Acta Neuropathologica

, Volume 127, Issue 3, pp 441–450 | Cite as

Staging TDP-43 pathology in Alzheimer’s disease

  • Keith A. JosephsEmail author
  • Melissa E. Murray
  • Jennifer L. Whitwell
  • Joseph E. Parisi
  • Leonard Petrucelli
  • Clifford R. Jack
  • Ronald C. Petersen
  • Dennis W. Dickson
Original Paper


TDP-43 immunoreactivity occurs in 19–57 % of Alzheimer’s disease (AD) cases. Two patterns of TDP-43 deposition in AD have been described involving hippocampus (limbic) or hippocampus and neocortex (diffuse), although focal amygdala involvement has been observed. In 195 AD cases with TDP-43, we investigated regional TDP-43 immunoreactivity with the aim of developing a TDP-43 in AD staging scheme. TDP-43 immunoreactivity was assessed in amygdala, entorhinal cortex, subiculum, hippocampal dentate gyrus, occipitotemporal, inferior temporal and frontal cortices, and basal ganglia. Clinical, neuroimaging, genetic and pathological characteristics were assessed across stages. Five stages were identified: stage I showed scant-sparse TDP-43 in the amygdala only (17 %); stage II showed moderate-frequent amygdala TDP-43 with spread into entorhinal and subiculum (25 %); stage III showed further spread into dentate gyrus and occipitotemporal cortex (31 %); stage IV showed further spread into inferior temporal cortex (20 %); and stage V showed involvement of frontal cortex and basal ganglia (7 %). Cognition and medial temporal volumes differed across all stages and progression across stages correlated with worsening cognition and medial temporal volume loss. Compared to 147 AD patients without TDP-43, only the Boston Naming Test showed abnormalities in stage I. The findings demonstrate that TDP-43 deposition in AD progresses in a stereotypic manner that can be divided into five distinct topographic stages which are supported by correlations with clinical and neuroimaging features. Given these findings, we recommend sequential regional TDP-43 screening in AD beginning with the amygdala.


Alzheimer disease TDP-43 Amygdala TDP-43 type Staging MRI 



This study was funded by the US National Institute of Aging (NIA) grants R01-AG037491 (to KAJ), R21-AG038736 (to JLW), P01-AG003949 (to DWD) and P50-AG016574 (to RCP). We wish to thank the families of the patients who donated their brains to science allowing completion of this study. We further wish to thank Kris Johnson, Linda Rousseau, Virginia Phillips and Monica Casey-Castanedes for pathological support.

