Neuropathology of frontotemporal lobar degeneration: A review

Bahia, Valéria Santoro; Takada, Leonel Tadao; Deramecourt, Vincent

doi:10.1590/S1980-57642013DN70100004

ABSTRACT

Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. Three main clinical variants are widely recognized within the FTLD spectrum: the behavioural variant of frontotemporal dementia (bvFTD), semantic dementia (SD) and progressive non-fluent aphasia (PNFA). FTLD represents a highly heterogeneous group of neurodegenerative disorders which are best classified according to the main protein component of pathological neuronal and glial inclusions. The most common pathological class of FTLD is associated with the TDP-43 protein (FTLD-TDP), while FTLD-Tau is considered slightly less common while the FTLD-FUS (Fused in sarcoma protein) pathology is rare. In this review, these three major pathological types of FTLD are discussed.

Key words:
frontotemporal lobar degeneration; pathology; TAU; TDP; FUS

RESUMO

A degeneração lobar frontotemporal (DLFT) é a segunda principal causa de demência pré-senil. Sob o diagnóstido de DLFT, há três principais diagnósticos clínicos: demência frontotemporal variante comportamental (DFTvc), demência semântica (DS) e a afasia progressiva não Fluente (APNF). A DLFT representa um grupo heterogêneo de desordens degenerativas que são classificadas de acordo com o componente proteico patológico das inclusões neuronais e gliais. A classe patológica mais comum das DLFT é associada com a proteína TDP-43 (DLFT-TDP), seguida pela DLFT-Tau, enquanto a DLFT-FUS é rara. Nesta revisão, nós iremos discutir os três principais subtipos patológicos da DLFT.

