Identification of Prodromal Neurodegeneration in Serotonergic-Induced REM sleep Behavior Disorder

血清素诱导的快速眼动睡眠行为障碍中前驱神经变性的鉴定

• 批准号: 10734350
• 负责人: Michael J Howell
• 金额: $ 77.48万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734350
• 关键词: Affect; Alzheimer' s disease related dementia; Antidepressive Agents; Biological Markers; Biopsy; Brain Stem; Central Nervous System; Clinical; Clinical Research; Clinical Trials; Cognitive; Color Visions; Complex; Cutaneous; Data; Dementia with Lewy Bodies; Deposition; Development; Disease; Disease Progression; Dreams; Early Diagnosis; Early identification; Elderly; Evaluation; Goals; Histopathology; Impaired cognition; Impairment; Individual; Investigation; Lesion; Lewy Bodies; Lewy Body Disease; Lewy body pathology; Magnetic Resonance; Magnetic Resonance Imaging; Masks; Methods; Motor; Multiple System Atrophy; National Institute on Aging; Natural History; Nerve Degeneration; Nerve Fibers; Neurodegenerative Disorders; Neurologic Dysfunctions; Neuronal Plasticity; Neurons; Paralysed; Parkinson Disease; Participant; Pathologic; Pathology; Patients; Peripheral Nervous System; Persons; Phosphorylation; Physiological; Pontine structure; Prospective Studies; REM Sleep; REM Sleep Behavior Disorder; Research; Selective Serotonin Reuptake Inhibitor; Serotonin; Severities; Signal Transduction; Skeletal Muscle; Skin; Somatotype; Speech; Speed; Structure; Symptoms; Syndrome; Techniques; Testing; Therapeutic Trials; Toxic effect; Violence; Work; alpha synuclein; biomarker identification; cognitive testing; cohort; comparison control; demented; detection sensitivity; experience; insight; method development; mild cognitive impairment; motor deficit; multimodality; neuroimaging; neuromelanin; neuroprotection; prevent; prospective; rapid eye movement; synucleinopathy; technology development; therapy development

Abstract The majority of Dementia with Lewy bodies (DLB) patients have a clinical syndrome of dream enactment that typically develops years before the onset of cognitive impairment. Under normal physiological conditions, rapid eye movement (REM) sleep is characterized by vivid dream mentation combined with skeletal muscle atonia. This REM paralysis is lost in REM sleep Behavior Disorder (RBD), resulting in patients who trash, punch and kick at night. RBD is a common condition affecting 80 million people worldwide and >5% of those older than 70. The presence of RBD is highly indicative of underlying neurodegeneration as nearly 75% will develop a neurodegenerative disorder in 12 years, most commonly DLB or other disorder of alpha-synuclein pathology such as Parkinson's disease (PD). Among patients with RBD approximately half have developed, or have had exacerbated, their dream enactment after starting a serotonergic antidepressant (usually a selective serotonin reuptake inhibitor-SSRI). This emergence of dream enactment after starting an SSRI, is termed serotonergic RBD (5-HT RBD) and was until recently assumed to be caused by a toxic effect on REM sleep circuitry. However, careful scrutiny of patients with 5-HT RBD reveals neurodegenerative findings suggestive of impending DLB, such as impaired color vision, mild cognitive impairment and subclinical motor deficits. These insights suggest that SSRI antidepressants do not induce RBD but instead unmask RBD in an individual who is already burdened by early alpha-synuclein pathology. However, this has not been proven, and it remains critical to understand whether 5-HT RBD is, as we suspect, an indicator of prodromal Lewy-body type pathology. This project will test the hypotheses that people with 5-HT RBD have systemic alpha-synuclein pathology, brainstem lesions in regions that control REM sleep, and prodromal DLB signs. AIM 1 will seek to detect abnormally phosphorylated alpha-synuclein aggregates on skin biopsy in a cohort of people with 5-HT RBD and matched controls (taking SSRIs but without RBD). Aim 2 will use ultra-high field MRI at 7T to examine the pontine region of the coeruleus/subcoeruleus complex for evidence of neurodegeneration as well as segment and parcellate REM sleep related neuronal structures. Aim 3 will test for prodromal deficits in speech consistent with Lewy body disease. While these Aims are independent we suspect that the severity of speech deficits will correlate with loss of neuromelanin signal on MRI and pathology on skin biopsy. These studies are important because confirming neurodegeneration in 5-HT RBD would be a breakthrough in understanding the natural history and progression of DLB pathology. Most importantly, by identifying an early prodromal syndrome and biomarkers of disease progression, this project will help speed up the development of therapies to impede or prevent the progression of Lewy body pathology.

抽象的 Lewy身体（DLB）患者的大多数痴呆症患有临床综合症的梦境综合症 通常在认知障碍发作之前发展几年。在正常的生理条件下，快速 眼睛运动（REM）睡眠的特征是生动的梦想与骨骼肌肉atonia结合在一起。 这种REM麻痹在REM睡眠行为障碍（RBD）中丢失，导致患者垃圾，打孔和 晚上踢。 RBD是一种常见的状况，影响了全球8000万人，> 5％的人比 70。RBD的存在高度指示潜在的神经变性，因为将近75％会发展 神经退行性疾病在12年内，最常见的是DLB或其他α-突触核蛋白病理学的疾病 例如帕金森氏病（PD）。在RBD的患者中，大约一半已经发展或 加剧了他们开始使用5-羟色胺抗抑郁药（通常是选择性5-羟色胺）之后的梦境 再摄取抑制剂-SSRI）。启动SSRI后，梦颁布的出现被称为血清素能 RBD（5-HT RBD），直到最近才被认为是由对REM睡眠电路的有毒作用引起的。 然而，对5-HT RBD患者的仔细审查显示神经退行性发现提示 即将进行的DLB，例如彩色障碍，轻度认知障碍和亚临床运动缺陷。这些 见解表明，SSRI抗抑郁药不会引起RBD，而是在一个人中揭露RBD 已经受到早期α-突触核蛋白病理的负担。但是，这尚未得到证明，并且仍然存在 正如我们所怀疑的那样 病理。该项目将测试5-HT RBD的人具有全身性α-核素的假设 病理学，控制REM睡眠的区域中的脑干病变和前驱DLB标志。 AIM 1将寻求 检测异常磷酸化的α-突触核蛋白聚集体在一群患有5-HT的人群中皮肤活检 RBD和匹配的控件（服用SSRI，但没有RBD）。 AIM 2将使用7T的超高场MRI到 还要检查核/亚焦点络合物的丘脑区域以及神经退行性的证据 作为段和层状REM睡眠相关的神经元结构。 AIM 3将测试前驱缺陷 语音与Lewy身体疾病一致。尽管这些目标是独立的，但我们怀疑 语音缺陷将与MRI和皮肤活检病理学上的神经苯胺信号丧失有关。这些 研究很重要，因为确认5-HT RBD中的神经退行性将是一个突破 了解DLB病理学的自然历史和进展。最重要的是，通过确定早期 前驱综合征和疾病进展的生物标志物，该项目将有助于加快发展 疗法阻碍或防止Lewy身体病理的进展。