Objective: To determine the pathologic substrates in patients with rapid eye movement (REM) sleep behavior disorder (RBD) with or without a coexisting neurologic disorder. Methods: The clinical and neuropathologic findings were analyzed on all autopsied cases from one of the collaborating sites in North America and Europe, were evaluated from January 1990 to March 2012, and were diagnosed with polysomnogram (PSG)-proven or probable RBD with or without a coexisting neurologic disorder. The clinical and neuropathologic diagnoses were based on published criteria. Results: 172 cases were identified, of whom 143 (83%) were men. The mean ± SD age of onset in years for the core features were as follows - RBD, 62 ± 14 (range, 20-93), cognitive impairment (n = 147); 69 ± 10 (range, 22-90), parkinsonism (n = 151); 68 ± 9 (range, 20-92), and autonomic dysfunction (n = 42); 62 ± 12 (range, 23-81). Death age was 75 ± 9 years (range, 24-96). Eighty-two (48%) had RBD confirmed by PSG, 64 (37%) had a classic history of recurrent dream enactment behavior, and 26 (15%) screened positive for RBD by questionnaire. RBD preceded the onset of cognitive impairment, parkinsonism, or autonomic dysfunction in 87 (51%) patients by 10 ± 12 (range, 1-61) years. The primary clinical diagnoses among those with a coexisting neurologic disorder were dementia with Lewy bodies (n = 97), Parkinson's disease with or without mild cognitive impairment or dementia (n = 32), multiple system atrophy (MSA) (n = 19), Alzheimer's disease (AD)(n = 9) and other various disorders including secondary narcolepsy (n = 2) and neurodegeneration with brain iron accumulation-type 1 (NBAI-1) (n = 1). The neuropathologic diagnoses were Lewy body disease (LBD)(n = 77, including 1 case with a duplication in the gene encoding α-synuclein), combined LBD and AD (n = 59), MSA (n = 19), AD (n = 6), progressive supranulear palsy (PSP) (n = 2), other mixed neurodegenerative pathologies (n = 6), NBIA-1/LBD/tauopathy (n = 1), and hypothalamic structural lesions (n = 2). Among the neurodegenerative disorders associated with RBD (n = 170), 160 (94%) were synucleinopathies. The RBD-synucleinopathy association was particularly high when RBD preceded the onset of other neurodegenerative syndrome features. Conclusions: In this large series of PSG-confirmed and probable RBD cases that underwent autopsy, the strong association of RBD with the synucleinopathies was further substantiated and a wider spectrum of disorders which can underlie RBD now are more apparent.
Bibliographical noteFunding Information:
We are grateful to the many sources of funding and clinicopathologic case material. These sources the include the National Institute on Aging grant AG015866 – Neuropsychology of Dementia with Lewy Bodies, the National Institute on Aging grant AG006786 – Mayo Clinic Study of Aging, the National Institute on Aging grant AG016574 - Mayo Alzheimer’s Disease Research Center, the Mayo Clinic Morris K. Udall Center grants P50NS072187 and P50 NS072187-01S2 , the Banner Sun Health Research Institute Brain and Body Donation Program [supported by the National Institute of Neurological Disorders and Stroke ( U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging grant AG19610 Arizona Alzheimer’s Disease Core Center, the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium), the National Parkinson Foundation, the Michael J. Fox Foundation for Parkinson’s Research, and the Fondo de Investigaciones Sanitarias (FISS) and Instituo de Salud Carlos III, the Maraton of TV3 Foundation.
Dr. Jacobson has no relevant disclosures for this paper. She receives royalties from American Psychiatric Publishing for the books Laboratory Medicine in Psychiatry and Behavioral Science (2012) and Clinical Manual of Geriatric Psychopharmacology (2007). She also receives salary support from Elan, Wyeth, Pfizer, Eli Lilly, BMS, Bayer, Avid, Genentec, the Michael J. Fox Foundation, and the National Institute on Aging.
Dr. Tolosa has no relevant disclosures for this paper. He has received research grants from the spanish Fondo de Investigaciones Sanitarias (FISS) and Instituo de Salud Carlos III, the Maraton of TV3 Foundation and the MJFox Foundation. He has also received honoraria for consultancies or lectures from Boehringer Ingelheim, Novartis, UCB, GSK, Solvay, Abbott, Merck, Merck Serono, Teva and Lundbeck.
- Dementia with Lewy bodies
- Lewy body disease
- Multiple system atrophy
- Parkinson's disease
- REM sleep behavior disorder