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.     

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.     

The LRRK2 G2385R variant is a risk factor for sporadic Parkinson's disease in the Korean population

The G2385R (SNP accession no. rs34778348) and R1628P (rs33949390) variants of leucine-rich repeat kinase 2 (LRRK2, PARK8) are emerging as an important risk factor for Parkinson's disease (PD) in the ethnic Chinese and Japanese populations. The purpose of this study was to investigate whether these variants are a genetic risk factor in sporadic PD patients in the Korean population. A total of 923 patients and 422 healthy subjects were included. The variants were screened by a SNaPshot assay. The LRRK2 G2385R variant was detected in 82 PD patients (8.9%, two homozygous and 80 heterozygous) and in 21 normal controls (5.0%, all heterozygous). The frequency of the LRRK2 G2385R variant in PD was significantly higher than in normal controls (adjusted odds ratio 1.83, p = 0.0170, 95% confidence interval 1.11–3.00). There were no differences in the mean age at onset or gender between the G2385R carriers and the non-carriers in PD patients. The LRRK2 R1628P variant was very rare (0.78% in patients versus 0.26% in controls) in the tested 384 patient–control pairs, and was not a significant risk factor. This study supports that the LRRK2 G2385R variant may be a genetic risk factor for sporadic PD in the Korean population.     

Neuropathology of Parkinson's disease with the R1441G mutation in LRRK2

We report the neuropathological findings in a patient with Parkinson's disease (PD) associated with Basque R1441G‐LRRK2/dardarin mutation. The patient was a man with disease onset at 68 years of age, with unilateral rest tremor; the Parkinsonism was well controlled with medication for 15 years. He died at the age of 86, after 18 years of evolution. The neuropathological examination disclosed mild neuronal loss in the substantia nigra pars compacta without α‐synuclein, tau, LRRK2, or ubiquitin cytoplasmic inclusions. Lewy bodies and Lewy neurites were absent. This is the first neuropathological study of PD associated with brain with the R1441G mutation in LRRK2. © 2009 Movement Disorder Society     

Penetrance of LRRK2 G2385R and R1628P is modified by common PD-associated genetic variants

Variants in the LRRK2 gene are well-characterized genetic predisposing factors for PD worldwide, and LRRK2-associated PD is often indistinguishable from idiopathic PD (IPD). However, considerable heterogeneity of LRRK2-PD suggests the existence of additional genetic and/or environmental modifiers for LRRK2 carriers, which have yet to be confirmed by large-scale human studies. In a Chinese cohort consisting of 2013 sporadic PD patients and 1971 controls, we investigated the modification of the two Asian-specific LRRK2 variants, G2385R and R1628P, by variants of five other PD-associated genes/loci (SNCA, MAPT, GBA, BST1, PARK16). Of all the PD patients, 13.1% carried LRRK2 G2385R and/or R1628P variant. Among these carriers, a total of 15 different polygenic genotypes were detected representing different combination patterns between LRRK2 variants and those of the other genes/loci, which, alone or in combination, significantly modified the LRRK2-related risk for PD and the patients’ ages at onset (AAOs). These results not only represent the largest replication data affirming the association between PD and all the six genes/loci in Chinese, but for the first time suggest that multiple PD-associated genetic factors modify both the penetrance and AAO of LRRK2 parkinsonism. This finding may have important implications for elucidating pathophysiologic mechanisms relevant to both LRRK2-associated and idiopathic PD. However, testing interactions among multiple genes by genetic association studies is still challenging. Future studies with much larger sample sizes are needed to confirm our findings.     

The G2019S LRRK2 Mutation is Rare in Korean Patients with Parkinson's Disease and Multiple System Atrophy

Background and Purpose

The LRRK2 (PARK8; OMIM607060) substitution was recently identified as a causative mutation for Parkinson''s disease (PD). The pathologic heterogeneity of LRRK2-positive patients suggests that mutation of the LRRK2 gene is associated with the pathogenesis of PD and Parkinson-plus disorders, such as multiple system atrophy (MSA). We previously reported that the G2019S LRRK2 mutation-which is the most common LRRK2 mutation-was not found in a sample of 453 Korean PD patients. In the present study, we extended the screening for the G2019S mutation to a larger group of PD and MSA patients.

