Longitudinal Morphometric Study of Genetic Influence of APOE e4 Genotype on Hippocampal Atrophy - An N=1925 Surface-based ADNI Study

abstract: The apolipoprotein E (APOE) e4 genotype is the most prevalent known genetic risk factor for Alzheimer's disease (AD). In this paper, we examined the longitudinal effect of APOE e4 on hippocampal morphometry in Alzheimer's Disease Neuroimaging Initiative (ADNI). Generally, atrophy of hippocampus has more chance occurs in AD patients who carrying the APOE e4 allele than those who are APOE e4 noncarriers. Also, brain structure and function depend on APOE genotype not just for Alzheimer's disease patients but also in health elderly individuals, so APOE genotyping is considered critical in clinical trials of Alzheimer's disease. We used a large sample of elderly participants, with the help of a new automated surface registration system based on surface conformal parameterization with holomorphic 1-forms and surface fluid registration. In this system, we automatically segmented and constructed hippocampal surfaces from MR images at many different time points, such as 6 months, 1- and 2-year follow up. Between the two different hippocampal surfaces, we did the high-order correspondences, using a novel inverse consistent surface fluid registration method. At each time point, using Hotelling's T^2 test, we found significant morphological deformation in APOE e4 carriers relative to noncarriers in the entire cohort as well as in the non-demented (pooled MCI and control) subjects, affecting the left hippocampus more than the right, and this effect was more pronounced in e4 homozygotes than heterozygotes.Dissertation/ThesisMasters Thesis Computer Science 201

Influence of APOE Genotype on Hippocampal Atrophy over Time - An N=1925 Surface-Based ADNI Study

abstract: The apolipoprotein E (APOE) e4 genotype is a powerful risk factor for late-onset Alzheimer’s disease (AD). In the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, we previously reported significant baseline structural differences in APOE e4 carriers relative to non-carriers, involving the left hippocampus more than the right—a difference more pronounced in e4 homozygotes than heterozygotes. We now examine the longitudinal effects of APOE genotype on hippocampal morphometry at 6-, 12- and 24-months, in the ADNI cohort. We employed a new automated surface registration system based on conformal geometry and tensor-based morphometry. Among different hippocampal surfaces, we computed high-order correspondences, using a novel inverse-consistent surface-based fluid registration method and multivariate statistics consisting of multivariate tensor-based morphometry (mTBM) and radial distance. At each time point, using Hotelling’s T[superscript 2] test, we found significant morphological deformation in APOE e4 carriers relative to non-carriers in the full cohort as well as in the non-demented (pooled MCI and control) subjects at each follow-up interval. In the complete ADNI cohort, we found greater atrophy of the left hippocampus than the right, and this asymmetry was more pronounced in e4 homozygotes than heterozygotes. These findings, combined with our earlier investigations, demonstrate an e4 dose effect on accelerated hippocampal atrophy, and support the enrichment of prevention trial cohorts with e4 carriers.The article is published at http://journals.plos.org/plosone/article?id=10.1371/journal.pone.015290

Surface fluid registration of conformal representation: Application to detect disease burden and genetic influence on hippocampus

abstract: In this paper, we develop a new automated surface registration system based on surface conformal parameterization by holomorphic 1-forms, inverse consistent surface fluid registration, and multivariate tensor-based morphometty (mTBM). First, we conformally map a surface onto a planar rectangle space with holomorphic 1-forms. Second, we compute surface conformal representation by combining its local conformal factor and mean curvature and linearly scale the dynamic range of the conformal representation to form the feature image of the surface. Third, we align the feature image with a chosen template image via the fluid image registration algorithm, which has been extended into the curvilinear coordinates to adjust for the distortion introduced by surface parameterization. The inverse consistent image registration algorithm is also incorporated in the system to jointly estimate the forward and inverse transformations between the study and template images. This alignment induces a corresponding deformation on the surface. We tested the system on Alzheimer's Disease Neuroimaging Initiative (ADNI) baseline dataset to study AD symptoms on hippocampus. In our system, by modeling a hippocampus as a 3D parametric surface, we nonlinearly registered each surface with a selected template surface. Then we used mTBM to analyze the morphometry difference between diagnostic groups. Experimental results show that the new system has better performance than two publicly available subcortical surface registration tools: FIRST and SPHARM. We also analyzed the genetic influence of the Apolipoprotein E(is an element of)4 allele (ApoE4), which is considered as the most prevalent risk factor for AD. Our work successfully detected statistically significant difference between ApoE4 carriers and non-carriers in both patients of mild cognitive impairment (MCI) and healthy control subjects. The results show evidence that the ApoE genotype may be associated with accelerated brain atrophy so that our work provides a new MRI analysis tool that may help presymptomatic AD research.NOTICE: this is the author’s version of a work that was accepted for publication in NEUROIMAGE. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Neuroimage, 78, 111-134 [2013] http://dx.doi.org/10.1016/j.neuroimage.2013.04.01

Building a Surface Atlas of Hippocampal Subfields from MRI Scans using FreeSurfer, FIRST and SPHARM

