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Neal Hermanowicz,1 Maria Cristina Ospina,2 Yasar Torres-Yaghi,3 Sherrie Gould,4 Kelly Papesh,5 Jason A Rivera,6 Susan Miller,6 Sarah Jones,6 Kelli Musick,7 Damian May7 1Christus-St. Vincent Neurology Specialists, Santa Fe, NM, USA; 2Regional Parkinson Center, Phoenix, AZ, USA; 3MedStar Georgetown University Hospital, Washington, DC, USA; 4Scripps Clinic Movement Disorder Center, La Jolla, CA, USA; 5Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA; 6Parkinson and Movement Disorder Alliance (PMD Alliance), Tucson, AZ, USA; 7ACADIA Pharmaceuticals Inc, San Diego, CA, USACorrespondence: Neal Hermanowicz, Tel +1 (505) 913-3877, Email nshermano@icloud.comPurpose: As the COVID-19 pandemic resulted in social restrictions around the globe, this cross-sectional survey aimed to assess the impact of social isolation on self- or proxy-reported symptoms of Parkinson’s disease (PD) during the pandemic.Patients and Methods: The survey was distributed among 7109 subscribers of the Parkinson and Movement Disorders Alliance (PMD Alliance) News and Information list and was open only to people with PD (PwP) and care partners (CP, defined as main caregivers of PwP and serving as proxy respondents). No attempt was made to identify PwP and CP pairs. The survey was distributed online using Survey Monkey between 01/06/2021 and 02/27/2021. Respondents were grouped by level of social support from outside of their household during the pandemic (decreased or maintained [ie, the same as pre-pandemic or increased]).Results: Of 7109 invited participants, 718 responded to the survey (response rate 10.1%). PwP (self-reports) accounted for 70.6% of respondents and CP (proxy reports) for 29.4%. Decreased social support from outside of the household during the COVID-19 pandemic (58.5% of all responses) was significantly associated with increases in sadness/depression and anxiety, compared with maintained levels of social support (p < 0.0001 for both comparisons). It was also associated with increased burden of several non-motor (decline in memory, problem solving, or communication, p = 0.0009; new or worsening confusion, p < 0.0001; new or worsening delusions, p = 0.018) and motor PD symptoms.Conclusion: Decline in social support from outside of the household during the COVID-19 pandemic showed a statistically significant and negative association with the burden of mood and non-motor symptoms of PD. These results call for increased vigilance towards non-motor symptoms in PwP experiencing social isolation and highlight the need for stronger provider focus on encouraging PwP and their CPs to build and maintain social connections and engagements.Keywords: Parkinson’s disease, social isolation, anxiety, depression, non-motor symptoms, COVID-19

Yasar Torres-Yaghi, Amelia Carwin, Jacob Carolan, Steven Nakano, Fahd Amjad, Fernando Pagan Department of Neurology, National Parkinson’s Foundation Center for Excellence, Translational Neurotherapeutics Program, Movement Disorders Program, MedStar Georgetown University Hospital, Washington, DC, USACorrespondence: Yasar Torres-YaghiMedStar Georgetown University Hospital, Department of Neurology, National Parkinson’s Foundation Center for Excellence, Translational Neurotherapeutics Program, Movement Disorders Program, 3800 Reservoir Road, NW, Washington, DC, 20007, USATel +1 202-444-6087Fax +1 202-444-2186Email yasaryaghi@gmail.comAbstract: In addition to the classic motor symptoms of Parkinson’s disease (PD), people with PD frequently experience nonmotor symptoms that can include autonomic dysfunction and neuropsychiatric symptoms such as PD psychosis (PDP). Common patient characteristics, including older age, use of multiple medications, and arrhythmias, are associated with increased risk of corrected QT interval (QTc) prolongation, and treatments for PDP (antipsychotics, dementia medications) may further increase this risk. This review evaluates how medications used to treat PDP affect QTc interval from literature indexed in the PubMed and Embase databases. Although not indicated for the treatment of psychosis, dementia therapies such as donepezil, rivastigmine, memantine, and galantamine are often used with or without antipsychotics and have minimal effects on QTc interval. Among the antipsychotics, data suggesting clinically meaningful QTc interval prolongation are limited. However, many antipsychotics have other safety concerns. Aripiprazole, olanzapine, and risperidone negatively affect motor function and are not recommended for PDP. Quetiapine is often sedating, can exacerbate underlying neurogenic orthostatic hypotension, and may prolong the QTc interval. Pimavanserin was approved by the US Food and Drug Administration (FDA) in 2016 and remains the only FDA-approved medication available to treat hallucinations and delusions associated with PDP. However, pimavanserin can increase QTc interval by approximately 5– 8 ms. The potential for QTc prolongation should be considered in patients with symptomatic cardiac arrhythmias and those receiving QT-prolonging medications. In choosing a medication to treat PDP, expected efficacy must be balanced with potential safety concerns for individual patients.Keywords: QTc interval prolongation, antipsychotic agents, clozapine, quetiapine, pimavanserin

