Nerve Axonal Degeneration Research Articles

NLRX1 limits inflammatory neurodegeneration in the anterior visual pathway

Chronic innate immune activation in the central nervous system (CNS) significantly contributes to neurodegeneration in progressive multiple sclerosis (MS). Using multiple experimental autoimmune encephalomyelitis (EAE) models, we discovered that NLRX1 protects neurons in the anterior visual pathway from inflammatory neurodegeneration. We quantified retinal ganglion cell (RGC) density and optic nerve axonal degeneration, gliosis, and T-cell infiltration in Nlrx1−/− and wild-type (WT) EAE mice and found increased RGC loss and axonal injury in Nlrx1−/− mice compared to WT mice in both active immunization EAE and spontaneous opticospinal encephalomyelitis (OSE) models. To minimize the effects of Nlrx1−/− on peripheral lymphocyte priming during EAE, we performed adoptive transfer experiments, in which activated myelin-specific T cells were transferred into lymphocyte-deficient Rag−/− or Nlrx1−/−Rag−/− mice. In this model, we found more severe microgliosis and astrogliosis in the optic nerve of Nlrx1−/−Rag−/− mice compared to Rag−/− mice, suggesting a regulatory role of NLRX1 in innate immune cells. Transcriptome analysis in primary astrocytes activated with LPS and IFNγ demonstrated that NLRX1 suppresses NF-κB activation and regulates mitochondrial oxidative phosphorylation in inflammatory reactive astrocytes. The novel pharmacologic NLRX1 activators NX-13 and LABP-66 decreased LPS-mediated gene expression of inflammatory cytokines and chemokines in mixed glial cultures. Moreover, treating EAE mice with oral LABP-66, compared to vehicle, after the onset of paralysis resulted in less anterior visual pathway neurodegeneration. These data suggest that pharmacologic NLRX1 activators have the potential to limit inflammatory neurodegeneration. This study highlights that NLRX1 could serve as a promising target for neuroprotection in progressive MS and other neurodegenerative diseases. Further studies are needed to better understand the cell-specific mechanisms underlying the neuroprotective role of NLRX1 in response to inflammation in the CNS.

Suspected fenugreek (Trigonella foenum-graecum L.) toxicosis in a herd of Saskatchewan beef cattle.

An apparent outbreak of fenugreek forage toxicosis occurred in a beef cattle herd near Moose Jaw, Saskatchewan in February-May 2022. The herd had consumed fenugreek hay from late fall to early winter. Clinical signs included various degrees of weakness, ataxia, knuckling, walking on hocks, and recumbency. All adult cattle in the herd eventually died or were euthanized. Feed analysis did not reveal nutritional deficiencies or mycotoxin contamination. Liver mineral and vitamin status of affected animals did not indicate any consistent abnormality. The last live cow in the herd was presented to a veterinary teaching hospital for evaluation and subsequent postmortem examination. Major postmortem findings included emaciation, and sciatic nerve and spinal cord axonal degeneration. Histologic examination of the sciatic nerve showed Wallerian-like axonal degeneration, increased Schwann cell nuclei, and endoneurial fibrosis. Histologic examination of the spinal cord showed infrequent myelin sheath dilation and digestion chambers within white matter. These results are consistent with other reports of natural and experimental outbreaks of fenugreek poisoning in livestock. To our knowledge, fenugreek toxicosis has not been reported previously in Canada. We conclude that caution should be taken when feeding fenugreek hay to cattle.

Hereditary sensory autonomic neuropathy type VI in the age of genetic testing

AbstractBackgroundHereditary sensory and autonomic neuropathy type VI (HSAN VI) is a rare recessive genetic disorder caused by mutations in the human dystonin (DST) gene. We report a novel homozygous alternate transcript mutation in the DST gene causing a severe neonatal form of HSAN VI.Patient DescriptionThis baby boy was born with severe hypotonia, respiratory distress, dysmorphic features, and bilateral club feet. Imaging, karyotyping, Prader–Willi assay, spinal muscular atrophy genetic panel and myotonic dystrophy genetic panel were all negative. A comprehensive neuropathy panel detected a homozygous pathogenic variant in the DST gene—alternate transcript NM_015546.4:c.1357G>A (p.Trp4525*). Nerve conduction studies revealed mixed axonal and demyelinating sensorimotor neuropathy, suggesting the possibility of motor involvement in severe forms of this rare condition. The infant ultimately developed sepsis and died from cardiorespiratory arrest. Neuropathological findings of focal and mild spinal nerve axonal degeneration were nonspecific.ConclusionCollective analysis of these patients would help to further characterize the spectrum of disease pathology and could provide insight into the neurophysiology and neuropathology of this rare condition.

