Acta Neuropathologica

, Volume 120, Issue 1, pp 43–54 | Cite as

TDP-43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer disease

  • Eileen H. BigioEmail author
  • Manjari Mishra
  • Kimmo J. Hatanpaa
  • Charles L. WhiteIII
  • Nancy Johnson
  • Alfred Rademaker
  • Bing Bing Weitner
  • Han-Xiang Deng
  • Steven D. Dubner
  • Sandra Weintraub
  • Marsel Mesulam
Original Paper


The clinical syndrome of primary progressive aphasia (PPA) can be associated with a variety of neuropathologic diagnoses at autopsy. Thirty percent of cases have Alzheimer disease (AD) pathology, most often in the usual distribution, which defies principles of brain–behavior organization, in that aphasia is not symptomatic of limbic disease. The present study investigated whether concomitant TDP-43 pathology could resolve the lack of clinico-anatomic concordance. In this paper, 16 cases of clinical PPA and 10 cases of primarily non-aphasic frontotemporal dementia (FTD), all with AD pathology, were investigated to determine whether their atypical clinical phenotypes reflected the presence of additional TDP-43 pathology. A comparison group consisted of 27 cases of pathologic AD with the typical amnestic clinical phenotype of probable AD. Concomitant TDP-43 pathology was discovered in only three of the FTD and PPA but in more than half of the typical amnestic clinical phenotypes. Hippocampal sclerosis (HS) was closely associated with TDP-43 pathology when all groups were combined for analysis. Therefore, the clinical phenotypes of PPA and FTD in cases with pathologic AD are only rarely associated with TDP-43 proteinopathy. Furthermore, medial temporal TDP-43 pathology is more tightly linked to HS than to clinical phenotype. These findings challenge the current notions about clinicopathologic correlation, especially about the role of multiple pathologies.


Primary progressive aphasia Frontotemporal dementia Alzheimer disease FTLD-TDP TDP-43 proteinopathy Hippocampal sclerosis 



We are grateful to John Trojanowski and Virginia Lee for their helpful discussions and for sharing their TDP-43 immunoprotocol with us. We are most grateful to those patients and family members who so willingly participated in our research programs, without whom our studies are not possible. The study was supported in part by NIH grants AG13854, AG12300, P30 AG012300, Winspear Family Center for Research on the Neuropathology of Alzheimer Disease, and McCune Foundation.


