Validation of the Center for Neurologic Study Bulbar Function Scale-Chinese version in a population with amyotrophic lateral sclerosis.

OBJECTIVE: The Center for Neurologic Study Bulbar Function Scale (CNS-BFS) was specifically designed as a self-reported measure of bulbar function. The purpose of this research was to validate the Chinese translation of the CNS-BFSC as an effective measurement for the Chinese population with ALS. METHODS: A total of 111 ALS patients were included in this study. The CNS-BFSC score, three bulbar function items from the ALSFRS-R, and visual analog scale (VAS) score for speech, swallowing and salivation were assessed in the present study. Forty-six ALS patients were retested on the same scale 5-10 days after the first evaluation. RESULTS: The CNS-BFSC sialorrhea, speech and swallowing subscores were separately correlated with the VAS subscores (p < 0.001). The CNS-BFSC total score and sialorrhea and speech scores were significantly correlated with the ALSFRS-R bulbar subscore (p < 0.001). The CNS-BFSC total score and ALSFRS-R bulbar subscale score were highly predictive of a clinician diagnosis of impaired bulbar function (area under the receiver operating characteristic curve, 0.947 and 0.911, respectively; p < 0.001). A cutoff value for the CNS-BFSC total score was selected by maximizing Youden's index; this cutoff score was 33, with 86.4% sensitivity and 93.3% specificity. The CNS-BFSC total score and the sialorrhea, speech and swallowing subscores had good-retest reliability (p > 0.05). The Cronbach's α of the CNS-BFSC was 0.972. CONCLUSION: The Chinese version of the CNS-BFSC has acceptable efficacy and reliability for the assessment of bulbar dysfunction in ALS patients.

RhPro-UK in acute ischemic stroke within 4.5 hours of stroke onset trial-2(The PROST-2 study): Rationale and design of a multicenter, prospective, randomized, open-label, blinded-endpoint, controlled phase 3 non-inferiority trial.

BACKGROUND: Recombinant human prourokinase (rhPro-UK) is a specific plasminogen activator, which has been approved to treat acute myocardial infarction in China. AIM: This phase III trial aimed to further demonstrate the efficacy and safety of rhPro-UK in patients with acute ischemic stroke (AIS) within 4.5 hours of symptom onset. METHODS AND DESIGN: RhPro-UK in AIS within 4.5 hours of stroke onset trial-2 (PROST-2) is a multicenter, prospective randomized, open-label, blinded end-point, non-inferiority, recombinant tissue plasminogen activator (rt-PA)-controlled, phase 3 trial. A total of 1,552 patients who are eligible for intravenous thrombolytic therapy from 72 clinical sites will be randomly assigned to receive either rhPro-UK 35 mg (15 mg bolus+ 20 mg infusion/30 minutes) or rt-PA 0.9 mg/kg (10% bolus +90% infusion/1 hour). STUDY OUTCOMES: The primary outcome is the proportion of patients with a modified Rankin Scale (mRS) score of 0-1 at 90 days. Secondary efficacy outcomes include the proportion of patients with mRS score of 0-2, the distribution of mRS, self-care ability in daily life on the Barthel Index at 90 days, the proportion of subjects with ≥ 4 points decrease in National Institutes of Health Stroke Scale (NIHSS) score or NIHSS score ≤ 1 from baseline at 24 hours and 7 days after treatment. Safety outcomes are symptomatic intracranial hemorrhage (sICH) and major systematic bleeding within 7 days as well as death from all causes within 90 days. DISCUSSION: The results from the PROST-2 trial will comprehensively elucidate the efficacy and safety profile of rhPro-UK as a potential alternative agent for stroke thrombolysis. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT05700591.

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.

Multicenter and multimodal imaging study reveals rare fundus lesions in patients after SARS-CoV-2 infection.

