Basic Science and Pathogenesis.

Background: Limbic-predominant age-related TDP-43 encephalopathy (LATE) has been recently recognized as a cause of dementia in the elderly. LATE and Alzheimer's disease (AD) share similar clinical presentations, and their neuropathological changes-LATE-NC and ADNC-commonly co-occur in the brains of individuals with dementia. Frontotemporal degeneration (FTLD-TDP) represents another group of TDP-43-associated neurodegenerative diseases. Still, the morphological and molecular features of TDP-43 lesions in different diseases remain under-researched. Here, we investigated distinct TDP-43 lesions and immunoreactive species in cases of AD with LATE-NC, pure LATE (ABC score < 1), and FTLD-TDP.

Method: We performed immunohistochemistry in paraffin-embedded tissue from the hippocampus, amygdala, temporal and frontal cortices of 22 non-demented cases, 24 AD cases with comorbid LATE-NC, 9 pure LATE and 22 FTLD-TDP cases (subtypes A-C). We semiquantitatively assessed the severity of neuronal cytoplasmic inclusions and dystrophic neurites using antibodies against different TDP-43 epitopes: pS409/pS403, pS403/pS404 and non-phosphorylated C- and N-terminal TDP-43. We also assessed general neuropathological parameters among the groups.

Result: LATE cases were older at death and exhibited lower neuronal density in the hippocampus compared to the remaining groups, supporting the hypothesis of a slower disease course in LATE compared to AD. AD and LATE did not differ in LATE-NC stages. Morphologically, pure LATE cases showed higher severity levels of hippocampal dystrophic neurites compared to AD with LATE-NC and FTLD-TDP cases. The severity of neuronal cytoplasmic inclusions was similar among groups. AD cases showed an overall predominance of pS409/pS410 TDP-43 species, however LATE and FTLD-TDP cases showed no significant differences in burden of all TDP-43 species except N-terminal TDP-43, which showed lower severity in all groups. LATE cases also exhibited decreased burdens of TDP-43 species in the frontal cortex compared to FTLD-TDP.

Conclusion: These results suggest that TDP-43 assumes distinct patterns of immunoreactivity in dementia, especially in the hippocampus. LATE and FTLD-TDP cases showed a similar, but non-identical patterns of TDP-43 immunoreactive species, patterns which were different in turn from LATE-NC in ADNC. These data may also support the concept of LATE as a separate disease with high burdens of different TDP-43 species restricted to the limbic system in the absence of moderate-high ADNC.