Intracellular proteinaceous aggregates (inclusion bodies) are almost always detectable at autopsy in brains of elderly individuals. Inclusion bodies composed of TDP-43 and tau proteins often coexist in the same brain, and each of these pathologic biomarkers is associated independently with cognitive impairment. However, uncertainties remain about how the presence and neuroanatomical distribution of inclusion bodies correlate with underlying diseases including Alzheimer's disease (AD). To address this knowledge gap, we analyzed data from the University of Kentucky AD Center autopsy series (n = 247); none of the brains had frontotemporal lobar degeneration. A specific question for this study was whether neurofibrillary tangle (NFT) pathology outside of the Braak NFT staging scheme is characteristic of brains with TDP-43 pathology but lacking AD, that is those with cerebral age-related TDP-43 with sclerosis (CARTS). We also tested whether TDP-43 pathology is associated with comorbid AD pathology, and whether argyrophilic grains are relatively likely to be present in cases with, vs. without, TDP-43 pathology. Consistent with prior studies, hippocampal TDP-43 pathology was associated with advanced AD – Braak NFT stages V/VI. However, argyrophilic grain pathology was not more common in cases with TDP-43 pathology in this data set. In brains with CARTS (TDP-43[+]/AD[−] cases), there were more NFTs in dentate granule neurons than were seen in TDP-43[−]/AD[−] cases. These dentate granule cell NFTs could provide a proxy indicator of CARTS pathology in cases lacking substantial AD pathology. Immunofluorescent experiments in a subsample of cases found that, in both advanced AD and CARTS, approximately 1% of dentate granule neurons were PHF-1 immunopositive, whereas ∼25% of TDP-43 positive cells showed colocalized PHF-1 immunoreactivity. We conclude that NFTs in hippocampal dentate granule neurons are often present in CARTS, and TDP-43 pathology may be secondary to or occurring in parallel with tauopathy.
|Number of pages||10|
|State||Published - Mar 2018|
Bibliographical noteFunding Information:
We are deeply grateful to the study participants and clinicians who made this research possible. The authors thank Sonya Anderson and Ela Patel for technical support. Study funding: P30 AG028383 from the National Institutes of Health. Thanks also to Dr. Peter Davies (PHF-1) and Dr. Manuela Neumann (1D3) for generously providing antibody. The corresponding author Dr. Peter Nelson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
© 2017 International Society of Neuropathology
- hippocampal sclerosis
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Neuroscience (all)
- Clinical Neurology