To define the characteristics of fundus manifestations in patients after SARS-CoV-2 infection with multimodal imaging techniques. This is a retrospective multicenter and multimodal imaging study including 90 patients. All patients with a visual complaint occurring immediately after SARS-CoV-2 infection were referred to six clinics between December 2022 and February 2023. Demographic information and the temporal relationship between SARS-CoV-2 infection and visual symptoms were documented. The characteristics of the fundus lesions were evaluated using multimodal imaging. Ninety patients from six hospitals were included in this study, including 24 males (26.67%) and 66 (73.33%) females. Seventy-eight patients (86.66%) (146 eyes) were diagnosed with Acute Macular Neuroretinopathy (AMN). The AMN patients were primarily young women (67.95%). Sixty-eight patients (87.18%) had AMN in both eyes. Thirty-eight eyes (24.36%) included Purtscher or Purtscher-like lesions. optical coherence tomography and infrared retinal photographs can show AMN lesions well. Eleven cases were diagnosed with simple Purtscher or Purtscher-like retinopathy (2 cases, 2.22%), Vogt‒Koyanagi‒Harada (VKH) syndrome or VKH-like uveitis (3 cases, 3.33%), multiple evanescent white-dot syndrome (MEWDS) (2 cases, 2.22%), and rhino-orbital-cerebral mucormycosis (ROCM) (5 cases, 5.56%). After SARS-CoV-2 infection, diversified fundus lesions were evident in patients with visual complaints. In this report, AMN was the dominant manifestation, followed by Purtscher or Purtscher-like retinopathy, MEWDS, VKH-like uveitis, and ROCM.

Chinese Translation and Validation of the Center for Neurologic Study Lability Scale.

INTRODUCTION: Pseudobulbar palsy is a common symptom in patients with amyotrophic lateral sclerosis (ALS), but it is often underdiagnosed or misdiagnosed as other diseases. The Center for Neurologic Study Lability Scale (CNS-LS) is a self-report scale consisting of seven questions designed for evaluating pseudobulbar affect (PBA). The current study aimed to validate a Chinese version of the CNS-LS. METHODS: The Chinese version of the CNS-LS was obtained through a standardized forward-backward translation and cultural adaptation. A total of 105 patients with ALS were recruited from the ALS database of Peking University Third Hospital in Beijing, China, to complete the CNS-LS. The reliability of the Chinese version was determined by the test-retest method, and receiver operating characteristic (ROC) analysis was performed for criterion validity. RESULTS: Of 105 patients with ALS, 37 had symptoms of PBA and were diagnosed with that condition by neurologists. Forty-two patients completed the CNS-LS twice, and there was no statistically significant difference between the scores (Z = -0.896, p = 0.37). The Spearman correlation coefficient between the test and retest scores was 0.940 (p < 0.0005), and the Cronbach alpha coefficient was high (α = 0.905, n = 105). Scores of 12 or higher on the CNS-LS identified PBA with sensitivity of 0.919 and specificity of 0.882. The area under the ROC curve was 0.924. CONCLUSION: The Chinese version of the CNS-LS demonstrated good sensitivity and specificity in the group of patients with ALS enrolled in this study. The CNS-LS should be a useful instrument for clinical and research purposes for patients in this language group.

Essential Nutrients and White Matter Hyperintensities: A Two-Sample Mendelian Randomization Study.

Stroke and dementia have been linked to the appearance of white matter hyperintensities (WMHs). Meanwhile, diffusion tensor imaging (DTI) might capture the microstructural change in white matter early. Specific dietary interventions may help to reduce the risk of WMHs. However, research on the relationship between specific nutrients and white matter changes is still lacking. We aimed to investigate the causal effects of essential nutrients (amino acids, fatty acids, mineral elements, and vitamins) on WMHs and DTI measures, including fraction anisotropy (FA) and mean diffusivity (MD), by a Mendelian randomization analysis. We selected single nucleotide polymorphisms (SNPs) associated with each nutrient as instrumental variables to assess the causal effects of nutrient-related exposures on WMHs, FA, and MD. The outcome was from a recently published large-scale European Genome Wide Association Studies pooled dataset, including WMHs (N = 18,381), FA (N = 17,663), and MD (N = 17,467) data. We used the inverse variance weighting (IVW) method as the primary method, and sensitivity analyses were conducted using the simple median, weighted median, and MR-Egger methods. Genetically predicted serum calcium level was positively associated with WMHs risk, with an 8.1% increase in WMHs risk per standard deviation unit increase in calcium concentration (OR = 1.081, 95% CI = 1.006-1.161, p = 0.035). The plasma linoleic acid level was negatively associated with FA (OR = 0.776, 95% CI = 0.616-0.978, p = 0.032). Our study demonstrated that genetically predicted calcium was a potential risk factor for WMHs, and linoleic acid may be negatively associated with FA, providing evidence for interventions from the perspective of gene-environment interactions.

