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01-01-2020 | Frontotemporal Dementia | Original Paper

Subcortical TDP-43 pathology patterns validate cortical FTLD-TDP subtypes and demonstrate unique aspects of C9orf72 mutation cases

Authors: Ian R. Mackenzie, Manuela Neumann

Published in: Acta Neuropathologica | Issue 1/2020

Abstract

Frontotemporal lobar degeneration with TDP-43 immunoreactive (TDP-ir) inclusions (FTLD-TDP) is sub-classified based on the pattern of neocortical pathology, with each subtype showing clinical and genetic correlations. Recent studies indicate that accurate subtyping of cases may be important to help identify genetic risk factors and develop biomarkers. Although most FTLD-TDP cases are easily classified, some do not match well to one of the existing subtypes. In particular, cases with the C9orf72 repeat expansion (C9+) have been reported to show FTLD-TDP type A, type B or a combination of A and B pathology (A + B). In our series of FTLD-TDP cases, we found that those lacking the C9orf72 mutation (non-C9) were all readily classified as type A (n = 29), B (n = 16) or C (n = 18), using current criteria and standard observational methods. This classification was validated using non-biased hierarchical cluster analysis (HCA) of neocortical pathology data. In contrast, only 14/28 (50%) of the C9+ cases were classified as either pure type A or pure type B, with the remainder showing A + B features. HCA confirmed separation of the C9+ cases into three groups. We then investigated whether patterns of subcortical TDP-ir pathology helped to classify the difficult cases. For the non-C9 cases, each subtype showed a consistent pattern of subcortical involvement with significant differences among the groups. The most distinguishing features included white matter threads, neuronal intranuclear inclusions in hippocampus and striatum, and delicate threads in CA1 in type A; glial cytoplasmic inclusions in white matter and neuronal cytoplasmic inclusions (NCI) in lower motor neurons in type B; compact NCI in striatum in type C. HCA of the C9+ cases based on subcortical features increased the number that clustered with the non-C9 type A (46%) or non-C9 type B (36%); however, there remained a C9+ group with A + B features (18%). These findings suggest that most FTLD-TDP cases can be classified using existing criteria and that each group also shows characteristic subcortical TDP-ir pathology. However, C9+ cases may be unique in the degree to which their pathology overlaps between FTLD-TDP types A and B.

Alafuzoff I, Pikkarainen M, Neumann M, Arzberger T, Al-Sarraj S, Bodi I et al (2015) Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions: an inter-laboratory study by the BrainNet Europe consortium. J Neural Transm 122:957–972. https://doi.org/10.1007/s00702-014-1304-1 CrossRefPubMed

Armstrong RA, Ellis W, Hamilton RL, Mackenzie IR, Hedreen J, Gearing M et al (2010) Neuropathological heterogeneity in frontotemporal lobar degeneration with TDP-43 proteinopathy: a quantitative study of 94 cases using principal components analysis. J Neural Transm 117:227–239. https://doi.org/10.1007/s00702-009-0350-6 CrossRefPubMed

Bigio EH, Weintraub S, Rademakers R, Baker M, Ahmadian SS, Rademaker A et al (2013) Frontotemporal lobar degeneration with TDP-43 proteinopathy and chromosome 9p repeat expansion in C9ORF72: clinicopathologic correlation. Neuropathology 33:122–133. https://doi.org/10.1111/j.1440-1789.2012.01332.x CrossRefPubMed

Boeve BF, Boylan KB, Graff-Radford NR, DeJesus-Hernandez M, Knopman DS, Pedraza O et al (2012) Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 135:765–783. https://doi.org/10.1093/brain/aws004 CrossRefPubMedPubMedCentral

Brandmeir NJ, Geser F, Kwong LK, Zimmerman E, Qian J, Lee VM et al (2008) Severe subcortical TDP-43 pathology in sporadic frontotemporal lobar degeneration with motor neuron disease. Acta Neuropathol 115:123–131. https://doi.org/10.1007/s00401-007-0315-5 CrossRefPubMed

Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ 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. https://doi.org/10.1007/s00401-007-0237-2 CrossRefPubMedPubMedCentral

