Huntington's Disease (HD) is a rare condition that has been under-researched by the medical professions and psychologists alike. There is a clear lack of psychological literature on the subject of HD and furthermore, there are no adequate QoL scales available for use by spousal carers. The development of a HD specific QoL scale (HDQoL-C) for this special population, brings together theoretical constructs and practical application in order to produce a user-friendly QoL measurement for spousal carers of HD patients.

Bakgrund: Huntingtons sjukdom innebär ofta såväl motoriska, kognitiva som psykiatriska symtom. Chorea är ett tidigt motoriskt symtom och innebär överrörelser som kan förekomma i hela kroppen. Få studier beskriver den subjektiva upplevelsen av chorea.   Syfte: Att undersöka upplevelser av chorea hos fem personer med Huntingtons sjukdom samt att undersöka hur chorean påverkade deras förmåga till fysisk aktivitet.    Design och metod: Explorativ kvalitativ design. Semistrukturerade intervjuer med fem personer med Huntingtons sjukdom. En kvalitativ innehållsanalys användes för databearbetning.   Resultat: Utifrån studiens två frågeställningar identifierades tre teman: Att finna sin plats i tillvaron; Att finna sig i förändring; Att omvärdera rörelse. Dessa teman består av nio kategorier: Oro; Vardagliga hinder; En kropp som inte lyder; Förståelse från andra; Ett accepterande förhållningssätt; Omgivning; Att möta motgångar; Hitta rätt tillvägagångssätt; Att inse sina begränsningar.   Konklusion: För vissa av informanterna rådde en omedvetenhet kring chorea, medan den för andra låg till grund för stort lidande. De påtalade även hur chorea på olika sätt utgjorde en fysisk begränsning. Detta bör fungera som ett incitament för personcentrering i mötet med personer med Huntingtons sjukdom. / Background: Huntington's disease results in a combination of motor, cognitive and psychiatric symptoms. Chorea is an early symptom which entails involuntary movements that can affect various body parts. There are few studies addressing the subjective experiences of having chorea.   Purpose: To investigate experiences of having chorea in five people with Huntington's disease and to investigate how the chorea affected their ability to be physically active.   Design and method: Explorative qualitative design. Semi-structured interviews of five people with Huntington's disease. A qualitative content analysis was conducted. Results: Based on the two questions of the study, three themes were identified: Finding your place; Finding yourself in change; Revaluating movement. These themes consist of nine categories: Concern; Everyday obstacles; A disobedient body; Comprehension from others; An accepting approach; Surroundings; Facing setbacks; Finding the right strategies; Realizing your limitations.   Conclusion: Some of the informants were unaware of their chorea while in others it caused a great suffering. They also underlined how chorea in different ways could imply a physical limitation. This could function as an incentive for person-centered care when meeting people with Huntington's disease.

Neurodegeneration is a chronic, progressive and debilitating condition that affects majority of the World's elderly population who are at greater risk. Numerous scientific studies suggest that there could be a common underlying molecular mechanism that promotes the degeneration and the subsequent neuronal loss, however so far the progress in this direction is rather limited. Abnormal protein misfoldings, as well as protein plaque formations in the brain, are some of the hallmark characteristic features of neurodegenerative disorders (NDDs). Genetic and environmental factors, oxidative stress, excessive reactive oxygen species formation, mitochondrial dysfunction, energy depletion and autophagy disruption etc. are some of the widely suspected mechanisms that manifest the cognitive, motor and emotional symptoms of these NDDs. Motivated by some molecular traits found in common in several NDDs, network-based systems biology tools and techniques were used in this study to identify critical molecular players and underlying biological processes that are common for Parkinson's, Alzheimer's and Huntington's disease. Utilizing multiple microarray gene expression datasets, several biomolecular networks such as direct interaction, shortest path, and microRNA regulatory networks were constructed and analyzed for each of the disease conditions. The network-based analysis revealed 26 genes of potential interest in Parkinson's, 16 in Alzheimer's and 30 in Huntington's disease. Many new microRNA-target regulatory interactions were identified. For each disorder, several routes for possible disease initiation and protection scenarios were uncovered. A unified neurodegeneration mechanism network was constructed by utilizing the significantly differentially expressed genes found in common in Parkinson's, Alzheimer's and Huntington's microarray datasets. In this integrated network many key molecular partakers and several biological processes that were significantly affected in all three NDDs were uncovered. The integrated network also revealed complex dual-level interactions that occur between disease contributing and protecting entities. Possibilities of microRNA-target interactions were explored and many such pairs of potential interest in NDDs were suggested. Investigating the integrated network mechanism, we have identified several routes for disease initiating, as well as alleviating ones that could be utilized in common for Parkinson's, Alzheimer's and Huntington's disease. Finding such crucial and universal molecular players in addition to maintaining a delicate balance between neurodegeneration promoters and protectors is vital for restoring the homeostasis in the three NDDs.

