Metabolic Syndrome and Risk of Amyotrophic Lateral Sclerosis: Insights from a Large-Scale Prospective Study.

OBJECTIVE: Although metabolic abnormalities are implicated in the etiology of neurodegenerative diseases, their role in the development of amyotrophic lateral sclerosis (ALS) remains a subject of controversy. We aimed to identify the association between metabolic syndrome (MetS) and the risk of ALS. METHODS: This study included 395,987 participants from the UK Biobank to investigate the relationship between MetS and ALS. Cox regression model was used to estimate hazard ratios (HR). Stratified analyses were performed based on gender, body mass index (BMI), smoking status, and education level. Mediation analysis was conducted to explore potential mechanisms. RESULTS: In this study, a total of 539 cases of ALS were recorded after a median follow-up of 13.7 years. Patients with MetS (defined harmonized) had a higher risk of developing ALS after adjusting for confounding factors (HR: 1.50, 95% CI: 1.19-1.89). Specifically, hypertension and high triglycerides were linked to a higher risk of ALS (HR: 1.53, 95% CI: 1.19-1.95; HR: 1.31, 95% CI: 1.06-1.61, respectively). Moreover, the quantity of metabolic abnormalities showed significant results. Stratified analysis revealed that these associations are particularly significant in individuals with a BMI <25. These findings remained stable after sensitivity analysis. Notably, mediation analysis identified potential metabolites and metabolomic mediators, including alkaline phosphatase, cystatin C, γ-glutamyl transferase, saturated fatty acids to total fatty acids percentage, and omega-6 fatty acids to omega-3 fatty acids ratio. INTERPRETATION: MetS exhibits a robust association with an increased susceptibility to ALS, particularly in individuals with a lower BMI. Furthermore, metabolites and metabolomics, as potential mediators, provide invaluable insights into the intricate biological mechanisms. ANN NEUROL 2024.

How inflammation dictates diabetic peripheral neuropathy: An enlightening review.

BACKGROUND: Diabetic peripheral neuropathy (DPN) constitutes a debilitating complication associated with diabetes. Although, the past decade has seen rapid developments in understanding the complex etiology of DPN, there are no approved therapies that can halt the development of DPN, or target the damaged nerve. Therefore, clarifying the pathogenesis of DPN and finding effective treatment are the crucial issues for the clinical management of DPN. AIMS: This review is aiming to summary the current knowledge on the pathogenesis of DPN, especially the mechanism and application of inflammatory response. METHODS: We systematically summarized the latest studies on the pathogenesis and therapeutic strategies of diabetic neuropathy in PubMed. RESULTS: In this seminal review, the underappreciated role of immune activation in the progression of DPN is scrutinized. Novel insights into the inflammatory regulatory mechanisms of DPN have been unearthed, illuminating potential therapeutic strategies of notable clinical significance. Additionally, a nuanced examination of DPN's complex etiology, including aberrations in glycemic control and insulin signaling pathways, is presented. Crucially, an emphasis has been placed on translating these novel understandings into tangible clinical interventions to ameliorate patient outcomes. CONCLUSIONS: This review is distinguished by synthesizing cutting-edge mechanisms linking inflammation to DPN and identifying innovative, inflammation-targeted therapeutic approaches.

How vitamins act as novel agents for ameliorating diabetic peripheral neuropathy: A comprehensive overview.

Diabetic peripheral neuropathy (DPN) is a pervasive and incapacitating sequela of diabetes, affecting a significant proportion of those diagnosed with the disease, yet an effective treatment remains elusive. Vitamins have been extensively studied, emerging as a promising target for diagnosing and treating various systemic diseases, but their role in DPN is not known. This review collates and synthesizes knowledge regarding the interplay between vitamins and DPN, drawing on bibliographies from prior studies and relevant articles, and stratifying the therapeutic strategies from prophylactic to interventional. In addition, the clinical evidence supporting the use of vitamins to ameliorate DPN is also evaluated, underscoring the potential of vitamins as putative therapeutic agents. We anticipate that this review will offer novel insights for developing and applying vitamin-based therapies for DPN.

Vitamin D and diabetic peripheral neuropathy: A multi-centre nerve conduction study among Chinese patients with type 2 diabetes.

