Acta Neuropathologica

, Volume 112, Issue 5, pp 551–559 | Cite as

Dementia lacking distinctive histology (DLDH) revisited

  • Ian R. A. Mackenzie
  • Jing Shi
  • Catherine L. Shaw
  • Daniel DuPlessis
  • David Neary
  • Julie S. Snowden
  • David M. A. Mann
Original Paper

Abstract

Although immunohistochemistry has helped to classify the histology of frontotemporal lobar degeneration (FTLD), there have been many cases, described in the literature as showing “dementia lacking distinctive histology” (DLDH), in which this technique has failed to disclose signature pathological changes. Using an automated procedure we have repeated immunostaining for ubiquitin protein (UBQ) in 41 patients with FTLD, 25 of whom were previously considered, on the basis of UBQ immunostaining performed in Manchester, UK, to show FTLD-ubiquitin (FTLD-U) histology and 16 described as DLDH. Both the quality and amount of UBQ immunoreactive (UBQ-ir) pathology (neurites and intraneuronal cytoplasmic inclusions) was significantly increased using the newer staining method. Although the original histological diagnosis was confirmed in the 25 cases previously classified as FTLD-U, the median UBQ score for slides stained in Vancouver increased significantly compared to those stained in Manchester. More importantly, however, some degree of UBQ-ir changes was now disclosed in 13 of the 16 cases previously classified as DLDH and these were now classed as definite or probable FTLD-U. Of the remaining three DLDH cases, clinical diagnostic uncertainties could have explained the lack of specific pathology in two instances. Hence, we conclude that DLDH is a very rare disorder, and that lack of sensitivity for UBQ immunostaining is likely responsible for the failure to disclose this pathology and to provide a diagnosis of FTLD-U.