The Injury Progression in Acute Blast-Induced Mild Traumatic Brain Injury in Rats Reflected by Diffusion Tensor Imaging and Immunohistochemical Examination.

Diffusion tensor imaging (DTI) has emerged as a promising neuroimaging tool for detecting blast-induced mild traumatic brain injury (bmTBI). However, lack of refined acute-phase monitoring and reliable imaging biomarkers hindered its clinical application in early diagnosis of bmTBI, leading to potential long-term disability of patients. In this study, we used DTI in a rat model of bmTBI generated by exposing to single lateral blast waves (151.16 and 349.75 kPa, lasting 47.48 ms) released in a confined bioshock tube, to investigate whole-brain DTI changes at 1, 3, and 7 days after injury. Combined assessment of immunohistochemical analysis, transmission electron microscopy, and behavioral readouts allowed for linking DTI changes to synchronous cellular damages and identifying stable imaging biomarkers. The corpus callosum (CC) and brainstem were identified as predominantly affected regions, in which reduced fractional anisotropy (FA) was detected as early as the first day after injury, with a maximum decline occurring at 3 days post-injury before returning to near normal levels by 7 days. Axial diffusivity (AD) values within the CC and brainstem also significantly reduced at 3 days post-injury. In contrast, the radial diffusivity (RD) in the CC showed acute elevation, peaking at 3 days after injury before normalizing by the 7-day time point. Damages to nerve fibers, including demyelination and axonal degeneration, progressed in lines with changes in DTI parameters, supporting a real-time macroscopic reflection of microscopic neuronal fiber injury by DTI. The most sensitive biomarker was identified as a decrease in FA, AD, and an increase in RD within the CC on the third day after injury, supporting the diagnostic utility of DTI in cases of bmTBI in the acute phase.

BDNF and cAMP are neuroprotective in a porcine model of traumatic optic neuropathy.

Traumatic optic neuropathy (TON) is a devastating condition that can occur after blunt or penetrating trauma to the head, leading to visual impairment or blindness. Despite these debilitating effects, no clinically available therapeutic targets neuroprotection or promotes axon regeneration in this or any optic neuropathy. Limited data in large-animal models are a major obstacle to advancing treatments toward clinical therapeutics. To address this issue, we refined a surgical model of TON in Yucatan minipigs. First, we validated the model by demonstrating visual impairment by flash visual-evoked potential and retinal ganglion cell degeneration and death. Next, we developed and optimized a delivery method and nontoxic dosing of intravitreal brain-derived neurotrophic factor (BDNF) and cAMP. Finally, we showed that intravitreal injection of BDNF and cAMP rescued visual function and protected against retinal ganglion cell death and optic nerve axon degeneration. Together these data in a preclinical large-animal model advance our understanding of and ability to model TON and further identify and develop candidate clinical therapeutics.

The Correlation between Trigeminal Neuralgia and Local Anesthetics Neurotoxicity Associated with Acute Inflammation: A Cross-sectional Study

