Leucine-rich Repeat Kinase 2 G2385R Research Articles

Connectivity of corticostriatal circuits in nonmanifesting LRRK2 G2385R and R1628P carriers.

Neuroimaging studies have shown that the functional connectivity (FC) of corticostriatal circuits in nonmanifesting leucine-rich repeat kinase 2 (LRRK2) G2019S mutation carriers mirrors neural changes in idiopathic Parkinson's disease (PD). In contrast, neural network changes in LRRK2 G2385R and R1628P mutations are unclear. We aimed to investigate the FC of corticostriatal circuits in nonmanifesting LRRK2 G2385R and R1628P mutation carriers (NMCs). Twenty-three NMCs, 28 PD patients, and 29 nonmanifesting noncarriers (NMNCs) were recruited. LRRK2 mutation analysis was performed on all participants. Clinical evaluation included MDS-UPDRS. When compared to NMNCs, NMCs showed significantly reduced FC between the caudate nucleus and superior frontal gyrus and cerebellum, and between the nucleus accumbens and parahippocampal gyrus, amygdala, and insula. We also found increased striatum-cortical FC in NMCs. Although the corticostriatal circuits have characteristic changes similar to PD, the relatively intact function of the sensorimotor striatum-cortical loop may result in less possibility of developing parkinsonian motor symptoms for the NMCs. This study helps explain why LRRK2 G2385R and R1628P mutations are risk factors rather than pathogenic mutations for PD and suggests that various LRRK2 mutations have distinct effects on neural networks.

Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson’s disease

Missense variants in leucine-rich repeat kinase 2 (LRRK2) lead to familial and sporadic Parkinson’s disease (PD). The pathological features of PD patients with LRRK2 variants differ. Here, we report an autopsy case harboring the LRRK2 G2385R, a risk variant for PD occurring mainly in Asian populations. The patient exhibited levodopa-responsive parkinsonism at the early stage and visual hallucinations at the advanced stage. The pathological study revealed diffuse Lewy bodies with neurofibrillary tangles, amyloid plaques, and mild signs of neuroinflammation. Biochemically, detergent-insoluble phospho-α-synuclein was accumulated in the frontal, temporal, entorhinal cortexes, and putamen, consistent with the pathological observations. Elevated phosphorylation of Rab10, a substrate of LRRK2, was also prominent in various brain regions. In conclusion, G2385R appears to increase LRRK2 kinase activity in the human brain, inducing a deleterious brain environment that causes Lewy body pathology.

A 10-Year Community-Based Study of Leucine-Rich Repeat Kinase 2 G2385R Carriers' Conversion to Parkinson's Disease.

The G2385R variant of leucine-rich repeat kinase 2 (LRRK2) is mainly associated with Parkinson's disease(PD) in Asian populations. The aim of this study was to investigate the PD conversion rate and clinical characteristics of LRRK2 G2385R nonmanifesting carriers. All participants were from the community-based longitudinal cohort of Shanghai Ruijin Hospital. The G2385R carriers and noncarriers were screened by Sanger sequencing and received face-to-face interviews at baseline and follow-up assessments. The Kaplan-Meier method was used to compare the conversion rate of PD. Cox regression models were used to estimate the risk of G2385R variant for PD. In the combined cohort, 26 (7.9%) people developed PD in 329 carriers versus 9 (2.6%) in 345 noncarriers (P= 0.0016). Cox regression model confirmed that the G2385R variant was a strong risk factor for PD in a Chinese population older than 50 years (hazard ratio,3.314; 95% confidence interval,1.551-7.078; P= 0.002). No difference was found in clinical symptoms between carriers and noncarriers. We confirmed an increased conversion of PD in leucine-rich repeat kinase 2 G2385R carriers during a 10-year follow-up. © 2022 International Parkinson and Movement Disorder Society.

Penetrance of Parkinson disease LRRK2 G2385R-associated variant in the Chinese population.