The hippocampus is widely studied with neuroimaging techniques given its importance in learning and memory and its potential as a biomarker for brain disorders such as Alzheimer's disease and epilepsy. However, its complex folding anatomy often presents analytical challenges. In particular, the critical hippocampal subfield information is usually ignored by hippocampal registration in detailed morphometric studies. Such an approach is thus inadequate to accurately characterize hippocampal morphometry and effectively identify hippocampal structural changes related to different conditions. To bridge this gap, we present our initial effort towards building a computational framework for subfield-guided hippocampal morphometry. This initial effort is focused on surface-based morphometry and aims to build a surface atlas of hippocampal subfields. Using the FreeSurfer software package, we obtain valuable hippocampal subfield information. Using the FIRST software package, we extract reliable hippocampal surface information. Using SPHARM, we develop an approach to create an atlas by mapping interpolated subfield information onto an average surface. The empirical result using ADNI data demonstrates the promise and good reproducibility of the proposed method

Genetic clustering on the hippocampal surface for genome-wide association studies

Imaging genetics aims to discover how variants in the human genome influence brain measures derived from images. Genome-wide association scans (GWAS) can screen the genome for common differences in our DNA that relate to brain measures. In small samples, GWAS has low power as individual gene effects are weak and one must also correct for multiple comparisons across the genome and the image. Here we extend recent work on genetic clustering of images, to analyze surface-based models of anatomy using GWAS. We performed spherical harmonic analysis of hippocampal surfaces, automatically extracted from brain MRI scans of 1254 subjects. We clustered hippocampal surface regions with common genetic influences by examining genetic correlations (rg) between the normalized deformation values at all pairs of surface points. Using genetic correlations to cluster surface measures, we were able to boost effect sizes for genetic associations, compared to clustering with traditional phenotypic correlations using Pearson's r

Investigating brain alterations in the Dp1Tyb mouse model of Down syndrome

Down syndrome (DS) is one of the most common birth defects and the most prevalent genetic form of intellectual disability. DS arises from trisomy of chromosome 21, but its molecular and pathological consequences are not fully understood. In this study, we compared Dp1Tyb mice, a DS model, against their wild-type (WT) littermates of both sexes to investigate the impact of DS-related genetic abnormalities on the brain phenotype. We performed in vivo whole brain magnetic resonance imaging (MRI) and hippocampal 1H magnetic resonance spectroscopy (MRS) on the animals at 3 months of age. Subsequently, ex vivo MRI scans and histological analyses were conducted post-mortem. Our findings unveiled the following neuroanatomical and biochemical alterations in the Dp1Tyb brains: a smaller surface area and a rounder shape compared to WT brains, with DS males also presenting smaller global brain volume compared with the counterpart WT. Regional volumetric analysis revealed significant changes in 26 out of 72 examined brain regions, including the medial prefrontal cortex and dorsal hippocampus. These alterations were consistently observed in both in vivo and ex vivo imaging data. Additionally, high-resolution ex vivo imaging enabled us to investigate cerebellar layers and hippocampal subregions, revealing selective areas of decrease and remodelling in these structures. An analysis of hippocampal metabolites revealed an elevation in glutamine and the glutamine/glutamate ratio in the Dp1Tyb mice compared to controls, suggesting a possible imbalance in the excitation/inhibition ratio. This was accompanied by the decreased levels of taurine. Histological analysis revealed fewer neurons in the hippocampal CA3 and DG layers, along with an increase in astrocytes and microglia. These findings recapitulate multiple neuroanatomical and biochemical features associated with DS, enriching our understanding of the potential connection between chromosome 21 trisomy and the resultant phenotype

Computer aided diagnosis in temporal lobe epilepsy and Alzheimer's dementia

Computer aided diagnosis within neuroimaging must rely on advanced image processing techniques to detect and quantify subtle signal changes that may be surrogate indicators of disease state. This thesis proposes two such novel methodologies that are both based on large volumes of interest, are data driven, and use cross-sectional scans: appearance-based classification (ABC) and voxel-based classification (VBC).The concept of appearance in ABC represents the union of intensity and shape information extracted from magnetic resonance images (MRI). The classification method relies on a linear modeling of appearance features via principal components analysis, and comparison of the distribution of projection coordinates for the populations under study within a reference multidimensional appearance eigenspace. Classification is achieved using forward, stepwise linear discriminant analyses, in multiple cross-validated trials. In this work, the ABC methodology is shown to accurately lateralize the seizure focus in temporal lobe epilepsy (TLE), differentiate normal aging individuals from patients with either Alzheimer's dementia (AD) or Mild Cognitive Impairment (MCI), and finally predict the progression of MCI patients to AD. These applications demonstrated that the ABC technique is robust to different signal changes due to two distinct pathologies, to low resolution data and motion artifacts, and to possible differences inherent to multi-site acquisition.The VBC technique relies on voxel-based morphometry to identify regions of grey and white matter concentration differences between co-registered cohorts of individuals, and then on linear modeling of variables extracted from these regions. Classification is achieved using linear discriminant analyses within a multivariate space composed of voxel-based morphometry measures related to grey and white matter concentration, along with clinical variables of interest. VBC is shown to increase the accuracy of prediction of one-year clinical status from three to four out of five TLE patients having undergone selective amygdalo-hippocampectomy. These two techniques are shown to have the necessary potential to solve current problems in neurological research, assist clinical physicians with their decision-making process and influence positively patient management