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Tau pathology in frontotemporal lobar degeneration with C9ORF72 hexanucleotide repeat expansion

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Abstract

An expanded GGGGCC hexanucleotide repeat in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration associated with TDP-43 pathology (FTLD-TDP). In addition to TDP-43-positive neuronal and glial inclusions, C9ORF72-linked FTLD-TDP has characteristic TDP-43-negative neuronal cytoplasmic and intranuclear inclusions as well as dystrophic neurites in the hippocampus and cerebellum. These lesions are immunopositive for ubiquitin and ubiquitin-binding proteins, such as sequestosome-1/p62 and ubiquilin-2. Studies examining the frequency of the C9ORF72 mutation in clinically probable Alzheimer’s disease (AD) have found a small proportion of AD cases with the mutation. This prompted us to systematically explore the frequency of Alzheimer-type pathology in a series of 17 FTLD-TDP cases with mutations in C9ORF72 (FTLD-C9ORF72). We identified four cases with sufficient Alzheimer-type pathology to meet criteria for intermediate-to-high-likelihood AD. We compared AD pathology in the 17 FTLD-C9ORF72 to 13 cases of FTLD-TDP linked to mutations in the gene for progranulin (FTLD-GRN) and 36 cases of sporadic FTLD (sFTLD). FTLD-C9ORF72 cases had higher Braak neurofibrillary tangle stage than FTLD-GRN. Increased tau pathology in FTLD-C9ORF72 was assessed with thioflavin-S fluorescent microscopy-based neurofibrillary tangle counts and with image analysis of tau burden in temporal cortex and hippocampus. FTLD-C9ORF72 had significantly more neurofibrillary tangles and higher tau burden compared with FTLD-GRN. The differences were most marked in limbic regions. On the other hand, sFTLD and FTLD-C9ORF72 had a similar burden of tau pathology. These results suggest FTLD-C9ORF72 has increased propensity for tau pathology compared to FTLD-GRN, but not sFTLD. The accumulation of tau as well as lesions immunoreactive for ubiquitin and ubiquitin-binding proteins (p62 and ubiquilin-2) suggests that mutations in C9ORF72 may involve disrupted protein degradation that favors accumulation of multiple different proteins.

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References

  1. Al-Sarraj S, King A, Troakes C et al (2011) p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol 122:691–702

    Article  PubMed  CAS  Google Scholar 

  2. 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  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  4. Babu JR, Geetha T, Wooten MW (2005) Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J Neurochem 94:192–203

    Article  PubMed  CAS  Google Scholar 

  5. Behrens MI, Mukherjee O, Tu PH et al (2007) Neuropathologic heterogeneity in HDDD1: a familial frontotemporal lobar degeneration with ubiquitin-positive inclusions and progranulin mutation. Alzheimer Dis Assoc Disord 21:1–7

    Article  PubMed  Google Scholar 

  6. Boeve BF, Boylan KB, Graff-Radford NR et al (2012) Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 135:765–783

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  8. Brettschneider J, Van Deerlin VM, Robinson JL et al (2012) Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion. Acta Neuropathol 123:825–839

    Article  PubMed  Google Scholar 

  9. Cairns NJ, Bigio EH, Mackenzie IR et al (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 114:5–22

    Article  PubMed  Google Scholar 

  10. Dai RM, Li CC (2001) Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin-proteasome degradation. Nat Cell Biol 3:740–744

    Article  PubMed  CAS  Google Scholar 

  11. DeJesus-Hernandez M, Mackenzie IR, Boeve BF et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256

    Article  PubMed  CAS  Google Scholar 

  12. Deng HX, Chen WJ, Hong ST et al (2011) Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477:211–215

    Google Scholar 

  13. Dickson DW, Crystal HA, Mattiace LA et al (1992) Identification of normal and pathological aging in prospectively studied nondemented elderly humans. Neurobiol Aging 13:179–189

    Article  PubMed  CAS  Google Scholar 

  14. Dickson DW, Wertkin A, Kress Y, Ksiezak-Reding H, Yen SH (1990) Ubiquitin immunoreactive structures in normal human brains. Distribution and developmental aspects. Lab Invest 63:87–99

    PubMed  CAS  Google Scholar 

  15. Forman MS, Mackenzie IR, Cairns NJ et al (2006) Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations. J Neuropathol Exp Neurol 65:571–581

