What question did this study set out to answer?

The research aims to explore potential causes of REM sleep behavior disorder in the context of dementia with Lewy bodies but without usual synuclein pathology.

February 20, 2026

Rapid Eye Movement Sleep Behavior Disorder with Clinical Dementia with Lewy Bodies Phenotype but Lacking Postmortem Central Nervous System Synuclein Pathology: Alternate Etiologies

Key Points

The research aims to explore potential causes of REM sleep behavior disorder in the context of dementia with Lewy bodies but without usual synuclein pathology.
Analysis of cerebrospinal fluid for alpha-synuclein seeding amplification assay (SAA)
Longitudinal follow-up of an 80-year-old male patient diagnosed with IRBD and dementia with Lewy bodies
Neuropathological examination post-mortem to identify proteinopathies
Assessment of brainstem nuclei related to REM sleep
Negative CSF alpha-synuclein SAA indicates absence of synuclein-related pathology
Post-mortem analysis revealed aging-related tau astrogliopathy and other proteinopathies
Lewy pathology was nearly absent, with minimal neuritic involvement
Brainstem nuclei that modulate REM sleep were largely unaffected

Abstract

Abstract Introduction Idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD) has been linked to the synucleinopathies. Methods and results An 80‐year‐old man treated with venlafaxine for depression presented with IRBD. Cerebrospinal fluid (CSF) α ‐synuclein seeding amplification assay (SAA) was negative. During 16 years of follow up he was diagnosed with dementia with Lewy bodies. He died at the age of 96 years. Neuropathology revealed aging‐related tau astrogliopathy, limbic‐predominant age‐related TDP‐43 encephalopathy, primary age‐related tauopathy, and diffuse small vessel disease. Lewy pathology was nearly absent with isolated neurites confined to the dorsal motor nucleus of the vagus nerve. Brainstem nuclei that modulate REM sleep were spared. Conclusions RBD may arise independently of α ‐synuclein pathology. In the present case, RBD might be caused by dysregulation of the brainstem REM sleep‐related structures due to age‐related proteinopathies impairing the limbic system, and venlafaxine overactive monoaminergic transmission. In neuroprotective trials, CSF α ‐synuclein SAA may be useful to exclude IRBD patients without synuclein pathology. © 2026 International Parkinson and Movement Disorder Society.

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