Young-onset Parkinson's Disease Patients Research Articles

Usage of modern technologies like VR therapy, physio therapy along with levodopa in Young-Onset Parkinson's disease patients

Usage of modern technologies like VR therapy, physio therapy along with levodopa in Young-Onset Parkinson's disease patients

Cognitive impairment and dementia in young onset Parkinson's disease.

Patients with young-onset Parkinson's disease (YOPD) have a slower progression. Our aim was to analyze the change in cognitive function in YOPD compared to patients with a later onset and controls. Patients with Parkinson's disease (PD) and controls from the COPPADIS cohort were included. Cognitive function was assessed with the Parkinson's Disease Cognitive Rating Scale (PD-CRS) at baseline (V0), 2-year ± 1month (V2y), and 4-year ± 3months follow-up (V4y). Regarding age from symptoms onset, patients were classified as YOPD (< 50years) or non-YOPD (≥ 50). A score in the PD-CRS < 81 was defined as cognitive impairment (CI): ≤ 64 dementia; 65-80 mild cognitive impairment (MCI). One-hundred and twenty-four YOPD (50.7 ± 7.9years; 66.1% males), 234 non-YOPD (67.8 ± 7.8years; 59.3% males) patients, and 205 controls (61 ± 8.3years; 49.5% males) were included. The score on the PD-CRS and its subscore domains was higher at all visits in YOPD compared to non-YOPD patients and to controls (p < 0.0001 in all analysis), but no differences were detected between YOPD patients and controls. Only non-YOPD patients had significant impairment in their cognitive function from V0 to V4y (p < 0.0001). At V4y, the frequency of dementia and MCI was 5% and 10% in YOPD compared to 25.2% and 22.3% in non-YOPD patients (p < 0.0001). A lower score on the Parkinson's Disease Sleep Scale at baseline was a predictor of CI at V4y in YOPD patients (Adjusted R2 = 0.61; OR = 0.965; p = 0.029). Cognitive dysfunction progressed more slowly in YOPD than in non-YOPD patients.

Genome-Wide Polygenic Score Predicts Large Number of High Risk Individuals in Monogenic Undiagnosed Young Onset Parkinson's Disease Patients from India.

Parkinson's disease (PD) is a genetically heterogeneous neurodegenerative disease with poorly defined environmental influences. Genomic studies of PD patients have identified disease-relevant monogenic genes, rare variants of significance, and polygenic risk-associated variants. In this study, whole genome sequencing data from 90 young onset Parkinson's disease (YOPD) individuals are analyzed for both monogenic and polygenic risk. The genetic variant analysis identifies pathogenic/likely pathogenic variants in eight of the 90 individuals (8.8%). It includes large homozygous coding exon deletions in PRKN and SNV/InDels in VPS13C, PLA2G6, PINK1, SYNJ1, and GCH1. Eleven rare heterozygous GBA coding variants are also identified in 13 (14.4%) individuals. In 34 (56.6%) individuals, one or more variants of uncertain significance (VUS) in PD/PD-relevant genes are observed. Though YOPD patients with a prioritized pathogenic variant show a low polygenic risk score (PRS), patients with prioritized VUS or no significant rare variants show an increased PRS odds ratio for PD. This study suggests that both significant rare variants and polygenic risk from common variants together may contribute to the genesis of PD. Further validation using a larger cohort of patients will confirm the interplay between monogenic and polygenic variants and their use in routine genetic PD diagnosis and risk assessment.

Deep Brain Stimulation and Treatment Outcomes of Young- and Late-Onset (≤55 Years) Parkinson's Disease: A Population-Based Study.

