Changes In Peripheral Nerves Research Articles

Single-cell profiling of cellular changes in the somatic peripheral nerves following nerve injury.

Injury to the peripheral nervous system disconnects targets to the central nervous system, disrupts signal transmission, and results in functional disability. Although surgical and therapeutic treatments improve nerve regeneration, it is generally hard to achieve fully functional recovery after severe peripheral nerve injury. A better understanding of pathological changes after peripheral nerve injury helps the development of promising treatments for nerve regeneration. Single-cell analyses of the peripheral nervous system under physiological and injury conditions define the diversity of cells in peripheral nerves and reveal cell-specific injury responses. Herein, we review recent findings on the single-cell transcriptome status in the dorsal root ganglia and peripheral nerves following peripheral nerve injury, identify the cell heterogeneity of peripheral nerves, and delineate changes in injured peripheral nerves, especially molecular changes in neurons, glial cells, and immune cells. Cell-cell interactions in peripheral nerves are also characterized based on ligand-receptor pairs from coordinated gene expressions. The understanding of cellular changes following peripheral nerve injury at a single-cell resolution offers a comprehensive and insightful view for the peripheral nerve repair process, provides an important basis for the exploration of the key regulators of neuronal growth and microenvironment reconstruction, and benefits the development of novel therapeutic drugs for the treatment of peripheral nerve injury.

The Protective Role of Caffeine against Histological and Ultrastructural Changes of Peripheral Nerve in Type 2 Diabetic Rats

The Protective Role of Caffeine against Histological and Ultrastructural Changes of Peripheral Nerve in Type 2 Diabetic Rats

Ultrasonographic Evaluation of Morphological Changes in Peripheral Nerves after Traumatic Injury and Nerve Repair - A Prospective Study.

Purpose Ultrasound (US) has gained in importance for the visualization of morphological changes of injured nerves. After surgical repair, changes in neural structures are seen over time. The correlation of morphologic changes in US with the corresponding nerve function is uncertain. The aim of this study is to determine a correlation of post-traumatic morphological nerve changes with US and with nerve function after surgery. Materials and Methods This dual-center, prospective cohort study was conducted between 2017 and 2022 and included 20 mixed sensory motor nerve lesions. Patients were followed up clinically (sensitivity, pain, and motor function) with US and electroneuromyography. We determined the US changes of the nerves including the interaction of the tissue after nerve repair and any correlation with nerve function. With US nerve cross-sectional area (CSA), the number of traversing fascicles, hypo-echogenicity, and presence of perineural scar were analyzed. Results 20 lesions (12 median and 8 ulnar nerves) of 18 patients with intraoperatively confirmed nerve injury of at least 50% in the forearm were included. The average CSA was over 20 mm 2 throughout the follow-up period, corresponding to a neuroma in continuity compared to the opposite side (10.75 mm 2 ). Sensibility and motor function at 12 months were 6xS3/4 and 10xM3-5. There was a statistically significant correlation between continuous fascicles on US at 6 months and sensitivity at 12 months. Conclusion This study supports the presence of post-traumatic morphological changes in nerve fibers with US after traumatic injury. Morphological changes in nerve structure after trauma can be detected with US indicating a correlation between continuity of nerve fascicles and development of sensitivity and motor function.

Lifelong dietary protein restriction induces denervation and skeletal muscle atrophy in mice

As a widespread global issue, protein deficiency hinders development and optimal growth in offspring. Maternal low-protein diet influences the development of age-related diseases, including sarcopenia, by altering the epigenome and organ structure through potential increase in oxidative stress. However, the long-term effects of lactational protein restriction or postnatal lifelong protein restriction on the neuromuscular system have yet to be elucidated. Our results demonstrated that feeding a normal protein diet after lactational protein restriction did not have significant impacts on the neuromuscular system in later life. In contrast, a lifelong low-protein diet induced a denervation phenotype and led to demyelination in the sciatic nerve, along with an increase in the number of centralised nuclei and in the gene expression of atrogenes at 18 months of age, indicating an induced skeletal muscle atrophy. These changes were accompanied by an increase in proteasome activity in skeletal muscle, with no significant alterations in oxidative stress or mitochondrial dynamics markers in skeletal muscle later in life. Thus, lifelong protein restriction may induce skeletal muscle atrophy through changes in peripheral nerves and neuromuscular junctions, potentially contributing to the early onset or exaggeration of sarcopenia.

