Combined With Functional Magnetic Resonance To Evaluate The Clinical Research Of Wenshen Jiannao Decoction In The Treatment Of Multiple System Atrophy

Multiple System Atrophy（MSA）is a neurodegenerative disease with the main clinical features of progressive autonomic dysfunction with Parkinson’s symptoms,cerebellar ataxia symptoms,and pyramidal beam signs,which is usually onset on Middle-aged and elderly.At present,there is still a lack of effective therapy for MSA in the international scope,and the effectiveness of traditional Chinese medicine in the treatment of MSA is also lack of verification.From the perspective of the assessment of the condition and the evaluation of the efficacy,the assessment of MSA is based on the Unified Multiple System Atrophy Scale（UMSARS）and lacks a comprehensive assessment of non-motor symptoms in MSA patients,Lack of objective evaluation of efficacy.This study puts forward the Core pathogenesis of MSA based on "Brain-Brain Spirit-Brain Qi ",which is used as a guide to develop a "the formula of warming kidney and strengthening brain ".It was found that the formula of warming kidney and strengthening brain could delay the disease progression and improve the non-motor symptoms of MSA patients in the previous study.At the same time a scale was developed in prior research to evaluate MSA non-motor symptoms named Multiple system atrophy non-motor symptoms scale（MSA-NMSS）which had good content validity and structural validity.Therefore,this research wants to explain the core pathogenesis of MSA,perfect the evaluation of validity and reliability of MSA-NMSS From the perspective of functional magnetic resonance imaging（fMRI）to explore MSA imaging features of different types.We use MSA-NMSS,fMRI as curative effect evaluation method,through clinical trials to verify the curative effect of "the formula of warming kidney and strengthening brain ",in the hope that provide scientific basis for the treatment of MSA with traditional Chinese medicine.Objective:Study 1:From the perspective of " Brain-Brain Spirit-Brain Qi" to understand MSA,Put forward the basis of " the formula of warming kidney and strengthening brain ",provides a theoretical basis for " the formula of warming kidney and strengthening brain " to treat multiple system atrophy.Study 2:Verify the reliability and validity of MSA-NMSS,and provide a new assessment scale for non-motor symptoms of MSA.Study 3:The differences of fMRI in different types of patients with MSA are compared to provide objective imaging means for the evaluation of MSA.Study 4:Clinical trials are conducted with UMSARS,MSA-NMSS and fMRI as evaluation methods,to verify the efficacy of "the formula of warming kidney and strengthening brain ",aim to provide new drugs for the treatment of MSA.Method:Study 1:Understanding multiple system atrophy from the Angle of "Brain-Brain Spirit-Brain Qi"In this study,we expound the concept of "Brain-Brain Spirit-Brain Qi " and explain the link between clinical symptoms of MSA and "Brain-Brain Spirit-Brain Qi ",we establish the core pathogenesis system and with this as guide we elaborate the treatment methods and principles of medication of MSA.Study 2:The reliability and validity evaluation of Multiple system atrophy non-motor symptoms scaleOn the first day of enrollment,primary evaluator A evaluate the patients with MSA-NMSS and UMSARS scale to evaluate the criterion validity,the construct validity is investigated through exploratory factor analysis.Sub-evaluator B repeatedly evaluate the patient with the MSA-NMSS scale within 1h of the same day to verify the reliability of the raters.The MSA-NMSS scale is re-measured by the primary evaluator A one week after enrollment to verify the retest reliability.Study 3:fMRI characteristics in patients with multisystem atrophyMSA-C and MSA-P patients are selected in this study,and healthy people matching their age and gender is included for control.All subjects are subjected to a resting state fMRI,amplitude of low-Frequency fluctuation,regional homogeneity and functionalconnectivity are chosed to exam.Patients with MSA are assessed using the UMSARS scale.Study 4:Controlled clinical trials of" the formula of warming kidney and strengthening brain" in the treatment of multiple system atrophyMSA patients in western medicine group and Chinese medicine group are included in this