Palavras-chave:
degeneração lobar frontotemporal; patologia; TAU; TDP; FUS

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REFERENCES

Ratnavalli E, Brayne C, Dawson K, Hodges JR. The prevalence of frontotemporal dementia. Neurology 2002;58:1615-1621.
Johnson JK, Dichl J, Mendez MF, et al. Frontotemporal lobar degeneration. Demographic characteristics of 353 patients. Arch Neurol 2005; 62:925-930.
Rosso SM, Kaat LD, Baks T, et al. Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain 2003;126:2016-2022.
Harvey RJ, Skelton-Robinson M, Rossor MN. The prevalence and causes of dementia in people under the age of 65 years. J Neurol Neurosurg Psychiatry 2003;74:1206-1209.
Knopman DS, Roberts RO. Estimating the number of persons with frontotemporal lobar degeneration in the US population. J Mol Neurosci 2011;45:330-335.
Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration. A consensus on clinical diagnostic criteria.. Neurology 1998; 51:1546-1554.
Lomen-Hoerth C, Anderson T, Miller B. The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology2002;59:1077-1079.
Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain2011;1-22.
Mesulan MM. Primary Progressive Aphasia. Ann Neurol 2001;49: 425-432.
Mesulan MM. Primary Progressive Aphasia: a language based dementia. N Engl J Med 2003;349:1535-1542.
Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology2011;76:1006-1014.
Rohrer JD, Lashley T, Schott JM, et al. Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration. Brain2011;134:2565-2581.
Scarpini E, Galimberti D. Clinical phenotypes and genetic biomarkers of FTLD. J Neural Transm 2012;119:851-860.
Broe M, Hodges JR, Schofield E, et al. Staging disease severity in pathologically confirmed cases of frontotemporal dementia. Neurology2003;60:1005-1011.
Josephs KA, Hodges JR, Snowden JS, et al. Neuropathological background of phenotypical variability in frontotemporal dementia. Acta neuropathol 2011;122:137-153.
Hutton N, Lendon CL, Rizzu P, et al. Association of missense and 5'-splice-site mutations in TAU with the inherited dementia FTDP-17. Nature 1998;393:702-705.
Arai T, Hasegawa M, Akiyama H, 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 2006;351:602-611.
Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314:130-133.
Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science2009;323:1205-8.
Munoz DG, Dickson DW, Bergeron C, et al. The neuropathology and biochemistry of frontotemporal dementia. Ann Neurol2003;54: S24-S28.
Dickson DW, Kouri N, Murray ME, Josephs KA. Neuropathology of frontotemporal lobar degeneration-tau (FTLD-TAU). J Mol Neurosci2011;45:384-389.
Bigio EH. TDP-43 variants of frontotemporal lobar degeneration. J Mol Neurosci2011;45:390-401.
Boxer AL, Gold M, Huey E, et al. Frontotemporal degeneration, the next therapeutic frontier: Molecules and animal models for frontotemporal degeneration drug development. Alzheimers Dement 2012:S1552-5260(12)01750-5.
Weintraub S, Mesulam M. With or without FUS, it is the anatomy that dictates the dementia phenotype. Brain2009;132:2906-2908.
Kim EJ, Sidhu M, Gaus SE, et al. Selective frontoinsular von Economo neuron and fork cell loss in early behavioral variant frontotemporal dementia. Cereb Cortex 2012;22:251-259.
Goedert M, Spillantini MG, Potier MC, et al. Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. Embo J 1989;8:393-399.
Goedert M, Spillantini MG. Pathogenesis of the tauopathies. J Mol Neurosci2011;45:425-431.
Hong M, Zhukareva V, Vogelsberg-Ragaglia V, et al.Mutation specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science1998;282:1914-1917.
Deramecourt V, Lebert F, Maurage CA, et al. Clinical, neuropathological, and biochemical characterization of the novel tau mutation P332S. J Alzheimers Dis 2012;31:741-749.
Cruts M, Theuns J, Van Broeckhoven C. Locus-specific mutation databases for neurodegenerative brain diseases. Human Mutation 2012;33: 1340-1344.
Cohn-Hokke PE, Elting MW, Pijnenburg YA, van Swieten JC. Genetics of dementia: update and guidelines for the clinician. Am J Med Genet B Neuropsychiatr Genet 2012;159B:628-643.
Rosso SM, van Swieten JC.New developments in frontotemporal dementia and parkinsonism linked to chromosome 17. Curr Opin Neurol 2002;15:423-428.
Cairns NJ, LeeVM, Trojanowski JQ. The cytoskeleton in neurodegenerative diseases. J Pathol 2004;204:438-449
Cairns NJ, Bigio EH, Mackenzie IR, et al. Consortium for Frontotemporal Lobar Degeneration. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 2007; 114:5-22.
Mackenzie IR, Neumann M, Bigio EH, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol2010;119:1-4.
Mendez MF, Joshi A, Tassniyom K, et al. Clinicopathologic differences among patients with behavioral variant frontotemporal dementia. Neurology2013;16 jan. [Epub ahead of print].
Deramecourt V, Lebert F, Debachy B, et al.. Prediction of pathology in primary progressive language and speech disorders. Neurology2010; 74:42-49
Piguet O, Halliday GH, Reid WGJ, et al. Clinical phenotypes in autopsy-confirmed Pick disease. Neurology 2011;76:253-259.
