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01-07-2015 | Original Paper

Atypical multiple system atrophy is a new subtype of frontotemporal lobar degeneration: frontotemporal lobar degeneration associated with α-synuclein

Authors: Naoya Aoki, Philip J. Boyer, Cheryl Lund, Wen-Lang Lin, Shunsuke Koga, Owen A. Ross, Myron Weiner, Anne Lipton, James M. Powers, Charles L. White III, Dennis W. Dickson

Published in: Acta Neuropathologica | Issue 1/2015

Abstract

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease clinically characterized by cerebellar signs, parkinsonism, and autonomic dysfunction. Pathologically, MSA is an α-synucleinopathy affecting striatonigral and olivopontocerebellar systems, while neocortical and limbic involvement is usually minimal. In this study, we describe four patients with atypical MSA with clinical features consistent with frontotemporal dementia (FTD), including two with corticobasal syndrome, one with progressive non-fluent aphasia, and one with behavioral variant FTD. None had autonomic dysfunction. All had frontotemporal atrophy and severe limbic α-synuclein neuronal pathology. The neuronal inclusions were heterogeneous, but included Pick body-like inclusions. The latter were strongly associated with neuronal loss in the hippocampus and amygdala. Unlike typical Pick bodies, the neuronal inclusions were positive on Gallyas silver stain and negative on tau immunohistochemistry. In comparison to 34 typical MSA cases, atypical MSA had significantly more neuronal inclusions in anteromedial temporal lobe and limbic structures. While uncommon, our findings suggest that MSA may present clinically and pathologically as a frontotemporal lobar degeneration (FTLD). We suggest that this may represent a novel subtype of FTLD associated with α-synuclein (FTLD-synuclein).

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Ahmed Z, Asi YT, Sailer A, Lees AJ, Houlden H, Revesz T, Holton JL (2012) The neuropathology, pathophysiology and genetics of multiple system atrophy. Neuropathol Appl Neurobiol 38:4–24PubMedCrossRef

Beach TG, White CL, Hamilton RL, Duda JE, Iwatsubo T, Dickson DW, Leverenz JB, Roncaroli F, Buttini M, Hladik CL, Sue LI, Noorigian JV, Adler CH (2008) Evaluation of alpha-synuclein immunohistochemical methods used by invited experts. Acta Neuropathol 116:277–288PubMedCentralPubMedCrossRef

Boeve BF, Lang AE, Litvan I (2003) Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia. Ann Neurol 54(Suppl 5):S15–S19PubMedCrossRef

Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259PubMedCrossRef

Duda JE, Giasson BI, Mabon ME, Miller DC, Golbe LI, Lee VM, Trojanowski JQ (2002) Concurrence of alpha-synuclein and tau brain pathology in the Contursi kindred. Acta Neuropathol 104:7–11PubMedCrossRef

Fanciulli A, Wenning GK (2015) Multiple-system atrophy. N Engl J Med 372:249–263PubMedCrossRef

Fujishiro H, Imamura AY, Lin WL, Uchikado H, Mark MH, Golbe LI, Markopoulou K, Wszolek ZK, Dickson DW (2013) Diversity of pathological features other than Lewy bodies in familial Parkinson’s disease due to SNCA mutations. Am J Neurodegener Dis 2:266–275PubMedCentralPubMed

Gai WP, Power JH, Blumbergs PC, Blessing WW (1998) Multiple-system atrophy: a new alpha-synuclein disease? Lancet 352:547–548PubMedCrossRef

Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, Wood NW, Colosimo C, Durr A, Fowler CJ, Kaufmann H, Klockgether T, Lees A, Poewe W, Quinn N, Revesz T, Robertson D, Sandroni P, Seppi K, Vidailhet M (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71:670–676PubMedCentralPubMedCrossRef

10.

Graham JG, Oppenheimer DR (1969) Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy. J Neurol Neurosurg Psychiatry 32:28–34PubMedCentralPubMedCrossRef

11.

Grossman M (2010) Primary progressive aphasia: clinicopathological correlations. Nat Rev Neurol 6:88–97PubMedCentralPubMedCrossRef

12.

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 99:663–672PubMedCrossRef

13.

Horoupian DS, Dickson DW (1991) Striatonigral degeneration, olivopontocerebellar atrophy and “atypical” Pick disease. Acta Neuropathol 81:287–295PubMedCrossRef

14.

Ishizawa T, Mattila P, Davies P, Wang D, Dickson DW (2003) Colocalization of tau and alpha-synuclein epitopes in Lewy bodies. J Neuropathol Exp Neurol 62:389–397PubMed

15.

