Robert D Abbott1, G Webster Ross2, John E Duda2, Chol Shin2, Jane H Uyehara-Lock2, Kamal H Masaki2, Lenore J Launer2, Lon R White2, Caroline M Tanner2, Helen Petrovitch2. 1. From the Institute of Human Genomic Study (R.D.A., C.S.), Korea University College of Medicine, Ansan-si, Gyeonggi-do, South Korea; the Pacific Health Research and Education Institute (R.D.A., G.W.R., L.R.W., H.P.), Honolulu, HI; the Departments of Medicine (G.W.R.) and Pathology (J.H.U.-L.) and the John A. Hartford Foundation Center of Excellence in Geriatrics, Department of Geriatric Medicine (G.W.R., K.H.M., H.P.), John A. Burns School of Medicine, University of Hawaii, Honolulu; the Veterans Affairs Pacific Islands Health Care System (G.W.R., L.R.W., H.P.), Honolulu, HI; the Michael J. Crescenz Veterans Affairs Medical Center and the University of Pennsylvania Perelman School of Medicine (J.E.D.), Philadelphia; Kuakini Medical Center (K.H.M.), Honolulu, HI; the National Institute on Aging (L.J.L.), Bethesda, MD; and the San Francisco Veterans Affairs Medical Center and the Department of Neurology (C.M.T.), University of California-San Francisco. rda3e@virginia.edu. 2. From the Institute of Human Genomic Study (R.D.A., C.S.), Korea University College of Medicine, Ansan-si, Gyeonggi-do, South Korea; the Pacific Health Research and Education Institute (R.D.A., G.W.R., L.R.W., H.P.), Honolulu, HI; the Departments of Medicine (G.W.R.) and Pathology (J.H.U.-L.) and the John A. Hartford Foundation Center of Excellence in Geriatrics, Department of Geriatric Medicine (G.W.R., K.H.M., H.P.), John A. Burns School of Medicine, University of Hawaii, Honolulu; the Veterans Affairs Pacific Islands Health Care System (G.W.R., L.R.W., H.P.), Honolulu, HI; the Michael J. Crescenz Veterans Affairs Medical Center and the University of Pennsylvania Perelman School of Medicine (J.E.D.), Philadelphia; Kuakini Medical Center (K.H.M.), Honolulu, HI; the National Institute on Aging (L.J.L.), Bethesda, MD; and the San Francisco Veterans Affairs Medical Center and the Department of Neurology (C.M.T.), University of California-San Francisco.
Abstract
OBJECTIVE: While excessive daytime sleepiness (EDS) can predate the clinical diagnosis of Parkinson disease (PD), associations with underlying PD pathogenesis are unknown. Our objective is to determine if EDS is related to brain Lewy pathology (LP), a marker of PD pathogenesis, using clinical assessments of EDS with postmortem follow-up. METHODS: Identification of LP was based on staining for α-synuclein in multiple brain regions in a sample of 211 men. Data on EDS were collected at clinical examinations from 1991 to 1999 when participants were aged 72-97 years. RESULTS: Although EDS was more common in the presence vs absence of LP (p = 0.034), the association became stronger in neocortical regions. When LP was limited to the olfactory bulb, brainstem, and basal forebrain (Braak stages 1-4), frequency of EDS was 10% (4/40) vs 17.5% (20/114) in decedents without LP (p = 0.258). In contrast, compared to the absence of LP, EDS frequency doubled (36.7% [11/30], p = 0.023) when LP reached the anterior cingulate gyrus, insula mesocortex, and midfrontal, midtemporal, and inferior parietal neocortex (Braak stage 5). With further infiltration into the primary motor and sensory neocortices (Braak stage 6), EDS frequency increased threefold (51.9% [14/27], p < 0.001). Findings were similar across sleep-related features and persisted after adjustment for age and other covariates, including the removal of PD and dementia with Lewy bodies. CONCLUSIONS: The association between EDS and PD includes relationships with extensive topographic LP expansion. The neocortex could be especially vulnerable to adverse relationships between sleep disorders and aggregation of misfolded α-synuclein and LP formation.
OBJECTIVE: While excessive daytime sleepiness (EDS) can predate the clinical diagnosis of Parkinson disease (PD), associations with underlying PD pathogenesis are unknown. Our objective is to determine if EDS is related to brain Lewy pathology (LP), a marker of PD pathogenesis, using clinical assessments of EDS with postmortem follow-up. METHODS: Identification of LP was based on staining for α-synuclein in multiple brain regions in a sample of 211 men. Data on EDS were collected at clinical examinations from 1991 to 1999 when participants were aged 72-97 years. RESULTS: Although EDS was more common in the presence vs absence of LP (p = 0.034), the association became stronger in neocortical regions. When LP was limited to the olfactory bulb, brainstem, and basal forebrain (Braak stages 1-4), frequency of EDS was 10% (4/40) vs 17.5% (20/114) in decedents without LP (p = 0.258). In contrast, compared to the absence of LP, EDS frequency doubled (36.7% [11/30], p = 0.023) when LP reached the anterior cingulate gyrus, insula mesocortex, and midfrontal, midtemporal, and inferior parietal neocortex (Braak stage 5). With further infiltration into the primary motor and sensory neocortices (Braak stage 6), EDS frequency increased threefold (51.9% [14/27], p < 0.001). Findings were similar across sleep-related features and persisted after adjustment for age and other covariates, including the removal of PD and dementia with Lewy bodies. CONCLUSIONS: The association between EDS and PD includes relationships with extensive topographic LP expansion. The neocortex could be especially vulnerable to adverse relationships between sleep disorders and aggregation of misfolded α-synuclein and LP formation.
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