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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 cross-sectional 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.

SUBMITTER: Pontillo G

PROVIDER: S-EPMC7506188 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Pontillo Giuseppe G Dubbioso Raffaele R Cocozza Sirio S Tozza Stefano S Severi Daniele D Iodice Rosa R Tedeschi Enrico E Elefante Andrea A Brunetti Arturo A Manganelli Fiore F Quarantelli Mario M

Frontiers in neurology 20200908

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 cross-sectional study, from May 2017 to May 2019, we acquired 3T MRI brain scans of genetically confirmed CMT1A patients and age- and sex-comparable healthy contr ...[more]

PMID: 33013613

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Project description:OBJECTIVE:Charcot-Marie-Tooth 1A (CMT1A) disease is the most common inherited neuropathy that lacks of therapy and of molecular markers to assess disease severity. Herein, we have pursued the identification of potential biomarkers in plasma samples and skin biopsies that could define the phenotype of CMT1A patients at mild (Mi), moderate (Mo) and severe (Se) stages of disease as assessed by the CMT neuropathy score to contribute to the understanding of CMT pathophysiology and eventually inform of the severity of the disease. METHODS:We have used: (i) a high-throughput untargeted metabolomic approach of plasma samples in a cohort of 42 CMT1A patients and 15 healthy controls (CRL) using ultrahigh liquid chromatography coupled to mass spectrometry and (ii) reverse phase protein microarrays to quantitate the expression of some proteins of energy metabolism and of the antioxidant response in skin biopsies of a cohort of 70 CMT1A patients and 13 healthy controls. RESULTS:The metabolomic approach identified 194 metabolites with significant differences among the four groups (Mi, Mo, Se, CRL) of samples. A multivariate Linear Discriminant Analysis model using 12 metabolites afforded the correct classification of the samples. These metabolites indicate an increase in protein catabolism and the mobilization of membrane lipids involved in signaling inflammation with severity of CMT1A. A concurrent depletion of leucine, which is required for the biogenesis of the muscle, is also observed in the patients. Protein expression in skin biopsies indicates early loss of mitochondrial and antioxidant proteins in patients' biopsies. CONCLUSION:The findings indicate that CMT1A disease is associated with a metabolic state resembling inflammation and sarcopenia suggesting that it might represent a potential target to prevent the nerve and muscle wasting phenotype in these patients. The observed changes in metabolites could be useful as potential biomarkers of CMT1A disease after appropriate validation in future longitudinal studies.

Project description:Charcot-Marie-Tooth disease type 1A, caused by a duplication of the gene peripheral myelin protein 22 kDa, is the most frequent subtype of hereditary peripheral neuropathy with an estimated prevalence of 1:5000. Patients suffer from sensory deficits, muscle weakness and foot deformities. There is no treatment approved for this disease. Outcome measures in clinical trials were based mainly on clinical features but did not evaluate the actual nerve damage. In our case-control study, we aimed to provide objective and reproducible outcome measures for future clinical trials. We collected skin samples from 48 patients with Charcot-Marie-Tooth type 1A, 7 patients with chronic inflammatory demyelinating polyneuropathy, 16 patients with small fibre neuropathy and 45 healthy controls. To analyse skin innervation, 40-µm cryosections of glabrous skin taken from the lateral index finger were double-labelled by immunofluorescence. The disease severity of patients with Charcot-Marie-Tooth type 1A was assessed by the Charcot-Marie-Tooth neuropathy version 2 score, which ranged from 3 (mild) to 27 (severe) and correlated with age (P < 0.01, R = 0.4). Intraepidermal nerve fibre density was reduced in patients with Charcot-Marie-Tooth type 1A compared with the healthy control group (P < 0.01) and negatively correlated with disease severity (P < 0.05, R = -0.293). Meissner corpuscle (MC) density correlated negatively with age in patients with Charcot-Marie-Tooth type 1A (P < 0.01, R = -0.45) but not in healthy controls (P = 0.07, R = 0.28). The density of Merkel cells was reduced in patients with Charcot-Marie-Tooth type 1A compared with healthy controls (P < 0.05). Furthermore, in patients with Charcot-Marie-Tooth type 1A, the fraction of denervated Merkel cells was highly increased and correlated with age (P < 0.05, R = 0.37). Analysis of nodes of Ranvier revealed shortened paranodes and a reduced fraction of long nodes in patients compared with healthy controls (both P < 0.001). Langerhans cell density was increased in chronic inflammatory demyelinating polyneuropathy, but not different in Charcot-Marie-Tooth type 1A compared with healthy controls. Our data suggest that intraepidermal nerve fibre density might be used as an outcome measure in Charcot-Marie-Tooth type 1A disease, as it correlates with disease severity. The densities of Meissner corpuscles and Merkel cells might be an additional tool for the evaluation of the disease progression. Analysis of follow-up biopsies will clarify the effects of Charcot-Marie-Tooth type 1A disease progression on cutaneous innervation.

Dataset Information

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

Publications

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

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