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Microglia in frontotemporal lobar degeneration with progranulin or C9ORF72 mutations

Nobutaka Sakae1, Shanu F Roemer1, Kevin F Bieniek2

  • 1Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.

Annals of Clinical and Translational Neurology
|August 27, 2019
PubMed
Abstract

Insights

Frontotemporal lobar degeneration (FTLD) linked to progranulin (FTLD-GRN) mutations shows distinct clinical and neuropathological features compared to FTLD linked to chromosome 9 open reading frame 72 (FTLD-C9ORF72) mutations, particularly in microglial responses.

Area of Science:

  • Neuroscience
  • Neuropathology
  • Genetics

Background:

  • Frontotemporal lobar degeneration (FTLD) is a group of neurodegenerative diseases.
  • Mutations in progranulin (GRN) and chromosome 9 open reading frame 72 (C9ORF72) are common genetic causes of FTLD.
  • Distinct clinicopathological features may exist between FTLD-GRN and FTLD-C9ORF72.

Purpose of the Study:

  • To compare clinicopathological differences between FTLD-GRN and FTLD-C9ORF72.
  • To investigate the role of microglia in these distinct FTLD subtypes.

Main Methods:

  • Quantitative neuropathological comparison of FTLD-C9ORF72 and FTLD-GRN cases, focusing on microglia.
  • Clinical data analysis included cases with high-quality medical documentation and expert consensus diagnoses.
  • Immunohistochemistry for pTDP-43, IBA-1, CD68, and GFAP was performed; microglial morphology was assessed in blinded cortical sections.

Main Results:

  • FTLD-GRN patients exhibited more asymmetric clinical features (aphasia, apraxia) and cortical atrophy.
  • FTLD-C9ORF72 showed greater hippocampal tau pathology and more TDP-43 inclusions.
  • FTLD-GRN displayed increased neocortical microvacuolation and more ameboid microglia (IBA-1 positive) in superficial cortical layers and white matter, with signs of apoptosis.

Conclusions:

  • Significant differences in microglial morphology and distribution exist between FTLD-GRN and FTLD-C9ORF72.
  • These findings suggest a differential contribution of microglial dysfunction in the pathogenesis of FTLD-GRN and FTLD-C9ORF72.
  • Observed clinical, neuroimaging, and pathological variations may be partly attributed to distinct microglial responses.

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