study.The western medicine group are mainly symptomatically therapy（Co-enzyme Q10,butyphthalide,idebenone,Vitamin B,antiparkinson drugsand so on）,when the Chinese medicine group added "the formula of warming kidney and strengthening brain ".The treatment cycle is 6 months.UMSARS,MSA-NMSS scores and nocturia frequency are evaluated at baseline,3 and 6 months.fMRI was performed before and after treatment in part of the TCM group.Adverse events during treatment are also monitored.Results:Study 1:This study indicates that MSA belongs to the category of brain,It is pointed out that brain injury is the basis of MSA,Brain damage due to deficiency and toxicity with kidney essence deficiency as the fundamental.The brain-spirit is the external manifestation of brain,manifested as the disorder of spiritual activity and perception.The transmission of the brain-spirit depends on the Brain-qi,which is composed of lung,spleen and kidney qi,the spleen and kidney are the dominent.The main treatment is to nourish brain,improve brain-spirit and brain-qi.So,we create " the formula of warming kidney and strengthening brain "to treat the MSA.Study 2:A total of 100 MSA patients are included in this study.（1）Reliability evaluation:①Internal consistency:MSA-NMSS consists of 12 dimensions and 35 items in total.The Cronbach’s coefficient of the total scale is 0.812,and the Cronbach’s coefficient of the total scale is not significantly changed after deleting items（P>0.05）.②Retest reliability:the retest correlation coefficient of the total scale is 0.998（P<0.01）.The retest correlation coefficients for each dimension range from 0.939 to 1.000（P<0.01）.③Evaluator reliability:the correlation coefficient of different evaluator reliability in the total scale is 0.984（P<0.01）,and the correlation coefficient of each dimension range from 0.493 to 0.984（P<0.01）.（2）Validity evaluation:①Construct validity:the correlation coefficient of each dimension with total score range from 0.200 to 0.743,of which the correlation is from high to low in order:systemic symptoms,urinary function,head symptoms,cold-feeling adaptation regulation,defecation function（correlation coefficient>0.500）,followed by cognitive function,cardio-body symptoms,Digestive function,heat adjustment regulation,sleep symptoms,sweatfunction,the lowest correlation is sexual function.The main component analysis is carried out,14 factors are analyzed,and the cumulative contribution rate is 72.062%.②Criterion validity:The correlation coefficient between MSA-NMSS and UMSARS-I,UMSAR-Ⅳ is 0.694（P<0.001）and 0.549（P<0.001）.Study 3:The study include 20 cases of MSA-C patients,10 cases of MS A-P patients and 10 cases of healthy subjects with matching age and gender.In patients with MSA-C type,the ALFF is increased in the left Cerebellum Posterior Lobe（P<0.05）,the ReHo is decreased in left Cerebellum Anterior Lobe and increased in Frontal_Mid_L,Frontal_Mid_Orb_R（P<0.05）.Whole-brain functional connectivity is analyzed according to seed point coordinates（-12-51-39）,the functional connectivity decrease in right Extra-Nuclear,Temporal_Inf_R,right Vermis₈,left Inferior Occipital Gyrus,right Lingual Gyrus,Frontal_Mid_Orb_R,bilateral Superior Frontal Gyrus,Hippocampus_L,Frontal Mid L and Frontal_Sup_Medial_L（P<0.05）.In patients with MS A-P type,the ALFF is increased in the left Cerebellum Posterior Lobe and decreased in the left Corpus Callosum（P<0.05）,there is increased ReHo in the Cingulum_Mid R and decreased ReHo in the Lingual_R,Occipital_Mid_L（P<0.05）.Whole-brain functional connectivity is analyzed according to seed point coordinate s（-21 36-12）,the whole-brain functional connectivity decreased in Fusiform_R,Calcarine_L,left Cerebellum Anterior Lobe,Thalamus_L,Occipital_Mid_L,bilateral Occipital_Sup,right Parietal Lobe,SupraMarginal_L,Precuneus_L,bilateral Cingulum_Mid and Precuneus_R（P<0.05）.There are diferences between MSA-C and MSA-P,Compared with MSA-C,patients with MSA-P type usally have decreased ALFF in the left Cerebellum Anterior Lobe and increased ALFF in the Supp_Motor Area_R,right Precentral Gyrus,right Frontal Lobe,right Parietal Lobe and left Cingulate Gyrus（P<0.05）.There is no significant difference in ReHo（P>0.05）.According to the seed point coordinates（-9-51-30）,the connection analysis of whole brain function is conducted.Compared with MSA-C,patients with MSA-P type usally have