La Maladie de Huntington (MH) reste à ce jour une pathologie neurodégénérative dévastatrice pour laquelle aucun traitement n'est disponible. L'agrégation de la Huntingtine Mutante (Htt PolyQ) joue un rôle majeur dans les processus pathologiques. Dans ce contexte, des études récentes ont démontré que la partie N-terminale de la Huntingtine Humaine (Htt wt) ou de son Homologue drosophile (dHtt) sont toutes deux capables de réduire l'agrégation et la toxicité de Htt PolyQ. En se basant sur cette observation, le travail de thèse décrit dans ce manuscrit a mis au point un découpage du fragment N-terminal de Htt wt de manière à isoler en son sein, une courte séquence de 23 acides aminés (nommée P42), capable d'inhiber spécifiquement l'agrégation de Htt PolyQ en modèle cellulaire. L'effet protecteur de ce peptide a été confirmé in vivo, sur un modèle drosophile de la MH. Le potentiel thérapeutique que représente P42 a servi de point de départ à une étude menée sur le modèle murin R6/2 de la MH. L'effet de P42 a été potentialisé par l'ajout du peptide de transduction TAT de manière à faciliter son entrée dans les cellules cibles. Puis, la protéine fusion P42-TAT a été vectorisée sous forme de microémulsion de manière à assurer à la fois une administration simple de la molécule, et un accès au système nerveux central. Ce protocole original a permis d'observer des bénéfices sans précédent sur les phénotypes comportementaux, histologiques et moléculaires que présentent les souris R6/2.Au-delà de son aspect thérapeutique, P42 est avant tout une séquence méconnue située dans une région cruciale de la Huntingtine. L'étude du rôle physiologique de ce site, a mené à une meilleure compréhension de la fonction sauvage de la protéine toute entière. En outre, une analyse biochimique a montré la capacité du fragment N-terminal de Htt wt à se lier aux microtubules. Cette interaction avec le cytosquelette dépend de plusieurs processus (clivages, dimérisation) et semble affilier la Huntingtine à la grande famille des MAP.L'identification de P42 ouvre donc une voie nouvelle vers la compréhension du rôle physiologique de la Huntingtine, mais représente surtout un espoir thérapeutique captivant. / Huntington's disease (HD) is a devastating and incurable neurodegenerative disorder. Aggregation processes of mutant Huntingtin (Htt PolyQ) play a central part in the pathology onset. In this context, recent studies pointed out the capacities of wild-type Huntingtin N-terminus to reduce both aggregation and toxicity associated with Htt PolyQ. The drosophila Homologue shares the sames properties. Basing on these observations, the present work realised a cut of human Huntingtin N-terminus in order to identify the region responsible for therapeutic benefits. This screen highlighted a 23 amino-acid sequence (noted P42), that inhibits Htt PolyQ aggregation in a HeLa cells model. Then, the protective effect of this peptide was confirmed in vivo, in a HD drosophila model.P42 therapeutic potential was explored in the R6/2 HD mouse model. The entry of the peptide into cells, was potentialised by grafting to P42, the transduction sequence of TAT. Then, the fusion protein P42-TAT was vectorised in microemulsion, in order to enhance the delivery of the peptide to the brain by resorting to a non-invasive administration way. This original protocol exhibited highly-significant rescues on behavioural, histological and molecular R6/2 phenotypes..Over the therapeutic aspect, P42 also represents an important region of Huntingtin. The study of this site led to a better understanding of Huntingtin physiological function. Biochemestrial experiments underlined the binding of Htt N-terminus on microtubules networks. This interaction depends on a range of complex processes (dimerization, cleavage) and suggests that the Huntingtin belongs to the family of Structual MAPs.In summary, the identification of P42 enhances the knowledge about Huntingtin function, and opens a new promising therapeutical avenue for HD.