Methods

We performed a genetic analysis of the G2019S mutation in 877 patients with PD and 199 patients with MSA using a standard PCR and restriction digestion method.

Results

None of the subjects carried the G2019S mutation.

Conclusions

The results of the present study support that the G2019S mutation is extremely rare in PD and is unlikely to be associated with MSA in the Korean population.     

Olfactory deficits and cardiac 123I‐MIBG in Parkinson's disease related to the LRRK2 R1441G and G2019S mutations

It has been proposed that olfactory tests and metaiodobenzylguanidine cardiac scintigraphy may help diagnose idiopathic Parkinson's disease in the premotor phase. However, it is not clear what value these tests have in all patients with Parkinson's disease and, particularly, in those who carry mutations in LRRK2. The objective was to analyze olfactory dysfunction and the changes in cardiac I‐metaiodobenzylguanidine uptake in patients with Parkinson's disease carrying the R1441G and G2019S mutations in LRRK2, and in patients with Parkinson's disease with no known mutations. Patients with Parkinson's disease were screened for R1441G and G2019S LRRK2 gene mutations and classified as LRRK2 mutation carriers or noncarriers. A total of 190 patients with Parkinson's disease (44 LRRK2 mutation carriers) were tested for olfactory dysfunction using the Brief Smell Identification Test. Cardiac ¹²³I‐metaiodobenzylguanidine scintigraphy was performed on 90 patients with Parkinson's disease (27 LRRK2 mutation carriers). Thirty‐six percent of patients with LRRK2 mutations have hyposmia, compared to 75% of noncarrier patients with Parkinson's disease (P < .001). Sixty‐six percent of LRRK2 mutation carriers have low early metaiodobenzylguanidine uptake, compared to 86% of noncarriers (P = .048). Similarly, the heart/mediastinum ratio in delayed metaiodobenzylguanidine images appeared to differ between these groups of patients with Parkinson's disease, although these results did not reach statistical significance. The data obtained indicate that olfactory and cardiac impairment is less prevalent when Parkinson's disease is associated with mutations in LRRK2, although the underlying mechanisms for this difference remain unclear. Thus, such screening would be less useful to detect the premotor phase in asymptomatic relatives who carry mutations in LRRK2 than in cases not associated with LRRK2. © 2011 Movement Disorder Society     

Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia

The goal of genetic association studies is to identify common (>5%) risk factors in complex disease traits. Herein we describe the first replicable 'functional' risk allele for Parkinson's disease. The leucine-rich repeat kinase 2 (Lrrk2) G2385R substitution is associated with familial parkinsonism, late-, and early-onset Parkinson's disease in ethnic Chinese Taiwanese. Crucially, we provide evidence of identity-by-descent and suggest that Lrrk2 G2385R carriers originate from one ancestor some 4800 years ago, at the start of Chinese civilization. Moreover, our findings demonstrate that common genetic coding variants contribute to Parkinson's disease in a population specific manner which may have important implications for future genome-wide association studies.     

The prevalence of LRRK2 Gly2385Arg variant in Chinese Han population with Parkinson's disease.

We conducted a case-control study to determine the prevalence of the LRRK2 Gly2385Arg variant in patients with Parkinson's disease in Han population in mainland China. Heterozygous LRRK2 Gly2385Arg variant was identified in 14 of 235 patients with Parkinson's disease (5.69%), but not in 214 unrelated healthy controls. Multivariate analysis indicated the frequency of Gly2385Arg variant in the female patients with early age at onset is higher than their male counterparts. The founder haplotype analysis showed the variant carriers shared the same founder. Clinically, the LRRK2 Gly2385Arg carriers presented with classical Parkinson's disease symptoms. Our study indicates that the LRRK2 Gly2385Arg variant is a potential ethnic-specific genetic risk factor of Parkinson's disease within Chinese Han ethnicity.     

