The underacknowledged PPA-ALS: A unique clinicopathologic subtype with strong heritability

Area of Science:

• Neuroscience
• Genetics
• Neuropathology

Background:

• Primary progressive aphasia (PPA) is a neurodegenerative condition affecting language. Amyotrophic lateral sclerosis (ALS) is a motor neuron disease. The overlap and genetic underpinnings between PPA and ALS require further investigation.
• Frontotemporal lobar degeneration (FTLD) is a key pathology in PPA and ALS, with TDP-43 proteinopathy (FTLD-TDP) being a common subtype.

Purpose of the Study:

• To determine the incidence and heritability of ALS in a large Australian cohort of patients with PPA.
• To investigate the neuropathology, including FTLD-TDP, associated with PPA-ALS.
• To identify genetic factors contributing to PPA and PPA-ALS, particularly in familial cases.

Main Methods:

• A cohort of 130 patients with nonfluent (nfvPPA) or semantic (svPPA) variants of PPA were assessed for ALS and family history of neurodegenerative diseases.
• Neuropathologic examination was performed on autopsy cases (n=36).
• Genetic analysis was conducted on familial PPA and PPA-ALS cases to identify mutations in known FTD/ALS genes.

Main Results:

• ALS was present in 18% of nfvPPA and 5% of svPPA cases. Overall, 12% of the PPA cohort had concomitant ALS.
• A strong family history was associated with PPA-ALS and FTLD-TDP pathology.
• FTLD-TDP was found in all PPA-ALS autopsy cases. Genetic analysis revealed mutations in known FTD/ALS genes in familial PPA, but only 50% of familial PPA-ALS cases, suggesting novel genetic variants.

Conclusions:

• The incidence of ALS in PPA is significant (12%), comparable to overall FTD rates, indicating a substantial proportion of FTD-ALS patients present with primary language deficits.
• Assessing for ALS in PPA patients is critical, as PPA-ALS demonstrates a strong clinicopathologic association.
• The genetic landscape of PPA-ALS may involve novel genetic variants beyond those currently known in FTD/ALS genes.