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.

摘要 大多数路易体痴呆症（DLB）患者都有一种梦境发生的临床综合征， 通常在认知障碍发作前几年就出现了。在正常生理条件下， 眼球运动（REM）睡眠的特征是生动的梦心理状态与骨骼肌无力相结合。 这种快速眼动麻痹在快速眼动睡眠行为障碍（RBD）中消失，导致患者乱扔垃圾，拳打脚踢， 晚上踢。RBD是一种常见的疾病，影响全球8000万人，超过5%的老年人 70. RBD的存在高度表明潜在的神经退行性变，因为近75%的人将发展为神经退行性变。 12年内患有神经退行性疾病，最常见的是DLB或其他α-突触核蛋白病理学疾病 例如帕金森病（PD）。在患有RBD的患者中，大约一半已经发展或已经 在开始服用β-羟色胺能抗抑郁药（通常是选择性5-羟色胺）后， 再摄取通道-SSRI）。这种在开始SSRI后出现的梦的实施，被称为多巴胺能 RBD（5-HT RBD），直到最近才被认为是由对REM睡眠回路的毒性作用引起的。 然而，对5-HT RBD患者的仔细检查揭示了神经退行性发现，提示 即将发生的DLB，如色觉受损、轻度认知障碍和亚临床运动缺陷。这些 有观点认为，SSRI抗抑郁药不会诱导RBD，而是在患有RBD的个体中暴露RBD。 已经被早期的α-突触核蛋白病理学所拖累。然而，这一点尚未得到证实，它仍然存在。 关键是要了解5-HT RBD是否如我们所怀疑的那样是前驱路易体型的指标 病理这个项目将测试假设，5-HT RBD的人有系统的α-突触核蛋白 病理学、控制REM睡眠区域的脑干病变和前驱DLB体征。AIM 1将寻求 在一组5-HT患者的皮肤活检中检测异常磷酸化的α-突触核蛋白聚集体 RBD和匹配的对照组（服用SSRIs但不服用RBD）。Aim 2将使用7 T的超高场MRI， 检查蓝斑/蓝斑下复合体的脑桥区域，以寻找神经变性的证据， 作为与REM睡眠相关的神经元结构的节段和包裹。Aim 3将测试以下患者的前驱缺陷： 与路易体病相符虽然这些目标是独立的，但我们怀疑， 语言缺陷与MRI上神经黑色素信号的丢失和皮肤活检的病理学有关。这些 研究是重要的，因为证实5-HT RBD中的神经变性将是一个突破， 了解DLB病理学的自然史和进展。最重要的是，通过识别早期 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， 阻止或防止路易体病理学进展的治疗。