Central Neuropathy Research Articles

Quantification of white matter hyperintensities in type 1 diabetes and its relation to neuropathy and clinical characteristics

AimsThe aims were to quantify periventricular and deep white matter hyperintensities (WMHs) in adults with type 1 diabetes with different neuropathic phenotypes and to correlate WMH measurements to explanatory factors in diabetes. MethodsWMH measurements were obtained from brain magnetic resonance imaging of 56 adults with type 1 diabetes in subgroups including painful diabetic peripheral neuropathy (DPN), painless DPN, without DPN and 20 healthy controls using Fazekas scale and automatic segmentation analysis. ResultsNo differences in Fazekas assessed WMHs were found (individuals with periventricular lesions: diabetes 66 % vs. controls 40 %,p = 0.063, deep lesions: diabetes 52 % vs. controls 50 %,p = 1.0). Using automatic detection, there were no significant differences in count of periventricular (p = 0.30) or deep (p = 0.31) WMHs. Higher periventricular lesion burden was present in diabetes compared with controls (0.21 % vs. 0.06 %,p = 0.048), which was associated with more severe DPN, increased age, decreased cognitive function, and reduced volumetric and metabolic brain measures (all p < 0.05). ConclusionsOur findings indicate increased burden of periventricular WMHs in diabetes which were associated to DPN severity and measures reflecting neurodegeneration. Deep WMHs, often considered as chronic ischemic, were not significantly different. Mechanisms reflecting neurodegeneration and accelerated brain aging could be an overlooked aspect of peripheral and central neuropathy.

ZiBu PiYin recipe regulates central and peripheral Aβ metabolism and improves diabetes-associated cognitive decline in ZDF rats

Ethnopharmacological relevanceCognitive impairment caused by central neuropathy in type 2 diabetes mellitus (T2DM), namely diabetes-associated cognitive decline (DACD), is one of the common complications in patients with T2DM. Studies have shown that brain β-amyloid (Aβ) deposition is a typical pathological change in patients with DACD, and that there is a close relationship between intestinal microorganisms and cognitive impairment. However, the specific mechanism(s) of alteration in Aβ metabolism in DACD, and of the correlation between Aβ metabolism and intestinal microorganisms remain unknown. Aim of the studyRevealing the mechanism of ZBPYR regulating Aβ metabolism and providing theoretical basis for clinical evaluation and diagnosis of DACD. Materials and methodsWe characterized Aβ metabolism in the central and peripheral tissues of Zucker diabetic fatty (ZDF) rats with DACD, and then explored the preventive and therapeutic effects of ZiBu PiYin Recipe (ZBPYR). Specifically, we assessed these animals for the formation, transport, and clearance of Aβ; the morphological structure of the blood-brain barrier (BBB); and the potential correlation between Aβ metabolism and intestinal microorganisms. ResultsZBPYR provided improvements in the structure of the BBB, attenuation of Aβ deposition in the central and peripheral tissues, and a delay in the development of DACD by improving the expression of Aβ production, transport, and clearance related protein in ZDF rats. In addition, ZBPYR improved the diversity and composition of intestinal microorganisms, decreased the abundance of Coprococcus, a bacterium closely related to Aβ production, and up regulate the abundance of Streptococcus, a bacterium closely related to Aβ clearance. ConclusionThe mechanism of ZBPYR ability to ameliorate DACD may be closely related to changes in the intestinal microbiome.

Peripheral and central pathogenesis of postherpetic neuralgia.

Postherpetic neuralgia (PHN) is a classic chronic condition with multiple signs of peripheral and central neuropathy. Unfortunately, the pathogenesis of PHN is not well defined, limiting clinical treatment and disease management. To describe the peripheral and central pathological axes of PHN, including peripheral nerve injury, inflammation induction, central nervous system sensitization, and brain functional and structural network activity. A bibliographic survey was carried out, selecting relevant articles that evaluated the characterization of the pathogenesis of PHN, including peripheral and central pathological axes. Currently, due to the complexity of the pathophysiological mechanisms of PHN and the incomplete understanding of the exact mechanism of neuralgia. It is essential to conduct in-depth research to clarify the origins of PHN pathogenesis and explore effective and comprehensive therapies for PHN.

