Acta Neuropathologica

, Volume 138, Issue 5, pp 783–793 | Cite as

Increased prevalence of granulovacuolar degeneration in C9orf72 mutation

  • Yuichi Riku
  • Charles DuyckaertsEmail author
  • Susana Boluda
  • Isabelle Plu
  • Isabelle Le Ber
  • Stéphanie Millecamps
  • François Salachas
  • Brainbank NeuroCEB Neuropathology Network
  • Mari Yoshida
  • Takashi Ando
  • Masahisa Katsuno
  • Gen Sobue
  • Danielle Seilhean
Original Paper


Granulovacuolar degeneration (GVD) is usually found in Alzheimer’s disease (AD) cases or in elderly individuals. Its severity correlates positively with the density of neurofibrillary tangles (NFTs). Mechanisms underlying GVD formation are unknown. We assessed the prevalence and distribution of GVD in cases with TDP-43-related frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS-TDP). Consecutively autopsied cases with FTLD/ALS-TDP and C9orf72 mutations (FTLD/ALS-C9; N = 29), cases with FTLD/ALS-TDP without C9orf72 mutations (FTLD/ALS-nonC9; N = 46), and age-matched healthy controls (N = 40) were studied. The prevalence of GVD was significantly higher in the FTLD/ALS-C9 cases (26/29 cases) than in the FTLD/ALS-nonC9 cases (15/46 cases; Fisher exact test; p < 2×10−6) or in the control group (12/40 individuals; p < 1×10−6). Average Braak stages and ages of death were not significantly different among the groups. The CA2 sector was most frequently affected in the FTLD/ALS-C9 group, whereas the CA1/subiculum was the most vulnerable area in the other groups. Extension of GVD correlated with the clinical duration of the disease in the FTLD/ALS-C9 cases but not in the FTLD/ALS-nonC9 cases. The GVD-containing neurons frequently had dipeptide repeat (DPR) protein inclusions. GVD granules labeled with antibodies directed against charged multivesicular body protein 2B or casein kinase 1δ were attached to DPR inclusions within GVD. Our results suggest that development of GVD and DPR inclusions is related to common pathogenic mechanisms and that GVD is not only associated with NFTs seen in AD cases or aging individuals.


ALS C9orf72 Dipeptide repeat FTLD Granulovacuolar degeneration TDP-43 



This study is supported by Grants for aid from Uehara Memorial Foundation, Kanae Foundation for the Promotion of Medical Science, and Mochida Memorial Foundation for Medical and Pharmacological Research. The NeuroCEB Brainbank is funded by the patient associations ARSEP (multiple sclerosis), CSC (Connaître les Syndromes Cérébelleux), France Alzheimer, France Parkinson, ARSLA (Association pour la recherche sur la SLA), France DFT (Dégénérescence Fronto-Temporale), and CADASIL France. We also give special thanks to the technicians of the Department of Neuropathology, Pitié-Salpêtrière Hospital. Members of the NeuroCEB Brainbank Neuropathology Network: Letournel F, Martin-Négrier M-L, Chapon F, Godfraind C, Maurage C-A, Deramecourt V, Meyronet D, Streichenberger N, Maues de Paula A, Rigau V, Vandenbos-Burel F, Milin S, Chiforeanu DC, Laquerrière A, and Lannes B.

Author contributions

Study concept: YR, DS, and CD; pathologic data acquisition: YR and DS; clinical data acquisition: FS, IL; genetic tests: SM, IL; autopsy, and tissue archive: SB, IP, DS, and CD; technical instructions: MY, GS, TA, and MK; drafting manuscript: YR; supervisor: DS and CD.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Yuichi Riku
    • 1
    • 6
  • Charles Duyckaerts
    • 1
    • 2
    • 3
    Email author
  • Susana Boluda
    • 1
    • 3
  • Isabelle Plu
    • 1
    • 2
  • Isabelle Le Ber
    • 3
    • 4
  • Stéphanie Millecamps
    • 3
  • François Salachas
    • 5
  • Brainbank NeuroCEB Neuropathology Network
  • Mari Yoshida
    • 7
  • Takashi Ando
    • 6
  • Masahisa Katsuno
    • 6
  • Gen Sobue
    • 8
  • Danielle Seilhean
    • 1
    • 2
    • 3
  1. 1.Raymond Escourolle Neuropathology DepartmentGroupe Hospitalier Pitié-Salpêtrière Charles Foix, AP-HPParisFrance
  2. 2.Faculty of MedicineSorbonne UniversityParisFrance
  3. 3.Institut du Cerveau et de la Moelle épinière (ICM), Inserm U 1127, CNRS UMR7225, Sorbonne UniversityParisFrance
  4. 4.National Reference Center for Rare or Early Dementias, Institute of Memory and Alzheimer’s Disease (IM2A), Center of Excellence of Neurodegenerative Disease (CoEN), Department of NeurologyGroupe Hospitalier Pitié-Salpêtrière Charles Foix AP-HPParisFrance
  5. 5.Reference Center for ALS, Department of NeurologyGroupe Hospitalier Pitié-Salpêtrière Charles Foix, AP-HPParisFrance
  6. 6.Department of NeurologyNagoya UniversityNagoyaJapan
  7. 7.Institute for Medical Science of AgingAichi Medical UniversityAichiJapan
  8. 8.Graduate School of MedicineNagoya UniversityNagoyaJapan

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