Introduction: Adjunctive therapies to treat OFF episodes resulting from long-term levodopa treatment in Parkinson disease (PD) are hampered by safety and tolerability issues. Istradefylline offers an alternative mechanism (adenosine A2A receptor antagonist) and therefore potentially improved tolerability., Methods: A systematic review of PD adjuncts published in 2011 was updated to include randomized controlled trials published from January 1, 2010-April 15, 2019. Pairwise meta-analyses were updated, and Bucher indirect comparisons were used to generate estimates of relative safety, presented as odds ratio (OR) and 95% confidence interval (CI) for comparators versus istradefylline., Results: Fifty-seven randomized controlled trials involving 11,517 patients were included in the meta-analysis. Relative to istradefylline, dopamine agonists and catechol-O-methyl transferase (COMT) inhibitors had statistically significant higher odds of dyskinesia and somnolence. Monoamine oxidase-B inhibitors had significantly higher odds of hypotension. Amantadine extended-release (ER) had statistically significant higher odds of hallucination, orthostatic hypotension, insomnia, and withdrawals due to adverse events. All interventions combined had significantly higher odds of dyskinesia versus istradefylline 20 mg and somnolence versus istradefylline 40 mg. Considering overall incidence of adverse events, COMT inhibitors and amantadine ER had statistically significant higher odds versus both istradefylline doses (COMT versus istradefylline 40 mg, OR: 1.33; 95% CI: 1.03, 1.75; versus istradefylline 20 mg, OR: 1.32; 95% CI: 1.01, 1.72; amantadine ER versus istradefylline 40 mg, OR: 3.45; 95% CI: 1.85, 6.25; versus istradefylline 20 mg, OR: 3.33; 95% CI: 1.82, 6.25)., Conclusion: Istradefylline was associated with a generally favorable safety profile relative to other adjunct medications in this study., Competing Interests: Conflicts of Interest and Source of Funding: J.Q. and H.C. are currently employed by Kyowa Kirin, Inc., and received compensation from Kyowa Kirin, Inc. H.S. and S.I. are currently employed by Kyowa Kirin Co., Ltd., and received compensation from Kyowa Kirin Co., Ltd. This study was funded by Kyowa Kirin, Inc., (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc.)

Parkinson's disease (PD) is associated with the development of psychosis (PDP), including hallucinations and delusions, in more than half of the patient population. Optimal PD management must therefore involve considerations about both motor and non-motor symptoms. Often, clinicians fail to diagnosis psychosis in patients with PD and, when it is recognized, treat it suboptimally, despite the availability of multiple interventions. In this paper, we provide a summary of the current guidelines and clinical evidence for treating PDP with antipsychotics. We also provide recommendations for diagnosis and follow-up. Finally, an updated treatment algorithm for PDP that incorporates the use of pimavanserin, the only US FDA-approved drug for the treatment of PDP, was developed by extrapolating from a limited evidence base to bridge to clinical practice using expert opinion and experience. Because pimavanserin is only approved for the treatment of PDP in the US, in other parts of the world other recommendations and algorithms must be considered., (© 2024. The Author(s).)