Neuropathic phenotypes of type 1 diabetes are related to different signatures of magnetic resonance spectroscopy-assessed brain metabolites

ObjectivesThe study aimed to investigate brain metabolites in type 1 diabetes and the associations with disease characteristics. We explored the metabolic profiles predicting different neuropathic phenotypes using multiple linear regression analyses. MethodsWe compared brain metabolites in 55 adults with type 1 diabetes (including painful diabetic peripheral neuropathy (DPN), painless DPN, without DPN) with 20 healthy controls. Proton magnetic resonance spectroscopy measurements (N-acetylaspartate (NAA), glutamate (glu), myo-inositol (mI), and glycerophosphocholine (GPC) were obtained in ratios to creatine (cre)) from the parietal region, anterior cingulate cortex and thalamus. ResultsThe overall diabetes group revealed decreased parietal NAA/cre compared to healthy controls (1.41 ± 0.12 vs. 1.55 ± 0.13,p < 0.001) and increased mI/cre (parietal: 0.62 ± 0.08 vs. 0.57 ± 0.07,p = 0.025, cingulate: 0.65 ± 0.08 vs. 0.60 ± 0.08,p = 0.033). Reduced NAA/cre was associated with more severe DPN (all p ≤ 0.04) whereas increased mI/cre was associated with higher hemoglobin A1c (HbA1c) (p = 0.02). Diabetes was predicted from decreased parietal NAA/cre, increased parietal ml/cre, and decreased thalamic glu/cre. DPN was predicted from decreased parietal NAA/cre and increased GPC/cre. Painful DPN was predicted from increased parietal GPC/cre and thalamic glu/cre. ConclusionsSpecific metabolic brain profiles were linked to the different phenotypes of diabetes, DPN and painful DPN. SignificanceAssessment of metabolic profiles could be relevant for detailed understanding of central neuropathy in diabetes.

Correlation between cerebral neurotransmitters levels by proton magnetic resonance spectroscopy and HbA1c in patients with type 2 diabetes

BACKGROUND Cognitive dysfunction is the main manifestation of central neuropathy. Although cognitive impairments tend to be overlooked in patients with diabetes mellitus (DM), there is a growing body of evidence linking DM to cognitive dysfunction. Hyperglycemia is closely related to neurological abnormalities, while often disregarded in clinical practice. Changes in cerebral neurotransmitter levels are associated with a variety of neurological abnormalities and may be closely related to blood glucose control in patients with type 2 DM (T2DM). AIM To evaluate the concentrations of cerebral neurotransmitters in T2DM patients exhibiting different hemoglobin A1c (HbA1c) levels. METHODS A total of 130 T2DM patients were enrolled at the Department of Endocrinology of Shanghai East Hospital. The participants were divided into four groups according to their HbA1c levels using the interquartile method, namely Q1 (&lt; 7.875%), Q2 (7.875%-9.050%), Q3 (9.050%-11.200%) and Q4 (≥ 11.200%). Clinical data were collected and measured, including age, height, weight, neck/waist/hip circumferences, blood pressure, comorbidities, duration of DM, and biochemical indicators. Meanwhile, neurotransmitters in the left hippocampus and left brainstem area were detected by proton magnetic resonance spectroscopy. RESULTS The HbA1c level was significantly associated with urinary microalbumin (mALB), triglyceride, low-density lipoprotein cholesterol (LDL-C), homeostasis model assessment of insulin resistance (HOMA-IR), and beta cell function (HOMA-β), N-acetylaspartate/creatine (NAA/Cr), and NAA/choline (NAA/Cho). Spearman correlation analysis showed that mALB, LDL-C, HOMA-IR and NAA/Cr in the left brainstem area were positively correlated with the level of HbA1c (P &lt; 0.05), whereas HOMA-β was negatively correlated with the HbA1c level (P &lt; 0.05). Ordered multiple logistic regression analysis showed that NAA/Cho [Odds ratio (OR): 1.608, 95% confidence interval (95%CI): 1.004-2.578, P &lt; 0.05], LDL-C (OR: 1.627, 95%CI: 1.119-2.370, P &lt; 0.05), and HOMA-IR (OR: 1.107, 95%CI: 1.031-1.188, P &lt; 0.01) were independent predictors of poor glycemic control. CONCLUSION The cerebral neurotransmitter concentrations in the left brainstem area in patients with T2DM are closely related to glycemic control, which may be the basis for the changes in cognitive function in diabetic patients.

