Multiparametric Quantitative MRI of Peripheral Nerves to Differentiate Demyelinating from Axonal Polyneuropathies

Background Differentiating demyelinating from axonal polyneuropathies is essential for accurate diagnosis and treatment. We hypothesized that multiparametric quantitative MRI (qMRI) of peripheral nerves can differentiate demyelination from axonal loss. This retrospective study leveraged genetically defined demyelinating and axonal polyneuropathies to test this concept.

Multiparametric qMRI data of proximal (sciatic) and distal (tibial) nerves were acquired on 3T MRI, including magnetization transfer ratio (MTR), MT saturation index (MTsat), T *, T, proton density (PD), fractional anisotropy (FA), mean/axial/radial diffusivities (MD, AD, RD), and fascicular volume (fVol). Data were analyzed from patients with Charcot-Marie-Tooth type 1 (CMT1, de-/dys-myelinating, n=19), CMT2 (axonal, n=12), hereditary neuropathy with liability to pressure palsies (HNPP, a cohort who often has intermediate changes between the two classifications, n=25), and health controls (HC, n=25). A composite qMRI score, as CMT Imaging Score (CMTIS), was developed to predict disease severity using the CMT Neuropathy Score version-2 (CMTNSv2) as a clinical reference. Receiver operating characteristic (ROC) analyses assessed diagnostic performance.

CMT1 showed significantly increased fVol versus HCs, while CMT2 demonstrated reduced T2*. Both CMT1 and CMT2 exhibited reduced FA, MTsat, and AD, along with elevated T1 and RD, with larger abnormalities in CMT1. ROC analyses demonstrated strong discrimination of CMT1 and CMT2 (AUCs: 0.95 and 0.85 for sciatic; 0.89 and 0.73 for tibial nerves). CMTIS correlated strongly with CMTNSv2 (r=0.67 sciatic; r=0.72 tibial; r=0.79 combined).

Multiparametric qMRI identifies distinct imaging signatures of demyelinating versus axonal hereditary polyneuropathies. The CMTIS shows strong potential as a biomarker for disease monitoring. DATA AVAILABILITY Anonymized data used in this study is available from the corresponding author upon request and subject to institutional approvals. What is already known on this topic Current electrophysiological tools are limited in their ability to differentiate demyelinating from axonal polyneuropathies when pathology occurs in proximal nerves. Quantitative MRI (qMRI) can assess proximal demyelination and axonal loss; however, individual qMRI metrics lack sufficient sensitivity for reliable differentiation. What this study adds This proof-of-concept study demonstrates the feasibility of using multiparametric qMRI for patient stratification and for distinguishing demyelinating from axonal inherited polyneuropathies. The proposed composite qMRI score shows a strong correlation with clinical disease severity. How this study might affect research, practice, or policy This study suggests that multiparametric qMRI of peripheral nerves can serve as a non-invasive adjunct to distal nerve conduction studies for improving diagnosis and treatment management of polyneuropathies. The composite qMRI score also shows potential as a monitoring biomarker for tracking disease progression. Competing Interest Statement The authors have declared no competing interest. Funding Statement Research reported in this publication was supported in part by the National Institutes of Health (NIH) under award numbers R61NS119434 (Y.C. and J.L.) and R21TR003312 (J.L. and R.D.D.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Part of the MRI data was acquired using the Cima.X 3T MRI scanner at the MR Core Research Facility of Wayne State University, supported by NIH under award number S10OD028724. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the local institutional review board (IRB) at Wayne State University (WSU, Detroit, MI, USA) and Houston Methodist Hospital (HMH, Houston, TX, USA) following NIH single IRB requirement (protocol #020519MP2F). Written consent was acquired for each participant at enrollment. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes ↵# J. Li and Y. Chen are joint senior authors.

We gratefully acknowledge the participants and the MR technologists at Wayne State University and Houston Methodist Research Institute. The authors thank Stephanie Yan Xuan for her assistance in study coordination. Funding Research reported in this publication was supported in part by the National Institutes of Health (NIH) under award numbers R61NS119434 (Y.C. and J.L.) and R21TR003312 (J.L. and R.D.D.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Part of the MRI data was acquired using the Cima.X 3T MRI scanner at the MR Core Research Facility of Wayne State University, supported by NIH under award number S10OD028724. Competing Interests None declared. Data Availability Anonymized data used in this study is available from the corresponding author upon request and subject to institutional approvals.