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)的特征是缺乏与快速眼动相关的肌肉张力，伴有痉挛和反映快速眼动相关精神状态的运动行为。后来认识到iRBD是a-突触核病的前驱阶段，如帕金森病(PD)、路易体痴呆或多系统萎缩，这表明临床上孤立的iRBD可能为定义新的生物标记物、帮助阐明可识别的前驱神经退行性变状态和确定治疗靶点提供了独特的机会。在过去的几十年里，对帕金森病的神经影像研究和各种动物模型一直表明，纹状体内的多巴胺能不均衡，纹状体的后壳核受累更严重，尾状核头部相对较少。这种不对称的从后到前的功能梯度似乎不会随着疾病的进展而发生实质性的变化。然而，最近，早期尾状核功能障碍的发生被认为增加了非运动性并存疾病的负担，如抑郁和认知障碍，总体预后较差。与此一致，一些作者假设，在神经退行性变过程中，RBD或PD的较早发病可能取决于最初涉及脑干的背侧或腹侧部分。因此，如果病变开始于桥脑尾腹侧交界处，疾病过程中的睡眠问题更有可能首先出现。当存在诸如溶酶体降解系统和葡萄糖脑苷酶(由GBA1编码)的异常等遗传因素时，它们也被证明出现得较早。GBA1突变已被证明显著增加了发生a-突触核病症的风险。令人惊讶的是，到目前为止，人们对iRBD的宏观和微观睡眠结构知之甚少，更不知道它与纹状体内多巴胺能缺陷的关系，以及其他a-突触核病症状的出现。使用临床翻译成像和脑电方法，该项目将首先描述GBA1突变小鼠在衰老期间(阶段1)清醒和睡眠期间的异常大脑活动。这些发现将有助于进一步建立病理神经回路的模型，使用化学和光遗传学方法结合功能磁共振(FMR；阶段2)精确定位大脑区域和细胞亚群。最后的临床阶段(阶段3)将以此为基础，同时将重点放在RBD上，作为PD的一个重要的非运动症状。事实上，iRBD有时是正在进行的潜在神经退变的唯一第一个迹象，这为治疗干预提供了无与伦比的机会。不幸的是，人们对其背后的神经回路知之甚少。有趣的是，我们最近的工作表明，一种新的大脑皮层体感空间导航系统参与了定义RBD的夜间剧烈身体运动，这可能导致严重的睡眠相关损伤。在这里，将使用神经刺激/高密度FMR-EEG成像来探索和确定其在RBD记忆和睡眠障碍中的作用。这项PHD研究的主要目的将是在GBA1 iRBD动物模型中探索早期睡眠变化、神经回路适应和纹状体功能之间的关系。这样做是为了确定潜在的早期帕金森病和其他a-突触核病的前驱疾病，并确定这种神经退行性障碍的潜在治疗靶点。

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.