Abstract
Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Recent descriptions of a pathological sub-type that is ubiquitin positive, TDP-43 negative and immunostains positive for the Fused in Sarcoma protein (FUS) raises the question whether it is associated with a distinct clinical phenotype identifiable on clinical grounds, and whether mutations in the Fused in Sarcoma gene (FUS) might also be associated with FTLD. Examination of a pathological series of 118 cases of FTLD from two centres, showing tau-negative, ubiquitin-positive pathology, revealed FUS pathology in five patients, four classified as atypical FTLD with ubiquitin inclusions (aFTLD-U), and one as neuronal intermediate filament inclusion disease (NIFID). The aFTLD-U cases had youthful onset (22–46 years), an absence of strong family history, a behavioural syndrome consistent with frontotemporal dementia (FTD) and severe caudate atrophy. Their cognitive/behavioural profile was distinct, characterised by prominent obsessionality, repetitive behaviours and rituals, social withdrawal and lack of engagement, hyperorality with pica, and marked stimulus-bound behaviour including utilisation behaviour. They conformed to the rare behavioural sub-type of FTD identified previously by us as the “stereotypic” form, and linked to striatal pathology. Cognitive evaluation revealed executive deficits in keeping with subcortical-frontal dysfunction, but no cortical deficits in language, perceptuospatial skills or praxis. The patient with NIFID was older and exhibited aphasia and dyspraxia. No patient had clinical evidence of motor neurone disease during life, or a mutation in the FUS gene. In the complementary clinical study of 312 patients with clinical syndromes of FTLD, genetic analysis revealed a 6 bp deletion in FUS in 3 patients, of questionable significance. One presented a prototypical picture of FTD, another expressive language disorder, and the third semantic dementia. None showed the early onset age or distinctive ‘stereotypic’ picture of patients with aFTLD-U. We conclude that aFTLD-U is associated with a distinct clinical form of frontotemporal dementia, potentially allowing identification of such patients in life with a high degree of precision. Whether mutations in the FUS gene cause some cases of FTLD remains unresolved.
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Amici S, Gorno-Tempini M-L, Ogar JM, Dronkers NF, Miller BL (2006) An overview of primary progressive aphasia and its variants. Behav Neurol 17:77–87
Baborie A, Griffiths TD, Jaros E, Richardson A, Ferrari R, Moreno J, Momeni P, McKeith IG, Burn DJ, Duplessis D, Pal P, Rollinson S, Pickering-Brown SM, Thompson JC, Neary D, Snowden JS, Perry R, Mann DMA (2011) Pathological correlates of frontotemporal lobar degeneration in the elderly. Acta Neuropathol 121:365–371
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265
Bathgate D, Snowden JS, Varma A, Blackshaw A, Neary D (2001) Behaviour in frontotemporal dementia: a comparison with Alzheimer’s disease and vascular dementia. Acta Neurol Scand 103:367–373
Cairns NJ, Grossman M, Arnold SE, Burn DJ, Jaros E, Perry RH, Duyckaerts C, Stankoff B, Pillon B, Skullerud K, Cruz-Sanchez FF, Bigio EH, Mackenzie IR, Gearing M, Juncos JL, Glass JD, Yokoo H, Nakazato Y, Mosaheb S, Thorpe JR, Uryu K, Lee VM, Trojanowski JQ (2004) Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease. Neurology 63:1376–1384
Cairns NJ, Bigio EH, Mackenzie IRA, Neumann M, Lee VMY, Hatanpaa KJ, White CL III, Schneider JA, Tenenholz Grinberg L, Halliday G, Duyckaerts C, Lowe JS, Holm IE, Tolnay M, Okamoto K, Yokoo H, Murayama S, Woulfe J, Munoz DG, Dickson DW, Ince PG, Trojanowski JQ, Mann DMA (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 114:2–22