Penetrance estimates of the leucine-rich repeat kinase 2 (LRRK2) variants for Parkinson disease (PD) vary widely. G2385R is one of the most common LRRK2 variants in Asian populations, and its penetrance is currently unknown. We aimed to estimate the penetrance of G2385R in the Chinese population. The G2385R variant was tested by Sanger sequencing in 6386 participants older than 50 years, all from the community cohort established by Shanghai Ruijin Hospital in 2009-2011. G2385R carriers and matched noncarriers underwent a brief questionnaire survey (including sex, current age, PD diagnosis, and age at onset) and face-to-face PD assessment during 2020-2021. The penetrance of PD was estimated by the Kaplan-Meier method. A total of 396 G2385R carriers and 415 noncarriers were included, after excluding those with a baseline diagnosis of PD or unwilling to participate. In G2385R carriers, the penetrance of PD was 1.64% at 70 years, 10.26% at 80 years, and 18.49% at 90 years, and reached 25.90% at 95 years. The penetrance of PD in G2385R carriers was higher than in noncarriers (p= 0.0071). In noncarriers, only 0%, 3.72%, and 9.66% developed parkinsonism by 70, 80, and 90 years of age. Among carriers and noncarriers, there were no statistically significant differences in penetrance comparisons between males and females, or between urban and rural. The lifetime penetrance of LRRK2 G2385R in the Chinese population was 25.9%. The penetrance modifier of G2385R in our study was age-related. Further investigation of genetic and environmental modifiers affecting G2385R penetrance is warranted.

Sex effects on clinical features in LRRK2 G2385R carriers and non-carriers in Parkinson's disease

BackgroundDifferences of genotypes between male and female have been studied in Parkinson’s disease (PD), but limited research has focused on the comparison between sexes with LRRK2 G2385 variant.ObjectiveThe aim of this study was to explore sex effects in the same genetic subtype and role of leucine-rich repeat kinase 2 (LRRK2) G2385R variants in the same sex in PD.Methods613 PD patients were recruited from the Movement Disorders Clinic in Ruijin Hospital. We did not include healthy controls in this study. The data collected includes demographic information, disease history, scores of motor and non-motor symptoms scales, midbrain transcranial sonography and DNA. Binary logistic regression analysis was performed to evaluate the association between clinical features and sex in LRRK2 G2385R carriers and non-carriers, as well as the association between the clinical features and LRRK2 G2385R variants in male and female sex.ResultsSex distribution is similar in LRRK2 G2385R carriers and non-carriers. In male sex, LRRK2 G2385R carriers showed lower risk in cognitive impairment compared with non-carriers (OR = 0.301, p = 0.003, 95%CI 0.135–0.668). In female sex, LRRK2 G2385R carriers showed lower risk in autonomic dysfunction compared with non-carrier (OR = 0.401, p = 0.040, 95%CI 0.167–0.960). In LRRK2 G2385R non-carriers, female sex showed lower risk of impairment in activity of daily living (OR = 0.610, p = 0.021, 95%CI 0.400–0.928), excessive daytime sleepiness (OR = 0.555, p = 0.007, 95%CI 0.361–0.853), substantia nigra hyperechogenicity (OR = 0.448, p = 0.019, 95%CI 0.228–0.878), autonomic dysfunction frequency (OR = 0.626, p = 0.016, 95%CI 0.428–0.917) and higher risk in mood disorders (OR = 1.691, p = 0.022, 95%CI 1.078–2.654) compared with male. In LRRK2 G2385R carriers, female sex showed a lower risk of autonomic dysfunction (OR = 0.294, p = 0.024, 95%CI 0.102–0.849) compared with male.ConclusionIn contrast to male PD patients, a more benign disease course was observed in female in both LRRK2 G2385R carriers and non-carriers. However, sex differences were less notable in PD with LRRK2 G2385R variants.