References

  1. 1.
    Bergmann M, Kuchelmeister K, Schmid KW, Kretzschmar HA, Schroder R (1996) Different variants of frontotemporal dementia: a neuropathological and immunohistochemical study. Acta Neuropathol 92:170–179PubMedCrossRefGoogle Scholar
  2. 2.
    Bigio EH, Lipton AM, White CL, Dickson DW, Hirano A (2003) Frontotemporal and motor neurone degeneration with neurofilament inclusion bodies: additional evidence for overlap between FTD and ALS. Neuropathol Appl Neurobiol 29:239–253PubMedCrossRefGoogle Scholar
  3. 3.
    Brun A, Englund E, Gustafson L, Passant U, Mann DMA, Neary D, Snowden JS (1994) Clinical, neuropsychological and neuropathological criteria for fronto-temporal dementia. J Neurol Neurosurg Psychiatry 57:416–418CrossRefGoogle Scholar
  4. 4.
    Cairns NJ, Perry RH, Jaros E, Burn D, McKeith IG, Lowe JS, Holton J, Rossor MN, Skullerud K, Duyckaerts C, Cruz-Sanchez FF, Lantos PL (2003) Patients with a novel neurofilamentopathy: dementia with neurofilament inclusions. Neurosci Lett 341:177–180PubMedCrossRefGoogle Scholar
  5. 5.
    Cairns NJ, Zhukareva V, Uryu K, Zhang B, Bigio E, Mackenzie IRA, Gearing M, Duyckaerts C, Yokoo H, Nakazato Y, Jaros E, Perry RH, Lee VM-Y, Trojanowski JQ (2004) α-Internexin is present in the pathological inclusions of neuronal intermediate filament inclusion disease. Am J Pathol 164:2153–2161PubMedGoogle Scholar
  6. 6.
    Forman MS, Farmer J, Johnson JK, Clark CM, Arnold SE, Coslett HB, Chatterjee A, Hurtig HI, Karlawish JH, Rosen HJ, Van Deerlin V, Lee VM-Y, Miller BL, Trojanowski JQ, Grossman M (2006) Frontotemporal dementia: clinicopathological correlations. Ann Neurol 59:952–962PubMedCrossRefGoogle Scholar
  7. 7.
    Froelich Fabre S, Axelman P, Almkvist A, Basun H, Lannfelt L (2003) Extended investigation of tau and mutation screening of other candidate genes on chromosome 17q21 in a Swedish FTDP-17 family. Am J Med Genet Part B (Neuropsychiatr Genet) 121B:112–118CrossRefGoogle Scholar
  8. 8.
    Giannakopoulos P, Hof PR, Bouras C (1995) Dementia lacking distinctive histopathology: clinicopathological evaluation of 32 cases. Acta Neuropathol 89:346–355PubMedGoogle Scholar
  9. 9.
    Hodges JR, Davies RR, Xuereb JH, Casey B, Broe M, Bak TH, Kril JJ, Halliday GM (2004) Clinicopathological correlates in frontotemporal dementia. Ann Neurol 56:399–406PubMedCrossRefGoogle Scholar
  10. 10.
    Jackson M, Lennox G, Lowe J (1996) Motor neurone disease-inclusion dementia. Neurodegeneration 5:339–350PubMedCrossRefGoogle Scholar
  11. 11.
    Johnson JK, Diehl J, Mendez MF, Neuhaus J, Shapira JS, Forman M, Chute DJ, Roberson ED, Pace-Savitsky C, Neumann M, Chow TW, Rosen HJ, Forstl H, Kurz A, Miller BL (2005) Frontotemporal lobar degeneration: demographic characteristics of 353 patients. Arch Neurol 62:925–930PubMedCrossRefGoogle Scholar
  12. 12.
    Josephs KA, Holton JL, Rossor MN, Braendgaard H, Osawa T, Fox NC, Petersen RC, Pearl GS, Ganguly M, Rosa P, Laursen H, Parisi JE, Waldemar G, Quinn NP, Dickson DW, Revesz T (2003) Neurofilament inclusion body disease: a new proteinopathy? Brain 126:2291–2303PubMedCrossRefGoogle Scholar
  13. 13.
    Josephs KA, Holton JL, Rossor MN, Godbolt AK, Osawa T, Strand K, Khan N, Al-Sarraj S, Revesz T (2004) Frontotemporal lobar degeneration and ubiquitin immunohistochemistry. Neuropathol Appl Neurobiol 30:369–373PubMedCrossRefGoogle Scholar
  14. 14.
    Katsuse O, Dickson DW (2005) Ubiquitin immunohistochemistry of frontotemporal lobar degeneration differentiates cases with and without motor neurone disease. Alzheimer Dis Assoc Disord 19(suppl1):S37–S43PubMedCrossRefGoogle Scholar
  15. 15.
    Kertesz A, McMonagle P, Blair M, Davidson W, Munoz DG (2005) The evolution and pathology of frontotemporal dementia. Brain 128:1996–2005PubMedCrossRefGoogle Scholar
  16. 16.
    Knopman D, Mastri AR, Frey WH, Sung JH, Rustan T (1990) Dementia lacking distinctive histologic features: a common non-Alzheimer degenerative dementia. Neurology 40:251–256PubMedGoogle Scholar
  17. 17.
    Kovari E, Gold G, Giannakopoulos P, Bouras C (2004) Cortical ubiquitin-positive inclusions in frontotemporal dementia without motor neurone disease: a quantitative immunocytochemical study. Acta Neuropathol 108:207–212PubMedCrossRefGoogle Scholar
  18. 18.
    Lipton AM, White CL III, Bigio EH (2004) Frontotemporal lobar degeneration with motor neuron disease-type inclusions predominates in 76 cases of frontotemporal degeneration. Acta Neuropathol 108:379–385PubMedCrossRefGoogle Scholar
  19. 19.
