Patterns of TDP-43 Deposition in Brains with LRRK2 G2019S Mutations

Abstract

Objective: To assess for TDP-43 deposits in brains with and without a LRRK2 G2019S mutation.

Background: LRRK2 G2019S mutations have been associated with parkinsonism and a wide range of pathological findings. There are no systematic studies examining the frequency and extent of TDP-43 deposits in neuropathological samples from LRRK2 G2019S carriers.

Methods: Twelve brains with LRRK2 G2019S mutations were available for study from the New York Brain Bank at Columbia University; 11 of them had samples available for TDP-43 immunostaining. Clinical, demographic, and pathological data are reported for 11 brains with a LRRK2 G2019S mutation and compared to 11 brains without GBA1 or LRRK2 G2019S mutations with a pathologic diagnosis of Parkinson's disease (PD) or diffuse Lewy body disease. They were frequency matched by age, gender, parkinsonism age of onset, and disease duration.

Results: TDP-43 aggregates were present in 73% (n = 8) of brains with a LRRK2 mutation and 18% (n = 2) of brains without a LRRK2 mutation (P = 0.03). In one brain with a LRRK2 mutation, TDP-43 proteinopathy was the primary neuropathological change.

Conclusions: Extranuclear TDP-43 aggregates are observed with greater frequency in LRRK2 G2019S autopsies compared to PD cases without a LRRK2 G2019S mutation. The association between LRRK2 and TDP-43 should be further explored. © 2023 International Parkinson and Movement Disorder Society.

Keywords: LRRK2; TDP-43; neuropathology.

Figure 1 Legend:

Photomicrographs of immunohistochemical stains against non-phosphorylated TDP-43. A: Arrow pointing to dystrophic neurites in amygdala of case 8. Original magnification 400X; TDP-43. B: Arrows pointing to dystrophic neurites in substantia nigra of case 1. Original magnification 400X; TDP-43. C: Arrow pointing to a long, thick dystrophic neurite in the motor cortex of case 7 with a pathologic diagnosis of FTLD type C. Original magnification 630X; TDP-43.