Crawford J, Garthwaite PH (2002) Investigation of the single case in neuropsychology: confidence limits on the abnormality of test scores and test score differences. Neuropsychologia 40:1196–1208
Crawford J, Howell DC (1998) Comparing an individual’s test score against norms derived from small samples. Clin Neuropsychol 12:482–486
Davidson Y, Kelley T, Mackenzie IR, Pickering-Brown SM, Du Plessis D, Neary D, Snowden JS, Mann DMA (2007) Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol 113:521–533
de Bakker PI, Yelensky R, Pe’er I, Gabriel SB, Daly MJ, Altshuler D (2005) Efficiency and power in genetic association studies. Nat Genet 37:1217–1223
Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229
Gorno-Tempini ML, Dronkers NF, Rankin KP, Ogar JM, Phengrasamy L, Rosen HJ, Johnson JK, Weiner MW, Miller B (2004) Cognition and anatomy of three variants of primary progressive aphasia. Ann Neurol 55:335–346
Josephs KA, Petersen RC, Knopman DS, Boeve BF, Whitwell JL, Duffy JR, Parisi JE, Dickson DW (2006) Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP. Neurology 66:41–48
Josephs KA, Duffy JR, Strand EA, Whitwell JL, Layton KF, Parisi JE, Hauser MF, Witte RJ, Boeve BF, Knopman DS, Dickson DW, Jack CR Jr, Petersen RC (2006) Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech. Brain 129:1385–1398
Josephs KA, Stroh A, Dugger B, Dickson DW (2009) Evaluation of subcortical pathology and clinical correlations in FTLD-U subtypes. Acta Neuropathol 118:349–358
Josephs KA, Whitwell JL, Parisi JE, Petersen RC, Boeve BF, Jack CR, Dickson DW (2010) Caudate atrophy on MRI is a characteristic feature of FTLD-FUS. Eur J Neurol 17:969–975
Kelley BJ, Haidar W, Boeve BF, Baker M, Graff-Radford NR, Krefft T, Frank AR, Jack CR Jr, Shiung M, Knopman DS, Josephs KA, Parashos SA, Rademakers R, Hutton M, Pickering-Brown S, Adamson J, Kuntz KM, Dickson DW, Parisi JE, Smith GE, Ivnik RJ, Petersen RC (2009) Prominent phenotypic variability associated with mutations in progranulin. Neurobiol Aging 30:739–751
Kwiatkowski TJ, Bosco DA, LeClerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PA, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, Kenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208
Loy CT, McCusker E, Kril JJ, Kwok JB, Brooks WS, McCann H, Isaacs A, Halliday GM (2010) Very early-onset frontotemporal dementia with no family history predicts underlying fused in sarcoma pathology. Brain 133:e158
Mackenzie IRA (2007) The neuropathology and clinical phenotype of FTD with progranulin mutations. Acta Neuropathol 114:49–54
Mackenzie IRA, Baborie A, Pickering-Brown S, Du Plessis D, Jaros E, Perry RH, Neary D, Snowden JS, Mann DMA (2006) Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol 112:539–549
Mackenzie IRA, Foti D, Woulfe J, Hurwitz TA (2008) Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions. Brain 131:1282–1293
Mackenzie IRA, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, Kovacs GG, Ghetti B, Halliday G, Holm IE, Ince PG, Kamphorst W, Revesz T, Rozemuller AJM, Kumar-Singh S, Akiyama H, Baborie A, Spina S, Dickson DW, Trojanowski JQ, Mann DMA (2009) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 117:15–18
Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, Kovacs GG, Ghetti B, Halliday G, Holm IE, Ince PG, Kamphorst W, Revesz T, Rozemuller AJM, Kumar-Singh S, Akiyama H, Baborie A, Spina S, Dickson DW, Trojanowski JQ, Mann DMA (2010) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations: an update. Acta Neuropathol 119:1–4
