A peculiar constellation of tau pathology defines a subset of dementia in the elderly


Sporadic tauopathies are characterized by differential cellular and topographical predominance of phospho-tau immunoreactivity and biochemical distinction of the tau protein. Established entities include progressive supranuclear palsy, corticobasal degeneration, Pick’s disease, and argyrophilic grain disease. During a community-based longitudinal study on aging, we detected tau pathologies not compatible with these categories. We immunostained for different phospho-tau epitopes, 4R and 3R tau isoforms, α-synuclein, amyloid-β, and phospho-TDP-43, analyzed the MAPT and ApoE genes, and performed western blotting for the tau protein. The mean age of patients (4 women, 3 men) was 83.8 years. Clinical presentations combined dementia with psychiatric symptoms and/or parkinsonism. In addition to neurofibrillary tangles and diffuse neuronal cytoplasmic tau immunoreactivity, the neuropathology was characterized by peculiar cytopathologies (diffuse granular immunopositivity of astrocytic processes and patchy accumulation of thin threads) in a distinctive distribution (frontal and temporal cortices, hippocampus, amygdala, basal ganglia, locus coeruleus, and substantia nigra). Argyrophilic grains were detected in four patients. Few to moderate densities of neuritic plaques but widespread phospho-TDP-43 pathology was observed in five patients. There was variability in the H1/H2 and ApoE alleles and biochemical features of tau protein. We propose these cases as complex tauopathy with a characteristic constellation: some features of primary tauopathies and Alzheimer’s disease mixed with additional cytopathologies including a distinctive astrogliopathy, in a characteristic distribution of lesions. These complex tauopathies in the elderly deserve specific diagnostic and eventually therapeutic considerations.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8


  1. 1.

    Arai T, Mackenzie IR, Hasegawa M, Nonoka T, Niizato K, Tsuchiya K, Iritani S, Onaya M, Akiyama H (2009) Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies. Acta Neuropathol 117:125–136

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Botez G, Probst A, Ipsen S, Tolnay M (1999) Astrocytes expressing hyperphosphorylated tau protein without glial fibrillary tangles in argyrophilic grain disease. Acta Neuropathol 98:251–256

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404

    PubMed  Article  Google Scholar 

  4. 4.

    Braak H, Braak E (1998) Argyrophilic grain disease: frequency of occurrence in different age categories and neuropathological diagnostic criteria. J Neural Transm 105:801–819

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211

    PubMed  Article  Google Scholar 

  7. 7.

    Brayne C, Richardson K, Matthews FE, Fleming J, Hunter S, Xuereb JH, Paykel E, Mukaetova-Ladinska EB, Huppert FA, O’Sullivan A, Dening T (2009) Neuropathological correlates of dementia in over-80-year-old brain donors from the population-based Cambridge city over-75 s cohort (CC75C) study. J Alzheimers Dis 18:645–658

    PubMed  Google Scholar 

  8. 8.

    Caffrey TM, Joachim C, Paracchini S, Esiri MM, Wade-Martins R (2006) Haplotype-specific expression of exon 10 at the human MAPT locus. Hum Mol Genet 15:3529–3537

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, White CL 3rd, Schneider JA, Grinberg LT, 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 DM (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 114:5–22

    PubMed  Article  Google Scholar 

  10. 10.

    Cummings JL (2003) Toward a molecular neuropsychiatry of neurodegenerative diseases. Ann Neurol 54:147–154

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Davidson Y, Amin H, Kelley T, Shi J, Tian J, Kumaran R, Lashley T, Lees AJ, DuPlessis D, Neary D, Snowden J, Akiyama H, Arai T, Hasegawa M, Bandopadhyay R, Sikkink S, Pickering-Brown S, Mann DM (2009) TDP-43 in ubiquitinated inclusions in the inferior olives in frontotemporal lobar degeneration and in other neurodegenerative diseases: a degenerative process distinct from normal ageing. Acta Neuropathol 118:359–369

    PubMed  Article  CAS  Google Scholar 

  12. 12.

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

    PubMed  Article  Google Scholar 

  13. 13.

