Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Neuropathology
• Genetics

Background:

• Frontotemporal lobar degeneration with TDP-43 (FTLD-TDP) and limbic-predominant, age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) exhibit overlapping histological features.
• This overlap has prompted debate regarding whether these conditions represent a disease spectrum.

Purpose of the Study:

• To investigate whether FTLD-TDP Type A and LATE-NC are distinct entities or part of a disease spectrum.
• To compare the clinical, genetic, and neuropathological characteristics of FTLD-TDP Type A and LATE-NC.

Main Methods:

• Comparative analysis of demographic, clinical, and genetic data from 148 FTLD-TDP cases (Types A-D, unclassifiable) and 42 LATE-NC cases.
• Focus on TDP-Type A and Type U cases, with and without coexisting Alzheimer's disease neuropathologic changes (ADNC), compared to LATE-NC.
• Blinded assessment of the middle frontal gyrus by four raters to evaluate diagnostic differentiation between Type A and LATE-NC Stage 3.

Main Results:

• FTLD-TDP Type A cases presented with earlier symptom onset, age at death, and shorter disease duration compared to LATE-NC.
• LATE-NC was exclusively diagnosed in sporadic cases, while FTLD-TDP Type A was frequently genetic.
• FTLD-TDP Type A was associated with frontotemporal dementia syndromes, whereas LATE-NC often correlated with amnestic (Alzheimer's disease-associated) syndromes.

Conclusions:

• Despite shared histological features, FTLD-TDP Type A and LATE-NC are distinct diseases.
• Differences in clinical presentation, genetic associations, and regional pathology support their classification as separate entities.
• Maintaining distinct diagnostic terminology for FTLD-TDP Type A and LATE-NC is appropriate.