Angiotensin II Type 1 receptor blockade attenuates the neuropathological changes in the spinal cords of diabetic rats with modulation of nuclear factor erythroid 2-related factor 2/ heme oxygenase 1 system

Peripheral and central neuropathies frequently complicate worldwide diabetes. Compared to peripheral neuropathy, central neuropathy didn`t gain a major research interest. Angiotensin II is reported to be involved in diabetic neuropathic pain but its role in the central pathological changes in the spinal cord is not clear. Here, we study the role of Losartan; an Angiotensin II receptor 1 (AT1) antagonist in suppression of the diabetes-induced changes in the spinal cord. Three groups of rats were applied; a negative control group, a streptozotocin (STZ) diabetic group, and a group receiving STZ and Losartan. After two months, the pathological alteration in the spinal cord was investigated, and an immunohistochemical study was performed for neuronal, astrocytic, and microglial markers; nuclear protein (NeuN), Glial fibrillary acidic protein (GFAP), and Ionized calcium-binding adaptor molecule 1 (Iba1), respectively, and for an apoptosis marker; caspase-3, and the inflammatory marker; nuclear factor kappa B (NF-kB) signaling, heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2); physiological antioxidant system. The results showed that Losartan caused recovery of spinal cord changes, by inhibiting the microglial and astrocytic activation, suppressing neuronal apoptosis and NF-kB expression with activation of Nrf2/HO-1 (P<0.0005). It is suggested, herein, that Losartan can suppress diabetes-induced glial activation, inflammation, neuronal apoptosis, and oxidative stress in the spinal cord; the mechanisms that may underlie the role of AT1 antagonism in suppressing diabetic neuropathic pain.

The Effects of the S1P Receptor Agonist Fingolimod (FTY720) on Central and Peripheral Myelin in Twitcher Mice.

Krabbe's disease (KD) is caused by mutations in the lysosomal enzyme galactocerebrosidase and is associated with psychosine toxicity. The sphingosine 1-phosphate receptor (S1PR) agonist fingolimod (FTY720) attenuates psychosine-induced cell death of human astrocytes, demyelination in cerebellar slices, as well as demyelination in the central nervous system of twitcher mice. Psychosine also accumulates in the peripheral nervous system in twitcher mice; however, effects of fingolimod on this peripheral myelin have not been examined. The aim of this study was to investigate the effects of fingolimod administration on peripheral and central markers of myelination. Here, we report that fingolimod administration (1 mg/kg/day) from postnatal day 5 (PND) onwards did not alter peripheral demyelination in the sciatic nerve of twitcher mice, despite significantly reducing myelin debris, glial reactivity, and neuronal damage in the cerebellum. We also find fingolimod administration improves twitching and mobility scores in twitcher mice. Importantly, we find that fingolimod significantly increases the lifespan of twitcher mice by approximately 5 days. These findings suggest differential effects of fingolimod on peripheral and central neuropathy in twitcher mice, which may explain its modest efficacy on behavior and lifespan.

Multiomic analysis in fibroblasts of patients with inborn errors of cobalamin metabolism reveals concordance with clinical and metabolic variability

