Chiung Mei Chen

Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease

Common genetic variants that increase the risk for Parkinsons disease may differentiate patient subgroups and influence future individualized therapeutic strategies. Herein we show evidence for leucine‐rich repeat kinase 2 (LRRK2) c.4883G>C (R1628P) as a risk factor in ethnic Chinese populations. A study of 1,986 individuals from 3 independent centers in Taiwan and Singapore demonstrates that Lrrk2 R1628P increases risk for Parkinsons disease (odds ratio, 1.84; 95% confidence interval, 1.20–2.83; p = 0.006). Haplotype analysis suggests an ancestral founder for carriers approximately 2,500 years ago. These findings support the importance of LRRK2 variants in sporadic Parkinsons disease. Ann Neurol 2008

Patients’ versus caregivers’ report of poor memory in relation to dementia and tested abilities

Complaints of poor memory are common among older individuals, but their clinical significance remains unclear. We compared patients’ self-report of poor memory with their caregivers’ report, and to compare the two reports’ associations with the patients’ dementia status and tested cognitive performance. Participants included 709 patients at the Memory Clinic of the Taipei Veterans General Hospital and their primary caregivers. A total of 493 of the patients were diagnosed with dementia according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV),1 including 78% with probable AD, 15% with vascular dementia, and 7% with mixed or other types of dementia. The diagnosis of dementia and its subtypes was made by a neurologist based on interview, physical examination, cognitive test, and laboratory findings. Each patient and caregiver was asked separately by a neuropsychologist to describe the patient’s memory as being good/average or poor. They also answered questions for the …

Genetic testing in spinocerebellar ataxia in Taiwan: Expansions of trinucleotide repeats in SCA8 and SCA17 are associated with typical Parkinson's disease

DNA tests in normal subjects and patients with ataxia and Parkinsons disease (PD) were carried out to assess the frequency of spinocerebellar ataxia (SCA) and to document the distribution of SCA mutations underlying ethnic Chinese in Taiwan. MJD/SCA3 (46%) was the most common autosomal dominant SCA in the Taiwanese cohort, followed by SCA6 (18%) and SCA1 (3%). No expansions of SCA types 2, 10, 12, or dentatorubropallidoluysian atrophy (DRPLA) were detected. The clinical phenotypes of these affected SCA patients were very heterogeneous. All of them showed clinical symptoms of cerebellar ataxia, with or without other associated features. The frequencies of large normal alleles are closely associated with the prevalence of SCA1, SCA2, MJD/SCA3, SCA6, and DRPLA among Taiwanese, Japanese, and Caucasians. Interestingly, abnormal expansions of SCA8 and SCA17 genes were detected in patients with PD. The clinical presentation for these patients is typical of idiopathic PD with the following characteristics: late onset of disease, resting tremor in the limbs, rigidity, bradykinesia, and a good response to levodopa. This study appears to be the first report describing the PD phenotype in association with an expanded allele in the TATA‐binding protein gene and suggests that SCA8 may also be a cause of typical PD.

The use of evoked potentials for clinical correlation and surgical outcome in cervical spondylotic myelopathy with intramedullary high signal intensity on MRI

Objective: To investigate the use of motor evoked potentials (MEPs) and somatosensory evoked potentials (SEPs) for clinical significance and surgical outcome in patients with cervical spondylotic myelopathy (CSM) with intramedullary high signal intensity on T2 weighted MRI. Methods: Forty nine patients were scored according to the modified Japanese Orthopaedic Association (JOA) score for cervical myelopathy. MEP and SEP studies were performed and the results were categorised as normal or abnormal. Thirty nine patients who had received surgical decompression were re-evaluated after 6 months. Surgical outcome was represented by the recovery ratio of the JOA score. Results: Abnormal MEPs were observed in 44 patients (arm: 43; leg: 30). Abnormal SEPs were found in 32 patients: (median: 24; tibial: 23). Patients with abnormal SEPs had a worse JOA score than those with normal SEPs. Thirty nine patients received surgical treatment. Patients younger than 55 had better recovery ratios than those who were 55 or older (p = 0.005, two sample Student’s t test). Patients with normal median SEPs also had better recovery ratios than those with abnormal median SEPs (p = 0.007, two sample Student’s t test). Among median SEP variables, only N9-20 was significantly associated with recovery ratio (p = 0.016, stepwise linear regression), with age factor controlled (p = 0.025, stepwise linear regression). Conclusion: Arm MEP was the most sensitive EP test for detecting myelopathy in patients with chronic CSM. Median and tibial SEPs correlated well with the severity of myelopathy while normal median SEPs correlated with good surgical outcome. Among median SEP variables, only N9-20 correlated with surgical outcome.

Hypokalemic thyrotoxic periodic paralysis: clinical characteristics and predictors of recurrent paralytic attacks

Background and purpose:  To study the clinical characteristics of hypokalemic thyrotoxic periodic paralysis (hoTPP) and identify the predictors of recurrent paralytic attacks before achieving the euthyroid status.

