Asymmetric TDP-43 distribution in primary progressive aphasia with progranulin mutation

Area of Science:

• Neuroscience
• Neuropathology
• Genetics

Background:

• Primary progressive aphasia (PPA) is characterized by language hemisphere degeneration, often linked to Alzheimer disease (AD) or frontotemporal lobar degeneration (FTLD).
• Progranulin gene mutations are a known cause of FTLD pathology.

Observation:

• This study examined brain tissue from a patient with PPA, a progranulin gene mutation, and FTLD pathology.
• Immunohistochemistry for TDP-43 was performed on various cortical and hippocampal regions.
• Stereologic analysis quantified neuronal intranuclear inclusions, cytoplasmic inclusions, and dystrophic neurites.

Findings:

• TDP-43 inclusions demonstrated a significant leftward asymmetry in all analyzed cortical regions.
• These inclusions were more prevalent in language-associated areas compared to memory-related regions.
• This leftward asymmetry of TDP-43 pathology correlates with the clinical presentation of PPA.

Implications:

• The findings suggest a strong link between TDP-43 pathology and neuronal dysfunction in PPA-FTLD.
• This contrasts with PPA-AD, where tau and amyloid deposits show different distribution patterns.
• TDP-43 inclusions may be a more direct marker of neuronal death in PPA-FTLD than AD-related pathologies in PPA-AD.