Abstract
In this study, we used immunohistochemistry to screen for α-synuclein pathology in the brains of 241 individuals without clinical evidence of neurologic disease, and discovered 36 cases (15%) with incidental Lewy bodies (LBs) and one case, a 96-year-old woman (0.4%), with inclusions similar to those seen in multiple system atrophy (MSA), a non-familial neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction and α-synuclein immunoreactive glial cytoplasmic inclusions (GCI). In a routine hospital autopsy series of 125 brains, we detected GCI in a neurologically normal 82-year-old man (0.8%). Both cases showed widespread GCI in the central nervous system, as well as a few neuronal cytoplasmic inclusions, but no neuronal loss or gliosis in vulnerable brain regions, including the substantia nigra, putamen, inferior olive and pontine base. Applying a recently proposed grading scale for MSA, the two cases showed pathology far below that detected in patients with clinically overt MSA, suggesting the possibility that these two individuals had preclinical MSA. The prevalence of clinically overt MSA is estimated to be about 4 per 100,000 persons (0.004%), which is far less than the frequency of GCI in this series (0.4–0.8%). Further studies are needed to determine if GCI in neurologically normal elderly represents prodromal MSA or a rare non-progressive age-related α-synucleinopathy.
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Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD, Grandinetti A, Blanchette PL, Popper JS, Ross GW (2001) Frequency of bowel movements and the future risk of Parkinson’s disease. Neurology 57:456–462
Berendse HW, Booij J, Francot CM, Bergmans PL, Hijman R, Stoof JC, Wolters EC (2001) Subclinical dopaminergic dysfunction in asymptomatic Parkinson’s disease patients’ relatives with a decreased sense of smell. Ann Neurol 50:34–41
Boeve BF, Dickson DW, Olson EJ, Shepard JW, Silber MH, Ferman TJ, Ahlskog JE, Benarroch EE (2007) Insights into REM sleep behavior disorder pathophysiology in brainstem-predominant Lewy body disease. Sleep Med 8:60–64
Bower JH, Maraganore DM, McDonnell SK, Rocca WA (1997) Incidence of progressive supranuclear palsy and multiple system atrophy in Olmsted County, Minnesota, 1976 to 1990. Neurology 49:1284–1288
Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259
Dickson DW, Fujishiro H, Delledonne A, Menke J, Ahmed Z, Klos KJ, Josephs KA, Frigerio R, Burnett M, Parisi JE, Ahlskog JE (2008) Evidence that incidental Lewy body disease is pre-symptomatic Parkinson’s disease. Acta Neuropathol 115:437–444
Dorsey ER, Constantinescu R, Thompson JP, Biglan KM, Holloway RG, Kieburtz K, Marshall FJ, Ravina BM, Schifitto G, Siderowf A, Tanner CM (2007) Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 68:384–385
Gibb WR, Lees AJ (1988) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatr 51:745–752
Gilman S, Low PA, Quinn N, Albanese A, Ben-Shlomo Y, Fowler CJ, Kaufmann H, Klockgether T, Lang AE, Lantos PL, Litvan I, Mathias CJ, Oliver E, Robertson D, Schatz I, Wenning GK (1999) Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci 163:94–98
Glass GA, Josephs KA, Ahlskog JE (2006) Respiratory insufficiency as the primary presenting symptom of multiple-system atrophy. Arch Neurol 63:978–981
Gwinn-Hardy K, Mehta ND, Farrer M, Maraganore D, Muenter M, Yen SH, Hardy J, Dickson DW (2000) Distinctive neuropathology revealed by alpha-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p. Acta Neuropathol 99:663–672
Inoue M, Yagishita S, Ryo M, Hasegawa K, Amano N, Matsushita M (1997) The distribution and dynamic density of oligodendroglial cytoplasmic inclusions (GCIs) in multiple system atrophy: a correlation between the density of GCIs and the degree of involvement of striatonigral and olivopontocerebellar systems. Acta Neuropathol 93:585–591
Iranzo A, Molinuevo JL, Santamaria J, Serradell M, Marti MJ, Valldeoriola F, Tolosa E (2006) Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study. Lancet Neurol 5:572–577
Jellinger KA, Seppi K, Wenning GK (2005) Grading of neuropathology in multiple system atrophy: proposal for a novel scale. Mov Disord 20(Suppl 12):S29–S36
Klos KJ, Ahlskog JE, Josephs KA, Apaydin H, Parisi JE, Boeve BF, DeLucia MW, Dickson DW (2006) Alpha-synuclein pathology in the spinal cords of neurologically asymptomatic aged individuals. Neurology 66:1100–1102
Kovacs T, Papp MI, Cairns NJ, Khan MN, Lantos PL (2003) Olfactory bulb in multiple system atrophy. Mov Disord 18:938–942
McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872
Parkkinen L, Hartikainen P, Alafuzoff I (2007) Abundant glial alpha-synuclein pathology in a case without overt clinical symptoms. Clin Neuropathol 26:276–283
Schrag A, Ben-Shlomo Y, Quinn NP (1999) Prevalence of progressive supranuclear palsy and multiple system atrophy: a cross-sectional study. Lancet 354:1771–1775
Togo T, Cookson N, Dickson DW (2002) Argyrophilic grain disease: neuropathology, frequency in a dementia brain bank and lack of relationship with apolipoprotein E. Brain Pathol 12:45–52
Trojanowski JQ, Revesz T (2007) Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy. Neuropathol Appl Neurobiol 33:615–620
Uchikado H, DelleDonne A, Uitti R, Dickson DW (2006) Coexistence of PSP and MSA: a case report and review of the literature. Acta Neuropathol 111:186–192
Wakabayashi K, Mori F, Nishie M, Oyama Y, Kurihara A, Yoshimoto M, Kuroda N (2005) An autopsy case of early (“minimal change”) olivopontocerebellar atrophy (multiple system atrophy-cerebellar). Acta Neuropathol 110:185–190
Watanabe H, Saito Y, Terao S, Ando T, Kachi T, Mukai E, Aiba I, Abe Y, Tamakoshi A, Doyu M, Hirayama M, Sobue G (2002) Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients. Brain 125:1070–1083
Wenning GK, Colosimo C, Geser F, Poewe W (2004) Multiple system atrophy. Lancet Neurol 3:93–103
Wenning GK, Quinn N, Magalhaes M, Mathias C, Daniel SE (1994) “Minimal change” multiple system atrophy. Mov Disord 9:161–166
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Supported by NIH grants P50-AG16574, P50-NS40256 and R01-AG15866, Pacific Alzheimer Research Foundation (PARF) grant C06-01.
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Fujishiro, H., Ahn, TB., Frigerio, R. et al. Glial cytoplasmic inclusions in neurologically normal elderly: prodromal multiple system atrophy?. Acta Neuropathol 116, 269–275 (2008). https://doi.org/10.1007/s00401-008-0398-7
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DOI: https://doi.org/10.1007/s00401-008-0398-7