Este trabalho teve como objetivo analisar os efeitos comportamentais e morfológicos da exposição ao campo magnético contínuo em um modelo experimental de doença de Huntington. Foram utilizados 68 ratos Wistar, machos, divididos em 6 grupos: GC (controle, n=12), GS (sham, n=12), GSM (sham magnético, n=8), GL (lesão, n=12), GEPS (polo sul, n=12) e GEPN (polo norte, n=12). O animais passaram por habituação ao Rota Rod durante 3 dias pré-cirúrgicos e por habituação ao monitor de atividade 24 horas antes da cirurgia. Após procedimentos cirúrgicos adequados, os GL, GEPS e GEPN receberam administração de ácido quinolínico (120nmol/2L) no núcleo estriado esquerdo. Os GS e GSM receberam administração de 2L de salina na mesma região. Ainda, nos GEPS e GEPN foi implantado no crânio de cada animal um magneto circular de neodímio (8x3mm) com potência de 3200 Gauss e no GSM foi realizado implante do mesmo material, sem estar magnetizado. No 7º dia pós-cirúrgico, os animais foram avaliados em relação à atividade motora espontânea no monitor de atividades, após 5 minutos da injeção subcutânea de apomorfina (2,5 mg/Kg), sendo que os animais do GC não receberam esta injeção, e atividade motora forçada no Rota Rod. Posteriormente aos experimentos os animais foram perfundidos e os encéfalos retirados para histologia. Os resultados da avaliação comportamental espontânea evidenciaram, para o comportamento de distância percorrida, um aumento significativo do GEPS em relação aos GC, GL e GEPN, e também do GSM e GS em relação ao GC, GL e GEPN. Observamos também uma diminuição significativa do GEPN em relação aos GS, GSM, GL e GEPS [F(5,62) = 3,19; p0,05]. Para o tempo de atividade, um aumento significativo do GEPS em relação aos GC e GEPN, e também do GSM e GS em relação ao GC, GL e GEPN. Observamos também uma diminuição significativa do GEPN em relação aos GS, GSM, GL e GEPS [F(5,62) = 5,46; p0,05]. Para o comportamento de cruzamentos, um aumento significativo do GEPS em relação aos GC e GEPN e também do GSM e GS em relação ao GC, GL e GEPN. Observamos também uma diminuição significativa do GEPN em relação aos GS, GSM, GL, e GEPS [F(5,62) = 3,31; p0,05]. E para o comportamento de giros anti-horários (ipsilaterais a lesão) um aumento significativo dos GL, GEPS e GEPN em relação aos GC, GS e GSM. Observamos também uma diminuição significativa dos GEPN e GEPS em relação ao GL e ainda uma diminuição do GEPN em relação ao GEPS [F(5,62) = 16,01; p0,05]. Os resultados referentes ao Rota Rod (atividade motora forçada) revelaram diminuição significativa do tempo de permanência no aparato do GL em relação aos demais GC, GS, GSM, GEPS e GEPN [(F(5,62) = 5,46; p0,05)]. A análise histológica revelou uma perda significativa de neurônios no núcleo estriado esquerdo do GL em relação aos demais GC, GS, GSM, GEPS e GEPN [(F(5,66) = 5,13; p0,05)]. Dessa forma, os resultados obtidos sugerem que a estimulação magnética exerce efeito neuroprotetor, com