Nutritional Metabolic Status, Blood-brain Barrier Function And Related Prognostic Analysis In Patients With Amyotrophic Lateral Sclerosi

Part 1.Factors affecting nutritional status and its prognostic value in patients with amyotrophic lateral sclerosisBackground and objective:Amyotrophic lateral sclerosis(ALS)is a rare neurodegenerative disease characterized by progressive loss of motor neurons.The purpose of this study was to observe the nutritional status and its changes in ALS patients from China through various methods of nutritional assessment and to further study the effect of nutritional status on prognosis.Methods:This study consecutively included patients diagnosed with ALS along with age and sex-matched healthy controls from October 2020 to January 2022.Demographic information and clinical characteristics of the patients were collected by questionnaires.Anthropometric assessments were performed at enrollment,including height,weight,body mass index(BMI),waist-to-hip ratio(WHR),and body composition.Parameters of body composition included fat-free mass(FFM),muscle mass(MM),fat mass(FM),bone mass(BM),and visceral fat index(VFI).Comprehensive Food Frequency Questionnaire and 9-item patients’ Health Questionnaire were used to evaluate appetite and depression in ALS patients respectively.Correlation analysis and regression analysis were used to explore the factors affecting the nutritional status in ALS patients.All patients were followed up every 6 months,and functional status at follow-ups was assessed using the revised ALS functional rating scale(ALSFRS-R).The monthly decline slope of ALSFRS-R was defined as the rate of disease progression,and linear regression was used to explore the effect of nutritional status on disease progression in ALS patients.Results:A total of 222 ALS patients and 55 healthy controls were included in this study.The mean BMI was significantly lower in ALS patients than normal controls(p<0.01),and the difference of body composition was most significant in FM between the two groups(p<0.05).Patients with bulbar onset had lower premorbid body weight and BMI than those with spinal onset(p<0.05),and the differences were more significant when comparing weight and BMI at baseline(p<0.001).Body composition analysis found significantly lower FFM,MM,FM,and BM in patients with bulbar onset than those with spinal onset(p<0.01).65.5%(110/168)of patients had a loss of appetite with significantly lower weight,FFM,MM,and BM than those with intact appetite.69.9%(116/166)of patients were diagnosed with depression with a significantly lower weight than those without depression(p=0.034),while no significant difference in body composition was found between the two groups.Weight loss at baseline was found in 118(53.2%)patients.Older onset age,predominant involvement of lower motor neurons,and higher premorbid weight were independent risk factors for early weight loss in ALS patients.Until January 2022,ten patients died,2 patients underwent a tracheotomy.During follow-ups,57 patients(42.9%)had weight loss.Depression and bulbar onset were independently associated with weight loss during follow-up.Twenty-five patients reassessed body composition at follow-ups,and FFM,MM,and BM decreased significantly in ALS patients during the follow-ups(p<0.05).The mean rate of disease progression was 1.12,and lower baseline VFI and weight loss at follow-ups were independently associated with rapid disease progression(p<0.05).Conclusion:Malnutrition is common in ALS patients from China,with multiple factors involved in the pathophysiological process.As the disease progressed,the nutritional status of ALS patients further worse with wasting of muscle mass and bone mass.Malnutrition in ALS patients is associated with poor prognosis,and higher fat mass may have a protective effect on disease progression in ALS patients.Part 2.Alterations in metabolic biomarkers and its correlation with disease progression in amyotrophic lateral sclerosisBackground and objective:Metabolic dysfunction has been suggested to be involved in the pathophysiological process of amyotrophic lateral sclerosis(ALS).This study aimed to investigate the potential role of metabolic biomarkers in the progression of ALS,through which to increase the understanding of the possible underlying metabolic mechanisms.Methods:In this study,52 ALS patients and 24 normal controls were enrolled.Blood samples were collected and metabolic factors were measured in all subjects.Using Bio-Rad’s multifactor kit to measure serum levels of metabolic factors,including adipokines(adiponectin,adipsin,leptin,resistin,and visfatin)and other metabolic biomarkers[C-peptide,insulin,ghrelin,gastric inhibitory peptide(GIP),glucagon-like peptide 1(GLP-1),glucagon,plasminogen activator inhibitor type 1(PAI-1)].All the patients met the diagnosis of clinically definite,clinically probable,or laboratory-supported probable ALS according to the revised El Escorial criteria.Demographic data,clinical data,and anthropometric measurements were collected in ALS patients during enrollment.Appetite was also evaluated by the Comprehensive Food Frequency Questionnaire(CNAQ)in ALS patients.The disease progression rate(DPR)was calculated using the revised ALS functional rating scale(ALSFRS-R)during the 6-month follow-up.Results:ALS patients had higher levels of adipokines(adiponectin,adipsin,resistin,and visfatin)and other metabolic biomarkers(C-peptide,glucagon,GLP-1,GIP,and PAI-1)than controls.Leptin levels were slightly higher in the patients than in the control group,but the difference did not reach significance.Leptin levels in serum were positively correlated with body mass index(BMI),body fat,and visceral fat index(VFI).Adiponectin was positively correlated with VFI and showed a positive correlation with ALSFRS-R.There was a correlation between visceral fat and VFI,but the results were not statistically significant.Thirty-three ALS patients completed the CNAQ questionnaire,and 12(36.4%)had loss of appetite.A positive correlation was found between PAI-1 and CNAQ scores in the correlation analysis between metabolic factors and appetite.Patients with lower levels of body fat,VFI,and fat in limbs showed fast disease progression during follow-ups.Adiponectin and leptin was negatively correlated with disease progression rate at follow-ups.After adjusting for confounders,lower adiponectin levels and higher visfatin levels were independently correlated with faster disease progression.Conclusion:The current study found altered levels of metabolic biomarkers in ALS patients,which may play a potential role in the pathophysiologic process of ALS.Adiponectin and visfatin represent potential biomarkers in the prediction of disease progression in ALS.Part 3.Blood-brain barrier dysfunction in patients with amyotrophic lateral sclerosis and its impact on survivalObjective:We aim to investigate blood-brain barrier(BBB)dysfunction in patients with amyotrophic lateral sclerosis and further determine its effect on the survival of ALS.Methods:This was a retrospective study of 125 ALS patients and 40 disease controls hospitalized between September 2013 and October 2020.Of all ALS patients,12 were also diagnosed with frontotemporal dementia(FTD).The CSF parameters including total protein(TP),albumin(Alb),and immunoglobulin-G(IgG)were collected and compared between groups.The CSF-TP,CSF-Alb,CSF-IgG,and CSF/serum quotients of Alb and IgG(QA1b,QIgG)were used to reflect the BBB status.Patients were followed up until December 2020.Cox regression and Kaplan-Meier method were used for survival analysis.Results:The CSF-TP,CSF-Alb,and CSF-IgG concentrations were significantly higher in patients than controls(p<0.01).Increased CSF-TP and CSF-IgG was found in 45(39.8%)and 27(23.9%)ALS patients,while in 7(58.3%)and 5(41.7%)ALS-FTD patients respectively.The level of CSF-Alb and CSF-IgG were significantly higher in patients with ALS-FTD than pure ALS.Kaplan-Meier analysis indicated that a higher CSF-TP,CSF-IgG,QigG,or QA1b was significantly associated with shorter survival.Cox regression model showed that CSF-TP and QA1b were independent predictors of survival in ALS patients.Conclusion:Our findings suggested that BBB dysfunction is common in ALS patients,which is also more prominent in ALS patients with FTD than those with pure ALS.The dysfunction of BBB was associated with a worse prognosis in ALS patients.