Prevalence of pre-diagnostic symptoms did not differ between LRRK2-related, GBA-related and idiopathic patients with Parkinson's disease

IntroductionGlucocerebrosidase (GBA) mutations and leucine-rich repeat kinase 2 (LRRK2) variants are the most common genetic risk factors for late-onset Parkinson's disease (PD). In this study, we aimed to investigate the differences in pre-diagnostic symptoms of PD associated with the variants. MethodsThe participants were recruited from 24 centers across China and genotyped for LRRK2 G2385R and R1628P variants and GBA L444P mutation. Participants were surveyed with structural questionnaires for history of environmental exposure and living habits and interviewed to collect the time at onset of each symptoms before diagnosis. We compared the cumulative prevalence and manifestation pattern of symptoms between groups using multiple logistic regression, adjusting age and gender. ResultsTotal 1799 PD patients were recruited, including 226 patients with LRRK2 G2385R or R1628P variant, 44 with GBA L444P mutation, three with both LRRK2 and GBA mutation, and 1526 idiopathic patients. The cumulative prevalence of non-motor and typical motor symptoms did not differ between groups before diagnosis (P > 0.05). The manifestation sequences of non-motor symptoms were indistinguishable between the LRRK2-carriers, GBA-carriers, and idiopathic PD subjects, and followed the sequence of constipation, hyposmia, sleep disorders, anxiety and depression, sexual dysfunction, urinary incontinency, dizziness and cognition. Slightly higher prevalence of hypomimia and micrographia were detected in the GBA-carriers. ConclusionsThe prevalence of pre-diagnostic symptoms is almost indistinguishable between the LRRK2-carriers, GBA-carriers, and idiopathic PD before diagnosis; the sequence of the manifestation of non-motor symptoms largely conforms to the Braak stage for both genetic-related and idiopathic late-onset PD.

Fatigue correlates with LRRK2 G2385R variant in Chinese Parkinson's disease patients

IntroductionFatigue is common in patients with Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) G2385R variant predisposes individuals to develop PD in China. The aim of this study was to evaluate whether the LRRK2 G2385R variant is associated with fatigue in patients with PD. MethodsFatigue was evaluated by the Parkinson Fatigue Scale (PFS) in 329 PD patients and 180 controls, a cut-off score of ≥3.3 was used to define the presence of fatigue. All the enrolled PD patients were assessed by a comprehensive battery of motor and non-motor questionnaires. PD patients were genotyped for the G2385R variant. Associations of fatigue with the clinical assessments and with the G2385R variant in PD patients were analyzed by logistic regression. ResultsFatigue frequency was 55.62%. A logistic regression model found that the female sex (OR = 10.477; 95%CI: 2.806–39.120; p < 0.001), motor function (OR = 1.060; 95%CI: 1.012–1.110; p = 0.013), sleep disturbance (OR = 0.943; 95%CI: 0.910–0.976; p = 0.001) and depression severity (OR = 0.843; 95%CI: 0.736–0.965; p = 0.013) collectively predict the presence of fatigue in PD patients. After adjustment for demographics and associated clinical factors, the G2385R variant was associated with an increased risk for the presence of fatigue (OR = 10.699; 95% CI = 2.387–47.958; p = 0.002) in the PD population in this study. ConclusionWe confirm that fatigue in PD patients is common, and we have strengthened the associations between fatigue and female sex, motor severity and non-motor symptoms, particularly depression and sleep disturbances. Overall, we found that carriers of the G2385R variant were more prone to fatigue than non-carriers in PD patients.

Effect of a Leucine-rich Repeat Kinase 2 Variant on Motor and Non-motor Symptoms in Chinese Parkinson's Disease Patients.

The G2385R variant of the leucine-rich repeat kinase 2 (LRRK2) is strongly associated with Parkinson’s disease (PD) in Asian populations. However, it is still unclear whether the clinical phenotype of PD patients with the G2385R variant can be distinguished from that of patients with idiopathic PD. In this study, we investigated motor and non-motor symptoms of LRRK2 G2385R variant carriers in a Chinese population. We genotyped 1031 Chinese PD patients for the G2385R variant of the LRRK2 gene, and examined the demographic and clinical characteristics of LRRK2 G2385R variant carrier and non-carrier PD patients. LRRK2 G2385R variant carriers were more likely to present the postural instability and gait difficulty dominant (PIGD) phenotype. This variant was also significantly associated with motor fluctuations and the levodopa equivalent dose (LED). G2385R variant carriers had higher REM sleep behavior disorder (RBD) screening questionnaire (RBDSQ) score and more RBD symptoms compared with non-carriers. We concluded that the G2385R variant could be a risk factor for the PIGD phenotype, motor fluctuations, LED values and RBD symptoms.