reversão das alterações comportamentais e morfológicas promovidas pelo ácido quinolínico. / The aim of this study was to analyze the behavioral and morphologic effects of the static magnetic field exposition in an animal model of Huntingtons disease. Sixty- eight male Wistar rats were used, placed in 6 groups: GC (control group, n=12), GS (sham group, n=12), GSM (sham magnetic group, n=8), GL (lesion group, n=12), GEPS (south pole stimulated group, n=12) and GEPN (north pole stimulated group, n=12). The animals passed through habituation to Rota Rod, during the 3 days pre-surgical, and to habituation to the activity monitor, 24 hours before surgery. After appropriate surgical procedures GL, GEPS and GEPN received administration of quinolinic acid (120nmol/ 2L) in the left striatum. The GS and GSM received administration of 2L of saline in the same region. Also, in GEPS and GEPN was implanted, on the skull of each animal, a circular neodymium magnet (8x3mm) with a power of 3200 gauss, the GSM was performed the implant of the same material, without being magnetized. On the seventh after surgery day, the animals were evaluated referring to spontaneous motor activity in the activity monitor, 5 minutes after subcutaneous injection of apomorphine (2.5 mg / kg), whereas the animals of the CG did not receive this injection, and forced motor activity in Rota Rod. Subsequently the experiments the animals were perfused and their brains removed for histology. The results showed to spontaneous behavioral assessment, related to the behavior of distance travelled, significant increase in GEPS compared to GC, GL e GEPN, and also in GSM and GS compared to GC, GL, and GEPN, and a decrease in GEPN compared to GC, GS, GSM, GL e GEPS [F (5,62) = 3.19, p 0.05]; for time of activity, a significant increase in GEPS compared to GC and GEPN, and also in GSM and GS compared to GC, GL and GEPN, and a decrease in GEPN compared to GS, GSM, GL e GEPS [F (5,62) = 5.46, p 0.05]; for the behavior of crossings, a significant increase in GEPS compared to GC and GEPN, and also in GSM and GS compared to GC, GL and GEPN, and a decrease in GEPN compared to GS, GSM, GL, e GEPS [F (5,62) = 3.31, p 0.05]; and to the behavior of anti hourly rotations, significant increase in GL, GEPS and GEPN compared to GC, GS, GSM, significant decrease in GEPN and GEPS compared to GL and also a decrease in GEPN compared to GEPS [F (5 , 62) = 16.01, p 0.05]. The results for the Rota Rod indicated a significant decrease in the permanency time on apparatus to GL compared to GC, GS, GSM, GEPS and GEPN [(F (5, 62) = 5.46, p 0.05)]. The histological analysis revealed a significant reduction in the number of neurons in the animals of GL compared to the others groups [F (5, 66) = 5, 13, p 0.05]. Therefore, the results suggest that magnetic stimulation exerts neuroprotective effect, with reversal of behavioral and morphological changes caused by quinolinic acid.