Ultrasound assessment of structural changes in peripheral nerves of extremities after amputation in case of gunshot injury

Ultrasound assessment of structural changes in peripheral nerves of extremities after amputation in case of gunshot injury

Diagnosis of diabetic polyneuropathy in type 2 diabetes mellitus: focus on changes in peripheral nerves according to ultrasonic research method

Diagnosis of diabetic polyneuropathy in type 2 diabetes mellitus: focus on changes in peripheral nerves according to ultrasonic research method

Ultrasound Features of the Peroneal Nerve in Type 2 Diabetes Mellitus

The aim of the work is to study the ultrasound features of the peroneal nerves in people with type 2 diabetes mellitus and compare them with the symptoms of diabetic peripheral neuropathy and the characteristics of diabetes. The study included 67 patients (average age 59,4 ± 9.7 years) with type 2 diabetes mellitus duration least 7 years. All patients underwent standard general clinical and biochemical examinations, insulin and proinflammatory biomarkers blood levels were assessed. Diabetic peripheral neuropathy was diagnosed by assessing pain, tactile and vibration sensitivity. The presence and severity of neuropathic pain were determined on the basis of a DN4 questionnaire and a visual analog scale. All patients underwent ultrasound examination of the peroneal nerves: the cross-sectional area of the nerve, its echogenicity and structure were studied. The results of the study allow us to state in the overwhelming majority of people with a long course of type 2 diabetes mellitus and unsatisfactory glycemic control the presence of significant changes in peripheral nerves according to ultrasound examination (92,5 % of cases), including in the absence of clinical manifestations of diabetic peripheral neuropathy. Among patients with clinical manifestations of diabetic peripheral neuropathy (49,3 %), significant ultrasound changes in the peroneal nerves were more common than in those with no symptoms of this complication and correlated with the prescription of diabetes mellitus, glycated hemoglobin levels, age, manifestations of metabolic syndrome and the presence of other micro- and macrovascular complications. The study results suggest the possibility of wider use of peroneal nerves ultrasound examination for early diagnosis of diabetic peripheral neuropathy, its course prediction and, probably, can be used to improve the principles of choosing therapeutic tactics in patients with type 2 diabetes mellitus.

Assessment of Skin Biopsy as a Diagnostic Biomarker in CSF1R-Related Disorder.

To validate a recently published study in which skin biopsy was reported as a valuable alternative to brain biopsy in diagnosing CSF1R-related disorder (CSF1R-RD). Blinded evaluation of skin samples was performed by independent reviewers using light and electron microscopy collected from a group of CSF1R variant carriers (n = 10) with various genotypes (mono and biallelic), different stages of the disease (asymptomatic and symptomatic), and exposed to different therapies (glucocorticoids, hematopoietic stem cell transplantation, and TREM2 agonist), and from a group of healthy controls (n = 5). Biopsies from patients with CSF1R-RD at various disease stages were indistinguishable from controls determined using light microscopy and electron microscopy. We found no distinctive axonal pathology in skin biopsies collected from CSF1R variant carriers at all stages of the disease. Our results are consistent with clinical and neurophysiologic features of the CSF1R-RD, in that peripheral nervous system involvement has not been reported. Studies aiming to discover new biomarkers are important, but the results must be validated with larger numbers of patients and healthy controls. Based on blinded light and electron microscopic studies of skin biopsies, there is no evidence that CSF1R-RD is associated with distinctive changes in cutaneous peripheral nerves. This suggests that skin biopsy is not useful in diagnosis of CSF1R-RD. This study provides Class III evidence that skin biopsy does not distinguish those with CSF1R-RD, or carriers, from normal controls.

