Journal Article

Post-mortem neuropathology of idiopathic rapid eye movement sleep behaviour disorder: a case series

Gelpi, Ellen, Gaig, Carles, Sánchez-Valle, Raquel, Santamaria, Joan, Aldecoa, Iban, Iranzo, Alex, Serradell, Monica, Mayà, Gerard, Molina-Porcel, Laura

2024

Overview

Idiopathic rapid eye movement (REM) sleep behaviour disorder (IRBD) is thought to be an early stage of α-synuclein-related neurodegenerative diseases. Nevertheless, the definitive identification of its biological substrate can be determined only by post-mortem neuropathology. We aimed to describe the post-mortem neuropathology of individuals with IRBD who developed or did not develop a neurodegenerative disease before death. In this case series at the Hospital Clinic de Barcelona, Barcelona, Spain, we examined post-mortem brain tissue and spinal cords from individuals diagnosed with IRBD by video polysomnography who became donors to the Neurological Tissue Bank between May 28, 2005, and March 23, 2023. We performed post-mortem neuropathology to assess the presence and distribution of neuronal loss, gliosis, and protein aggregates using antibodies against α-synuclein, amyloid β, phosphorylated tau, three-repeat and four-repeat tau isoforms, and TDP-43. Comparative statistical analyses were not done because of the small sample size, but differences observed across the nuclei and brain structures were described. The brains and spinal cords of 20 individuals with IRBD were examined (19 [95%] men, one [5%] woman). Their clinical antemortem diagnoses were of IRBD without any other neurological disorder in three (15%), Parkinson's disease without dementia in two (10%), Parkinson's disease dementia (PDD) in three (15%), and dementia with Lewy bodies (DLB) in 12 (60%) individuals. Post-mortem neuropathological diagnoses were Lewy body disease in 19 (95%) and multiple system atrophy (MSA) in one (5%). All participants with Lewy body disease and MSA showed neuronal loss, gliosis, and α-synuclein deposits in neurons and astrocytes. In all participants, α-synuclein was found in the structures that regulate REM sleep atonia (eg, subcoeruleus nucleus, gigantocellular reticular nucleus, laterodorsal tegmentum, and amygdala). Coexistent pathologies were found in all participants, including Alzheimer's disease pathology (amyloid β plaques and neurofibrillary tangles) in 14 (70%), ageing-related tau astrogliopathy in 12 (60%), cerebral amyloid angiopathy in 11 (55%), argyrophilic grain disease in four (20%), limbic-predominant age-related TDP-43 encephalopathy in four (20%), and early changes indicative of progressive supranuclear palsy in three (15%). In individuals with IRBD without any other neurological disorder and in those who developed Parkinson's disease without dementia, α-synuclein was found in the brainstem and limbic system and rarely in the cortex, whereas coexisting proteinopathies were few and showed mild pathological burden. In contrast, in individuals who developed PDD or DLB, α-synuclein had diffuse distribution in the brainstem, limbic system, and cortex, and multiple comorbid pathologies were common, particularly those related to Alzheimer's disease. Although limited by a relatively small sample size, our observations provide strong neuropathological evidence that IRBD is an early stage of α-synuclein-related neurodegenerative disease. Concomitant pathologies are frequent and their role remains to be clarified: some might have contributed to the development of dementia, but some might be age-related changes. Our findings could inform the design of clinical trials of compounds that target specific pathological proteins (eg, α-synuclein and amyloid β) in people with IRBD. Fundación BBVA–Hospital Clínic de Barcelona.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Aged / Aged, 80 and over / Aging / alpha-Synuclein - metabolism / Alzheimer's disease / Amygdala / Amyloid beta-Peptides - metabolism / Astrocytes / Atrophy / Autopsies / Autopsy / Behavior disorders / Brain - pathology / Brain research / Brain stem / Cerebral amyloid angiopathy / Clinical trials / Cognitive ability / Dementia / Dementia disorders / Disease / Encephalopathy / Eye movements / Female / Gliosis / Gliosis - pathology / Hospitals / Humans / Immunohistochemistry / Isoforms / Lewy bodies / Lewy body disease / Lewy Body Disease - metabolism / Lewy Body Disease - pathology / Limbic system / Localization / Male / Middle Aged / Movement disorders / Neurodegenerative diseases / Neurofibrillary tangles / Neuropathology / Parkinson Disease - pathology / Parkinson's disease / Pathology / Polysomnography / Proteins / REM sleep / REM Sleep Behavior Disorder - pathology / Sleep disorders / Spinal Cord - pathology / Statistical analysis / Synuclein / tau Proteins - metabolism / Tegmentum