1. Clinical and neuroimaging markers of prodromal neurodegeneration in rapid eye movement sleep behaviour disorder
- Author
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Barber, Thomas R., Husain, Masud, Mackay, Clare, and Hu, Michele
- Subjects
616.8 - Abstract
Patients with rapid eye movement sleep behaviour disorder (RBD) have a high long-term risk of developing Parkinson’s disease or a related synucleinopathy. Their individual trajectories are enormously varied, however, causing considerable prognostic uncertainty. This thesis examined aspects of the clinical and neuroimaging phenotype of RBD patients which might shed light on the underlying neurodegenerative process and thereby contribute to future risk stratification. We found that across a range of clinical prodromal features, RBD patients were at least as impaired as those with established Parkinson’s and that neuropsychiatric disorders were particularly prominent in RBD patients. Genetic, environmental and demographic factors differed between PD and RBD groups. In a multi-centre longitudinal analysis, the outcomes of simple in-clinic tests were shown to substantially affect the risk of phenoconversion. Using ioflupane SPECT, we found that 43% of RBD patients already had evidence of dopaminergic deficit, and that this declines by an estimated 7% per year. Neuromelaninsensitive and susceptibility weighted MRI of the substantia nigra revealed signal changes in RBD patients consistent with early neurodegeneration. A combination of these novel MRI markers accurately distinguished PD patients from controls, suggesting an ability to capture the hallmark pathological process. We found that apathy was common and under-recognised in RBD patients and dissociable from other neuropsychiatric features. SPECT neuroimaging data revealed that apathy was correlated with serotonin levels in the dorsal raphe nucleus, but not with dopaminergic availability. We used an eye-tracking paradigm to show that reward sensitivity is blunted in RBD patients, but that this relates to dopaminergic decline rather than clinical apathy. Overall, our data indicate that RBD patients have extensive evidence of underlying neurodegeneration, which manifests as a clinical phenotype with unique characteristics, suggesting that RBD may represent the prodromal phase of a particular synucleinopathy subtype. Multimodal assessment with in-clinic measures, neuroimaging and biometric data has the potential to facilitate risk stratification on an individual basis and will be important in selecting high-risk RBD patients for neuroprotective clinical trials.
- Published
- 2020