    Article  PubMed  CAS  Google Scholar 

  16. Gass J, Cannon A, Mackenzie IR et al (2006) Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 15:2988–3001

    Article  PubMed  CAS  Google Scholar 

  17. Graff-Radford NR, Woodruff BK (2007) Frontotemporal dementia. Semin Neurol 27:48–57

    Article  PubMed  Google Scholar 

  18. Hiltunen M, Lu A, Thomas AV et al (2006) Ubiquilin 1 modulates amyloid precursor protein trafficking and Abeta secretion. J Biol Chem 281:32240–32253

    Article  PubMed  CAS  Google Scholar 

  19. Hsiung GYR, DeJesus-Hernandez M, Feldman HH et al (2012) Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain 135:709–722

    Article  PubMed  Google Scholar 

  20. 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  PubMed  CAS  Google Scholar 

  21. 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 56:1095–1097

    Article  PubMed  CAS  Google Scholar 

  22. Jellinger KA, Attems J (2008) Prevalence and impact of vascular and Alzheimer pathologies in Lewy body disease. Acta Neuropathol 115:427–436

    Article  PubMed  Google Scholar 

  23. 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  Google Scholar 

  24. 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

    Article  PubMed  Google Scholar 

  25. 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  PubMed  CAS  Google Scholar 

  26. Kelley BJ, Haidar W, Boeve BF et al (2009) Prominent phenotypic variability associated with mutations in Progranulin. Neurobiol Aging 30:739–751

    Article  PubMed  CAS  Google Scholar 

  27. Khachaturian ZS (1985) Diagnosis of Alzheimer’s disease. Arch Neurol 42:1097–1105

    Article  PubMed  CAS  Google Scholar 

  28. Kuusisto E, Salminen A, Alafuzoff I (2001) Ubiquitin-binding protein p62 is present in neuronal and glial inclusions in human tauopathies and synucleinopathies. NeuroReport 12:2085–2090

    Article  PubMed  CAS  Google Scholar 

  29. Kuusisto E, Salminen A, Alafuzoff I (2002) Early accumulation of p62 in neurofibrillary tangles in Alzheimer’s disease: possible role in tangle formation. Neuropathol Appl Neurobiol 28:228–237

    Article  PubMed  CAS  Google Scholar 

  30. Lendon CL, Lynch T, Norton J et al (1998) Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22. Neurology 50:1546–1555

    Article  PubMed  CAS  Google Scholar 

  31. Lomen-Hoerth C, Anderson T, Miller B (2002) The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology 59:1077–1079

    Article  PubMed  Google Scholar 

  32. Lomen-Hoerth C, Murphy J, Langmore S et al (2003) Are amyotrophic lateral sclerosis patients cognitively normal? Neurology 60:1094–1097

    Article  PubMed  CAS  Google Scholar 

  33. Mackenzie IRA, 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

    Article  PubMed  Google Scholar 

  34. Mackenzie IRA, Neumann M, Baborie A et al (2011) A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 122:111–113

    Article  PubMed  Google Scholar 

  35. Mah AL, Perry G, Smith MA, Monteiro MJ (2000) Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein accumulation. J Cell Biol 151:847–862

    Article  PubMed  CAS  Google Scholar 

  36. Mahoney CJ, Beck J, Rohrer JD et al (2012) Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. Brain 135:736–750

    Article  PubMed  Google Scholar 

  37. Murray ME, DeJesus-Hernandez M, Rutherford NJ et al (2011) Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol 122:673–690

    Article  PubMed  CAS  Google Scholar 

  38. Murray ME, Graff-Radford NR, Ross OA et al (2011) Neuropathologically defined subtypes of Alzheimer’s disease with distinct clinical characteristics: a retrospective study. Lancet Neurol 10:785–796

    Article  PubMed  Google Scholar 

  39. Neumann M, Rademakers R, Roeber S et al (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132:2922–2931

    Article  PubMed  Google Scholar 

  40. Parkinson N, Ince PG, Smith MO et al (2006) ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B). Neurology 67:1074–1077

    Article  PubMed  CAS  Google Scholar 

  41. Rademakers R, Baker M, Gass J et al (2007) Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C → T (Arg493X) mutation: an international initiative. Lancet Neurol 6:857–868

    Article  PubMed  CAS  Google Scholar 

  42. Renton AE, Majounie E, Waite A et al (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268

    Article  PubMed  CAS  Google Scholar 

  43. Ringholz GM, Appel SH, Bradshaw M et al (2005) Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology 65:586–590

    Article  PubMed  CAS  Google Scholar 

  44. Rutherford NJ, Zhang YJ, Baker M et al (2008) Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet 4:e1000193

    Article  PubMed  Google Scholar 

  45. Simon-Sanchez J, Dopper EGP, Cohn-Hokke PE et al (2012) The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions. Brain 135:723–735

