Microglia in frontotemporal lobar degeneration with progranulin or C9ORF72 mutations

Nobutaka Sakae, Shanu F. Roemer, Kevin F. Bieniek, Melissa E. Murray, Matthew C. Baker, Koji Kasanuki, Neill R. Graff-Radford, Leonard Petrucelli, Marka Van Blitterswijk, Rosa Rademakers, Dennis W. Dickson

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2 Scopus citations


Objective: To identify clinicopathological differences between frontotemporal lobar degeneration (FTLD) due to mutations in progranulin (FTLD-GRN) and chromosome 9 open reading frame 72 (FTLD-C9ORF72). Methods: We performed quantitative neuropathologic comparison of 17 FTLD-C9ORF72 and 15 FTLD-GRN with a focus on microglia. For clinical comparisons, only cases with high quality medical documentation and concurring diagnoses by at least two neurologists were included (14 FTLD-GRN and 13 FTLD-C9ORF72). Neuropathological analyses were limited to TDP-43 Type A to assure consistent assessment between the groups, acknowledging that Type A is a minority of C9ORF72 patients. Furthermore, only cases with sufficient tissue from all regions were studied (11 FTLD-GRN and 11 FTLD-C9ORF72). FTLD cases were also compared to age– and sex–matched normal controls. Immunohistochemistry was performed for pTDP-43, IBA-1, CD68, and GFAP. Morphological characterization of microglia was performed in sections of cortex blinded to clinical and genetic information. Results: FTLD-GRN patients had frequent asymmetric clinical features, including aphasia and apraxia, as well as more asymmetric cortical atrophy. Neuropathologically, FTLD-C9ORF72 had greater hippocampal tau pathology and more TDP-43 neuronal cytoplasmic inclusions. FTLD-GRN had more neocortical microvacuolation, as well as more IBA-1–positive ameboid microglia in superficial cortical layers and in subcortical white matter. FTLD-GRN also had more microglia with nuclear condensation, possibly indicating apoptosis. Microglial morphology with CD68 immunohistochemistry in FTLD-GRN and FTLD-C9ORF72 differed from controls. Interpretation: Our findings underscore differences in microglial response in FTLD-C9ORF72 and FTLD-GRN as shown by significant differences in ameboid microglia in gray and white matter. These results suggest the differential contribution of microglial dysfunction in FTLD-GRN and FTLD-C9ORF72 and suggest that clinical, neuroimaging and pathologic differences could in part be related to differences in microglia response.

Original languageEnglish (US)
Pages (from-to)1782-1796
Number of pages15
JournalAnnals of Clinical and Translational Neurology
Issue number9
StatePublished - Sep 1 2019

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

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    Sakae, N., Roemer, S. F., Bieniek, K. F., Murray, M. E., Baker, M. C., Kasanuki, K., Graff-Radford, N. R., Petrucelli, L., Van Blitterswijk, M., Rademakers, R., & Dickson, D. W. (2019). Microglia in frontotemporal lobar degeneration with progranulin or C9ORF72 mutations. Annals of Clinical and Translational Neurology, 6(9), 1782-1796. https://doi.org/10.1002/acn3.50875