Nilotinib Effects on Safety, Tolerability, and Biomarkers in Alzheimer's Disease.

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 Aß40 was reduced at 6 months and Aß42 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.

Systematic Review of Preventive and Acute Treatment of Menstrual Migraine.

OBJECTIVE: The aim of this systematic review is to identify the efficacy of different categories of treatments for menstrual migraines as found in randomized controlled trials or open label studies with similar efficacy endpoints. BACKGROUND: Menstrual migraine is very common and approximately 50% of women have increased risk of developing migraines related to the menstrual cycle. Attacks of menstrual migraine are usually more debilitating, of longer duration, more prone to recurrence, and less responsive to acute treatment than nonmenstrual migraine attacks. METHODS: Search for evidence was done in 4 databases that included PubMed, EMBASE, Science Direct, and Web of Science. Eighty-four articles were selected for full text review by 2 separate readers. Thirty-six of the 84 articles were selected for final inclusion. Articles included randomized controlled and open label trials that focused on efficacy of acute and preventative therapies for menstrual migraine. Secondary analyses where excluded because the initial study population was not women with menstrual migraine. RESULTS: After final screening, 11 articles were selected for acute and 25 for preventive treatment of menstrual migraine. These were further subdivided into treatment categories. For acute treatment: triptans, combination therapy, prostaglandin synthesis inhibitor, and ergot alkaloids. For preventive treatment: triptans, combined therapy, oral contraceptives, estrogen, nonsteroidal anti-inflammatory drug, phytoestrogen, gonadotropin-releasing hormone agonist, dopamine agonist, vitamin, mineral, and nonpharmacological therapy were selected. Overall, triptans had strong evidence for treatment in both acute and short term prevention of menstrual migraine. CONCLUSIONS: Based on this literature search, of all categories of treatment for menstrual migraine, triptans have the most extensive research with strong evidence for both acute and preventive treatment of menstrual migraine. Further randomized controlled trials should be performed for other therapies to strengthen their use in the care of menstrual migraine patients.

Action-effect binding is decreased in motor conversion disorder: implications for sense of agency.

The abnormal movements seen in motor conversion disorder are affected by distraction and entrainment, similar to voluntary movement. Unlike voluntary movement, however, patients lack a sense of control for the abnormal movements, a failure of "self-agency." The action-effect binding paradigm has been used to quantify the sense of self-agency, because subjective contraction of time between an action and its effect only occurs if the patient feels that they are the agent responsible for the action. We used this paradigm, coupled with emotional stimuli, to investigate the sense of agency with voluntary movements in patients with motor conversion disorder. Twenty patients with motor conversion disorder and 20 age-matched and sex-matched healthy volunteers used a rotating clock to judge the time of their own voluntary key presses (action) and a subsequent auditory tone (effect) after they completed conditioning blocks in which high, medium, and low tones were coupled to images of happy, fearful, and neutral faces. The results replicated those produced previously: it was reported that an effect after a voluntary action occurred earlier, and the preceding action occurred later, compared with trials that used only key presses or tones. Patients had reduced overall binding scores relative to healthy volunteers, suggesting a reduced sense of agency. There was no effect of the emotional stimuli (faces) or other interaction effects. Healthy volunteers with subclinical depressive symptoms had higher overall binding scores. We demonstrate that patients with motor conversion disorder have decreased action-effect binding for normal voluntary movements compared with healthy volunteers, consistent with the greater experience of lack of control.

Economic Role of Population Density during Pandemics-A Comparative Analysis of Saudi Arabia and China.