Background: Trigeminal neuralgia (TN) represents a subject of importance in oral medicine due to the large number of patients complaining of TN who are aware that the orofacial pain has a dental origin and therefore seek initial care from the dentist. The reasons for the majority of TN cases remain controversial, but nearly 10% of patients have an obvious pathological condition, such as intracranial pathology. Aim: This study aimed to assess the correlation between idiopathic trigeminal neuralgia and local anesthetic overdose and/or repeated injections caused by dental malpractice. Patients and Methods: An adequate sample of thirty-four patients was selected from the teaching clinic of oral medicine in the College of Dentistry, the University of Karbala, Iraq. All patients were fit for the inclusion criteria and subjected to a thorough oral examination to exclude any organic diseases that cause orofacial pain. Also, they were subjected to a medical examination by multiple neurologists using magnetic resonance imaging and other medical investigations to ensure that all patients did not suffer from intracranial pathology. Results: The patients were statistically distributed by their ages into two sub-groups. The first group (25-48 years old) represented 52.94% of all patients, and the second group (49-72 years old) included 47.06%. The percentage of disease according to sex was 79.4% in males and 20.6% in females. 3-6 dental carpules containing lidocaine (2%) with epinephrine were given to patients. The data of the studied sample were analyzed by using the statistical package of social sciences (SPSS) version 25. The chi-square test was used to test the effect of the type of dental procedure before pain in the two age groups and the two sex groups. For the age group, the difference was significant (p-value < 0.05), which indicated an increased incidence of nerve damage caused by local anesthesia in older patients. For the sex group, the chi-square test exhibited a value of 2.45, with no significant difference (p-value > 0.05). The main theory suggested for the occurrence of local neuropathies and the initiation of TN was the demyelination of nerve, which may be due to the neurotoxic effects of local anesthesia administered at high concentrations and for prolonged exposure times (repeated injections at the site of the dental infection after failure of LA) that may activate the intrinsic pathway of apoptosis through cytochrome C release. The local anesthetic-related neurotoxicity has thus been found to have harmful effects on the nerve tissue, including demyelination and axonal degeneration. Conclusion: The malpractice of local anesthesia in dentistry may lead to dysesthesia, allodynia, and trigeminal neuralgia with different degrees and severity due to the neurotoxicity of the peripheral nerve fiber. The nerve damage may occur in many forms, such as demyelination, apoptosis, axonal degeneration, and hypoxia due to thrombosis. So, dentists should recognize the risk of repeated injections or high dose solution (4%) of LA in the inflamed tissues when inducing analgesia for their dental operations that might initiate the primary trigeminal neuralgia.

Association of chronic periodontitis with multiple sclerosis: A systematic review and meta-analysis.

Chronic periodontitis (CP) is a multifactorial, chronic inflammatory disease of microbial etiology that manifests as a result of the dysfunction of the immune mechanism, culminating in the destruction of the alveolar bone of the jaws. Multiple sclerosis (MS) is an autoimmune disorder that affects the central nervous system (CNS), leads to demyelination and degeneration of nerve axons and often causes severe physical and/or cognitive impairment. As CP and MS involve inflammatory mechanisms and immune dysfunction, researchers have attempted to study the association between them. To systematically review the literature on the epidemiological association between CP and MS in adults. PRISMA 2020 statement was used in the study protocol. The design was done according to the Cochrane methodology. A comprehensive literature search was performed in PubMed, Scopus and Cochrane databases; a manual search and evaluation of the gray literature was also performed. The meta-analysis was performed by Review Manager (RevMan) 5.4. Odds ratio (OR) with 95% confidence interval (CI) was defined as the effect size of the outcome. Heterogeneity was assessed by Chi-square and I2. The articles evaluated were written in English, without a time limit, concern observational studies (patient-controls) and report the diagnostic criteria of the diseases. Duplicate entries were excluded. To evaluate the reliability of the results of each study, Newcastle-Ottawa Scale (NOS) and GRADE tools were used. Two independent reviewers did all evaluations with a resolution of discrepancies by a third. Meta-analysis included three observation studies examined 3376 people. MS patients are significantly more likely to be diagnosed with CP than healthy controls (OR 1.93, 95% CI 1.54-2.42, p<0.0001). A high prevalence of CP was found among MS patients compared with healthy controls. Healthcare professionals should be aware of the association between these pathological entities to provide patients with high-quality care through an effective and holistic diagnostic and therapeutic approach.

Unexpected neurotoxicity in chronic toxicity studies with a HBV viral expression inhibitor

The non-clinical safety profile of the small molecule hepatitis B virus viral expression inhibitor RG7834 was studied in a package consisting of safety pharmacology, genotoxicity, repeat dose toxicity and reproductive toxicity studies. The chronic monkey toxicity study identified dose- and time-dependent symptoms of polyneuropathy, with correlating nerve conduction velocity reductions and axonal degeneration in peripheral nerves and spinal cord, in all compound treatment groups with no evidence of reversibility after approximately 3 months of treatment cessation. Similar histopathological findings were observed in the chronic rat toxicity study. Subsequent in vitro neurotoxicity investigations and ion channel electrophysiology did not elucidate a potential mechanism for the late toxicity. However, based on similar findings observed with a structurally different molecule, an inhibition of their common pharmacological targets, PAPD5 & PAPD 7, was considered as a possible mechanism of toxicity. In conclusion, the marked neuropathies, only observed after chronic dosing, did not support further clinical development of RG7834 because of its foreseen clinical treatment duration of up to 48 weeks in chronic HBV patients.