    Dickson DW, Bergeron C, Chin SS, Duyckaerts C, Horoupian D, Ikeda K, Jellinger K, Lantos PL, Lippa CF, Mirra SS, Tabaton M, Vonsattel JP, Wakabayashi K, Litvan I (2002) Office of rare diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol 61:935–946

    PubMed  CAS  Google Scholar 

  14. 14.

    Dickson DW, Rademakers R, Hutton ML (2007) Progressive supranuclear palsy: pathology and genetics. Brain Pathol 17:74–82

    PubMed  Article  CAS  Google Scholar 

  15. 15.

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

    PubMed  CAS  Google Scholar 

  16. 16.

    Fischer P, Jungwirth S, Zehetmayer S, Weissgram S, Hoenigschnabl S, Gelpi E, Krampla W, Tragl KH (2007) Conversion from subtypes of mild cognitive impairment to Alzheimer dementia. Neurology 68:288–291

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Fujishiro H, Uchikado H, Arai T, Hasegawa M, Akiyama H, Yokota O, Tsuchiya K, Togo T, Iseki E, Hirayasu Y (2009) Accumulation of phosphorylated TDP-43 in brains of patients with argyrophilic grain disease. Acta Neuropathol 117:151–158

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Geser F, Robinson JL, Malunda JA, Xie SX, Clark CM, Kwong LK, Moberg PJ, Moore EM, Van Deerlin VM, Lee VM, Arnold SE, Trojanowski JQ (2010) Pathological 43-kDa transactivation response DNA-binding protein in older adults with and without severe mental illness. Arch Neurol 67:1238–1250

    PubMed  Article  Google Scholar 

  19. 19.

    Hamilton R, Patel S, Lee EB, Jackson EM, Lopinto J, Arnold SE, Clark CM, Basil A, Shaw LM, Xie SX, Grady MS, Trojanowski JQ (2010) Lack of shunt response in suspected idiopathic normal pressure hydrocephalus with Alzheimer disease pathology. Ann Neurol 68:535–540

    PubMed  Article  Google Scholar 

  20. 20.

    Hanger DP, Byers HL, Wray S, Leung KY, Saxton MJ, Seereeram A, Reynolds CH, Ward MA, Anderton BH (2007) Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. J Biol Chem 282:23645–23654

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Hauw JJ, Daniel SE, Dickson D, Horoupian DS, Jellinger K, Lantos PL, McKee A, Tabaton M, Litvan I (1994) Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology 44:2015–2019

    PubMed  CAS  Google Scholar 

  22. 22.

    Hazrati LN, Bergeron C (2008) Neuropathology and genetics of corticobasal degeneration. Handb Clin Neurol 89:523–532

    PubMed  Article  Google Scholar 

  23. 23.

    Higashi S, Iseki E, Yamamoto R, Minegishi M, Hino H, Fujisawa K, Togo T, Katsuse O, Uchikado H, Furukawa Y, Kosaka K, Arai H (2007) Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res 1184:284–294

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Horiguchi T, Uryu K, Giasson BI, Ischiropoulos H, LightFoot R, Bellmann C, Richter-Landsberg C, Lee VM, Trojanowski JQ (2003) Nitration of tau protein is linked to neurodegeneration in tauopathies. Am J Pathol 163:1021–1031

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Hu WT, Josephs KA, Knopman DS, Boeve BF, Dickson DW, Petersen RC, Parisi JE (2008) Temporal lobar predominance of TDP-43 neuronal cytoplasmic inclusions in Alzheimer disease. Acta Neuropathol 116:215–220

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Ikeda K, Akiyama H, Arai T, Nishimura T (1998) Glial tau pathology in neurodegenerative diseases: their nature and comparison with neuronal tangles. Neurobiol Aging 19:S85–S91

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Jellinger KA, Attems J (2010) Prevalence of dementia disorders in the oldest-old: an autopsy study. Acta Neuropathol 119:421–433

    PubMed  Article  Google Scholar 

  28. 28.

    Kadokura A, Yamazaki T, Lemere CA, Takatama M, Okamoto K (2009) Regional distribution of TDP-43 inclusions in Alzheimer disease (AD) brains: their relation to AD common pathology. Neuropathology 29:566–573

    PubMed  Article  Google Scholar 

  29. 29.

