Dashtipour, Khashayar

Objective: To determine and compare DNA methylation patterns between patients with Parkinson’s disease (PD) and age- and sex-similar matched non-PD controls. Background: Epigenetic regulation is one of the major mechanisms for an organism to respond to the environment through changes in gene expression and has been implicated in numerous disease processes. We would like to examine epigenetic modification patterns that may predispose or protect against PD. Methods: Frozen tissue samples of the human cerebral cortex from 12 PD patients and 12 subjects without PD pathology were obtained. Genome-wide DNA methylation profiling was performed using the Illumina HumanMethylation450 BeadChip array. Differential methylation was defined as a mean methylation level difference (delta β) of at least 0.20 (Δβ ≥ 0.20). Methylation regions with an absolute delta β value ≥ 0.20 were selected for further gene function studies. Results: We identified 2795 differentially methylated CpG sites in the frontal cortex of PD cases with a detection p-value of ≤ 0.01 and 328 differentially methylated CpG sites with a detection p-value of ≤ 0.001. A pattern of robust hypermethylation of synphilin-1, α-synuclein-interacting protein (SNCAIP) gene was found in the brain of PD cases (p = 4.93 × 10−7 and delta β = 0.60). Conclusion: Our findings support a link between SNCAIP methylation and PD risk. Hypomethylation of SNCAIP may function to protect against PD. The current results may suggest that the methylation status of SNCAIP could be useful as a marker in PD diagnosis and treatment and warrants further investigation.

Objectives: This is the first of a pair of studies designed to assess efficacy, safety and tolerability of onabotulinumtoxinA (BOTOX®) as headache prophylaxis in adults with chronic migraine. Methods: The Phase III REsearch Evaluating Migraine Prophylaxis Therapy 1 (PREEMPT 1) is a phase 3 study, with a 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections every 12 weeks of onabotulinumtoxinA (155 U–195 U; n = 341) or placebo ( n = 338) (two cycles). The primary endpoint was mean change from baseline in headache episode frequency at week 24. Results: No significant between-group difference for onabotulinumtoxinA versus placebo was observed for the primary endpoint, headache episodes (−5.2 vs. −5.3; p = 0.344). Large within-group decreases from baseline were observed for all efficacy variables. Significant between-group differences for onabotulinumtoxinA were observed for the secondary endpoints, headache days ( p = .006) and migraine days ( p = 0.002). OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few subjects discontinued due to adverse events. Conclusions: There was no between-group difference for the primary endpoint, headache episodes. However, significant reductions from baseline were observed for onabotulinumtoxinA for headache and migraine days, cumulative hours of headache on headache days and frequency of moderate/severe headache days, which in turn reduced the burden of illness in adults with disabling chronic migraine.