LATE-NC Stage 3: a diagnostic rubric to differentiate severe LATE-NC from FTLD-TDP

Area of Science:

• Neuropathology
• Neurodegenerative Diseases
• TDP-43 Proteinopathies

Background:

• Distinguishing limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) from frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is challenging, especially in LATE-NC Stage 3 due to TDP-43 pathology in the middle frontal gyrus (MFG).
• TDP-43 proteinopathies are a significant cause of cognitive decline and dementia, necessitating accurate diagnostic criteria.

Purpose of the Study:

• To develop and validate a diagnostic rubric to differentiate LATE-NC Stage 3 from FTLD-TDP and other TDP-43 proteinopathies.
• To investigate the clinical and genetic characteristics associated with LATE-NC Stage 3.

Main Methods:

• Analysis of TDP-43 proteinopathy in large brain bank cohorts (University of Kentucky, 90+ Study, Mayo Clinic).
• Quantification of pathology burden using digital pathology and manual counting methods.
• Evaluation of clinical and genetic data from NACC and ADGC, including GRN, TMEM106B, and APOE variants.

Main Results:

• A data-driven rubric successfully classified over 90% of cases as either LATE-NC Stage 3 or FTLD-TDP.
• Identified diagnostically challenging scenarios, including FTLD-TDP Type B and a novel TDP-43 subtype.
• Found preferential association of the GRN (rs5848) risk allele with LATE-NC Stage 3, but not TMEM106B or APOE variants.

Conclusions:

• A reliable diagnostic rubric for LATE-NC Stage 3 and FTLD-TDP was developed, improving classification of TDP-43 proteinopathies.
• The rubric accounts for potential diagnostic pitfalls, enhancing neuropathologic assessment.
• Genetic analysis suggests specific allele associations with LATE-NC Stage 3, warranting further investigation.