The high variability in clinical and metabolic presentations of inborn errors of cobalamin (cbl) metabolism (IECM), such as the cblC/epicblC types with combined deficits in methylmalonyl-coA mutase (MUT) and methionine synthase (MS), are not well understood. They could be explained by the impaired expression/activity of enzymes from other metabolic pathways. We performed metabolomic, genomic, proteomic, and post-translational modification (PTM) analyses in fibroblasts from three cblC cases and one epi-cblC case compared with three cblG cases with specific MS deficits and control fibroblasts. CblC patients had metabolic profilings consistent with altered urea cycle, glycine, and energy mitochondrial metabolism. Metabolomic analysis showed partial disruption and increased glutamate/ketoglutarate anaplerotic pathway of the tricarboxylic acid cycle (TCA), in patient fibroblasts. RNA-seq analysis showed decreased expression of MT-TT (mitochondrial tRNA threonine), MT-TP (mitochondrial tRNA proline), OXCT1 (succinyl CoA:3-oxoacid CoA transferase deficiency), and MT-CO1 (cytochrome C oxidase subunit 1). Proteomic changes were observed for key mitochondrial enzymes, including NADH:ubiquinone oxidoreductase subunit A8 (NDUFA8), carnitine palmitoyltransferase 2 (CPT2), and ubiquinol-cytochrome C reductase, complex III subunit X (UQCR10). Propionaldehyde addition in ornithine aminotransferase was the predominant PTM in cblC cells and could be related with the dramatic cellular increase in propionate and methylglyoxalate. It is consistent with the decreased concentration of ornithine reported in 3 cblC cases. Whether the changes detected after multi-omic analyses underlies clinical features in cblC and cblG types of IECM, such as peripheral and central neuropathy, cardiomyopathy, pulmonary hypertension, development delay, remains to be investigated. The omics-related effects of IECM on other enzymes and metabolic pathways are consistent with the diversity and variability of their age-related metabolic and clinical manifestations. PTMs are expected to produce cumulative effects, which could explain the influence of age on neurological manifestations. French Agence Nationale de la Recherche (Projects PREDICTS and EpiGONE) and Inserm.

Management of Neuropathic Pain Using Natural Products in Different Animal Models: A Review

The focus of this review is on how natural products and their bioactive ingredients can treat neuropathic pain disorders by acting as neuroprotective agents. which includes information about neuropathic pain and their types, namely central neuropathy and peripheral neuropathy with their mechanistic involvement of various pathways may contribute to the development of neuropathic pain. It also includes information about treatment modalities for peripheral neuropathy i.e., first-line therapy includes, tricyclic antidepressant, antiepileptic, anticonvulsants and serotonin- noradrenaline reuptake inhibitors (SNRIs) and second-line therapy (opioids, topical capsaicin, lidocaine patch). Several alternative remedies exist, includes non-pharmacological treatments that play a key part in the reduction of neuropathic pain. Bioactive ingredients, provide great efficacy with minimal side effects correlated with synthetic compounds. The main focus is on animal models utilised for the evaluation of neuropathic pain, Which include several animal models such as, Streptozotocin Induced diabetic neuropathy in rats and mice is a widely used animal model for assessment of neuropathic pain. Other animal models include, Alloxan-Induced Diabetic Neuropathy, the Spinal Cord Injury (SCI) model, the Chronic Construction Injury model (CCI), the Partial sciatic Nerve Injury model (PNI), Anticancer agents induced neuropathy (vincristine and paclitaxel and Oxaliplatin-induced Neuropathic pain and spinal nerve ligation (SNL) model of neuropathic pain.

Mild cognitive impairment in type 2 diabetes is associated with fibrinogen-to-albumin ratios.

Cognitive impairment is the main manifestation of diabetes central neuropathy. Currently, there is no effective dementia treatment; early diagnosis and treatment are particularly crucial. Inflammation index fibrinogen-to-albumin ratio (FAR) has been shown to predict complications of type 2 diabetes (diabetic kidney disease and diabetes-related arteriosclerosis), but its relationship with mild cognitive impairment (MCI) in type 2 diabetes (T2D) is undetermined. In this study, we examined the association between the FAR and mild cognitive impairment in type 2 diabetes. This is a retrospective and cross-sectional study. From January 2022 to December 2022, we have retrieved 328 inpatient medical records for T2D patients hospitalized at the First Hospital of Harbin Medical University from the hospital's electronic system. Subjects' cognitive function was assessed and grouped by the MoCA scales. Subjects' demographic and various laboratory indicators were collected. Using Spearman's bivariate correlation analysis, the FAR and other clinical variables were analyzed for association strength. A multiple linear regression analysis was conducted to determine the independent relationship between FAR and MoCA scores. Multivariate logistic regression was used to analyze the independent relationship between FAR and MCI. The capacity of the FAR to detect MCI was carried using receiver operating characteristic (ROC) analysis. The included participants' (n = 328; 61.9% male) mean age was 52.62 ± 10.92 years. MoCA scores and MCI prevalence significantly differed (p < 0.05) between the four subgroups of FAR quartiles. The FAR and the MoCA score were significantly negatively correlated in the entire population (p < 0.05). Based on the multiple linear regression analysis, lnFAR and lnMoCA are significantly correlated (β = -0.449, t = -8.21, p < 0.05, R2 = 0.469). In multivariate logistic regression analysis, FAR and MCI were independently correlated after adjusting for covariates (OR 95% CI 34.70 [13.90-86.66]). Finally, the analysis of receptor working characteristics shows that the optimal FAR cut-off value was 0.08 (sensitivity: 95.81%, specificity: 84.47%) for detecting MCI in type 2 diabetes. In type 2 diabetes, the FAR was positive associations with MCI and negative associations with MoCA score. The high FAR was associated with an increased risk of MCI. FAR maybe a appropriate indicator of MCI risk for type 2 diabetes.

