Candidate imaging biomarkers for PMP22‐related inherited neuropathies

Abstract

Objective Charcot–Marie–Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsy (HNPP) are caused by mutations to the peripheral myelin protein 22 (PMP22) gene. A need exists for sensitive and reliable biomarkers of progression and treatment response. Magnetic resonance imaging (MRI) metrics of nerve pathology and morphology were investigated for this purpose. Methods MRI was performed at 3.0 T in the thigh of CMT1A (N = 11) and HNPP patients (N = 12) and controls (N = 23). Three potential imaging biomarkers of the sciatic nerve were investigated: 1) magnetization transfer ratio (MTR), which assays myelin content, and 2) cross‐sectional area (CSA) and 3) circularity, which assay morphological changes. Potential imaging biomarkers were compared across cohorts and assessed for relationships with disability in the legs (CMTESL), compound motor action potentials (CMAP), and motor conduction velocities (MCV). Inter‐rater reliability and test–retest repeatability were established for each imaging metric. Results Significant differences in MTR, CSA, and circularity were observed in CMT1A relative to controls (p = 0.02, p < 0.001, and p = 0.003, respectively, via Wilcoxon rank‐sum tests). Differences were not observed in the HNPP cohort. Significant relationships were observed between MTR and clinical metrics (CMTESL: p = 0.003, CMAP: p = 0.03, MCV: p = 0.01); and between CSA and electrophysiology (CMAP: p = 0.002, MCV: p < 0.001). All metrics were reliable and repeatable with MTR the most reliable (intraclass correlation coefficient [ICC] >0.999, CV = 0.30%) and repeatable (ICC = 0.84, CV = 3.16%). Interpretation MTR, CSA, and circularity showed promise as reliable and sensitive biomarkers of CMT1A, but not HNPP. These warrant longitudinal investigation as response biomarkers in upcoming clinical trials of CMT1A, while other methods should be considered for HNPP.

Anesthetic Considerations for Patients with Hereditary Neuropathy with Liability to Pressure Palsies: A Narrative Review

“…Diffusion tensor imaging has shown white matter changes in HNPP patients with a tendency to affect frontal lobes [73]. One small case series obtained high MRIs of HNPP and CMT1A patients when evaluating for magnetic transfer ratio (an indirect measure of myelination) and nerve cross section; morphological circularity of the nerves proposed said measures as reliable and sensitive for CMT1A only [74]. Fatty infiltration of muscle in a proximal dependent fashion has been both suggested as further evidence of a length dependent process and as a biomarker of HNPP disease progression in general [71].…”

Magnetic resonance imaging and ultrasound elastography in the context of preclinical pharmacological research: significance for the 3R principles

“…However, the demanding technical nature of DTI requiring specialized expertise and long measurement times (12 h were reported for excised rat nerves; Boyer et al, 2015 ) might be challenges for its routine application to preclinical pharmacological examinations in small rodents. Finally, MTR has been established in the clinic as reliable and reproducible ( Preisner et al, 2021 ; Chen et al, 2023 ) and provides a means to examine peripheral nerve injury and neuropathies ( Dortch et al, 2014 ; Kollmer et al, 2020 ; Roth et al, 2022 ), thereby enhancing the translational potential of the activities described here for small rodents.…”

Multiparametric Quantitative MRI of Peripheral Nerves in the Leg: A Reliability Study

“…8 Nerve qMRI is able to evaluate distal-to-proximal changes along the nerve in both myelin content and microstructural integrity (e.g., axonal loss). 1,[9][10][11] Furthermore, nerve qMRI is a non-invasive technique that enables longitudinal studies and is increasingly available through vendor-provided sequences, facilitating its widespread adoption.…”

“…To overcome this, researchers previously proposed targeting the proximal nerves via quantitative magnetic resonance imaging (qMRI) to directly assess the pathology of interest, while minimizing potential floor effects from the length‐dependent axonal loss 8 . Nerve qMRI is able to evaluate distal‐to‐proximal changes along the nerve in both myelin content and microstructural integrity (e.g., axonal loss) 1,9–11 . Furthermore, nerve qMRI is a non‐invasive technique that enables longitudinal studies and is increasingly available through vendor‐provided sequences, facilitating its widespread adoption.…”

“…While previous studies have investigated various nerve qMRI sequences in isolation, 1,9–11 their performances have not been systematically characterized, which is a critical step in the biomarker development pipeline. Therefore, the goals of this study are to optimize the acquisition and develop the processing pipeline of the multiparametric qMRI method of the lower extremity to systematically assess sciatic and tibial nerve pathologies, to characterize normative distal‐to‐proximal changes of nerve qMRI parameters in healthy volunteers, and to investigate the test–retest repeatability and the inter‐rater reliability of the qMRI method.…”