psychosis and can predict illness onset among those at high risk of developing the illness. Additionally, these deficits often persist during symptomatic remissions in patients, and are relatively stable across time both in patients and in individuals at risk for schizophrenia. Despite clear evidence that cognitive impairment can predict functional outcome in chronic schizophrenia, results of studies examining this relationship in the early phase of psychosis have been mixed. Recent data, however, strongly suggest that interventions targeting early cognitive deficits may be crucial to the prevention of chronic disability, and thus should be a prominent target for therapy. Finally, it is vital to keep schizophrenia patients consistently on their antipsychotic medications. A novel method of examining intracortical myelin volume indicated that the choice of antipsychotic treatment had a differential impact on frontal myelination. These data suggest that long acting injectable antipsychotic medication may prevent patients from declining further through a combination of better adherence and pharmacokinetics.

Younger age of dementia diagnosis in a Hispanic population in southern California.

Abstract: Objective Prior studies of US Hispanics, largely performed on the East Coast, have found a younger age of dementia onset than in White non-Hispanics. We performed a cross-sectional study to examine clinical and sociodemographic variables associated with age of dementia diagnosis in older Hispanics and White, non-Hispanics in southern California. Methods Two hundred ninety (110 Hispanic and 180 White non-Hispanic) community dwelling, cognitively symptomatic subjects, aged 50 years and older, were assessed and diagnosed with probable Alzheimer's disease or probable vascular dementia. Apolipoprotein E (APOE) genotype was assessed in a subset of cases. Analysis of variance and multiple stepwise linear regression were used to assess main effects and interactions of ethnicity with dementia severity (indexed by mini mental state examination scores) and other sociodemographic and clinical variables on age of dementia diagnosis. Results Hispanics were younger by an average of 4 years at the time of diagnosis, regardless of dementia subtype, despite a similar prevalence of the APOE e4 genotype. The earlier age at diagnosis for Hispanics was not explained by gender, dementia severity, years of education, history of hypercholesterolemia, hypertension, or diabetes. Only ethnicity was significantly associated with age of onset. Conclusions These findings confirm that US Hispanics living in the southwestern USA tend to be younger at the time of dementia diagnosis than their White non-Hispanic counterparts. As this is not explained by the presence of the APOE e4 genotype, further studies should explore other cultural, medical, or genetic risk factors influencing the age of dementia onset in this population. Copyright © 2014 John Wiley & Sons, Ltd.

Regional Differences in White Matter Breakdown Between Frontotemporal Dementia and Early-Onset Alzheimer's Disease

Abstract: Background: White matter abnormalities have been associated with both behavioral variant frontotemporal dementia (bvFTD) and Alzheimer’s disease (AD). Objective: Using MRI diffusion tensor imaging (DTI) measures, we compared white matter integrity between patients with bvFTD and those with early-onset AD and correlated these biomarkers with behavioral symptoms involving emotional blunting. Methods: We studied 8 bvFTD and 12 AD patients as well as 12 demographically-matched healthy controls (NCs). Using four DTI metrics (fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity), we assessed the frontal lobes (FWM) and genu of the corpus callosum (GWM), which are vulnerable late-myelinating regions, and a contrasting early-myelinating region (splenium of the corpus callosum). The Scale for Emotional Blunting Scale (SEB) was used to assess emotional functioning of the study participants. Results: Compared to AD patients and NCs, the bvFTD subjects exhibited significantly worse FWM and GWM integrity on all four DTI metrics sensitive to myelin and axonal integrity. In contrast, AD patients showed a numerical trend toward worse splenium of the corpus callosum integrity than bvFTD and NC groups. Significant associations between SEB ratings and GWM DTI measures were demonstrated in the combined bvFTD and AD sample. When examined separately, these relationships remained robust for the bvFTD group but not the AD group. Conclusions: The regional DTI alterations suggest that FTD and AD are each associated with a characteristic distribution of white matter degradation. White matter breakdown in late-myelinating regions was associated with symptoms of emotional blunting, particularly within the bvFTD group.

