Mapping apathy in Huntington's disease: a combined dimensional neuroimaging approach

[eng] What would it feel like to not feel? To go through life with an ‘empty mind’, unable to generate thoughts, plans, actions, or the motivation to carry out these processes? What would it be like to be defined by what you lack? These notions fall in line with the clinical syndrome of apathy: a- (without) -pathos (feeling). More recently, apathy has been defined as a reduction in goal-directed behavior and motivation. The proposed etiology of apathy is multidimensional, signifying that it can stem from deficits in self-activation, emotional affect, and the cognitive faculties required to plan and manage goals. However, the precise neurobiological mechanisms underlying each apathy dimension remain largely unknown, resulting in a dearth of validated treatment, despite its far-reaching negative impact. While apathy can occur in the general population, it is much more prevalent in those suffering from neurodegenerative disease, including Huntington’s disease. Due to its genetic etiology, it is possible to identify Huntington’s disease mutation carriers through predictive testing prior to symptom onset. This renders Huntington’s disease a suitable model for the study of neurodegeneration. Despite being diagnosed by motor onset, cognitive decline and psychiatric disturbances such as apathy are prevalent and can manifest years prior. Meanwhile, apathy is the only psychiatric feature that has consistently been shown to track disease progression. As such, the overarching aim of this Doctoral Thesis was to describe apathy as a multidimensional construct in Huntington’s disease, while investigating its structural neural underpinnings through MRI as well as its longitudinal relationship with associated psychiatric features of the disease. First, Study 1 provided evidence that the short-Lille Apathy Rating Scale could quantify three apathy subdimensions in Huntington’s disease in line with the triadic model of apathy. These dimensions subsume cognitive, auto-activation, and emotional apathy. Patients with greater severity in cognitive and auto-activation apathy demonstrated decreased white matter microstructural connectivity in specific frontostriatal tracts. Overall, these findings underscored that white matter dysfunction may contribute to the heterogeneous nature of apathy in Huntington's disease, with implications for treatment selection. Next, Study 2 highlighted that individual differences in global apathy progression in Huntington’s disease may be explained by variability in brain atrophy in the right middle cingulate cortex, an area implicated in action-initiation. Moreover, initial vulnerabilities in this region predicted those individuals who would later develop more severe and worsening apathy over time. These results were specific to apathy; neither depression nor cognitive scores were related with volume loss in this region. As a whole, these results evince that specific regional vulnerabilities may facilitate the prediction of an apathetic profile in HD, permitting targeted, time-sensitive interventions. Returning to the study of multidimensional apathy, Study 3 demonstrated that the short-Lille Apathy Rating Scale exhibited satisfactory reliability and clinical validity in Huntington’s disease and a three-dimensional factor structure in line with the triadic model of apathy. Neurobiologically, apathy profiles in Huntington’s disease were underpinned by reduced gray matter volume in nodes within functionally diverse and large-scale motor, cognitive, and limbic networks. Such findings promote the continued use of the short-Lille Apathy Rating Scale to comprehensively characterize apathy in neurological populations in clinical practice. Finally, Study 4 utilized a novel machine-learning approach to stratify Huntington’s disease patients into unique longitudinal psychiatric trajectories. Two main psychiatric signatures were revealed, the first defined by a pattern of increasing irritability and no depression, and the second by rise-and-fall depression and no irritability. Interestingly, both signatures consisted of both premanifest and manifest Huntington’s disease individuals. Notably, the severity of apathy and perseveration/obsessive-compulsiveness were increased at clinically relevant levels in both longitudinal profiles. This work opens doors for patient stratification leveraging real-world data with the potential to enhance prognostic indicators and therapeutics. Collectively, the four studies presented in this Doctoral Thesis exemplify crucial insights regarding the underlying neural basis and progression profile of apathy in Huntington’s disease. By addressing these questions, this work advances understanding of the pathological mechanisms of apathy, a syndrome that strips an individual of their productivity, passions, and functional independence. Ultimately, this research lays the groundwork for critically examining individual differences within a certain disease diagnosis, with promise to further personalized, precision, and preventative medicine in Huntington’s disease and beyond.