Lipin2 ameliorates diabetic encephalopathy via suppressing JNK/ERK-mediated NLRP3 inflammasome overactivation.

Diabetic encephalopathy (DE) is a common complication of diabetes in the central nervous system, which can cause cognitive dysfunction in patients. However, its pathophysiological mechanism has not been elucidated, and thus effective prevention and treatment methods are still lacking.Previous studies reported that neuroinflammation involved in the central neuropathy, while lipin2 plays an important role in inflammatory response.Therefore, we aimed to investigate the effects of lipin2 on regulating inflammatory response in the pathogenesis of DE. BV2 cells were treated with high glucose and infected with lipin2 overexpression or knockdown virus to observe the cell viability. Then, we constructed a mouse model of DE, and constructed a lipin2 knockdown or overexpression model by injecting lentivirus into the brain with stereotaxis. The expression of lipin2 in inflammatory bodies and related inflammatory factor signaling pathway-related proteins were examined by western blot and quantitative real-time PCR. Morris water maze was used to evaluate the spatial learning and memory of mice. High glucose decreased the expression of lipin2 in BV2 cells, while overexpression of lipin2 in BV2 cells significantly suppressed the inflammatory response and apoptosis induced by high glucose. Meanwhile, the expression of lipin2 was down-regulated in the hippocampus in a DE mice model. Up-regulation of lipin2 in the hippocampus of DE mice inhibited JNK/ERK signaling pathway, reduced NLRP3 inflammasome-mediated inflammatory response, down-regulated IL-1/TNF-α expression, and improved synaptic plasticity and cognitive dysfunction in mice. Conversely, knockdown of lipin2 increased NLRP3 inflammasome overactivation, caused neuronal abnormalities and cognitive impairment in mice. Lipin2 may play a neuroprotective role in DE by inhibiting JNK/ERK-mediated NLRP3 inflammasome overactivation and subsequent inflammatory responses. It may be a potential therapeutic target for DE therapy.

Suppression of neuronal apoptosis and glial activation with modulation of Nrf2/HO-1 and NF-kB signaling by curcumin in streptozotocin-induced diabetic spinal cord central neuropathy.

Diabetes is a global disease, commonly complicated by neuropathy. The spinal cord reacts to diabetes by neuronal apoptosis, microglial activation, and astrocytosis, with a disturbance in neuronal and glial Nuclear factor erythroid 2-related factor/Heme oxygenase-1 (Nrf2/HO-1) and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling. Curcumin, a bioactive natural substance, showed neuroprotective role in many diseases. However, its role in the treatment of the diabetic central neuropathy of spinal cord and the underlying mechanisms still need clarification. The present study tried to evaluate the role of curcumin in diabetes-induced central neuropathy of the spinal cord in rats. Twenty rats were divided into three groups; group 1: a negative control group; group 2: received streptozotocin (STZ) to induce type I diabetes, and group 3: received STZ + Curcumin (150 mg/kg/day) for eight weeks. The spinal cords were examined for histopathological changes, and immunohistochemical staining for Glia fibrillary acidic protein (GFAP); an astrocyte marker, Ionized calcium-binding adaptor molecule 1 (Iba1), a microglial marker, neuronal nuclear protein (NeuN); a neuronal marker, caspase-3; an apoptosis marker, Nrf2/HO-1, NF-kB, and oxidative stress markers were assessed. Curcumin could improve spinal cord changes, suppress the expression of Iba1, GFAP, caspase-3, and NF-kB, and could increase the expression of NeuN and restore the Nrf2/HO-1 signaling. Curcumin could suppress diabetic spinal cord central neuropathy, glial activation, and neuronal apoptosis with the regulation of Nrf2/HO-1 and NF-kB signaling.

