There is a critical need for careful and independent validation of reported symptomatic efficacy and dopaminergic biomarker changes induced by nilotinib in Parkinson disease (PD).OBJECTIVES To assess safety and tolerability of nilotinib in participants with moderately advanced PD. Secondary and exploratory objectives were to assess its affect on PD disability, pharmacokinetics, cerebrospinal fluid (CSF) penetration, and biomarkers. DESIGN, SETTING, AND PARTICIPANTSThis was a 6-month, multicenter, randomized parallel-group, double-blind, placebo-controlled trial. Recruitment was from November 20, 2017, to December 28, 2018, and follow-up ended on September 9, 2019. The study was conducted at 25 US sites. The study approached 173 patients, of whom 48 declined, 125 were screened, and 76 who received a stable regimen of PD medications were enrolled (39% screen failure).INTERVENTIONS Participants were randomized 1:1:1 to placebo, 150-mg nilotinib, or 300-mg nilotinib once daily orally for 6 months, followed by 2-month off-drug evaluation. MAIN OUTCOMES AND MEASURESThe primary outcomes were safety and tolerability. The tolerability end point was defined as the ability to complete the study while receiving the assigned dose. An active arm was considered tolerable if the percentage of participants meeting the tolerability end point for that group was not significantly lower than the percentage observed in the placebo group. Secondary outcomes included change in PD disability (Movement Disorder Society Unified Parkinson's Disease Rating Scale [MDS-UPDRS], Part II OFF/ON). Exploratory outcomes included serum and CSF pharmacokinetic profile, and CSF dopaminergic biomarkers.RESULTS At baseline, mean (SD) participants' age was 64.6 (7.5) years, 52 were male (68%), mean (SD) disease duration was 9.9 years (4.7), MDS-UPDRS Part 1-3 OFF score was 66.4 (19.3), ON score was 48.4 (16.2), and Montreal Cognitive Assessment score was 27.1 (2.2). The number of participants who completed the study receiving the assigned dose were 21 (84%), 19 (76%), and 20 (77%) in the placebo, 150-mg, and 300-mg arms, respectively. Both active doses had acceptable safety profile. The most common reasons for drug suspension were asymptomatic, dose-dependent elevations of amylase, and/or lipase. Nilotinib, 150 mg and 300 mg, exhibited worse MDS-UPDRS-3 ON scores compared with placebo, achieving significance for nilotinib, 300 mg, at month 1 (P < .01). There was no difference in the change of MDS-UPDRS-3 OFF from baseline to 6 months between groups (P = .17). Cerebrospinal fluid/serum ratio of nilotinib concentration was 0.2% to 0.3%. There was no evidence of treatment-related alteration of dopamine metabolites in the CSF.CONCLUSIONS AND RELEVANCE While we demonstrated acceptable safety and tolerability of nilotinib in our cohort, the low CSF exposure and lack of biomarkers effect combined with the efficacy data trending in the negative direction indicate that nilotinib should not be further tested in PD.

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Many reading comprehension measures require the student to read silently. When students read silently, important information (e.g., consistent reading errors) may not be identified. It may also be difficult to detect a student who is choosing not to read the passage. For this reason, investigating whether there is a significant difference in comprehension under silent and aloud reading conditions is important to determine under what conditions reading comprehension should be measured accurately. This study was designed to investigate possible differences between silent and aloud reading comprehension scores on Maze assessment probes. Pearson product correlations were used to investigate possible relationships between Maze comprehension scores (silent and aloud), WCPM, and the Broad Reading Cluster Score of the Woodcock -Johnson III Tests of Achievement (WJ-III ACH). Participants were 89 first-and second-grade students from an elementary school located in the Southeastern United States. Each student was exposed to four assessment conditions, which included WCPM, three tests from the WJ-III ACH, and Maze reading comprehension passages. Significant correlations were found for WCPM, aloud and silent Maze, and the WJ-III ACH Broad Reading Cluster Score. No significant difference was found between aloud and silent reading comprehension, which suggests that reading comprehension can be measured accurately under either reading condition. C

Symptom attribution-based diagnoses differ when using status quo versus the SACA. The MMPI-2-RF F-scale, compared with the Validity-10 and Letter Memory Test, may be more precise in identifying questionably valid profiles for mTBI + BH. The SACA provides a framework to inform clinical practice, resource allocation, and future research.