Abstract
Functional compensation demonstrated as mechanism to offset neuronal loss in early Alzheimer disease may also occur in other adult-onset neurodegenerative diseases, particularly Huntington disease (HD) with its genetic determination and gradual changes in structural integrity. In HD, neurodegeneration typically initiates in the dorsal striatum, successively affecting ventral striatal areas. Investigating carriers of the HD mutation with evident dorsal, but only minimal or no ventral striatal atrophy, we expected to find evidence for compensation of ventral striatal functioning. We investigated 14 pre- or early symptomatic carriers of the mutation leading to HD and 18 matched healthy controls. Participants underwent structural T1 magnetic resonance imaging (MRI) and functional MRI during a reward task that probes ventral striatal functioning. Motor functioning and attention were assessed with reaction time (RT) tasks. Structural images confirmed a specific decrease of dorsal striatal but only marginal ventral striatal volume in HD relative to control subjects, paralleling prolonged RT in the motor response tasks. While behavioral performance in the reward task during fMRI scanning was unimpaired, reward-related fMRI signaling in the HD group was differentially enhanced in the bilateral ventral striatum and in bilateral orbitofrontal cortex/anterior insula, as another region sensitive to reward processing. We provide evidence for the concept of functional compensation in premanifest HD which may suggest a defense mechanism in neurodegeneration. Given the so far inevitable course of HD with its genetically determined endpoint, this disease may provide another model to study the different aspects of the concept of functional compensation.
Highlights
Adult-onset neurodegenerative diseases are supposedly preceded by an extended prodromal phase [1], which is of great interest as it provides an opportunity for insights into disease pathogenesis
Using structural and functional magnetic resonance imaging (MRI), we investigated the hypothesis of functional compensation of early neurodegeneration in prodromal Huntington disease
In this context, beginning degeneration is thought to be compensated by increased activation of the remaining neurons in the same brain region and in a wider sense by activation of additional parts of cerebral networks resulting in equal behavioural performance between affected and non-affected subjects
Summary
Adult-onset neurodegenerative diseases are supposedly preceded by an extended prodromal phase [1], which is of great interest as it provides an opportunity for insights into disease pathogenesis. Functional imaging in people at genetic risk for Alzheimer disease revealed increased circuit activation in risk carriers versus controls without differences in actual task performance or marked atrophy [4]. This suggests that in the prodromal phase affected brain regions compensate impending functional deficits by mobilizing a certain activity reserve and that this compensation can be investigated as an even earlier marker of disease progression than actual atrophy. We hypothesized that beginning but still subliminal degeneration of ventral striatal neurons in HD should be reflected by correlates of functional compensation in blood oxygenation level dependent (BOLD) signalling as measured with fMRI along with preserved functioning in prodromal gene carriers relative to controls. To fulfil an important criterion when defining functional compensation we expected unaffected behavioural performance in the reward task in the HD group as compared to healthy controls
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