Kouri N, Whitwell JL, Josephs KA, Rademakers R, Dickson DW. Corticobasal degeneration: a pathologically distinct 4R tauopathy. Nat Rev Neurol. 2011;7:263-272.
Buée L, Delacourte A. Comparative biochemistry of tau in progressive supranuclear palsy, corticobasal degeneration, FTDP-17 and Pick's disease. BrainPathol 1999;9:681-693.
Ikeda K. Clinical aspects of dementia with argyrophilic grains. Handb Clin Neurol 2008;89:549-552.
Pham CT, de Silva R, Haïk S, et al. Tau-positive grains are constant in centenarians' hippocampus. Neurobiol Aging 2011;32:1296-303.
Tolnay M, Probst A. Argyrophilic grain disease.. Handb Clin Neurol 2008;89:553-563.
Josephs KA, Whitwell JL, Parisi JE, Knopman DS, et al. Argyrophilic grains: a distinct disease or an additive pathology? Neurobiol Aging2008; \29:566-573.
Ahmed Z, Doherty KM, Silveira-Moriyama L, et al. Globular glial tauopathies (GGT) presenting with motor neuron disease or frontotemporal dementia: an emerging group of 4-repeat tauopathies.. Acta Neuropathol 2011;122:415-428.
Knopman DS. Overview of dementia lacking distinctive histology: pathological designation of a progressive dementia. Dementia 1993;4: 132-136.
Josephs KA, Holton JL, Rossor MN et al. Frontotemporal Lobar Degeneration and ubiquitin immunohistochemistry. Neuropathol Appl Neurobiol 2004;30:369-373.
Harper JW, Tan MK. Ubiquitin pathway proteomics. Mol Cell Proteomics 2012;11:1541-1650.
Baker M, Mackenzie IR, Pickering-Brown SM, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature2006;442:916-919.
Cruts M, Gijselinck I, Van Der Zee J, et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature2006;442:920-924.
Buratti E, Baralle FE. Multiple roles of the TDP-43 in gene expression, splicing regulation, and human disease. Front Biosci 2008;13:867-878.
Sleegers K, Cruts M, Van Broeckhoven C.Molecular pathways of frontotemporal lobar degeneration. Annu Rev Neurosci 2010;33:71-88.
Rabinovici GD, Miller BL. Frontotemporal Lobar degeneration. Epidemiology, pathophysiology, diagnosis and management. CNS Drugs 2010; 24:375-398.
Dickson DW. TDP-43 immunoreactivity in neurodegenerative disorders: disease versus mechanism specificity. Acta Neuropathol2008;115: 147-149.
Kumar-Singh S. Progranulin and TDP-43: mechanistic links and future directions. J Mol Neurosc 2011;45:561-573.
Mackenzie IR, Neumann M, Bigio EH, et al. Nomenclature for neuropathological subtypes of frototemporal lobar degeneration: consensus recommendations. Acta Neuropathol2006;117:15-18.
Sampathu DM, Neumann M, Kwong LK, et al. Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immune-histochemistry and novel monoclonal antibodies. Am J Pathol2006;169:1343-1352
Mackenzie IR, Neumann M, Barborie A, et al. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol2011;122:111-113.
Tsuji H, Arai T, Kametani F, et al. Molecular analysis and biochemical classification of TDP-43 proteinopathy. Brain2012;135:3380-3391.
Strong MJ and Yang W. The frontemporal syndromes of ALS. Clicopathological correlates. J Mol Neurosc i2011;45:648-655.
Borroni B, Bonvicini C, Alberici A, et al. Mutation within TARDBP leads to frontotemporal dementia without motor neuron disease. Hum Mutat 2009;30:E974-983.
Borroni B, Archetti S, Del Bo R, et al. TARDBP mutations in frontotemporal lobar degeneration: frequency, clinical features, and disease course. Rejuvenation Res 2010;13:509-517.
Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011;72:257-68.
Vance C, Rogelj B, Hortobagyi T et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science2009;323:1208-1211.
Munoz DG, Neumann M, Kusaka H, et al. FUS pathology in basophilic inclusion body disease. Acta Neuropathol2009;118:617-627.
Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA,. Mackenzie IR A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain2009;132:2922-2931.
Neumann M, Roeber S, Kretzschmar HA, Rademakers R, Baker M,. Mackenzie IR Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol2009;118: 605-616.
Snowden JS, Hu Q, Rollinson S, et al. The most common type of FTLD-FUS (FTLD-U) is associated with a distinct clinical form of frontotemporal dementia but is not related to mutations in the FUS gene. Acta neuropathol2011;122:99-110.
Seelaar H, Rohrer JD, Pijnenburg YA, Fox NC, van Swieten J. Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. J Neurol Neurosurg Psychiatry2011;82:476-486.
Lashley T,Rohrer JD, Bandopadhyay R, et al. A comparative clinical, pathological, biochemical and genetic study of fused in sarcoma proteinopathies. Brain2011;134:2548-2564.
McKhann GM, Albert MS, Grossman M, et al. Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementiaand Pick's disease. Arch Neurol2001;58: 1803-1809.
Loy CT, Kril JJ, et al. Very early-onset frontotemporal dementia with no family history predicts underlying fused in sarcoma pathology. Brain2010;133:e158
Langenhove T, Van Der Zee J, Sleegers K, et al. Genetic contribution of FUS to frontotemporal lobar degeneration. Neurology 2010;74: 366-371.
Mackenzie IR, Neumann M, Cairns NJ, Munoz DG, Isaacs AM. Novel types of frontotemporal lobar degeneration: beyond tau and TDP-43. J Mol Neurosc i2011;45:402-408.