PEG-PVP-Assisted Hydrothermal Synthesis and Electrochemical Performance of N-Doped MoS2/C Composites as Anode Material for Lithium-Ion Batteries.

Molybdenum disulfide shows promise as an anode material for lithium-ion batteries. However, its commercial potential has been constrained due to the poor conductivity and significant volume expansion during the charge/discharge cycles. To address these issues, in this study, N-doped MoS2/C composites (NMC) were prepared via an enhanced hydrothermal method, using ammonium molybdate and thiourea as molybdenum and sulfur sources, respectively. Polyethylene glycol 400 (PEG400) and polyvinylpyrrolidone (PVP) were added in the hydrothermal procedure as soft template surfactants and nitrogen/carbon sources. The crystal structure, morphology, elemental composition, and surface valence state of the N-doped MoS2/C composites were characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), high-resolution transmission electron microscopy (HRTEM), and X-ray photoelectron spectroscopy (XPS), respectively. The results indicate that the NMC prepared by this method are spherical particles with a nanoflower-like structure composed of MoS2 flakes, having an average particle size of about 500 nm. XPS analysis shows the existence of C and N elements in the samples as C-N, C-C, and pyrrolic N. As anodes for LIBs, the NMC without annealing deliver an initial discharge capacity of 548.2 mAh·g-1 at a current density of 500 mA·g-1. However, this capacity decays in the following cycles with a discharge capacity of 66.4 mAh·g-1 and a capacity retention rate of only 12% after 50 cycles. In contrast, the electrochemical properties of the counterparts are enhanced after annealing, which exhibits an initial discharge capacity of 575.9 mAh·g-1 and an ultimate discharge capacity of 669.2 mAh·g-1 after 70 cycles. The capacity retention rate decreases initially but later increases and elevated afterward to reach 116% at the 70th cycle, indicating an improvement in charge-discharge performance. The specimens after annealing have a smaller impedance, which indicates better charge transport and lithium-ion diffusion performance.

Immune-mediated diseases are associated with a higher risk of ALS incidence: a prospective cohort study from the UK Biobank.

Objective: The occurrence of immune-mediated diseases (IMDs) in amyotrophic lateral sclerosis (ALS) patients is widely reported. However, whether IMDs and ALS is a simple coexistence or if there exists causal relationships between the two has been a subject of great interest to researchers. Methods: A total of 454,444 participants from the prospective cohort of UK Biobank were recruited to investigate the longitudinal association between IMDs and ALS. Previously any IMDs and organ specific IMDs were analyzed in relation to the following incident ALS by Cox-proportional hazard models. Subgroup analyses were performed to explore the covariates of these relationships. Results: After adjusting for potential covariates, the multivariate analysis showed that any IMDs were associated with an increased risk of ALS incidence (HR:1.42, 95%CI:1.03-1.94). IMDs of the endocrine-system and the intestinal-system were associated with increased risk of ALS incidence (endocrine-system IMDs: HR:3.01, 95%CI:1.49-6.06; intestinal system IMDs: HR:2.07, 95%CI: 1.14-3.77). Subgroup analyses revealed that immune burden, including IMD duration and the severity of inflammation had specific effects on the IMD-ALS association. In participants with IMD duration≥10 years or CRP≥1.3mg/L or females, previous IMDs increased the risk of incident ALS; however, in participants with IMD duration <10 years or CRP<1.3mg/L or males, IMDs had no effect on incident ALS. Interpretation: Our study provides evidence that previous any IMDs and endocrine-system and the intestinal-system specific IMDs are associated with an increased risk of developing ALS in females, but not in males.

Penthorum chinense Pursh inhibits ferroptosis in cellular and Caenorhabditis elegans models of Alzheimer's disease.

