Kai-Hsiang Chen

The COMT L allele modifies the association between MAOB polymorphism and PD in Taiwanese

Objective: Reports suggest that catechol-O-methyltransferase (COMTL/L) (Val158/Met) and monoamine oxidase B (MAOB) intron 13 genotype polymorphism is associated with PD. To understand the ethnicity-specific effects of genetic polymorphism, we performed a case-control study of the association between PD susceptibility and polymorphism of MAOB and COMT, both separately and in combination, in Taiwanese. Methods: Two hundred twenty-four patients with PD and 197 controls, matched for age, sex, and birthplace, were recruited. MAOB and COMT polymorphism genotyping was performed by using PCR-based restriction fragment length polymorphism (RFLP) analyses. χ2, OR, and Fisher’s exact tests were used to compare differences in allelic frequencies and genotypes. Results: The MAOB G genotype (G in men and G/G in women) was associated with a 2.07-fold increased relative risk of PD. COMT polymorphism, considered alone, showed no correlation with PD risk; however, a significant synergistic enhancement was found in PD patients harboring both the COMTL and MAOB G genotypes. Conclusions: These results suggest that, in Taiwanese, PD risk is associated with MAOB G intron 13 polymorphism, and this association is augmented in the presence of the COMTL genotype, indicating an interaction of these two dopamine-metabolizing enzymes in the pathogenesis of sporadic PD. However, the relatively low frequencies of these combined genotypes in our study necessitates confirmation with a larger sample size.

Elucidating the role of the A2A adenosine receptor in neurodegeneration using neurons derived from Huntington's disease iPSCs

Huntingtons disease (HD) is an autosomal-dominant degenerative disease caused by a cytosine-adenine-guanine trinucleotide expansion in the Huntingtin (htt) gene. The most vulnerable brain areas to mutant HTT-evoked toxicity are the striatum and cortex. In spite of the extensive efforts that have been devoted to the characterization of HD pathogenesis, no disease-modifying therapy for HD is currently available. The A2A adenosine receptor (A2AR) is widely distributed in the brain, with the highest level observed in the striatum. We previously reported that stimulation of the A2AR triggers an anti-apoptotic effect in a rat neuron-like cell line (PC12). Using a transgenic mouse model (R6/2) of HD, we demonstrated that A2AR-selective agonists effectively ameliorate several major symptoms of HD. In the present study, we show that human iPSCs can be successfully induced to differentiate into DARPP32-positive, GABAergic neurons which express the A2AR in a similar manner to striatal medium spiny neurons. When compared with those derived from control subjects (CON-iPSCs), these HD-iPSC-derived neurons exhibited a higher DNA damage response, based on the observed expression of γH2AX and elevated oxidative stress. This is a critical observation, because oxidative damage and abnormal DNA damage/repair have been reported in HD patients. Most importantly, stimulation of the A2AR using selective agonists reduced DNA damage and oxidative stress-induced apoptosis in HD-iPSC-derived neurons through a cAMP/PKA-dependent pathway. These findings support our hypothesis that human neurons derived from diseased iPSCs might serve as an important platform to investigate the beneficial effects and underlying mechanisms of A2AR drugs.

Vitamin D receptor genetic variants and Parkinson's disease in a Taiwanese population

Patients with Parkinsons disease (PD) have hypovitaminosis D status and genetic variants of vitamin D receptor (VDR) gene are recently shown to be associated with PD in a large-scale genome-wide association study in a Caucasian population. Few studies examined VDR genetic variants in large-scale Asian patients with PD. We therefore genotyped 6 VDR genetic variants in a total of 1492 Taiwanese subjects, including 700 patients with PD and 792 age and/or gender matched control subjects. We did not observe any significant associations between the studied genetic variants of VDR and the risk of PD. Our data suggest that genetic variations of the VDR gene did not play a major role in a Taiwanese PD population. Further studies of VDR and its interaction with serum vitamin D levels are warranted to clarify the potential role of vitamin D in PD pathogenesis.

Proteinuria independently predicts unfavorable outcome of ischemic stroke patients receiving intravenous thrombolysis.