AIMS: Increasing numbers of reports link vitamin D deficiency to diabetic peripheral neuropathy (DPN), yet evidence regarding neurological deficits and electromyogram is scarce. The present multi-centre study sought to investigate these associations based on objective quantifications. MATERIALS AND METHODS: Information on DPN-related symptoms, signs, all diabetic microvascular complications, and nerve conduction abilities (quantified by nerve conduction amplitude and velocity, F-wave minimum latency (FML) of peripheral nerves) were collected from a derivation cohort of 1192 patients with type 2 diabetes (T2D). Correlation, regression analysis, and restricted cubic splines (RCS) were used to explore linear and non-linear relationships between vitamin D and DPN, which were validated in an external cohort of 223 patients. RESULTS: Patients with DPN showed lower levels of vitamin D than those without DPN; patients with vitamin D deficiency (<30 nmol/L) tended to suffer more DPN-related neurological deficits (paraesthesia, prickling, abnormal temperature, ankle hyporeflexia, and distal pall hypoesthesia correlating with MNSI-exam score (Y = -0.005306X + 2.105, P = 0.048). Worse nerve conduction abilities (decreased motor nerve amplitude, sensory nerve amplitude, motor nerve velocity, and increased FML) were also observed in these patients. Vitamin D had a significant threshold association with DPN (adjusted OR = 4.136, P = 0.003; RCS P for non-linearity = 0.003) and correlates with other microvascular complications (diabetic retinopathy and diabetic nephropathy). CONCLUSIONS: Vitamin D is associated with the conduction ability of peripheral nerves and may have a nerve- and threshold-selective relationship with the prevalence and severity of DPN among patients with T2D.

Neuron-specific enolase in hypertension patients with acute ischemic stroke and its value forecasting long-term functional outcomes.

BACKGROUND: Neuron Specific Enolase (NSE), a neuro-biochemical protein marker, may correlate with the prognosis of stroke patients. Moreover, hypertension is the most common comorbidities in patients with acute ischemic stroke (AIS), and the relationship between NSE levels and long-term functional outcomes in such an increasingly large population is unclear. The aim of the study was to investigate the relationships mentioned above and optimize the prediction models. METHODS: From 2018 to 2020, 1086 admissions for AIS were grouped as hypertension and non-hypertension, while hypertension group was randomly divided into development and validation cohorts for internal validation. The severity of the stroke was staged by National Institutes of Health Stroke Scale (NIHSS) score. Stroke prognosis after 1 year of follow up was documented by modified Rankin Scale (mRS) score. RESULTS: Analysis revealed the following findings:(i) Serum NSE levels increased greatly in hypertension subjects with poor functional outcomes(p = 0.046). However, there was no association in non-hypertension individuals(p = 0.386). (ii) In addition to the conventional factors (age and NIHSS score), NSE (OR:1.241, 95% CI: 1.025-1.502) and prothrombin time were significantly related to the incidence of unfavorable outcomes. (iii)Based on the above four indicators, a novel nomogram was established to predict the prognosis of stoke in hypertension patients with the c-index values of 0.8851. CONCLUSIONS: Overall, high baseline NSE is associated with poor 1-year AIS outcomes in hypertension patients, suggesting NSE may be a potential prognostic and therapeutic target for stroke in hypertension patients.

Leukocyte indicators and variations predict worse outcomes after intravenous thrombolysis in patients with acute ischemic stroke.

Leukocytes are systematic inflammation indicators related to stroke prognosis and can exhibit large dynamic waves before and after recombinant tissue plasminogen activator (r-tPA) therapy. However, additional evidence is needed to determine the prognostic significance of various leukocytes including both static and dynamic data among patients who underwent r-tPA therapy. A total of 251 patients treated with r-tPA were included; their leukocyte data were collected at two time points, and patients were followed up for three months. Analysis revealed the following findings. (i) Patients with hemorrhagic transformation (HT) and unfavorable outcomes had a higher level of leukocytes after r-tPA therapy (leukocyte count (adjusted OR (aOR) 1.191 for HT and 1.184 for unfavorable outcomes), neutrophil count (aOR 1.215 and 1.214), neutrophil-to-lymphocyte ratio (NLR; aOR 1.084 and 1.091)) and larger dynamic leukocyte changes. (ii)Among all leukocytes, the NLR after r-tPA administration demonstrated the strongest correlation with HT and unfavorable outcomes. (iii) Patients with an NLR ≥ 3.322 had a 3.492-fold increased risk for HT, and those with an NLR ≥ 5.511 had a 3.024-fold increased risk for functional outcomes. Overall, this study shows that leukocytes, especially leukocyte count, neutrophil count and the NLR, are independently associated with HT and functional outcomes in stroke patients.

Monocyte-to-lymphocyte ratio affects prognosis in LAA-type stroke patients.

