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IMPORTANCE: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. OBJECTIVE: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. DESIGN, PARTICIPANTS, AND SETTING: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington&rsquo, s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington&rsquo, s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression.

BackgroundThere are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis.MethodsWe enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis.ResultsOf 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.ConclusionsIn a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Diffusion MRI tractography has been used to map the axonal structure of human brain, but its ability to detect neuronal injury is yet to be explored. Here we report differential tractography, a new type of tractography that utilizes repeat MRI scans and a novel tracking strategy to map the exact segment of fiber pathways with a neuronal injury. We examined differential tractography on multiple sclerosis, Huntington disease, amyotrophic lateral sclerosis, and epileptic patients. The results showed that the affected pathways shown by differential tractography matched well with the unique clinical symptoms of the patients, and the false discovery rate of the findings could be estimated using a sham setting to provide a reliability measurement. This novel approach enables a quantitative and objective method to monitor neuronal injury in individuals, allowing for diagnostic and prognostic evaluation of brain diseases.

Background Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and − 10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. Methods SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100 mg/day) or placebo for 96 weeks. Imaging is conducted every 24 weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. Results A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. Conclusion SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.

Object The optimal age and disease duration for consideration of deep brain stimulation (DBS) surgery are not well characterized in patients with Parkinson disease. The aim of this study was to assess variation in motor response to surgery among subgroups stratified by age and disease duration. Methods A total of 46 patients referred for DBS were recruited for the study. Preoperative dyskinesia and rigidity scores were recorded, and then patients received bilateral subthalamic nucleus stimulation. Preoperative motor scores were then compared with postoperative scores over 1 year. Results At 1 year postoperatively, patients with ≤ 10 years' disease duration showed a significant (45%) reduction in rigidity and a significant (64%) reduction in dyskinesia. Patients with > 10 years disease also showed a significant (70%) reduction in dyskinesia at 1 year postoperatively, but failed to show significant improvement in rigidity (31% reduction). Patients < 70 years old showed a significant (58%) improvement in rigidity and a significant (53%) improvement in dyskinesia. Finally, patients ≥ 70 years old showed a significant (90%) improvement in dyskinesia, but failed to show any significant change in rigidity at 1 year postoperatively. Conclusions The postoperative improvement in rigidity for younger patients with shorter disease duration may indicate that performing early surgery maximizes the benefit of DBS. However, older patients with primarily dyskinesia symptoms also appear to have significant clinical improvement, and DBS can offer relief from this common consequence of long-term levodopa use.

Diffusion MRI enabled in vivo microstructural imaging of the fiber tracts in the brain resulting in its application in a wide range of settings, including in neurological and neurosurgical disorders. Conventional approaches such as diffusion tensor imaging (DTI) have been shown to have limited applications due to the crossing fiber problem and the susceptibility of their quantitative indices to partial volume effects. To overcome these limitations, the recent focus has shifted to the advanced acquisition methods and their related analytical approaches. Advanced white matter imaging techniques provide superior qualitative data in terms of demonstration of multiple crossing fibers in their spatial orientation in a three dimensional manner in the brain. In this review paper, we discuss the advancements in diffusion MRI and introduce their roles. Using examples, we demonstrate the role of advanced diffusion MRI-based fiber tracking in neuroanatomical studies. Results from its preliminary application in the evaluation of intracranial space occupying lesions, including with respect to future directions for prognostication, are also presented. Building upon the previous DTI studies assessing white matter disease in Huntington's disease and Amyotrophic lateral sclerosis; we also discuss approaches which have led to encouraging preliminary results towards developing an imaging biomarker for these conditions.

Hepatocyte growth factor (HGF) and epidermal growth factor (EGF) are primary mitogens for hepatocytes in culture. hepatocytes express the HGF-receptor MET but not HGF itself. To investigate the influence of autocrine HGF expression on the proliferative potential of hepatocytes, primary cultures were submitted to retrovirus-mediated transduction of the human hgf (huHGF) cDNA. Expression of the transduced cDNA revealed a minimum 2-fold increase in HGF-mRNA, whereas expression of the Escherichia coli β-galactosidase gene remained even. Estimation of huHGF copy numbers showed there was a minimum 4-fold increase, suggesting an increase in the population of transduced cells. Immunoprecipitation of excreted huHGF and growth bioassays proofed that HGF was present and functional. HGF is excreted into the medium and therefore, by diffusion, available to transduced and non-transduced cells. The increase in huHGF-transduced cells suggests that the autocrine pathway as opposed to the paracrine pathway, which are both present at the same time, confers a growth advantage to these cells.

The optimal age and disease duration for consideration of deep brain stimulation (DBS) surgery are not well characterized in patients with Parkinson disease. The aim of this study was to assess variation in motor response to surgery among subgroups stratified by age and disease duration.A total of 46 patients referred for DBS were recruited for the study. Preoperative dyskinesia and rigidity scores were recorded, and then patients received bilateral subthalamic nucleus stimulation. Preoperative motor scores were then compared with postoperative scores over 1 year.At 1 year postoperatively, patients with ≤ 10 years' disease duration showed a significant (45%) reduction in rigidity and a significant (64%) reduction in dyskinesia. Patients with10 years disease also showed a significant (70%) reduction in dyskinesia at 1 year postoperatively, but failed to show significant improvement in rigidity (31% reduction). Patients70 years old showed a significant (58%) improvement in rigidity and a significant (53%) improvement in dyskinesia. Finally, patients ≥ 70 years old showed a significant (90%) improvement in dyskinesia, but failed to show any significant change in rigidity at 1 year postoperatively.The postoperative improvement in rigidity for younger patients with shorter disease duration may indicate that performing early surgery maximizes the benefit of DBS. However, older patients with primarily dyskinesia symptoms also appear to have significant clinical improvement, and DBS can offer relief from this common consequence of long-term levodopa use.

Diffusion MRI enabled in vivo microstructural imaging of the fiber tracts in the brain resulting in its application in a wide range of settings, including in neurological and neurosurgical disorders. Conventional approaches such as diffusion tensor imaging (DTI) have been shown to have limited applications due to the crossing fiber problem and the susceptibility of their quantitative indices to partial volume effects. To overcome these limitations, the recent focus has shifted to the advanced acquisition methods and their related analytical approaches. Advanced white matter imaging techniques provide superior qualitative data in terms of demonstration of multiple crossing fibers in their spatial orientation in a three dimensional manner in the brain. In this review paper, we discuss the advancements in diffusion MRI and introduce their roles. Using examples, we demonstrate the role of advanced diffusion MRI-based fiber tracking in neuroanatomical studies. Results from its preliminary application in the evaluation of intracranial space occupying lesions, including with respect to future directions for prognostication, are also presented. Building upon the previous DTI studies assessing white matter disease in Huntington's disease and Amyotrophic lateral sclerosis; we also discuss approaches which have led to encouraging preliminary results towards developing an imaging biomarker for these conditions.