BACKGROUND: Ferroptosis, a unique type of cell death triggered by iron-dependent lipid peroxidation, plays a critical role in the pathogenesis of Alzheimer's disease (AD), a debilitating condition marked by memory loss and cognitive impairment due to the accumulation of beta-amyloid (Aß) and hyperphosphorylated Tau protein. Increasing evidence suggests that inhibitors of ferroptosis could be groundbreaking in the treatment of AD. METHOD: In this study, we established in vitro ferroptosis using erastin-, RSL-3-, hemin-, and iFSP1-induced PC-12 cells. Using MTT along with Hoechst/PI staining, we assessed cell viability and death. To determine various aspects of ferroptosis, we employed fluorescence probes, including DCFDA, JC-1, C11 BODIPY, Mito-Tracker, and PGSK, to measure ROS production, mitochondrial membrane potential, lipid peroxidation, mitochondrial morphology, and intracellular iron levels. Additionally, Western blotting, biolayer interferometry technology, and shRNA were utilized to investigate the underlying molecular mechanisms. Furthermore, p-CAX APP Swe/Ind- and pRK5-EGFP-Tau P301L overexpressing PC-12 cells, along with Caenorhabditis elegans (C. elegans) strains CL4176, CL2331, and BR5270, were employed to examine ferroptosis in AD models. RESULTS: Here, we conducted a screening of our natural medicine libraries and identified the ethanol extract of Penthorum chinense Pursh (PEE), particularly its ethyl acetate fraction (PEF), displayed inhibitory effects on ferroptosis in cells. Specifically, PEF inhibited the generation of ROS, lipid peroxidation, and intracellular iron levels. Furthermore, PEF demonstrated protective effects against H2O2-induced cell death, ROS production, and mitochondrial damage. Mechanistic investigations unveiled PEF's modulation of intracellular iron accumulation, GPX4 expression and activity, and FSP1 expression. In p-CAX APP Swe/Ind and pRK5-EGFP-Tau P301L overexpressing PC-12 cells, PEF significantly reduced cell death, as well as ROS and lipid peroxidase production. Moreover, PEF ameliorated paralysis and slowing rate in Aß and Tau transgenic C. elegans models, while inhibiting ferroptosis, as evidenced by decreased DHE intensity, lipid peroxidation levels, iron accumulation, and expression of SOD-3 and gst-4. CONCLUSION: Our findings highlight the suppressive effects of PEF on ferroptosis in AD cellular and C. elegans models. This study helps us better understand how ferroptosis affects AD and emphasizes the potential of PCP as a candidate for AD intervention.

Quasi-targeted metabolomics revealed isoliquiritigenin and lauric acid associated with resistance to tobacco black shank.

Tobacco black shank (TBS), caused by Phytophthora nicotianae, is a severe disease. Plant root exudates play a crucial role in mediating plant-pathogen interactions in the rhizosphere. However, the specific interaction between key secondary metabolites present in root exudates and the mechanisms of disease resistance remains poorly understood. This study conducted a comprehensive comparison via quasi-targeted metabolomic analysis on the root exudate metabolites from the tobacco cultivar Yunyan87 and K326, both before and after inoculation with P. nicotianae. The results showed that the root exudate metabolites changed after P. nicotianae inoculation, and the root exudate metabolites of different tobacco cultivar was significantly different. Furthermore, homovanillic acid, lauric acid, and isoliquiritigenin were identified as potential key compounds for TBS resistance based on their impact on the mycelium growth of the pathogens. The pot experiment showed that isoliquiritigenin reduced the incidence by 55.2%, while lauric acid reduced it by 45.8%. This suggests that isoliquiritigenin and lauric acid have potential applications in the management of TBS. In summary, this study revealed the possible resistance mechanisms of differential metabolites in resistance of commercial tobacco cultivar, and for the first time discovered the inhibitory effects of isoliquiritigenin and homovanillic acid on P. nictianae, and attempt to use plants secondary metabolites of for plant protection.

Genetic control of DNA methylation is largely shared across European and East Asian populations.

