Sirs: Hypocretins/orexins are hypothalamic neuropeptides that are related to sleep-wake regulation [1,10]. It has been reported that cerebrospinal fluid (CSF) hypocretin-1/orexin-A level is dramatically decreased in narcolepsy-cataplexy [4,8,9,11]. Narcolepsy is also known to occur secondary to hypothalamic lesions caused by tumors, stroke, multiple sclerosis (MS) or acute disseminated encephalomyelitis, and the CSF hypocretin-1 level is decreased in some of them [5][6][7]12]. However, it remains unclear whether CSF hypocretin level correlates with the severity of hypersomnia and the REM pathology.We reported the MRI finding of bilateral hypothalamic lesions in a case of MS presenting with hypersomnia [3]. We further examined details of sleep investigations and correlated them with CSF hypocretin-1 level and the MRI findings.A 22-year-old woman was admitted to our hospital one week after the acute onset of hypersomnia. She had developed diplopia as an initial symptom of MS one year before the onset of hypersomnia. She also complained of numbness of the lower extremities and polyuria. She did not experience any narcolepsy-related symptoms such as cataplexy, sleep paralysis and hypnagogic hallucination. MRI revealed bilateral FLAIR hyperintensity in the hypothalamus [3].

Creutzfeldt-Jakob disease (CJD) is characterized by rapidly progressive dementia with a variety of neurological disorders and a fatal outcome. The authors present a case with visual disturbance as a leading symptom and rapid deterioration in global cognitive functions. The cerebrospinal fluid was positive for 14-3-3 protein, and diffusion-weighted magnetic resonance imaging (MRI) showed marked hyperintensity in the parieto-occipital cortices, where hypometabolism was clearly detected on positron emission tomography (PET). Pattern-reversal visual evoked potentials showed prolonged P100 latencies and increased N/5/P100 amplitudes. All these findings supported a diagnosis of the Heidenhain variant of CJD, whereas a long clinical course, a lack of myoclonus, and an absence of periodic synchronous discharges on electroencephalography were atypical. Diffusion-weighted MRI and PE1 in combination with visual evoked potential recording and 14-3-3 protein detection may be useful for the early diagnosis of CJD.

IntroductIonA myotrophic laterals sclerosis (als) is a devastating neurodegenerative disease that selectively involves motor neurons in the brain and spinal cord. als leads to muscle weakness, paralysis, and respiratory failure within 5 years of onset. Familial als (fals) accounts for about 10% of all als cases, and approximately 25% of fals cases are due to mutations in superoxide dismutase [cu-Zn] (sod1).

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Familial amyotrophic lateral sclerosis (fALS) accounts for 10% of ALS cases, and about 25% of fALS cases are due to mutations in superoxide dismutase 1 (SOD1). Mutant SOD1-mediated ALS is caused by a gain of toxic function of the mutant protein, and the SOD1 level in non-neuronal neighbors, including astrocytes, determines the progression of ALS (non-cell-autonomous toxicity). Therefore, we hypothesized that small molecules that reduce SOD1 protein levels in astrocytes might slow the progression of mutant SOD1-mediated ALS. We developed and optimized a cell-based, high-throughput assay to identify low molecular weight compounds that decrease SOD1 expression transcriptionally in human astrocyte-derived cells. Screening of a chemical library of 9,600 compounds with the assay identified two hit compounds that selectively and partially downregulate SOD1 expression in a dose-dependent manner, without any detectable cellular toxicity. Western blot analysis showed that one hit compound significantly decreased the level of endogenous SOD1 protein in H4 cells, with no reduction in expression of β-actin. The assay developed here provides a powerful strategy for discovering novel lead molecules for treating familial SOD1-mediated ALS.