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 大多数路易体痴呆 (DLB) 患者都患有梦境表现临床综合征， 通常在认知障碍发生前数年出现。在正常生理条件下，快速 眼动 (REM) 睡眠的特点是生动的梦境思维与骨骼肌肌无力。 这种 REM 麻痹在 REM 睡眠行为障碍 (RBD) 中消失，导致患者乱扔垃圾、拳打脚踢和 晚上踢。 RBD 是一种常见疾病，影响着全球 8000 万人，其中超过 5% 的人年龄超过 70. RBD 的存在高度表明潜在的神经变性，因为近 75% 的人会发展为神经变性。 12 年神经退行性疾病，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 RBD 患者中，大约一半已经出现或已经患有 RBD 在开始使用血清素能抗抑郁药（通常是选择性血清素）后，他们的梦想更加严重 再摄取抑制剂-SSRI)。开始使用 SSRI 后出现的梦境表现被称为血清素能 RBD (5-HT RBD) 直到最近还被认为是由快速眼动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，例如色觉受损、轻度认知障碍和亚临床运动缺陷。这些 研究表明，SSRI 抗抑郁药不会诱发 RBD，而是会暴露个体的 RBD 已经受到早期α-突触核蛋白病理学的负担。但这一点尚未得到证实，目前仍存在 正如我们怀疑的那样，了解 5-HT RBD 是否是前驱路易体类型的指标至关重要 病理。该项目将测试 5-HT RBD 患者具有全身性 α-突触核蛋白的假设 病理学、控制快速眼动睡眠区域的脑干病变以及前驱 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 和匹配对照（服用 SSRI 但不含 RBD）。目标 2 将使用 7T 超高场 MRI 检查蓝斑/蓝斑下复合体的脑桥区域是否有神经变性的证据 作为与 REM 睡眠相关的神经元结构的节段和块状。目标 3 将测试前驱缺陷 言语符合路易体病。虽然这些目标是独立的，但我们怀疑这些目标的严重性 言语缺陷与 MRI 和皮肤活检病理学中神经黑色素信号的丧失有关。这些 研究很重要，因为确认 5-HT RBD 中的神经退行性疾病将是一个突破 了解 DLB 病理学的自然史和进展。最重要的是，通过尽早识别 前驱综合症和疾病进展的生物标志物，该项目将有助于加快发展 阻碍或预防路易体病理进展的疗法。