QS2: Schwann Cell Characteristics, Myelination Parameters and Histomorphometric Analysis of Nerve Biopsies in Polyneuropathy Patients Compared to Controls

Abstract

Purpose:Polyneuropathy is a debilitating condition characterized by distal sensory and motoric deficits. Common risk factors in Western countries include diabetes, alcohol abuse, cytostatic drugs and cardiovascular disease. Vascular and neurochemical factors affect cells of the peripheral nervous system. Schwann cell dysfunction and impaired nerve regeneration are important pathophysiological mechanisms that are associated with changes in cellular metabolism, signal transduction and neurotrophic signaling. In experimental models of polyneuropathy, Schwann cell dysfunction and altered myelination were described. Clinically, there is very limited knowledge about Schwann cell characteristics and function in polyneuropathy patients. In this study, we investigated Schwann cell characteristics, nerve fibers and myelination parameters in nerve biopsies obtained from polyneuropathy patients compared to controls.Methods:Nerve tissue was obtained from polyneuropathy patients (n = 10) undergoing diagnostic sural nerve biopsies. Biopsies of healthy peripheral nerves (n = 10) were harvested during reconstructive procedures (e.g. sural nerve grafts, denervation of muscle flaps). Exclusion criteria for the healthy control group included recent neurological trauma, diabetes, neurological and cardiovascular disease, as well as treatment with cytotoxic medication in the previous 12 months. The over-all architecture of nerve sections and myelination parameters were histomorphometrically analyzed. Immunofluorescent imaging was used to evaluate Schwann cell phenotypes, senescence markers and myelination parameters. Immunofluorescent signals were quantified using NIS-Elements imaging software (Nikon Instruments Inc.).Results:The mean age of the included polyneuropathy patients (7 male and 3 female) undergoing diagnostic sural nerve biopsy was 57.3 years (SD 13.04; range 29 - 76 years). Control biopsies were obtained from patients undergoing reconstructive procedures. Three sural nerves, 3 obturator nerves, 2 thoracodorsal nerves, 1 superficial peroneal nerve and 1 medial antebrachial cutaneous nerve were analyzed. In the control group which included 2 male and 8 female patients, the mean age was 46 years (SD 13.384; range 28 - 64 years). Histomorphometric analysis of nerve biopsies showed a significant reduction in axon numbers from 3184 in the control group to 1373.3 in the polyneuropathy group (p = 0.035). Axon density and G-ratio were also significantly lower in polyneuropathy patients (p = 0.001 and p = 0.015, respectively). Immunofluorescent staining concurred with histomorphometric findings, as S-100 (p = 0.0017) and Neurofilament-H (p < 0.0001) signals were significantly reduced compared to controls. Immature p75-positive Schwann cells were identified in nerve biopsies of polyneuropathy patients. Myelin-basic protein was significantly reduced in the polyneuropathy group compared to the control (p < 0.0001).Conclusion:Significantly lower axon numbers, reduced myelination and the presence of immature Schwann cell phenotypes were identified in nerve biopsies of polyneuropathy patients compared to control patients. This underlines the clinical importance of Schwann cell dysfunction in polyneuropathy.