Anterior insula is more vulnerable than posterior insula to TDP-43 pathology in common dementias and ALS

Riley H. Lochner, Anithachristy S. Arumanayagam, Suzanne Z. Powell, Joseph C. Masdeu, Belen Pascual, Matthew D. Cykowski

Research output: Contribution to journalArticlepeer-review

Abstract

Based on the anatomic proximity, connectivity, and functional similarities between the anterior insula and amygdala, we tested the hypothesis that the anterior insula is an important focus in the progression of TDP-43 pathology in LATE-NC. Blinded to clinical and neuropathologic data, phospho-TDP (pTDP) inclusion pathology was assessed in paired anterior and posterior insula samples in 105 autopsied patients with Alzheimer disease, Lewy body disease, LATE-NC and hippocampal sclerosis (HS), amyotrophic lateral sclerosis (ALS), and other conditions. Insular pTDP pathology was present in 34.3% of the study cohort, most commonly as neuronal inclusions and/or short neurites in lamina II, and less commonly as subpial processes resembling those described in the amygdala region. Among positive samples, pTDP pathology was limited to the anterior insula (41.7%), or occurred in both anterior and posterior insula (58.3%); inclusion density was greater in anterior insula across all diseases (p < .001). pTDP pathology occurred in 46.7% of ALS samples, typically without a widespread TDP-43 proteinopathy. In LATE-NC, it was seen in 30.4% of samples (mostly LATE-NC stages 2 and 3), often co-occurring with basal forebrain pathology and comorbid HS, suggesting this is an important step in the evolution of this pathology beyond the medial temporal lobe.

Original languageEnglish (US)
Pages (from-to)307-317
Number of pages11
JournalJournal of Neuropathology and Experimental Neurology
Volume83
Issue number5
DOIs
StatePublished - May 1 2024

Keywords

  • Agranular insula
  • Amygdala
  • Amyotrophic lateral sclerosis (ALS)
  • Anterior insula
  • Limbic-predominant age-related TDP-43 encephalopathy (LATE)
  • Posterior insula
  • TAR DNA-binding protein 43 kDa (TDP-43)
  • lower motor neuron
  • Neurons/pathology
  • Humans
  • TDP-43 Proteinopathies/pathology
  • Amyotrophic Lateral Sclerosis/complications
  • Dementia
  • DNA-Binding Proteins

ASJC Scopus subject areas

  • Medicine(all)

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