Objective: The causes of “delayed-on” and “no-on” phenomena in Parkinson disease (PD) are thought to have some impact on the progress of L-DOPA from the time of ingestion until it reaches the brain ...and is converted to dopamine. Dysphagia can cause fluctuating symptom expression in L-DOPA therapy for PD. Case Description: A 69-year-old man with PD presented with “delayed-on” and “no-on” phenomena. The patient developed a gait disorder at age 60 years, and he began coughing on his food during breakfast at age 64 years. Even though he was independent in daily life, he could not eat because of dysphagia in an “off” state. Videofluoroscopic examination of swallowing in an “off” state revealed bradykinesia of the tongue and the retention of tablets in the epiglottic vallecula. We trained him to keep his tongue in strong contact with the upper incisors before swallowing. After rehabilitation of dysphagia, the frequency of “delayed-on” and “no-on” phenomena decreased, and his peak L-DOPA plasma concentration was elevated. Additionally, transdermal rotigotine (RTG) was initiated at a maintenance dose of 9.0 mg. The patient reported improvement in swallowing, and the frequency of “no-on” phenomena decreased. Conclusion: In PD patients, the “no-on” phenomenon can be caused by posterior contractile dysfunction of the tongue, and it can be improved with training of the tongue and transdermal RTG administration.
To assess the effect of genetic factors on sporadic Parkinson disease, we performed a case-control study of a variant (G2385R) in Leucine-Rich Repeat kinase 2 among the Japanese population. The ...G2385R (c.7153G>A) variant was reported as a risk factor for sporadic Parkinson disease in the Chinese population from Taiwan and Singapore. Genotyping was conducted in 448 Parkinson disease patients and 457 healthy controls. The frequency of A allele in Parkinson disease was significantly higher than in the control (P=1.24x10(-4), odds ratio 2.63, 95% confidence interval 1.56-4.35). Our results suggest that the G2385R variant is a risk factor for sporadic Parkinson disease in the Asian population.
Abstract Background We previously classified camptocormia of Parkinson's disease (PD) into upper and lower types based on the inflection point, and reported improvement of upper camptocormia after ...lidocaine injection into the external oblique. However, the exact pathophysiology of this phenomenon remains obscure. Methods Surface electromyography (sEMG) was recorded in 11 PD patients with upper camptocormia, 11 PD patients with lower camptocormia, and 10 age-matched PD patients without postural deformity. Electrodes were positioned above the external oblique, hip flexors and paraspinal muscles at Th11 level bilaterally. Recording commenced with the patient in supine position on a tilt table, and continued when the table was tilted up to vertical position. Lidocaine was injected into the external oblique in patients with upper camptocormia and the psoas major in patients with lower camptocormia. Results All patients with upper and lower camptocormia developed the corresponding camptocormic posture during tilt up. The onset of camptocormic posture was preceded by the appearance of sEMG activity in the external oblique in 10 out of 11 patients with upper camptocormia, but less frequently in patients with lower camptocormia and the controls. Hip flexors sEMG activity was recorded in almost all patients. Posture was improved in 8 out of 9 patients with upper camptocormia, and 9 out of 11 patients with lower camptocormia following injections of lidocaine. Conclusions The results suggest the external oblique is involved, at least in part, in the development of upper camptocormia. Although EMG findings cannot differentiate pathogenicity, the psoas major is probably involved in lower camptocormia.
Abstract Mutations in the glucosamine (UDP- N -acetyl)-2-epimerase/ N -acetylmannosamine kinase gene cause GNE myopathy, a mildly progressive autosomal recessive myopathy. We performed a prospective ...natural history study in 24 patients with GNE myopathy to select evaluation tools for use in upcoming clinical trials. Patient clinical conditions were evaluated at study entry and one-year follow-up. Of the 24 patients, eight (33.3%) completed a standard 6-min walk test without assistance. No cardiac events were observed. Summed manual muscle testing of 17 muscles, grip power, and percent force vital capacity (%FVC) were significantly reduced ( p < 0.05), and scores for 6-min walk test and gross motor function measure were decreased ( p < 0.1) after one year. The decrement in %FVC was significant among non-ambulant patients, whereas the decrement in grip power tended to be greater among ambulant patients. The 6-min walk test, gross motor function measure, manual muscle testing, grip power, and %FVC reflect annual changes and are thus considered good evaluation tools for clinical trials.
Objectives:
Levodopa-carbidopa intestinal gel (LCIG) was developed to reduce motor complications in Parkinson’s disease (PD) caused by pulsatile levodopa plasma concentrations following oral levodopa ...administration. Dyskinesia and ‘wearing off’ symptoms can vary between Asian and Caucasian patients with PD, thus highlighting the importance of assessing the effectiveness of LCIG in an Asian population. Efficacy and safety of LCIG were previously assessed in a 12-week open-label study; we report the efficacy and safety of at least 52 weeks of LCIG treatment in Japanese, Taiwanese, and Korean patients with advanced PD in the ongoing extension study.
