Inosine 5'-Monophosphate to Raise Serum Uric Acid Level in Multiple System Atrophy (IMPROVE-MSA study).

The aim of this trial was to investigate the safety, tolerability, and capability of serum uric acid (UA) elevation of inosine 5'-monophosphate (IMP) in multiple system atrophy (MSA). The IMPROVE-MSA trial was a randomized, double-blind, placebo-controlled trial in patients with MSA with no history of hyperuricemia-related disorders. The participants were assigned to placebo (n = 25) or IMP (n = 30) in a 1 to 1 ratio, and then followed up for 24 weeks. The primary end points included safety, tolerability, and alteration of the serum UA level during the follow-up period. The secondary end points were changes in scores of the unified MSA rating scale (UMSARS) and the Mini-Mental Status Examination (MMSE) and Montreal Cognitive Assessment (MoCA). The total number of adverse events (AEs) and serious AEs was comparable between the active and placebo groups. Serum UA level (mg/dL) was significantly increased from baseline (active vs. placebo, 4.57 vs. 4.58; P = 0.98) to study end point (6.96 vs. 4.43; P < 0.001) in the active group compared with the placebo group (time × group interaction; P < 0.001). The change in UMSARS scores did not differ between the active and placebo groups. However, the active group showed better alterations in MoCA scores with nominal significance (P < 0.001) and tendency for better alterations in MMSE scores (P = 0.09) than the placebo group. Our data demonstrated that IMP treatment was generally safe and well-tolerated in patients with MSA. A further trial with a long-term follow-up is required to examine whether UA elevation will slow clinical progression in early MSA.

Early-onset mild cognitive impairment in Parkinson's disease: Altered corticopetal cholinergic network.

Degeneration of the substantia innominata (SI) is significantly correlated with cognitive performance in Parkinson's disease (PD). We examined functional and structural patterns of SI degeneration in drug-naïve PD patients according to the duration of parkinsonism before mild cognitive impairment (MCI) diagnosis. Twenty PD patients with a shorter duration (PD-MCI-SD, <1 year), 18 patients with a longer duration (PD-MCI-LD, ≥1 year), and 29 patients with intact cognition (PD-IC) were included. Seed-based resting-state functional connectivity (rsFC) analysis using bilateral SI seed and region-of-interest-based volumetric analysis were performed. Compared to PD-IC, the collapsed PD-MCI group showed altered rsFC in the right frontal and bilateral parietal areas. PD-MCI-SD showed rsFC alteration in broader frontal and parietal areas compared to the other groups. Decreased rsFC in the right frontal area was also significantly correlated with shorter disease duration. No significant SI volume change was found between the groups. Altered rsFC between the SI and the frontal and parietal areas might be relevant to cognitive dysfunction in PD. Decreased rsFC between the SI and frontal area might be associated with early-onset MCI, suggesting that cholinergic deficits in the frontal brain areas might play an important role in the acceleration of cognitive decline in PD.

Feasibility and Efficacy of Intra-Arterial Administration of Mesenchymal Stem Cells in an Animal Model of Double Toxin-Induced Multiple System Atrophy.

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease of the central and autonomic nervous system. Because no drug treatment consistently benefits MSA patients, neuroprotective strategy using mesenchymal stem cells (MSCs) has a lot of concern for the management of MSA. In this study, we investigated the safety and efficacy of intra-arterial administration of MSCs via internal carotid artery (ICA) in an animal model of MSA. The study was composed of feasibility test using a ×10 and ×50 of a standard dose of MSCs (4 × 107 MSCs) and efficacy test using a ×0.2, ×2, and ×20 of the standard dose. An ultrasonic flow meter and magnetic resonance imaging (MRI) showed that no cerebral ischemic lesions with patent ICA blood flow was were observed in animals receiving a ×10 of the standard dose of MSCs. However, no MSA animals receiving a ×50 of the standard dose survived. In efficacy test, animals injected with a ×2 of the standard dose increased nigrostriatal neuronal survival relative to a ×0.2 or ×20 of the standard dose. MSA animals receiving MSCs at ×0.2 and ×2 concentrations of the standard dose exhibited a significant reduction in rotation behavior relative to ×20 of the standard dose of MSCs. Cerebral ischemic lesions on MRI were only observed in MSA animals receiving a ×20 of the standard dose. The present study revealed that if their concentration is appropriate, intra-arterial injection of MSCs is safe and exerts a neuroprotective effect on striatal and nigral neurons with a coincidental improvement in motor behavior. Stem Cells Translational Medicine 2017;6:1424-1433.