Publication Dates

Publication in this collection
Jan-Mar 2013

History

Received
20 Oct 2012
Accepted
10 Jan 2013

This is an open-access article distributed under the terms of the Creative Commons Attribution License

[1] Ratnavalli E, Brayne C, Dawson K, Hodges JR. The prevalence of frontotemporal dementia. Neurology 2002;58:1615-1621.

[2] Johnson JK, Dichl J, Mendez MF, et al. Frontotemporal lobar degeneration. Demographic characteristics of 353 patients. Arch Neurol 2005; 62:925-930.

[3] Rosso SM, Kaat LD, Baks T, et al. Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain 2003;126:2016-2022.

[4] Harvey RJ, Skelton-Robinson M, Rossor MN. The prevalence and causes of dementia in people under the age of 65 years. J Neurol Neurosurg Psychiatry 2003;74:1206-1209.

[5] Knopman DS, Roberts RO. Estimating the number of persons with frontotemporal lobar degeneration in the US population. J Mol Neurosci 2011;45:330-335.

[6] Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration. A consensus on clinical diagnostic criteria.. Neurology 1998; 51:1546-1554.

[7] Lomen-Hoerth C, Anderson T, Miller B. The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology2002;59:1077-1079.

[8] Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain2011;1-22.

[9] Mesulan MM. Primary Progressive Aphasia. Ann Neurol 2001;49: 425-432.

[10] Mesulan MM. Primary Progressive Aphasia: a language based dementia. N Engl J Med 2003;349:1535-1542.

[11] Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology2011;76:1006-1014.

[12] Rohrer JD, Lashley T, Schott JM, et al. Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration. Brain2011;134:2565-2581.

[13] Scarpini E, Galimberti D. Clinical phenotypes and genetic biomarkers of FTLD. J Neural Transm 2012;119:851-860.

[14] Broe M, Hodges JR, Schofield E, et al. Staging disease severity in pathologically confirmed cases of frontotemporal dementia. Neurology2003;60:1005-1011.

[15] Josephs KA, Hodges JR, Snowden JS, et al. Neuropathological background of phenotypical variability in frontotemporal dementia. Acta neuropathol 2011;122:137-153.

[16] Hutton N, Lendon CL, Rizzu P, et al. Association of missense and 5'-splice-site mutations in TAU with the inherited dementia FTDP-17. Nature 1998;393:702-705.

[17] Arai T, Hasegawa M, Akiyama H, 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 2006;351:602-611.

[18] Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314:130-133.

[19] Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science2009;323:1205-8.

[20] Munoz DG, Dickson DW, Bergeron C, et al. The neuropathology and biochemistry of frontotemporal dementia. Ann Neurol2003;54: S24-S28.

[21] Dickson DW, Kouri N, Murray ME, Josephs KA. Neuropathology of frontotemporal lobar degeneration-tau (FTLD-TAU). J Mol Neurosci2011;45:384-389.

[22] Bigio EH. TDP-43 variants of frontotemporal lobar degeneration. J Mol Neurosci2011;45:390-401.

[23] Boxer AL, Gold M, Huey E, et al. Frontotemporal degeneration, the next therapeutic frontier: Molecules and animal models for frontotemporal degeneration drug development. Alzheimers Dement 2012:S1552-5260(12)01750-5.

[24] Weintraub S, Mesulam M. With or without FUS, it is the anatomy that dictates the dementia phenotype. Brain2009;132:2906-2908.

[25] Kim EJ, Sidhu M, Gaus SE, et al. Selective frontoinsular von Economo neuron and fork cell loss in early behavioral variant frontotemporal dementia. Cereb Cortex 2012;22:251-259.