Evolution of peripheral nerve changes in early multiple sclerosis-a longitudinal MR neurography study.

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system. Increasing evidence indicates additional peripheral nerve involvement in early and chronic disease stages. To investigate the evolution of peripheral nerve changes in patients first diagnosed with MS using quantitative MR neurography. This prospective study included 19 patients with newly diagnosed MS according to the revised McDonald criteria (16 female, mean 30.2 ± 7.1 years) and 19 age-/sex-matched healthy volunteers. High-resolution 3 T MR neurography of the sciatic nerve using a quantitative T2-relaxometry sequence was performed, which yielded the biomarkers of T2 relaxation time (T2app) and proton spin density (PSD). Follow-up scans of patients were performed after median of 12 months (range 7-16). Correlation analyses considered clinical symptoms, intrathecal immunoglobulin synthesis, nerve conduction study, and lesion load on brain and spine MRI. Patients showed increased T2app and decreased PSD compared to healthy controls at initial diagnosis and follow-up (p < 0.001 each). Compared to the initial scan, T2app further increased in patients at follow-up (p = 0.003). PSD further declined by at least 10% in 9/19 patients and remained stable in another 9/19 patients. Correlation analyses did not yield significant results. Peripheral nerve involvement in MS appears at initial diagnosis and continues to evolve within 1 year follow-up with individual dynamics. Quantitative MRN provides non-invasive biomarkers to detect and monitor peripheral nerve changes in MS.

Experimental research progress in traditional Chinese medicine prevention and treatment of diabetic peripheral neuropathy based on autophagy

Diabetic peripheral neuropathy(DPN) is a chronic complication resulted from peripheral nerve injury in the late stage of diabetes. It involves a variety of pathological changes such as oxidative stress, endoplasmic reticulum stress, neuroinflammation, and apoptosis of Schwann cells(SCs). DPN is the main factor leading to lower limb disability or amputation in diabetic patients, with high incidence, long disease course, and poor prognosis. The modern medicine treatment of DPN mainly focuses on controlling blood glucose and improving microcirculation and nerve nutrition, which can only mitigate the clinical symptoms and not fundamentally reverse the pathological changes of peripheral nerves. Autophagy is a self-clearing mechanism that maintains cellular homeostasis by removing excess metabolites. Traditional Chinese medicine(TCM), featuring the holistic concept and syndrome differentiation, can treat chronic diseases in a multi-target, multi-pathway, and wide-range manner. Modern studies have shown that the occurrence and development of DPN are related to a variety of pathological changes, and autophagy is a key mechanism associated with DPN. The environment with persistent high glucose can lead to the inhibition or over-activation of peripheral nerve cells, which causes irreversible damage of nerve cells and the occurrence and development of DPN. Therefore, restoring autophagy balance and reducing nerve damage is one of the key ways to treat DPN. The recent studies have confirmed that some active ingredients in traditional Chinese medicines and TCM compound prescriptions can inhibit the oxidative stress, endoplasmic reticulum stress, mitochondrial damage, inflammation, and apoptosis of SCs in DPN by regulating the autophagy pathway, thus playing a role in the prevention and treatment of DPN. However, the systematic induction in this field remains to be carried out. This paper reviewed the relevant literature, explained the mechanism of TCM in the prevention and treatment of DPN by regulating autophagy, and summarized the potential targets of TCM in the treatment of DPN, with a view to providing new ideas for clinical research and drug development.

Microstructural changes of peripheral nerves in early multiple sclerosis: A prospective magnetic resonance neurography study.

