Huntington’s disease (HD) is an intractable neurodegenerative disorder caused by mutant Huntingtin (HTT) proteins that adversely affect various biomolecules and genes. MicroRNAs (miRNAs), which are ...functional small non-coding RNAs, are also affected by mutant HTT proteins. Here, we show amelioration in motor function and lifespan of HD-model mice, R6/2 mice, by supplying miR-132 to HD brains using a recombinant adeno-associated virus (rAAV) miRNA expression system. miR-132 is an miRNA related to neuronal maturation and function, but the level of miR-132 in the brain of R6/2 mice was significantly lower than that of wild-type mice. Our miR-132 supplemental treatment, i.e., supplying miR-132 to the brain, produced symptomatic improvement or retarded disease progression in R6/2 mice; interestingly, it had little effect on disease-causing mutant HTT mRNA expression and its products. Therefore, the findings suggest that there may be a therapeutic way to treat HD without inhibiting and/or repairing disease-causing HTT genes and gene products. Although miR-132 supplement may not be a definitive treatment for HD, it may become a therapeutic method for relieving HD symptoms and delaying HD progression.
Rotigotine, a non-ergot dopamine receptor agonist, offers potential for continuous dopaminergic stimulation that could avoid the fluctuations observed with traditional treatments. We conducted a ...randomized, double-blind, placebo-controlled trial in Japanese patients with advanced Parkinson’s disease (PD) to investigate the efficacy and safety of rotigotine. Inclusion criteria included the presence of motor complications, such as wearing off, on–off, delayed-on/no-on, any circumstances that could interfere with levodopa dose escalation because of side effects, or declining levodopa efficacy. The enrolled patients received once-daily applications of rotigotine transdermal patches or matched placebo patches. A total of 174 patients were randomly assigned to rotigotine (87 patients) or placebo (87 patients). The full analysis set included 172 patients (86 for the rotigotine group and 86 for the placebo group). The maximum maintenance dose of rotigotine was set at 16 mg/24 h. The changes in unified PD rating scale Part III scores from baseline to the end of the trial were −10.1 ± 9.0 (mean ± standard deviation) in the rotigotine group and −4.4 ± 7.4 in the placebo group (
p
< 0.001). There was a significantly greater reduction in the off-time (
p
= 0.014) in the rotigotine group. Rotigotine was well tolerated, with serious adverse events being reported in only three patients in each group. Rotigotine at doses of up to 16 mg/24 h is efficacious and safe in Japanese patients with advanced PD.
Purpose The Swallowing Disturbance Questionnaire (SDQ) was developed as a self-rated screening tool for dysphagia in patients with Parkinson's disease (PD). We developed the Japanese version of this ...questionnaire (SDQ-J), according to the cross-cultural adaptation guidelines, and examined its reliability. Methods Subjects were 61 Japanese patients with PD (mean age, 67.0 ± 9.2 years) who answered the SDQ-J before undergoing videofluoroscopic examination of swallowing (VF). We compared the findings of the questionnaire with the patients' aspiration status during VF. Results Cronbach's alpha coefficient for the 15 questions of the SDQ-J was 0.84. According to the SDQ-J, 15 patients (24.6%) were diagnosed with dysphagia, while 9 patients (14.8%) aspirated liquid during VF. The sensitivity and specificity of the SDQ-J in predicting aspiration were 77.8 and 84.6%, respectively; therefore, the SDQ-J significantly predicted aspiration during VF (P < 0.01). The positive predictive value (PPV) and negative predictive value (NPV) for the SDQ-J were 0.46 and 0.96, respectively. Conclusions The SDQ-J appears to be a reliable and useful screening tool for Japanese PD patients with aspiration. As the NPV was higher than the PPV in the SDQ-J, this questionnaire could potentially be used for early identification of severe dysphagia in patients with PD.
We consider nonlinear scalar field equations involving the Sobolev-critical exponent at high frequencies ω. Since the limiting profile of the ground states as ω→∞ is the Aubin–Talenti function and ...degenerate in a certain sense, from the point of view of perturbation methods, the nondegeneracy problem for the ground states at high frequencies is subtle. In addition, since the limiting profile (Aubin–Talenti function) fails to lie in L2(Rd) for d=3,4, the nondegeneracy problem for d=3,4 is more difficult than that for d≥5 and an applicable methodology is not known. In this paper, we solve the nondegeneracy problem for d=3,4 by modifying the arguments in Akahori et al. (2020) and Akahori et al. (2019). We also show that the linearized operator around the ground state has exactly one negative eigenvalue.
ABSTRACT
Introduction: Needle electromyography (EMG) has been an important diagnostic tool, although discomfort may limit its use in some children. We investigated the diagnostic utility of the ...clustering index (CI) method, a quantitative analysis for surface EMG (SEMG), in children. Methods: SEMG was recorded from the tibialis anterior muscle. Discriminant analysis between patients with neurogenic disorders and patients with myopathy was performed for whole epochs by using the CI and area values. Results: Forty‐five children (29 with myopathy, 16 with neurogenic disorders; age 9 ± 3.9 years) were enrolled. The mean discriminant function value of the neurogenic group was 0.58 ± 0.88 (−0.48–2.30), whereas that of the myopathic group was −0.55 ± 0.70 (−2.38–0.68). When the cutoff value was set at the limit of the other group, 17 of 29 children with myopathy and 7 of 16 children with neurogenic disorders were correctly classified. Discussion: The CI method can be a useful noninvasive diagnostic tool in children with neuromuscular disorders. Muscle Nerve 58:824–827, 2018
Little is known about the relationship between Becker Muscular Dystrophy (BMD) and developmental problems, school life, employment, and mental problems. We aimed to clarify whether BMD is a risk ...factor for developmental disorders, problematic behavior, psychiatric diseases, and other social difficulties in school life and employment.