[26] Goedert M, Spillantini MG, Potier MC, et al. Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. Embo J 1989;8:393-399.

[27] Goedert M, Spillantini MG. Pathogenesis of the tauopathies. J Mol Neurosci2011;45:425-431.

[28] Hong M, Zhukareva V, Vogelsberg-Ragaglia V, et al.Mutation specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science1998;282:1914-1917.

[29] Deramecourt V, Lebert F, Maurage CA, et al. Clinical, neuropathological, and biochemical characterization of the novel tau mutation P332S. J Alzheimers Dis 2012;31:741-749.

[30] Cruts M, Theuns J, Van Broeckhoven C. Locus-specific mutation databases for neurodegenerative brain diseases. Human Mutation 2012;33: 1340-1344.

[31] Cohn-Hokke PE, Elting MW, Pijnenburg YA, van Swieten JC. Genetics of dementia: update and guidelines for the clinician. Am J Med Genet B Neuropsychiatr Genet 2012;159B:628-643.

[32] Rosso SM, van Swieten JC.New developments in frontotemporal dementia and parkinsonism linked to chromosome 17. Curr Opin Neurol 2002;15:423-428.

[33] Cairns NJ, LeeVM, Trojanowski JQ. The cytoskeleton in neurodegenerative diseases. J Pathol 2004;204:438-449

[34] Cairns NJ, Bigio EH, Mackenzie IR, et al. Consortium for Frontotemporal Lobar Degeneration. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 2007; 114:5-22.

[35] Mackenzie IR, Neumann M, Bigio EH, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol2010;119:1-4.

[36] Mendez MF, Joshi A, Tassniyom K, et al. Clinicopathologic differences among patients with behavioral variant frontotemporal dementia. Neurology2013;16 jan. [Epub ahead of print].

[37] Deramecourt V, Lebert F, Debachy B, et al.. Prediction of pathology in primary progressive language and speech disorders. Neurology2010; 74:42-49

[38] Piguet O, Halliday GH, Reid WGJ, et al. Clinical phenotypes in autopsy-confirmed Pick disease. Neurology 2011;76:253-259.

[39] Kouri N, Whitwell JL, Josephs KA, Rademakers R, Dickson DW. Corticobasal degeneration: a pathologically distinct 4R tauopathy. Nat Rev Neurol. 2011;7:263-272.

[40] Buée L, Delacourte A. Comparative biochemistry of tau in progressive supranuclear palsy, corticobasal degeneration, FTDP-17 and Pick's disease. BrainPathol 1999;9:681-693.

[41] Ikeda K. Clinical aspects of dementia with argyrophilic grains. Handb Clin Neurol 2008;89:549-552.

[42] Pham CT, de Silva R, Haïk S, et al. Tau-positive grains are constant in centenarians' hippocampus. Neurobiol Aging 2011;32:1296-303.

[43] Tolnay M, Probst A. Argyrophilic grain disease.. Handb Clin Neurol 2008;89:553-563.

[44] Josephs KA, Whitwell JL, Parisi JE, Knopman DS, et al. Argyrophilic grains: a distinct disease or an additive pathology? Neurobiol Aging2008; \29:566-573.

[45] Ahmed Z, Doherty KM, Silveira-Moriyama L, et al. Globular glial tauopathies (GGT) presenting with motor neuron disease or frontotemporal dementia: an emerging group of 4-repeat tauopathies.. Acta Neuropathol 2011;122:415-428.

[46] Knopman DS. Overview of dementia lacking distinctive histology: pathological designation of a progressive dementia. Dementia 1993;4: 132-136.

[47] Josephs KA, Holton JL, Rossor MN et al. Frontotemporal Lobar Degeneration and ubiquitin immunohistochemistry. Neuropathol Appl Neurobiol 2004;30:369-373.

[48] Harper JW, Tan MK. Ubiquitin pathway proteomics. Mol Cell Proteomics 2012;11:1541-1650.

[49] Baker M, Mackenzie IR, Pickering-Brown SM, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature2006;442:916-919.