Methods:
In this interim analysis of a phase III, open-label, multicenter extension study in Japan, South Korea, and Taiwan ClinicalTrials.gov identifier: NCT02082249/JapiCTI-142482, the mean change from baseline to final visit in ‘off’ time, as reported in the PD symptom diary, was normalized to a 16-h waking day. Changes in Parkinson’s Disease Questionnaire-39 (PDQ-39) summary index and domains scores were also analyzed. Adverse events (AEs) were recorded.
Results:
Of the 28 patients enrolled (21 Japanese, 3 Taiwanese, 4 Korean), 27 completed at least 52 total weeks of treatment, and 25 patients were continuing in the study at data cutoff. The mean standard deviation (SD) ‘off’ time was significantly reduced by 4.6 (3.1) h/day (p < 0.001, n = 28). Patients experienced significant improvements in quality of life, as recorded by the mean change from baseline in PDQ-39 summary index (p < 0.001). All patients had at least one AE; three patients (11%) discontinued due to an AE. There were two deaths (sepsis and drowning), both of which the investigator considered unrelated to LCIG treatment.
Conclusions:
These data suggest that LCIG treatment is efficacious, safe, and well tolerated in Japanese, Taiwanese, and Korean patients with advanced PD, thus confirming the consistency of LCIG treatment in patients with advanced PD.
We previously reported transcriptional repression-induced atypical cell death of neuron (TRIAD), a new type of necrosis that is mainly regulated by Hippo pathway signaling and distinct from ...necroptosis regulated by RIP1/3 pathway. Here, we examined the ultrastructural and biochemical features of neuronal cell death in the brains of human HD patients in parallel with the similar analyses using mutant Htt-knock-in (Htt-KI) mice. LATS1 kinase, the critical regulator and marker of TRIAD, is actually activated in cortical neurons of postmortem human HD and of Htt-KI mouse brains, while apoptosis promoter kinase Plk1 was inactivated in human HD brains. Expression levels of YAP/YAPdeltaC were decreased in cortical neurons of human HD brains. Ultra-structural analyses revealed extreme enlargement of endoplasmic reticulum (ER), which characterizes TRIAD, in cortical neurons of human HD and those of Htt-KI mice. These biochemical and morphological results support that TRIAD occurs in human and mouse neurons under the HD pathology.
α-synuclein (SNCA) is an established susceptibility gene for Parkinson's disease (PD), one of the most common human neurodegenerative disorders. Increased SNCA is considered to lead to PD and ...dementia with Lewy bodies. Four single-nucleotide polymorphisms (SNPs) in SNCA 3' region were prominently associated with PD among different ethnic groups. To examine how these SNPs influence disease susceptibility, we analyzed their potential effects on SNCA gene expression. We found that rs356219 showed allele-specific features. Gel shift assay using nuclear extracts from SH-SY5Y cells showed binding of one or more proteins to the protective allele, rs356219-A. We purified the rs356219-A-protein complex with DNA affinity beads and identified a bound protein using mass spectrometry. This protein, YY1 (Yin Yang 1), is an ubiquitous transcription factor with multiple functions. We next investigated SNCA expression change in SH-SY5Y cells by YY1 transfection. We also analyzed the expression of antisense noncoding RNA (ncRNA) RP11-115D19.1 in SNCA 3'-flanking region, because rs356219 is located in intron of RP11-115D19.1. Little change was observed in SNCA expression levels; however, RP11-115D19.1 expression was prominently stimulated by YY1. In autopsied cortices, positive correlation was observed among RP11-115D19.1, SNCA and YY1 expression levels, suggesting their functional interactions in vivo. Knockdown of RP11-115D19.1 increased SNCA expression significantly in SH-SY5Y cells, suggesting its repressive effect on SNCA expression. Our findings of the protective allele-specific YY1 and antisense ncRNA raised a novel possible mechanism to regulate SNCA expression.
We studied 20 single nucleotide polymorphisms in 18 candidate genes for association with Parkinson's disease. We found that homozygosity for the V66M polymorphism of the brain‐derived neurotrophic ...factor (BDNF) gene occurs more frequently in patients with Parkinson's disease than in unaffected controls (χ2 = 5.46) and confirmed an association with the S18Y polymorphism of the UCH‐L1 gene. Our results provide genetic evidence supporting a role for BDNF in the pathogenesis of Parkinson's disease.
Highlights • We describe Duchenne muscular dystrophy (DMD) patients with treatable renal failure. • CystatinC is a useful marker of kidney function in reduced muscle mass cases. • Non-ambulatory DMD ...patients are at a risk of reduced kidney perfusion.
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