    Kovacs GG, Botond G, Budka H (2010) Protein coding of neurodegenerative dementias: the neuropathological basis of biomarker diagnostics. Acta Neuropathol 119:389–408

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Kovacs GG, Botond G, Molnar K, Laszlo L, Ströbel T, Fischer P, Budka H (2010) Complex tauopathies in the elderly. Dementia Geriatr Cogn Dis 30(Suppl 1):33

    Google Scholar 

  31. 31.

    Kovacs GG, Budka H (2010) Current concepts of neuropathological diagnostics in practice: neurodegenerative diseases. Clin Neuropathol 29:271–288

    PubMed  CAS  Google Scholar 

  32. 32.

    Lace G, Savva GM, Forster G, de Silva R, Brayne C, Matthews FE, Barclay JJ, Dakin L, Ince PG, Wharton SB (2009) Hippocampal tau pathology is related to neuroanatomical connections: an ageing population-based study. Brain 132:1324–1334

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Ling H, O’Sullivan SS, Holton JL, Revesz T, Massey LA, Williams DR, Paviour DC, Lees AJ (2010) Does corticobasal degeneration exist? A clinicopathological re-evaluation. Brain 133:2045–2057

    PubMed  Article  Google Scholar 

  34. 34.

    Mackenzie IR, Baborie A, Pickering-Brown S, Du Plessis D, Jaros E, Perry RH, Neary D, Snowden JS, Mann DM (2006) Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol 112:539–549

    PubMed  Article  Google Scholar 

  35. 35.

    Maurage CA, Sergeant N, Schraen-Maschke S, Lebert F, Ruchoux MM, Sablonniere B, Pasquier F, Delacourte A (2003) Diffuse form of argyrophilic grain disease: a new variant of four-repeat tauopathy different from limbic argyrophilic grain disease. Acta Neuropathol 106:575–583

    PubMed  Article  Google Scholar 

  36. 36.

    Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486

    PubMed  CAS  Google Scholar 

  37. 37.

    Nakashima-Yasuda H, Uryu K, Robinson J, Xie SX, Hurtig H, Duda JE, Arnold SE, Siderowf A, Grossman M, Leverenz JB, Woltjer R, Lopez OL, Hamilton R, Tsuang DW, Galasko D, Masliah E, Kaye J, Clark CM, Montine TJ, Lee VM, Trojanowski JQ (2007) Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol 114:221–229

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Ohara S, Tsuyuzaki J, Oide T, Arai H, Higuchi S, Hasegawa M, Iwatsubo T (2002) A clinical and neuropathological study of an unusual case of sporadic tauopathy. A variant of corticobasal degeneration? Neurosci Lett 330:84–88

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Prohovnik I, Perl DP, Davis KL, Libow L, Lesser G, Haroutunian V (2006) Dissociation of neuropathology from severity of dementia in late-onset Alzheimer disease. Neurology 66:49–55

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Saito Y, Ruberu NN, Sawabe M, Arai T, Tanaka N, Kakuta Y, Yamanouchi H, Murayama S (2004) Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol 63:911–918

    PubMed  Google Scholar 

  41. 41.

    Sakai K, Piao YS, Kikugawa K, Ohara S, Hasegawa M, Takano H, Fukase M, Nishizawa M, Kakita A, Takahashi H (2006) Corticobasal degeneration with focal, massive tau accumulation in the subcortical white matter astrocytes. Acta Neuropathol 112:341–348

    PubMed  Article  Google Scholar 

  42. 42.

    Sakai K, Yamada M (2011) Early-stage progressive supranuclear palsy with degenerative lesions confined to the subthalamic nucleus and substantia nigra. Neuropathology 31:77–81

    PubMed  Article  Google Scholar 

  43. 43.

    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

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Santpere G, Ferrer I (2009) Delineation of early changes in cases with progressive supranuclear palsy-like pathology. Astrocytes in striatum are primary targets of tau phosphorylation and GFAP oxidation. Brain Pathol 19:177–187

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Schneider JA, Aggarwal NT, Barnes L, Boyle P, Bennett DA (2009) The neuropathology of older persons with and without dementia from community versus clinic cohorts. J Alzheimers Dis 18:691–701

    PubMed  Google Scholar 

  46. 46.