Background and Purpose Patients with low estimated glomerular filtration rate (eGFR) and proteinuria may be at increased risk for stroke. This study investigated whether low eGFR and proteinuria are outcome predictors in stroke patients treated with intravenous thrombolysis. Methods We studied 432 consecutive stroke patients who received thrombolysis from January 2006 to December 2012, in Taiwan. Unfavorable outcome was defined as modified Rankin scale ≥2 at 3 months after stroke. Proteinuria was classified as negative or trace, mild, and moderate to severe. Using logistic regression analysis, we identified independent factors for unfavorable outcome after thrombolysis. Results Of all patients, 32.7% had proteinuria. Patients with proteinuria were older, had higher frequencies of diabetes mellitus, hyperlipidemia, atrial fibrillation, lower eGFR, and greater severity of stroke upon admission than those without proteinuria. Proteinuria, not low eGFR, was an independent predictor for unfavorable outcome for stroke (ORu200a=u200a2.00 for mild proteinuria, pu200a=u200a0.035; ORu200a=u200a2.54 for moderate to severe proteinuria, pu200a=u200a0.035). However, no clear relationship was found between proteinuria and symptomatic hemorrhage after thrombolysis. Conclusions Proteinuria is an independent predictor of unfavorable outcome for acute ischemic stroke in patients treated with intravenous thrombolysis, indicating the crucial role of chronic kidney disease on the effectiveness of thrombolysis.

Genetic polymorphism of the CYP2E1 gene and susceptibility to Parkinson's disease in Taiwanese

Summary. Cytochrome P450IIE1 (CYP2E1), an ethanol-inducible cytochrome P450 enzyme, is expressed in the basal ganglia and is probably involved in the activation of neurotoxicants, producing free radical metabolites and resulting in oxidative stress. To examine the association between CYP2E1 polymorphism and the risk of Parkinsons disease (PD), we performed a case-control study on a large population of Taiwanese PD patients, focusing especially on early-onset PD patients (onset at, or before, the age of 50). Two hundred and thirty-four PD patients and 251 age- and sex-matched controls were recruited. A much higher frequency of the uncommon c2 allele was seen in our control subjects than in Caucasians (0.23 vs. 0.02). There were no significant differences between PD patients and controls in the distribution of either allelic or genotype frequencies. Our results suggest that CYP2E1 is not a major or independent determinant in the occurrence of PD in Taiwanese.

Development of method for quantifying essential tremor using a small optical device

BACKGROUNDnClinical assessment scales are the most common means used by physicians to assess tremor severity. Some scientific tools that may be able to replace these scales to objectively assess the severity, such as accelerometers, digital tablets, electromyography (EMG) measurement devices, and motion capture cameras, are currently available. However, most of the operational modes of these tools are relatively complex or are only able to capture part of the clinical information; furthermore, using these tools is sometimes time consuming. Currently, there is no tool available for automatically quantifying tremor severity in clinical environments.nnnNEW METHODnWe aimed to develop a rapid, objective, and quantitative system for measuring the severity of finger tremor using a small portable optical device (Leap Motion).nnnRESULTSnA single test took 15s to conduct, and three algorithms were proposed to quantify the severity of finger tremor. The system was tested with four patients diagnosed with essential tremor.nnnCOMPARISON WITH EXISTING METHODnThe proposed algorithms were able to quantify different characteristics of tremor in clinical environments, and could be used as references for future clinical assessments.nnnCONCLUSIONSnA portable, easy-to-use, small-sized, and noncontact device (Leap Motion) was used to clinically detect and record finger movement, and three algorithms were proposed to describe tremor amplitudes.

