Wing Lok Au

Multiple LRRK2 variants 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. Hum Mutat 31:561–568, 2010.

Progression of Parkinson's disease as evaluated by Hoehn and Yahr stage transition times

This study was carried out to evaluate progression in Parkinsons disease (PD) by analyzing time taken to transit from one Hoehn and Yahr (H&Y) stage to the next stage and to investigate the variables that would be associated with H&Y transition times using a large PD database that contained prospectively collected information. Data were obtained from the movement disorder database of the National Neuroscience Institute in Singapore. Kaplan‐Meier (KM) survival analysis was adopted to investigate the time taken to progress through various H&Y stages. Cox regression analysis was used to examine the association between the baseline variables at the entry point of each H&Y stage and the progression to the next stage. A total of 695 patients (mean age: 65.2, male: 57.3%) were studied. Using KM analysis, the median time taken to transit from H&Y stage 1 to 2, 2 to 2.5, 2.5 to 3 were 20, 62, and 25 months, respectively; whereas the median time taken to progress from stage 3 to 4 and 4 to 5 were 24 and 26 months, respectively. Cox regression analysis revealed that older age‐at‐diagnosis, longer PD duration, and higher Unified Parkinsons Disease Rating Scale (UPDRS) motor scores at baseline were associated with a significantly faster progression through various H&Y stages. Gender and ethnicity were not associated with disease progression. In conclusion, H&Y transition time is a useful measure of disease progression in PD and may be utilized in clinical studies evaluating therapeutic interventions and prognostic factors in PD.

Cognitive decline in early Parkinson's disease†

Data on the prevalence and severity of cognitive impairment among patients with newly diagnosed idiopathic Parkinsons disease (PD) is limited. Using a prospectively collected clinical database, we studied the longitudinal trend of mini‐mental state examination (MMSE) change and baseline factors predictive for MMSE decline. One hundred six patients with mean age of 61.2 years and mean baseline MMSE of 27.8 ± 2.3 were studied. MMSE increased by 0.4 points/year among patients without cognitive decline (n = 73) and decreased by 2.39 points/year among patients with cognitive decline (n = 33). Univariate analysis demonstrated education, age of diagnosis, depression, and diabetes mellitus to be associated with cognitive decline. Motor scores and hallucination were not associated with cognitive decline. Multivariate analysis demonstrated higher level of education to be protective (HR = 0.91, 95% CI 0.82–0.99, P = 0.047) and depression having borderline significance in predicting cognitive decline (HR = 2.00, 95% CI 0.97–4.15, P = 0.061). We found that 31% of newly diagnosed idiopathic PD patients have measurable cognitive decline at an early stage of disease. Higher education is protective while depression may be predictive of cognitive decline.

Asymmetrical diffusion tensor imaging indices of the rostral substantia nigra in Parkinson's disease.

OBJECTIVEnMotor asymmetry in Parkinsons disease (PD) is evident clinically and on functional neuroimaging, but not reported in diffusion tensor imaging (DTI). We aim to determine if asymmetry in fractional anisotropy (FA) and apparent diffusion coefficient (ADC) can be detected in the substantia nigra (SN) of PD subjects.nnnMETHODSnDTI scans were performed on 11 PD and 12 healthy subjects. Regions of interest (ROIs) were drawn by 2 independent raters at the caudal, middle and rostral SN on each side. FA and ADC were extracted from the ROIs.nnnRESULTSnSignificant asymmetry was observed in the FA (p < 0.005) and ADC (p < 0.00005) at the rostral SN of PD subjects. The differences in FA and ADC across the left and right rostral SN were significantly different between PD and healthy subjects, p < 0.05 and p < 0.02 respectively. PD subjects had significantly higher ADC at the left rostral SN than healthy subjects (p < 0.01). Significant correlation between the Unified Parkinsons Disease Rating Scale (UPDRS) motor scores and the FA was noted in the left rostral SN (r = 0.7, p < 0.03).nnnCONCLUSIONSnAsymmetry in DTI indices was noted at the rostral SN of PD subjects. The relationship between FA in the SN and UPDRS motor score was studied. Our findings may provide a model for better understanding of the implication of FA reduction in the SN.

A rare lysosomal enzyme gene SMPD1 variant (p.R591C) associates with Parkinson's disease

To investigate the role of mutations in the sphingomyelin phosphodiesterase (SMPD1) gene in Parkinsons disease (PD) we sequenced all the exons of this gene in 198 Chinese PD cases and matched healthy control subjects. We identified 4 rare variants in SMPD1 (p.P332R, p.Y500H, p.P533L, and p.R591C) that were present only in cases and not in control subjects. Interestingly, 2 of these variants were previously reported in Chinese Niemann-Pick disease patients. Next, we genotyped these variants in another 806 PD cases and 7481 control subjects. We identified a novel, rare SMPD1 variant (p.R591C) which increased the risk of PD (pxa0= 0.009).