increased in Temporal_Mid_L,right Frontal Lobe,Frontal_Mid_Orb_L,Hippocampus_L,Frontal_Inf_Orb_L and Frontal_Med_Orb_R（P<0.05）.Study 4:A total of 77 MSA patients are included in the study,including 50 in the traditional Chinese medicine group and 27 in the western medicine group.In the TCM group,8 patients undergo fMRI before and after treatment.A total of 60 of the 77 patients complete the study.The efficacy evaluation:（1）UMSARS:After 3 months of treatment,the swallowing function,fall,urinary function and intestinal function of the TCM group are improved,but no significant statistical significance is found（P>0.05）,while the western medicine group is aggravated（P>0.05）.Compared with the two groups,the average progress of UMSARS-I is 0.27±1.10 points/month in TCM group and 0.42±0.71 points/month in the western medicine group,with no statistical difference（P>0.05）.There is no statistical difference in the change of each item of UMSARS-I（P>0.05）.After 6 months of treatment,the personal hygiene and walking are aggravated,and fall is improved in TCM group（P<0.05）.Compared with the two groups,the average progress of UMSARS-I is 0.32±0.69 points/month in TCM group and 0.26±0.41 points/month in the western medicine group,with no statistical difference（P>0.05）.There is no statistical difference in the change of each item of UMSARS-I（P>0.05）.（2）MSA-NMSS:After 3 months of treatment,MSA-NMSS score in TCM group decrease,and RBD symptoms significantly improved（P<0.01）.The MSA-NMSS score increase in the western medicine group,and the fever symptoms worsened（P<0.05）.Patients in the TCM group are better than those in the western medicine group in terms of sleepiness,fatigue,faint low voice,sore muscle,urgency of urination,uracratia,difficulty in defecation,constipate,and fear of heat（P<0.05）.Compared with the two groups,the curative effect of the TCM group is significantly better than that of the western medicine group（P<0.05）..After 6 months of treatment,MSA-NMSS score of the TCM group decrease,dizziness and RBD are significantly improved（P<0.05）.The non-motor symptoms in the western medicine group get worsen,and there is a significant difference compared with the TCM group（P<0.05）.Patients in the TCM group are better than those in the western medicine group in terms of drooling,difficulty in defecation,insomnia.（3）Nocturia frequency:the nocturia frequency of MSA patients in the traditional Chinese medicine group is basically stable,while that in the western medicine group increase gradually,The change of nocturia frequency of western medicine group is significantly higher than that of TCM group after 6 months of treatment（P<0.05）..（4）fMRI:After the treatment of "the formula of warming kidney and strengthening brain ",the ALFF in the right occipital lobe of patients with MSA-C type increase,but the difference is not statistically significant（P=0.06>0.05）,and the ReHo and FC of patients with MSA-C type do not change significantly（P>0.05）.conclusion:Study 1:" The formula of warming kidney and strengthening brain " is a prescription for MSA based on the theroy of "Brain-Brain Spirit-Brain Qi "Study 2:MSA-NMSS has good reliability and validity,but some items of the scale need to be further revised.MSA-NMSS can be used to evaluate non-motor symptoms in patients with MSA.Study 3:There are abnormalities of ALFF,ReHo and FC in patients with MSA in resting state fMRI,and there are differences in ALFF,ReHo and FC in the two types of MSA,which are related to the pathological mechanism and clinical manifestations of MSA.Study 4:" The formula of warming kidney and strengthening brain " can delay the progress of MSA,and the non-motor symptoms of MSA patients can be effectively improved,which are mainly manifested in the improvement of symptoms of sleepiness,fatigue,faint low voice,sore muscle,urgency of urination,uracratia,difficulty in defecation,constipate,and fear of heat..The longer the treatment lasted,the more nonmotor symptoms improved.After treatment,ALFF in the right occipital lobe increase and neuronal activity compensatory increase in patients with MSA-C type in the traditional Chinese medicine group,suggesting that " the formula of warming kidney and strengthening brain " may reduce movement disorders by stimulating compensatory increase in neuronal activity in the occipital lobe of the brain to provide visual compensation.