Cairns NJ, Neumann M, Bigio EH, Holm IE, Troost D, Hatanpaa KJ et al (2007) TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 171:227–240. https://doi.org/10.2353/ajpath.2007.070182 CrossRefPubMedPubMedCentral

DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256. https://doi.org/10.1016/j.neuron.2011.09.011 CrossRefPubMedPubMedCentral

Dobson-Stone C, Hallupp M, Bartley L, Shepherd CE, Halliday GM, Schofield PR et al (2012) C9ORF72 repeat expansion in clinical and neuropathologic frontotemporal dementia cohorts. Neurology 79:995–1001. https://doi.org/10.1212/WNL.0b013e3182684634 CrossRefPubMedPubMedCentral

10.

Forman MS, Mackenzie IR, Cairns NJ, Swanson E, Boyer PJ, Drachman DA et al (2006) Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations. J Neuropathol Exp Neurol 65:571–581. https://doi.org/10.1097/00005072-200606000-00005 CrossRefPubMed

11.

Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G et al (2012) A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol 11:54–65. https://doi.org/10.1016/S1474-4422(11)70261-7 CrossRefPubMed

12.

Gijselinck I, Van Mossevelde S, van der Zee J, Sieben A, Philtjens S, Heeman B et al (2015) Loss of TBK1 is a frequent cause of frontotemporal dementia in a Belgian cohort. Neurology 85:2116–2125. https://doi.org/10.1212/WNL.0000000000002220 CrossRefPubMedPubMedCentral

13.

Hatanpaa KJ, Bigio EH, Cairns NJ, Womack KB, Weintraub S, Morris JC et al (2008) TAR DNA-binding protein 43 immunohistochemistry reveals extensive neuritic pathology in FTLD-U: a midwest-southwest consortium for FTLD study. J Neuropathol Exp Neurol 67:271–279CrossRef

14.

Hirsch-Reinshagen V, Alfaify OA, Hsiung GR, Pottier C, Baker M, Perkerson RB III et al (2019) Clinicopathologic correlations in a family with a TBK1 mutation presenting as primary progressive aphasia and primary lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. https://doi.org/10.1080/21678421.2019.1632347 CrossRefPubMed

15.

Hsiung GY, DeJesus-Hernandez M, Feldman HH, Sengdy P, Bouchard-Kerr P, Dwosh E et al (2012) Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain 135:709–722. https://doi.org/10.1093/brain/awr354 CrossRefPubMedPubMedCentral

16.

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. https://doi.org/10.1007/s00401-009-0547-7 CrossRefPubMedPubMedCentral

17.

Koriath CA, Bocchetta M, Brotherhood E, Woollacott IO, Norsworthy P, Simon-Sanchez J et al (2017) The clinical, neuroanatomical, and neuropathologic phenotype of TBK1-associated frontotemporal dementia: a longitudinal case report. Alzheimers Dement 6:75–81. https://doi.org/10.1016/j.dadm.2016.10.003 CrossRef

18.

Laferriere F, Maniecka Z, Perez-Berlanga M, Hruska-Plochan M, Gilhespy L, Hock EM et al (2019) TDP-43 extracted from frontotemporal lobar degeneration subject brains displays distinct aggregate assemblies and neurotoxic effects reflecting disease progression rates. Nat Neurosci 22:65–77. https://doi.org/10.1038/s41593-018-0294-y CrossRefPubMed

19.

Lamb R, Rohrer JD, Real R, Lubbe SJ, Waite AJ, Blake DJ et al (2019) A novel TBK1 mutation in a family with diverse frontotemporal dementia spectrum disorders. Cold Spring Harb Mol Case Stud. https://doi.org/10.1101/mcs.a003913 CrossRefPubMedPubMedCentral

20.

Lee EB, Porta S, Michael Baer G, Xu Y, Suh E, Kwong LK et al (2017) Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration. Acta Neuropathol 134:65–78. https://doi.org/10.1007/s00401-017-1679-9 CrossRefPubMedPubMedCentral

21.

Mackenzie IR (2007) The neuropathology and clinical phenotype of FTD with progranulin mutations. Acta Neuropathol 114:49–54. https://doi.org/10.1007/s00401-007-0223-8 CrossRefPubMed

22.