Pattern Mining of Multichannel sEMG for Tremor Classification

Tremor is defined as the involuntary rhythmic or quasi-rhythmic oscillation of a body part, resulting from alternating or simultaneous contractions of antagonistic muscle groups. While tremor may be physiological, those who have disabling pathological tremors find that performing typical activities for daily living to be physically challenging and emotionally draining. Detecting the presence of tremor and its proper identification are crucial in prescribing the appropriate therapy to lessen its deleterious physical, emotional, psychological, and social impact. While diagnosis relies heavily on clinical evaluation, pattern analysis of surface electromyogram (sEMG) signals can be a useful diagnostic aid for an objective identification of tremor types. Using sEMG system attached to several parts of the patients body while performing several tasks, this research aims to develop a classifier system that automates the process of tremor types recognition. Finding the optimal model and its corresponding parameters is not a straightforward process. The resulting workflow, however, provides valuable information in understanding the interplay and impact of the different features and their parameters to the behavior and performance of the classifier system. The resulting model analysis helps identify the necessary locations for the placement of sEMG electrodes and relevant features that have significant impact in the process of classification. These information can help clinicians in streamlining the process of diagnosis without sacrificing its accuracy.

Identification of a novel risk variant in the FUS gene in essential tremor

Objective: A nonsense mutation in the amyotrophic lateral sclerosis gene FUS has been found to segregate in a large family with essential tremor (ET). Coding variants in this gene have not been comprehensively evaluated in ET. We conducted a genetic analysis of FUS for pathogenic and novel coding variants in 2 case-control cohorts among ethnic Chinese. Methods: In a study that involved 7,548 subjects, we first sequenced all the exon and exon-intronic boundaries of FUS in 84 ET samples. Potential causative variants that were identified were then genotyped in 2 separate case-control cohorts involving 263 additional ET samples and 5,919 controls (set 1) and 250 ET cases and 250 controls (set 2), and 782 diseased controls of Chinese ethnicity from 2 different Asian countries. Results: We identified a novel variant, Met392Ile, in exon 12 of the FUS gene. This variant was associated with ET in set 1 (odds ratio = 4.72 [95% confidence interval = 1.90–11.71], p = 0.0037). The association was subsequently validated in set 2 (joint analysis odds ratio = 3.92 [95% confidence interval = 1.57–9.82], p = 8.6 × 10−4). No association was observed in another neurologic cohort of patients with Parkinson disease, and no other potential pathogenic mutations were identified. Conclusion: We identified a novel risk variant, Met392Ile, in the FUS gene that increases susceptibility of ET among ethnic Chinese. Further studies in other ethnic populations are needed to determine whether this is an ethnic-specific risk factor.

Absence of A673T amyloid-β precursor protein variant in alzheimer's disease and other neurological diseases

The rare variant A673T in the amyloid-β precursor protein (APP) gene has been shown to reduce the risk of cognitive impairment. We genotyped the variant in 8721 Asian individuals comprising 552 with Alzheimers disease and vascular dementia, 790 with Parkinsons disease, and 7379 controls. The A673T variant was absent in all of the subjects. Our finding suggests that the A673T protective variant is not relevant in our Asian population. Studies in other ethnic populations would clarify whether this variant is specific to specific races/ethnicities.

Levodopa and the Feedback Process on Set-Shifting in Parkinson's Disease

Objective: To study the interaction between levodopa and the feedback process on set‐shifting in Parkinsons disease (PD). Methods: Functional magnetic resonance imaging (fMRI) studies were performed on 13 PD subjects and 17 age‐matched healthy controls while they performed a modified card‐sorting task. Experimental time periods were defined based on the types of feedback provided. PD subjects underwent the fMRI experiment twice, once during “off” medication (PDoff) and again after levodopa replacement (PDon). Results: Compared with normal subjects, the cognitive processing times were prolonged in PDoff but not in PDon subjects during learning through positive outcomes. The ability to set‐shift through negative outcomes was not affected in PD subjects, even when “off” medication. Intergroup comparisons showed the lateral prefrontal cortex was deactivated in PDoff subjects during positive feedback learning, especially following internal feedback cues. The cortical activations were increased in the posterior brain regions in PDoff subjects following external feedback learning, especially when negative feedback cues were provided. Levodopa replacement did not completely restore the activation patterns in PD subjects to normal although activations in the corticostriatal loops were restored. Conclusion: PD subjects showed differential ability to set‐shift, depending on the dopamine status as well as the types of feedback cues provided. PD subjects had difficulty performing set‐shift tasks through positive outcomes when “off” medication, and showed improvement after levodopa replacement. The ability to set‐shift through negative feedback was not affected in PD subjects even when “off” medication, possibly due to compensatory changes outside the nigrostriatal dopaminergic pathway. Hum Brain Mapp, 2012.

LRRK2 A419V Is Not Associated with Parkinson's Disease in Different Chinese Populations

It has been suggested that a common LRRK2 polymorphic variant (A419V (rs34594498 C >T)) may be a risk factor among Asians (especially in Taiwan). In this study, we examined this variant in a larger and independent Taiwan cohort. We found the frequency of the variant (A419V) to be very rare in our Taiwan PD and controls (?0.6%). Further studies were conducted in two other Chinese populations (Singapore and China), comprising of a total of 3004 subjects including 1517 PD patients and 1487 control subjects. However, our multi-center Chinese study revealed that the frequency of the variant was rare (?0.4%) and was not associated with risk of PD, suggesting that the variant is not a major risk factor for PD among Chinese, at least in our study population.