Brain stem auditory evoked potentials in type 2 diabetes mellitus patients at varying frequencies.

As per the World Health Organization, in 2005, more than 180 million people had diabetes worldwide. This figure will be more than double by 2030. Neuropathy is common and late complication of diabetes mellitus (DM). Sensory neural hearing loss which is severe at higher frequencies has been reported in Type 2 DM patients. Auditory nerve tract damage increases the latency and reduces the amplitude of the response. Evoked potential recordings evaluate the neural pathways in the central nervous system. Brainstem auditory evoked potentials (BAEP) localize anatomic structures using different waves and detect acoustic and central neuropathy (CN). Hence, brainstem evoked response of audiometry (BERA) is used widely in clinical set up. 1. To record BERA waves in normal subjects with normal blood sugar levels (hemoglobin A1C [HbA1C] <5.4. 2. To record BERA waves in Type 2 DM patients. (HbA1C >6.5). To study the BERA parameters with the normal subjects with blood sugar subjects and compare them with Type 2 DM patients. n = 30, Type 2 DM patients between the age of 35-50 years of either sex were chosen from the Diabetic Clinic of GMC, Aurangabad, Maharashtra. HbA1C test for glycemic control and BERA waves to assess CN were recorded. n = 30 normal subjects with normal blood sugar with age and sex-matched above tests were performed. Unpaired Student's t-test. Mean ± Standard deviation of the absolute latency and interpeak latency of BERA waves at 2, 4, and 6 KHz at 80 dB in Type 2 DM patients were delayed and found to be significant as compared to control group. The above study explains that if BAEP is recorded at higher frequencies like 6 KHz and at 80 dB, CN involvement can be detected earlier in diabetic patients. Hence, it is recommended to carry out BERA in diabetic patients at least once in a year.

Study of Auditory Brainstem Evoked Response at Varying Frequencies in Subclinical Hypothyroid Subjects.

Hearing deterioration in hypothyroid subject was documented by Kemp. Cristiane et al. reported delayed waves latency in subclinical hypothyroid subjects. Recording of auditory brain stem evoked response in subclinical hypothyroid subjects at 80 dB and varying frequencies has been done. Case control study. Group 1, N = 30 control subjects, free T3, free T4, thyroid stimulating hormone (TSH) within normal range. Group 2, N = 30 subclinical hypothyroid subjects, TSH was between 4.6-8 microIU/L. Student Unpaired t test was done. Those on epileptic, neuroleptics, depression, psychosis drugs, inflammatory, proliferative, traumatic ear disorder, smokers, on tobacco, COVID-19 positive subjects, altered sensorium, drug abuse, diabetes mellitus, neuropathy, hypertension, cardiac arrhythmia, family history of hearing disorder, and furosemide drug were excluded. Auditory brainstem evoked response (ABER) done. Mean ± SD of Brainstem evoked response auditory (BERA) waves III, V, interpeak latencies at 80 dB, 2, 4,6 KHz reported delay and significant in subclinical hypothyroid group as compared to control. BERA study at 6 KHz and 80 dB detects central neuropathy earlier in subclinical hypothyroid patients.

Association of Serum BDNF with Severity of Cognitive Disorders in Patients with Type 2 Diabetes

Background: Cognitive disorders are common in patients with type 2 diabetes mellitus (DM2) and affect the quality of life, work and social adaptation. Diagnosis of cognitive disorders is carried out using various tests, each of which has its own advantages and disadvantages. Aim: To study of the association between serum level of BDNF and the severity of cognitive disorders in patients with DM2. Materials and methods: Included in the study 61 patients with DM2 complicated by central neuropathy with cognitive disorders and 28 clinically healthy volunteers without DM2. The cognitive and depressive disorders were evaluated using the Montreal Cognitive Assessment (MoCA), Frontal Assessment Batter (FAB), Hospital Anxiety and Depression Scale (HADS). The serum level of BDNF was determined via the method of enzyme-linked immunosorbent assay ac[1]cording. Results: Cognitive disorders in patients with DM2 manifests in the form of disorders of spatial orientation, attention and short-term memory. Frontal dysfunction, mainly in the form of impaired conceptualization and grasping reflexes, was recorded in 30% of patients with DM2. The serum level of BDNF in patients with DM2 is significantly lower than in healthy volunteers and is associated with the duration of DM2, the serum level of HbA1c. Conclusion: Serum level of BDNF may by potential biochemical marker of metabolic cognitive disorders in DM2.