Non-motor symptoms in Chinese Parkinson's disease patients with and without LRRK2 G2385R and R1628P variants.

Non-motor symptoms (NMS) are common among patients with Parkinson's disease (PD). However, reports on NMS in Chinese PD population are scarce. Little is known about NMS in patients with Asian specific leucine-rich repeat kinase 2 (LRRK2) variants in G2385R and R1628P. This study aimed to elucidate the clinical characteristics of NMS in Chinese PD patients and to ascertain if there were differences in NMS between PD patients with and without LRRK2 variants. A multicenter, observational study was conducted with 1,225 sporadic PD (sPD) patients recruited from a PD cohort of the Chinese National Consortium on neurodegenerative diseases, 163 participants had the LRRK2 variants. The Non-motor Symptom Questionnaire (NMSQ) was used to screen for the presence of NMS. This study found the majority of sPD patients (97.6%) had at least one NMS. A mean of 8.72 NMS (SD=5.43) was reported per patient. Forgetfulness, constipation and daytime sleepiness were found to be the most frequent NMS. Moreover, the number of NMS was positively correlated with the age, disease duration, Hoehn & Yahr stage and the motor scores of the unified Parkinson's disease rating scale. Although no discrepancy was found in the number of NMS between sPD patients with and without LRRK2 variants, nocturia was less common in LRRK2 variants carriers than in non-carriers (P=0.045). NMS appear to be prevalent in Chinese sPD population. There are no differences in the NMS phenotype between LRRK2 and no LRRK2 patients.

MAPT IVS1+124 C>G modifies risk of LRRK2 G2385R for Parkinson's disease in Chinese individuals

Variants of the MAPT gene have been suggested to be associated with Parkinson's disease (PD) and to modify the risk for leucine-rich repeat kinase 2 (LRRK2) Parkinsonism. However, this has not been confirmed in Asians with ethnicity-specific variants of MAPT and LRRK2. In this study, Asian-specific LRRK2 p.G2385R variant and IVS1+124 C>G, a functional single-nucleotide polymorphism located in the MAPT promoter region, were genotyped in 561 Chinese PD patients and 556 control subjects. Allelic and genotypic frequencies of the 2 variants were compared between cases and control subjects independently and in combination. As a result, the LRRK2 p.G2385R variant alone was associated with an increased risk for PD (Odds ratio, 1.86; 95% confidence intervals, 1.08–3.19; p = 0.014), whereas MAPT IVS1+124 C>G was not (p = 0.34). However, the coexistence of MAPT IVS1+124C>G significantly enhanced the LRRK2 G2385R-conferred risk for PD (Odds ratio, 2.30; 95% confidence intervals, 1.14–4.54; p = 0.012). These results provide further evidence supporting the interaction between MAPT and LRRK2 genes, which increases the susceptibility to PD in Chinese individuals.

The LRRK2 R1628P Variant Plays a Protective Role in Han Chinese Population with Alzheimer's Disease

