Acta Neuropathologica

, 116:215 | Cite as

Temporal lobar predominance of TDP-43 neuronal cytoplasmic inclusions in Alzheimer disease

  • William T. Hu
  • Keith A. Josephs
  • David S. Knopman
  • Bradley F. Boeve
  • Dennis W. Dickson
  • Ronald C. Petersen
  • Joseph E. Parisi
Original Paper

Abstract

TAR DNA binding protein-43 (TDP-43) immunoreactive neuronal inclusions are detected in 20–30% of Alzheimer disease (AD) brains, but the distribution of this pathology has not been rigorously studied. In this report, we describe region-specific distribution and density of TDP-43 positive neuronal cytoplasmic inclusions (NCIs) in clinically demented individuals with high probability AD pathology, all with Braak neurofibrillary tangle stages of V or VI. Sections of hippocampus, amygdala, as well as temporal, frontal, and parietal neocortex, were analyzed with TDP-43 immunohistochemistry, and the density of NCIs was assessed using a semiquantitative scoring method. Of the 29 cases, six had TDP-43 positive NCIs in the amygdala only and seven had TDP-43 inclusions restricted to amygdala and hippocampus. In 16 cases, TDP-43 immunoreactivity was more widespread, affecting temporal, frontal or parietal neocortex. These findings indicate that medial temporal lobe limbic structures are vulnerable to TDP-43 pathology in advanced AD, and that the amygdala appears to be the most susceptible region. The distribution of the lesions in this cross-sectional analysis may suggest a progression of TDP-43 pathology in AD, with limbic structures in the medial temporal lobe affected first, followed by higher order association cortices.