A digital assessment system for evaluating kinetic tremor in essential tremor and Parkinson’s disease

BackgroundSpiral drawing on papers is a common tremor evaluation tool for diagnosing patients with essential tremor (ET) or Parkinson’s disease (PD). No standard drawing methods and parameters that use graphic tablets are yet available for objective evaluation.MethodsThis study established a tremor assessment system for tremor severity by using graphic tablets. Twelve patients with ET and twelve patients with PD were tested to establish system algorithms, and six additional patients were tested with the developed system to evaluate its performance. The patients also performed spiral drawing with three guiding paradigms on a graphic tablet: traced along a given spiral (S1), performed freehand drawing (S2), and traced along a guiding point (S3). Three parameters were calculated to quantify tremor severity: the means of radial difference per radian (|dr/dθ|), the means of radial difference per second (|dr/dt|), and the area under curve (AUC) of the frequency spectrum of the velocity. Each patient’s drawing was also evaluated using a visual rating scale (VRS) by experienced physicians. The interrater reliability was examined to identify the most consistent test paradigm.ResultsThe parameter |dr/dθ| and AUC correlated well with the VRS (Ru2009>u20090.8) in S1, S2 and S3 tests. The S1 test presented the best interrater reliability (Weighted Kappa coefficient, ku2009=u20090.80) among three tests. The Weighted Kappa coefficients are 0.67 and 0.71 in S2 and S3 tests, respectively.ConclusionsWe developed three different guiding paradigms for spiral drawing on a digital graphic tablet for clinical tests. Three parameters were calculated to represent the tremor severity in spiral drawing and used to quantify temporal and spatial characteristics of tremor, and provided good correlation with current clinical assessments. The test “traced along a given spiral” is recommended due to its good interrater reliability.

Mutational analysis of SYNJ1 gene (PARK20) in Parkinson's disease in a Taiwanese population

Whole-exome sequencing recently identified a homozygous truncating mutation in Synaptojanin 1 (SYNJ1, PARK20), p.Arg258Gln, in 2 independent families with autosomal recessive young-onset parkinsonism with seizures and cognitive decline. This mutations role in typical Parkinsons disease (PD) is unclear. We sequenced all coding exons and exon-intron boundaries of SYNJ1 gene in a total of 700 participants: 250 early-onset PD patients, 100 familial PD patients with family history, and 350 age/sex-matched controls from Taiwan. No patients harbored homozygous or compound heterozygous mutations of SYNJ1 gene in our study population. We observed 1 novel missense substitution, p.Ala551Val, in a single heterozygous state in 1 early-onset PD patient. This variant was not observed in controls with total 700 normal alleles. The clinical phenotype of this genetic variant carrier is similar to that seen in idiopathic PD, with motor fluctuation after 11 years of PD diagnosis and comorbidity with dementia after 13 years of motor symptoms. Our results suggest that mutations in SYNJ1 gene do not play a major role in early-onset or familial PD in our population.

Psychotic-affective symptoms and multiple system atrophy expand phenotypes of spinocerebellar ataxia type 2

Spinocerebellar ataxia type 2 (SCA2) is a progressive neurodegenerative disorder, characterised by ataxic gait, slow saccades and peripheral neuropathy. Levodopa-responsive parkinsonism could be a clinical phenotype of SCA2, especially those of Chinese origin. In addition to these motor symptoms, SCA2 has been associated with depression and cognitive dysfunction, with only rare reports of psychosis. The authors report the presence of severe psychosis, major depression and multiple system atrophy in affected subjects of a Taiwanese family with intermediate CAG repeats within the ATXN2 gene. The identification of this rare and distinctive SCA2 phenotype expands the current knowledge of the phenotypic variability of SCA2 and suggests that modifier genes could influence the clinical phenotype of SCA2.

Brain abscess as an initial presentation in a patient of hereditary haemorrhagic telangiectasia caused by a novel ENG mutation.

Hereditary haemorrhagic telangiectasia (HHT) is a rare inherited autosomal-dominant vascular dysplasia involving multiple organs. Brain abscess is an uncommon and potential fatal complication. We report a case of HHT caused by a novel ENG mutation who initially presented as brain abscess. The patient, with a family history of epistaxis, presented with fever, headache and right-sided haemiparesis. Upon examination, brain MRI showed a contrast-enhanced abscess on the left fronto-parietal region. Open brain drainage was performed and pus culture yielded Actinomyces meyeri. The chest image revealed multiple pulmonary arterio-venous fistulas. HHT was diagnosed according to Curacao criteria. Genetic analysis revealed a novel duplication on exon 6 of ENG gene, which segregates with symptomatic subjects in her family. Clinicians should be cautiously aware of HHT as a differential diagnosis if patients presented with an unknown entry source of intracerebral infections.