    Mackenzie IRA, Feldman H (2003) The relationship between extramotor ubiquitin-immunoreactive neuronal inclusions and dementia in motor neurone disease. Acta Neuropathol 105:98–102PubMedGoogle Scholar
  20. 20.
    Mackenzie IR, Baker M, West G, Woulfe J, Qadi N, Gass J, Cannon A, Adamson J, Feldman H, Lindholm C, Melquist S, Pettman R, Sadovnick AD, Dwosh E, Whiteheart SW, Huton M, Pickering-Brown SM (2006) A family with tau-negative dementia and neuronal intranuclear inclusions linked to chromosome 17. Brain 129:853–867PubMedCrossRefGoogle Scholar
  21. 21.
    Mann DMA (2005) The genetics and molecular pathology of frontotemporal lobar degeneration. In: Burns A, O’Brien J, Ames D (eds) Dementia 3rd edn. Hodder Arnold, London, pp 689–701Google Scholar
  22. 22.
    Mott RT, Dickson DW, Trojanowski JQ, Zhukareva V, Lee VM, Forman M, Van Deerlin V, Ervin JF, Wang DS, Schmechel DE, Hulette CM (2005) Neuropathologic, biochemical, and molecular characterization of the frontotemporal dementias. J Neuropathol Exp Neurol 64:420–428PubMedGoogle Scholar
  23. 23.
    Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:1546–1554PubMedGoogle Scholar
  24. 24.
    Neary D, Snowden JS, Mann DMA (2005) Frontotemporal dementia. Lancet Neurology 4:771–779PubMedCrossRefGoogle Scholar
  25. 25.
    Okamoto K, Murakami N, Kusaka H, Yoshida M, Hashizume Y, Nakazato Y, Matsubara E, Hirai H (1992) Ubiquitin-positive intraneuronal inclusions in the extramotor cortices of presenile dementia patients with motor neuron disease. J Neurol 239:426–430PubMedCrossRefGoogle Scholar
  26. 26.
    Rademakers R, Cruts M, Dermaut B, Sleegers K, Rosso SM, Van Den Broeck M, Backhovens H, van Swieten JC, van Duijn CM, van Broeckhoven C (2002) Tau-negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8-cm interval. Mol Psychiatry 7:1064–1074PubMedCrossRefGoogle Scholar
  27. 27.
    Rosso SM, Kamphorst W, de Graaf B, Willemsen R, Ravid R, Niermeijer MF, Spillantini MG, Heutink P, van Swieten JC (2001) Familial frontotemporal dementia with ubiquitin positive inclusions is linked to chromosome 17q21–22. Brain 124:1948–1957PubMedCrossRefGoogle Scholar
  28. 28.
    Rosso SM, Donker Kaat L, Baks T, Joosse M, de Koning I, Pijnenburg Y, de Jong D, Dooijes D, Kamphorst W, Ravid R, Niermeijer MF, Verheij F, Kremer HP, Scheltens P, van Duijn CM, Heutink P, van Swieten JC (2003) Frontotemporal dementia in the Netherlands: patient characteristics and prevalence estimates from a population based study. Brain 126:2016–2022PubMedCrossRefGoogle Scholar
  29. 29.
    Shi J, Shaw CL, Richardson AMT, Bailey K, Tian J, Varma AR, Neary D, Snowden JS, Mann DMA (2005) Histopathological changes underlying frontotemporal lobar degeneration with clinicopathological correlation. Acta Neuropathol 110:501–512PubMedCrossRefGoogle Scholar
  30. 30.
    Snowden JS, Neary D, Mann DMA (1996) Fronto-temporal lobar degeneration: Fronto-temporal dementia, progressive aphasia, semantic dementia. Edinburgh, Churchill Livingstone 1–227Google Scholar
  31. 31.
    Snowden JS, Neary D, Mann DMA (2004) Autopsy proven frontotemporal dementia, due to microvacuolar-type histology, with onset at 21 years of age. J Neurol Neurosurg Psychiatry 75:1337–1339PubMedCrossRefGoogle Scholar
  32. 32.
    Taniguchi S, McDonagh AM, Pickering-Brown SM, Umeda Y, Iwatsubo T, Hasegawa M, Mann DMA (2004) The neuropathology of frontotemporal lobar degeneration with respect to the cytological and biochemical characteristics of tau protein. Neuropathol Appl Neurobiol 30:1–18PubMedCrossRefGoogle Scholar
  33. 33.
    Wightman G, Anderson VER, Martin J, Swash M, Anderton BH, Neary D, Mann DMA, Luthert P, Leigh PN (1992) Hippocampal and neocortical ubiquitin-immunoreactive inclusions in amyotrophic lateral sclerosis with dementia. Neurosci Lett 139:269–274PubMedCrossRefGoogle Scholar
  34. 34.
    Woulfe J, Kertesz A, Munoz D (2001) Frontotemporal dementia with ubiquitinated cytoplasmic and intranuclear inclusions. Acta Neuropathol 102:94–102PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Ian R. A. Mackenzie
    • 1
  • Jing Shi
    • 2
    • 3
  • Catherine L. Shaw
    • 2
  • Daniel DuPlessis
    • 2
  • David Neary
    • 2
  • Julie S. Snowden
    • 2
  • David M. A. Mann
    • 2
  1. 1.Department of PathologyVancouver General HospitalVancouverCanada
  2. 2.Clinical Neuroscience Research GroupUniversity of Manchester, Greater Manchester Neurosciences Centre, Hope HospitalSalfordUK
  3. 3.Department of Care of the Elderly, Dongzhimen HospitalBeijing University of Chinese MedicineBeijingPeople’s Republic of China

Personalised recommendations