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. 1.
    Amador-Ortiz C, Lin WL, Ahmed Z et al (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    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 351:602–611PubMedCrossRefGoogle Scholar
  3. 3.
    Arai T, Mackenzie IR, Hasegawa M et al (2009) Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies. Acta Neuropathol 117:125–136PubMedCrossRefGoogle Scholar
  4. 4.
    Bigio EH, Mishra M, Hatanpaa KJ et al (2010) TDP-43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer disease. Acta Neuropathol 120:43–54. doi: 10.1007/s00401-010-0681-2 PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Bigio EH, Wu JY, Deng HX et al (2013) Inclusions in frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP) and amyotrophic lateral sclerosis (ALS), but not FTLD with FUS proteinopathy (FTLD-FUS), have properties of amyloid. Acta Neuropathol 125:463–465. doi: 10.1007/s00401-013-1089-6 PubMedCrossRefGoogle Scholar
  6. 6.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259PubMedCrossRefGoogle Scholar
  7. 7.
    Brettschneider J, Del Tredici K, Toledo JB et al (2013) Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol 74:20–38. doi: 10.1002/ana.23937 PubMedCrossRefGoogle Scholar
  8. 8.
    Crook R, Hardy J, Duff K (1994) Single-day apolipoprotein E genotyping. J Neurosci Methods 53:125–127PubMedCrossRefGoogle Scholar
  9. 9.
    Davidson YS, Raby S, Foulds PG et al (2011) TDP-43 pathological changes in early onset familial and sporadic Alzheimer’s disease, late onset Alzheimer’s disease and Down’s syndrome: association with age, hippocampal sclerosis and clinical phenotype. Acta Neuropathol 122:703–713. doi: 10.1007/s00401-011-0879-y PubMedCrossRefGoogle Scholar
  10. 10.
    Dickson DW, Davies P, Bevona C et al (1994) Hippocampal sclerosis: a common pathological feature of dementia in very old (>or =80 years of age) humans. Acta Neuropathol 88:212–221PubMedCrossRefGoogle Scholar
  11. 11.
    Dickson DW, Baker M, Rademakers R (2010) Common variant in GRN is a genetic risk factor for hippocampal sclerosis in the elderly. Neurodegener Dis 7:170–174. doi: 10.1159/000289231 PubMedCrossRefGoogle Scholar
  12. 12.
    Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198PubMedCrossRefGoogle Scholar
  13. 13.
    Geser F, Robinson JL, Malunda JA et al (2010) Pathological 43-kDa transactivation response DNA-binding protein in older adults with and without severe mental illness. Arch Neurol 67:1238–1250. doi: 10.1001/archneurol.2010.254 PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Higashi S, Iseki E, Yamamoto R et al (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. doi: 10.1016/j.brainres.2007.09.048 PubMedCrossRefGoogle Scholar
  15. 15.
    Hu WT, Josephs KA, Knopman DS et al (2008) Temporal lobar predominance of TDP-43 neuronal cytoplasmic inclusions in Alzheimer disease. Acta Neuropathol 116:215–220PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Jack CR Jr, Lowe VJ, Senjem ML et al (2008) 11C PiB and structural MRI provide complementary information in imaging of Alzheimer’s disease and amnestic mild cognitive impairment. Brain J Neurol 131:665–680. doi: 10.1093/brain/awm336 CrossRefGoogle Scholar
  17. 17.
    Josephs KA, Tsuboi Y, Cookson N, Watt H, Dickson DW (2004) Apolipoprotein E epsilon 4 is a determinant for Alzheimer-type pathologic features in tauopathies, synucleinopathies, and frontotemporal degeneration. Arch Neurol 61:1579–1584. doi: 10.1001/archneur.61.10.1579 PubMedCrossRefGoogle Scholar
  18. 18.
    Josephs KA, Whitwell JL, Knopman DS et al (2008) Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype. Neurology 70:1850–1857PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Josephs KA, Stroh A, Dugger B, Dickson DW (2009) Evaluation of subcortical pathology and clinical correlations in FTLD-U subtypes. Acta Neuropathol 118:349–358PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    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. Neuropathol Off J Jpn Soc Neuropathol 29:566–573. doi: 10.1111/j.1440-1789.2009.01017.x CrossRefGoogle Scholar
  21. 21.
    Kaplan E, Goodglass H, Weintraub S (1978) The Boston Naming Test. Veterans Administration Medical Center, CityGoogle Scholar
  22. 22.
    King A, Sweeney F, Bodi I, Troakes C, Maekawa S, Al-Sarraj S (2010) Abnormal TDP-43 expression is identified in the neocortex in cases of dementia pugilistica, but is mainly confined to the limbic system when identified in high and moderate stages of Alzheimer’s disease. Neuropathol Off J Jpn Soc Neuropathol 30:408–419. doi: 10.1111/j.1440-1789.2009.01085.x CrossRefGoogle Scholar