Background: No studies have reported the rate of motor complications (MC) and response to medical and surgical treatment in a population-based cohort of young-onset Parkinson's Disease (YOPD) patients and a cohort of sex-matched late-onset Parkinson's Disease (LOPD).Objective: To assess the outcomes of dopaminergic treatment in YOPD and LOPD, explore treatment-induced MC, medical adjustment, and rate of deep brain stimulation (DBS).Methods: We used the expanded Rochester Epidemiology Project (eREP) to investigate a population-based cohort of YOPD between 2010 and 2015 in 7 counties in Minnesota. Cases with onset ≤55 years of age were included as YOPD. An additional sex-matched cohort of LOPD (onset at ≥56 years of age) was included for comparison. All medical records were reviewed to confirm the diagnoses.Results: In the seven counties 2010–15, there were 28 YOPD patients, which were matched with a LOPD cohort. Sixteen (57%) YOPD had MC, as compared to 9 (32%) LOPD. In YOPD, 9 had motor fluctuations (MF) and Levodopa-induced dyskinesia (LID) together, whereas 3 had LID only and 4 MF only. In LOPD, 3 had MF and LID, 3 MF only, and 3 LID only. Following medical treatment for MC, 6/16 YOPD (38%) and 3/9 (33%) LOPD had symptoms resolution. In YOPD, 11/16 (69%) were considered for DBS implantation, in LOPD they were 2/9 (22%), but only 7 (6 YOPD and 1 LOPD) underwent the procedure. YOPD had significantly higher rates in both DBS candidacy and DBS surgery (respectively, p = 0.03 and p = 0.04). Among DBS-YOPD, 5/6 (83%) had positive motor response to the surgery; the LOPD case had a poor response. We report the population-based incidence of both YOPD with motor complications and YOPD undergoing DBS, which were 1.17 and 0.44 cases per 100,000 person-years, respectively.Conclusion: Fifty-seven percent of our YOPD patients and 32% of the LOPD had motor complications. Roughly half of both YOPD and LOPD were treatment resistant. YOPD had higher rates of DBS candidacy and surgery. Six YOPD and 1 LOPD underwent DBS implantation and most of them had a positive motor response after the surgery.

Impact of Mild Cognitive Impairment on Quality of Life in Young and Typical Onset Parkinson's Disease.

Younger age of onset and mild cognitive impairment (MCI) are both independently associated with poorer quality of life (QOL) in Parkinson's disease (PD). The primary objective was to determine whether MCI differentially impacts QOL in young-onset PD (YOPD) and typical-onset PD (TOPD). YOPD patients (n=77) were diagnosed at age 50 or younger, TOPD (n=77) were diagnosed after age 50, and the groups were matched for cognitive status, education, and disease duration. Patients' cognitive status was classified as MCI or cognitively normal (CN) based on MDS Level II criteria. QOL was assessed using the Parkinson's Disease Questionnaire (PDQ-39). ANCOVAs were conducted for each PDQ-39 subscale, with age of onset and cognitive status as between-subjects factors and several covariates included. An interaction for the Cognition domain revealed that in TOPD, PD-MCI patients reported poorer QOL than CN patients, whereas there was no effect of MCI on cognitive satisfaction in YOPD. There was a main effect of age on Emotional Well-Being, as YOPD reported poorer QOL than TOPD in this domain. There were main effects of cognitive status, with PD-MCI patients reporting worse QOL than CN patients in the domains of Social Support, Communication, ADLs, and Mobility. The interaction revealed that PD-MCI has a greater impact on degree of cognitive concerns ("cognitive QOL") in TOPD versus YOPD. A more nuanced understanding of the effects of age of onset, MCI, and their interactions on QOL in PD will inform interventions aimed at improving quality of life in this population.

Negative α-synuclein pathology in the submandibular gland of patients carrying PRKN pathogenic variants

IntroductionAlpha-synuclein (AS) pathology in the peripheral nervous tissue is a potential pathological biomarker in Parkinson disease (PD). Several studies reported the excellent specificity of the AS pathology of the submandibular gland (SMG) biopsy in PD. PRKN pathogenic variant is one of the major genetic causes of young-onset PD without Lewy pathology in the brain. In this study, we evaluated peripheral AS pathology in the SMG biopsy of patients with PRKN pathogenic variants. MethodsWe enrolled three young-onset PD patients with PRKN pathogenic variants. Two patients were compound heterozygous for trans-exon 3 and 4 deletions and one patient was heterozygous for an exon 2 duplication. We obtained two submandibular gland tissues with core needle biopsy (18G). The neural structures were identified using neurofilament (NF) immunostaining and the neural tissue in the adjacent section were stained with 129 phophorylated α-synuclein (pAS) antibody.Results: pAS staining in the SMG was negative in all cases with the PRKN pathogenic variants. ConclusionsOur data may support the high specificity of the AS pathology of SMG in α-synuclein associated parkinsonism. Future studies evaluating peripheral neural tissue including the SMG in the elderly healthy population are required to validate the role of peripheral AS pathology as a biomarker in PD.