    Schneider JA, Arvanitakis Z, Bang W, Bennett DA (2007) Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 69:2197–2204

    PubMed  Article  Google Scholar 

  47. 47.

    Sergeant N, Delacourte A, Buee L (2005) Tau protein as a differential biomarker of tauopathies. Biochim Biophys Acta 1739:179–197

    PubMed  CAS  Google Scholar 

  48. 48.

    Sergeant N, Wattez A, Delacourte A (1999) Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal degeneration: tau pathologies with exclusively “exon 10” isoforms. J Neurochem 72:1243–1249

    PubMed  Article  CAS  Google Scholar 

  49. 49.

    Tan CF, Piao YS, Kakita A, Yamada M, Takano H, Tanaka M, Mano A, Makino K, Nishizawa M, Wakabayashi K, Takahashi H (2005) Frontotemporal dementia with co-occurrence of astrocytic plaques and tufted astrocytes, and severe degeneration of the cerebral white matter: a variant of corticobasal degeneration? Acta Neuropathol 109:329–338

    PubMed  Article  Google Scholar 

  50. 50.

    Tolnay M, Clavaguera F (2004) Argyrophilic grain disease: a late-onset dementia with distinctive features among tauopathies. Neuropathology 24:269–283

    PubMed  Article  Google Scholar 

  51. 51.

    Uchikado H, Lin WL, DeLucia MW, Dickson DW (2006) Alzheimer disease with amygdala Lewy bodies: a distinct form of alpha-synucleinopathy. J Neuropathol Exp Neurol 65:685–697

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Uryu K, Nakashima-Yasuda H, Forman MS, Kwong LK, Clark CM, Grossman M, Miller BL, Kretzschmar HA, Lee VM, Trojanowski JQ, Neumann M (2008) 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

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    van Eersel J, Bi M, Ke YD, Hodges JR, Xuereb JH, Gregory GC, Halliday GM, Gotz J, Kril JJ, Ittner LM (2009) Phosphorylation of soluble tau differs in Pick’s disease and Alzheimer’s disease brains. J Neural Transm 116:1243–1251

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Williams DR, Holton JL, Strand C, Pittman A, de Silva R, Lees AJ, Revesz T (2007) Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson’s syndrome. Brain 130:1566–1576

    PubMed  Article  Google Scholar 

  55. 55.

    Williams DR, Lees AJ (2009) Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol 8:270–279

    PubMed  Article  Google Scholar 

  56. 56.

    Wray S, Saxton M, Anderton BH, Hanger DP (2008) Direct analysis of tau from PSP brain identifies new phosphorylation sites and a major fragment of N-terminally cleaved tau containing four microtubule-binding repeats. J Neurochem 105:2343–2352

    PubMed  Article  CAS  Google Scholar 

  57. 57.

    Yokota O, Davidson Y, Bigio EH, Ishizu H, Terada S, Arai T, Hasegawa M, Akiyama H, Sikkink S, Pickering-Brown S, Mann DM (2010) Phosphorylated TDP-43 pathology and hippocampal sclerosis in progressive supranuclear palsy. Acta Neuropathol 120:55–66

    PubMed  Article  Google Scholar 

Download references


The technical assistance of Irene Leisser, Elisabeth Dirnberger, and Sabine Kaindl is highly appreciated. Lajos László’s, Kinga Molnár’s and Gergö Botond’s investigations were financially supported by the Hungarian Scientific Research Fund (OTKA-NK78012) and the European Social Fund (TÁMOP 4.2.1./B-09/1/KMR-2010-0003.

Author information



Corresponding author

Correspondence to Gabor G. Kovacs.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kovacs, G.G., Molnár, K., László, L. et al. A peculiar constellation of tau pathology defines a subset of dementia in the elderly. Acta Neuropathol 122, 205–222 (2011). https://doi.org/10.1007/s00401-011-0819-x

Download citation


  • Alzheimer’s disease
  • Argyrophilic grain disease
  • Corticobasal degeneration
  • Dementia
  • Progressive supranuclear palsy
  • Phospho-tau epitope
  • Tau
  • TDP-43