Effect of age on virtual reality-assisted subjective visual vertical and subjective visual horizontal at different head-tilt angles

ObjectiveSubjective Visual Vertical (SVV) and Subjective Visual Horizontal (SVH) values may reflect bilateral utricle asymmetry. Bilateral utricle static tension balance can be used to evaluate bilateral otolith lesions and otolith-related central neuropathy. Few studies have examined Virtual Reality (VR)-assisted SVV and SVH values at various head-tilt angles across age groups. The present study aimed to determine the effects of age on VR-assisted SVV and SVH values at different head-tilt angles. MethodsWe divided 180 healthy subjects into 6 age groups (n = 30 in each group). VR-assisted SVV and SVH measurements were performed at 9 head-tilt angles (head held vertically, 0°; head tilted 30°, 45°, 60°, and 90° to the left/right) in the roll plane. ResultsSVV and SVH values significantly differed with head-tilt angle (p < 0.05). No significant difference was detected in the SVH and SVV values between different age groups (p = 0.632 and p = 0.810, respectively), and no interaction between the age group and the head-tilt angle was found for the SVH and SVV values (p = 0.670 and p = 0.084, respectively). ConclusionThese results suggest that age may have little effect on VR-assisted SVV and SVH at different head-tilt angles. Therefore, VR-assisted SVV and SVH can be evaluated as an effective, fast, and simple way to evaluate utricle function. Level of EvidenceLevel 4.

Botulinum Neurotoxins beyond Neurons: Interplay with Glial Cells.

In recent years, numerous studies have highlighted the significant use of botulinum neurotoxins (BoNTs) in the human therapy of various motor and autonomic disorders. The therapeutic action is exerted with the selective cleavage of specific sites of the SNARE’s protein complex, which plays a key role in the vesicular neuroexocytosis which is responsible for neural transmission. The primary target of the BoNTs’ action is the peripheral neuromuscular junction (NMJ), where, by blocking cholinergic neurons releasing acetylcholine (ACh), they interfere with neural transmission. A great deal of experimental evidence has demonstrated that BoNTs are also effective in blocking the release of other neurotransmitters or neuromodulators, such as glutamate, substance-P, and CGRP, and they can interfere with the function of glial cells, both at the peripheral and central level. The purpose of this review is to provide an update on the available experimental data from animal models that suggest or confirm the direct interactions between BoNTs and glial cells. From the data collected, it appears evident that, through mechanisms that are not yet fully understood, BoNTs can block the activation of spinal glial cells and their subsequent release of pro-inflammatory factors. BoNTs are also able to promote peripheral regeneration processes after nerve injury by stimulating the proliferation of Schwann cells. The data will be discussed in consideration of the possible therapeutic implications of the use of BoNTs on those pathological conditions where the contribution of glial cell activation is fundamental, such as in peripheral and central neuropathies.

Disrupted white matter integrity in the brain of type 1 diabetes is associated with peripheral neuropathy and abnormal brain metabolites