La maladie de Huntington (MH) est une maladie neurodégénérative héréditaire, incurable.Elle est due à une mutation dans le gène HD codant l'huntingtine (htt). Cette mutation setraduit dans la protéine par une augmentation de l'expansion polyglutamine (polyGln) qui larend toxique. Bien que la htt soit ubiquitaire dans le système nerveux central, ladégénérescence touche préférentiellement le striatum. Un patron d'expression de gènesspécifiques du striatum pourrait expliquer cette vulnérabilité préférentielle. Nous avons étudiéles effets "modificateurs" de 5 gènes préférentiellement exprimés dans le striatum vis-à-visde la toxicité de la htt mutée par une approche lentivirale chez la souris. Nous avonscaractérisé les effets de ces marqueurs striataux sur la toxicité induite par la htt mutée pardifférentes approches histologiques. Les "modificateurs" de la MH ont été étudiés plus endétail. Nous avons examiné leur localisation et les mécanismes sous-jacents à leurs effetsneuroprotecteurs. Outre une meilleure compréhension du striatum, cette étude a permis ladécouverte de candidat neuroprotecteur qui pourrait permettre de développer de nouvellesthérapies. / Huntington's disease (HD) is an incurable inherited neurodegenerative disease. HD iscaused by a mutation in the HD gene coding huntingtin (htt). This mutation leads to anexpanded polyglutamine tract (polyQ) in the protein which is toxic to neurons. Although thehtt is ubiquitously expressed in the central nervous system, the first area which degeneratesis the striatum. A pattern of genes selectively expressed into the striatum may confer itsvulnerability to mutated htt. We have studied the modifying effects of five newly identifiedstriatal markers against the toxicity induced by mutated htt using lentiviral strategy in miceand histological approaches. For one of these markers, Double Cortin Kinase Like 3(DCLK3), we have further determined their cellular localization and the potential mechanismsunderlying their neuroprotector effects. The present work led to a better understanding of thefunction of the newly identified markers in the striatum and their potential roles in thepreferential vulnerability of the striatum in HD.

Rather than designing focused experiments to test individual hypotheses, scientists now commonly acquire measurements using massively parallel techniques, for post hoc interrogation. The resulting data is both high-dimensional and structured, in that observed variables are grouped and ordered into related subspaces, reflecting both natural physical organization and factorial experimental designs. Such structure encodes critical constraints and clues to interpretation, but typical unsupervised learning methods assume exchangeability and fail to account adequately for the structure of data in a flexible and interpretable way. In this thesis, I develop computational methods for exploratory analysis of structured high-dimensional data, and apply them to study gene expression regulation in Parkinson’s (PD) and Huntington’s diseases (HD). BOMBASTIC (Block-Organized, Model-Based, Tree-Indexed Clustering) is a methodology to cluster and visualize data organized in pre-specified subspaces, by combining independent clusterings of blocks into hierarchies. BOMBASTIC provides a formal specification of the block-clustering problem and a modular implementation that facilitates integration, visualization, and comparison of diverse datasets and rapid exploration of alternative analyses. These tools, along with standard methods, were applied to study gene expression in mouse models of neurodegenerative diseases, in collaboration with Dr. Myriam Heiman and Dr. Robert Fenster. In PD, I analyzed cell-type-specific expression following levodopa treatment to study mechanisms underlying levodopa-induced dyskinesia (LID). I identified likely regulators of the transcriptional changes leading to LID and implicated signaling pathways amenable to pharmacological modulation (Heiman, Heilbut et al, 2014). In HD, I analyzed multiple mouse models (Kuhn, 2007), cell-type specific profiles of medium spiny neurons (Fenster, 2011), and an RNA-Seq dataset profiling multiple tissue types over time and across an mHTT allelic series (CHDI, 2015). I found evidence suggesting that altered activity of the PRC2 complex significantly contributes to the transcriptional dysregulation observed in striatal neurons in HD.

