Beom S. Jeon

Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: A case-control study

BACKGROUND Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinsons disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. METHODS LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinsons Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. FINDINGS 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15-1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35-3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0·82, 0·72-0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20-2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36-1·07; p=0·087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33-15·09; p=0·012). INTERPRETATION The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity. FUNDING Michael J Fox Foundation and National Institutes of Health.

Seven‐tesla magnetic resonance images of the substantia nigra in Parkinson disease

To investigate anatomical changes in the substantia nigra (SN) of Parkinson disease (PD) patients with age‐matched controls by using ultra‐high field magnetic resonance imaging (MRI).

Association of DRD3 and GRIN2B with impulse control and related behaviors in Parkinson's disease†

We aimed to assess whether allelic variants of dopamine receptor, glutamate receptor, and serotonin transporter genes are associated with the appearance of impulse control and related behaviors (ICRB) in Parkinsons disease (PD) with dopamine replacement therapy (DRT). We surveyed ICRB in consecutive Korean patients with PD who were treated with stable DRT using modified Minnesota Impulsive Disorders Interview over a period of 4 months. In the 404 patients who completed the interview and the 559 Korean healthy normal controls, genotyping was performed for variants of the DRD3 p.S9G, DRD2 Taq1A, GRIN2B c.366C>G, c.2664C>T and c.‐200T>G, and the promoter region of the serotonin transporter gene (5‐HTTLPR). Behavioral abnormalities suggestive of ICRB including compulsive buying, gambling, sexual behavior and eating, and punding, were present in 14.4% of the patients. Variants of DRD2 and 5‐HTTLPR were not associated with the risk of developing ICRB. However, the AA genotype of DRD3 p.S9G and the CC genotype of GRIN2B c.366C>G were more frequent in patients with ICRB than in nonaffected patients (odds ratio [OR] = 2.21, P = 0.0094; and 2.14, P = 0.0087, after adjusting for age and sex). After controlling for clinical variables in the multivariate analysis, carriage of either AA genotype of DRD3 or CC genotype of GRIN2B was identified as an independent risk factor for ICRB (adjusted OR: 2.57, P = 0.0087). Variants of DRD3 p.S9G and GRIN2B c.366C>G may be associated with the appearance of ICRB in PD.

Large-scale replication and heterogeneity in Parkinson disease genetic loci

Objective: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown. Methods: Investigators from the Genetic Epidemiology of Parkinsons Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry. Results: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78–0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14–1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I2 estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD. Conclusion: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity. Neurology® 2012;79:659–667

Chronic subthalamic deep brain stimulation improves pain in Parkinson disease

BackgroundPain is a well recognized feature of Parkinson disease (PD). Like motor fluctuations, pain in PD may fluctuate as ‘non-motor fluctuations’. Subthalamic deep brain stimulation (STN DBS) is an established treatment for motor fluctuations in PD. However, the effect of STN DBS on the pain in PD is only partially investigated.MethodsPD patients who were considered for STN DBS were asked if they had pain. The severity of pain was scored in each body part. In patients with motor fluctuation, the pain in the ‘on’ and ‘off ’ state were recorded separately. Patients were evaluated preoperatively and 3 months after surgery. Some patients were followed for 6 months.ResultsTwenty-three of 29 patients had pain preoperatively. Of 24 with motor fluctuation, 21 had pain, and 18 had fluctuating pain. Pain improved in 20 out of 23 with preoperative pain at 3 months postoperatively. Of 18 with fluctuating pain, 12 reported a decrease in, and 5 complete disappearance of the ‘off ’ pain. Of 4 with nonfluctuating preoperative pain, 2 reported improvement. Pain was severe and functionally disabling in some. The STN DBS improved pain to a tolerable degree. In 7 of 29, new pain developed during the 3 month follow-up. Sixteen patients were followed for 6 months. All 11 patients who had improvement at 3 months continued to get benefit from STN DBS. Two additional patients who had no improvement at 3 months reported improvement at 6 months.ConclusionsPain is frequent in PD and STN DBS improves pain, especially the ‘off ’ pain in PD.