DNA methylation is an ideal trait to study the extent of the shared genetic control across ancestries, effectively providing hundreds of thousands of model molecular traits with large QTL effect sizes. We investigate cis DNAm QTLs in three European (n = 3701) and two East Asian (n = 2099) cohorts to quantify the similarities and differences in the genetic architecture across populations. We observe 80,394 associated mQTLs (62.2% of DNAm probes with significant mQTL) to be significant in both ancestries, while 28,925 mQTLs (22.4%) are identified in only a single ancestry. mQTL effect sizes are highly conserved across populations, with differences in mQTL discovery likely due to differences in allele frequency of associated variants and differing linkage disequilibrium between causal variants and assayed SNPs. This study highlights the overall similarity of genetic control across ancestries and the value of ancestral diversity in increasing the power to detect associations and enhancing fine mapping resolution.

Sublingual Edaravone Dexborneol for the Treatment of Acute Ischemic Stroke: The TASTE-SL Randomized Clinical Trial.

Importance: Sublingual edaravone dexborneol, which can rapidly diffuse and be absorbed through the oral mucosa after sublingual exposure, is a multitarget brain cytoprotection composed of antioxidant and anti-inflammatory ingredients edaravone and dexborneol. Objective: To investigate the efficacy and safety of sublingual edaravone dexborneol on 90-day functional outcome in patients with acute ischemic stroke (AIS). Design, Setting, and Participants: This was a double-blind, placebo-controlled, multicenter, parallel-group, phase 3 randomized clinical trial conducted from June 28, 2021, to August 10, 2022, with 90-day follow-up. Participants were recruited from 33 centers in China. Patients randomly assigned to treatment groups were aged 18 to 80 years and had a National Institutes of Health Stroke Scale score between 6 and 20, a total motor deficit score of the upper and lower limbs of 2 or greater, a clinically diagnosed AIS symptom within 48 hours, and a modified Rankin Scale (mRS) score of 1 or less before stroke. Patients who did not meet the eligibility criteria or declined to participate were excluded. Intervention: Patients were assigned, in a 1:1 ratio, to receive sublingual edaravone dexborneol (edaravone, 30 mg; dexborneol, 6 mg) or placebo (edaravone, 0 mg; dexborneol, 60 µg) twice daily for 14 days and were followed up until 90 days. Main Outcomes and Measures: The primary efficacy outcome was the proportion of patients with mRS score of 1 or less on day 90 after randomization. Results: Of 956 patients, 42 were excluded. A total of 914 patients (median [IQR] age, 64.0 [56.0-70.0] years; 608 male [66.5%]) were randomly allocated to the edaravone dexborneol group (450 [49.2%]) or placebo group (464 [50.8%]). The edaravone dexborneol group showed a significantly higher proportion of patients experiencing good functional outcomes on day 90 after randomization compared with the placebo group (290 [64.4%] vs 254 [54.7%]; risk difference, 9.70%; 95% CI, 3.37%-16.03%; odds ratio, 1.50; 95% CI, 1.15-1.95, P = .003). The rate of adverse events was similar between the 2 groups (89.8% [405 of 450] vs 90.1% [418 of 464]). Conclusion and Relevance: Among patients with AIS within 48 hours, sublingual edaravone dexborneol could improve the proportion of those achieving a favorable functional outcome at 90 days compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04950920.

Variation in Resting Metabolic Rate Affects Identification of Metabolic Change in Geographically Distinct Cohorts of Patients With ALS.

