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Neuropathology of Frontotemporal Lobar Degeneration-Tau (FTLD-Tau)

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Abstract

A clinically and pathologically heterogeneous type of frontotemporal lobar degeneration has abnormal tau pathology in neurons and glia (FTLD-tau). Familial FTLD-tau is usually due to mutations in the tau gene (MAPT). Even FTLD-tau determined by MAPT mutations has clinical and pathologic heterogeneity. Tauopathies are subclassified according to the predominant species of tau that accumulates, with respect to alternative splicing of MAPT, with tau proteins containing three (3R) or four repeats (4R) of ~32 amino acids in the microtubule binding domain. In Pick's disease (PiD), 3R tau predominates, whereas 4R tau is characteristic of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Depending upon the specific mutation in MAPT, familial FTLD-tau can have 3R, 4R or a combination of 3R and 4R tau. PiD is the least common FTLD-tau characterized by neuronal Pick bodies in a stereotypic neuroanatomical distribution. PSP and CBD are more common than PiD and have extensive clinical and pathologic overlap, with no distinctive clinical syndrome or biomarker that permits their differentiation. Diagnosis rests upon postmortem examination of the brain and demonstration of globose tangles, oligodendroglial coiled bodies and tufted astrocytes in PSP or threads, pretangles and astrocytic plaques in CBD. The anatomical distribution of tau pathology determines the clinical presentation of PSP and CBD, as well as PiD. The basis for this selective cortical vulnerability in FTLD-tau is unknown.

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References

  • Ahmed Z, Josephs KA, Gonzalez J, Delledonne A, Dickson DW (2008) Clinical and neuropathologic features of progressive supranuclear palsy with severe pallido-nigro-luysial degeneration and axonal dystrophy. Brain 131:460–472

    Article  PubMed  Google Scholar 

  • Andreadis A, Brown WM, Kosik KS (1992) Structure and novel exons of the human tau gene. Biochemistry 31:10626–10633

    Article  PubMed  CAS  Google Scholar 

  • Arai T, Ikeda K, Akiyama H et al (2004) Identification of amino-terminally cleaved tau fragments that distinguish progressive supranuclear palsy from corticobasal degeneration. Ann Neurol 55:72–79

    Article  PubMed  CAS  Google Scholar 

  • Baker M, Litvan I, Houlden H et al (1999) Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 8:711–715

    Article  PubMed  CAS  Google Scholar 

  • Baker M, Mackenzie IR, Pickering-Brown SM et al (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–919

    Article  PubMed  CAS  Google Scholar 

  • Barker WW, Luis CA, Kashuba A et al (2002) Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer Dis Assoc Disord 16:203–212

    Article  PubMed  Google Scholar 

  • Bergeron C, Pollanen MS, Weyer L, Black SE, Lang AE (1996) Unusual clinical presentations of cortical–basal ganglionic degeneration. Ann Neurol 40:893–900

    Article  PubMed  CAS  Google Scholar 

  • Bigio EH, Brown DF, White CL III (1999) Progressive supranuclear palsy with dementia: cortical pathology. J Neuropathol Exp Neurol 58:359–364

    Article  PubMed  CAS  Google Scholar 

  • Binder LI, Frankfurter A, Rebhun LI (1985) The distribution of tau in the mammalian central nervous system. J Cell Biol 101:1371–1378

    Article  PubMed  CAS  Google Scholar 

  • Boeve BF, Maraganore DM, Parisi JE et al (1999) Pathologic heterogeneity in clinically diagnosed corticobasal degeneration. Neurology 53:795–800

    PubMed  CAS  Google Scholar 

  • Bronner IF, Ter Meulen BC, Azmani A et al (2005) Hereditary Pick's disease with the G272V tau mutation shows predominant three-repeat tau pathology. Brain 128:2645–2653

