Involvement of cortical dysfunction in frequent falls in patients with Parkinson's disease.

INTRODUCTION: Gait and balance disorders are common clinical features of Parkinson's disease (PD). Although falls significantly affect the activities of daily living (ADL) and quality of life (QOL) of patients with PD, the underlying neural mechanisms associated with frequent falls in PD patients are still unclear. METHODS: Hypothesizing that the cerebral cortex would contribute to frequent falls in PD, we obtained 3D T1-weighted images from 91 non-dementia patients with PD and performed voxel-based morphometric analysis (VBM). Gray matter volume was compared between patients with and without frequent falls to investigate the structural basis for frequent falls in PD. As an ancillary analysis, we also performed resting-state functional magnetic resonance analysis using data from 58 patients. RESULTS: Among the 91 patients, 36 had experienced frequent falls. Gray matter volume in the right superior temporal gyrus (STG) and the right inferior parietal lobule (IPL) of these patients was significantly lower than that of the non-frequent fallers. There was also a significant correlation between fall frequency and gray matter volume in these two regions. Additionally, resting-state functional analysis revealed lower connectivity in the right posterior perisylvian region, including in the IPL and STG, in frequent fallers than in non-frequent fallers. CONCLUSION: Frequent falls in PD are associated with structural and functional abnormality of the cerebral cortex including the right IPL and STG.

Critical role for constitutive type I interferon signaling in the prevention of cellular transformation.

Interferons-alpha/beta, which are produced upon viral infection, are key soluble factors for the establishment of an antiviral state, but are also produced at low levels in the absence of infection. Herein, we demonstrate that a weak signal by these constitutively produced IFN-alpha/beta show a preventive role in cellular transformation. Ifnar1-deficient (Ifnar1(-/-)) MEF, which are devoid of IFN-alpha/beta signal, undergo a spontaneous transformation during long-term cell culture. Similar to Irf1(-/-) MEF, primary Ifnar1(-/-) MEF become tumorigenic in nude mice by the expression of activated c-Ha-Ras oncoprotein. However, Ifnar1(-/-) MEF do not show any abnormal growth properties. A similar observation is made in Ifnb(-/-) MEF that fail to produce constitutive IFN-alpha/beta, whereas such a transforming property is not found in MEF that lack any of the IFN receptor downstream molecules including Stat1, IRF9 and IRF1. Furthermore, Ifnar1(-/-) mice develop chemically-induced skin papilloma more severely than wild-type mice. In addition, the expression levels of IFNAR1 mRNA are significantly decreased in human gastric cancer tissues. These results suggest a cell-intrinsic role of the weak signal by constitutively produced IFN-alpha/beta to prevent cells from transformation, which may be mediated by a hitherto-unknown pathway(s) downstream of the IFN-alpha/beta receptor.