Synergistic role of resveratrol and exercise training in management of diabetic neuropathy and myopathy via SIRT1/NGF/GAP43 linkage

AimsOxidative stress also plays an important role in the pathogenesis of diabetic neuropathy (DN). Both resveratrol (RES) and exercise (EX) have potent anti-oxidative benefits. Low levels of nerve growth factor (NGF) and SIRT1 (a member of sirtuin family) have been reported in patients with DN. The current study has been designed to investigate the role of serum NGF and SIRT1 on DN-induced hyperalgesia and motor incoordination and to evaluate the possible protective role of RES and/or EX. Main methodsA total of 40 male adult albino rats divided into five groups; control, DN, DN + RES, DN + EX, and DN + RES and EX. DN was confirmed by sensorimotor disturbance and diminished nerve conduction velocity (NCV). NGF and SIRT1 levels were measured by western blot. Calcitonin gene-related peptide (CGRP) was measured by PCR. Myofibrillar degeneration and inflammation scores were revealed via H&E microscopic analysis of the gastrocnemius muscle. Immunohistochemical evaluation of caspase3 and TNF-α was performed in the lumber segment of spinal cord and gastrocnemius muscle sections. Ultrastructural evaluation of sciatic nerve axonal degeneration has also been assessed. Key findingsDN group showed decreased SIRT1 level, decreased NGF level and correlated with CGRP level and Na+/K+ ATPase. Treatment with RES and/or EX resulted in improvement of sensorimotor disturbance. DN characterized by reduced SOD level, whereas RES and/or EX could limit oxidative damage by up-regulation Bcl2, Akt and GAP-43 and down-regulation of caspase3 and TNF-α. In conclusion, increased level of SIRT1and NGF by incorporation of RES (natural supplementation) and EX (life style modification) could improve the neuroinflammatory state in DN.

Inhibitory Effect of α1 Receptor Antagonists on Paclitaxel-Induced Peripheral Neuropathy in a Rodent Model and Clinical Database.

The anticancer drug, paclitaxel, is widely used for ovarian, breast, non-small cell lung, and gastric cancers; however, it induces peripheral neuropathy as a side effect. There is insufficient evidence-based prophylaxis, and new prophylaxis and treatment methods are required. We examined the effect of α1-receptor antagonists on paclitaxel-induced peripheral neuropathy using Sprague-Dawley rats and a large adverse event database. The repeated administration of doxazosin or tamsulosin significantly reduced the response threshold to paclitaxel administration in animal models. In the sciatic nerve tissue, axonal degeneration and myelopathy were significantly suppressed. Furthermore, an analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) database suggested that the group using α1 inhibitors showed a lower reporting rate for paclitaxel-related peripheral neuropathy than the group that did not use these inhibitors (odds ratio (95% confidence interval): tamsulosin 0.21 (0.08-0.56), p &lt; 0.01, doxazosin 0.41 (0.10-1.65), p = 0.195; any α1 receptor antagonist 0.54 (0.38-0.76), p &lt; 0.01). Thus, doxazosin and tamsulosin may inhibit the development of paclitaxel-induced peripheral neuropathy by suppressing neurodegeneration, particularly axonal degeneration and myelopathy.

Omeprazole Suppresses Oxaliplatin-Induced Peripheral Neuropathy in a Rodent Model and Clinical Database.

(1) Background: Oxaliplatin is used as first-line chemotherapy not only for colorectal cancer but also for gastric and pancreatic cancers. However, it induces peripheral neuropathy with high frequency as an adverse event, and there is no effective preventive or therapeutic method. (2) Methods: The effects of omeprazole, a proton pump inhibitor (PPI), on oxaliplatin-induced peripheral neuropathy (OIPN) was investigated using an in vivo model and a real-world database. (3) Results: In a rat model, oxaliplatin (4 mg/kg, i.p., twice a week for 4 weeks) caused mechanical hypersensitivity accompanied by sciatic nerve axonal degeneration and myelin sheath disorder. Repeated injection of omeprazole (5–20 mg/kg, i.p., five times per week for 4 weeks) ameliorated these behavioral and pathological abnormalities. Moreover, omeprazole did not affect the tumor growth inhibition of oxaliplatin in tumor bearing mice. Furthermore, clinical database analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) suggests that the group using omeprazole has a lower reporting rate of peripheral neuropathy of oxaliplatin-treated patients than the group not using (3.06% vs. 6.48%, p < 0.001, reporting odds ratio 0.44, 95% confidence interval 0.32–0.61). (4) Conclusions: These results show the preventing effect of omeprazole on OIPN.