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system (CNS). However, there is increasing evidence of peripheral nerve involvement. This study aims to characterize the pattern of peripheral nerve changes in patients with newly diagnosed MS using quantitative magnetic resonance (MR) neurography. In this prospective study, 25 patients first diagnosed with MS according to the revised McDonald criteria (16 female, mean age = 32.8 ± 10.6 years) and 14 healthy controls were examined with high-resolution 3-T MR neurography of the sciatic nerve using diffusion kurtosis imaging (DKI; 20 diffusional directions, b = 0, 700, 1200 s/mm2 ) and magnetization transfer imaging (MTI). In total, 15 quantitative MR biomarkers were analyzed and correlated with clinical symptoms, intrathecal immunoglobulin synthesis, electrophysiology, and lesion load on brain and spine MR imaging. Patients showed decreased fractional anisotropy (mean = 0.51 ± 0.04 vs. 0.56 ± 0.03, p < 0.001), extra-axonal tortuosity (mean = 2.32 ± 0.17 vs. 2.49 ± 0.17, p = 0.008), and radial kurtosis (mean = 1.40 ± 0.23 vs. 1.62 ± 0.23, p = 0.014) and higher radial diffusivity (mean = 1.09 ∙ 10-3 mm2 /s ± 0.16 vs. 0.98 ± 0.11 ∙ 10-3 mm2 /s, p = 0.036) than controls. Groups did not differ in MTI. No significant association was found between MR neurography markers and clinical/laboratory parameters or CNS lesion load. This study provides further evidence of peripheral nerve involvement in MS already at initial diagnosis. The characteristic pattern of DKI parameters indicates predominant demyelination and suggests a primary coaffection of the peripheral nervous system in MS. This first human study using DKI for peripheral nerves shows its potential and clinical feasibility in providing novel biomarkers.

Thymoquinone Alleviates Paclitaxel-Induced Peripheral Neuropathy through Regulation of the TLR4-MyD88 Inflammatory Pathway.

Paclitaxel-induced peripheral neuropathy (PIPN) is one of the common adverse effects during the paclitaxel (PTX) treatment of cancer. In this study, we investigated the neuroprotective effects and mechanisms of thymoquinone (TQ) in the PIPN model. Through pain behavioral assays and histological assessment, we demonstrated that TQ significantly alleviated the nociceptive behavior, modulated the pathological changes in peripheral nerves, and decreased the expression of inflammatory factors TNF-α, IL-1β, and IL-6 induced by PIPN in mice. In addition, TQ significantly reversed the reduced viability and inflammatory response of primary DRG neurons caused by PTX. Moreover, the gene expression of related pathways was detected by Western blot, qPCR, and immunofluorescence, and the results showed that TQ exerts neuroprotective effects by regulating TLR4/MyD88 and its downstream NF-κB and MAPKs inflammatory pathways in vivo and in vitro. The treatment with TLR4 antagonist TAK-242 further indicated the important role of the TLR4/MyD88 signaling pathway in PIPN. Furthermore, molecular docking and a cellular thermal shift assay were used to confirm the interaction of TQ with TLR4. In summary, our study shows that TQ can inhibit inflammatory responses against PIPN by regulating TLR4 and MyD88 and its downstream inflammatory pathways.

Difficult patient with polyneuropathy: CIDP associated with type 1 diabetes mellitus

Polyneuropathies are a heterogeneous group of diseases that can be caused both by a primary lesion of peripheral nerves, and secondarily, against the background of various somatic diseases. The most common cause of chronic polyneuropathy is distal symmetrical diabetic polyneuropathy. In clinical practice, it is important to be aware of dysimmune polyneuropathy, such as Guillain Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and paraproteinemic polyneuropathy, which lead to severe motor impairment and disability in patients. Identification of the cause of polyneuropathy requires real art, which includes knowledge of the clinical, electrophysiological picture and variants of the course of the disease, as well as a wide range of conditions leading to their development. Timely diagnosis of polyneuropathies and early assignment of etiological and pathogenetic therapy reduce the risk of developing irreversible changes in peripheral nerves caused by axonal degeneration. In the treatment of polyneuropathy of various origins, a special place is occupied by B vitamins, which have a neurotropic effect. Cyanocobalamin is a pathogenetic therapy in patients with diabetes who take metformin for a long time and who developed polyneuropathy due to vitamin B12 deficiency. In one patient, a combination of several variants of polyneuropathies is possible. The article presents a clinical case of a patient with type 1 diabetes mellitus (DM) who developed dysimmune chronic inflammatory demyelinating polyneuropathy (CIDP) associated with DM on the background of distal symmetrical painless diabetic polyneuropathy after a COVID- 19 infection. A feature of the development of CIDP was the acute onset of the disease. Variants of the clinical picture, ENMG criteria, as well as features of treatment, the effectiveness of therapy and the prognosis of CIDP in patients with DM are discussed.

