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Whole-brain Segmentation and Change-point Analysis of Anatomical Brain MRI—Application in Premanifest Huntington's Disease
Published on: June 9, 2018
Overlap between age-at-onset and disease-progression determinants in Huntington disease
N Ahmad Aziz1, Jorien M M van der Burg2, Sarah J Tabrizi2
1From the Department of Neurodegenerative Disease (N.A.A., S.J.T.), UCL Huntington's Disease Centre, University College London Institute of Neurology, UK; Departments of Neurology (N.A.A.) and Public Health and Primary Care (J.M.M.v.d.B.), Leiden University Medical Centre, the Netherlands; Department of Population Health Sciences (N.A.A.), German Center for Neurodegenerative Diseases (DZNE), Bonn; and Department of Neurology (G.B.L.), Ulm University Hospital, Germany. Ahmad.Aziz@dzne.de N.A.Aziz@lumc.nl.
Insights
In Huntington disease (HD), the same factors largely influence both disease onset and progression, particularly CAG repeat length. However, weight loss progression is independent of these factors.
Area of Science:
- Neuroscience
- Genetics
- Clinical Neurology
Background:
- Huntington disease (HD) pathogenesis remains incompletely understood, particularly concerning the determinants of disease onset versus progression.
- Clarifying these determinants is critical for developing and timing effective disease-modifying therapies for HD.
Purpose of the Study:
- To assess the overlap between factors influencing age at onset and disease progression in Huntington disease.
- To quantify the variability in disease progression rates using a novel method.
Main Methods:
- Utilized observational data from Enroll-HD, the world's largest Huntington disease patient cohort.
- Employed linear mixed-effect models to quantify disease progression variability.
- Included 3,411 patients meeting inclusion criteria.
Main Results:
- Identified that approximately two-thirds of functional, motor, and cognitive progression rates are governed by the same factors determining age at onset, with CAG repeat expansion being a major driver.
- Observed that while expanded HTT CAG repeat size impacts body weight, the rate of weight loss is largely independent of age-at-onset determinants.
- Found that one-third of factors influencing functional, motor, and cognitive progression rates differ from those dictating age at onset, requiring further investigation.
Conclusions:
- Targeting CAG repeat-dependent mechanisms, such as gene silencing, is expected to influence functional, motor, and cognitive decline in Huntington disease.
- Weight loss progression in manifest HD mutation carriers appears to be regulated by distinct factors unrelated to age at onset determinants.
Objective:
A fundamental but still unresolved issue regarding Huntington disease (HD) pathogenesis is whether the factors that determine age at onset are the same as those that govern disease progression. Because elucidation of this issue is crucial for the development as well as optimal timing of administration of novel disease-modifying therapies, we aimed to assess the extent of overlap between age-at-onset and disease-progression determinants in HD.
Methods:
Using observational data from Enroll-HD, the largest cohort of patients with HD worldwide, in this study we present, validate, and apply an intuitive method based on linear mixed-effect models to quantify the variability in the rate of disease progression in HD.
Results:
A total of 3,411 patients with HD met inclusion criteria. We found that (1) about two-thirds of the rate of functional, motor, and cognitive progression in HD is determined by the same factors that also determine age at onset, with CAG repeat-dependent mechanisms having by far the largest effect; (2) although expanded HTT CAG repeat size had a large influence on average body weight, the rate of weight loss was largely independent of factors that determine age at onset in HD; and (3) about one-third of the factors that determine the rate of functional, motor, and cognitive progression are different from those that govern age at onset and need further elucidation.
Conclusion:
Our findings imply that targeting of CAG repeat-dependent mechanisms, for example through gene-silencing approaches, is likely to affect the rate of functional, motor, and cognitive impairment, but not weight loss, in manifest HD mutation carriers.
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