  1. 1.
    Amador-Ortiz C, Lin W-L, Ahmed Z et al (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445CrossRefPubMedGoogle Scholar
  2. 2.
    Anonymous (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol Aging 18:S1–S2Google Scholar
  3. 3.
    Arai T, Hasegawa M, Akiyama H et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611CrossRefPubMedGoogle Scholar
  4. 4.
    Arai T, Mackenzie IRA, Hasegawa M et al (2009) Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies. Acta Neuropathol 117:125–136CrossRefPubMedGoogle Scholar
  5. 5.
    Baker M, Mackenzie IR, Pickering-Brown SM et al (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–919CrossRefPubMedGoogle Scholar
  6. 6.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259CrossRefPubMedGoogle Scholar
  7. 7.
    Cairns NJ, Neumann M, Bigio EH et al (2007) TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 171:227–240CrossRefPubMedGoogle Scholar
  8. 8.
    Cruts M, Gijselinck I, van der Zee J et al (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920–924CrossRefPubMedGoogle Scholar
  9. 9.
    Davidson Y, Kelley T, Mackenzie IR et al (2007) Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol 113:521–533CrossRefPubMedGoogle Scholar
  10. 10.
    Deng HX, Shi Y, Furukawa Y et al (2006) Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria. Proc Natl Acad Sci USA 103:7142–7147CrossRefPubMedGoogle Scholar
  11. 11.
    Farrer MJ, Hulihan MM, Kachergus JM et al (2008) DCTN1 mutations in Perry syndrome. Nat Genet 41:163–165CrossRefGoogle Scholar
  12. 12.
    Freeman SH, Spires-Jones T, Hyman BT, Growden JH, Frosch MP (2008) TAR-DNA binding protein 43 in Pick disease. J Neuropathol Exp Neurol 67:62–67CrossRefPubMedGoogle Scholar
  13. 13.
    Fujishiro H, Uchikado H, Arai T et al (2009) Accumulation of phosphorylated TDP-43 in brains of patients with argyrophilic grain disease. Acta Neuropathol 117:151–158CrossRefPubMedGoogle Scholar
  14. 14.
    Geser F, Winton MJ, Kwong LK et al (2008) Pathological TDP-43 in parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol 115:133–145CrossRefPubMedGoogle Scholar
  15. 15.
    Hasegawa M, Arai T, Akiyama H et al (2007) TDP-43 is deposited in the Guam parkinsonism-dementia complex brains. Brain 130:1386–1394CrossRefPubMedGoogle Scholar
  16. 16.
    Hatanpaa K, Bigio E, Cairns NJ et al (2008) TAR DNA-binding protein 43 immunohistochemistry reveals extensive neuritic pathology in FTLD-U: a Midwest-Southwest Consortium for FTLD Study. J Neuropathol Exp Neurol 67:271–279CrossRefPubMedGoogle Scholar
  17. 17.
    Higashi S, Iseki E, Yamamoto R et al (2007) Concurrence of TDP-43, tau and α-synuclein pathology in brains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res 1184:284–294CrossRefPubMedGoogle Scholar
  18. 18.
    Hu WT, Josephs KA, Knopman DS et al (2008) Temporal lobar predominance of TDP-43 neuronal cytoplasmic inclusions in Alzheimer disease. Acta Neuropathol 116:215–220CrossRefPubMedGoogle Scholar
  19. 19.
    Josephs KA, Holton JL, Rossor MN et al (2004) Frontotemporal lobar degeneration and ubiquitin immunohistochemistry. Neuropathol Appl Neurobiol 30:369–373CrossRefPubMedGoogle Scholar
  20. 20.
    Josephs KA, Whitwell JL, Duffy JR et al (2008) Progressive aphasia secondary to Alzheimer disease vs FTLD pathology. Neurology 70:25–34CrossRefPubMedGoogle Scholar
  21. 21.
    Josephs KA, Whitwell JL, Knopman DS et al (2008) Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype. Neurology 70:1850–1857CrossRefPubMedGoogle Scholar
  22. 22.
    Lipton AM, White CL III, Bigio EH (2004) FTD-MND predominates in 76 cases of frontotemporal degeneration. Acta Neuropathol 108:379–385CrossRefPubMedGoogle Scholar
  23. 23.
    Mackenzie IRA, Bigio EH, Ince PG et al (2007) Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 61:427–434CrossRefPubMedGoogle Scholar
  24. 24.
    Mackenzie IRA, Neumann M, Bigio EH et al (2010) Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 119:1–4CrossRefPubMedGoogle Scholar
  25. 25.
    Mackenzie IR, Shi J, Shaw CL et al (2006) Dementia lacking distinctive histology (DLDH) revisited. Acta Neuropathol 112:551–559CrossRefPubMedGoogle Scholar
  26. 26.
    McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan E (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944PubMedGoogle Scholar
  27. 27.