The Effect of Distraction Osteogenesis on Peripheral Nerve Regeneration in Rats: A Preliminary Study In Vivo

Distraction osteogenesis (DO) is a widely employed method for the treatment of limb discrepancies and deformity correction. This study aimed at observing the histomorphological and ultrastructural changes of peripheral nerves around the distraction area during DO and investigating the self-repair mechanism of peripheral nerves in a rat DO model. Sixty rats underwent right femoral DO surgery and were randomly separated into six groups: Control (latency, no distraction, n = 10), Group 0-week (after distraction, n = 10), Group 2-week (n = 10), Group 4-week (n = 10), Group 6-week (n = 10), and Group 8-week (n = 10) at consolidation phase. The right femur of rats in Group 0-week, Group 2-week, Group 4-week, Group 6-week, and Group 8-week was subjected to continuous osteogenesis distraction at a rate of 0.5 mm/day for 10 days. Motor nerve conduction velocity (MNCV) of the sciatic nerve, sciatic function index (SFI), histological analyses, and transmission electron microscopy were conducted to evaluate nerve function. The MNCV and SFI of Group 0-week, Group 2-week, Group 4-week, and Group 6-week were significantly lower than the Control ( P &lt; 0.05 ). No statistical differences were found between the Control and Group 8-week in terms of MNCV and SFI ( P &gt; 0.05 ). Injuries to nerve fibres and nodes of Ranvier were observed in the Group 0-week, whereas the nerve fibres returned to the normal arrangement in the Group 8-week and oedema of myelin disappeared, with the continuity of axons and lamellar structure of myelin being restored. Femoral DO in rats with a rate of 0.5 mm/day may cause sciatic neurapraxia, which can be self-repaired after 8 weeks of consolidation. The paraneurium around the sciatic nerve enables it to glide during the distraction phase to reduce the occurrence of injurious changes.

Multiparametric Quantitative MRI of Peripheral Nerves to Differentiate Axonal from Demyelinating Neuropathies (P11-8.002)

<h3>Objective:</h3> To develop a multiparametric quantitative MRI (qMRI) method to track pathological changes of peripheral nerves in patients with peripheral neuropathies. <h3>Background:</h3> Irrespective of the causes or types of polyneuropathies, peripheral nerves are mainly afflicted by two kinds of pathologies – axonal loss and demyelination. It is critical to differentiate the two as treatments are different for the two conditions. While nerve conduction studies (NCS) have been used to differentiate the two pathologies in the distal nerves, there are no tools to probe the pathologies in the proximal peripheral nerves. This is particularly needed when distal nerves become non-responsive in NCS. <h3>Design/Methods:</h3> We have developed a multiparametric qMRI method that quantifies the sciatic and tibial nerves with 10 parameters that are sensitive to different aspects of myelin and axonal pathologies: magnetization transfer ratio (MTR), magnetization transfer saturation index (MTsat), longitudinal relaxation time (T1), proton density (PD), effective transverse relaxation time (T2*), fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and nerve fascicular volume (fVol). In this pilot study, we studied 4 patients with Charcot-Marie-Tooth type-1A (CMT1A), 2 patients with CMT type-2S (CMT2S), and 17 healthy controls. <h3>Results:</h3> Compared with healthy controls, patients with CMT2S (reportedly as axonal type) had comparable MTR, MTsat, T1, PD and fVol, but reduced T2*. While patients with CMT1A (dysmyelinating type) had reduced MTR and MTsat, increased fVol, T1 and PD, and comparable T2*. All the 6 patients shared changes of reduced FA which was driven by a reduced AD and an increased RD. <h3>Conclusions:</h3> The data show different qMRI patterns between axonal and demyelinating neuropathies. The differential changes will be further verified in a larger cohort of patients with peripheral neuropathies. <b>Disclosure:</b> Dr. Chen has nothing to disclose. Mr. Baraz has nothing to disclose. Ms. Xuan has nothing to disclose. Sadaf Saba has nothing to disclose. Dr. Yang has nothing to disclose. Dr. Castoro has nothing to disclose. Yang Xuan has nothing to disclose. Dr. Roth has nothing to disclose. The institution of Dr. Dortch has received research support from NIH. The institution of Dr. Dortch has received research support from DOD. Dr. Li has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Guidepoint. The institution of Dr. Li has received research support from NIH. Dr. Li has a non-compensated relationship as a Board of Directors with ANA that is relevant to AAN interests or activities.