Cognitive dysfunction in Parkinson's disease related to the R1441G mutation in LRRK2

ObjectiveThe neuropsychological characteristics of patients with Parkinson's Disease (PD) associated with R1441G mutation in the LRRK2 gene (R1441G-PD) are not well known. The aim of this study was to examine the cognitive status and mood of R1441G-PD patients.MethodsThirty patients with R1441G-PD were compared with thirty idiopathic PD (i-PD) patients who were matched by age, sex, education, disease onset age and duration, using a comprehensive battery of neuropsychological test, and considering the Movement Disorder Society (MDS) criteria for the diagnosis of Mild Cognitive Impairment (PD-MCI) and dementia (PD-Dementia).ResultsThe mean scores in the depression and anxiety scales were similar in the two groups. Depressive symptoms were detected in 31.8% of R1441G-PD and 25% of i-PD patients and anxiety symptoms were evident in 4.5% and 15%, respectively, but the differences were not significant. The only neuropsychological test on which there was a significantly worse performance in the R1441G-PD group was the Boston naming test but the difference became not significant when Bonferroni's correction was applied. The prevalence of PD-MCI was 30% in both R1441G-PD and i-PD, with no differences in the number and type of domains altered given that executive function, memory and attention were mainly affected. PD-Dementia was diagnosed in 13.3% (n = 4) of R1441G-PD and 26.7% (n = 8) of i-PD patients (difference was not significant).ConclusionIn conclusion, significant differences were not detected between R1441G-PD and i-PD in cognitive, depression and anxiety scales, or PD-MCI and PD-Dementia prevalence, and the cognitive profile was identical in the two groups.     

LRRK2 Quantification in Cerebrospinal Fluid of Patients with Parkinson's Disease and Atypical Parkinsonian Syndromes

Background

The alteration of leucine-rich repeat kinase 2 (LRRK2) kinase activity is thought to be involved in Parkinson's disease (PD) pathogenesis beyond familiar cases, and LRRK2 inhibitors are currently under investigation. Preliminary data suggest a relationship between LRRK2 alteration and cognitive impairment in PD.

Objective

To investigate cerebrospinal fluid (CSF) LRRK2 levels in PD and other parkinsonian disorders, also correlating them with cognitive impairment.

Methods

In this study, we retrospectively investigated by means of a novel highly sensitive immunoassay the levels of total and phosphorylated (pS1292) LRRK2 in CSF of cognitively unimpaired PD (n = 55), PD with mild cognitive impairment (n = 49), PD with dementia (n = 18), dementia with Lewy bodies (n = 12), atypical parkinsonian syndromes (n = 35), and neurological controls (n = 30).

Results

Total and pS1292 LRRK2 levels were significantly higher in PD with dementia with respect to PD with mild cognitive impairment and PD, and also showed a correlation with cognitive performances.

Conclusions

The tested immunoassay may represent a reliable method for assessing CSF LRRK2 levels. The results appear to confirm an association of LRRK2 alteration with cognitive impairment in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Prevalence of cancer in Parkinson's disease related to R1441G and G2019S mutations in LRRK2

An inverse relationship between Parkinson's disease (PD) and cancer has been described. However, the association between cancers and genetic forms of PD, in particular the R1441G mutation in the LRRK2 gene, is not well known. The objective of this work was to analyze cancer prevalence in PD patients with R1441G or G2019S mutations in LRRK2, and in idiopathic PD (iPD). A total of 732 patients with PD (70 and 25 carriers of R1441G or G2019S mutations, respectively), and 177 controls, were linked using a population‐based cancer registry of the Spanish province of Gipuzkoa. Cancer prevalence was not significantly higher in PD‐G2019S carriers (20%) than in PD‐R1441G carriers (14.3%), iPD (13.8%), or controls (12.5%). With the exception of a high prevalence of hematological cancers (crude odds ratio of 7.1) in the R1441G group, specific cancer types were not increased in PD mutation carriers. In both the carrier and iPD groups, cancers were diagnosed after the onset of PD. PD patients had a similar prevalence of cancer to control subjects. There was no increased association between G2019S or R1441G mutations and any type of cancer. Although there was a higher prevalence of hematological cancers in the R1441G group, the low number of such cancers overall makes this finding of uncertain significance. There was a slightly higher but not statistically significant prevalence of non‐skin cancers in the G2019S group, suggesting that further study to evaluate the association should be undertaken prior to ascribing an increased cancer risk to this population. © 2013 International Parkinson and Movement Disorder Society