Age-dependent efficacy of subthalamic nucleus deep brain stimulation in young- and late-onset Parkinson's disease based on a 10 year follow-up

IntroductionLong-term efficacy and safety of subthalamic nucleus deep brain stimulation (STN DBS) in patients with young-onset Parkinson's disease (YOPD) and late-onset PD (LOPD) (i.e. motor symptom initial appearance at ages ≤40 and > 40 years, respectively) was compared to identify relationships between PD onset age and the efficacy of DBS. MethodsStatistical analyses compared specific motor and non-motor features among 13 patients with YOPD and 11 with LOPD. Medication reduction patterns and dyskinesia severity scores at baseline and after 1, 3, 5, and 10 years of follow-up were also analyzed using a repeated measures ANOVA tests. Lastly, a correlation analysis identified relationships between the impact of DBS settings (volume of activated tissue) and levodopa equivalent daily dose (LED), dyskinesia severity scores, Unified Parkinson's Disease Rating Scale (UPDRS) part III, and UPDRS part II (disability) scores. ResultsTen years after DBS surgery, the reduction of LED from baseline (85.9 ± 592.6 mg versus 623.2 ± 464.9 mg; p = .023) and levodopa-induced dyskinesia (LID) scores (Unified Dyskinesia Rating Scale [UDysRS] parts III items 16–22; 1.6 ± 2.8 versus 5.5 ± 4.1; p = .013) were significantly lower in YOPD patients than LOPD patients. There were no significant differences between the two groups regarding UPDRS part III score improvement in response to levodopa, psychosis occurrence, or adverse effects. ConclusionTen years after STN DBS surgery, LOPD patients showed greater LED reduction, and YOPD patients showed greater LID improvement, although the general long-term outcomes were similar between YOPD and LOPD patients.

Real-world pharmacological treatment patterns of patients with young-onset Parkinson's disease in Japan: a medical claims database analysis.

Young-onset Parkinson's disease is reported to comprise 5-10% of all Parkinson's disease cases; however, as physicians encounter a limited number of these patients, their treatment patterns are still unclear. We performed a descriptive study using the large Japanese medical claims database to describe the epidemiology and real-world pharmacological treatment patterns of newly diagnosed patients with young-onset Parkinson's disease. Patients aged 21-50years in whom Parkinson's disease was newly diagnosed between January 1, 2005 and March 31, 2016 were included. We excluded individuals with Parkinson's-related diseases and those using antipsychotics to eliminate the possibility of drug-induced parkinsonism. The patients' demographics, comorbidities, prescribing patterns, and changes in levodopa equivalent daily dose were analyzed. We identified 131 newly diagnosed young-onset Parkinson's disease patients (median age, 44.2years). The most common comorbidities were depression (23.7%), hypertension (23.7%), and insomnia (22.9%). Of these patients, 122 were prescribed antiparkinson drugs. During the study period, the proportion of patients who were prescribed dopamine agonists, levodopa, and anticholinergics were 77.1%, 44.3%, and 27.5%, respectively. Dopamine agonists (49.2%) were most commonly prescribed initially, followed by anticholinergics (23.8%), levodopa (19.7%), and others (4.1%). The levodopa equivalent daily dose increased steadily with longer disease duration. Dopamine agonists were most frequently prescribed during the study period and were the initial treatment of choice. We also observed a change in levodopa equivalent daily dose over the disease course. This study provides a descriptive overview of real-world prescribing patterns in young-onset Parkinson's disease patients.

Characteristic Motor and Nonmotor Symptoms Related to Quality of Life in Drug-Naïve Patients with Late-Onset Parkinson Disease

Background/Aims: Unlike young-onset Parkinson disease (YOPD), characteristics of late-onset PD (LOPD) have not yet been clearly elucidated. We investigated characteristic features and symptoms related to quality of life (QoL) in LOPD patients. Methods: We recruited drug-naïve, early PD patients. The patient cohort was divided into 3 subgroups based on patient age at onset (AAO): the YOPD group (AAO <50 years), the middle-onset PD (MOPD) group, and the LOPD group (AAO ≥70 years). Using various scales for motor symptoms (MS) and non-MS (NMS) and QoL, we compared the clinical features and impact on QoL. Results: Of the 132 enrolled patients, 26 were in the YOPD group, 74 in the MOPD group, and 32 in the LOPD group. Among parkinsonian symptoms, patients in the LOPD group had a lower score on the Korean version of the Montreal Cognitive Assessment than the other groups. Logistic regression analysis showed genitourinary symptoms were related to the LOPD group. Linear regression analysis showed both MS and NMS were correlated with QoL in the MOPD group, but only NMS were correlated with QoL in the LOPD group. Particularly, anxiety and fatigue affected QoL in the LOPD group. Conclusion: LOPD patients showed different characteristic clinical features, and different symptoms were related with QoL for LOPD than YOPD and MOPD patients.