  23. 23.
    King OD, Gitler AD, Shorter J (2012) The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res 1462:61–80. doi: 10.1016/j.brainres.2012.01.016 PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Lin WL, Dickson DW (2008) Ultrastructural localization of TDP-43 in filamentous neuronal inclusions in various neurodegenerative diseases. Acta Neuropathol 116:205–213. doi: 10.1007/s00401-008-0408-9 PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Mackenzie IR, Baborie A, Pickering-Brown S et al (2006) Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol 112:539–549. doi: 10.1007/s00401-006-0138-9 PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Mackenzie IR, Neumann M, Baborie A et al (2011) A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 122:111–113. doi: 10.1007/s00401-011-0845-8 PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Mattis S (1988) Dementia rating scale. Psychological Assessment Resources, CityGoogle Scholar
  28. 28.
    Mirra SS, Heyman A, McKeel D et al (1991) The consortium to establish a registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486PubMedCrossRefGoogle Scholar
  29. 29.
    Morris JC (1993) The clinical dementia rating (CDR): current version and scoring rules. Neurology 43:2412–2414PubMedCrossRefGoogle Scholar
  30. 30.
    Nelson PT, Schmitt FA, Lin Y et al (2011) Hippocampal sclerosis in advanced age: clinical and pathological features. Brain J Neurol 134:1506–1518. doi: 10.1093/brain/awr053 CrossRefGoogle Scholar
  31. 31.
    Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133PubMedCrossRefGoogle Scholar
  32. 32.
    Pao WC, Dickson DW, Crook JE, Finch NA, Rademakers R, Graff-Radford NR (2011) Hippocampal sclerosis in the elderly: genetic and pathologic findings, some mimicking Alzheimer disease clinically. Alzheimer Dis Assoc Disord 25:364–368. doi: 10.1097/WAD.0b013e31820f8f50 PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Robinson JL, Geser F, Corrada MM et al (2011) Neocortical and hippocampal amyloid-beta and tau measures associate with dementia in the oldest-old. Brain J Neurol 134:3708–3715. doi: 10.1093/brain/awr308 CrossRefGoogle Scholar
  34. 34.
    Sampathu DM, Neumann M, Kwong LK et al (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. doi: 10.2353/ajpath.2006.060438 PubMedCrossRefGoogle Scholar
  35. 35.
    Sled JG, Zijdenbos AP, Evans AC (1998) A nonparametric method for automatic correction of intensity nonuniformity in MRI data. IEEE Trans Med Imaging 17:87–97PubMedCrossRefGoogle Scholar
  36. 36.
    Tzourio-Mazoyer N, Landeau B, Papathanassiou D et al (2002) Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. NeuroImage 15:273–289PubMedCrossRefGoogle Scholar
  37. 37.
    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 67:555–564PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Whitwell JL, Jack CR Jr, Przybelski SA et al (2011) Temporoparietal atrophy: a marker of AD pathology independent of clinical diagnosis. Neurobiol Aging 32:1531–1541PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Whitwell JL, Dickson DW, Murray ME et al (2012) Neuroimaging correlates of pathologically defined subtypes of Alzheimer’s disease: a case-control study. Lancet Neurol 11:868–877. doi: 10.1016/S1474-4422(12)70200-4 PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Working Group (1997) Consensus recommendation for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for Neuropathologic Assessment of Alzheimer’s Disease. Neurobiol Aging 18(1):1–2CrossRefGoogle Scholar
  41. 41.
    Yokota O, Davidson Y, Bigio EH et al (2010) Phosphorylated TDP-43 pathology and hippocampal sclerosis in progressive supranuclear palsy. Acta Neuropathol 120:55–66. doi: 10.1007/s00401-010-0702-1 PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Zhang YJ, Xu YF, Cook C et al (2009) Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc Natl Acad Sci USA 106:7607–7612. doi: 10.1073/pnas.09006881060900688106 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Keith A. Josephs
    • 1
    Email author
  • Melissa E. Murray
    • 4
  • Jennifer L. Whitwell
    • 2
  • Joseph E. Parisi
    • 3
  • Leonard Petrucelli
    • 4
  • Clifford R. Jack
    • 2
  • Ronald C. Petersen
    • 1
  • Dennis W. Dickson
    • 4
  1. 1.Division of Behavioral Neurology, Department of NeurologyMayo ClinicRochesterUSA
  2. 2.Department of RadiologyMayo ClinicRochesterUSA
  3. 3.Department of Laboratory Medicine and PathologyMayo ClinicRochesterUSA
  4. 4.Department of NeuroscienceMayo ClinicJacksonvilleUSA

Personalised recommendations