Structural brain signature of FTLD driven by Granulin mutation

Area of Science:

• Neuroscience
• Genetics
• Radiology

Background:

• Frontotemporal lobar degeneration (FTLD) is linked to various gene mutations, including Granulin (GRN).
• GRN Thr272fs mutation carriers (FTLD-GRN(m+)) exhibit more severe MRI abnormalities than sporadic FTLD patients (FTLD-GRN(m-)).

Purpose of the Study:

• To investigate the relationship between grey matter (GM) and white matter (WM) microstructural damage in FTLD patients with and without GRN mutations.
• To correlate imaging findings with neuropsychological deficits.

Main Methods:

• MRI scans including volumetric and diffusion imaging were performed on 23 FTLD patients (6 GRN(m+) and 17 GRN(m-)) and 12 healthy controls.
• Grey matter (GM) atrophy was assessed using voxel-based morphometry.
• White matter (WM) integrity of the corpus callosum was evaluated using diffusion tractography, comparing mean diffusivity and fractional anisotropy.

Main Results:

• FTLD patients displayed widespread GM atrophy and altered corpus callosum diffusion indices compared to controls.
• GRN(m+) patients showed greater left frontal GM atrophy and reduced fractional anisotropy/increased mean diffusivity in the left anterior corpus callosum compared to GRN(m-) patients.
• Significant correlations between GM and WM damage were observed in GRN(m+) patients, predicting neuropsychological deficits.

Conclusions:

• GRN mutations in FTLD are associated with more pronounced WM involvement, potentially due to GRN gene expression in microglia.
• This WM damage may contribute to additional GM atrophy through disconnection mechanisms.
• The findings highlight the distinct pathological mechanisms in GRN-associated FTLD.