    Article  PubMed  Google Scholar 

  46. Stieren ES, El Ayadi A, Xiao Y et al (2011) Ubiquilin-1 is a molecular chaperone for the amyloid precursor protein. J Biol Chem 286:35689–35698

    Article  PubMed  CAS  Google Scholar 

  47. Thal DR, Rub U, Orantes M, Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800

    Article  PubMed  Google Scholar 

  48. Togo T, Cookson N, Dickson DW (2002) Argyrophilic grain disease: neuropathology, frequency in a dementia brain bank and lack of relationship with apolipoprotein E. Brain Pathol 12:45–52

    Article  PubMed  Google Scholar 

  49. Troakes C, Maekawa S, Wijesekera L et al (2011) An MND/ALS phenotype associated with C9orf72 repeat expansion: Abundant p62-positive, TDP-43-negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline. Neuropathology 32:505–514

    Google Scholar 

  50. 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 65:685–697

    Article  PubMed  CAS  Google Scholar 

  51. 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  PubMed  CAS  Google Scholar 

  52. van Harten AC, Kester MI, Visser PJ et al (2011) Tau and p-tau as CSF biomarkers in dementia: a meta-analysis. Clin Chem Lab Med 49:353–366

    PubMed  Google Scholar 

  53. Watts GDJ, Wymer J, Kovach MJ et al (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36:377–381

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We are grateful to all patients, family members, and caregivers who agreed to brain donation, without which these studies would have been impossible. We also acknowledge expert technical assistance of Linda Rousseau and Virginia Phillips for histology and John Gonzalez, Beth Marten, Pamela Desaro and Amelia Johnston for brain banking. This research was funded by Mayo Foundation (Jacoby Professorship of Alzheimer Research, Research Committee CR Program; ALS Center donor funds); National Institutes of Health (P50-AG16574, P50-NS72187, P01-AG03949, R01-AG37491, R01-NS65782 and R01-AG26251), CurePSP, The Society for Progressive Supranuclear Palsy; and the State of Florida Alzheimer Disease Initiative.

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Authors and Affiliations

  1. Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Kevin F. Bieniek, Melissa E. Murray, Nicola J. Rutherford, Monica Castanedes-Casey, Mariely DeJesus-Hernandez, Amanda M. Liesinger, Matthew C. Baker, Rosa Rademakers & Dennis W. Dickson

  2. Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Kevin B. Boylan

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  1. Kevin F. Bieniek
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Correspondence to Dennis W. Dickson.

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401_2012_1048_MOESM1_ESM.tif

Supplementary Fig. 1 Quantitative analysis of PHF-1 immunostaining in the CA1 of a FTLD-C9ORF72 case (Case 10). The CA1 sector of hippocampus is selected as a region of interest. A color deconvolution algorithm, tuned to PHF-1 staining with DAB chromogen, was applied to the image to detect the number of pixels that are strongly immunostained (red) compared to the unstained background (blue). The percentage of these strongly stained pixels is outputted as a quantitative variable and statistically analyzed. (bar = 200 µm) (TIFF 10365 kb)

401_2012_1048_MOESM2_ESM.tif

Supplementary Fig. 2 Double-labeling of ubiquitin-binding proteins p62 and Ubqln2 in the cerebellum of a FTLD-C9ORF72 case (Case 16). Staining was processed on the Dako Autostainer using the Dako EnVision™ G|2 Doublestain system (DAKO, Carpinteria, CA, USA). P62 lesions are labeled with the diaminobenzidine chromogen (brown) and the Ubqln2 lesions labeled with the Vector Blue chromogen (blue)(Vector Laboratories, Burlingame, CA, USA). P62-immunopositive NCIs are seen in both Purkinje and granule cells whereas Ubqln2-immunopositive NCIs are seen in the granule cell layer. There is variable overlap in immunoreactivity between these two proteins. (bar = 20 µm, inset approx. 50 µm) (TIFF 9300 kb)

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Bieniek, K.F., Murray, M.E., Rutherford, N.J. et al. Tau pathology in frontotemporal lobar degeneration with C9ORF72 hexanucleotide repeat expansion. Acta Neuropathol 125, 289–302 (2013). https://doi.org/10.1007/s00401-012-1048-7

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