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent neurodegenerative disorders that may share some overlapping etiologies. Mutations within leucine-rich repeat kinase 2 (LRRK2) have been reported to be responsible for PD, and the location of LRRK2 is within a linkage peak for sporadic AD (SAD). The aim of this study was to investigate two Asian-specific LRRK2 variants, R1628P and G2385R, with the association of Han Chinese SAD. Genotyping of R1628P and G2385R was performed by PCR-restriction fragment length polymorphism (RFLP) analysis in 390 patients with SAD and 545 unrelated age- and sex-matched healthy controls. The frequency of the C allele within R1628P was more than three times higher in control group (1.7%) than in patients with SAD (0.5%) (OR 0.264; 95% CI, 0.088-0.792, P = 0.018). After stratification by the presence of one or two apolipoprotein E ε4 alleles, the protective effect becomes stronger (ε44: OR 0.028; 95% CI, 0.003-0.303, P = 0.003; ε4: OR 0.104; 95% CI, 0.013-0.818, P = 0.031). However, no difference was found in G2385R variant. Our study suggested that R1628P variant within LRRK2 plays a protective role in Han Chinese population with SAD and such effect has an interaction with the APOE genotype.

A case of α‐synuclein gene duplication presenting with head‐shaking movements

PARK4 is a candidate locus for familial Parkinson's disease (PD), combined with multiplication of the α-synuclein gene (SNCA). The eventual phenotype is dependent on the copy number of SNCA. Mutations in leucine-rich repeat kinase 2 (LRRK2) are also causative of parkinsonism. This report describes a man who presented at our hospital complaining of a stagger after running and difficulty in handling the mouse of a personal computer, having suffered tremors since his twenties. Nine months after treatment and discharge, he developed titubation and began to drag his right foot. We examined the patient's family pedigree for SNCA dosage, using quantitative polymerase chain reaction. We also screened this pedigree for mutations in parkin and LRRK2, using gene-sequencing techniques. We identified the proband, his sister, and his paternal uncle as carrying a duplication of SNCA. In addition, we found that the proband and his mother carried the G2385R variant of the LRRK2, a strong risk factor for PD in Asians and the rare V1450I variant, although only the proband showed symptoms of parkinsonism. No mutations were found in parkin. The combination of SNCA gene duplication and LRRK2 G2385R variant may explain the early onset of disease in this patient.

LRRK2 R1628P contributes to Parkinson's disease susceptibility in Chinese Han populations from mainland China

Common genetic variants that increase the risk for Parkinson's disease (PD) may differentiate patient subgroups and influence future individual therapeutic strategies. Previous studies have found associations between PD and polymorphisms located within the leucine-rich repeat kinase 2 ( LRRK2) gene in ethnic Han Chinese from Taiwan and Singapore. Herein, we performed a case-control study and provide evidence supporting the LRRK2 R1628P variant as a risk factor for PD in 2 separate Chinese Han populations from mainland China. A total of 328 PD patients and 300 control individuals were genotyped using PCR-restriction fragment length polymorphism analysis. Differences in genotype frequencies between groups were assessed by the chi-square test. In the PD group, 17 patients (5.2%) were heterozygous for the R1628P variant. This was significantly higher than for the control group [2.0%, P < 0.05].No one carrier of the LRRK2 G2385R variant was detected in all the carriers of the R1628P variant. Our results confirm that the LRRK2 R1628P variant contributes to the pathogenesis of PD in Chinese Han populations.

Essential tremor and the common LRRK2 G2385R variant

Co-existence of Parkinson's disease (PD) and essential tremor (ET) suggests a possible overlapping pathophysiology between these two conditions. PD patients with leucine-rich repeat kinase-2 ( LRRK2) mutations have been reported to present initially with ET. A common LRRK2 Gly2385Arg variant has been widely shown to be associated with a two fold increased risk of PD in various Asian populations. We analyzed the Gly2385Arg variant in a cohort of ET and controls. A total of 419 subjects comprising of 172 ET and 247 controls were included. The mean age, age at onset of ET, and age of controls were 52.1 ± 19.6, 41.8 ± 21.6, and 62.2 ± 11.6 years, comprising of 53.0% and 54.3% men, respectively. The Gly2385Arg variant was demonstrated in 5/172 (2.9%) ET patients compared to 10/247 (4.0%) of controls (odds ratio = 0.72, 95% CI 0.24, 2.1, p = 0.6). All the Gly2385Arg carriers were heterozygotes. The LRRK2 Gly2385Arg variant is not a significant risk factor for ET in our population.