Mateen FJ, Josephs KA (2009) The clinical spectrum of stereotypies in frontotemporal lobar degeneration. Mov Disord 24:1237–1240
Menon R, Baborie A, Jaros E, Mann DMA, Ray PS, Larner AJ (2010) What’s in a name? Neuronal intermediate filament inclusion disease (NIFID), frontotemporal lobar degeneration-intermediate filament (FTLD-IF) or frontotemporal lobar degeneration-fused in sarcoma (FTLD-FUS)? J Neurol Neurosurg Psychiatry doi:10.1136/jnnp.2010.220947
Molina-Porcel L, Llado A, Rey MJ, Molinuevo JL, Martinez-Lage M, Esteve FX, Ferrer I, Tolosa E, Blesa R (2008) Clinical and pathological heterogeneity of neuronal intermediate filament inclusion disease. Arch Neurol 65:272–275
Munoz DG, Neumann M, Kusaka H, Yokota O, Ishihara K, Terada S, Kuroda S, Mackenzie IRA (2009) FUS pathology in basophilic inclusion body disease. Acta Neuropathol 118:617–627
Neary D, Snowden JS, Mann DMA, Northen B, Goulding PJ, MacDermott N (1990) Frontal lobe dementia and motor neurone disease. J Neurol Neurosurg Psychiatry 53:23–32
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 51:1546–1554
Neary D, Snowden JS, Mann DMA (2005) Frontotemporal dementia. Lancet Neurol 4:771–780
Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar H, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133
Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IRA (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132:2922–2931
Neumann M, Roeber S, Kretzchmar HA, Rademakers R, Baker M, Mackenzie IRA (2009) Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol 118:605–616
Nyatsanza S, Shetty T, Gregory C, Lough S, Dawson K, Hodges JR (2003) A study of stereotypic behaviours in Alzheimer’s disease and frontal and temporal variant frontotemporal dementia. J Neurol Neurosurg Psychiatry 74:1398–1402
Pickering-Brown SM, Richardson AM, Snowden JS, McDonagh AM, Burns A, Braude W, Baker M, Liu W-K, Yen S-H, Hardy J, Hutton M, Davies Y, Allsop D, Craufurd D, Neary D, Mann DMA (2002) Inherited frontotemporal dementia in 9 British families associated with intronic mutations in the tau gene. Brain 125:732–751
Pickering-Brown SM, Rollinson S, Du Plessis D, Morrison KE, Varma A, Richardson AMT, Neary D, Snowden JS, Mann DMA (2008) Frequency and clinical characteristics of progranulin mutation carriers in the Manchester Frontotemporal Lobar Degeneration cohort: comparison to patients with MAPT and no known mutations. Brain 131:721–731
Piguet O, Hornberger M, Shelley BP, Kipps CM, Hodges JR (2009) Sensitivity of current criteria for the diagnosis of behavioural variant frontotemporal dementia. Neurology 72:732–737
Roeber S, Mackenzie IR, Kretzchmar HA, Neumann M (2008) TDP-43-negative FTLD-U is a significant new clinico-pathological subtype of FTLD. Acta Neuropathol 116:147–157
Rohrer JD, Lashley T, Holton J, Revesz T, Urwin H, Isaacs AM, Fox NC, Rossor MN, Warren J (2010) The clinical and neuroanatomical phenotype of FUS associated frontotemporal lobar degeneration. J Neurol Neurosurg Psychiatry doi:10.1136/jnnp.2010.214437
Sampathu DM, Neumann M, Kwong LK, Chou TT, Micsenyi M, Truax A, Bruce J, Grossman M, Trojanowski JQ, Lee VM (2006) Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies. Am J Pathol 169:1343–1352
Seelaar H, Klijnsma KY, de Koning I, van der Lugt A, Zheng Chiu W, Azmani A, Rozemuller AJM, Van Swieten JC (2010) Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration. J Neurol 257:747–753
Snowden JS, Neary D, Mann DMA (1996) Frontotemporal lobar degeneration: frontotemporal dementia progressive aphasia and semantic dementia. Churchill Livingstone, London