Reduced saccadic velocity and pupillary width in young onset Parkinson’s disease

BackgroundPatients with Young onset Parkinson disease patients (YODP) are individuals with motor complications identical to late onset Parkinson’s disease (PD) but onset in early age. YOPD is a specific subgroup of PD and their performance on saccadic eye movements is not well established. This study evaluated saccadic eye movements in patients with YOPD (< 40 years at onset of illness). MethodsEye movements were recorded during saccadic eye movement tasks, induced by presentation of a visual target and reflexive saccadic task was administered. ResultsYOPD patients showed reduced saccadic velocity on reflexive saccadic task (Gap task) as compared to their age matched healthy controls. Additionally, pupil width in gap period and at saccade onset was measured. Pupil width was significantly smaller in patients with YOPD as compared to control subjects. ConclusionsReduced saccadic velocity implies that Parkinson’s disease affects saccadic circuitry in patients with YOPD reflecting impaired circuitry at the brainstem level. The reduced pupillary response in gap condition is attributed to deficits in motor preparedness in patients compared to controls.

Screening for TMEM230 mutations in young-onset Parkinson's disease

TMEM230 gene mutations have been reported to be linked with Parkinson's disease (PD) recently. To investigate the prevalence of this gene in southeastern Chinese patients with PD, whole exome sequencing was performed in young-onset and familial PD patients and healthy controls in our Asian population. One heterozygous missense p.Phe121Ser mutation was detected in a healthy 76-year-old control subject and no other TMEM230 mutations were found in PD patients and controls. These data suggest that TMEM230 mutation might be a rare cause of Chinese familial and sporadic PD patients and a larger sample size will be needed to evaluate the association of TMEM230 polymorphic variants with PD.

Quality of sleep in young onset Parkinson's disease: Any difference from older onset Parkinson's disease?

Background: Sleep disorders occur commonly in Parkinson's disease and are often under-recognized and under treated in clinical practice. Objectives: To determine the quality of sleep in patients with Young onset Parkinson's disease (YOPD) and to note whether there is any difference in quality of sleep from those patients with older onset Parkinson's disease (OOPD). Methods: One hundred and fifty six patients with Parkinson's disease (YOPD-51, OOPD-105) were clinically examined and quality of sleep was determined using Pittsburgh sleep quality index (PSQI), Parkinson's disease Sleep Scale (PDSS) and Epworth Sleep Scale (ESS). Other scales included Unified Parkinson's Disease Rating Scale -part III (UPDRS-III), Hoehn & Yahr Stage, Mini Mental Status Examination, Hamilton anxiety rating scale and Hamilton depression rating scale. Results: The frequency of insomnia was higher in OOPD (55.2%) as compared to YOPD (27.5%) group (p1⁄4 0.001). The frequency of nightmareswas lower in YOPD (7.8%) when compared to OOPD (24.8%) group (p1⁄4 0.012). The mean hours of actual sleep per night were higher in YOPD patients. Global PSQI score was better in YOPD indicating good overall sleep quality in YOPD patients. The total ESS score was significantly lower in YOPD (p 1⁄4 0.019). The total PDSS score was significantly better in YOPD patients (p 1⁄4 0.018). Conclusions: Patients with YOPD had an overall better quality of sleep with lesser incidence of insomnia, nightmares, daytime sleepiness and restlessness during sleep. © 2015 Elsevier Ltd. All rights reserved.

Quality of sleep in young onset Parkinson's disease: Any difference from older onset Parkinson's disease.

