IMPORTANCE This study evaluated nilotinib safety and its effects on biomarkers as a potential disease-modifying drug in Parkinson disease.OBJECTIVES To assess nilotinib effects on safety and pharmacokinetics and measure the change in exploratory biomarkers in patients with moderately severe Parkinson disease. DESIGN, SETTING, AND PARTICIPANTSThis was a single-center, phase 2, randomized, double-blind, placebo-controlled trial with 300 patients approached in clinic; of these, 200 declined to participate, 100 were screened, 25 were excluded, and 75 were randomized 1:1:1 into placebo; nilotinib, 150-mg; or nilotinib, 300-mg groups. Recruitment started on May 17, 2017, and ended April 28, 2018, and follow-up ended August 10, 2019. Parkinson disease was confirmed according to the UK Brain Bank diagnostic criteria and symptoms were stabilized with use of optimal levodopa and/or dopamine agonists and other medications used in Parkinson disease.INTERVENTIONS Nilotinib vs placebo, administered orally once daily for 12 months followed by a 3-month washout period.MAIN OUTCOMES AND MEASURES It was hypothesized that nilotinib is safe and can be detected in the cerebrospinal fluid, where it alters exploratory biomarkers via inhibition of Abelson tyrosine kinase and potentially improves clinical outcomes. RESULTSOf the 75 patients included in the study, 55 were men (73.3%); mean (SD) age was 68.4 (8.2) years. Doses of 150 or 300 mg of nilotinib were reasonably safe, although more serious adverse events were detected in the nilotinib (150 mg: 6 [24%]; 300 mg: 12 [48%]) vs placebo (4 [16%]) groups. The 150-mg nilotinib group showed an increase in cerebrospinal fluid levels of the dopamine metabolites homovanillic acid (159.80nM; 90% CI, 7.04-312.60nM; P = .04) and 3,4-dihydroxyphenylacetic acid (4.87nM; 90% CI, 1.51-8.23nM; P = .01), and the 300-mg nilotinib group showed an increase in 3,4-dihydroxyphenylacetic acid (7.52nM; 90% CI, 2.35-12.69nM; P = .01). The nilotinib 150-mg but not the nilotinib 300-mg group demonstrated a reduction of α-synuclein oligomers (−0.04 pg/mL; 90% CI, −0.08 to 0.01 pg/mL; P = .03). A significant reduction of hyperphosphorylated tau levels was seen in the nilotinib 150-mg (−10.04 pg/mL; 90% CI, −17.41 to −2.67 pg/mL; P = .01) and nilotinib 300-mg (−12.05 pg/mL; 90% CI, −19.21 to −4.90 pg/mL; P = .01) groups.CONCLUSIONS AND RELEVANCE In this study, nilotinib appeared to be reasonably safe and detectable in the cerebrospinal fluid. Exploratory biomarkers were altered in response to nilotinib. Taken together, these data will guide the development of a phase 3 study to investigate the effects of nilotinib therapy in patients with Parkinson disease. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02954978

Objective Preclinical evidence with nilotinib, a US Food and Drug Administration (FDA)‐approved drug for leukemia, indicates improvement in Alzheimer's disease phenotypes. We investigated whether nilotinib is safe, and detectable in cerebrospinal fluid, and alters biomarkers and clinical decline in Alzheimer's disease. Methods This single‐center, phase 2, randomized, double‐blind, placebo‐controlled study investigated the safety, tolerability, and pharmacokinetics of nilotinib, and measured biomarkers in participants with mild to moderate dementia due to Alzheimer's disease. The diagnosis was supported by cerebrospinal fluid or amyloid positron emission tomography biomarkers. Nilotinib 150 mg versus matching placebo was taken orally once daily for 26 weeks followed by nilotinib 300 mg versus placebo for another 26 weeks. Results Of the 37 individuals enrolled, 27 were women and the mean (SD) age was 70.7 (6.48) years. Nilotinib was well‐tolerated, although more adverse events, particularly mood swings, were noted with the 300 mg dose. In the nilotinib group, central nervous system (CNS) amyloid burden was significantly reduced in the frontal lobe compared to the placebo group. Cerebrospinal fluid Aβ40 was reduced at 6 months and Aβ42 was reduced at 12 months in the nilotinib group compared to the placebo. Hippocampal volume loss was attenuated (−27%) at 12 months and phospho‐tau‐181 was reduced at 6 months and 12 months in the nilotinib group. Interpretation Nilotinib is safe and achieves pharmacologically relevant cerebrospinal fluid concentrations. Biomarkers of disease were altered in response to nilotinib treatment. These data support a larger, longer, multicenter study to determine the safety and efficacy of nilotinib in Alzheimer's disease. ANN NEUROL 2020 ANN NEUROL 2020;88:183–194