Snowden JS, Bathgate B, Varma A, Blackshaw A, Gibbons ZC, Neary D (2001) Distinct behavioural profiles in frontotemporal dementia and semantic dementia. J Neurol Neurosurg Psychiatry 70:323–332
Snowden JS, Neary D, Mann DMA (2007) Frontotemporal lobar degeneration: clinical and pathological relationships. Acta Neuropathol 114:31–38
Stephens M, Donnelly P (2003) A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73:1162–1169
Stone J, Griffiths TD, Rastogi S, Perry RH, Cleland PG (2003) Non-Picks frontotemporal dementia imitating schizophrenia in a 22-year-old man. J Neurol 250:369–370
Strong MJ, Grace GM, Freedman M, Lomen-Hoerth C, Woolley S, Goldstein LH, Murphy J, Shoesmith C, Rosenfeld J, Leigh PN, Bruijn L, Ince P, Figlewicz D (2009) Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 10:131–146
Tateishi T, Hokonohara T, Yamasaki R, Miura S, Kikuchi H, Iwaki A, Tashiro H, Furuya H, Nagara Y, Ohyagi Y, Nukina N, Iwaki T, Fukumaki Y, Kira JI (2010) Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation. Acta Neuropathol 119:355–364
Urwin H, Josephs KA, Rohrer JD, Mackenzie IR, Neumann M, Authier A, Seelaar H, Van Swieten JC, Brown JM, Johannsen P, Nielsen JE, Holm IE, Consortium The FReJA, Dickson DW, Rademakers R, Graff-Radford NR, Parisi JE, Petersen RC, Hatanpaa KJ, White CL III, Weiner MF, Geser F, Van Deerlin VM, Trojanowski JQ, Miller BL, Seeley WW, van der Zee J, Kumar-Singh S, Engelborghs S, De Deyn PP, Van Broeckhoven C, Bigio EH, Deng HX, Halliday GM, Kril JJ, Munoz DG, Mann DM, Pickering-Brown SM, Doodeman V, Adamson G, Ghazi-Noori S, Fisher EM, Holton JL, Revesz T, Rossor MN, Collinge J, Mead S, Isaacs AM (2010) FUS pathology defines the majority of tau-and TDP-43-negative frontotemporal lobar degeneration. Acta Neuropathol 120:33–41
Vance C, Roegelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211
Van Langenhove T, van der Zee J, Sleegers K, Engelborghs S, Vandenberghe R, Gijselinck I, Van den Broeck M, Mattheijssens M, Peeters K, De Deyn PP, Cruts M, Van Broeckhoven C (2010) Genetic contribution of FUS to frontotemporal lobar degeneration. Neurology 74:366–371
Yokota O, Tsuchiya K, Terada S, Ishizu H, Uchikado H, Ikeda M, Oyanagi K, Nakazano I, Murayama S, Kuroda S, Akiyama H (2008) Basophilic inclusion body disease and neuronal intermediate filament inclusion disease: a comparative clinicopathological study. Acta Neuropathol 115:561–575
Acknowledgments
We thank all staff at the Neuropathology Department, Newcastle General Hospital, and Histopathology Department, Salford Royal Hospitals NHS Foundation Trust, for technical assistance, particularly Andrew Brown and Janet Thompson at Newcastle for cutting and staining of the sections and Lynne Ramsay for the TDP43 staining. Dr E. Jaros, Andrew Brown and Lynne Ramsay have been supported by the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Hospitals NHS Foundation Trust. Quan Hu is supported through 111 Project funding to Professor Jinzhou Tian from People’s Republic of China. We also acknowledge the support of Alzheimer’s Research Trust and Alzheimer’s Society through their funding of the Manchester Brain Bank under the Brains for Dementia Research (BDR) initiative. D.M.A.M. and S.P.B. also receive funding from MRC and Wellcome Trust which supported this study in part.
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Snowden, J.S., Hu, Q., Rollinson, S. et al. The most common type of FTLD-FUS (aFTLD-U) is associated with a distinct clinical form of frontotemporal dementia but is not related to mutations in the FUS gene. Acta Neuropathol 122, 99–110 (2011). https://doi.org/10.1007/s00401-011-0816-0
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DOI: https://doi.org/10.1007/s00401-011-0816-0