Sleep disorders occur commonly in Parkinson's disease and are often under-recognized and under treated in clinical practice. To determine the quality of sleep in patients with Young onset Parkinson's disease (YOPD) and to note whether there is any difference in quality of sleep from those patients with older onset Parkinson's disease (OOPD). One hundred and fifty six patients with Parkinson's disease (YOPD-51, OOPD-105) were clinically examined and quality of sleep was determined using Pittsburgh sleep quality index (PSQI), Parkinson's disease Sleep Scale (PDSS) and Epworth Sleep Scale (ESS). Other scales included Unified Parkinson's Disease Rating Scale -part III (UPDRS-III), Hoehn & Yahr Stage, Mini Mental Status Examination, Hamilton anxiety rating scale and Hamilton depression rating scale. The frequency of insomnia was higher in OOPD (55.2%) as compared to YOPD (27.5%) group (p = 0.001). The frequency of nightmares was lower in YOPD (7.8%) when compared to OOPD (24.8%) group (p = 0.012). The mean hours of actual sleep per night were higher in YOPD patients. Global PSQI score was better in YOPD indicating good overall sleep quality in YOPD patients. The total ESS score was significantly lower in YOPD (p = 0.019). The total PDSS score was significantly better in YOPD patients (p = 0.018). Patients with YOPD had an overall better quality of sleep with lesser incidence of insomnia, nightmares, daytime sleepiness and restlessness during sleep.

Long-term outcome of young onset Parkinson's disease after subthalamic stimulation—A cross-sectional study

ObjectiveAge of onset is considered a poor prognostic factor for subthalamic deep brain stimulation (STN-DBS) outcome in the case of Parkinson's disease (PD). The goal of current study is to identify the long-term impact of STN-DBS for young onset PD (YOPD) patients. Methods17 YOPD patients with a mean disease onset at 32.3 years were prospectively followed up at 1, 2, 5 and 7 years after STN-DBS. Unified Parkinson's disease rating scale (UPDRS) was evaluated in 4 combinations of Med/DBS on/off. ResultsUPDRS part II–IV improved significantly 7 years after operation. While a slowly progressive worsening of levodopa response on part III, synergistic effect of medication and stimulation consistently improves motor disabilities. STN-DBS could remarkably reduce levodopa equivalent daily dose at 7 years. The morbidity rates were low. However, these patients seem to have more transient stimulation dyskinesia (47.1%) and dopamine dysregulation syndrome (11.8%) after surgery. ConclusionsSTN-DBS remains effective to improve motor disabilities over 7 years for YOPD and is a safe procedure concerning cognitive outcome and morbidity. However, stimulation dyskinesia and dopamine dysregulation syndrome deserve attention for the causal relationship between DBS surgery and behavioral outcomes.

Anxiety disorders in Parkinson's disease: Prevalence and risk factors

Anxiety disorders are common in Parkinson's disease (PD) patients, yet are poorly studied. We examined the prevalence of anxiety disorders in PD, investigated the association between anxiety, and presentation and progression of PD, and studied for the first time the contribution of putative risk factors for anxiety in PD. A case-series of 79 PD patients recruited from neurology out-patient clinics was examined for anxiety disorders using the DSM-IV criteria. The Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr Staging of PD were employed to understand the relationship between anxiety disorders, and the clinical presentation and severity of PD. A validated survey assessed putative risk factors for anxiety in PD. Twenty-five percent of PD patients were diagnosed with anxiety. Panic disorder, generalised anxiety disorder and social phobia were prevalent anxiety disorders. Comorbid depression with anxiety was observed (14%). The severity but not the duration of PD was positively related to anxiety. PD patients with postural instability and gait dysfunction symptom clustering were more likely to experience anxiety than tremor-dominant patients. While levodopa dosage had no relationship to anxiety, experience of dyskinesias or on/off fluctuations increased the risk. Lateralisation of PD had no association with anxiety. Anxiety disorders decreased with age and young onset PD patients were more likely to experience anxiety than the late onset subjects. Anxiety adds to the complexity of PD, lowering patients' quality of life. Future research can be directed to identify reactive and organic nature of anxiety in PD.

