Comparison Study of Polysomnographic Features in Multiple System Atrophy-cerebellar Types Combined with and without Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: The brain stem is found to be impaired in multiple system atrophy-cerebellar types (MSA-C). Rapid eye movement (REM) sleep behavior disorder (RBD) is reported as a marker of progressive brain stem dysfunction. Few systematic studies about the sleep disturbances in MSA-C patients combined with or without RBD were reported. This study aimed to explore the polysomnographic (PSG) features of sleep disturbances between MSA-C patients with and without RBD. METHODS: Totally, 46 MSA-C patients (23 with RBD, and 23 without RBD) were enrolled in this study. All patients underwent a structured interview for their demographic data, history of sleep pattern, and movement disorders; and then, overnight video-PSG was performed in each patient. All the records were evaluated by specialists at the Sleep Medicine Clinic for RBD and the Movement Disorder Clinic for MSA-C. The Student's t-test, Mann-Whitney U-test for continuous variables, and the Chi-square test for categorical variables were used in this study. RESULTS: MSA-C patients with RBD had younger visiting age (52.6 ± 7.4 vs. 56.7 ± 6.0 years, P = 0.046) and shorter duration of the disease (12.0 [12.0, 24.0] vs. 24.0 [14.0, 36.0] months, P = 0.009) than MSA-C patients without RBD. MSA-C with RBD had shorter REM sleep latency (111.7 ± 48.2 vs. 157.0 ± 68.8 min, P = 0.042), higher percentage of REM sleep (14.9% ±4.0% vs. 10.0% ± 3.2%, P = 0.019), and lower Stage I (9.5% ±7.2% vs. 15.9% ±8.0%, P = 0.027) than MSA-C without RBD. Moreover, MSA-C patients with RBD had more decreased sleep efficiency (52.4% ±12.6% vs. 65.8% ±15.9%, P = 0.029) than that without RBD. CONCLUSIONS: In addition to the RBD, MSA-C patients with RBD had other more severe sleep disturbances than those without RBD. The sleep disorders of MSA patients might be associated with the progress of the disease.

Deletion of Inpp5a causes ataxia and cerebellar degeneration in mice.

The progressive and permanent loss of cerebellar Purkinje cells (PC) is a hallmark of many inherited ataxias. Mutations in several genes involved in the regulation of Ca(2+) release from intracellular stores by the second messenger IP3 have been associated with PC dysfunction or death. While much is known about the defects in production and response to IP3, less is known about the defects in breakdown of the IP3 second messenger. A mutation in Inpp4a of the pathway is associated with a severe, early-onset PC degeneration in the mouse model weeble. The step preceding the removal of the 4-phosphate is the removal of the 5-phosphate by Inpp5a. Gene expression analysis was performed on an Inpp5a (Gt(OST50073)Lex) mouse generated by gene trap insertion using quantitative real-time PCR (qRT-PCR), immunohistochemistry, and Western blot. Phenotypic analyses were performed using rotarod, ß-galactosidase staining, and phosphatase activity assay. Statistical significance was calculated. The deletion of Inpp5a causes an early-onset yet slowly progressive PC degeneration and ataxia. Homozygous mutants (90%) exhibit perinatal lethality; surviving homozygotes show locomotor instability at P16. A consistent pattern of PC loss in the cerebellum is initially detectable by weaning and widespread by P60. Phosphatase activity toward phosphoinositol substrates is reduced in the mutant relative to littermates. The ataxic phenotype and characteristics neurodegeneration of the Inpp5a (Gt(OST50073)Lex) mouse indicate a crucial role for Inpp5a in PC survival. The identification of the molecular basis of the selective PC survival will be important in defining a neuroprotective gene applicable to establishing a disease mechanism.

[Molecular biological analysis of the development of the mammalian central nervous system].

Analysis of the neuropathological mutant animals offers us great information on the development and differentiation of the nervous system. I have here introduced two examples of the analyses of the various kinds of neuropathological mutant mice. First one is the mutant mice where Purkinje neurons in the cerebellum are absent. High molecular weight protein, P400, enriched in the Purikinje cells in the cerebellum was greatly decreased in the Purkinje cell deficient mutant mice, nervous, pcd, Lurcher. We demonstrated that P400 is equivalent to IP3 receptor type 1. We found that IP3 receptor type 1 plays an important role in Ca2+ wave in fertilization and long term depression in the cerebellum which is one of the typical example of neuronal plasticity in the cerebellum. Second mutant is reeler mice where neuronal positioning in the brain is abnormal. We found CR50 antigen, reelin is the key molecule as a secreted molecule from Cajal-Retzius neuron for the neuronal positioning. We produced IP3 receptor deficient mice by gene targeting. The birth rate was one fifth of the control and the animals die before 25 postnatal days. They showed cerebellar ataxia and epileptic seizure.

Development of the cerebellar defect in ataxic SELH/Bc mice.

In SELH/Bc mice, 5-10% of young adults are ataxic, due to a midline cleft in the cerebellum. An additional 10-20% of SELH/Bc embryos have exencephaly and die at birth. All SELH/Bc embryos omit a normal step in cranial neural tube closure, initiation of fusion at Closure 2. In the 80-90% that complete cranial neural tube closure, the last region of closure, on late D9, is the region of the prospective cerebellum, and its closure is late. We postulated that the cleft cerebellum in ataxic SELH/Bc mice derives from this delay in neural tube closure and predicted that we would see evidence of a cerebellar midline cleft in all earlier stages after cranial neural tube closure is normally complete. In the present study we show that the cerebellum is cleft in a 7-9% proportion of SELH/Bc D16 fetuses (2/28) and D11 embryos (15/167), and that the defect is detectable on D10. In these abnormal D16 fetuses, D11 and D10 embryos, there is a gap in midline continuity of cerebellar neuroepithelium, a finding consistent with our hypothesis that the neuroepithelium in this region fails to complete fusion in those embryos. We also show that cerebella of adult SELH/Bc ataxic mice have no obvious deficiency of lobules, or disorganization of tissue as in the Wnt-1 mutants.