This dissertation studies prediction and classification models for disease risk through semiparametric modeling and statistical learning. It consists of three parts. In the first part, we propose several survival models to analyze the Cooperative Huntington's Observational Research Trial (COHORT) study data accounting for the missing mutation status in relative participants (Kieburtz and Huntington Study Group, 1996a). Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expansion of cytosine-adenine-guanine (CAG) repeats at the IT15 gene. A CAG repeat number greater than or equal to 36 is defined as carrying the mutation and carriers will eventually show symptoms if not censored by other events. There is an inverse relationship between the age-at-onset of HD and the CAG repeat length; the greater the CAG expansion, the earlier the age-at-onset. Accurate estimation of age-at-onset based on CAG repeat length is important for genetic counseling and the design of clinical trials for HD. Participants in COHORT (denoted as probands) undergo a genetic test and their CAG repeat number is determined. Family members of the probands do not undergo the genetic test and their HD onset information is provided by probands. Several methods are proposed in the literature to model the age specific cumulative distribution function (CDF) of HD onset as a function of the CAG repeat length. However, none of the existing methods can be directly used to analyze COHORT proband and family data because family members' mutation status is not always known. In this work, we treat the presence or absence of an expanded CAG repeat in first-degree family members as missing data and use the expectation-maximization (EM) algorithm to carry out the maximum likelihood estimation of the COHORT proband and family data jointly. We perform simulation studies to examine finite sample performance of the proposed methods and apply these methods to estimate the CDF of HD age-at-onset from the COHORT proband and family combined data. Our results show a slightly lower estimated cumulative risk of HD with the combined data compared to using proband data alone. We then extend the approach to predict the cumulative risk of disease accommodating predictors with time-varying effects and outcomes subject to censoring. We model the time-specific effect through a nonparametric varying-coefficient function and handle censoring through self-consistency equations that redistribute the probability mass of censored outcomes to the right. The computational procedure is extremely convenient and can be implemented by standard software. We prove large sample properties of the proposed estimator and evaluate its finite sample performance through simulation studies. We apply the method to estimate the cumulative risk of developing HD from the mutation carriers in COHORT data and illustrate an inverse relationship between the cumulative risk of HD and the length of CAG repeats at the IT15 gene. In the second part of the dissertation, we develop methods to accurately predict whether pre-symptomatic individuals are at risk of a disease based on their various marker profiles, which offers an opportunity for early intervention well before definitive clinical diagnosis. For many diseases, existing clinical literature may suggest the risk of disease varies with some markers of biological and etiological importance, for example age. To identify effective prediction rules using nonparametric decision functions, standard statistical learning approaches treat markers with clear biological importance (e.g., age) and other markers without prior knowledge on disease etiology interchangeably as input variables. Therefore, these approaches may be inadequate in singling out and preserving the effects from the biologically important variables, especially in the presence of potential noise markers. Using age as an example of a salient marker to receive special care in the analysis, we propose a local smoothing large margin classifier implemented with support vector machine to construct effective age-dependent classification rules. The method adaptively adjusts age effect and separately tunes age and other markers to achieve optimal performance. We derive the asymptotic risk bound of the local smoothing support vector machine, and perform extensive simulation studies to compare with standard approaches. We apply the proposed method to two studies of premanifest HD subjects and controls to construct age-sensitive predictive scores for the risk of HD and risk of receiving HD diagnosis during the study period. In the third part of the dissertation, we develop a novel statistical learning method for longitudinal data. Predicting disease risk and progression is one of the main goals in many clinical studies. Cohort studies on the natural history and etiology of chronic diseases span years and data are collected at multiple visits. Although kernel-based statistical learning methods are proven to be powerful for a wide range of disease prediction problems, these methods are only well studied for independent data but not for longitudinal data. It is thus important to develop time-sensitive prediction rules that make use of the longitudinal nature of the data. We develop a statistical learning method for longitudinal data by introducing subject-specific long-term and short-term latent effects through designed kernels to account for within-subject correlation of longitudinal measurements. Since the presence of multiple sources of data is increasingly common, we embed our method in a multiple kernel learning framework and propose a regularized multiple kernel statistical learning with random effects to construct effective nonparametric prediction rules. Our method allows easy integration of various heterogeneous data sources and takes advantage of correlation among longitudinal measures to increase prediction power. We use different kernels for each data source taking advantage of distinctive feature of data modality, and then optimally combine data across modalities. We apply the developed methods to two large epidemiological studies, one on Huntington's disease and the other on Alzhemeier's Disease (Alzhemeier's Disease Neuroimaging Initiative, ADNI) where we explore a unique opportunity to combine imaging and genetic data to predict the conversion from mild cognitive impairment to dementia, and show a substantial gain in performance while accounting for the longitudinal feature of data.

