Louis C.S. Tan

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.

PINK1 mutations in sporadic early‐onset Parkinson's disease

Pathogenic PINK1 mutations have been described in PARK6‐linked Parkinsons disease (PD) patients of Asian origin. However, data on the frequency of PINK1 mutations in sporadic early‐onset Parkinsons disease (EOPD) Asian patients are lacking. The objectives of this study were to report the frequency of PINK1 mutations of sporadic EOPD in an Asian cohort comprising of ethnic Chinese, Malays, and Indians, and to highlight a PINK1‐positive patient who presented with restless legs symptoms. Eighty consecutive sporadic EOPD patients from the movement disorder clinics of two major tertiary institutions in the country were included. We performed sequence analysis of all the coding and exon–intron junctions of the PINK1 using specific primer sets. In addition, we genotyped polymorphisms detected from the analysis in a group of sporadic PD patients and controls. Three different mutations (two homozygous nonsense and one heterozygous missense) in the putative kinase domain were found in three patients, giving a 3.7% frequency of PINK1 mutations in our EOPD cohort. All the mutations were absent in 200 healthy controls. One patient with a novel homozygous nonsense PINK1 mutation presented unusually with restless legs symptoms. Separately, analysis of the frequency of four PINK1 polymorphisms in a group of sporadic PD and controls did not reveal any significant differences. We highlight a 3.7% frequency of PINK1 mutations in an Asian cohort (ethnic Chinese, Malay, and Indian) of EOPD. The phenotypic spectrum associated with PINK1‐positive patients may be wider than previously reported. Polymorphisms of PINK1 do not appear to modulate risk of PD in our population.

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.

Use of complementary therapies in patients with Parkinson's disease in singapore

To determine the frequency and spectrum of complementary therapy (CT) use and its association with sociodemographic or disease‐specific characteristics among Asian patients with Parkinsons disease (PD) in Singapore, we interviewed 159 patients using a structured questionnaire. Sixty‐one percent (95% CI = 55–67) of participants used at least one type of CT for PD, of which the most common were traditional medicine, acupuncture, and vitamins/health supplements. Among CT users, 40% (95% CI = 32–48) subjectively reported some improvement of their symptoms. However, only 16% informed their physicians of their use of CT. Due to unequal follow‐up times, a survival analysis approach was adopted for statistical analysis. The rate of starting CT use was 1.2/100 person months. At 3 years after PD diagnosis, 48% had started using CT. Among a subgroup of participants, those with a baseline Unified Parkinsons Disease Rating Scale motor score of more than 16 were 2.5 times more likely to use CT compared to those with a baseline score of 16 or less (P = 0.031; 95% CI = 1.1–5.8). CT use was not associated with age of onset of PD or other sociodemographic factors. The use of CT is high among Asian PD patients. Patients with more severe motor dysfunction at onset are more likely to use CT.

Valproate-induced Parkinsonism in epilepsy patients

We systematically examined 226 epilepsy patients in a tertiary‐referral center and found 6 (5.04%) to have valproate‐induced Parkinsonism. There was a significantly higher prevalence of patients with Parkinsonism in the group of patients treated with valproate compared to those who were on other antiepileptic drugs (6 [5.04%] of 119 vs. 0 [0%] of 107; χ 2 = 5.54; P = 0.025). These six patients had been on valproate for more than 3 years (mean, 75.67 ± 25.32 months) at an average dose of 750 ± 273.86 mg/day. The valproate doses were decreased or discontinued with supplementation from another antiepileptic medication. The mean UPDRS motor score significantly improved from 10.67 ± 5.1 to 4.75 ± 2.75 (P < 0.05). There was no relapse of seizures. Clinicians working in tertiary‐referral centers should have a high index of suspicion for valproate‐induced Parkinsonism. Early recognition and switching into another antiepileptic medication may help reduce unnecessary suffering in these patients.

Factors affecting health-related quality of life amongst Asian patients with Parkinson’s disease

Background and purpose:  This cross‐sectional study was carried out to identify factors predicting health‐related quality of life (HRQoL) amongst Asian patients with Parkinson’s disease (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.

Clinical evolution of Parkinson's disease and prognostic factors affecting motor progression: 9‐year follow‐up study

There have been few long‐term studies that have characterized and charted the clinical progression of Parkinsons disease (PD). This study was therefore undertaken to understand the natural clinical evolution of treated PD patients and to identify the variables that predict greater progression in these patients.

Cerebral white matter hyperintensity in Parkinson's disease: A major risk factor for mild cognitive impairment

BACKGROUND Mild cognitive impairment (MCI) and dementia contribute to a poor quality of life among patients with PD. The influence of cerebral ischemia as a risk factor for MCI in PD has not been adequately investigated. To address this issue, we examined the influence of the volume and distribution of white matter hyperintensity (WMH) as a risk factor for MCI in early PD. METHODS Prospective study of patients with early idiopathic PD. All patients had baseline MRI-FLAIR, clinical assessment and detailed neuropsychological evaluation. Data on demographics, vascular risk factors, cognitive performance and WMH volumes were analyzed. RESULTS 91 patients; mean age 64.9 years, mean education of 10.5 years. 24 patients fulfilled the Movement Disorder Society criteria for MCI and were classified as PD-MCI while the rest were classified as PD with no cognitive impairment (PD-NCI). Patients with PD-MCI and PD-NCI did not differ in Hoehn & Yahr staging. PD-MCI patients had a higher prevalence of diabetes mellitus, hypertension and hyperlipidemia. PD-MCI patients had significantly greater volume of periventricular (6.04 ml vs. 2.66 ml, p = 0.001) and deep subcortical WMH (2.16 vs.1.44, p = 0.002). Regional WMH was significantly greater among PD-MCI in the frontal, parietal and occipital regions. Logistic regression analyses demonstrated WMH to be associated with PD-MCI independent of age, education, and vascular risk factors. Increasing WMH volume was associated with lower performance on executive function, memory and language. CONCLUSIONS WMH is an important risk factor for PD-MCI independent of vascular risk factors. PD patients with WMH should be regularly screened for MCI.

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

OBJECTIVE Motor 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. METHODS DTI 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. RESULTS Significant 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). CONCLUSIONS Asymmetry 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.