As a novel infection with relatively high contagiousness, the coronavirus disease emerged as the most pertinent threat to the global community in the twenty-first century. Due to Covid-19's severe economic impacts, the establishment of reliable determining factors can help to alleviate future pandemics. While a population density is often cited as a major determinant of infectious cases and mortality rates, there are both proponents and opponents to this claim. In this framework, the study seeks to assess the role of population density as a predictor of Covid-19 cases and deaths in Saudi Arabia and China during the Covid-19 pandemic. With high infectivity and mortality being a definitive characteristic of overpopulated regions, the authors propose that Henry Kissinger's population reduction theory can be applied as a control measure to control future pandemics and alleviate social concerns. If high-density Chinese regions are more susceptible to Covid-19 than low-density Saudi cities, the authors argue that Neo-Malthusian models can be used as a basis for reducing the impacts of the coronavirus disease on the economic growth in countries with low population density. However, the performed correlation analysis and simple linear regression produced controversial results with no clear connection between the three studied variables. By assessing population density as a determinant of health crises associated with multiple socio-economic threats and epidemiological concerns, the authors seek to reinvigorate the scholarly interest in Neo-Malthusian models as a long-term solution intended to mitigate future disasters. The authors recommend that future studies should explore additional confounding factors influencing the course and severity of infectious diseases in states with different population densities.

Nilotinib Effects on Safety, Tolerability, and Potential Biomarkers in Parkinson Disease: A Phase 2 Randomized Clinical Trial.

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 Participants: This 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. Results: Of 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.

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease.

Nilotinib is a broad-based tyrosine kinase inhibitor with the highest affinity to inhibit Abelson (c-Abl) and discoidin domain receptors (DDR1/2). Preclinical evidence indicates that Nilotinib reduces the level of brain alpha-synuclein and attenuates inflammation in models of Parkinson's disease (PD). We previously showed that Nilotinib penetrates the blood-brain barrier (BBB) and potentially improves clinical outcomes in individuals with PD and dementia with Lewy bodies (DLB). We performed a physiologically based population pharmacokinetic/pharmacodynamic (popPK/PD) study to determine the effects of Nilotinib in a cohort of 75 PD participants. Participants were randomized (1:1:1:1:1) into five groups (n = 15) and received open-label random single dose (RSD) 150:200:300:400 mg Nilotinib vs placebo. Plasma and cerebrospinal fluid (CSF) were collected at 1, 2, 3, and 4 hours after Nilotinib administration. The results show that Nilotinib enters the brain in a dose-independent manner and 200 mg Nilotinib increases the level of 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), suggesting alteration to dopamine metabolism. Nilotinib significantly reduces plasma total alpha-synuclein and appears to reduce CSF oligomeric: total alpha-synuclein ratio. Furthermore, Nilotinib significantly increases the CSF level of triggering receptors on myeloid cells (TREM)-2, suggesting an anti-inflammatory effect. Taken together, 200 mg Nilotinib appears to be an optimal single dose that concurrently reduces inflammation and engages surrogate disease biomarkers, including dopamine metabolism and alpha-synuclein.

Middle ear myoclonus: two informative cases and a systematic discussion of myogenic tinnitus.

BACKGROUND: The term middle ear myoclonus (mem) has been invoked to explain symptoms of tinnitus presumably caused by the dysfunctional movement of either of the two muscles that insert in the middle ear: tensor tympani and stapedius. MEM has been characterized through heterogeneous case reports in the otolaryngology literature, where clinical presentation is variable, phenomenology is scarcely described, the pathogenic muscle is usually not specified, natural history is unknown, and the presumptive definitive treatment, tensor tympani or stapedius tendon lysis, is inconsistently effective. It is not surprising that no unique acoustogenic mechanism or pathophysiologic process has been identified to explain MEM, one of several descriptive diagnoses associated with the complicated disorders of myogenic tinnitus. METHODS: Here, we explore MEM from the neurologist's perspective. Following the detailed descriptions of two informative cases from our clinic, we systematically evaluate the different mechanisms and movement disorder phenomena that could lead to a diagnosis of MEM. RESULTS: From a functional neuroanatomic perspective, we explain how tensor tympani MEM is best explained as a form of peritubal myogenic tinnitus, similar to the related disorder of essential palatal tremor. From a pathogenic perspective, we discuss how MEM symptomatology may reflect different mechanical and neurologic processes. We emphasize the diagnostic imperative to recognize when myogenic tinnitus is consistent with a psychogenic origin. DISCUSSION: Both individual patient care and further elucidation of MEM will rely on more detailed clinical characterization as well as multidisciplinary input from neurology, otolaryngology, and dentistry.