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特集 前頭側頭葉変性症
文献概要
はじめに
筋萎縮性側索硬化症（amyotrophic lateral sclerosis：ALS）の舌下神経核や脊髄前角運動ニューロンにみられるユビキチン免疫染色に陽性を示す線維状封入体skein-like inclusions（SLI）あるいは球状のround inclusions（RI）1，2），そして認知症を伴う筋萎縮性側索硬化症（ALS with dementia：ALS-D)3，4）やユビキチン陽性封入体を伴う前頭側頭葉変性症（frontotemporal lobar degeneration with ubiquitinated inclusions：FTLD-U)5）の海馬歯状回顆粒細胞や前頭側頭葉皮質の神経細胞に出現するタウやシヌクレインに陰性でユビキチンにのみ陽性を示す封入体（ubiquitinated inclusions：UI)6－8）はALS，ALS-D，FTLD-Uの病理診断の指標となっていたが，UIの本体は長い間不明であった。2006年にNeumannらとわが国のAraiらによってUIの構成蛋白がTAR DNA-binding protein of 43 kDa（TDP-43）であることが同定された9－11）。ALSやFTLD-Uの病理所見で観察されるUIが免疫組織学的にTDP-43に陽性を示すことが確認され，疾患解明の大きな突破口となっている（Fig.1）。本稿ではALSからFTLD-Uの病理像をTDP-43陽性封入体と後述するサブタイプの所見とともに解説し代表的な症例を紹介する。
筋萎縮性側索硬化症（amyotrophic lateral sclerosis：ALS）の舌下神経核や脊髄前角運動ニューロンにみられるユビキチン免疫染色に陽性を示す線維状封入体skein-like inclusions（SLI）あるいは球状のround inclusions（RI）1，2），そして認知症を伴う筋萎縮性側索硬化症（ALS with dementia：ALS-D)3，4）やユビキチン陽性封入体を伴う前頭側頭葉変性症（frontotemporal lobar degeneration with ubiquitinated inclusions：FTLD-U)5）の海馬歯状回顆粒細胞や前頭側頭葉皮質の神経細胞に出現するタウやシヌクレインに陰性でユビキチンにのみ陽性を示す封入体（ubiquitinated inclusions：UI)6－8）はALS，ALS-D，FTLD-Uの病理診断の指標となっていたが，UIの本体は長い間不明であった。2006年にNeumannらとわが国のAraiらによってUIの構成蛋白がTAR DNA-binding protein of 43 kDa（TDP-43）であることが同定された9－11）。ALSやFTLD-Uの病理所見で観察されるUIが免疫組織学的にTDP-43に陽性を示すことが確認され，疾患解明の大きな突破口となっている（Fig.1）。本稿ではALSからFTLD-Uの病理像をTDP-43陽性封入体と後述するサブタイプの所見とともに解説し代表的な症例を紹介する。
参考文献
1) Leigh PN, Anderton BH, Dodson A, Gallo JM, Swash M, et al: Ubiquitin deposits in anterior horn cells in motor neurone disease. Neurosci Lett 93: 197-203, 1988
2) Lowe J, Lennox G, Jefferson D, Morrell K, McQuire D, et al: A filamentous inclusion body within anterior horn neurones in motor neurone disease defined by immunocytochemical localisation of ubiquitin. Neurosci Lett 94: 203-210, 1988
3) 湯浅亮一: 痴呆を伴う筋萎縮性側索硬化症. 臨床神経10: 569-577, 1970
4) Mitsuyama Y, Takamiya S: Presenile dementia with motor neuron disease in Japan. A new entity? Arch Neurol 36: 592-593, 1979
5) Snowden JS, Neary D, Mann DM: Fronto-temporal lobar degeneration; fronto-temporal dementia, progressive aphasia, semantic dementia. New York, Churchill Livingstone, 1996
6) Okamoto K, Hirai S, Yamazaki T, Sun X, Nakazato Y: New ubiquitin-positive intraneuronal inclusions in the extra-motor cortices in patients with amyotrophic lateral sclerosis. Neurosci Lett 129: 233-236, 1991
7) Wightman G, Anderson VE, Martin J, Swash M Anderton BH, et al: Hippocampal and neocortical ubiquitin-immunoreactive inclusions in amyotrophic lateral sclerosis with dementia. Neurosci Lett 139: 269-274, 1992
8) Okamoto K, Murakami N, Kusaka H, Yoshida M, Hashizume Y, et al: Ubiquitin-positive intraneuronal inclusions in the extramotor cortices of presenile dementia patients with motor neuron disease. J Neurol 239: 426-430, 1992
9) Ou SH, Wu F, Harrich D, Garcia-Martinez LF, Gaynor RB, et al: Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J Virol 69: 3584-96, 1995
10) Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, et al: Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314: 130-133, 2006
11) Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, et al: TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351: 602-611, 2006
12) Piao YS, Wakabayashi K, Kakita A, Yamada M, Hayashi S, et al: Neuropathology with clinical correlations of sporadic amyotrophic lateral sclerosis: 102 autopsy cases examined between 1962 and 2000. Brain Pathol 13: 10-22, 2003
13) 吉田眞理, 村上信之, 橋詰良夫, 高橋 昭: 痴呆を伴う筋萎縮性側索硬化症13例の臨床病理学的検討. 臨床神経32: 1193-1202, 1992
14) Yoshida M: Amyotrophic lateral sclerosis with dementia: the clinicopathological spectrum. Neuropathology 24: 87-102, 2004
15) Tan CF, Eguchi H, Tagawa A, Onodera O, Iwasaki T, et al: TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation. Acta Neuropathol 113: 535-542, 2007
16) Fujita Y, Mizuno Y, Takatama M, Okamoto K: Anterior horn cells with abnormal TDP-43 immunoreactivities show fragmentation of the Golgi apparatus in ALS. J Neurol Sci 269: 30-34, 2008