The effects of bilateral Subthalamic Nucleus Deep Brain Stimulation (STN DBS) on cognition in Parkinson disease

The effects of subthalamic nucleus (STN) stimulation on cognition and mood have not been well established. The authors estimated cognitive and mood effects of bilateral subthalamic nucleus deep brain stimulation (STN DBS) in patients with Parkinsons disease (PD) at 6 months and 1 year postoperatively. Forty-six patients were recruited from the Movement Disorder Center at Seoul National University Hospital. Neuropsychologic tests were performed three times, before, 6 months after, and 1 year after surgery. Mean patient age was 58 and mean education duration 8 years. Eighteen of the 46 patients were men. The instruments used for assessing cognitive functions were; the Mini-Mental Status Examination (MMSE), the Trail Making Test (TMT), the Korean Boston Naming Test (K-BNT), the Rey-Kim Memory Battery, the Grooved pegboard test, the Stroop test, a fluency test, the Wisconsin Card Sorting test (WCST), and the Beck depression inventory (BDI). Of these tests, the verbal memory test, the Stroop test, and the fluency test showed statistically significant changes. The verbal memory test using the Rey-Kim memory battery showed a decline in delayed recall and recognition at 6 months and 1 year postoperatively, whereas nonverbal memory showed no meaningful change. In terms of frontal lobe function tests, Stroop test and fluency test findings were found to be aggravated at 6 months and this continued at 1 year postoperatively. Previous studies have consistently reported a reduction in verbal fluency and improvements in self-reported symptoms of depression after STN DBS. However, in the present study, Beck depression inventory (B.D.I.) was not significantly changed. Other tests, namely, MMSE, TMT, K-BNT, Grooved pegboard test, and the WCST also failed to show significant changes. Of the baseline characteristics, age at onset, number of years in full-time education, and L-dopa equivalent dosage were found to be correlated with a postoperative decline in neuropsychological test results. The correlation of motor improvement and cognitive deterioration was not significant, which suggests that the stimulation effect is rather confined to the motor-related part in the STN. In conclusion, bilateral STN DBS in Parkinsons disease did not lead to a significant global deterioration in cognitive function. However, our findings suggest that it has minor detrimental long-term impacts on memory and frontal lobe function.

α-Synuclein induces apoptosis by altered expression in human peripheral lymphocyte in Parkinson’s disease

Though the etiology of Parkinson’s disease (PD) remains unclear, α‐synuclein (α‐SN) is regarded as a major causative agent of PD. Several lines of evidence indicate that immunological abnormalities are associated with PD for unknown reasons. The present study was performed to assess whether peripheral blood mononuclear cells (PBMCs) show altered α‐SN expression in PD patients and to identify its functions, which may be related to peripheral immune abnormalities in PD. α‐SN was found to be expressed more in 151 idiopathic PD (IPD) patients than in 101 healthy controls, who nevertheless showed as age‐dependent increases. By in vitro transfection, α‐SN expression was shown to be correlated with glucocorticoid sensitive apoptosis, possibly caused by the enhanced expression of glucocorticoid receptor (GR), caspase activations (caspase‐8, caspase‐9), CD95 up‐regulation, and reactive oxygen species (ROS) production. An understanding of the correlation between α‐SN levels and apoptosis in the presence of the coordinated involvement of multiple processes would provide an insight into the molecular basis of the disease. The present study provides a clue that the α‐SN may be one of the primary causes of the immune abnormalities observed in PD and offers new targets for pharmacotherapeutic intervention.

A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants

Background Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. Methods and results We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. Conclusions Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

Direct visualization of Parkinson's disease by in vivo human brain imaging using 7.0T magnetic resonance imaging†

Parkinsons disease (PD) is a neurodegenerative disorder resulting from progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta. Therefore, imaging of the SN has been regarded to hold greatest potential for use in the diagnosis of PD. At the 7.0T magnetic resonance imaging (MRI), it is now possible to delineate clearly the shapes and boundaries of the SN. We scanned eight early and two advanced PD patients, along with nine age‐matched control subjects, using a 7.0T MRI in an attempt to directly visualize the SN and quantify the differences in shape and boundaries of SN between PD subjects in comparison with the normal control subjects. In the normal controls, the boundaries between the SN and crus cerebri appear smooth, and clean “arch” shapes that stretch ventrally from posterior to anterior. In contrast, these smooth and clean arch‐like boundaries were lost in PD subjects. The measured correlation analyses show that, in PD patients, there is age‐dependent correlation and substantially stronger UPDRS motor score‐dependent correlation. These results suggest that, by using 7.0T MRI, it appears possible to use these visible and distinctive changes in morphology as a diagnostic marker of PD.

Nervous system involvement by metastatic hepatocellular carcinoma

Nineteen patients with nervous system metastasis of hepatocellular carcinoma (HCC) were evaluated retrospectively. Nervous system metastasis was frequently initial presentation of HCC (seven out of 19 patients). Seven patients had metastases of the brain, of whom four had a stroke-like presentation. CT or MRI in these patients showed intracerebral hematomas in watershed areas. Enhancing lesion or edema adjacent to the hematoma helped differentiate these lesions from classical hypertensive hematomas. One patient with metastasis to the clivus presented with isolated six nerve palsy. The remaining 11 patients had spinal epidural metastases producing myelopathy in seven and radiculopathy in four. Radiation therapy failed to control the clinical course.