Intraepineurial Fat Fraction: A Novel MR Neurography-Based Biomarker in Transthyretin Amyloidosis Polyneuropathy

Hereditary transthyretin amyloid polyneuropathy (ATTRv-PN) is a rare and progressive neurodegenerative disorder characterized by axonal neuropathy and amyloid deposits. Early detection of disease onset and progression is crucial for timely therapeutic intervention. Quantitative MRI (qMRI) can be used to measure potential biomarkers. Intraepineurial fat fraction (ieFF) may reflect lipid droplets in amyloid deposits as described in histological studies or the replacement of nerve fiber loss with fatty-rich interfascicular epineurium. This study investigates the potential utility of ieFF as a novel imaging-related biomarker in differentiating ATTRv-PN, asymptomatic carriers (ATTRv-C), and healthy controls (HCs).

Fifty-three patients with TTR mutations were imaged (31 ATTRv-PN patients, 22 ATTRv-C, and 24 HC) and both clinical and electrophysiological parameters were quantified. 3D volume, ieFF, and magnetization transfer ratio (MTR) were quantified in sciatic and tibial nerves using qMRI.

Symptomatic ATTRv-PN patients exhibited significantly higher ieFF in both sciatic (32.4% IQR [24.4-38.1]) and tibial nerves (13.7%, IQR [9.97-20.7]) compared to controls (sciatic 22.3%, IQR [16.6-28.5]; tibial 9.74%, IQR [6.36-12.5]) (p < 0.05). ieFF values were positively correlated in both uni and multivariate analyses with the main clinical scores and electrophysiological measures. ATTRv-C also showed increased ieFF values compared to controls (p < 0.05). Comparatively, MTR and nerve volumes exhibited less pronounced differences across groups.

This study demonstrates that ieFF effectively differentiates symptomatic and asymptomatic ATTRv patients from HC and correlates strongly with electrophysiological and clinical severity parameters. Furthermore, we compare ieFF with conventional qMRI biomarkers, highlighting its superior potential for monitoring nerve structural impairment.