Sexual and Relationship Satisfaction among Persons with Young-Onset Parkinson's Disease

Parkinson's disease (PD) presents unique personal and social challenges, particularly for those with onset before the age of 50 years. The aim of this article is to evaluate sexual and non-sexual aspects of relationship satisfaction among persons with young-onset PD and their partners. The main outcome measures were Index of Sexual Satisfaction (ISS) and Golombok-Rust Inventory of Marital State (GRIMS). Persons with PD (PWP) and partners who attended the 2005 National Parkinson Foundation Young Onset Network Conference were asked to complete a survey. Each survey included demographics, a clinical history questionnaire, the Beck Depression Inventory (BDI), ISS, and GRIMS. Sixty PWP (63% men, 85% in a relationship) responded to the survey. Median age was 50 years (range 29-62), with a median age at symptom onset of 43 years (range 17-55). ISS scores indicated clinically significant sexual dissatisfaction in 37%. Relationship dissatisfaction measured by the GRIMS was scored as "poor" or worse in 57%. Depressive symptomatology was severe in 19% and mild in 33%. Sexual dissatisfaction (ISS) correlated with relationship dissatisfaction (GRIMS) (correlation coefficient [CC] = 0.58, P < 0.001). Relationship dissatisfaction (GRIMS) correlated with depressive symptomatology (BDI) (CC = 0.38, P = 0.007). No correlations were found with any demographic or disease characteristics. Thirty-two couples (both the PWP and their partner) completed the surveys. Sexual and relationship dissatisfaction among PWP paralleled that of their partner (ISS: CC = 0.48, P = 0.005; GRIMS: CC = 0.61, P < 0.001). Depressive symptomatology of the PWP correlated with their partners' relationship dissatisfaction (CC = 0.46, P = 0.010). In this study, sexual and relationship dissatisfaction were prevalent among young-onset PD patients. PD patients were similar to their partners in their level of sexual and relationship dissatisfaction. The degree of dissatisfaction did not correlate with demographics or self-reported disease characteristics. Self-reported depressive symptomatology among PD patients was adversely associated with both their and their partner's relationship satisfaction. Wiel

Impact of Subthalamic Nucleus Stimulation on Young-Onset Parkinson’s Disease

Objective. To clarify the efficacy of subthalamic nucleus (STN) stimulation in young-onset Parkinson's disease (PD), we compared the effects of STN stimulation on the motor symptoms between young-onset PD (YOPD) and late-onset PD (LOPD). Methods. We analyzed the effects of STN stimulation on motor function and motor fluctuations in 15 patients with YOPD, and 113 patients with LOPD who underwent STN stimulation during the same period. The Unified Parkinson's Disease Rating Scale (UPDRS) was evaluated during the on-period and off-period, which are defined as the times at which the motor symptoms are the best and worst during the daily active time with sustaining anti-parkinsonian drugs. The dyskinesia severity rating scale (DSRS) also was employed to assess the severity of peak-dose dyskinesia. We analyzed the changes in levodopa equivalent daily dose (LED), motor fluctuations, DSRS, and UPDRS part 3 score after STN stimulation, and compared the changes in each score between the two groups (YOPD vs. LOPD). Results. The LED was reduced, and the on-off motor fluctuation index, dyskinesia rating scale score (on-period), and UPDRS part 3 score (on- and off-periods) were improved in both the YOPD and LOPD groups. The improvement rates of the UPDRS part 3 scores in both the on- and off-periods in the YOPD group were superior to those in the LOPD group. The results of multivariate logistic regression analysis demonstrated that YOPD itself is the best responder to STN stimulation. Conclusions. STN stimulation can reduce the LED and improve motor fluctuations in patients with YOPD. The effects of STN stimulation on the motor symptoms of YOPD patients are superior to those in LOPD. The present findings suggest that YOPD patients suffering from several problems related to pharmacological therapy are probably good candidates for STN stimulation.

MultipleLRRK2variants modulate risk of Parkinson disease: a Chinese multicenter study

We and others found two polymorphic LRRK2 (leucine-rich repeat kinase 2) variants (rs34778348:G>A; p.G2385R and rs33949390:G>C; p.R1628P) associated with Parkinson disease (PD) among Chinese patients, but the common worldwide rs34637584:G>A; p.G2019S mutation, was absent. Focusing exclusively on Han Chinese, we first sequenced the coding regions in young onset and familial PD patients and identified 59 variants. We then examined these variants in 250 patients and 250 control subjects. Among the 17 polymorphic variants, five demonstrated different frequency in cases versus controls and were considered in a larger sample of 1,363 patients and 1,251 control subjects. The relative risk of an individual with both p.G2385R and p.R1628P is about 1.9, and this is reduced to 1.5-1.6 if the individual also carries rs7133914:G>C; p.R1398H or rs7308720:C>A: p.N551K. The risk of a carrier with p.R1628P is largely negated if the individual also carries p.R1398H or p.N551K. In dopaminergic neuronal lines, p.R1398H had significantly lower kinase activity, whereas p.G2385R and p.R1628P showed higher kinase activity than wild type. We provided the first evidence that multiple LRRK2 variants exert an individual effect and together modulate the risk of PD among Chinese.