Quantitative MR Neurography in Multifocal Motor Neuropathy and Amyotrophic Lateral Sclerosis

The aim of this study was to assess the phenotype of multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis (ALS) in quantitative MR neurography. In this prospective study, 22 patients with ALS, 8 patients with MMN, and 10 healthy volunteers were examined with 3T MR neurography, using a high-resolution fat-saturated T2-weighted sequence, diffusion-tensor imaging (DTI), and a multi-echo T2-relaxometry sequence. The quantitative biomarkers fractional anisotropy (FA), radial and axial diffusivity (RD, AD), mean diffusivity (MD), cross-sectional area (CSA), T2-relaxation time, and proton spin density (PSD) were measured in the tibial nerve at the thigh and calf, and in the median, radial, and ulnar nerves at the mid-upper arm. MMN showed a characteristic imaging pattern of decreased FA (p = 0.018), increased RD (p = 0.014), increased CSA (p < 0.001), increased T2-relaxation time (p < 0.001), and increased PSD (p = 0.025) in the upper arm nerves compared to ALS and controls. ALS patients did not differ from controls in any imaging marker, nor were there any group differences in the tibial nerve (p > 0.05). MMN shows a characteristic pattern of quantitative DTI and T2-relaxometry parameters in the upper-arm nerves, primarily indicating demyelination. Peripheral nerve changes in ALS seem to be below the detection level of current state-of-the-art quantitative MR neurography.

Sciatic nerve fractional anisotropy and neurofilament light chain protein are related to sensorimotor deficit of the upper and lower limbs in patients with type 2 diabetes.

Diabetic sensorimotor polyneuropathy (DSPN) is one of the most prevalent and poorly understood diabetic microvascular complications. Recent studies have found that fractional anisotropy (FA), a marker for microstructural nerve integrity, is a sensitive parameter for the structural and functional nerve damage in DSPN. The aim of this study was to investigate the significance of proximal sciatic nerve's FA on different distal nerve fiber deficits of the upper and lower limbs and its correlation with the neuroaxonal biomarker, neurofilament light chain protein (NfL). Sixty-nine patients with type 2 diabetes (T2DM) and 30 healthy controls underwent detailed clinical and electrophysiological assessments, complete quantitative sensory testing (QST), and diffusion-weighted magnetic resonance neurography of the sciatic nerve. NfL was measured in the serum of healthy controls and patients with T2DM. Multivariate models were used to adjust for confounders of microvascular damage. Patients with DSPN showed a 17% lower sciatic microstructural integrity compared to healthy controls (p<0.001). FA correlated with tibial and peroneal motor nerve conduction velocity (NCV) (r=0.6; p<0.001 and r=0.6; p<0.001) and sural sensory NCV (r=0.50; p<0.001). Participants with reduced sciatic nerve´s FA showed a loss of function of mechanical and thermal sensation of upper (r=0.3; p<0.01 and r=0.3; p<0.01) and lower (r=0.5; p<0.001 and r=0.3; p=<0.01) limbs and reduced functional performance of upper limbs (Purdue Pegboard Test for dominant hand; r=0.4; p<0.001). Increased levels of NfL and urinary albumin-creatinine ratio (ACR) were associated with loss of sciatic nerve´s FA (r=-0.5; p<0.001 and r= -0.3, p= 0.001). Of note, there was no correlation between sciatic FA and neuropathic symptoms or pain. This is the first study showing that microstructural nerve integrity is associated with damage of different nerve fiber types and a neuroaxonal biomarker in DSPN. Furthermore, these findings show that proximal nerve damage is related to distal nerve function even before clinical symptoms occur. The microstructure of the proximal sciatic nerve and is also associated with functional nerve fiber deficits of the upper and lower limbs, suggesting that diabetic neuropathy involves structural changes of peripheral nerves of upper limbs too.