A dissertation submitted to the Faculty of Engineering and the Built Environment, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science in Engineering. Johannesburg, 2017 / This study presents the development of a potentially new biomarker for three different movement disorders: Huntington’s Disease (HD), Parkinson’s Disease (PD) and Essential Tremors (ET). A Leap Motion® gaming device was used to record the trajectories of subjects’ forefinger as they trace simple patterns in the air. The patterns used were stepfunction, triangle and circle. The recorded signals were analysed using transform functions and Fourier analysis. Both analysis types yielded features from which differences between the four categories studied: PD, HD, ET and control subjects, were sought and displayed in both graphical and numerical forms. The X-axis and Y-axis of the signals were separately analysed and yielded different results. For the step-function pattern, no distinct differences between the four categories were found from the transfer function analysis whereas the Y-axis of the signal could distinguish between the categories. For the triangle pattern, the X-axis features provided a discrimination between the categories while the Y-axis feature did not. For the circle pattern, neither X-axis nor Y-axis features were able to distinguish between the categories. A Fourier analysis showed a better discrimination ability for both X- and Y- axis. This study is a preliminary one and all results indicate that more subjects of all categories are needed to develop a bio-marker for the diseases studied and that a higher order transfer function analysis is required. However, the methodology outlined in this work, comprising of both the experimental system and the analysis showed a potential to produce a biomarker for movement disorders. / MT2018

The logistical complexities of performing multi-site longitudinal diffusion-weighted imaging (DWI) studies requires careful construction of analysis tools and procedures. Proposed clinical trials for therapies in neurodegenerative disease are known to re- quire several hundred subjects, thus mandating multiple site participation to obtain sufficient sample sizes. DWI is an important tool for monitoring diffusivity properties of white matter (WM) in disease progression. The multi-site nature of clinical trials requires new strategies in DWI processing and analysis to reliably measure longitudi- nal WM changes. This work describes the process of developing and validating robust analysis methodologies to process multi-site DWI data in a rare, neurodegenerative disease. Key processing components to accomplish a robust DWI processing system include: DICOM conversion, automated quality control, unbiased atlas construction, fiber tracking, and statistical analysis. Extensive validation studies were performed to characterize methodological results within and across the common confounds inherent in multi-site clinical trials. The conversion and automated quality control tools optimized for this work both enhanced the ability to reliably obtain repeat diffusion tensor image (DTI) scalar measurements in a reliability analysis of healthy controls scanned at multiple sites using multiple scanner vendors. A DTI scalar analysis performed on focused WM regions showed it was possible to detect significant mean differences of DTI scalars among separate groups of a neurodegenerative disease population. The DTI scalar analysis paved the way for an atlas-based cross-sectional fiber tracking analysis. In the cross-sectional fiber tracking analysis, multi-site data was brought into the same space, making major fiber tracts terminating in the focused WM regions of the scalar analysis from all participants comparable. Significant differences in diffusivity were found throughout each tract among separate groups of the neurodegenerative disease population. In addition, multiple neuropsychological cognitive variables that have a documented ability to track disease progression of the neurodegenerative disease, strongly correlated with many of the DTI scalars in each tract. The findings of the cross-sectional fiber tracking analysis were reinforced by similar findings produced by a longitudinal fiber tracking analysis. Collectively, these findings suggest that cogni- tive deficits seen in the neurodegenerative disease population could be explained by changes in diffusivity of the tracts explored in this work. In addition to the longi- tudinal fiber tracking analysis examining diffusivity, methods for a WM morphology analysis using parallel transport to apply longitudinal volume changes to a template was explored.