Carpal Tunnel Syndrome in Diabetes Mellitus.

The aim of the present brief review was to discuss carpal tunnel syndrome (CTS) in diabetes mellitus (DM). Generally, CTS is more common in DM, especially in subjects with coexisting diabetic polyneuropathy (DPN) and/or long DM duration. There is no agreement if it is more frequent in type 1 or type 2 DM. The precise underlying mechanisms are not entirely clear but appear to involve hyperglycaemia-induced median nerve oedema, increased sensitivity to exogenous trauma and nerve myelin ischaemia and axonal degeneration. More recently, increased vascular endothelial growth factor (VEGF) and advanced glycation endproducts (AGEs) appear to also play an important role. Median nerve conduction study remains the cornerstone of CTS diagnosis in DM, being more sensitive than clinical examination. CTS can be treated medically or surgically. The latter appears now to be equally effective in subjects with vs. without DM in terms of recurrence rates and quality of life.

Failed remyelination of the nonhuman primate optic nerve leads to axon degeneration, retinal damages, and visual dysfunction

White matter disorders of the central nervous system (CNS), such as multiple sclerosis (MS), lead to failure of nerve conduction and long-lasting neurological disabilities affecting a variety of sensory and motor systems, including vision. While most disease-modifying therapies target the immune and inflammatory response, the promotion of remyelination has become a new therapeutic avenue to prevent neuronal degeneration and promote recovery. Most of these strategies have been developed in short-lived rodent models of demyelination, which spontaneously repair and do not reflect the size, organization, and biology of the human CNS. Thus, well-defined nonhuman primate models are required to efficiently advance therapeutic approaches for patients. Here, we followed the consequence of long-term toxin-induced demyelination of the macaque optic nerve on remyelination and axon preservation, as well as its impact on visual functions. Findings from oculomotor behavior, ophthalmic examination, electrophysiology, and retinal imaging indicate visual impairment involving the optic nerve and retina. These visual dysfunctions fully correlated at the anatomical level, with sustained optic nerve demyelination, axonal degeneration, and alterations of the inner retinal layers. This nonhuman primate model of chronic optic nerve demyelination associated with axonal degeneration and visual dysfunction, recapitulates several key features of MS lesions and should be instrumental in providing the missing link to translate emerging repair promyelinating/neuroprotective therapies to the clinic for myelin disorders, such as MS.

Efficacy and safety of body-insulated acupuncture needle for electrical stimulation at rabbit scia-tic nerve trunk

To evaluate the efficacy and safety of electrical stimulation at the rabbit sciatic nerve trunk with the body-insulated acupuncture needle whose body is painted with insulating material. Eighteen male New Zealand rabbits were randomized into the body-insulated acupuncture needle (BIAN), the general acupuncture needle (GAN), and the blank control groups，with 6 rabbits in each group. The rats'sciatic nerve trunks in BIAN and GAN groups were stimulated by electroacupuncture with the body-insulated acupuncture needle (only allowing the uncoated needle handle and tip to conduct electricity) and the general acupuncture needle, separately. The current intensity was recorded when regular plantarflexion reflexes (sciatic nerve effector reflexes) were observed in the rabbit's foot. The pathological changes of the sciatic nerve at the acupuncture site were observed by H.E. staining, and the ultrastructural changes of the sciatic nerve trunk were observed by transmission electron microscope. The intensity of the current causing the regular plantar flexion reflection in BIAN group (［0.29±0.07］ mA) was significantly lower than that in the GAN group(［0.86±0.08］ mA, P<0.01). H.E. staining revealed nerve axon degeneration, forming eosinophilic bodies, nerve fiber edema, and focal loss of myelin sheath in the GAN group. While the nerve fiber damage was not obvious, and axons were only degenerated in a few areas in the BIAN group. Transmission electron microscopy observations showed that the nerve myelin sheath structure was separated, the layers were arranged disorderly and bubbled in the GAN group. while the nerve myelin sheath structure of the BIAN group was normal, and it presents a concentric circle-like light and dark lamellar structure, with fewer myelin vacuoles and fissures, only a small part of the mitochondria, microfilaments, and microtubules of the nerve axons were abnormal, and the overall vacuole-like degeneration was significantly reduced, with few of the myelinated fibers were slightly degenerated, and axonal disease was not obvious. Insulated acupuncture needle is more accurate and safer than ordinary acupuncture needle for electrical stimulation of rabbit sciatic nerve trunk, and the required electric current intensity is smaller.