Mackenzie IR, Baborie A, Pickering-Brown S, Du Plessis D, Jaros E, Perry RH et al (2006) Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol 112:539–549. https://doi.org/10.1007/s00401-006-0138-9 CrossRefPubMedPubMedCentral

23.

Mackenzie IR, Baker M, Pickering-Brown S, Hsiung GY, Lindholm C, Dwosh E et al (2006) The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain 129:3081–3090. https://doi.org/10.1093/brain/awl271 CrossRefPubMed

24.

Mackenzie IR, Neumann M (2016) Molecular neuropathology of frontotemporal dementia: insights into disease mechanisms from postmortem studies. J Neurochem 138(Suppl 1):54–70. https://doi.org/10.1111/jnc.13588 CrossRefPubMed

25.

Mackenzie IR, Neumann M (2017) Reappraisal of TDP-43 pathology in FTLD-U subtypes. Acta Neuropathol 134:79–96. https://doi.org/10.1007/s00401-017-1716-8 CrossRefPubMed

26.

Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E et al (2011) A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 122:111–113. https://doi.org/10.1007/s00401-011-0845-8 CrossRefPubMedPubMedCentral

27.

Mackenzie IR, Nicholson AM, Sarkar M, Messing J, Purice MD, Pottier C et al (2017) TIA1 mutations in amyotrophic lateral sclerosis and frontotemporal dementia promote phase separation and alter stress granule dynamics. Neuron 95(808–816):e809. https://doi.org/10.1016/j.neuron.2017.07.025 CrossRef

28.

Mahoney CJ, Beck J, Rohrer JD, Lashley T, Mok K, Shakespeare T et al (2012) Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. Brain 135:736–750. https://doi.org/10.1093/brain/awr361 CrossRefPubMedPubMedCentral

29.

Mann DM, Rollinson S, Robinson A, Bennion Callister J, Thompson JC, Snowden JS et al (2013) Dipeptide repeat proteins are present in the p62 positive inclusions in patients with frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72. Acta Neuropathol Commun 1:68. https://doi.org/10.1186/2051-5960-1-68 CrossRefPubMedPubMedCentral

30.

Murray ME, Dejesus-Hernandez M, Rutherford NJ, Baker M, Duara R, Graff-Radford NR et al (2011) Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol 122:673–690. https://doi.org/10.1007/s00401-011-0907-y CrossRefPubMedPubMedCentral

31.

Nelson PT, Schmitt FA, Lin Y, Abner EL, Jicha GA, Patel E et al (2011) Hippocampal sclerosis in advanced age: clinical and pathological features. Brain 134:1506–1518. https://doi.org/10.1093/brain/awr053 CrossRefPubMedPubMedCentral

32.

Neumann M, Kwong LK, Lee EB, Kremmer E, Flatley A, Xu Y et al (2009) Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. Acta Neuropathol 117:137–149. https://doi.org/10.1007/s00401-008-0477-9 CrossRefPubMedPubMedCentral

33.

Neumann M, Kwong LK, Truax AC, Vanmassenhove B, Kretzschmar HA, Van Deerlin VM et al (2007) TDP-43-positive white matter pathology in frontotemporal lobar degeneration with ubiquitin-positive inclusions. J Neuropathol Exp Neurol 66:177–183. https://doi.org/10.1097/01.jnen.0000248554.45456.58 CrossRefPubMed

34.

Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133. https://doi.org/10.1126/science.1134108 CrossRefPubMed

35.

Nishihira Y, Gefen T, Mao Q, Appin C, Kohler M, Walker J et al (2019) Revisiting the utility of TDP-43 immunoreactive (TDP-43-ir) pathology to classify FTLD-TDP subtypes. Acta Neuropathol 138:167–169. https://doi.org/10.1007/s00401-019-02024-w CrossRefPubMed

36.

Pikkarainen M, Hartikainen P, Alafuzoff I (2008) Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions visualized with ubiquitin-binding protein p62 immunohistochemistry. J Neuropathol Exp Neurol 67:280–298. https://doi.org/10.1097/NEN.0b013e31816a1da2 CrossRefPubMed

37.

