A randomized double-blind multi-center trial of hydrogen water for Parkinson's disease: protocol and baseline characteristics.

BACKGROUND: Our previous randomized double-blind study showed that drinking hydrogen (H2) water for 48 weeks significantly improved the total Unified Parkinson's Disease Rating Scale (UPDRS) score of Parkinson's disease (PD) patients treated with levodopa. We aim to confirm this result using a randomized double-blind placebo-controlled multi-center trial. METHODS: Changes in the total UPDRS scores from baseline to the 8(th), 24(th), 48(th), and 72(nd) weeks, and after the 8(th) week, will be evaluated. The primary endpoint of the efficacy of this treatment in PD is the change in the total UPDRS score from baseline to the 72(nd) week. The changes in UPDRS part II, UPDRS part III, each UPDRS score, PD Questionnaire-39 (PDQ-39), and the modified Hoehn and Yahr stage at these same time-points, as well as the duration until the protocol is finished because additional levodopa is required or until the disease progresses, will also be analyzed. Adverse events and screening laboratory studies will also be examined. Participants in the hydrogen water group will drink 1000 mL/day of H2 water, and those in the placebo water group will drink normal water. One-hundred-and-seventy-eight participants with PD (88 women, 90 men; mean age: 64.2 [SD 9.2] years, total UPDRS: 23.7 [11.8], with levodopa medication: 154 participants, without levodopa medication: 24 participants; daily levodopa dose: 344.1 [202.8] mg, total levodopa equivalent dose: 592.0 [317.6] mg) were enrolled in 14 hospitals and were randomized. DISCUSSION: This study will confirm whether H2 water can improve PD symptoms. TRIAL REGISTRATION: UMIN000010014 (February, 13, 2013).

The KIF3 motor transports N-cadherin and organizes the developing neuroepithelium.

In the developing brain, the organization of the neuroepithelium is maintained by a critical balance between proliferation and cell-cell adhesion of neural progenitor cells. The molecular mechanisms that underlie this are still largely unknown. Here, through analysis of a conditional knockout mouse for the Kap3 gene, we show that post-Golgi transport of N-cadherin by the KIF3 molecular motor complex is crucial for maintaining this balance. N-cadherin and beta-catenin associate with the KIF3 complex by co-immunoprecipitation, and colocalize with KIF3 in cells. Furthermore, in KAP3-deficient cells, the subcellular localization of N-cadherin was disrupted. Taken together, these results suggest a potential tumour-suppressing activity for this molecular motor.

Conditional deletion of neuronal cyclin-dependent kinase 5 in developing forebrain results in microglial activation and neurodegeneration.

Neuronal migration disorders are often identified in patients with epilepsy refractory to medical treatment. The prolonged or repeated seizures are known to cause neuronal death; however, the mechanism underlying seizure-induced neuronal death remains to be elucidated. An essential role of cyclin-dependent kinase 5 (Cdk5) in brain development has been demonstrated in Cdk5(-/-) mice, which show neuronal migration defects and perinatal lethality. Here, we show the consequences of Cdk5 deficiency in the postnatal brain by generating Cdk5 conditional knockout mice, in which Cdk5is selectively eliminated from neurons in the developing forebrain. The conditional mutant mice were viable, but exhibited complex neurological deficits including seizures, tremors, and growth retardation. The forebrain not only showed disruption of layering, but also neurodegenerative changes accompanied by neuronal loss and microglial activation. The neurodegenerative changes progressed with age and were accompanied by up-regulation of the neuronal tissue-type plasminogen activator, a serine protease known to mediate microglial activation. Thus age-dependent neurodegeneration in the Cdk5 conditional knockout mouse brain invoked a massive inflammatory reaction. These findings indicate an important role of Cdk5 in inflammation, and also provide a mouse model to examine the possible involvement of inflammation in the pathogenesis of progressive cognitive decline in patients with neuronal migration disorders.

Multiplex families with multiple system atrophy.

BACKGROUND: Multiple system atrophy (MSA) has been considered a sporadic disease, without patterns of inheritance. OBJECTIVE: To describe the clinical features of 4 multiplex families with MSA, including clinical genetic aspects. DESIGN: Clinical and genetic study. SETTING: Four departments of neurology in Japan. Patients Eight patients in 4 families with parkinsonism, cerebellar ataxia, and autonomic failure with age at onset ranging from 58 to 72 years. Two siblings in each family were affected with these conditions. MAIN OUTCOME MEASURES: Clinical evaluation was performed according to criteria by Gilman et al. Trinucleotide repeat expansion in the responsible genes for the spinocerebellar ataxia (SCA) series and for dentatorubral-pallidoluysian atrophy (DRPLA) was evaluated by polymerase chain reaction. Direct sequence analysis of coding regions in the alpha-synuclein gene was performed. RESULTS: Consanguineous marriage was observed in 1 of 4 families. Among 8 patients, 1 had definite MSA, 5 had probable MSA, and 2 had possible MSA. The most frequent phenotype was MSA with predominant parkinsonism, observed in 5 patients. Six patients showed pontine atrophy with cross sign or slitlike signal change at the posterolateral putaminal margin or both on brain magnetic resonance imaging. Possibilities of hereditary ataxias, including SCA1 (ataxin 1, ATXN1), SCA2 (ATXN2), Machado-Joseph disease/SCA3 (ATXN1), SCA6 (ATXN1), SCA7 (ATXN7), SCA12 (protein phosphatase 2, regulatory subunit B, beta isoform; PP2R2B), SCA17 (TATA box binding protein, TBP) and DRPLA (atrophin 1; ATN1), were excluded, and no mutations in the alpha-synuclein gene were found. CONCLUSIONS: Findings in these multiplex families suggest the presence of familial MSA with autosomal recessive inheritance and a genetic predisposition to MSA. Molecular genetic approaches focusing on familial MSA are expected to provide clues to the pathogenesis of MSA.