BACKGROUND AND OBJECTIVES: Altered metabolism is observed in amyotrophic lateral sclerosis (ALS). However, without a standardized methodology to define metabolic changes, our understanding of factors contributing to and the clinical significance of altered metabolism in ALS is limited. METHODS: We aimed to determine how geographic variation in metabolic rates influences estimates and accuracy of predicted resting energy expenditure (REE) in patients with ALS and controls, while validating the effectiveness of cohort-specific approaches in predicting altered metabolic rate in ALS. Participants from 3 geographically distinct sites across Australia, China, and the Netherlands underwent REE assessments, and we considered 22 unique equations for estimating REE. Analyses evaluated equation performance and the influence of demographics on metabolic status. Comparisons were made using standardized and local reference values to identify metabolic alterations. RESULTS: 606 participants were included from Australia (patients with ALS: 140, controls: 154), the Netherlands (patients with ALS: 79, controls: 37) and China (patients with ALS: 67, controls: 129). Measured REE was variable across geographic cohorts, with fat-free mass contributing to this variation across all patients (p = 0.002 to p < 0.001). Of the 22 predication equations assessed, the Sabounchi Structure 4 (S4) equation performed relatively well across all control cohorts. Use of prediction thresholds generated using data from Australian controls generally increased the prevalence of hypermetabolism in Chinese (55%, [43%-67%]) and Dutch (44%, [33%-55%]) cases when compared with Australian cases (30%, [22%-38%]). Adjustment of prediction thresholds to consider geographically distinct characteristics from matched control cohorts resulted in a decrease in the proportion of hypermetabolic cases in Chinese and Dutch cohorts (25%-31% vs 55% and 20%-34% vs 43%-44%, respectively), and increased prevalence of hypometabolism in Dutch cases with ALS (1% to 8%-10%). DISCUSSION: The identification of hypermetabolism in ALS is influenced by the formulae and demographic-specific prediction thresholds used for defining alterations in metabolic rate. A consensus approach is needed for identification of metabolic changes in ALS and will facilitate improved understanding of the cause and clinical significance of this in ALS.

Efficacy and safety of Y-2 sublingual tablet for patients with acute ischaemic stroke: protocol of a phase III randomised double-blind placebo-controlled multicentre trial.

BACKGROUND AND PURPOSE: Clinical studies have demonstrated that edaravone dexborneol can improve the functional outcomes in patients with acute ischaemic stroke (AIS). The present clinical trial aimed at testing the efficacy and safety of Y-2 sublingual tablet on 90-day functional outcome in patients with AIS. METHODS AND DESIGN: This is a randomised, double-blind, placebo-controlled, multicentre, parallel-group trial of Y-2 sublingual tablet on patients with AIS.An estimated 914 patients at age of 18-80 years with AIS within 48 hours after symptom onset from 40 hospitals will be randomly assigned to receive Y-2 sublingual tablet or placebo for 14 days. Patients are at score 6-20 points on National Institutes of Health Stroke Scale (NIHSS) and had a modified Rankin Scale (mRS) ≤1 before this stroke, except mechanical thrombectomy and neuroprotective agents treatment. STUDY OUTCOMES: The primary outcome is the proportion of patients with mRS ≤1 on day 90 after randomisation. Secondary efficacy outcomes include mRS score on day 90, the proportion of patients with mRS ≤2 on day 90; the change of NIHSS score from baseline to day 14 and the proportion of patients with NIHSS score ≤1 at the days 14, 30 and 90. DISCUSSION: This trial will provide valuable evidence for the efficacy and safety of Y-2 sublingual table for improving 90 days the functional outcomes in patients with AIS. TRIAL REGISTRATION NUMBER: NCT04950920.

A neuroimaging biomarker for Individual Brain-Related Abnormalities In Neurodegeneration (IBRAIN): a cross-sectional study.