Sensorimotor nerve lesion of upper airway in patients with obstructive sleep apnea

The pathogenesis of obstructive sleep apnea (OSA) remains controversial. The role of anatomic stenosis is indisputable, and neural regulation of the upper airway remains to be elucidated. The upper airway maintains patency through the upper airway reflex. Lesions in any link of the reflex can increase the collapsibility of the upper airway. In this study, we investigated sensorimotor nerve lesions and their possible relationship with OSA. Tissue samples were obtained from the pharyngopalatine arch in 47 patients with OSA and 45 control participants to examine changes in the expression levels of myelin basic protein (MBP) and agrin through immunohistochemistry and western blotting. Downregulation of MBP in the mucosa reflects myelinated degeneration of mucosal sensory nerve axons, whereas upregulation of agrin in the neuromuscular junction reflects synaptic regeneration following denervation. The two neural factors correlate significantly with polysomnographic parameters, such as the apnea hypopnea index and lowest oxygen saturation. Our findings suggest that sensorimotor nerve damage in the upper airway of patients with OSA may be associated closely with the mechanism of OSA.

Loss of Rbfox1 Does Not Affect Survival of Retinal Ganglion Cells Injured by Optic Nerve Crush.

Rbfox1 is a multifunctional RNA binding protein that regulates alternative splicing, transcription, mRNA stability and translation. Its roles in neurogenesis and neuronal functions are well established. Recent studies also implicate Rbfox1 in the regulation of gene networks that support cell survival during stress. We have earlier characterized the expression of Rbfox1 in amacrine and retinal ganglion cells (RGCs) and showed that deletion of Rbfox1 in adult animals results in depth perception deficiency. The current study investigates the effect of Rbfox1 downregulation on survival of RGCs injured by optic nerve crush (ONC). Seven days after ONC, animals sustained severe degeneration of RGC axons in the optic nerve and significant loss of RGC somas. Semi-quantitative grading of optic nerve damage in control + ONC, control + tamoxifen + ONC, and Rbfox1–/– + ONC groups ranged from 4.6 to 4.8 on a scale of 1 (normal; no degenerated axons were noted) to 5 (total degeneration; all axons showed degenerated organelles, axonal content, and myelin sheath), indicating a severe degeneration. Among these three ONC groups, no statistical significance was observed when any two groups were compared. The number of RGC somas were quantitatively analyzed in superior, inferior, nasal and temporal retinal quadrants at 0.5, 1, and 1.5 mm from the center of the optic disc. The average RGC densities (cells/mm2) were: control 6,438 ± 1,203; control + ONC 2,779 ± 573; control + tamoxifen 6,163 ± 861; control + tamoxifen + ONC 2,573 ± 555; Rbfox1–/– 6,437 ± 893; and Rbfox1–/– + ONC 2,537 ± 526. The RGC loss in control + ONC, control + tamoxifen + ONC and Rbfox1–/– + ONC was 57% (P = 1.44954E-42), 58% (P = 1.37543E-57) and 61% (P = 5.552E-59) compared to RGC numbers in the relevant uninjured groups, respectively. No statistically significant difference was observed between any two groups of uninjured animals or between any two ONC groups. Our data indicate that Rbfox1-mediated pathways have no effect on survival of RGCs injured by ONC.

Unwanted help from T cells in the aging central nervous system.

Groh and colleagues investigate the age-related degeneration of axons in the optic nerve and other brain regions and show that at least part of this degeneration is due to the presence of T cells.

Electrophysiological investigation of motor axonal excitability in a mouse model of nerve constriction injury.