Background: In patients with Parkinson's Disease (PD), two distinct motor subtypes, tremor dominant (TD) and postural instability and gait difficulty (PIGD), can be differentiated using Unified Parkinson's Disease Rating Scale (UPDRS) sub-scores. This post hoc analysis of pooled data from eight pivotal studies examined the effect of treatment with istradefylline, a selective adenosine A 2A receptor antagonist, on these subtypes., Methods: In eight randomized, placebo-controlled phase 2b/3 trials, patients on levodopa with carbidopa/benserazide experiencing motor complications received istradefylline (20 or 40 mg/day) or placebo for 12 or 16 weeks. TD subtype was defined by the UPDRS II/III items kinetic and postural tremor in right/left hand and (resting) tremor in the face, lips, chin, hands, or feet; PIGD items were freezing, walking, posture, gait, and postural instability. The ratio of mean scores from TD:PIGD items determined subtype (TD [TD:PIGD ratio ≥ 1.5], PIGD [TD:PIGD ratio ≤ 1.0], mixed-type [ratio 1-1.5])., Results: In total, 2719 patients were included (PIGD, n = 2165; TD, n = 118; mixed-type, n = 188; not evaluable, n = 248). Among TD subtype patients, the least-squares mean change from baseline versus placebo in UPDRS II/III TD-related total score was significant at 20 mg/day istradefylline (-2.21; 95 % CI, -4.05 to -0.36; p = 0.02). For PIGD subtype patients, there was a significant difference from placebo in UPDRS II/III PIGD-related total score at 40 mg/day istradefylline (-0.25; -0.43 to -0.06; p = 0.01)., Conclusions: The data from this analysis of UPDRS-based motor subtypes suggest that istradefylline can improve motor disability in PD patients with motor fluctuations regardless of PD subtype. Future research should characterize the effects of istradefylline on tremor., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yasar Torres-Yaghi served as a consultant/speaker for Abbott, AbbVie, Acadia, Amneal, Kyowa Kirin, Teva, and US WorldMeds. Nobutaka Hattori received research funding from/served as an investigator for AbbVie GK, Asahi Kasei, Astellas, Boston Scientific, Dai-Nippon Sumitomo, Daiichi Sankyo, Eisai, FP Pharmaceutical, Kyowa Hakko Kirin, Medtronic, Mitsubishi Tanabe, MiZ, Nihon Medi-physics, Nihon Pharmaceutical, Nippon Boehringer Ingelheim, OHARA, Ono Pharmaceutical, Otsuka, and Takeda; subcontracted trial cases for Biogen Japan, Hisamitsu, and Meiji Seika; did contract research for Biogen Japan and Mitsubishi Tanabe; served as an advisor/consultant for Dai-Nippon Sumitomo; served on advisory boards for Dai-Nippon Sumitomo, Kyowa Hakko Kirin, Otsuka, Sanofi KK, and Takeda; and received honoraria from AbbVie GK, Alexion, Boston Scientific, Dai-Nippon Sumitomo, Daiichi Sankyo, FP Pharmaceutical, Kyowa Hakko Kirin, Lundbeck Japan, Medtronic, MSD KK, Mylan, Nippon Boehringer Ingelheim, Novartis, Otsuka, Pfizer, and Takeda. Olivier Rascol received research funding from/served as an investigator for Agence Nationale de la Recherche (ANR), CHU de Toulouse, European Commission (FP7, H2020), France-Parkinson, INSERM-DHOS Recherche Clinique Translationnelle, Michael J. Fox Foundation, Programme Hospitalier de Recherche Clinique, and served as an advisor/consultant for AbbVie, Adamas, Acorda, Addex, AlzProtect, ApoPharma, AstraZeneca, Bial, Biogen, Britannia, Bukwang, Cerevel, CleveXel, IRLAB, Lilly, Lundbeck, Lupin, Merck, Mundipharma, NeurATRIS, Neuroderm, Novartis, ONO Pharma, Orion, Osmotica, Oxford Biomedica, Parexel, Pfizer, Prexton, Quintiles, Sanofi, Servier, Sunovion, Theranexus, Takeda, Teva, UCB, Watermark Research, XenoPort, XO, and Zambon. Yu Nakajima is an employee of Kyowa Kirin Co., Ltd. Shelby M. King is a former employee of Kyowa Kirin, Inc. Akihisa Mori is a former employee of Kyowa Kirin Co., Ltd. Fernando Pagan received educational/research grants from Medtronic, Sun Pharma, and US WorldMeds; served as a consultant/speaker for Acadia, Acorda, Amneal, AbbVie, Kyowa Kirin, Merz, Neurocrine, Sunovion, Supernus and US WorldMeds; and is a co-founder and shareholder of KeifeRx., (© 2023 Published by Elsevier Ltd.)

Dementia due to Parkinson's disease and Alzheimer's disease are associated with behavioural and psychological symptoms, including psychosis. Long-term management presents a challenge for health care providers and caregivers. Symptoms of psychosis include hallucinations and delusions; if untreated, these can lead to institutionalisation, decreased quality of life, and significant patient and caregiver distress. A critical step in the effective management of dementia-related psychosis (DRP) is the identification and diagnosis of affected patients. The lack of a standardised diagnostic approach presents a barrier to treatment and there are no consensus guidelines for DRP. Furthermore, there are no approved therapies for the treatment of DRP. Antipsychotic medications are often prescribed off-label, even though some are associated with an increased risk of adverse events or mortality. We present currently available screening tools and guidelines for the diagnosis and treatment of Parkinson's disease psychosis and DRP in the context of what is needed for effective management of psychosis.KEY POINTSWe present currently available screening tools and guidelines for Parkinson's disease psychosis and dementia-related psychosis, and discuss the unmet need for simple clinical diagnostic tools and treatment guidelines.The identification of psychosis is variable across different settings and specialties, without a unified approach to screening, definition, or diagnosis.Currently used tools for defining and assessing psychosis in a research setting are usually too cumbersome for everyday clinical practice.The development of a standardised set of diagnostic criteria would provide clinicians the opportunity to improve the detection, treatment, and quality of life of patients and their caregivers.

