Common genetic variants that increase the risk for Parkinson's 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 Parkinson's 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 Parkinson's disease. Ann Neurol 2008.

Maximum elbow flexor and extensor muscle strength was measured in 9 patients with Parkinson's disease on and off antiparkinsonian medication. In addition, the rate of force generation, the rate of actively returning force to resting levels, and passive release of force "relaxation" were measured in submaximal contractions. The measures of strength and contraction time were correlated with changes in clinical status as measured by the Unified Parkinson's Disease Rating Scale. When patients were off medication, their reduction in strength was significantly greater in extension than flexion. The reduction in flexion strength did not reach statistical significance. The extensor weakness was primarily due to decreased tonic activation of the extensor muscles and not to muscle coactivation. Muscle relaxation time was much more prolonged than was force generation time or active force return time. The increase in relaxation time and the decrease in extensor strength both correlated with changes in clinical status. Finally, changes in extensor torque correlated with the time to actively return force, suggesting that reduced strength is related to a reduced ability to generate rapid contractions in some patients with Parkinson's disease. These results suggest that there is an asymmetric distribution of muscle weakness in Parkinson's disease and that selected measures of muscle strength and muscle relaxation correlate with changes in clinical status.

Huntington’s disease (HD) is a neurodegenerative disorder that manifests with movement dysfunction. The expression of mutant Huntingtin (mHTT) disrupts the functions of brain cells. Galectin-3 (Gal3) is a lectin that has not been extensively explored in brain diseases. Herein, we showed that the plasma Gal3 levels of HD patients and mice correlated with disease severity. Moreover, brain Gal3 levels were higher in patients and mice with HD than those in controls. The up-regulation of Gal3 in HD mice occurred before motor impairment, and its level remained high in microglia throughout disease progression. The cell-autonomous up-regulated Gal3 formed puncta in damaged lysosomes and contributed to inflammation through NFκB- and NLRP3 inflammasome-dependent pathways. Knockdown of Gal3 suppressed inflammation, reduced mHTT aggregation, restored neuronal DARPP32 levels, ameliorated motor dysfunction, and increased survival in HD mice. Thus, suppression of Gal3 ameliorates microglia-mediated pathogenesis, which suggests that Gal3 is a novel druggable target for HD.

LOA from posterior dural sac and subjacent lamina is the most valuable finding in the diagnosis of Hirayama disease at neutral-position MR imaging.

Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. Here, we report that the transcript of the peroxisome proliferator-activated receptor-γ (PPARγ), a transcription factor that is critical for energy homeostasis, was markedly downregulated in multiple tissues of a mouse model (R6/2) of HD and in lymphocytes of HD patients. Therefore, downregulation of PPARγ seems to be a pathomechanism of HD. Chronic treatment of R6/2 mice with an agonist of PPARγ (thiazolidinedione, TZD) rescued progressive weight loss, motor deterioration, formation of mutant Htt aggregates, jeopardized global ubiquitination profiles, reduced expression of two neuroprotective proteins (brain-derived neurotrophic factor and Bcl-2) and shortened life span exhibited by these mice. By reducing HTT aggregates and, thus, ameliorating the recruitment of PPARγ into HTT aggregates, chronic TZD treatment also elevated the availability of the PPARγ protein and subsequently normalized the expression of two of its downstream genes (the glucose transporter type 4 and PPARγ coactivator-1 alpha genes). The protective effects described above appear to have been exerted, at least partially, via direct activation of PPARγ in the brain, as TZD was detected in the brains of mice treated with TZD and because a PPARγ agonist (rosiglitazone) protected striatal cells from mHTT-evoked energy deficiency and toxicity. We demonstrated that the systematic downregulation of PPARγ seems to play a critical role in the dysregulation of energy homeostasis observed in HD, and that PPARγ is a potential therapeutic target for this disease.

Background: Mutations in the glucocerebrosidase (GBA) gene have recently been identified as contributing to the development of Parkinson disease (PD) in Ashkenazi Jews. Methods: To investigate whether this finding can be confirmed in a Taiwanese population, we conducted a case control study in a cohort of 518 PD patients and 339 controls for the three common GBA mutations in Taiwan, L444P, RecNciI and R120W, using PCR restriction enzyme assay and DNA sequencing. Results: Heterozygous GBA mutations were detected in 16 PD patients (3.1%) and four controls (1.2%). Although this difference was not statistically significant (p = 0.0703), the average age at disease onset of the 16 PD patients (50.6 (12.3) years) was significantly younger than that of the total patient group (63.8 (10.5) years; p = 0.0007) and the noncarrier patient group (64.2 (10.2) years; p = 0.0005). After stratification by age, the frequency of mutation carriers was significantly higher for the early onset PD (EOPD, age at onset

No abstract

DNA tests in normal subjects and patients with ataxia and Parkinson's 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.