The Study On Association Between Clinical Characteristics And Brain Networks In Drug-na(?)ve Patients With Early Parkinson’s Disease

Aims:Early symptoms of Parkinson’s disease(PD)are complicated and often disguised.Additionally,the alteration of brain network of early PD patients remains unknown.The aims of this study are to explore and summarize the characteristics of symptoms of drug-na(?)ve patients with PD,as well as the alteration of resting-state functional magnetic resonance imaging(f MRI)and its relevance to clinical characteristics.Methods:Drug-na(?)ve patients with PD and age-matched healthy controls were recruited from the outpatient clinic of Wuhan Union Hospital.Motor and non-motor symptoms were evaluated for further analysis using the Unified Parkinson’s Disease Rating Scale(UPDRS)I,II,and Ⅲ;Sniffin’Sticks Screening 12 test;Mini-Mental State Exam(MMSE);Montreal Cognitive Assessment(Mo CA);Hamilton Anxiety Scale(HAMA);and Hamilton Depression Scale(HAMD)scores.The PD subtypes were then classified using the k-means clustering algorithm.Acute levodopa challenge test(ALCT)was performed.The motor section of the Unified Parkinson’s disease rating scale(UPDRS Ⅲ)was evaluated before,and 30,60,90,and 120 minutes after taking 250mg madopar,as well as the improvement rate.The total score of UPDRS Ⅲ was didvided into tremor sub-score,rigidity sub-score,bradykinesia sub-score and axial sub-score.The patients were didvided into two group according to the improvement rate 120 minutes after medication.Finally,f MRI data were collected.Functional brain connectivity was analyzed at the integrity,network,and edge levels.The relationship between f MRI and clinical features was analyzed by regression analysis.Results:We recruited 80 drug-na(?)ve patients with PD and 40 age-matched healthy controls.Among the patients included,the ratio of sex was 37:43,and the mean onset age was 59.96±10.40 years.The mean time from symptom onset to consulting a doctor was 16.69±13.40months.The mean UPDRS I,II,and Ⅲ;MMSE;Mo CA;HAMA;and HAMD scores were2.01±1.90,6.18±3.68,26.13±12.09,24.28±4.01,18.33±5.80,11.26±7.64,and 12.48±9.18,respectively.Clustering algorithm classified the subtypes of PD as early-onset tremor,late-onset demential-rigidity,and late-onset mixed.After ALCT,motor symptoms gradually improved over time,and more than 90%of patients had the highest improvement rate at 120 minutes after medication.The baseline UPDRS Ⅲ scores of good response group and poor response group were 24.49±11.51 vs.29.07±13.13;the average improvement rates were 10.50%vs.8.57%at 30 minutes,27.00%vs.13.13%at 60 minutes,37.24%vs.15.74%at 90 minutes,and 42.64%vs.17.27%at 120 minutes.The average improvement rates of tremor sub-scores of good response group and poor response group were 44.93%vs.14.45%;improvement rates of rigidity sub-score were 40.57%vs.16.51%;improvement rates of bradykinesia sub-score were 50.15%vs.20.9%;and improvement rates of axial score were 25.46%vs.12.89%.Compared with HCs,reduced functional connectivity were mainly observed in the visual(VSN),somatomotor(SMN),limbic(LBN),and deep gray matter networks(DGN)at integrity level(p<0.05,false discovery rate[FDR]corrected).Intra-network analysis indicated decreased functional connectivity in DGN,SMN,LBN,and ventral attention networks(VAN).Inter-network analysis indicated reduced functional connectivity in nine pairs of resting-state networks(p<0.05,FDR corrected).At the edge level,the LBN was the center of abnormal functional connectivity(p<0.05,FDR corrected).Regression analysis showed that the Mo CA score was associated with the intra-network functional connectivity strength(FC)of the DGN,and inter-network FC of the DGN-VAN.HAMA and HAMD scores were associated with the FC of the SMN,DGN,and either the LBN or VAN,respectively(p<0.05).Conclusion:Drug-na(?)ve PD patients demonstrated more severe motor dysfunction,poorer olfactory,declined cognitive,and more sever mood disorders,possibly due to the increased time from disease onset to hospital care.The proportion of non-tremor subtype in early PD patients was relatively high,which was prone to missed diagnosis and misdiagnosis.The symptoms of PD improved gradually after ALCT,and the higest improvement rate of most patients appeared at 120 minutes after medication.Among the four symptoms of PD,bradykinesia responsed to the ALCT best while axial symptoms worst.Clinicians should pay more attention to the follow-up drug response of patients with severe axial symptoms.The difference of patients’response to ALCT has no significant correlation with age,emotional disorder and UPDRS Ⅲ at baseline,but cognitive function has a tendency to be statistically different(p=0.06).The severity of bradykinesia at baseline may be related to the poor response to ALCT.We speculate that the difference of response to ALCT in PD may be related to the heterogeneity of PD.We demonstrated variations in whole brain connections of drug-na(?)ve patients with early PD,compared with age-matched HCs.Major changes involved the SMN,DGN,LBN,and VSN,which may be relevant to motor and non-motor symptoms of early PD.