D20 Operationalising compensation over time in neurodegenerative disease

Compensation is a concept that has been introduced in neurodegeneration to account for the common observation that macroscopic neurodegeneration is frequently evident in brain imaging many years prior to symptom onset with little or no deterioration in behaviour. It is proposed that this dissociation between brain pathology and normal behaviour early in neurodegenerative disease reflects some kind of neuronal compensation. However, models of compensation are often conceptual and not operationalised in a form that readily permits them to be tested. Recent reviews have proposed that to characterise compensation fully three different components and their relationship should be considered: brain activity, behaviour and pathology. We have previously devised an operational model of compensation that focusses on the relationship between brain activity and behaviour as a function of structural measures of disease load and successfully applied this to cross-sectional functional and structural imaging data obtained from the preclinical TrackOn-HD cohort.1 However, we postulate that compensatory behaviours in response to brain disease will change differentially over time, dependent on changes in neuronal pathology and existing motor and cognitive deficits. In such a situation, investigation of compensation at a single time point will not provide an adequate characterisation of compensation. We now extend our cross-sectional models to account for the longitudinal change characteristic of neurodegeneration and examine the theoretical and conceptual underpinnings. We consider two approaches to measuring longitudinal compensation. First, estimation of average compensation over time accounting for dependence due to repeated measures and second, estimation of change in compensation over time. Reference Kloppel S, Gregory S. Compensation in preclinical Huntington’s disease: evidence from the Track-On HD study. E Bio Medicine 2015