Peripheral nerve injuries caused by focal constriction are characterised by local nerve ischaemia, axonal degeneration, demyelination, and neuroinflammation. The aim of this study was to understand temporal changes in the excitability properties of injured motor axons in a mouse model of nerve constriction injury (NCI). The excitability of motor axons following unilateral sciatic NCI was studied in male C57BL/6J mice distal to the site of injury at the acute (6 hours-1 week) and chronic (up to 20 weeks) phases of injury, using threshold tracking. Multiple measures of nerve excitability, including strength-duration properties, threshold electrotonus, current-threshold relationship, and recovery cycle were examined using the automated nerve excitability protocol (TRONDNF). Acutely, injured motor axons developed a pattern of excitability characteristic of ischemic depolarisation. In most cases, the sciatic nerve became transiently inexcitable. When a liminal compound muscle action potential could again be recorded, it had an increase in threshold and latency, compared to both pre-injury baseline and sham-injured groups. These axons showed a greater threshold change in response to hyperpolarising threshold electrotonus and a significant upward shift in the recovery cycle. Mathematical modelling suggested that the changes seen in chronically injured axons involve shortened internodes, reduced myelination, and exposed juxtaparanodal fast K+ conductances. The findings of this study demonstrate long-term changes in motor excitability following NCI (involving alterations in axonal properties and ion channel activity) and are important for understanding the mechanisms of neurapraxic injuries and traumatic mononeuropathies.

Estimation of Median Nerve Axonal Degeneration without Needle Electromyography

Background and Aim: The present study aimed to use the median nerve Compound Muscle Action Potential (CMAP) amplitude by stimulation at the palm instead of Abductor Pollicis Brevis (APB) needle Electromyography (EMG) for determining axonal loss in patients with Carpal Tunnel Syndrome (CTS). Methods and Materials/Patients: This study was performed on 180 patients with CTS referred to the Electrodiagnostic (EDX) Center, Poursina Hospital, Guilan Province, Iran, in 2018-19. In this study, the APB needle EMG diagnostic test was used as the gold standard, and median nerve CMAP amplitude with stimulation at the palm and wrist were used to compare the two nerve stimulation tests. Results: All of the cases with abnormal amplitude loss detected by median nerve stimulation at the palm also had an axonal loss in the needle EMG of APB. So this test could be a good indicator of axonal loss if there is an abnormality (sensitivity: 73%, specificity: 100%). The results with wrist stimulation were not as accurate as of the palm stimulation, and some cases with decreased CMAP amplitude of median nerve had normal needle EMG of APB muscle (sensitivity: 86.6%, specificity: 94.9%). Conclusion: In cases with CTS, the abnormally decreased amplitude of the median nerve detected by stimulation at the palm could be a good indicator of axonal loss.

HEREDITARY NEUROPATHIES & ALS: P.107 Review of ophthalmologic findings following intrathecal gene transfer for giant axonal neuropathy

Giant Axonal Neuropathy (GAN) is an ultra-rare childhood onset neurodegenerative disorder of the peripheral and central nervous system. Recessive GAN mutations cause loss of function of gigaxonin, a cytoskeletal regulatory protein, leading to progressive sensorimotor and optic neuropathy, CNS involvement and respiratory failure. We report on the ophthalmologic findings of a single site, phase I, non-randomized, open label dose escalation gene transfer study for GAN (NCT02362438), a first-in-human intrathecal (IT) AAV9 mediated gene transfer. Data from 11 patients with GAN dosed at 3 dose levels; 3.5 × 1013 (1X), 1.2 × 1014 (3.3X), and 1.8 × 1014 (5X) with scAAV9-JeT-GAN with up to 3 years of follow up is analyzed. Ophthalmic evaluations include best-corrected visual acuity, color discrimination thresholds, fundus imaging, and measurement of retinal nerve fiber later (RNFL) thickness through optical coherence tomography. Photopic electroretinography including a photopic negative response and visual evoked potentials (VEP) were also recorded. GAN natural history study data is used for comparison of visual acuity and RNFL thickness as well as correlation of RNFL thickness with validated outcome measures of motor function. Cross sectional natural history analysis shows significant correlation between RNFL thickness and the MFM32 total score. Interim analysis reveals a trend towards stabilization and slowing of the expected decline in RNFL thickness and visual acuity compared to pre-trial lead in data and natural history. VEP results were variable with no consistent trends across natural history and clinical trial cohorts. The interim analysis of ophthalmologic assessments highlights several key aspects: 1) RNFL thickness, a structural assessment of optic nerve atrophy and axonal nerve degeneration at the level of the CNS is a biomarker strongly correlated to overall disease severity. In GAN patients, the decline in RNFL precedes change in visual acuity, and changes can be detected longitudinally. 2) The trend towards stabilization of RNFL thickness post gene transfer suggests that RNFL may be an objective and responsive biomarker of visual system involvement and overall nervous system degeneration in GAN. 3) Assessment of RNFL thickness post gene transfer may be used as an exploratory marker of feasibility of CNS transduction following IT gene transfer.