17) Tolnay M, Probst A: Frontal lobe degeneration: novel ubiquitin-immunoreactive neurites within frontotemporal cortex. Neuropathol Appl Neurobiol 21: 492-497, 1995
18) Iseki E, Li F, Odawara T, Hino H, Suzuki K, et al: Ubiquitin-immunohistochemical investigation of atypical Pick's disease without Pick bodies. J Neurol Sci 159: 194-201, 1998
19) Ikeda K, Akiyama H, Arai T, Ueno H, Tsuchiya K, et al: Morphometrical reappraisal of motor neuron system of Pick's disease and amyotrophic lateral sclerosis with dementia. Acta Neuropathol 104: 21-28, 2002
20) Jackson M, Lennox G, Lowe J: Motor neurone disease-inclusion dementia. Neurodegeneration 5: 339-350, 1996
21) Holton JL, Révész T, Crooks R, Scaravilli F: Evidence for pathological involvement of the spinal cord in motor neuron disease-inclusion dementia. Acta Neuropathol 103: 221-227, 2002
22) Knopman DS, Mastri AR, Frey WH 2nd, Sung JH, Rustan T: Dementia lacking distinctive histologic features: a common non-Alzheimer degenerative dementia. Neurology 40: 251-256, 1990
23) Mackenzie IR, Shi J, Shaw CL, Duplessis D, Neary D, et al: Dementia lacking distinctive histology (DLDH) revisited. Acta Neuropathol 112: 551-559, 2006
24) Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, et al: Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442: 916-919, 2006
25) Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, et al: Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442: 920-924, 2006
26) Mackenzie IR: The neuropathology and clinical phenotype of FTD with progranulin mutations. Acta Neuropathol 114: 49-54, 2007
27) Cairns NJ, Bigio Eh, Mackenzie IRA, Neumann M, Lee VM, et al: Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frnototemporal Lobar Degeneration. Acta Neuropathol 114: 5-22, 2007
28) Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, et al: Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 117: 15-18, 2009
29) Yokoo H, Oyama T, Hirato J, Sasaki A, Nakazato Y: A case of Pick's disease with unusual neuronal inclusions. Acta Neuropathol 88: 267-272, 1994
30) Cairns NJ, Grossman M, Arnold SE, Burn DJ, Jaros E, et al: Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease. Neurology 63: 1376-1384, 2004
31) Josephs KA, Lin WL, Ahmed Z, Stroh DA, Graff-Radford NR, et al: Frontotemporal lobar degeneration with ubiquitin-positive, but TDP-43-negative inclusions. Acta Neuropathol 116: 159-167, 2008
32) Sampathu DM, Neumann M, Kwong LK, Chou TT, Micsenyi M, et al: Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies. Am J Pathol 169: 1343-1352, 2006
33) Mackenzie IR, Baborie A, Pickering-Brown S, Du Plessis D, Jaros E, et al: Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol 112: 539-549, 2006
34) Zhang H, Tan CF, Mori F, Tanji K, Kakita A, et al: TDP-43-immunoreactive neuronal and glial inclusions in the neostriatum in amyotrophic lateral sclerosis with and without dementia. Acta Neuropathol 115: 115-122, 2008
35) Yokota O, Tsuchiya K, Arai T, Yagishita S, Matsubara O, et al: Clinicopathological characterization of Pick's disease versus frontotemporal lobar degeneration with ubiquitin/TDP-43-positive inclusions. Acta Neuropathol 117: 429-444, 2009
36) Josephs KA, Stroh A, Dugger B, Dickson DW: Evaluation of subcortical pathology and clinical correlations in FTLD-U subtypes. Acta Neuropathol 118: 349-358, 2009
37) Amador-Ortiz C, Lin WL, Ahmed Z, Personett D, Davies P, et al: TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease. Ann Neurol 61: 435-445, 2006
38) Nakashima-Yasuda H, Uryu K, Robinson J, Xie SX, Hurtig H, et al: Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol 114: 221-229, 2007
39) Uryu K, Nakashima-Yasuda H, Forman MS, Kwong LK, Clark CM, et al: Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol 67: 555-564, 2008
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