Pottier C, Ren Y, Perkerson RB III, Baker M, Jenkins GD, van Blitterswijk M et al (2019) Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD. Acta Neuropathol 137:879–899. https://doi.org/10.1007/s00401-019-01962-9 CrossRefPubMed

38.

Rademakers R, Eriksen JL, Baker M, Robinson T, Ahmed Z, Lincoln SJ et al (2008) Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia. Hum Mol Genet 17:3631–3642. https://doi.org/10.1093/hmg/ddn257 CrossRefPubMedPubMedCentral

39.

Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR et al (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268. https://doi.org/10.1016/j.neuron.2011.09.010 CrossRefPubMedPubMedCentral

40.

Rutherford NJ, Heckman MG, Dejesus-Hernandez M, Baker MC, Soto-Ortolaza AI, Rayaprolu S et al (2012) Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype. Neurobiol Aging 33(2950):e2955–e2957. https://doi.org/10.1016/j.neurobiolaging.2012.07.005 CrossRef

41.

Sampathu DM, Neumann M, Kwong LK, Chou TT, Micsenyi M, Truax A 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. https://doi.org/10.2353/ajpath.2006.060438 CrossRefPubMedPubMedCentral

42.

Shinagawa S, Naasan G, Karydas AM, Coppola G, Pribadi M, Seeley WW et al (2015) Clinicopathological study of patients with C9ORF72-associated frontotemporal dementia presenting with delusions. J Geriatr Psychiatry Neurol 28:99–107. https://doi.org/10.1177/0891988714554710 CrossRefPubMed

43.

Simon-Sanchez J, Dopper EG, Cohn-Hokke PE, Hukema RK, Nicolaou N, Seelaar H et al (2012) The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions. Brain 135:723–735. https://doi.org/10.1093/brain/awr353 CrossRefPubMed

44.

Snowden JS, Rollinson S, Thompson JC, Harris JM, Stopford CL, Richardson AM et al (2012) Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 135:693–708. https://doi.org/10.1093/brain/awr355 CrossRefPubMedPubMedCentral

45.

Tan RH, Shepherd CE, Kril JJ, McCann H, McGeachie A, McGinley C et al (2013) Classification of FTLD-TDP cases into pathological subtypes using antibodies against phosphorylated and non-phosphorylated TDP43. Acta Neuropathol Commun 1:33. https://doi.org/10.1186/2051-5960-1-33 CrossRefPubMedPubMedCentral

46.

van Blitterswijk M, Mullen B, Heckman MG, Baker MC, DeJesus-Hernandez M, Brown PH et al (2014) Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers. Neurobiol Aging 35(2421):e2413–e2427. https://doi.org/10.1016/j.neurobiolaging.2014.04.016 CrossRef

47.

van Blitterswijk M, Mullen B, Nicholson AM, Bieniek KF, Heckman MG, Baker MC et al (2014) TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia. Acta Neuropathol 127:397–406. https://doi.org/10.1007/s00401-013-1240-4 CrossRefPubMedPubMedCentral

48.

van Blitterswijk M, Mullen B, Wojtas A, Heckman MG, Diehl NN, Baker MC et al (2014) Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene. Mol Neurodegener 9:38. https://doi.org/10.1186/1750-1326-9-38 CrossRefPubMedPubMedCentral

49.

van der Zee J, Gijselinck I, Van Mossevelde S, Perrone F, Dillen L, Heeman B et al (2017) TBK1 mutation spectrum in an extended european patient cohort with frontotemporal dementia and amyotrophic lateral sclerosis. Hum Mutat 38:297–309. https://doi.org/10.1002/humu.23161 CrossRefPubMedPubMedCentral

Title: Subcortical TDP-43 pathology patterns validate cortical FTLD-TDP subtypes and demonstrate unique aspects of C9orf72 mutation cases
Authors: Ian R. Mackenzie
Manuela Neumann
Publication date: 01-01-2020
Publisher: Springer Berlin Heidelberg
Keywords: Frontotemporal Dementia
Frontotemporal Dementia
Pathology
Published in: Acta Neuropathologica / Issue 1/2020
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-02070-4

At a glance: The STEP trials

Springer Medicine

Subcortical TDP-43 pathology patterns validate cortical FTLD-TDP subtypes and demonstrate unique aspects of C9orf72 mutation cases

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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