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Modeling Variability in the Progression of Huntington's Disease A Novel Modeling Approach Applied to Structural Imaging Markers from TRACK-HD.

ABSTRACT: We present a novel, general class of disease progression models for Huntington's disease (HD), a neurodegenerative disease caused by a cytosine-adenine-guanine (CAG) triplet repeat expansion on the huntingtin gene. Models are fit to a selection of structural imaging markers from the TRACK 36-month database. The models are of mixed effects type and should be useful in predicting any continuous marker of HD state as a function of age and CAG length (the genetic factor that drives HD pathology). The effects of age and CAG length are modeled using flexible regression splines. Variability not accounted for by age, CAG length, or covariates is modeled using terms that represent measurement error, population variability (random slopes/intercepts), and variability due to the dynamics of the disease process (random walk terms). A Kalman filter is used to estimate variances of the random walk terms.

SUBMITTER: Warner JH

PROVIDER: S-EPMC4999607 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Modeling Variability in the Progression of Huntington's Disease A Novel Modeling Approach Applied to Structural Imaging Markers from TRACK-HD.

Warner J H JH Sampaio C C

CPT: pharmacometrics & systems pharmacology 20160802 8

We present a novel, general class of disease progression models for Huntington's disease (HD), a neurodegenerative disease caused by a cytosine-adenine-guanine (CAG) triplet repeat expansion on the huntingtin gene. Models are fit to a selection of structural imaging markers from the TRACK 36-month database. The models are of mixed effects type and should be useful in predicting any continuous marker of HD state as a function of age and CAG length (the genetic factor that drives HD pathology). Th ...[more]

PMID: 27481337

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Project description:IntroductionStrong evidence suggests a significant role for iron accumulation in the brain in addition to the well-documented neurodegenerative aspects of Huntington's disease (HD). The putative mechanisms by which iron is linked to the HD pathogenesis are multiple, including oxidative stress, ferroptosis and neuroinflammation. However, no previous study in a neurodegenerative disease has linked the observed increase of brain iron accumulation as measured by MRI with well-established cerebrospinal fluid (CSF) and blood biomarkers for iron accumulation, or with associated processes such as neuroinflammation. This study is designed to link quantitative data from iron levels and neuroinflammation metabolites obtained from 7T MRI of HD patients, with specific and well-known clinical biofluid markers for iron accumulation, neurodegeneration and neuroinflammation. Biofluid markers will provide quantitative measures of overall iron accumulation, neurodegeneration and neuroinflammation, while MRI measurements on the other hand will provide quantitative spatial information on brain pathology, neuroinflammation and brain iron accumulation, which will be linked to clinical outcome measures.MethodsThis is an observational cross-sectional study, IMAGINE-HD, in HD gene expansion carriers and healthy controls. We include premanifest HD gene expansion carriers and patients with manifest HD in an early or moderate stage. The study includes a 7T MRI scan of the brain, clinical evaluation, motor, functional, and neuropsychological assessments, and sampling of CSF and blood for the detection of iron, neurodegenerative and inflammatory markers. Quantitative Susceptibility Maps will be reconstructed using T2* weighted images to quantify brain iron levels and Magnetic Resonance Spectroscopy will be used to obtain information about neuroinflammation by measuring cell-specific intracellular metabolites' level and diffusion. Age and sex matched healthy subjects are included as a control group.DiscussionResults from this study will provide an important basis for the evaluation of brain iron levels and neuroinflammation metabolites as an imaging biomarker for disease stage in HD and their relationship with the salient pathomechanisms of the disease on the one hand, and with clinical outcome on the other.

Dataset Information

Modeling Variability in the Progression of Huntington's Disease A Novel Modeling Approach Applied to Structural Imaging Markers from TRACK-HD.

Publications

Modeling Variability in the Progression of Huntington's Disease A Novel Modeling Approach Applied to Structural Imaging Markers from TRACK-HD.

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