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Testing a longitudinal compensation model in premanifest Huntington's disease
Gregory, Sarah Long, Jeffrey D. Klöppel, Stefan Razi, Adeel Scheller, Elisa Minkova, Lora Johnson, Eileanoir B. Durr, Alexandra Roos, Raymund A. C. Leavitt, Blair R.
Gregory, Sarah
Long, Jeffrey D.
Klöppel, Stefan
Razi, Adeel
Scheller, Elisa
Minkova, Lora
Johnson, Eileanoir B.
Durr, Alexandra
Roos, Raymund A. C.
Leavitt, Blair R.
Author
Abstract
The initial stages of neurodegeneration are commonly marked by normal levels of cognitive and motor performance despite the presence of structural brain pathology. Compensation is widely assumed to account for this preserved behaviour, but despite the apparent simplicity of such a concept, it has proven incredibly difficult to demonstrate such a phenomenon and distinguish it from disease-related pathology. Recently, we developed a model of compensation whereby brain activation, behaviour and pathology, components key to understanding compensation, have specific longitudinal trajectories over three phases of progression. Here, we empirically validate our explicit mathematical model by testing for the presence of compensation over time in neurodegeneration. Huntington’s disease is an ideal model for examining longitudinal compensation in neurodegeneration as it is both monogenic and fully penetrant, so disease progression and potential compensation can be monitored many years prior to diagnosis. We defined our conditions for compensation as non-linear longitudinal trajectories of brain activity and performance in the presence of linear neuronal degeneration and applied our model of compensation to a large longitudinal cohort of premanifest and early-stage Huntington’s disease patients from the multisite Track-On HD study. Focusing on cognitive and motor networks, we integrated progressive volume loss, task and resting state functional MRI and cognitive and motor behaviour across three sequential phases of neurodegenerative disease progression, adjusted for genetic disease load. Multivariate linear mixed models were fitted and trajectories for each variable tested. Our conceptualization of compensation was partially realized across certain motor and cognitive networks at differing levels. We found several significant network trends that were more complex than that hypothesized in our model. These trends suggest changes to our theoretical model where the network effects are delayed relative to performance effects. There was evidence of compensation primarily in the prefrontal component of the cognitive network, with increased effective connectivity between the left and right dorsolateral prefrontal cortex. Having developed an operational model for the explicit testing of longitudinal compensation in neurodegeneration, it appears that general patterns of our framework are consistent with the empirical data. With the proposed modifications, our operational model of compensation can be used to test for both cross-sectional and longitudinal compensation in neurodegenerative disease with similar patterns to Huntington’s disease.
Keywords
compensation, neurodegeneration, Huntington’s disease, functional MRI
Date
2018
Type
Journal article
Journal
Brain
Book
Volume
141
Issue
7
Page Range
2156-2166
Article Number
ACU Department
School of Behavioural and Health Sciences
Faculty of Health Sciences
Faculty of Health Sciences
Relation URI
Source URL
Event URL
Open Access Status
Published as ‘gold’ (paid) open access
License
CC BY 4.0
File Access
Open
Notes
Izelle Labuschagne is a member of the Track-On investigators.