    Article  PubMed  CAS  Google Scholar 

  • Buee L, Delacourte A (1999) Comparative biochemistry of tau in progressive supranuclear palsy, corticobasal degeneration, FTDP-17 and Pick's disease. Brain Pathol 9:681–693

    Article  PubMed  CAS  Google Scholar 

  • Bugiani O, Murrell JR, Giaccone G et al (1999) Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau. J Neuropathol Exp Neurol 58:667–677

    Article  PubMed  CAS  Google Scholar 

  • Constantinidis J, Richard J, Tissot R (1974) Pick's disease. Histological and clinical correlations. Eur Neurol 11:208–217

    Article  PubMed  CAS  Google Scholar 

  • De Silva R, Lashley T, Strand C et al (2006) An immunohistochemical study of cases of sporadic and inherited frontotemporal lobar degeneration using 3R- and 4R-specific tau monoclonal antibodies. Acta Neuropathol 111:329–340

    Article  PubMed  Google Scholar 

  • Di Maria E, Tabaton M, Vigo T et al (2000) Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy. Ann Neurol 47:374–377

    Article  PubMed  Google Scholar 

  • Dickson DW (1999) Neuropathologic differentiation of progressive supranuclear palsy and corticobasal degeneration. J Neurol 246(Suppl 2):II6–II15

    Article  PubMed  Google Scholar 

  • Dickson DW, Bergeron C, Chin SS et al (2002) Office of Rare Diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol 61:935–946

    PubMed  CAS  Google Scholar 

  • Dickson DW, Ahmed Z, Algom AA, Tsuboi Y, Josephs KA (2010) Neuropathology of variants of progressive supranuclear palsy. Curr Opin Neurol 23:394–400

    Article  PubMed  Google Scholar 

  • Feany MB, Dickson DW (1995) Widespread cytoskeletal pathology characterizes corticobasal degeneration. Am J Pathol 146:1388–1396

    PubMed  CAS  Google Scholar 

  • Feany MB, Mattiace LA, Dickson DW (1996) Neuropathologic overlap of progressive supranuclear palsy, Pick's disease and corticobasal degeneration. J Neuropathol Exp Neurol 55:53–67

    Article  PubMed  CAS  Google Scholar 

  • Forman MS, Lee VM-Y, Trojanowski JQ (2005) Frontotemporal dementia with parkinsonism linked to chromosome 17. In: Beal MF, Lang AE, Ludolph A (eds) Neurodegenerative diseases: neurobiology, pathogenesis and therapeutics. Cambridge University Press, New York

    Google Scholar 

  • Fujino Y, Delucia MW, Davies P, Dickson DW (2004) Ballooned neurones in the limbic lobe are associated with Alzheimer type pathology and lack diagnostic specificity. Neuropathol Appl Neurobiol 30:676–682

    Article  PubMed  CAS  Google Scholar 

  • Goedert M, Spillantini MG, Potier MC, Ulrich J, Crowther RA (1989) 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 8:393–399

    PubMed  CAS  Google Scholar 

  • Graff-Radford NR, Damasio AR, Hyman BT et al (1990) Progressive aphasia in a patient with Pick's disease: a neuropsychological, radiologic, and anatomic study. Neurology 40:620–626

    PubMed  CAS  Google Scholar 

  • Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM (1986a) Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 261:6084–6089

    PubMed  CAS  Google Scholar 

  • Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986b) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A 83:4913–4917

    Article  PubMed  CAS  Google Scholar 

  • Hassan A, Whitwell JL, Boeve BF et al (2010) Symmetric corticobasal degeneration (S-CBD). Parkinsonism Relat Disord 16:208–214

    Article  PubMed  Google Scholar 

  • Hauw JJ, Daniel SE, Dickson D et al (1994) Preliminary NINDS neuropathologic criteria for Steele–Richardson–Olszewski syndrome (progressive supranuclear palsy). Neurology 44:2015–2019

    PubMed  CAS  Google Scholar 

  • Hogg M, Grujic ZM, Baker M et al (2003) The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy. Acta Neuropathol 106:323–336