A Multitracer Dopaminergic PET Study of Young-Onset Parkinsonian Patients With and Without Parkin Gene Mutations

The impact of parkin gene mutations on nigrostriatal dopaminergic degeneration is not well established. The purpose of this study was to characterize by PET using (18)F-fluoro-l-3,4-dihydroxyphenylalanine ((18)F-fluoro-l-DOPA), (11)C-PE2I, and (11)C-raclopride the pattern of dopaminergic lesions in young-onset Parkinson disease (YOPD) patients with or without mutations of the parkin gene and to correlate the clinical and neuropsychologic characteristics of these patients with PET results. A total of 35 YOPD patients were enrolled (16 with parkin mutation, 19 without). The uptake constant (K(i)) of (18)F-fluoro-l-DOPA and the binding potential (BP) of (11)C-PE2I (BP(DAT)) and of (11)C-raclopride (BP(D2)) were calculated in the striatum. Comparisons were made between the 2 groups of YOPD and between controls and patients. For each radiotracer, parametric images were obtained, and statistical parametric mapping (SPM) analysis using a voxel-by-voxel statistical t test was performed. Correlations between the cognitive and motor status and PET results were analyzed. In YOPD patients, (18)F-fluoro-l-DOPA K(i) values were reduced to 68% (caudate) and 40% (putamen) of normal values (P < 0.0001). This decrease was symmetric and comparable for nonparkin and parkin patients. No correlation was found between the K(i) values and cognitive or motor status. (11)C-PE2I BP(DAT) values in YOPD patients were decreased to 56% (caudate) and 41% (putamen) of normal values (P < 0.0001) and did not differ between the 2 YOPD populations. The mean (11)C-raclopride BP(D2) values were reduced to 72% (caudate) and 84% (putamen) of the normal values (P < 0.02) and did not differ between nonparkin and parkin patients. SPM analyses showed in patients an additional decrease of (11)C-raclopride in the frontal cortex and a decrease of (18)F-fluoro-l-DOPA and (11)C-PE2I uptake in the substantia nigra bilaterally (P < 0.05, false-discovery rate-corrected). Carriers of parkin mutations are indistinguishable on PET markers of dopaminergic dysfunction from other YOPD patients with long disease duration.

Non-synonymous GIGYF2 variants in Parkinson’s disease from two Asian populations

Mutations in the GIGYF2 gene at the PARK11 locus have recently been reported in Parkinson's disease (PD). However, the pathogenicity of some of these mutations has been debated. We conducted a comprehensive genetic analysis of the entire GIGYF2 gene in a cohort of young onset and familial PD patients, followed up with screening of specific variants in a separate group of PD and healthy controls. A total of 850 study subjects [450 Parkinson's disease (PD) patients and 400 controls] from two Asian countries were included. Our analysis revealed 17 variants distributed across the entire GIGYF2 gene. Ten of these were novel variants out of which eight were non-synonymous (all heterozygous). Out of these eight, half were novel polymorphic variants (0.2-2%) whereas four were novel non-synonymous variants which were not detected in healthy controls. The seven PD patients with non-synonymous variants had a mean age and age at onset of 55.3 and 50.9 years. All had typical features of PD and only one had a positive family history. The collective frequency of these non-synonymous variants was higher in PD compared to controls (1.6 vs. 0%, P = 0.016, relative risk 1.9, 95% CI 1.2, 1.9). None of the previously reported pathogenic mutations in Italian and French patients were present in our cohort. Our data suggest that GIGYF2 is unlikely to play a major role in our Asian populations. Rare non-synonymous variants appeared to be enriched in our PD patients compared to healthy controls. However, in vivo functional studies and segregation analysis in large pedigrees will be needed to determine if these single heterozygous variants represent rare mutations, risk alleles or benign polymorphisms.