Although there is no cure for Parkinson's disease (PD), there are several classes of medications with various mechanisms of action that can help improve the functionality of someone with PD. Dopamine derivatives are first line therapies for PD, hence dopamine receptor agonists (DAs) have been shown to improve functionality of symptoms in PD patients. The two main formulations of dopamine agonist medications in PD therapy are ergoline and non-ergoline derivatives. Additionally, it has been shown that PD can involve irregularities in other neurotransmitters, such as acetylcholine, norepinephrine, and serotonin, hence why non-dopaminergic medications are also vital in PD management. Examples include NMDA receptor antagonists, dopamine antagonists (i.e. neuroleptics), acetylcholine receptor antagonists, serotonin receptor 2A agonists, and adenosine A 2 antagonists. In general, dopaminergic medications are the most effective in improving motor involvement with PD, whereas non-dopaminergic medications tend to focus on the non-motor involvement of PD. In this chapter, we will focus on the chemistry and medication background on dopaminergic vs non-dopaminergic therapy, with a focus of adenosine A 2 antagonists at the end., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Hallucinations and delusions present with psychosis are debilitating non-motor symptoms of Parkinson's disease, with a prevalence of up to 50-70% at some point during the course of the disease. Often patients and caregivers do not report the presence of hallucinations or delusions unless specifically questioned. A panel of experts in neurology and geriatric psychiatry convened to develop a simple screening tool and guidance on diagnosis and treatment of Parkinson's disease psychosis (PDP)., Methods: The working group reviewed literature for existing PDP guidelines on diagnosis and management and identified gaps in recommendations. The group discussed and developed a screening tool and treatment guidance that addressed the gaps in existing methodology based on their clinical experience., Results: The proposed screening tool consists of two parts: (1) a brief pre-visit screening portion to be completed by the patient and caregiver, and (2) a clinician portion to be completed via clinical interview of the patient and caregiver. If psychotic symptoms are present, an appropriate treatment plan is developed for PDP based on evaluation., Conclusions: This simple screening tool and treatment guidance offers a practical clinical approach for clinicians in the diagnosis and management of PDP., (© 2022. The Author(s).)