Background Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with substantial morbidity and mortality. Its prevalence is currently rising partly due to population ageing. However, reported trends in incidence rates are conflicting, and the comparability of existing reports is limited due to methodological inconsistencies across studies. Purpose The main purpose of the current study was to investigate the prevalence of AF in the Danish adult population and time trends in incidence rates from 2004 through 2018. As a secondary purpose, the prevalence and incidence were compared to corresponding Norwegian estimates from 2004 through 2014 derived using the same methodology. Methods A register-based study was conducted including all individuals aged ≥18 years in Denmark from 2004–2018. AF cases were identified in the National Patient Register and the Cause of Death Register, which comprise information on all hospital contacts and deaths in Denmark, respectively. The prevalence of AF was calculated as the number of individuals alive at the end of the study period with at least one registered diagnosis from 1994 through 2018 divided by the number of Danish residents aged ≥18 years. Incidence rates were calculated as the number of annual AF cases with no previous diagnosis noted in the past 10 years divided by the person-time contributed by the population free of AF on 1 January in the same calendar year. All incidence rates were standardized according to a Nordic standard population. The comparison of the Danish and Norwegian incidence estimates focused solely on AF hospitalizations and deaths from 2004 through 2014. Results The cumulative prevalence of AF was 3.0% in the Danish adult population. The incidence increased from 391 per 100,000 person-years in 2004 to 481 per 100,000 person-years in 2015, after which it declined to 367 per 100,000 person-years in 2018 (Figure 1). On average, the incidence increased by 1.7% annually until 2015 (IRR: 1.017 (95% CI: 1.016–1.018); p<0.001) and then declined by 8.5% (IRR: 0.915 (95% CI: 0.909–0.921); p<0.001). Although the incidence rates generally were higher among men and older individuals, a similar time trend was observed in both men and women irrespective of age. Focusing solely on AF hospitalizations and deaths did not change the interpretation of the results. The comparable Norwegian estimates will be presented at the conference. Conclusions The prevalence of AF is currently around 3.0% in the Danish adult population, but the incidence rate has declined steeply since 2015. The observed decline in new cases is promising from a public health perspective and its underlying causes warrant further investigation. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Foundation Figure 1

Objective: To assess the frequency of proteus mirabilis infections in patients of rheumatoid arthritis. Study Design: Cross-sectional study. Place and Duration of Study: Combined Military Hospital, Rawalpindi Pakistan, from Jul 2018 to Jan 2019. Methodology: A total of 100 cases of rheumatoid arthritis with urinary tract infection were enrolled. Freshly voided urine samples were obtained and sent to the pathology lab. The serotypes of proteus mirabilis were evaluated by enzyme-linked immunosorbent assay (ELISA) and immunoblotting and presence of proteus mirabilis was noted. Results: A total of 100 cases of rheumatoid arthritis with urinary tract infection were recruited. The mean age of patients was 61.22 ± 10.18 years. There were total 67 (67%) females and 33 (33%) were males. About 79 (79%) patients had sedentary lifestyle while 21 (21%) had active lifestyle. There were 41 (41%) patients had positive urine culture with proteus mirabilis while 59 (59%) had other organism involved in urine infection. Conclusion: The high frequency of proteus mirabilis infection has been detected and the frequency was of females with complaint of urinary tract infection was high.