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(DLB)患者都有梦境发作的临床综合征 通常在认知障碍发作前数年发病。在正常生理条件下，迅速 眼动睡眠(REM)的特点是梦境逼真，并伴有骨骼肌张力。 这种REM瘫痪在REM睡眠行为障碍(RBD)中消失，导致患者将垃圾、拳头和 在晚上踢。RBD是一种常见的疾病，影响着全球8000万人，5%以上的老年人 70.RBD的存在高度预示着潜在的神经退变，因为近75%的人将发展为 12年内神经退行性疾病，最常见的是DLB或其他α-突触核蛋白病理障碍 例如帕金森氏病(PD)。在RBD患者中，大约有一半已经发生或已经发生 在开始服用5-羟色胺能抗抑郁剂(通常是选择性的5-羟色胺)后，他们的梦境变得更加糟糕 重摄取抑制物(SSRI)。这种在启动SSRI后出现的梦境实现被称为5-羟色胺能 RBD(5-羟色胺RBD)，直到最近还被认为是由REM睡眠电路的毒性作用引起的。 然而，对5-羟色胺RBD患者的仔细检查显示，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障碍。这些 研究表明，SSRI抗抑郁药不会诱发RBD，而是揭示出患有RBD的个体的RBD 已经背负着早期α-突触核蛋白病理的负担。然而，这一点尚未得到证实，它仍然存在。 了解5-羟色胺RBD是否如我们怀疑的那样是前驱路易体类型的指标至关重要 病理学。这个项目将检验5-羟色胺RBD患者有系统性α-突触核蛋白的假设 病理，控制快速眼动睡眠的区域的脑干病变，以及前驱DLB征。目标1将寻求 检测一组5-羟色胺患者皮肤活检中异常磷酸化的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将在7T使用超高场MRI 同时检查蓝斑/蓝斑下复合体的桥脑区，以寻找神经变性的证据。 作为与快速眼动睡眠相关的神经元结构的分段和分割。目标3将测试前驱体缺陷 言语与路易身体疾病相一致。虽然这些目标是独立的，但我们怀疑 语音缺陷将与核磁共振上的神经黑色素信号丢失和皮肤活检的病理相关联。这些 研究很重要，因为证实5-羟色胺RBD的神经变性将是 了解DLB病理的自然历史和进展。最重要的是，通过识别早期的 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 阻止或阻止路易体病理进展的治疗方法。