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

Author:

Lochner Riley H1,Arumanayagam Anithachristy S1,Powell Suzanne Z1234,Masdeu Joseph C235ORCID,Pascual Belen235ORCID,Cykowski Matthew D1345ORCID

Affiliation:

1. Department of Pathology and Genomic Medicine, Houston Methodist Hospital , Houston, Texas, USA

2. Houston Methodist Neurological Institute, Houston Methodist Hospital , Houston, Texas, USA

3. Institute of Academic Medicine at the Houston Methodist Research Institute, Houston Methodist Hospital , Houston, Texas, USA

4. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College , New York, New York, USA

5. Stanley H. Appel Department of Neurology, Houston Methodist Hospital , Houston, Texas, USA

Abstract

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.

Funder

NIH

NINDS

Houston Methodist Research Institute Cornerstone Award

Katz Investigator Award

Publisher

Oxford University Press (OUP)

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