Circuit Dysfunction And Related Behavioral Symptoms In Parkinson's Disease With REM Sleep Behavior Disorder

Background Parkinson's disease(PD)is a common neurodegenerative disease in older people,neuropathologically characterized by degeneration of dopaminergic neurons in the substantia nigra compacta coupled with intracytoplasmic inclusions known as Lewy bodies,and clinically characterized by rest tremor,rigidity,bradykinesia and postural instability.In addition to the typical motor symptoms,a large number of non-motor symptoms are common in PD,including hyposmia,gastrointestinal and genitourinary symptoms,cognitive impairment,sleep disorders,depression,and psychiatric symptoms.Dopamine deficiency does not explain all of PD symptoms,and dopamine replacement therapy could not relieve all of them.Therefore,PD is a complex multisystem neurodegenerative disease involving both dopaminergic and nondopaminergic pathological mechanisms.For example,it has been acknowledged that dopaminergic,cholinergic and noradrenergic systems are involved in cognitive impairment in PD.Many PD symptoms result directly from neurodegeneration;while others are driven by aberrant activity patterns in surviving neurons.Rapid eye movement sleep behavior disorder(RBD)is a parasomnia characterized by REM sleep without atonia and dream-enacting behaviors during REM sleep.RBD is closely related to ?-synuclein diseases,especially PD.RBD is by far the strongest clinical predictor of PD,it can precede the onset of motor symptoms by several years.Moreover,the presence of RBD in PD patients often represent a more severe clinical phenotype,including more severe motor and non-motor symptoms,and more rapid disease progression.Most notably,the presence of RBD is a vital risk for mild cognitive impairment in PD.Moreover,impulse control disorder(ICD),as a common and disturbing nonmotor symptom,has also been reported to be associated with RBD.Despite its important clinical relevance,the mechanism underlying RBD remains unclear.In recent years,neuroimaging techniques have been widely used in investigating neural mechanisms.Radionuclide imaging studies adopt specific tracers to visualize the neurotransmitter system in vivo.Functional connectivity analysis based on resting-state f MRI can reveal the functional networks related to neurotransmitters.In addition,the Parkinson's Progression Markers Initiative database provides conditions for investigating longitudinal imaging and clinical progression in patients with PD.ObjectiveBased on specific hypotheses,the present study aimed to explore the neural basis of PD with RBD from the perspective of neurotransmitter systems,by using resting state f MRI and single photon emission computed tomography techniques.(1)Previous studies have found that patients with PD and RBD have more severe clinical phenotypes,the present study aimed to investigate changes in local and global resting state activity in dopaminergic,cholinergic and noradrenergic pathways in patients with PD and RBD.(2)Previous cross-sectional studies have revealed a more rapid disease progression in patients with PD and RBD,however,longitudinal striatal dopaminergic imaging studies were still lacking.The present study aimed to use the PPMI database to investigate whether patients with PD and RBD show more rapid striatal dopaminergic loss.(3)Previous studies have shown that ICD is associated with RBD in PD,however,the results were controversial.Their association has not been investigated in drug-na?ve patients and longitudinal studies were lacking.The present study aimed to use the PPMI database to explore whether the presence of RBD at the onset of PD is related to more newly-onset ICD during a median of 5-year follow-up.Methods(1)According to clinical history and polysomnography,patients were divided into the PD-RBD group and the PD-n RBD group.For f MRI analyses,the transmitter-producing nuclei were selected as regions of interest,including the substantia nigra,the ventral tegmental area,the locus ceruleus nucleus,and the nucless basalis of Meynert.Functional connectivity between these regions of interest and the whole brain was calculated and compared between groups.(2)The data was obtained from the PPMI database.The patients were dividedn into the PD-p RBD group and the PD-np RBD group according to the RBD screening questionnaire.DAT scans were implemented at baseline,one year later,two years later and four years later.DAT binding levels were calculated for each striatal subregion(bilateral caudate and putamen).The more affected side and the less affected side of the striatum were defined according to the severity of motor symptoms.Repeated measure analysis of variance was used to compare the changes of DAT binding level in the striatum of the two groups over time.(3)The data was obtained from the PPMI database.Newly-diagnosed untreated PD patients were divided into the PD-p RBD group and the PD-np RBD group according to the baseline RBD symptoms.The QUIP-RS was used to diagnose ICD at baseline and annually thereafter.Logistic regression was used to compare the relationship between the presence of RBD and the prevalence of ICD at baseline.Patients who had no ICD symptoms at baseline were then included in a longitudinal cohort study.Cox regression analysis was used to compare the risk of newly-onset ICD in the two groups during a median of 5-year follow-up.Results(1)There were no significant differences in age,sex,education,disease course and severity between the PD-RBD group and the PD-n RBD group.Compared with the healthy controls,the local activity of the transmitter-producing nucleus was enhanced in PD patients,and there was no significant difference between the PD-RBD group and the PD-n RBD group.Patients in the PD-RBD group exhibited significantly decreased functional connectivity than the healthy controls or patients in the PD-n RBD group,including decreased functional connectivity between the substantia nigra and the bilateral cerebellum,bilateral middle temporal gyrus,bilateral frontal lobe,left insula,thalamus and the cingulate gyrus;decreased functional connectivity between the ventral tegmental area and the bilateral rectus gyrus and orbitofrontal cortex;as well as decreased functional connectivity between the nucless basalis of Meynert and the left parietal lobe.(2)There were no significant differences in age,gender,onset side and disease duration between the groups,but patients in the PD-p RBD group showed more severe motor symptoms and cognitive impairment.Similarly,patients in the PD-p RBD group showed a more severe reduction in striatal DAT binding at baseline and at follow-up.Repeated measure ANOVA showed that the DAT binding level showed faster decrease in the caudate in the PD-p RBD group than in the PD-np RBD group.The striatal DAT binding levels were significantly associated with motor symptoms,but not cognitive impairment.(3)At baseline,the presence of p RBD was significantly correlated with the prevelance of ICD.After controlling for possible confounders(age of onset,gender,disease duration,disease severity,anxiety,and depression),the risk of ICD in the PD-p RBD group was higher than that in the PD-np RBD group(OR=2.56,P =0.003).In the longitudinal cohort,multiple Cox regression showed that the presence of baseline p RBD was an independent risk factor for incident ICD during follow-up(HR=1.648,P=0.028).Other predictors of ICD included a younger age of onset(HR=0.973,P =0.026)and a higher state-trait anxiety score(HR=1.040,P <0.001).Conclusion(1)Patients with PD with RBD had abnormal resting-state functional connectivity between the neurotransmitter producing sites and the rest regions of the brain,which may account for the RBD-related clinical phenotype in PD.(2)Patients with PD and RBD have more severe and more rapid striatal dopaminergic loss,which may explain the more severe clinical phenotype in PD associated with RBD,especially the more rapid motor symptom progression.(3)Baseline RBD is an independent risk factor for ICD,and ICD symptoms need to be monitored more closely in PD patients with RBD,especially in patients receiving dopamine agonists.