Longitudinal transcriptomic analysis of mouse sciatic nerve reveals pathways associated with age-related muscle pathology.

Sarcopenia, the age-associated decline in skeletal muscle mass and strength, has long been considered a disease of muscle only, but accumulating evidence suggests that sarcopenia could originate from the neural components controlling muscles. To identify early molecular changes in nerves that may drive sarcopenia initiation, we performed a longitudinal transcriptomic analysis of the sciatic nerve, which governs lower limb muscles, in aging mice. Sciatic nerve and gastrocnemius muscle were obtained from female C57BL/6JN mice aged 5, 18, 21 and 24months old (n=6 per age group). Sciatic nerve RNA was extracted and underwent RNA sequencing (RNA-seq). Differentially expressed genes (DEGs) were validated using quantitative reverse transcription PCR (qRT-PCR). Functional enrichment analysis of clusters of genes associated with patterns of gene expression across age groups (adjusted P-value<0.05, likelihood ratio test [LRT]) was performed. Pathological skeletal muscle aging was confirmed between 21 and 24months by a combination of molecular and pathological biomarkers. Myofiber denervation was confirmed with qRT-PCR of Chrnd, Chrng, Myog, Runx1 and Gadd45ɑ in gastrocnemius muscle. Changes in muscle mass, cross-sectional myofiber size and percentage of fibres with centralized nuclei were analysed in a separate cohort of mice from the same colony (n=4-6 per age group). We detected 51 significant DEGs in sciatic nerve of 18-month-old mice compared with 5-month-old mice (absolute value of fold change>2; false discovery rate [FDR]<0.05). Up-regulated DEGs included Dbp (log2 fold change [LFC]=2.63, FDR<0.001) and Lmod2 (LFC=7.52, FDR=0.001). Down-regulated DEGs included Cdh6 (LFC=-21.38, FDR<0.001) and Gbp1 (LFC=-21.78, FDR<0.001). We validated RNA-seq findings with qRT-PCR of various up- and down-regulated genes including Dbp and Cdh6. Up-regulated genes (FDR<0.1) were associated with the AMP-activated protein kinase signalling pathway (FDR=0.02) and circadian rhythm (FDR=0.02), whereas down-regulated DEGs were associated with biosynthesis and metabolic pathways (FDR<0.05). We identified seven significant clusters of genes (FDR<0.05, LRT) with similar expression patterns across groups. Functional enrichment analysis of these clusters revealed biological processes that may be implicated in age-related changes in skeletal muscles and/or sarcopenia initiation including extracellular matrix organization and an immune response (FDR<0.05). Gene expression changes in mouse peripheral nerve were detected prior to disturbances in myofiber innervation and sarcopenia onset. These early molecular changes we report shed a new light on biological processes that may be implicated in sarcopenia initiation and pathogenesis. Future studies are warranted to confirm the disease modifying and/or biomarker potential of the key changes we report here.