Adults with genetically or immunohistochemically confirmed BMD from the Registry of Muscular Dystrophy in Japan (REMUDY) were asked to complete a questionnaire regarding patient history, school life, employment, and mental problems.
In total, 125 (68.3%) of 183 participants with BMD (median age, 37.2 years) completed the questionnaire. Of these, ten had developmental disorders (mental retardation, autism, and speech disturbance). Fifty-eight (44%) experienced bullying in school, and 39 felt the reason for bullying was physical handicap. Sixteen participants experienced problematic behavior such as cutting class, domestic violence, violent incidents, suicide attempts, or self-mutilation. Employment histories were noted by 92 (73%), of whom 15 could not continue to work due to physical handicaps. Fifteen participants had psychiatric disorders, with 5, 3 and 1 having neurosis, depression, and bipolar disorder, respectively. The other 6 participants with psychiatric disorders did not specify their diagnoses. Patients carrying a Dp140 expression change had significantly more incidences of developmental disorders, but not bullying, problematic behavior, workplace difficulties, or psychiatric disorders.
Patients with BMD risk bullying and workplace difficulties, as well as developing psychiatric disorders. Parents, teachers, and supporters should be mindful of the daily environment of BMD patients and provide support to help them cope with stress.
It is hypothesized that a common underlying mechanism links multiple neurodegenerative disorders. Here we show that transitional endoplasmic reticulum ATPase (TERA)/valosin-containing protein ...(VCP)/p97 directly binds to multiple polyglutamine disease proteins (huntingtin, ataxin-1, ataxin-7 and androgen receptor) via polyglutamine sequence. Although normal and mutant polyglutamine proteins interact with TERA/VCP/p97, only mutant proteins affect dynamism of TERA/VCP/p97. Among multiple functions of TERA/VCP/p97, we reveal that functional defect of TERA/VCP/p97 in DNA double-stranded break repair is critical for the pathology of neurons in which TERA/VCP/p97 is located dominantly in the nucleus in vivo. Mutant polyglutamine proteins impair accumulation of TERA/VCP/p97 and interaction of related double-stranded break repair proteins, finally causing the increase of unrepaired double-stranded break. Consistently, the recovery of lifespan in polyglutamine disease fly models by TERA/VCP/p97 corresponds well to the improvement of double-stranded break in neurons. Taken together, our results provide a novel common pathomechanism in multiple polyglutamine diseases that is mediated by DNA repair function of TERA/VCP/p97.
Niemann-Pick disease type C (NPC) is a lysosomal storage disorder with severe prognosis. Disease-specific therapy is crucial to prevent disease progression; however, diagnosing NPC is quite difficult ...because of remarkably variable clinical presentations. The NPC Suspicion Index (NPC-SI) was developed to overcome this problem. Identifying preclinical cases is important for prevention and therapy. Here, we report three newly diagnosed NPC cases, one typical juvenile-onset case and the cases of two sisters with symptoms neurologically/psychiatrically indistinguishable from dystonia and schizophrenia, respectively.
In Case 1, a 25-year-old man presented with a 14-year history of intellectual disability, clumsiness, spastic ataxia, dysphagia, and frequent falls. Neurological examination revealed vertical supranuclear gaze palsy and involuntary movements. Ultrasonography revealed mild splenomegaly, and filipin staining of skin fibroblasts was positive with a variant staining pattern. NPC1 gene analysis showed compound heterozygous mutations, including c.1421C > T (p.P474L), a known causative mutation, and c.3722 T > C (p.L1241S), a new mutation. In Case 2, a 28-year-old woman, the proband, who had marked splenomegaly in her childhood, survived well, contrary to the expected severe prognosis of infantile NPC. She had minor neuropsychiatric symptoms including auditory hallucinations, nocturnal urination, and sleep paralysis. At the age of 28 years, she presented with a 1-year history of orofacial and oromandibular painful dystonia. The patient's 35-year-old sister (Case 3) was diagnosed with schizophrenia. In both cases, filipin staining of skin fibroblasts was positive with variant staining patterns, as well as elevated levels of urinary bile acids. NPC1 gene analysis showed compound heterozygous mutations including c.3011C > T (p.S1004 L), a known causative mutation, and c.160_161insG (p.D54GfsX4), a new mutation. Their mother, who was under therapy with modafinil for narcolepsy, shared the latter mutation.
Marked clinical variability was observed in our three cases. NPC could masquerade as a pure neuropsychiatric disorder such as dystonia or schizophrenia. Abdominal ultrasonography, history evaluation, and neurological examination were quite important in the diagnostic process.
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