Resistance of Basal Forebrain Cholinergic Neurons to TDP-43 Proteinopathy in Primary Progressive Aphasia

Sara Rose Dunlop, Ivan Ayala, Callen Spencer, Margaret E. Flanagan, Marek Marsel Mesulam, Tamar Gefen, Changiz Geula

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Basal forebrain cholinergic neurons (BFCN) display accumulation of neurofibrillary tangles and degeneration in Alzheimer disease and are targets of therapeutic intervention. This study determined vulnerability of BFCN to accumulation of TDP-43 in primary progressive aphasia with TDP-43 proteinopathy (PPA-TDP). Brains from 16 PPA participants with pathologically confirmed TDP-43 proteinopathy, with available paraffin-embedded sections (Group 1), or systematically sampled frozen sections (Group 2), were studied. Immunohistochemistry was performed with an antibody against phosphorylated TDP-43. BFCN were identified by their magnocellular appearance in Nissl preparations. Presence of TDP-43 inclusions and preinclusions in BFCN was determined and quantitative analysis was performed in Group 2. In Group 1, BFCN were completely free of inclusions except for occasional dystrophic neurites. Sparse TDP-43 preinclusions with smooth or granular staining in BFCN were detected. In Group 2, extremely rare TDP-43 intranuclear inclusions were detected in 0.1% of BFCN per section, along with occasional dystrophic neurites. Although sparse, significantly more preinclusions (1.4% of BFCN) were present when compared with inclusions. No hemispheric differences were noted. Small neurons near BFCN contained more preinclusions compared with BFCN. Thus, BFCN in PPA-TDP are resistant to TDP-43 proteinopathy and degeneration, suggesting that cholinergic therapy is unlikely to be effective in this disorder.

Original languageEnglish (US)
Pages (from-to)910-919
Number of pages10
JournalJournal of Neuropathology and Experimental Neurology
Issue number11
StatePublished - Nov 1 2022
Externally publishedYes


  • Basal forebrain
  • Cholinergic neurons
  • Frontotemporal lobar degeneration
  • Inclusions
  • Primary progressive aphasia
  • TDP-43

ASJC Scopus subject areas

  • General Medicine


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