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

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

Brain Structure Changes over Time in Normal and Mildly Impaired Aged Persons

Structural brain changes in aging are known to occur even in the absence of dementia, but the magnitudes and regions involved vary between studies. To further characterize these changes, we analyzed paired MRI images acquired with identical protocols and scanner over a median 5.8-year interval. The normal study group comprised 78 elders (25M 53F, baseline age range 70-78 years) who underwent an annual standardized expert assessment of cognition and health and who maintained normal cognition for the duration of the study. We found a longitudinal grey matter (GM) loss rate of 2.56 ± 0.07 ml/year (0.20 ± 0.04%/year) and a cerebrospinal fluid (CSF) expansion rate of 2.97 ± 0.07 ml/year (0.22 ± 0.04%/year). Hippocampal volume loss rate was higher than the GM and CSF global rates, 0.0114 ± 0.0004 ml/year (0.49 ± 0.04%/year). Regions of greatest GM loss were posterior inferior frontal lobe, medial parietal lobe and dorsal cerebellum. Rates of GM loss and CSF expansion were on the low end of the range of other published values, perhaps due to the relatively good health of the elder volunteers in this study. An additional smaller group of 6 subjects diagnosed with MCI at baseline were followed as well, and comparisons were made with the normal group in terms of both global and regional GM loss and CSF expansion rates. An increased rate of GM loss was found in the hippocampus bilaterally for the MCI group

Blood and cerebrospinal fluid biomarkers for Alzheimer’s disease: from clinical to preclinical cohorts

Dementia is a major contributor to global morbidity, mortality and costs associated with health and social care. Alzheimer’s disease (AD) is a common pathology culminating in dementia, but it has a preclinical phase of one to two decades, with early brain deposition of amyloid and tau, followed by synaptic and neuronal degeneration. Early detection during the preclinical phase of AD might enable disease-modifying therapies to be applied during a window of opportunity in which they would be more likely to work. Currently the main biomarkers of AD pathology are neuroimaging markers, which can be costly, or cerebrospinal fluid markers, which require invasive sampling. Blood biomarkers would be relatively less invasive and could be a more cost-effective means for risk stratification, early detection, monitoring progression and measuring response to treatment. The work described here used sensitive assay technology including the Simoa digital immunoassay platform, in large and well-characterised cohorts, to examine candidate blood biomarkers linked to the core AD pathologies of amyloid, tau and neurodegeneration, as specified by the National Institute on Aging and Alzheimer’s Association 2018 research framework. Firstly, experiments on samples from a cognitive clinic cohort established the stability of the blood biomarkers Aβ40, Aβ42, total tau and neurofilament light chain (NFL – a marker of neurodegeneration) to multiple freeze-thaw cycles, and the optimal blood fraction to use for quantifying each of these biomarkers in onward studies. Secondly, an unique large preclinical cohort with life course data (Insight 46, the neuroscience sub-study of 502 individuals from the MRC National Survey of Health and Development; the 1946 British birth cohort) was used to examine the cross-sectional relationships between these blood biomarkers, neuroimaging biomarkers (18F-florbetapir amyloid PET, whole brain and hippocampal volumes, white matter hyperintensity volume and cortical thickness in an AD signature region) and cognitive performance (PACC: preclinical Alzheimer’s composite and its constituents). Through a collaboration with the University of Gothenburg, a novel liquid chromatography-mass spectrometry (LC-MS) method for quantification of plasma amyloid-β species was compared with the commercial Simoa assays in Insight 46. This was the first direct method comparison study of plasma amyloid-β species for the detection of preclinical cerebral amyloid deposition. It showed that the LC-MS method, when combined with age, sex and APOE #-4 carrier status, was able to distinguish PET amyloid status with an optimal (Youden’s cut point) sensitivity of 85.7% and specificity of 72.7%. The Simoa biomarkers of plasma total tau and serum NFL were confirmed to be potentially useful prognostic markers, as lower AD signature cortical thickness was associated with higher plasma total tau and serum NFL, lower whole brain volume was associated with higher plasma total tau, and higher ventricular volume was associated with higher serum NFL. Lower PACC scores were associated with higher serum NFL and lower scores for a paired associative memory test in particular were associated with higher plasma total tau and serum NFL. Thirdly, through a collaboration with Harvard University and the University of California San Diego, a new N-terminal tau biomarker was developed in CSF and plasma that showed good accuracy in distinguishing individuals with symptomatic CSF-defined AD pathology from healthy controls. Taken together, this work has demonstrated the impact of pre-analytical factors on measurements of AD blood biomarkers, validated these biomarkers as indicators of the core pathologies of AD and helped to develop a new tau blood biomarker in AD

Early Medial Temporal Atrophy Scale (EMTA)

186 p.[ES]La atrofia del lóbulo temporal medial puede ser medida a través del uso de escalas de atrofia visual tales como la escala de atrofia del lóbulo temporal medial (MTA). La escala MTA ha sido diseñada y validada para el estudio de pacientes con Enfermedad de Alzheimer moderada (EA). Sin embargo, la MTA no ha sido diseñada para medir los cambios de atrofia de bajo grado que ocurren en la etapa precoz y media del proceso de envejecimiento. El objetivo de este estudio fue desarrollar y validar una nueva MTA; La “Goiz” (en Euskera) GMTA o “Early” (en ingles) EMTA, una nueva escala diseñada para la valoración de la atrofia precoz del lóbulo temporal medial que tiene la capacidad de medir los cambios de atrofia de bajo grado.[EN]Medial temporal lobe atrophy can be measured through visual rating scales such us the medial temporal lobe atrophy scale (MTA). MTA has been designed and validated for the study of patients with mild to moderate Alzheimer disease (AD). However, MTA has not been designed to measure the low-grade atrophy changes that occur at the early and middle aging process. The aim of this study was develop and validate a new MTA; the early (“Goiz” in Basque language) medial temporal lobe atrophy scale (EMTA) that has the capability to measure the low-grade atrophy changes

