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Staging TDP-43 pathology in Alzheimer’s disease

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Abstract

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.

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References

  1. Amador-Ortiz C, Lin WL, Ahmed Z et al (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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 351:602–611

    Article  CAS  PubMed  Google Scholar 

  3. Arai T, Mackenzie IR, Hasegawa M et al (2009) Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies. Acta Neuropathol 117:125–136

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  8. Crook R, Hardy J, Duff K (1994) Single-day apolipoprotein E genotyping. J Neurosci Methods 53:125–127

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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 88:212–221

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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 12:189–198

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  15. Hu WT, Josephs KA, Knopman DS et al (2008) Temporal lobar predominance of TDP-43 neuronal cytoplasmic inclusions in Alzheimer disease. Acta Neuropathol 116:215–220

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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

    Article  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  18. Josephs KA, Whitwell JL, Knopman DS et al (2008) Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype. Neurology 70:1850–1857

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Josephs KA, Stroh A, Dugger B, Dickson DW (2009) Evaluation of subcortical pathology and clinical correlations in FTLD-U subtypes. Acta Neuropathol 118:349–358

    Article  PubMed Central  PubMed  Google Scholar 

  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

    Article  Google Scholar 

  21. Kaplan E, Goodglass H, Weintraub S (1978) The Boston Naming Test. Veterans Administration Medical Center, City

  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

    Article  Google Scholar 

  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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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

    Article  PubMed Central  PubMed  Google Scholar 

  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

    Article  PubMed Central  PubMed  Google Scholar 

  27. Mattis S (1988) Dementia rating scale. Psychological Assessment Resources, City

  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 41:479–486

    Article  CAS  PubMed  Google Scholar 

  29. Morris JC (1993) The clinical dementia rating (CDR): current version and scoring rules. Neurology 43:2412–2414

    Article  CAS  PubMed  Google Scholar 

  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

    Article  Google Scholar 

  31. Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  PubMed  Google Scholar 

  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

    Article  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  35. Sled JG, Zijdenbos AP, Evans AC (1998) A nonparametric method for automatic correction of intensity nonuniformity in MRI data. IEEE Trans Med Imaging 17:87–97

    Article  CAS  PubMed  Google Scholar 

  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 15:273–289

    Article  CAS  PubMed  Google Scholar 

  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 67:555–564

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Whitwell JL, Jack CR Jr, Przybelski SA et al (2011) Temporoparietal atrophy: a marker of AD pathology independent of clinical diagnosis. Neurobiol Aging 32:1531–1541

    Article  PubMed Central  PubMed  Google Scholar 

  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

    Article  PubMed Central  PubMed  Google Scholar 

  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):1–2

    Article  Google Scholar 

  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

    Article  PubMed Central  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

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.

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The authors declare that they have no conflicts of interest.

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Correspondence to Keith A. Josephs.

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Josephs, K.A., Murray, M.E., Whitwell, J.L. et al. Staging TDP-43 pathology in Alzheimer’s disease. Acta Neuropathol 127, 441–450 (2014). https://doi.org/10.1007/s00401-013-1211-9

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  • DOI: https://doi.org/10.1007/s00401-013-1211-9

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