[A 52-year-old woman with dyskinesia, epilepsy and gait disturbance].

We report a 52-year-old Japanese woman who developed dyskinesia, epilepsy, and gait disturbance. She was well until 35 years of age, when she noted the onset of gait disturbance. She also noted abnormal involuntary movements in her limbs. She also noted dysarthria at age 38. A neurologist examined her at age 41. The neurologist found cerebellar ataxia and dyskinesia. The atrophy of the brain stem and the cerebellum was on CT. She started to have generalized convulsion with loss of consciousness. Dementia became apparent at age 40. In October, 1993, she became psychotic in which she behaved violently taking off her clothes shouting as "Fire". She was treated with major tranquilizers and became quiet. However, choreic movements became prominent. Her subsequent course was complicated with dysphagia, dementia, convulsion, and frequent bouts of pneumonia. She expired on January 24, 2000 after developing pneumonia. Her father and one sibling had similar motor disturbances. She was discussed in a neurological CPC. The chief discussant arrived at conclusion that the patient had dentatorubral-pallidoluysian atrophy. Most of the participants agreed with this diagnosis. Postmortem examination revealed that entire brain looked smaller than normal including the brain stem and the cerebellum. The cerebellar dentate nucleus showed loss of neurons and gliosis; glumose degenerations were also seen. The external segment of the pallidum showed neuronal loss and gliosis. The subthalamic nucleus showed gliosis without neuronal loss. A demyelinated focus was found in the pons; the lesion looked similar to central pontine myelinolysis. The cerebral white matters were unremarkable. Other areas were unremarkable. The pathological diagnosis was dentatorubral-pallidoluysian atrophy. The pathologic lesion which might explain her dementia was not apparent.

Cdk5 is required for multipolar-to-bipolar transition during radial neuronal migration and proper dendrite development of pyramidal neurons in the cerebral cortex.

The mammalian cerebral cortex consists of six layers that are generated via coordinated neuronal migration during the embryonic period. Recent studies identified specific phases of radial migration of cortical neurons. After the final division, neurons transform from a multipolar to a bipolar shape within the subventricular zone-intermediate zone (SVZ-IZ) and then migrate along radial glial fibres. Mice lacking Cdk5 exhibit abnormal corticogenesis owing to neuronal migration defects. When we introduced GFP into migrating neurons at E14.5 by in utero electroporation, we observed migrating neurons in wild-type but not in Cdk5(-/-) embryos after 3-4 days. Introduction of the dominant-negative form of Cdk5 into the wild-type migrating neurons confirmed specific impairment of the multipolar-to-bipolar transition within the SVZ-IZ in a cell-autonomous manner. Cortex-specific Cdk5 conditional knockout mice showed inverted layering of the cerebral cortex and the layer V and callosal neurons, but not layer VI neurons, had severely impaired dendritic morphology. The amount of the dendritic protein Map2 was decreased in the cerebral cortex of Cdk5-deficient mice, and the axonal trajectory of cortical neurons within the cortex was also abnormal. These results indicate that Cdk5 is required for proper multipolar-to-bipolar transition, and a deficiency of Cdk5 results in abnormal morphology of pyramidal neurons. In addition, proper radial neuronal migration generates an inside-out pattern of cerebral cortex formation and normal axonal trajectories of cortical pyramidal neurons.

Perinatal abrogation of Cdk5 expression in brain results in neuronal migration defects.

Cyclin-dependent kinase 5 (Cdk5) is essential for the proper development of the CNS, as is evident from the perinatal lethality of conventional Cdk5 knockout (Cdk5-/-) mice. Cdk5 is also implicated in numerous complex functions of the adult CNS such as synaptic transmission, synaptic plasticity, and neuronal signaling. To elucidate the molecular roles of Cdk5 in the adult CNS, we have abrogated neuronal expression of Cdk5 in perinatal mice by using a cre-loxP system. The Cdk5-loxP flanked mice were crossed with the cre-transgenic mice in which the cre expression is driven by the murine neurofilament-heavy chain promoter, resulting in generation of viable Cdk5 conditional knockout mice with the restricted deletion of the Cdk5 gene in specific neurons beginning around embryonic day 16.5. Twenty-five percent of the Cdk5 conditional knockout mice carrying the heterozygous cre allele had neuronal migration defects confined to brain areas where neuronal migration continues through the perinatal period. These results indicate that abrogation of Cdk5 expression in mature neurons results in a viable mouse model that offers further opportunities to investigate the molecular roles of Cdk5 in the adult CNS.