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

特发性快速眼动（REM）睡眠行为障碍（iRBD），其特征为缺乏REM相关肌肉张力，伴有反映REM相关精神状态的抽搐和运动行为。后来认识到iRBD是α-突触核蛋白病的前驱期，如帕金森病（PD）、路易体痴呆或多系统萎缩，这表明临床分离的iRBD可能提供了一个独特的机会来定义新的生物标志物，以帮助阐明可识别的神经退行性疾病状态，并确定治疗靶点。在过去的几十年里，PD的神经影像学研究，以及各种动物模型，一直表现出不均匀的多巴胺能神经元的赤字纹状体内，更严重的参与后壳核和相对保留的头尾状核。这种不对称的后-前功能障碍梯度似乎不会随着疾病进展而发生实质性变化。然而，最近，早期尾状核功能障碍的发生被认为是非运动性共病（如抑郁症和认知障碍）的更高负担，总体预后更差。与此一致，一些作者假设，在神经变性过程中，RBD或PD的早期发作可能取决于最初是否涉及脑干的背侧或腹侧部分。因此，如果病变开始于尾腹侧桥脑连接处，则疾病过程中的睡眠问题更有可能首先出现。当存在遗传因素如溶酶体降解系统和葡萄糖脑苷脂酶（由GBA 1编码）的异常时，它们也会早期出现。GBA 1突变已被证明会显著增加发生α-突触核蛋白病的风险。到目前为止，令人惊讶的是，仍然很少有人知道宏观和微观睡眠结构的iRBD，甚至更少，所以它与多巴胺能缺陷纹状体内和其他α-突触核蛋白病症状的出现的关系。使用临床平移成像和EEG方法，该项目将首先在衰老过程中观察GBA 1小鼠清醒和睡眠期间的异常脑活动（第1阶段）。这些发现将有助于进一步模拟病理神经回路，通过化学和光遗传学方法精确靶向脑区域和细胞亚群，结合功能性MRI（fMR;第2阶段）。最后的临床阶段（3期）将以此为基础，同时将重点放在RBD上，作为PD的重要非运动症状。事实上，iRBD有时是正在进行的潜在神经变性的第一个和唯一的迹象，为治疗干预提供了无与伦比的机会。不幸的是，对它背后的神经回路仍然知之甚少。有趣的是，我们最近的工作表明，一种新的皮层体感空间导航系统参与了定义RBD的剧烈夜间身体运动，并可能导致严重的睡眠相关损伤。在这里，神经刺激/高密度fMR-EEG成像将用于探索和定义其在RBD记忆和睡眠缺陷中的作用。这项博士研究的首要目标是探索早期睡眠变化，神经回路适应和GBA 1 iRBD动物模型中纹状体功能之间的关系。这样做是为了确定潜在的早期PD和其他α-突触核蛋白病的前体，并确定这种神经退行性致残性疾病的潜在治疗靶点。

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.