Basic Science and Pathogenesis.

Area of Science:

• Neuropathology
• Neuroscience
• Geriatric Medicine

Background:

• Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a newly identified dementia cause.
• LATE and Alzheimer's disease (AD) share clinical symptoms and often co-occur neuropathologically.
• TDP-43 lesion morphology in dementia requires further investigation.

Purpose of the Study:

• To investigate TDP-43 lesion morphology and immunoreactive species in pure LATE and in cases with coexisting AD neuropathological changes (ADNC).
• To differentiate histopathological features of TDP-43 proteinopathy in LATE-NC versus ADNC+LATE-NC.

Main Methods:

• Immunohistochemistry on human autopsy brain tissue (hippocampus, amygdala, cortices) from 70 cases.
• Semi-quantitative assessment of TDP-43 neuronal cytoplasmic inclusions (NCIs) and dystrophic neurites (DNs).
• Analysis of various TDP-43 species (pS409/410, pS409/pS403, pS403/pS404, C- and N-terminal TDP-43).

Main Results:

• Pure LATE-NC cases predominantly showed a band-like pattern of dystrophic neurites in the hippocampus.
• Pure LATE-NC cases had a more severe burden of dystrophic neurites in the hippocampus, amygdala, and temporal cortex compared to ADNC+LATE-NC.
• ADNC+LATE-NC cases exhibited a higher predominance of neuronal cytoplasmic inclusions in the amygdala and distinct TDP-43 species profiles.

Conclusions:

• Histopathological features of TDP-43 proteinopathy differ between pure LATE-NC and coexisting ADNC.
• LATE-NC appears modified by the presence of moderate-to-high levels of ADNC.
• Distinct mechanisms may underlie TDP-43 aggregation in different dementias, with coexisting pathologies influencing each other.