Revealing the Timeline of Structural MRI Changes in Premanifest to Manifest Huntington Disease
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Abstract
Background and Objectives Longitudinal measurements of brain atrophy using structural MRI (sMRI) can provide powerful markers for tracking disease progression in neurodegenerative diseases. In this study, we use a disease progression model to learn individual-level disease times and hence reveal a new timeline of sMRI changes in Huntington disease (HD).
Methods We use data from the 2 largest cohort imaging studies in HD—284 participants from TRACK-HD (100 control, 104 premanifest, and 80 manifest) and 159 participants from PREDICT-HD (36 control and 128 premanifest)—to train and test the model. We longitudinally register T1-weighted sMRI scans from 3 consecutive time points to reduce intraindividual variability and calculate regional brain volumes using an automated segmentation tool with rigorous manual quality control.
Results Our model reveals, for the first time, the relative magnitude and timescale of subcortical and cortical atrophy changes in HD. We find that the largest (∼20% average change in magnitude) and earliest (∼2 years before average abnormality) changes occur in the subcortex (pallidum, putamen, and caudate), followed by a cascade of changes across other subcortical and cortical regions over a period of ∼11 years. We also show that sMRI, when combined with our disease progression model, provides improved prediction of onset over the current best method (root mean square error = 4.5 years and maximum error = 7.9 years vs root mean square error = 6.6 years and maximum error = 18.2 years).
Discussion Our findings support the use of disease progression modeling to reveal new information from sMRI, which can potentially inform imaging marker selection for clinical trials.
Glossary
- AD=
- Alzheimer disease;
- CAG=
- cytosine-adenine-guanine;
- DCM=
- dynamic causal model;
- EBM=
- event-based model;
- GP=
- Gaussian process;
- GPPM=
- GP progression model;
- HC=
- healthy control;
- HD=
- Huntington disease;
- PreHD=
- premanifest HD;
- SDMT=
- Symbol Digit Modalities Test;
- SM=
- survival model;
- sMRI=
- structural MRI;
- SWRT=
- Stroop Word Reading Test;
- TMS=
- Total Motor Score
Footnotes
↵* These authors are co–senior authors.
Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by the MRC and Wellcome Trust.
PREDICT-HD and TRACK-HD coinvestigators are listed in Appendix 2 at links.lww.com/NXG/A473.
- Received April 7, 2021.
- Accepted in final form July 6, 2021.
- Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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