Josephs KA, Hodges JR, Snowden JS, Mackenzie IR, Neumann M, Mann DM, Dickson DW (2011) Neuropathological background of phenotypical variability in frontotemporal dementia. Acta Neuropathol 122:137–153PubMedCentralPubMedCrossRef

16.

Katayama T, Yamaoka A, Yokokawa Y, Saito Y, Aiba L, Yasuda T, Yoshida M, Hashizume Y (2000) An autopsy case of multiple system atrophy (MSA) with marked temporal lobe atrophy and numerous Pick bodylike inclusions. Neuropathology 20:A29

17.

Kato S, Nakamura H (1990) Cytoplasmic argyrophilic inclusions in neurons of pontine nuclei in patients with olivopontocerebellar atrophy: immunohistochemical and ultrastructural studies. Acta Neuropathol 79:584–594PubMedCrossRef

18.

Kiely AP, Asi YT, Kara E, Limousin P, Ling H, Lewis P, Proukakis C, Quinn N, Lees AJ, Hardy J, Revesz T, Houlden H, Holton JL (2013) alpha-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson’s disease and multiple system atrophy? Acta Neuropathol 125:753–769PubMedCentralPubMedCrossRef

19.

Konagaya M, Sakai M, Yoshida M, Hashizume Y (2006) An autopsy case of long-course multiple system atrophy (MSA) with remarkable atrophy and numerous NCI in the temporal lobe. No To Shinkei 58:430–437PubMed

20.

Kouri N, Whitwell JL, Josephs KA, Rademakers R, Dickson DW (2011) Corticobasal degeneration: a pathologically distinct 4R tauopathy. Nat Rev Neurol 7:263–272PubMedCrossRef

21.

Lantos PL (1998) The definition of multiple system atrophy: a review of recent developments. J Neuropathol Exp Neurol 57:1099–1111PubMedCrossRef

22.

Lasagna-Reeves CA, Castillo-Carranza DL, Guerrero-Muoz MJ, Jackson GR, Kayed R (2010) Preparation and characterization of neurotoxic tau oligomers. Biochemistry 49:10039–10041PubMedCrossRef

23.

Lin WL, DeLucia MW, Dickson DW (2004) Alpha-synuclein immunoreactivity in neuronal nuclear inclusions and neurites in multiple system atrophy. Neurosci Lett 354:99–102PubMedCrossRef

24.

Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E, Perry RH, Trojanowski JQ, Mann DM, Lee VM (2011) A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 122:111–113PubMedCentralPubMedCrossRef

25.

Markopoulou K, Dickson DW, McComb RD, Wszolek ZK, Katechalidou L, Avery L, Stansbury MS, Chase BA (2008) Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson’s disease. Variability in familial Parkinson’s disease. Acta Neuropathol 116:25–35PubMedCentralPubMedCrossRef

26.

Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:1546–1554PubMedCrossRef

27.

Nishie M, Mori F, Yoshimoto M, Takahashi H, Wakabayashi K (2004) A quantitative investigation of neuronal cytoplasmic and intranuclear inclusions in the pontine and inferior olivary nuclei in multiple system atrophy. Neuropathol Appl Neurobiol 30:546–554PubMedCrossRef

28.

Obi T, Nishioka K, Ross OA, Terada T, Yamazaki K, Sugiura A, Takanashi M, Mizoguchi K, Mori H, Mizuno Y, Hattori N (2008) Clinicopathologic study of a SNCA gene duplication patient with Parkinson disease and dementia. Neurology 70:238–241PubMedCrossRef

29.

Ozawa T, Paviour D, Quinn NP, Josephs KA, Sangha H, Kilford L, Healy DG, Wood NW, Lees AJ, Holton JL, Revesz T (2004) The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain 127:2657–2671PubMedCrossRef

30.

Papp MI, Kahn JE, Lantos PL (1989) Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy–Drager syndrome). J Neurol Sci 94:79–100PubMedCrossRef

31.

Piao YS, Hayashi S, Hasegawa M, Wakabayashi K, Yamada M, Yoshimoto M, Ishikawa A, Iwatsubo T, Takahashi H (2001) Co-localization of alpha-synuclein and phosphorylated tau in neuronal and glial cytoplasmic inclusions in a patient with multiple system atrophy of long duration. Acta Neuropathol 101:285–293PubMed

32.