[50] Cruts M, Gijselinck I, Van Der Zee J, et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature2006;442:920-924.

[51] Buratti E, Baralle FE. Multiple roles of the TDP-43 in gene expression, splicing regulation, and human disease. Front Biosci 2008;13:867-878.

[52] Sleegers K, Cruts M, Van Broeckhoven C.Molecular pathways of frontotemporal lobar degeneration. Annu Rev Neurosci 2010;33:71-88.

[53] Rabinovici GD, Miller BL. Frontotemporal Lobar degeneration. Epidemiology, pathophysiology, diagnosis and management. CNS Drugs 2010; 24:375-398.

[54] Dickson DW. TDP-43 immunoreactivity in neurodegenerative disorders: disease versus mechanism specificity. Acta Neuropathol2008;115: 147-149.

[55] Kumar-Singh S. Progranulin and TDP-43: mechanistic links and future directions. J Mol Neurosc 2011;45:561-573.

[56] Mackenzie IR, Neumann M, Bigio EH, et al. Nomenclature for neuropathological subtypes of frototemporal lobar degeneration: consensus recommendations. Acta Neuropathol2006;117:15-18.

[57] Sampathu DM, Neumann M, Kwong LK, et al. Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immune-histochemistry and novel monoclonal antibodies. Am J Pathol2006;169:1343-1352

[58] Mackenzie IR, Neumann M, Barborie A, et al. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol2011;122:111-113.

[59] Tsuji H, Arai T, Kametani F, et al. Molecular analysis and biochemical classification of TDP-43 proteinopathy. Brain2012;135:3380-3391.

[60] Strong MJ and Yang W. The frontemporal syndromes of ALS. Clicopathological correlates. J Mol Neurosc i2011;45:648-655.

[61] Borroni B, Bonvicini C, Alberici A, et al. Mutation within TARDBP leads to frontotemporal dementia without motor neuron disease. Hum Mutat 2009;30:E974-983.

[62] Borroni B, Archetti S, Del Bo R, et al. TARDBP mutations in frontotemporal lobar degeneration: frequency, clinical features, and disease course. Rejuvenation Res 2010;13:509-517.

[63] Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011;72:257-68.

[64] Vance C, Rogelj B, Hortobagyi T et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science2009;323:1208-1211.

[65] Munoz DG, Neumann M, Kusaka H, et al. FUS pathology in basophilic inclusion body disease. Acta Neuropathol2009;118:617-627.

[66] Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA,. Mackenzie IR A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain2009;132:2922-2931.

[67] Neumann M, Roeber S, Kretzschmar HA, Rademakers R, Baker M,. Mackenzie IR Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol2009;118: 605-616.

[68] Snowden JS, Hu Q, Rollinson S, et al. The most common type of FTLD-FUS (FTLD-U) is associated with a distinct clinical form of frontotemporal dementia but is not related to mutations in the FUS gene. Acta neuropathol2011;122:99-110.

[69] Seelaar H, Rohrer JD, Pijnenburg YA, Fox NC, van Swieten J. Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. J Neurol Neurosurg Psychiatry2011;82:476-486.

[70] Lashley T,Rohrer JD, Bandopadhyay R, et al. A comparative clinical, pathological, biochemical and genetic study of fused in sarcoma proteinopathies. Brain2011;134:2548-2564.

[71] McKhann GM, Albert MS, Grossman M, et al. Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementiaand Pick's disease. Arch Neurol2001;58: 1803-1809.

[72] Loy CT, Kril JJ, et al. Very early-onset frontotemporal dementia with no family history predicts underlying fused in sarcoma pathology. Brain2010;133:e158

[73] Langenhove T, Van Der Zee J, Sleegers K, et al. Genetic contribution of FUS to frontotemporal lobar degeneration. Neurology 2010;74: 366-371.

[74] Mackenzie IR, Neumann M, Cairns NJ, Munoz DG, Isaacs AM. Novel types of frontotemporal lobar degeneration: beyond tau and TDP-43. J Mol Neurosc i2011;45:402-408.

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