Реактивные изменения соединительнотканных структур в периферических нервах овец при патологии печени

Experimental studies were carried out on sheep using a tetramethane model of hepatosis. Ultrastructural data made it possible to characterize morphofunctional changes in peripheral nerves in sheep, in particular, in myelinated and non-myelinated fibers, neurolemmocytes, and connective tissue structures. The pathological process in the peripheral nervous system initiates a combined pathology of the abdominal organs. This is due to the commonality of their innervation with the dorsal and ventral vagus, celiac, phrenic nerves, and branches of the solar plexus. A decrease in the trophic function of the nerves leads to morphological changes in the pancreas, adrenal glands, kidneys, stomach, and small intestine, which were recorded at the ultrastructural level. As a result, hypoxia, energy and plastic insecurity occur, which leads to destructive processes that involve neurolemmocytes, nerve fibers, neurocytes, connective tissue cells and collagen fibers. Structural and functional changes in sheep, with experimental hepatosis, contribute to quantitative and qualitative changes in the nucleoplasm, cytoplasm, swelling and detachment of the karyolemma. Destruction of organelles depends on the intimate processes of cytolysis. At the same time, the connective tissue in the peripheral nerves suffers significantly, and its functional state largely determines the reactivity of the body. It accumulates various substances. An ultrastructural study of clinically healthy animals shows that in the peripheral nerves, in addition to the nerve components, bundles of collagen fibers form a large volume, where they form a dense tie, passing in different directions. Each of them consists of thinner fibrils, which in turn are bundles of subfibrils. Among the fibers are fibroblasts, which have a different degree of differentiation. Thus, mature fibroblasts have a welldeveloped granular endoplasmic reticulum and numerous ribosomes, with an actively functioning Golgi apparatus, mitochondria, and few microfilaments. In pathology, the qualitative composition of fibroblasts changes, lysis of collagen fibers occurs, and communication with neurolemmocytes is lost. At the same time, fibroblasts strengthen contacts with each other. Such contacts between two, three or more fibroblasts are often seen. Others are located next to vascular endothelial cells and pericytes. Apparently, in pathology, fibroblasts require an informative field for the overall coordination of adaptive processes. On the other hand, it is known that fibroblasts begin to produce IL-1, which affects many processes in the body, in particular, it changes the synthetic functions. This is probably why the connective tissue framework in peripheral nerves changes, and their decay, in turn, stimulates the production of IL-1 by fibroblasts. The latter not only destroys connective tissue elements, but also activates the secretion of collagenase, the processes of proliferation and differentiation of fibroblasts. Fibroblasts activated by IL1 produce PGE2.

Electroneurological changes in peripheral nerves in patients post-COVID.

Various neurological manifestations are observed in about 36.4% of patients infected with SARS-CoV-2 and post-COVID neuropathy is one of them. There is lack of studies describing neurophysiological abnormalities in peripheral nerves in case of patients who had SARS-CoV-2 infection. The aim of this study was to analyze the changes in peripheral nervous system in case of COVID-19 survivors. In the presented study, 45 COVID-19 survivors who had nerve conduction study (NCS) were involved. Results were compared with control group consisting of healthy patients who had nerve conduction study before the COVID-19 pandemic. In our study group, neurophysiological abnormalities were present in the case of both sensory and motor nerve fibers. The most significant reduction of NCS parameters was observed in the case of sensory action potential amplitude of sural nerve. Moreover, that correlation was the most significant in the case of amplitude and conduction velocity in sensory and motor neuron fibers both in arms and legs. Those abnormalities were observed even 6 mo after COVID-19. Further investigation needs to be done regarding the polyneuropathies associated with human coronaviruses, and we should answer the question whether the virus directly damages peripheral nerves or factors mediating inflammatory response are responsible for the neural damage.NEW & NOTEWORTHY Various neurological manifestations are observed in about 36.4% of patients infected with SARS-CoV-2 and post-COVID neuropathy is one of them. There is lack of studies describing neurophysiological abnormalities in peripheral nerves in case of patients who had SARS-CoV-2 infection. The aim of this study was to analyze changes in peripheral nervous system in case of COVID-19 survivors.