| BackgroundParkinson’s disease(PD)is a common neurodegenerative disease in the elderly.It is characterized by the loss of dopaminergic neurons in substantia nigra and the formation of Lewy bodies by the aggregation of α-synuclein.In recent years,the deposition of phosphorylated α-synuclein(p-syn)has been found in the cutaneous nerves of sporadic and monogenic PD patients by the immunofluorescence or immunohistochemistry,which is similar to the deposition of p-syn in the substantia nigra of the midbrain,but not in normal people and patients with non synuclein disease,suggesting the possibility of skin p-syn as a biomarker of PD.LRRK2 gene mutation is the most common cause of autosomal dominant PD,and LRRK2 G2385R mutation is the most common risk factor of sporadic PD in Chinese population.However,there is no autopsy report on PD patients with LRRK2 G2385R mutation,and there is no research report on the deposition characteristics of p-syn in the skin of PD patients with LRRK2 G2385R mutation.ObjectiveTo investigate the characteristics of p-syn deposition and small fiber neuropathy in the skin of PD patients with LRRK2 G2385R variation.Methods1.Subjects:a total of 59 PD patients and 30 age and gender matched healthy controls were included in the skin biopsy database of the First Affiliated Hospital of Zhengzhou University from January 1,2019 to January 31,2020.The demographic data of the subjects and the relevant medical history of PD patients were collected.According to the clinical related scale:MDS-UPDRS-III,Hoehn&Yahr,SFN-SIQ,COMPASS-31,NMSS,MMSE,the clinical manifestations were evaluated.At the same time,the medication history,response to levodopa,LED and RBD were collected.2.Gene sequencing:Sanger sequencing was used to determine whether LRRK2 G2385R mutation was carried in the subjects.3.Skin biopsy:the samples were taken from the distal part of the body(10 cm above the lateral malleolus)and the proximal part of the body(cervical 7 vertebrae).The deposition of p-syn in cutaneous nerves was observed by immunofluorescence double staining with PGP 9.5 antibody and anti-p-syn antibody.The distribution of intraepidermal nerve fibers(IENF)was observed by immunohistochemical staining,and the density of IENFD was counted.Results1.Among 59 PD patients,12 cases were found with LRRK2 G2385R mutation and 47 cases were out of the mutation.No mutation was found in 30 healthy controls.2.Among the 12 PD patients with LRRK2 G2385R mutation,8 cases(66.7%)had p-syn deposition in the neck,7 cases(58.3%)had p-syn deposition in the distal leg.there was no statistical difference between the two parts(P=1.000).Among 47 PD patients without LRRK2 G2385R mutation,33 cases(70.2%)had p-syn deposition in neck,17 cases(36.2%)had p-syn deposition in distal leg.there was statistical difference between the two parts(P=0.001).3.There was no significant difference in the IENFD of the lateral malleolus between the LRRK2 G2385R mutation group and the non-mutation group(6.17±2.67 vs 6.13±3.40,P=0.971).The IENFD of the PD patients was significantly lower than that of the healthy control group(P=0.007).The IENFD value of the ankle in the whole group of PD patients was negatively correlated with the score of COMPASS-31(r=-0.271,P=0.038).4.Compared with LRRK2 G2385R non-mutation group,the mutation group had higher NMSS scale score(P<0.001),LED(P=0.001),COMPASS-31 scale score(P=0.011),more prone to RBD(P=0.012),secretomotor(P=0.035)and bladder dysfunction(P=0.03).ConclusionPD associated with LRRK2 G2385R mutation showed α-synuclein lesion in the skin.But the deposition characteristics of p-syn in skin and clinical manifestations of PD patients with G2385R mutation were different from PD patients without mutation,suggesting that PD associated with LRRK2 G2385R mutation is a relatively independent clinical subtype of PD. |
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