The distribution and dynamic density of oligodendroglial cytoplasmic inclusions (GCIs) were studied based on 30 cases of multiple system atrophy (MSA), including striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA) and Shy-Drager syndrome. GCIs were widely spread throughout the central nervous system, including the striatonigral and olivopontocerebellar systems. Inclusion-bearing cells appeared to be oligodendrocytes which usually had larger and lighter nuclei than those of normal-looking oligodendrocytes. The distribution of GCIs was similar in all cases, irrespective of the degrees of OPCA and SND, but the frequency of GCIs varied from case to case. We classified all the cases into two categories based on the degree of neuropathological changes of SND (mild and severe) and, independently, into three groups based on that of OPCA (minimal, moderate and severe), i.e., a total of six groups. An association between the frequency of GCIs and the severity of the lesions was obtained. For example, many GCIs were seen the cerebellar white matter in the cases in which OPCA was not histologically confirmed. More GCIs were seen in the cases with moderate OPCA. In the cases with severe OPCA, GCIs were rarer and smaller, in proportion to the devastation of fibers; no GCIs were seen in the cases with more severe OPCA. The incidence of GCIs showed a positive correlation to the severity of OPCA but not that of SND in the corticopontine tracts, of both OPCA and SND in the pyramidal tracts, and of SND but not of OPCA in the pencil fibers of the putamen. It is suggested that GCIs may represent either a change synchronous with neuronal degeneration or a phenomenon preceding neuronal changes, especially in the cerebellar white matter. Thus, they may represent the early changes in MSA and may be a useful neuropathological hallmark for diagnosis of MSA, even in cases with minimal OPCA and SND.

Leucine-rich repeat kinase 2 (LRRK2) is the causative molecule of the autosomal dominant hereditary form of Parkinson's disease (PD), PARK8, which was originally defined in a study of a Japanese family (the Sagamihara family) harboring the I2020T mutation in the kinase domain. Although a number of reported studies have focused on cell death mediated by mutant LRRK2, details of the pathogenetic effect of LRRK2 still remain to be elucidated. In the present study, to elucidate the mechanism of neurodegeneration in PD caused by LRRK2, we generated induced pluripotent stem cells (iPSC) derived from fibroblasts of PD patients with I2020T LRRK2 in the Sagamihara family. We found that I2020T mutant LRRK2 iPSC-derived neurons released less dopamine than control-iPSC-derived neurons. Furthermore, we demonstrated that patient iPSC-derived neurons had a lower phospho-AKT level than control-iPSC-derived neurons, and that the former showed an increased incidence of apoptosis relative to the controls. Interestingly, patient iPSC-derived neurons exhibited activation of glycogen synthase kinase-3β (GSK-3β) and high Tau phosphorylation. In addition, the postmortem brain of the patient from whom the iPSC had been established exhibited deposition of neurofibrillary tangles as well as increased Tau phosphorylation in neurons. These results suggest that I2020T LRRK2-iPSC could be a promising new tool for reproducing the pathology of PD in the brain caused by the I2020T mutation, and applicable as a model in studies of targeted therapeutics.

Fingolimod (FTY) is the first oral medication approved for treatment of relapsing–remitting multiple sclerosis (RRMS). Its effectiveness and safety were confirmed in several phase III clinical trials, but proper evaluation of safety in the real patient population requires long‐term post‐marketing monitoring. Since the approval of FTY for RRMS in Japan in 2011, it has been administered to approximately 5000 MS patients, and there have been side‐effect reports from 1750 patients. Major events included infectious diseases, hepatobiliary disorders, nervous system disorders and cardiac disorders. In the present review, we focus especially on central nervous system adverse events. The topics covered are: (i) clinical utility of FTY; (ii) safety profile; (iii) post‐marketing adverse events in Japan; (iv) white matter (tumefactive) lesions; (v) rebound after FTY withdrawal; (vi) relationship between FTY and progressive multifocal leukoencephalopathy; (vii) FTY and progressive multifocal leukoencephalopathy‐related immune reconstitution inflammatory syndrome; and (viii) neuromyelitis optica and leukoencephalopathy.

BackgroundVarious postural deformities appear during progression of Parkinson’s disease (PD), but the underlying pathophysiology of these deformities is not well understood. The angle abnormalities seen in individual patients may not be due to distinct causes, but rather they may have occurred in an interrelated manner to maintain a balanced posture.MethodsWe measured the neck flexion (NF), fore-bent (FB), knee-bent (KB) and lateral-bent (LB) angles in 120 PD patients, and examined their mutual relationships, and correlations with clinical predictors such as sex, age, disease duration, Hoehn and Yahr (H&Y) stage, medication dose (levodopa equivalent dose, LED; total dose of dopamine agonists, DDA). The relationship between the side of the initial symptoms and the direction of LB angle was also investigated.ResultsOur main findings were: (1) Significant relationships between NF and KB, NF and LB, FB and KB, KB and LB were observed. (2) NF angle was larger in males than in females, but FB, KB and LB angles showed no significant difference between the sexes. (3) FB and KB angles became larger with advancing age. (4) NF and FB angles were associated with disease duration. (5) NF, FB, KB and LB angles all increased significantly with increase of H&Y stage. (6) FB angle was significantly associated with LED, but DDA did not show a significant relationship with any of the measured angles. (7) Direction of LB angle was not associated with the side of initial symptoms.ConclusionsPostural abnormalities are interrelated, possibly to maintain a balanced posture.

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