SCA8 mRNA expression suggests an antisense regulation of KLHL1 and correlates to SCA8 pathology

An increasing number of inherited neurodegenerative diseases are known to be caused by the expansion of unstable trinucleotide repeat tracts. Spinocerebellar ataxia type 8 (SCA8) has been identified as being partly caused by a CTG expansion in an untranslated, endogenous antisense RNA that overlaps the Kelch-like 1 (KLHL1) gene. Clinically, SCA8 patients show similar features to those with the other SCAs, including limb and truncal ataxia, ataxic dysarthria and horizontal nystagmus, all of which are signs of dysfunction of the cerebellar system. However, allele sizes within the SCA8 proposed pathogenic range have been reported in patients with ataxia of unknown etiology, in individuals from pedigrees with other SCA or Friedreichs ataxia, and in patients with Alzheimers disease, schizophrenia or parkinsonism. These observations suggest that mutation of the SCA8 locus might affect neurons other than the cerebellum. Antisense transcripts are known to regulate complementary sense transcripts and are involved in several biologic functions, such as development, adaptive response, and viral infection. In order to test whether SCA8 affects the KLHL1 expression by antisense RNA in brain cells, we examined the expression pattern of KLHL1 and SCA8 in human tissues and in mouse brain regions. SCA8 expression was colocalized with KLHL1 transcript in many brain regions whose functions are correlated to the clinical symptoms of SCA8 patients. These findings lead to the hypothesis of a possible relevance that SCA8 transcript downregulates KLHL1 expression through an antisense mechanism, which then leads to SCA8 neuropathogenesis.

Retinal microvascular changes and subsequent vascular events after ischemic stroke.

Objectives: Retinal microvasculature changes are associated with vascular events including stroke in healthy populations. It is not known whether retinal microvascular changes predict recurrent vascular events after ischemic stroke. We examined the relationship between retinal microvascular signs and subsequent vascular events in a prospective cohort of 652 acute ischemic stroke patients admitted to a tertiary hospital in Singapore from 2005 to 2007. Methods: Retinal photographs taken within 1 week of stroke onset were assessed in a masked manner for quantitative and qualitative measures. Follow-up data over 2–4 years were obtained by standardized telephone interview and then were verified from medical records. Predictors of recurrent vascular events (cerebrovascular, coronary, vascular death, and composite vascular events) were determined using Cox regression models. Results: Follow-up data over a median of 29 months were obtained for 89% (652 patients) of the cohort. After adjustment for covariates including traditional risk factors and index stroke etiology, patients with severe arteriovenous nicking (AVN) were more likely to have a recurrent cerebrovascular event (hazard ratio [HR] 2.28, 95% confidence interval [CI] 1.20–4.33) compared with those without AVN. Patients with severe focal arteriolar narrowing (FAN) were more likely to have a recurrent cerebrovascular event (HR 2.75, 95% CI 1.14–6.63) or subsequent composite vascular event (HR 2.77, 95% CI 1.31–5.86) compared to those without FAN. Conclusions: Retinal microvascular changes predicted subsequent vascular events after ischemic stroke, independent of traditional risk factors and stroke subtype. Thus, retinal imaging has a potential role in predicting the risk of recurrent vascular events after ischemic stroke and in understanding novel vascular risk factors.

Neuroprotective effects of granulocyte‐colony stimulating factor in a novel transgenic mouse model of SCA17

J. Neurochem. (2011) 118, 288–303.

Interleukin-1α and -1β Promoter Polymorphisms in Taiwanese Patients with Dementia

Background: Inflammatory events may contribute to the pathogenesis of dementia and interleukin-1 (IL-1) may exert both neurotoxic and neuroprotective effects. We investigated whether IL-1α –889 C/T and IL-1β –511 C/T promoter polymorphisms are associated with the risk of Alzheimer’s disease (AD) and vascular dementia (VaD). Methods: AD patients (n = 219) and VaD patients (n = 82), who fulfilled the criteria of the NINCDS-ADRDA and NINDS-AIREN, and ethnic-matched and nondemented controls (n = 209) were analyzed by means of genotype association method. Results: No significant difference in the genotype distribution of the analyzed single nucleotide polymorphisms was found between AD or VaD cases and controls. However, the frequency of the IL-1α –889 CT genotype was notably lower in VaD patients aged over 70 years than the age-matched controls (9.1 vs. 22.9%, p = 0.036) andtheIL-1α –889 CT genotype demonstrated a trend toward decrease in risk of developing VaD (odds ratio: 0.34; 95% confidence interval: 0.12–0.83, p = 0.026). Multivariate analysis revealed that the IL-1β –511T-carrying genotype slightly strengthens the negative association of the IL-1α –889 CT genotype with VaD (odds ratio: 0.26; 95% confidence interval: 0.08–0.79, p = 0.024). Conclusion: Our data suggest a protective role of the IL-1α –889 CT genotype in VaD susceptibility among Taiwanese aged over 70 years.

LRRK2 G2385R modulates age at onset in Parkinson's disease: A multi-center pooled analysis.

LRRK2 G2385R Modulates Age at Onset in Parkinson’s Disease: A Multi-Center Pooled Analysis E.K. Tan, R. Peng, Y.R. Wu, R.M. Wu, Y.H. Wu-Chou, L.C. Tan, X.K. An, C.M. Chen, S. Fook-Chong, and C.S. Lu* Departments of Neurology and Clinical Research, Singapore General Hospital, National Neuroscience Institute, Singapore, Singapore Duke-NUS Graduate Medical School, Singapore, Singapore Department of Neurology, West China Hospital, Sichuan University, Chengdu, China Department of Neurology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taipei, Taiwan Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan Human Molecular Genetics Laboratory, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taipei, Taiwan