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P2‐205: Neuropathologic and genetic characterization of frontotemporal lobar degeneration with ubiquitin‐ and/or TDP‐43‐positive inclusions: A large series
Author(s) -
Spina Salvatore,
Murrell Jill R.,
Vidal Ruben,
Ghetti Bernardino
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.1280
Subject(s) - frontotemporal lobar degeneration , pathology , frontotemporal dementia , immunohistochemistry , pathological , ubiquitin , dementia , histopathology , medicine , biology , disease , genetics , gene
Background: Four different pathological subtypes of frontotemporal lobar degeneration with ubiquitin (Ub)-immunoreactive (ir) inclusions (FTLD-U) have been proposed. Aim of this study is to assess the applicability of this classification, based on combined Uband TDP-43-immunohistochemistry (IHC), to our series of FTLD-U cases. Methods: Uband TDP-43-IHC were carried out on tissue from 53 cases with neuropathological diagnosis of FTLD-U, ALS or dementia lacking distinctive histopathology (DLDH). Genetic analyses for Progranulin (PGRN), ValosinContaining Protein (VCP), Charged multivesicular body protein 2B (CHMP2B), and Superoxide dismutase-1 (SOD-1) genes were carried out on selected cases, as suggested by the corresponding neuropathological phenotype. Results: Twenty-five cases were classified according to the proposed criteria (type I: 5 cases; type II: 7 cases; type III: 9 cases; type IV: 4 cases). In 5 out of 9 type III cases, the disease was associated with a PGRN mutation: respectively, A9D, IVS6-2AG, Q358X, A472AfsX38 (c.1416_1417delTG) or R493X. All type 4 cases had a VCP mutation: R159C, R191Q and T262A (2 cases), respectively. Among the other 28 cases, 6 distinct groups were identified according to the respective clinicopathological characteristics: a) ALS with Ub and TDP-43 immunoreactive deposits confined to the motor neurons only (5 cases); b) ALS with Ub-ir but TDP-43-negative inclusions (4 cases); c) FTD with Ub-ir and TDP-43-ir inclusions limited to the dentate gyrus (DG) (4 cases); d) FTD with Ub-ir but TDP-43-negative inclusions limited to the DG (4 cases); e) FTD with FTLD-U type II-like pathology with Ub-ir but TDP-43negative inclusions (2 cases); f) DLDH (9 cases). No SOD-1 or CHMP2B mutations were identified in subjects belonging to the group (b) or (d), respectively. Conclusions: The use of Uband TDP-43 IHC allowed the classification of 47.1% of cases from our series, according to the criteria. 17% had a pathological diagnosis of DLDH. Among those cases not meeting criteria for inclusion in one of the proposed subtypes, new clinicopathological entities, potentially associated with novel biological mechanisms of neurodegeneration were observed. Supported by AG10133 and Alzheimer’s Association.