Journal article
Compensation in Preclinical Huntington's Disease: Evidence From the Track-On HD Study
EBioMedicine, Vol.2(10), pp.1420-1429
10/2015
DOI: 10.1016/j.ebiom.2015.08.002
PMCID: PMC4634199
PMID: 26629536
Abstract
Cognitive and motor task performance in premanifest Huntington's disease (HD) gene-carriers is often within normal ranges prior to clinical diagnosis, despite loss of brain volume in regions involved in these tasks. This indicates ongoing compensation, with the brain maintaining function in the presence of neuronal loss. However, thus far, compensatory processes in HD have not been modeled explicitly. Using a new model, which incorporates individual variability related to structural change and behavior, we sought to identify functional correlates of compensation in premanifest-HD gene-carriers.
We investigated the modulatory effects of regional brain atrophy, indexed by structural measures of disease load, on the relationship between performance and brain activity (or connectivity) using task-based and resting-state functional MRI.
Consistent with compensation, as atrophy increased performance-related activity increased in the right parietal cortex during a working memory task. Similarly, increased functional coupling between the right dorsolateral prefrontal cortex and a left hemisphere network in the resting-state predicted better cognitive performance as atrophy increased. Such patterns were not detectable for the left hemisphere or for motor tasks.
Our findings provide evidence for active compensatory processes in premanifest-HD for cognitive demands and suggest a higher vulnerability of the left hemisphere to the effects of regional atrophy.
•Huntington's disease (HD) is an ideal model for studying the earliest stages of neurodegeneration.•Pre-clinical HD gene-carriers maintain normal behavior across motor and cognitive domains despite neuronal degeneration.•We characterized neural compensation using functional MRI in combination with measures of disease load and task performance.•Evidence of hemisphere-specific compensation provides potential targets for future therapeutic trials in neurodegeneration.
We have developed a model which characterizes compensation in preclinical HD using functional MRI, volumetric disease load and task performance. By explicitly testing the relationship between cognitive performance and brain activity or connectivity, we have demonstrated that those closest to clinical diagnosis experience functional deterioration within the left hemisphere of the brain and localized compensation in the right. This pattern provides potential targets for future testing of HD modifying agents. Furthermore, HD acts as a model for studying the earliest stages of neurodegeneration and this new model of compensation can potentially be extended to other neurodegenerative diseases.
Details
- Title: Subtitle
- Compensation in Preclinical Huntington's Disease: Evidence From the Track-On HD Study
- Creators
- Sarah Gregory - Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, UKElisa Scheller - Albert-Ludwigs-University Freiburg, University Medical Center, Division Freiburg Brain Imaging, Freiburg, GermanyLora Minkova - Albert-Ludwigs-University Freiburg, University Medical Center, Division Freiburg Brain Imaging, Freiburg, GermanyAdeel Razi - Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, UKAlexandra Durr - APHP Department of Genetics, Groupe Hospitalier Pitié-Salpêtrière, UPMC Université Paris VI UMR_S1127, Paris FranceRaymund A.C Roos - Leiden University Medical Center, Department of Neurology, Leiden, The NetherlandsBlair R Leavitt - Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, CanadaMarina Papoutsi - Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UKG. Bernhard Landwehrmeyer - Department of Neurology, Ulm University, Ulm, GermanyRalf Reilmann - George-Huntington-Institute, Muenster, GermanyBeth Borowsky - CHDI Management/CHDI Foundation, Princeton, NJ, USAHans Johnson - Department of Electrical and Computer Engineering, University of Iowa, Iowa City, IA, USAJames A Mills - Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USAGail Owen - Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UKJulie Stout - School of Psychological Sciences and Institute of Clinical and Cognitive Neuroscience, Monash University, Melbourne, AustraliaRachael I Scahill - Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UKJeffrey D Long - Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USAGeraint Rees - Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, UKSarah J Tabrizi - Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UKTrack-On investigators
- Resource Type
- Journal article
- Publication Details
- EBioMedicine, Vol.2(10), pp.1420-1429
- DOI
- 10.1016/j.ebiom.2015.08.002
- PMID
- 26629536
- PMCID
- PMC4634199
- NLM abbreviation
- EBioMedicine
- ISSN
- 2352-3964
- eISSN
- 2352-3964
- Publisher
- Elsevier B.V
- Language
- English
- Date published
- 10/2015
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Psychiatry; Biostatistics; The Iowa Institute for Biomedical Imaging; The Iowa Initiative for Artificial Intelligence; Iowa Informatics Initiative
- Record Identifier
- 9984221630102771
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