    Mesulam M-M (2001) Primary progressive aphasia. Ann Neurol 49:425–432CrossRefPubMedGoogle Scholar
  28. 28.
    Mesulam M, Wicklund A, Johnson N et al (2008) Alzheimer and frontotemporal pathology in subsets of primary progressive aphasia. Ann Neurol 63:709–719CrossRefPubMedGoogle Scholar
  29. 29.
    Miklossy J, Steele JC, Yu S et al (2008) Enduring involvement of tau, beta-amyloid, alpha-synuclein, ubiquitin, and TDP-43 pathology in the amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam (ALS/PDC). Acta Neuropathol 116:625–637CrossRefPubMedGoogle Scholar
  30. 30.
    Mirra SS, Heyman A, McKeel D et al (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), II: standardization of neuropathological assessment of Alzheimer’s disease. Neurology 41:479–486PubMedGoogle Scholar
  31. 31.
    Munoz DG, Woulfe J, Kertesz A (2007) Argyrophilic thorny astrocyte clusters in association with Alzheimer’s disease pathology in possible primary progressive aphasia. Acta Neuropathol 114:347–357CrossRefPubMedGoogle Scholar
  32. 32.
    Nakashima-Yasuda H, Uryu K, Robinson J et al (2007) Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol 114:221–229CrossRefPubMedGoogle Scholar
  33. 33.
    Neary D, Snowden JS, Gustafson L et al (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:1546–1554PubMedGoogle Scholar
  34. 34.
    Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IRA (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132:2922–2931CrossRefPubMedGoogle Scholar
  35. 35.
    Neumann M, Roeber S, Kretzschmar HA, Rademakers R, Baker M, Mackenzie IRA (2009) Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol 118:605–616CrossRefPubMedGoogle Scholar
  36. 36.
    Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133CrossRefPubMedGoogle Scholar
  37. 37.
    Olivé M, Janué A, Moreno D, Gámez J, Torrejón-Escribano B, Ferrer I (2009) TAR DNA-binding protein 43 accumulation in protein aggregate myopathies. J Neuropathol Exp Neurol 68:262–273CrossRefPubMedGoogle Scholar
  38. 38.
    Probst A, Taylor KI, Tolnay M (2007) Hippocampal sclerosis dementia: a reappraisal. Acta Neuropathol 114:335–345CrossRefPubMedGoogle Scholar
  39. 39.
    Rohn TT (2008) Caspase-cleaved TAR DNA-binding protein-43 is a major pathological finding in Alzheimer’s disease. Brain Res 1228:189–198CrossRefPubMedGoogle Scholar
  40. 40.
    Schwab C, Arai T, Hasegawa M, Yu S, McGeer PL (2008) Colocalization of transactivation-responsive DNA-binding protein 43 and huntingtin in inclusions of Huntington Disease. J Neuropathol Exp Neurol 67:1159–1165CrossRefPubMedGoogle Scholar
  41. 41.
    Uryu K, Nakashima-Yasuda H, Forman MS et al (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 67:555–564CrossRefPubMedGoogle Scholar
  42. 42.
    Weihl CC, Temiz P, Miller SE et al (2008) TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia. J Neurol Neurosurg Psych 79:1186–1189CrossRefGoogle Scholar
  43. 43.
    Whitwell JL, Jack Jr CR, Przybelski SA et al (2009) Temporoparietal atrophy: a marker of AD pathology independent of clinical diagnosis. Neurobiol Aging. doi: 10.1016/j.neurobiolaging.2009.10.012
  44. 44.
    Wider C, Dickson DW, Stoessl AJ et al (2008) Pallidonigral TDP-43 pathology in Perry syndrome. Parkinsonism Relat Disord 15:281–286CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Eileen H. Bigio
    • 1
    • 2
    Email author
  • Manjari Mishra
    • 1
  • Kimmo J. Hatanpaa
    • 3
  • Charles L. WhiteIII
    • 3
  • Nancy Johnson
    • 1
    • 4
  • Alfred Rademaker
    • 1
    • 5
  • Bing Bing Weitner
    • 5
  • Han-Xiang Deng
    • 4
  • Steven D. Dubner
    • 1
    • 2
  • Sandra Weintraub
    • 1
    • 6
  • Marsel Mesulam
    • 1
    • 4
  1. 1.Cognitive Neurology and Alzheimer Disease CenterNorthwestern University Feinberg School of MedicineChicagoUSA
  2. 2.Department of PathologyNorthwestern University Feinberg School of MedicineChicagoUSA
  3. 3.Department of PathologyAlzheimer Disease Center, University of Texas Southwestern Medical CenterDallasUSA
  4. 4.Department of NeurologyNorthwestern University Feinberg School of MedicineChicagoUSA
  5. 5.Department of Preventive MedicineNorthwestern University Feinberg School of MedicineChicagoUSA
  6. 6.Department of PsychiatryNorthwestern University Feinberg School of MedicineChicagoUSA

Personalised recommendations