    Article  PubMed  Google Scholar 

  • Houlden H, Baker M, Morris HR et al (2001) Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype. Neurology 56:1702–1706

    PubMed  CAS  Google Scholar 

  • Hutton M, Lendon CL, Rizzu P et al (1998) Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705

    Article  PubMed  CAS  Google Scholar 

  • Ikeda K, Akiyama H, Iritani S et al (1996) Corticobasal degeneration with primary progressive aphasia and accentuated cortical lesion in superior temporal gyrus: case report and review. Acta Neuropathol 92:534–539

    Article  PubMed  CAS  Google Scholar 

  • Josephs KA, Boeve BF, Duffy JR et al (2005) Atypical progressive supranuclear palsy underlying progressive apraxia of speech and nonfluent aphasia. Neurocase 11:283–296

    Article  PubMed  CAS  Google Scholar 

  • Josephs KA, Katsuse O, Beccano-Kelly DA et al (2006) Atypical progressive supranuclear palsy with corticospinal tract degeneration. J Neuropathol Exp Neurol 65:396–405

    Article  PubMed  Google Scholar 

  • Josephs KA, Whitwell JL, Dickson DW et al (2008) Voxel-based morphometry in autopsy proven PSP and CBD. Neurobiol Aging 29:280–289

    Article  PubMed  Google Scholar 

  • Komori T, Arai N, Oda M et al (1998) Astrocytic plaques and tufts of abnormal fibers do not coexist in corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol 96:401–408

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Lang AE, Bergeron C, Pollanen MS, Ashby P (1994) Parietal Pick's disease mimicking cortical-basal ganglionic degeneration. Neurology 44:1436–1440

    PubMed  CAS  Google Scholar 

  • Ling H, O'sullivan SS, Holton JL et al (2010) Does corticobasal degeneration exist? A clinicopathological re-evaluation. Brain 133:2045–2057

    Article  PubMed  Google Scholar 

  • Litvan I, Grimes DA, Lang AE (2000) Phenotypes and prognosis: clinicopathologic studies of corticobasal degeneration. Adv Neurol 82:183–196

    PubMed  CAS  Google Scholar 

  • Mackenzie IR, Neumann M, Bigio EH et al (2009) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 117:15–18

    Article  PubMed  Google Scholar 

  • Mckhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ (2001) Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease. Arch Neurol 58:1803–1809

    Article  PubMed  CAS  Google Scholar 

  • Murrell JR, Spillantini MG, Zolo P et al (1999) Tau gene mutation G389R causes a tauopathy with abundant pick body-like inclusions and axonal deposits. J Neuropathol Exp Neurol 58:1207–1226

    Article  PubMed  CAS  Google Scholar 

  • Nilsson C, Markenroth Bloch K, Brockstedt S, Latt J, Widner H, Larsson EM (2007) Tracking the neurodegeneration of parkinsonian disorders—a pilot study. Neuroradiology 49:111–119

    Article  PubMed  CAS  Google Scholar 

  • Pittman AM, Myers AJ, Abou-Sleiman P et al (2005) Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration. J Med Genet 42:837–846

    Article  PubMed  CAS  Google Scholar 

  • Rademakers R, Melquist S, Cruts M et al (2005) High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy. Hum Mol Genet 14:3281–3292

    Article  PubMed  CAS  Google Scholar 

  • Rebeiz JJ, Kolodny EH, Richardson EP Jr (1967) Corticodentatonigral degeneration with neuronal achromasia: a progressive disorder of late adult life. Trans Am Neurol Assoc 92:23–26

    PubMed  CAS  Google Scholar 

  • Schellenberg GD (2010) A genome-wide association study of progressive supranuclear palsy and corticobasal degeneration: genes that modify risk. Dement Geriatr Cogn Disord 30(Suppl 1):18–19

