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.
Highlights
Compensation is presumed to account for preserved behaviour in neurodegeneration during the initial stages of disease
Our model integrated progressive brain volume loss, task and resting state functional MRI derived markers of compensation, and cognitive and motor behaviour to test for the presence of compensation across three sequential phases of neurodegenerative disease progression
We hypothesized that compensation would be evidenced by linear decline in brain volume, but a non-linear concavedown pattern of both brain activity and behaviour, with brain activity eventually declining at a slower rate and maintaining normal behaviour
Summary
Compensation is presumed to account for preserved behaviour in neurodegeneration during the initial stages of disease. It is unclear to what extent reported changes in brain activity represent compensation or reflect the deleterious effect of disease-related pathology The lack of both a well-defined characterization of compensation and a corresponding model for empirical investigation has resulted in only a partial understanding of the nature of compensation in neurodegeneration. Assuming that structural disease load increases steadily throughout, our model proposes that during the earliest phase, constant performance is maintained by increased brain activation; in the second phase, brain activation decreases as performance levels begin to deteriorate; and in the final stage, both brain activation and performance levels decrease rapidly, similar to brain volume This verbal description is operationalized through statistical models, and evidence of compensation for a particular dataset is evaluated with parameter estimates and statistical tests
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