Shibuya K, Nagatomo H, Iwabuchi K, Inoue M, Yagishita S, Itoh Y (2000) Asymmetrical temporal lobe atrophy with massive neuronal inclusions in multiple system atrophy. J Neurol Sci 179:50–58PubMedCrossRef

33.

Shinagawa S, Miller B (2015) Frontotemporal dementia. In: Rosenberg RN, Padcual JM (eds) Rosenberg’s molecular and genetic basis of neurological and psychiatric disease, vol 69, 5th edn. Elsevier, London, pp 779–791

34.

Sikorska B, Papierz W, Preusser M, Liberski PP, Budka H (2007) Synucleinopathy with features of both multiple system atrophy and dementia with Lewy bodies. Neuropathol Appl Neurobiol 33:126–129PubMed

35.

Snowden J, Neary D, Mann D (2007) Frontotemporal lobar degeneration: clinical and pathological relationships. Acta Neuropathol 114:31–38PubMedCrossRef

36.

Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M (1998) Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci Lett 251:205–208PubMedCrossRef

37.

Thal DR, Rub U, Orantes M, Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800PubMedCrossRef

38.

Tu PH, Galvin JE, Baba M, Giasson B, Tomita T, Leight S, Nakajo S, Iwatsubo T, Trojanowski JQ, Lee VM (1998) Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol 44:415–422PubMedCrossRef

39.

Uchihara T, Nakamura A, Mochizuki Y, Hayashi M, Orimo S, Isozaki E, Mizutani T (2005) Silver stainings distinguish Lewy bodies and glial cytoplasmic inclusions: comparison between Gallyas-Braak and Campbell-Switzer methods. Acta Neuropathol 110:255–260PubMedCrossRef

40.

Uchihara T, Tsuchiya K, Nakamura A, Akiyama H (2005) Silver staining profiles distinguish Pick bodies from neurofibrillary tangles of Alzheimer type: comparison between Gallyas and Campbell-Switzer methods. Acta Neuropathol 109:483–489PubMedCrossRef

41.

Uchikado H, Lin WL, DeLucia MW, Dickson DW (2006) Alzheimer disease with amygdala Lewy bodies: a distinct form of alpha-synucleinopathy. J Neuropathol Exp Neurol 65:685–697PubMedCrossRef

42.

Wakabayashi K, Takahashi H (2006) Cellular pathology in multiple system atrophy. Neuropathology 26:338–345PubMedCrossRef

43.

Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H (1998) Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 249:180–182PubMedCrossRef

44.

Wang L, Hashizume Y, Yoshdia M, Hishikawa N (2002) Temporal lobe lesions in multiple system atrophy. Neuropathology 22:A18

45.

Yokoyama T, Kusunoki JI, Hasegawa K, Sakai H, Yagishita S (2001) Distribution and dynamic process of neuronal cytoplasmic inclusion (NCI) in MSA: correlation of the density of NCI and the degree of involvement of the pontine nuclei. Neuropathology 21:145–154PubMedCrossRef

46.

Yuasa H, Mitake S, Yoshdia M, Hashizume Y, Ojika K (2002) An autopsy case of multiple system atrophy (MSA) with dementia and marked atrophy of the temporal lobe. Neuropathology 22:A18

47.

Zhang YJ, Xu YF, Cook C, Gendron TF, Roettges P, Link CD, Lin WL, Tong J, Castanedes-Casey M, Ash P, Gass J, Rangachari V, Buratti E, Baralle F, Golde TE, Dickson DW, Petrucelli L (2009) Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc Natl Acad Sci 106:7607–7612PubMedCentralPubMedCrossRef

48.

Zhukareva V, Mann D, Pickering-Brown S, Uryu K, Shuck T, Shah K, Grossman M, Miller BL, Hulette CM, Feinstein SC, Trojanowski JQ, Lee VM (2002) Sporadic Pick’s disease: a tauopathy characterized by a spectrum of pathological tau isoforms in gray and white matter. Ann Neurol 51:730–739PubMedCrossRef

Title: Atypical multiple system atrophy is a new subtype of frontotemporal lobar degeneration: frontotemporal lobar degeneration associated with α-synuclein
Authors: Naoya Aoki
Philip J. Boyer
Cheryl Lund
Wen-Lang Lin
Shunsuke Koga
Owen A. Ross
Myron Weiner
Anne Lipton
James M. Powers
Charles L. White III
Dennis W. Dickson
Publication date: 01-07-2015
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 1/2015
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-015-1442-z

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Atypical multiple system atrophy is a new subtype of frontotemporal lobar degeneration: frontotemporal lobar degeneration associated with α-synuclein

Abstract

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Abstract

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