Background: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that poses a worldwide public health challenge. A neuroimaging biomarker would significantly improve early diagnosis and intervention, ultimately enhancing the quality of life for affected individuals and reducing the burden on healthcare systems. Methods: Cross-sectional and longitudinal data (10,099 participants with 13,380 scans) from 12 independent datasets were used in the present study (this study was performed between September 1, 2021 and February 15, 2023). The Individual Brain-Related Abnormalities In Neurodegeneration (IBRAIN) score was developed via integrated regional- and network-based measures under an ensemble machine learning model based on structural MRI data. We systematically assessed whether IBRAIN could be a neuroimaging biomarker for AD. Findings: IBRAIN accurately differentiated individuals with AD from NCs (AUC = 0.92) and other neurodegenerative diseases, including Frontotemporal dementia (FTD), Parkinson's disease (PD), Vascular dementia (VaD) and Amyotrophic Lateral Sclerosis (ALS) (AUC = 0.92). IBRAIN was significantly correlated to clinical measures and gene expression, enriched in immune process and protein metabolism. The IBRAIN score exhibited a significant ability to reveal the distinct progression of prodromal AD (i.e., Mild cognitive impairment, MCI) (Hazard Ratio (HR) = 6.52 [95% CI: 4.42∼9.62], p < 1 × 10-16), which offers similar powerful performance with Cerebrospinal Fluid (CSF) Aß (HR = 3.78 [95% CI: 2.63∼5.43], p = 2.13 × 10-14) and CSF Tau (HR = 3.77 [95% CI: 2.64∼5.39], p = 9.53 × 10-15) based on the COX and Log-rank test. Notably, the IBRAIN shows comparable sensitivity (beta = -0.70, p < 1 × 10-16) in capturing longitudinal changes in individuals with conversion to AD than CSF Aß (beta = -0.26, p = 4.40 × 10-9) and CSF Tau (beta = 0.12, p = 1.02 × 10-5). Interpretation: Our findings suggested that IBRAIN is a biologically relevant, specific, and sensitive neuroimaging biomarker that can serve as a clinical measure to uncover prodromal AD progression. It has strong potential for application in future clinical practice and treatment trials. Funding: Science and Technology Innovation 2030 Major Projects, the National Natural Science Foundation of China, Beijing Natural Science Funds, the Fundamental Research Funds for the CentralUniversity, and the Startup Funds for Talents at Beijing Normal University.

Neutrophils: a subgroup of neglected immune cells in ALS.

Amyotrophic lateral sclerosis (ALS) is a chronic, progressive neurodegenerative disease characterized by the loss of motor neurons. Dysregulated peripheral immunity has been identified as a hallmark of ALS. Neutrophils, as the front-line responders of innate immunity, contribute to host defense through pathogen clearance. However, they can concurrently play a detrimental role in chronic inflammation. With the unveiling of novel functions of neutrophils in neurodegenerative diseases, it becomes essential to review our current understanding of neutrophils and to recognize the gap in our knowledge about their role in ALS. Thus, a detailed comprehension of the biological processes underlying neutrophil-induced pathogenesis in ALS may assist in identifying potential cell-based therapeutic strategies to delay disease progression.

Neutrophils Are Associated with Higher Risk of Incident Amyotrophic Lateral Sclerosis in a BMI- and Age-Dependent Manner.

OBJECTIVE: Peripheral immune markers have been associated with the progression and prognosis of amyotrophic lateral sclerosis (ALS). However, whether dysregulation of peripheral immunity is a risk factor for ALS or a consequence of motor neuron degeneration has not yet been clarified. We aimed to identify longitudinal associations between prediagnostic peripheral immunity and the risk of incident ALS. METHODS: A total of 345,000 individuals from the UK Biobank between 2006 and 2010 were included at the baseline. The counts of peripheral immune markers (neutrophils, lymphocytes, monocytes, platelets, and CRP) and its derived metrics (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], lymphocyte-to-monocyte ratio [LMR], and systemic immune-inflammation index [SII]) were analyzed in relation to the following incident ALS by Cox proportional hazard models. Subgroup and interaction analyses were performed to explore the covariates of these relationships further. RESULTS: After adjusting for all covariates, the multivariate analysis showed that high neutrophil counts and their derived metrics (NLR and SII) were associated with an increased risk of ALS incidence (per SD increment hazard ratio [HR] = 1.15, 95% confidence interval [CI] = 1.02-1.29 for neutrophils; HR = 1.15, 95% CI = 1.03-1.28 for NLR; and HR = 1.17, 95% CI = 1.05-1.30 for SII). Subgroup and interaction analyses revealed that body mass index (BMI) and age had specific effects on this association. In participants with BMI ≥ 25 or age < 65 years, higher neutrophil counts, and their metrics increased the risk of incident ALS; however, in participants with BMI < 25 or age ≥ 65 years, neutrophils had no effect on incident ALS. INTERPRETATION: Our study provides evidence that increased neutrophil levels and neutrophil-derived metrics (NLR and SII) are associated with an increased risk of developing ALS. ANN NEUROL 2023;94:942-954.