Nowadays, the prognostic prediction of acute ischemic stroke (AIS) patients is still challenging because of the limited predictive properties of existing models. Blood-based biomarkers may provide additional information to the established prognostic factors. Markers of atherosclerosis have been identified as one of the most promising biomarkers for predicting prognosis, and inflammation, in turn, affects atherosclerosis. According to previous studies, the ratio of monocytes to lymphocytes (MLR) has been reported as a novel indicator of inflammation. Thus, our study was the first to conduct more in-depth research on the relationship between MLR and the prognosis of large artery atherosclerosis (LAA)-type AIS patients. A total of 296 patients with LAA-type stroke were recruited. Of these, 202 patients were assigned to the development cohort, and 94 patients were assigned to the validation cohort. In the development cohort, 202 patients were divided into groups A, B, C, and D according to the quartile method of MLR levels. The one-year prognosis of patients was tracked, and the modified Rankin scale (MRS, with a score ranging from 0 to 6) was mainly selected as the measurement result of the function. The relationship between MLR and prognosis was analyzed by building logistics regression models. The models showed that MLR made significant predictions in poor outcomes of LAA-type stroke patients (odds ratio: 4.037; p = 0.048). At the same time, receiver operating characteristics (ROC) curves were used to compare the predictive values between MLR and clinical prediction score (Barthel Index). This study demonstrated that patients with LAA-type stroke and high MLR had a poor prognosis. MLR might be a reliable, inexpensive, and novel predictor of LAA-type stroke prognosis.

Liver function parameters aspartate aminotransferase and total protein predict functional outcome in stroke patients with non-cardioembolism.

Stroke, classified as cardioembolism and non-cardioembolism (non-CE), entails a large socioeconomic burden on the elderly. The morbidity and mortality of non-CE are high, whereas studies concerning prognostic factors impacting function outcome remain underdeveloped and understudied. Liver function parameters are convenient approaches to predicting prognosis in cardiovascular diseases, but their clinical significance has not been well characterized in stroke, especially in non-CE. In our study, a total of 576 patients with non-CE at 1 year of follow-up were enrolled in a cohort from a consecutive hospital-based stroke registry, with randomly 387 patients as the development cohort and 189 patients as the validation cohort. The univariate and multivariate analyses revealed the following novel findings: (i) The incidence of unfavorable functional outcomes after non-CE was significantly greater (p < 0.01) in patients with higher age, aspartate aminotransferase (AST), the National Institutes of Health Stroke Scale (NIHSS) score, and depressed total protein (TP); (ii) We established a novel model and nomogram to predict stroke prognosis, in addition to the known factors (age and the NIHSS score). The levels of AST and TP were independently correlated with the incidence of unfavorable outcomes [AST: odds ratio (OR) = 1.026, 95% CI (1.002-1.050); TP: OR = 0.944, 95% CI (0.899-0.991)]; (iii) The results persisted in further subgroup analysis stratified by age, gender, the NIHSS score, and other prespecified factors, especially in males 60 years or older. Overall, this study demonstrates that hepatic parameters (AST and TP) after non-CE are considered to be associated with functional outcomes at 1-year follow-up, especially in males aged ≥ 60 years.

Low T3 syndrome is associated with peripheral neuropathy in patients with type 2 diabetes mellitus.

INTRODUCTION/AIMS: Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes mellitus. Diabetic patients often have thyroid dysfunction. The aim of this study was to investigate the association between low triiodothyronine (T3) syndrome and DPN in patients with type 2 diabetes mellitus (T2DM). METHODS: A retrospective review was performed of 928 patients with T2DM for whom data was available for clinical manifestations and nerve conduction studies (NCS), and of 134 non-diabetic controls. The composite Z scores of conduction velocity and amplitude were calculated. Low T3 syndrome was defined as T3 levels below the lower limit of the reference interval. RESULTS: Among the patients with T2DM, 632 (68.1%) had DPN, and a larger proportion of these patients presented with low T3 syndrome than patients without DPN. After adjusting for potential confounders, low T3 syndrome was independently associated with the occurrence of DPN (odds ratio [OR] = 2.049, 95% confidence interval [CI] 1.319-3.181, p = .001) and the severity of DPN (OR = 1.597, 95% CI 1.030-2.476, p = .036). Adding the criterion of low T3 syndrome improved the prognostic performance of the traditional model (age + gender + diabetic duration + glycated hemoglobin [HbA1c]) for predicting DPN. DISCUSSION: Low T3 syndrome is associated with a higher risk and increased severity of DPN in patients with T2DM. These findings suggest that low T3 syndrome could be a predictor for risk stratification in patients with T2DM.