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

Abstract

Introduction: 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).

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: biomarkers; fat fraction; neurography; quantified MRI; transthyretin amyloid polyneuropathy.

FIGURE 1

Segmentation of sciatic and tibial nerves ROIs. Anatomical landmarks for segmentation limits are shown in the left column. At the thigh level (sciatic nerve), the short head of the biceps femoris insertion was used as the proximal limit (Diamond), and the rectus femoris distal insertion as the distal segmentation limit (Triangle). At the leg level (tibial nerve), the proximal insertion of the posterior tibialis was the proximal segmentation limit (Star), and the distal insertion of the gastrocnemius medialis was the distal segmentation limit (Square). Sciatic nerve (upper row) and tibial nerve (lower row) are marked with a white arrow (3D reconstruction images, central column) and colored in yellow (3D GRE WE axial projections, right column).

FIGURE 2

Nerve regions of interest enlarged view at tibial and sciatic levels in different pathological conditions. Tibial nerve ROI in a symptomatic ATTRv‐PN patient (a); ATTRv‐C patient (b) and healthy control (c); Sciatic nerve ROI in an ATTRv‐PN patient (d); ATTRv‐C patient (e) and healthy control (f).

FIGURE 3

Sciatic and tibial nerve fat fraction values in patients and controls. Fat fraction (FF) values in sciatic (a) and tibial (b) nerves in symptomatic patients (ATTRv‐PN), asymptomatic carriers (ATTRv‐C), and healthy controls (HC).

FIGURE 4

Correlations between FF values and electrophysiological and clinical scores. Correlations between tibial (a–c, e, f) and sciatic (d) nerves fat fraction and clinical scores and electrophysiological parameters. CMAP, Compound Muscle Action Potential; LL, Lower limb; ONLS, Overall Neuropathy Limitations Scale; PND, Peripheral Neuropathy Disability Score; TA, Anterior Tibialis. For each correlation, correlation coefficient ρ and p‐value are indicated in the top left.