Keywords

Amygdala FTLD-U FTLD-MND Frontotemporal dementia Motor neuron disease 

References

  1. 1.
    Amador-Ortiz C, Lin WL, Ahmed Z, Personett D, Davies P, Duara R, Graff-Radford NR, Hutton ML, Dickson DW (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445PubMedCrossRefGoogle Scholar
  2. 2.
    Anderson VE, Cairns NJ, Leigh PN (1995) Involvement of the amygdala, dentate and hippocampus in motor neuron disease. J Neurol Sci 129(Suppl):75–78Google Scholar
  3. 3.
    Barnes J, Whitwell JL, Frost C, Josephs KA, Rossor M, Fox NC (2006) Measurements of the amygdala and hippocampus in pathologically confirmed Alzheimer disease and frontotemporal lobar degeneration. Arch Neurol 63:1434–1439PubMedCrossRefGoogle Scholar
  4. 4.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259PubMedCrossRefGoogle Scholar
  5. 5.
    Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211PubMedCrossRefGoogle Scholar
  6. 6.
    Cairns NJ, Neumann M, Bigio EH, Holm IE, Troost D, Hatanpaa KJ, Foong C, White CL 3rd, Schneider JA, Kretzschmar HA, Carter D, Taylor-Reinwald L, Paulsmeyer K, Strider J, Gitcho M, Goate AM, Morris JC, Mishra M, Kwong LK, Stieber A, Xu Y, Forman MS, Trojanowski JQ, Lee VM, Mackenzie IR (2007) TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 171:227–240PubMedCrossRefGoogle Scholar
  7. 7.
    Chan D, Fox NC, Scahill RI, Crum WR, Whitwell JL, Leschziner G, Rossor AM, Stevens JM, Cipolotti L, Rossor MN (2001) Patterns of temporal lobe atrophy in semantic dementia and Alzheimer’s disease. Ann Neurol 49:433–442PubMedCrossRefGoogle Scholar
  8. 8.
    Galton CJ, Patterson K, Graham K, Lambon-Ralph MA, Williams G, Antoun N, Sahakian BJ, Hodges JR (2001) Differing patterns of temporal atrophy in Alzheimer’s disease and semantic dementia. Neurology 57:216–225PubMedGoogle Scholar
  9. 9.
    Geser F, Winton MJ, Kwong LK, Xu Y, Xie SX, Igaz LM, Garruto RM, Perl DP, Galasko D, Lee VM, Trojanowski JQ (2008) Pathological TDP-43 in parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol 115:133–145PubMedCrossRefGoogle Scholar
  10. 10.
    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 1184:284–294PubMedCrossRefGoogle Scholar
  11. 11.
    Hyman BT, Trojanowski JQ (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J Neuropathol Exp Neurol 56:1095–1097PubMedCrossRefGoogle Scholar
  12. 12.
    Josephs KA, Petersen RC, Knopman DS, Boeve BF, Whitwell JL, Duffy JR, Parisi JE, Dickson DW (2006) Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP. Neurology 66:41–48PubMedCrossRefGoogle Scholar
  13. 13.
    Josephs KA, Whitwell JL, Knopman DS, Hu WT, Stroh DA, Baker M, Rademakers R, Boeve BF, Parisi JE, Smith GE, Ivnik RJ, Petersen RC, Jack CR Jr, Dickson DW (2008) Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype. Neurology 70:1850–1857PubMedCrossRefGoogle Scholar
  14. 14.
    Katsuse O, Dickson DW (2005) Ubiquitin immunohistochemistry of frontotemporal lobar degeneration differentiates cases with and without motor neuron disease. Alzheimer Dis Assoc Disord 19(1):S37–43PubMedCrossRefGoogle Scholar
  15. 15.
    Kawashima T, Doh-ura K, Kikuchi H, Iwaki T (2001) Cognitive dysfunction in patients with amyotrophic lateral sclerosis is associated with spherical or crescent-shaped ubiquitinated intraneuronal inclusions in the parahippocampal gyrus and amygdala, but not in the neostriatum. Acta Neuropathol (Berl) 102:467–472Google Scholar
  16. 16.
    Kosaka K, Yoshimura M, Ikeda K, Budka H (1984) Diffuse type of Lewy body disease: progressive dementia with abundant cortical Lewy bodies and senile changes of varying degree–a new disease? Clin Neuropathol 3:185–192PubMedGoogle Scholar
  17. 17.
    Kril JJ, Halliday GM (2004) Clinicopathological staging of frontotemporal dementia severity: correlation with regional atrophy. Dement Geriatr Cogn Disord 17:311–315PubMedCrossRefGoogle Scholar
  18. 18.
    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 112:539–549PubMedCrossRefGoogle Scholar
  19. 19.
    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 41:479–486PubMedGoogle Scholar
  20. 20.
    Mitsuyama Y (1984) Presenile dementia with motor neuron disease in Japan: clinico-pathological review of 26 cases. J Neurol Neurosurg Psychiatry 47:953–959PubMedCrossRefGoogle Scholar
  21. 21.
    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 114:221–229PubMedCrossRefGoogle Scholar
  22. 22.
    Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133PubMedCrossRefGoogle Scholar
  23. 23.
    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 169:1343–1352PubMedCrossRefGoogle Scholar
  24. 24.
    Schneider JA, Arvanitakis Z, Bang W, Bennett DA (2007) Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 69:2197–2204PubMedCrossRefGoogle Scholar
  25. 25.
    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 65:685–697PubMedCrossRefGoogle Scholar
  26. 26.
    Wightman G, Anderson VE, Martin J, Swash M, Anderton BH, Neary D, Mann D, Luthert P, Leigh PN (1992) Hippocampal and neocortical ubiquitin-immunoreactive inclusions in amyotrophic lateral sclerosis with dementia. Neurosci Lett 139:269–274PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • William T. Hu
    • 1
    • 2
  • Keith A. Josephs
    • 1
  • David S. Knopman
    • 1
  • Bradley F. Boeve
    • 1
  • Dennis W. Dickson
    • 3
  • Ronald C. Petersen
    • 1
  • Joseph E. Parisi
    • 2
  1. 1.Department of NeurologyMayo ClinicRochesterUSA
  2. 2.Department of Laboratory Medicine and PathologyMayo ClinicRochesterUSA
  3. 3.Department of NeuroscienceMayo ClinicJacksonvilleFLUSA

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