AimsWe aimed to quantify microstructural white matter abnormalities using magnetic resonance imaging and examine their associations with 1) brain metabolite and volumes and 2) clinical diabetes-specific characteristics and complications in adults with type 1 diabetes mellitus (T1DM) and distal symmetric peripheral neuropathy (DSPN). MethodsDiffusion tensor images (DTI) obtained from 46 adults with T1DM and DSPN and 28 healthy controls were analyzed using tract-based spatial statistics and were then associated with 1) brain metabolites and volumes and 2) diabetes-specific clinical characteristics (incl. HbA1c, diabetes duration, level of retinopathy, nerve conduction assessment). ResultsAdults with T1DM and DSPN had reduced whole-brain FA skeleton (P = 0.018), most prominently in the inferior longitudinal fasciculus and retrolenticular internal capsule (P < 0.001). Reduced fractional anisotropy (FA) was associated with lower parietal N-acetylaspartate/creatine metabolite ratio (r = 0.399, P = 0.006), brain volumes (P ≤ 0.002), diabetes duration (r = −0.495, P < 0.001) and sural nerve amplitude (r = 0.296, P = 0.046). Additionally, FA was reduced in the subgroup with concomitant proliferative retinopathy compared to non-proliferative retinopathy (P = 0.03). No association was observed between FA and HbA1c. ConclusionsThis hypothesis-generating study provided that altered white matter microstructural abnormalities in T1DM with DSPN were associated with reduced metabolites central for neuronal communications and diabetes complications, indicating that peripheral neuropathic complications are often accompanied by central neuropathy.

Hippocampal proteins discovery of diabetes-induced central neuropathy based on proteomics.

Growing evidence suggests that diabetes can cause multifactorial damage to the central nervous system (CNS) and may lead to dementia. However, the underlying mechanism of diabetes-induced central neuropathy remains sparse. In recent years, proteomics has provided better methods and means in analyzing the molecular mechanisms of disease. We applied proteomics to investigate the changes of hippocampal proteins in diabetic rats, with a view to discover the biomarkers of diabetes-induced central neuropathy and elucidated the potential biological relationships. Male Wistar rats were randomly divided into the control group and model group. The model group rats were injected intraperitoneally with streptozotocin. Morris water maze test was performed to evaluate the learning and memory of rats, and the hippocampus was taken out. Proteomics were adopted to investigate the changes of differentially expressed proteins. Compared with the control group, the escape latency of the diabetic rats was significantly increased (P < 0.01, P < 0.05). It was presented that four differentially expressed proteins might be the potential biomarkers of diabetes-induced central neuropathy: septin 5, GRB2 related binding protein 2 (GAB2), casein kinase 1ε (CK1ε), aquaporin 4 (AQP4). These differentially expressed proteins were mainly involved in the following signaling pathways: apoptosis, glycine/serine/threonine metabolic and GTPase signaling pathway. These findings provided reference insights into the underlying molecular pathogenesis of diabetes-induced CNS neuropathy.

Colocalization Analysis of Peripheral Myelin Protein-22 and Lamin-B1 in the Schwann Cell Nuclei of Wt and TrJ Mice.

Myelination of the peripheral nervous system requires Schwann cells (SC) differentiation into the myelinating phenotype. The peripheral myelin protein-22 (PMP22) is an integral membrane glycoprotein, expressed in SC. It was initially described as a growth arrest-specific (gas3) gene product, up-regulated by serum starvation. PMP22 mutations were pathognomonic for human hereditary peripheral neuropathies, including the Charcot-Marie-Tooth disease (CMT). Trembler-J (TrJ) is a heterozygous mouse model carrying the same pmp22 point mutation as a CMT1E variant. Mutations in lamina genes have been related to a type of peripheral (CMT2B1) or central (autosomal dominant leukodystrophy) neuropathy. We explore the presence of PMP22 and Lamin B1 in Wt and TrJ SC nuclei of sciatic nerves and the colocalization of PMP22 concerning the silent heterochromatin (HC: DAPI-dark counterstaining), the transcriptionally active euchromatin (EC), and the nuclear lamina (H3K4m3 and Lamin B1 immunostaining, respectively). The results revealed that the number of TrJ SC nuclei in sciatic nerves was greater, and the SC volumes were smaller than those of Wt. The myelin protein PMP22 and Lamin B1 were detected in Wt and TrJ SC nuclei and predominantly in peripheral nuclear regions. The level of PMP22 was higher, and those of Lamin B1 lower in TrJ than in Wt mice. The level of PMP22 was higher, and those of Lamin B1 lower in TrJ than in Wt mice. PMP22 colocalized more with Lamin B1 and with the transcriptionally competent EC, than the silent HC with differences between Wt and TrJ genotypes. The results are discussed regarding the probable nuclear role of PMP22 and the relationship with TrJ neuropathy.