Unravelling brain activity and sleep disturbances in prodromal Parkinson's Disease

Idiopathic rapid eye movement (REM) sleep behaviour disorder (iRBD) characterised by the absence of REM-related muscle atonia, accompanied by jerks and motor behaviours reflecting REM-related mentation. Later recognition of iRBD as the prodromal stage of an a-synucleinopathy, such as Parkinson's disease (PD), dementia with Lewy bodies or multiple system atrophy, suggests that clinically isolated iRBD may present a unique opportunity to define novel biomarkers, to help elucidate recognizable precursory neurodegenerative states, and to identify treatment targets. Over the past few decades, neuroimaging studies of PD, and various animal models, have consistently demonstrated uneven dopaminergic deficit within the striatum, with more severe involvement of the posterior putamen and a relative sparing of the head of caudate nucleus. This asymmetrical posterior-to-anterior gradient of dysfunction does not appear to change substantially with disease progression. More recently, however, the occurrence of early caudate dysfunction has been proposed to confer higher burden of non-motor comorbidities, such as depression and cognitive impairment, with overall worse prognosis. In keeping with this, some authors have hypothesised that earlier onset of RBD or PD in a course of neurodegeneration may depend on whether the dorsal or ventral part of the brainstem are initially involved. Accordingly, sleep issues in the disease process are more likely to appear first if the lesions start in the caudoventral mesopontine junction. They have been also shown to appear early when genetic factors such as abnormalities of the lysosomal degradation system and that of glucocerebrosidase enzyme (encoded by GBA1) are present. The GBA1 mutation have been shown to significantly increase the risk of developing a-synucleinopathy. To date, surprisingly little is still known about macroscopic and microscopic sleep structure in iRBD, and even less so about its relationship with dopaminergic deficit within the striatum and the emergence of other a-synucleinopathy symptoms. Using clinically-translational imaging and EEG methods, this project will first characterise abnormal brain-activity during wakefulness and sleep in the GBA1 mutant-mice, during ageing (Phase-1). The findings will contribute toward further modelling of the pathological neural-circuitry, using precise targeting of brain regions and cellular subpopulations by chemo- and opto-genetic methodology, in conjunction with functional-MRI (fMR; Phase-2). The final, clinical phase (Phase-3), will build on this, whilst focusing on RBD, as an important non-motor symptom of PD. Indeed, iRBD is sometimes the firstand only sign of an ongoing underlying neurodegeneration that provides an unparalleled opportunity for therapeutic intervention. Unfortunately, very little is still understood about the neural-circuitries that underlie it. Intriguingly, our recent work suggests involvement of a novel cortical somatosensory-spatial-navigation-system in violent-nocturnal-body-movements that define RBD, and that can lead to serious sleep-related injuries. Here, neurostimulation/high-density-fMR-EEG imaging will be used to explore and define its role in memory and sleep deficits in RBD.

The overarching aim of this PhD study will be to explore the relationship between early sleep changes, neuro-circuitry adaptations and striatal functionality in GBA1 iRBD animal model. This will be done in order to define potential early PD and other a-synucleinopathies' precursors and to identify potential therapeutic targets for this neurodegenerative disabilitating disorder.