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

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.