Research Article Delphi definition of the EADC-ADNI Harmonized Protocol for hippocampal segmentation on magnetic resonance

Abstract: Background: This study aimed to have international experts converge on a harmonized definition of whole hippocampus boundaries and segmentation procedures, to define standard operating procedures for magnetic resonance (MR)-based manual hippocampal segmentation.

Rich Club Network Analysis Shows Distinct Patterns of Disruption in Frontotemporal Dementia and Alzheimer’s Disease

Abstract: Diffusion imaging and brain connectivity analyses can reveal the underlying organizational patterns of the human brain, described as complex networks of densely interlinked regions. Here, we analyzed 1.5-Tesla whole-brain diffusion-weighted images from 64 participants—15 patients with behavioral variant frontotemporal (bvFTD) dementia, 19 with early-onset Alzheimer’s disease (EOAD), and 30 healthy elderly controls. Based on whole-brain tractography, we reconstructed structural brain connectivity networks to map connections between cortical regions. We examined how bvFTD and EOAD disrupt the weighted ‘rich club’—a network property where high-degree network nodes are more interconnected than expected by chance. bvFTD disrupts both the nodal and global organization of the network in both low- and high-degree regions of the brain. EOAD targets the global connectivity of the brain, mainly affecting the fiber density of high-degree (highly connected) regions that form the rich club network. These rich club analyses suggest distinct patterns of disruptions among different forms of dementia.

Methodological improvements in voxel-based analysis of diffusion tensor images: applications to study the impact of apolipoprotein E on white matter integrity.

Abstract: Purpose To identify regional differences in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) using customized preprocessing before voxel-based analysis (VBA) in 14 normal subjects with the specific genes that decrease (apolipoprotein [APO] E e2) and that increase (APOE e4) the risk of Alzheimer's disease. Materials and Methods Diffusion tensor images (DTI) acquired at 1.5 Tesla were denoised with a total variation tensor regularization algorithm before affine and nonlinear registration to generate a common reference frame for the image volumes of all subjects. Anisotropic and isotropic smoothing with varying kernel sizes was applied to the aligned data before VBA to determine regional differences between cohorts segregated by allele status. Results VBA on the denoised tensor data identified regions of reduced FA in APOE e4 compared with the APOE e2 healthy older carriers. The most consistent results were obtained using the denoised tensor and anisotropic smoothing before statistical testing. In contrast, isotropic smoothing identified regional differences for small filter sizes alone, emphasizing that this method introduces bias in FA values for higher kernel sizes. Conclusion Voxel-based DTI analysis can be performed on low signal to noise ratio images to detect subtle regional differences in cohorts using the proposed preprocessing techniques. J. Magn. Reson. Imaging 2014;39:387–397. © 2013 Wiley Periodicals, Inc.

Degenerative Brain Diseases and White Matter Injury

Abstract: This chapter provides an overview of dynamic interdependence and complex signaling between all of the brain’s cellular elements with a special focus on glia and especially oligodendrocytes and their roles in achieving optimal brain function as well as triggering degenerative brain processes. The evidence suggests that recently evolved vulnerable aspects of the human brain such as myelin and the homeostatic repair mechanisms triggered by its breakdown may drive the slow and continually progressive processes that result in age-related cognitive decline as well as the pathology that define prevalent degenerative diseases such as Alzheimer’s disease. Furthermore, by altering central-peripheral signaling these degenerative brain processes may also contribute to peripheral metabolic derangements such as hypertension, insulin resistance, and obesity (e.g., metabolic syndrome). By highlighting the role of glia, this chapter strives to rebalances the historic focus on neurons and gray matter and highlights the importance of a systems-level understanding of healthy brain functioning and the interdependent age-related shifts in both central and peripheral homeostatic mechanisms that can lead to remarkably prevalent and devastating age-related diseases.