Tissue Damage Quantification in Alzheimer\u27s Disease Brain via Magnetic Resonance Gradient Echo Plural Contrast Imaging (GEPCI)

Alzheimer’s disease (AD) affected approximately 48 million people worldwide in 2015. Its devastating consequences have stimulated an intense search for AD prevention and treatment. Clinically, AD is characterized by memory deficits and progressive cognitive impairment, leading to dementia. Over the past two to three decades, researchers have found that amyloidbeta (Aβ) plaques and neurofibrillary tau tangles occur during a long pre-symptomatic period (preclinical stage) before the onset of clinical symptoms. As a result, identification of the preclinical stage is essential for the initiation of prevention trials in asymptomatic individuals. Currently, Positron Emission Tomography (PET) imaging with injected 11C or 18F containing radiotracers (e.g., Pittsburgh compound B, PiB or florbetapir-fluorine-18, 18F-AV-45) is widely used to detect amyloid deposition in vivo and to identify this preclinical stage. However, PET scans are time consuming (about 1 hour), require injection of a radiotracer, thus, exposing the patient to ionizing radiation. After the preclinical stage, AD patients begin to show clinical symptoms, referred as a very mild or mild AD group. Post-mortem studies show that neuronal damage is the most proximate pathological substrate of cognitive impairment in AD compared with amyloid and tau deposition. Thus, a diagnostic tool is needed for detection of neuronal loss in vivo. As a faster, non-invasive, and radiation free imaging technique, Magnetic Resonance Imaging (MRI) plays an important role in the diagnosis of cognitive diseases. Conventional MRI yields superb definition of brain anatomy and structure and provide important volumetric information (e.g., brain atrophy). However, conventional MRI cannot provide microstructural and functional insight into the pathology of AD. The approach developed in Yablonskiy’s lab is based on the Gradient Echo Plural Contrast Imaging (GEPCI) protocol, which provides quantitative in vivo measurements of transverse relaxation properties of the tissue water 1H spins as determined from the gradient echo MRI signal. The measurements are corrected for macroscopic magnetic field inhomogeneity effects and physiologic-motion-driven fluctuations in magnetic field as these are the major artifacts present with the gradient echo technique. The principal relaxation property used in this dissertation is the tissue-specific transverse relaxation rate constant, R2*. The R2* value reflects the microscopic and mesoscopic magnetic field inhomogeneities rising from the complex tissuewater-environment within the human brain. In turn, changes in R2* reflect changes in the tissue’s microscopic and mesoscopic tissue structure. However, because of the presence of the cerebral blood vessel network, the magneticsusceptibility-driven blood-oxygen-level dependent (BOLD) effect also makes a significant contribution to R2*. A previously developed approach, quantitative BOLD (qBOLD), allows the separation of R2* into a tissue specific R2t* without blood vessel effects and the BOLD component. Quantifying the BOLD component allows the calculation of cerebral hemodynamics parameters, such as oxygen extraction fraction (OEF) and deoxygenated cerebral blood volume (dCBV). These parameters (R2*, R2t*, OEF, dCBV) describe structural and functional properties of tissue at the microstructural level in the human brain. In the study of normal aging, quantitative GEPCI measurements showed that R2t* increases with age while hemodynamic parameters, i.e., relative OEF and dCBV remain constant in most cerebral cortical regions. The comparison between quantitative GEPCI measurements and literature information suggest that (a) age-related increases in the cortical R2t* mostly reflect the age-related increases in the cellular packing density (or neuronal density); (b) regions in a brain characterized by higher R2t* contain a higher concentration of neurons with less developed cellular processes (dendrites, spines, etc.); and (c) brain regions characterized by lower R2t* represent regions with lower concentration of neurons but more developed cellular processes. In the Alzheimer study, R2* and R2t* together demonstrated significant differences among the normal, preclinical and mild AD groups. First, the results uncovered strong correlations between R2* and Aβ deposition measured by the PiB PET-tracer in several cortical regions (e.g., medial temporal lobe and precuneus). This finding indicates that R2* may be a potential surrogate marker for Aβ deposition. The strongest correlation was found in the medial temporal lobe (MTL), particularly in the parahippocampal cortex, which can be used to distinguish the normal and preclinical groups. Second, R2t* in the hippocampus, which characterized the hippocampal cellular integrity demonstrated much stronger correlations with psychometric tests than volume quantification of hippocampal atrophy. Importantly, decreased R2t* characterizing cellular damage was detected even in the hippocampal areas not affected by atrophy. In addition, R2t* significantly decreased in the mild AD group but was preserved in the preclinical group compared with the normal group. These results indicate a significant cellular density decrease in the mild group but not in the preclinical group, which is consistent with previous histological studies. In summary, GEPCI provides a new approach for evaluation of AD-related tissue pathology in vivo in the preclinical and early symptomatic stages of AD. Since MRI is widely available worldwide and does not require radiation exposure, it provides the opportunity to obtain new information on the pathogenesis of AD and for pre-screening cohorts (stratification) for clinical drug trials

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