Brain Plasticity in Charcot-Marie-Tooth Type 1A Patients? A Combined Structural and Diffusion MRI Study

Abstract

Central nervous system involvement has been described in peripheral neuropathies, including different forms of Charcot-Marie-Tooth (CMT) disease. The aim of our study was to systematically investigate possible brain structural modifications in CMT1A patients, using volumetric MRI, and diffusion tensor imaging (DTI). In this prospective crosssectional study, from May 2017 to May 2019, we acquired 3T MRI brain scans of genetically confirmed CMT1A patients and age-and sex-comparable healthy controls. Patients also underwent clinical and electrophysiological examinations assessing motor and sensory domains. Voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) analyses were performed using a non-parametric approach based on permutations, including age and sex (and total intracranial volume for VBM) as nuisance covariates. When between-group differences emerged at VBM or TBSS analyses, the first eigenvariate was extracted from the cluster and its age-and sex-adjusted standardized residuals tested for correlation with clinical and electrophysiological variables. Twenty CMT1A patients (34.5 ± 11.1 years; M/F:11/9) were enrolled, along with 20 healthy controls (30.1 ± 10.2 years; M/F:11/9). The VBM analysis revealed clusters of significantly increased GM volume in CMT1A patients compared to healthy controls, encompassing the bilateral cerebellar lobules III-VI and the left hippocampus (all ps = 0.04), with no differences in terms of DTI metrics at the TBSS analysis. A negative correlation (r = −0.502, p = 0.03) emerged between ulnar compound motor action potential and the z-scores corresponding to the right cerebellar cluster of augmented GM volume. Our data show evidence of structural reorganization in the brain of CMT1A patients, possibly reflecting neural plasticity mechanisms in response to peripheral nerve pathology and modulating the effect of axonal degeneration on functional impairment.

Morc2a p.S87L mutant mice develop peripheral and central neuropathies associated with neuronal DNA damage and apoptosis

“…B6 .Morc2a S87L/+ mice showed cerebral cortex damage and cognitive disorder. In addition, cognitive impairment was identified in human CMT patients of various subtypes ( Kasselimis et al, 2020 ; Pontillo et al, 2020 ; Werheid et al, 2016 ). Moreover, CMT2Z patients can develop cognitive impairment ( Ando et al, 2017 ).…”

Diffuse brain connectivity changes in Charcot–Marie–Tooth type 1a patients: a resting‐state functional magnetic resonance imaging study

“…Second‐level RS‐fMRI analysis was performed using the biological parameter mapping toolbox (v3.1, https://www.nitrc.org/projects/rbpm) [19]: first‐level correlation maps of the two groups were statistically analysed to test for possible differences in the FC with the explored seeds, including age, sex and mean motion as confounding covariates. Grey matter (GM) density, provided by each patient's spatially normalized and smoothed GM map, was also included in the analysis as a voxelwise nuisance regressor, in order to correct for possible structural abnormalities [19] which have previously been shown in the brain of CMT1A patients [5,6]; to this end, the effective smoothness of FC maps was computed using AFNI’s 3dFHWMx tool (https://afni.nimh.nih.gov), and the amount of smoothing needed to match FC maps’ spatial resolution was applied to normalized GM maps obtained from T1‐weighted volumes in the fMRI data preprocessing pipeline. Differences were considered significant for P < 0.00125 (0.05 Bonferroni corrected, considering that 32 ROIs were tested separately), corrected for the family wise error rate at cluster level.…”

“…Although CMT1A is primarily a peripheral nervous system disease, central nervous system (CNS) involvement has been anecdotally reported in patients with PMP22 duplication [4], and previous studies demonstrated slight structural modifications in the CMT1A brain [5,6]. Furthermore, evidence of altered brain functional activation in response to different tasks has been reported in other peripheral neuropathies [7,8], along with modifications of resting-state networks, extending beyond the solely sensorimotor network involvement [9,10].…”

Hereditary Neuropathies

“…26 While not a common or prominent manifestation, there are some case reports of patients with CMT1A exhibiting central nervous system involvement, such as demyelinating lesions, decreased white matter volume on imaging, or cognitive disorders. [27][28][29] CMT1B is caused by heterozygous variations in MPZ, which encodes a transmembrane protein involved in the adhesion of myelin layers around nerve axons (FIGURE 10-2). 30 Typically CMT1B is clinically and electrophysiologically similar to CMT1A; however, MPZ variations can also cause an intermediate phenotype or a later-onset axonal CMT (CMT2J).…”