    Google Scholar 

  • Stanford PM, Halliday GM, Brooks WS et al (2000) Progressive supranuclear palsy pathology caused by a novel silent mutation in exon 10 of the tau gene: expansion of the disease phenotype caused by tau gene mutations. Brain 123(Pt 5):880–893

    Article  PubMed  Google Scholar 

  • Steele JC, Richardson JC, Olszewski J (1964) Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch Neurol 10:333–359

    PubMed  CAS  Google Scholar 

  • Tsuboi Y, Slowinski J, Josephs KA, Honer WG, Wszolek ZK, Dickson DW (2003) Atrophy of superior cerebellar peduncle in progressive supranuclear palsy. Neurology 60:1766–1769

    PubMed  CAS  Google Scholar 

  • Tsuboi Y, Josephs KA, Boeve BF et al (2005) Increased tau burden in the cortices of progressive supranuclear palsy presenting with corticobasal syndrome. Mov Disord 20:982–988

    Article  PubMed  Google Scholar 

  • Van Swieten J, Spillantini MG (2007) Hereditary frontotemporal dementia caused by Tau gene mutations. Brain Pathol 17:63–73

    Article  PubMed  Google Scholar 

  • Wadia PM, Lang AE (2007) The many faces of corticobasal degeneration. Parkinsonism Relat Disord 13(Suppl 3):S336–S340

    Article  PubMed  Google Scholar 

  • Wider C, Wszolek ZK (2008) Etiology and pathophysiology of frontotemporal dementia, Parkinson disease and Alzheimer disease: lessons from genetic studies. Neurodegener Dis 5:122–125

    Article  PubMed  CAS  Google Scholar 

  • Williams DR, De Silva R, Paviour DC et al (2005) Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism. Brain 128:1247–1258

    Article  PubMed  Google Scholar 

  • Williams DR, Holton JL, Strand K, Revesz T, Lees AJ (2007) Pure akinesia with gait freezing: a third clinical phenotype of progressive supranuclear palsy. Mov Disord 22:2235–2241

    Article  PubMed  Google Scholar 

  • Williams DR, Lees AJ, Wherrett JR, Steele JC (2008) J. Clifford Richardson and 50 years of progressive supranuclear palsy. Neurology 70:566–573

    Article  PubMed  Google Scholar 

  • Yamada T, Mcgeer PL, Mcgeer EG (1992) Appearance of paired nucleated, Tau-positive glia in patients with progressive supranuclear palsy brain tissue. Neurosci Lett 135:99–102

    Article  PubMed  CAS  Google Scholar 

  • Yoshimura N (1989) Topography of Pick body distribution in Pick's disease: a contribution to understanding the relationship between Pick's and Alzheimer's diseases. Clin Neuropathol 8:1–6

    PubMed  CAS  Google Scholar 

  • Zhukareva V, Mann D, Pickering-Brown S et al (2002) Sporadic Pick's disease: a tauopathy characterized by a spectrum of pathological tau isoforms in gray and white matter. Ann Neurol 51:730–739

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors thank Virginia Philips, Linda Rousseau and Monica Castanedes-Casey for their expert technical assistance. We appreciate the gift of CP13 from Peter Davies, Albert Einstein College of Medicine. Most of the cases used in this study were donated to the Society of Progressive Supranuclear Palsy brain bank and generous donations of family members in this endeavor are greatly appreciated. This study was supported by NIH grants P50-NS72187, P50-AG25711, P50-AG16574, P01-AG17216, R01-AG37491 and R21 AG38736, as well as The Robert E. Jacoby endowment and the Mayo Foundation for Education and Research.

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Correspondence to Dennis W. Dickson.

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Dickson, D.W., Kouri, N., Murray, M.E. et al. Neuropathology of Frontotemporal Lobar Degeneration-Tau (FTLD-Tau). J Mol Neurosci 45, 384–389 (2011). https://doi.org/10.1007/s12031-011-9589-0

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