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

揭示帕金森病前驱期的大脑活动和睡眠障碍

• 批准号: 2748501
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2748501
• 关键词: Unravelling; brain; activity; sleep; disturbances

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.

特发性快速眼动 (REM) 睡眠行为障碍 (iRBD) 的特征是缺乏 REM 相关的肌肉无力，并伴有反映 REM 相关精神状态的抽动和运动行为。后来人们认识到 iRBD 是 α-突触核蛋白病（例如帕金森病 (PD)、路易体痴呆或多系统萎缩症）的前驱阶段，这表明临床分离的 iRBD 可能提供一个独特的机会来定义新型生物标志物，帮助阐明可识别的前驱神经退行性状态，并确定治疗靶点。在过去的几十年里，PD的神经影像学研究和各种动物模型一致证明纹状体内多巴胺能缺陷不均匀，后壳核受累更严重，而尾状核头部相对较少。这种不对称的从后到前的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，最近有人提出，早期尾状核功能障碍的发生会带来更高的非运动合并症负担，例如抑郁和认知障碍，总体预后更差。与此相一致，一些作者假设，神经退行性变过程中 RBD 或 PD 的早期发作可能取决于脑干的背侧或腹侧部分是否最初受累。因此，如果病变始于尾腹侧中脑桥交界处，则疾病过程中的睡眠问题更有可能首先出现。当溶酶体降解系统和葡萄糖脑苷脂酶（由 GBA1 编码）异常等遗传因素存在时，它们也被证明会早期出现。 GBA1 突变已被证明会显着增加发生 α-突触核蛋白病的风险。迄今为止，令人惊讶的是，人们对 iRBD 的宏观和微观睡眠结构知之甚少，更不用说它与纹状体内多巴胺能缺陷以及其他 α-突触核蛋白病症状出现的关系。该项目将使用临床转化成像和脑电图方法，首先表征 GBA1 突变小鼠在衰老过程中清醒和睡眠期间的异常大脑活动（第一阶段）。这些发现将有助于进一步建立病理神经回路模型，通过化学和光遗传学方法精确定位大脑区域和细胞亚群，并结合功能性磁共振成像（fMR；第二阶段）。最后的临床阶段（第 3 阶段）将以此为基础，同时重点关注 RBD，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退行性变的第一个也是唯一的迹象，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，我们最近的研究表明，一种新型的皮质体感空间导航系统参与了定义 RBD 的夜间暴力身体运动，并且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 GBA1 iRBD 动物模型中早期睡眠变化、神经回路适应和纹状体功能之间的关系。这样做是为了定义潜在的早期帕金森病和其他α-突触核蛋白病的前兆，并确定这种神经退行性失能性疾病的潜在治疗靶点。