Introduction: Bosutinib, a dual Abelson/Src inhibitor, was investigated in individuals with dementia with Lewy bodies (DLB)., Methods: A single site, randomized, double-blind, placebo-controlled study of the effects of oral bosutinib, 100 mg once daily for 12 weeks on primary safety and pharmacokinetics and secondary biomarker outcomes., Results: Twenty-six participants were randomized and included male and female (12:1) in the bosutinib arm and all male (13) in the placebo arm. The average age was 72.9 ± 8.1 (year ± standard deviation). There were no serious adverse events and no dropouts. Bosutinib was measured in the cerebrospinal fluid (CSF) and inhibited Abelson. Bosutinib reduced CSF alpha-synuclein and dopamine catabolism., Discussion: Bosutinib is safe and well tolerated and penetrates the blood-brain barrier to inhibit Abelson and reduce CSF alpha-synuclein and dopamine catabolism, suggesting that bosutinib (100 mg) may be at or near the lowest effective dose in DLB. These results will guide adequately powered studies to determine the efficacy of a dose range of bosutinib and longer treatment in DLB., Highlights: Bosutinib is a dual Abl/Src inhibitor that penetrates the blood brain barrierBosutinib is safe and tolerated in individuals with dementia with Lewy bodiesBosutinib engages its target via inhibition of Abl and SrcBosutinib reduces CSF alpha-synuclein and attenuates breakdown of dopamineBosutinib improves activities of daily living in dementia with Lewy bodies., Competing Interests: Charbel Moussa is an inventor on a Georgetown University (GU) US and International Patent to use bosutinib in neurodegenerative diseases, including alpha‐synucleinopathies. GU exclusively licensed bosutinib use patent to KeifeRx LLC. Charbel Moussa and Fernando Pagan are founders and shareholders of KeiferX LLC, and Charbel Moussa and Jaeil Ahn are paid consultants to KeifeRX LLC. All other authors declare no conflict with this manuscript., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background and Objectives: We assessed longitudinal changes in CSF microRNAs (miRNAs) in patients with moderately severe Parkinson disease., Methods: We used next-generation whole-genome miRNA sequencing to determine CSF miRNA expression in 75 patients with Parkinson disease after single random ascending doses of nilotinib and longitudinal miRNA expression after daily nilotinib, 150 and 300 mg, vs placebo for 1 year., Results: Significant changes in the expression of miRNAs that control genes and pathways that regulate angiogenesis, autophagy, and the blood-brain-barrier components, primarily collagen, were observed over 1 year, suggesting impairment of these pathways in Parkinson progression in these patients. Different miRNAs that indicate activation of genes associated with autophagy flux and clearance and angiogenesis were significantly altered in the nilotinib, 300 mg vs 150 mg, or placebo group, and these changes correlated with clinical outcomes. No changes were observed in miRNAs after a single dose of nilotinib vs placebo., Discussion: This study suggests vascular and autophagy defects in Parkinson progression. Nilotinib, 300 mg, reverses these effects via alteration of miRNA expression, suggesting epigenomic changes that may underlie long-term disease-modifying effects., Trial Registration Information: Clinical trial registration number: NCT02954978., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Nilotinib is US Food and Drug Administration-approved for leukemia, and this open-label study investigated the safety, tolerability, and potential clinical effects of nilotinib in medically optimized patients with Parkinson's disease., Objectives: Safety and tolerability were the primary objectives, and clinical outcomes were exploratory., Methods: A total of 63 patients completed a 15-month phase 2, double-blind, placebo-controlled study and were rerandomized 1:1 into an open-label study of nilotinib 150 mg versus 300 mg for 12 months., Results: Nilotinib was safe and tolerated, and no adverse effects seemed to be related to the drug, and no differences in adverse events were observed between groups. Exploratory clinical outcomes showed that nilotinib 300 mg was remarkably stable from baseline to 27 months using partial and total Unified Parkinson's Disease Scale (UPDRS). Nilotinib 150 mg versus 300 mg, significantly declined using partial or the sum of UPDRS Parts I and II. There was no significant difference in nilotinib 150 mg versus 300 mg using UPDRS Part III (on levodopa) and total UPDRS Parts I to III. Subgroup analysis showed that late-start nilotinib 150 mg significantly worsened using the sum of UPDRS Parts II + III and total UPDRS Parts I to III compared with late-start nilotinib 300 mg. Quality of life using the Parkinson's Disease Questionnaire in nilotinib 150 mg significantly declined between 15 and 27 months compared with nilotinib 300 mg, and there was no change in cognition using the Montreal Cognitive Assessment between groups., Conclusions: This study provides evidence that nilotinib is safe and tolerated in Parkinson's disease. The exploratory clinical data will inform an adequately powered larger study to evaluate the efficacy of nilotinib 300 mg in Parkinson's disease. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Sialorrhea, or excessive saliva beyond the margin of the lip, is a common problem in many neurological diseases. Previously, sialorrhea has been underrecognized in Parkinson's disease (PD) patients. Despite this, many patients rank sialorrhea as one of the most debilitating complaints of Parkinson's disease. Previous treatment for sialorrhea has been suboptimal and has been plagued by significant side effects that are bothersome and can be dangerous in patients with a concurrent neurodegenerative disease. This review sought to review the anatomy, function, and etiology of sialorrhea in PD. It then sought to examine the evidence for the different treatments of sialorrhea in PD, and further examined newer evidence for safety and efficacy in minimally invasive treatment such as botulinum toxin.

The role of Discoidin Domain Receptors (DDRs) is poorly understood in neurodegeneration. DDRs are upregulated in Alzheimer's and Parkinson's disease (PD), and DDRs knockdown reduces neurotoxic protein levels. Here we show that potent and preferential DDR1 inhibitors reduce neurotoxic protein levels in vitro and in vivo. Partial or complete deletion or inhibition of DDR1 in a mouse model challenged with α-synuclein increases autophagy and reduces inflammation and neurotoxic proteins. Significant changes of cerebrospinal fluid microRNAs that control inflammation, neuronal injury, autophagy and vesicular transport genes are observed in PD with and without dementia and Lewy body dementia, but these changes are attenuated or reversed after treatment with the DDR1 inhibitor, nilotinib. Collectively, these data demonstrate that DDR1 regulates autophagy and reduces neurotoxic proteins and inflammation and is a therapeutic target in neurodegeneration., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

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.

The first Lewy Body Dementia Association (LBDA) Research Centers of Excellence (RCOE) Investigator's meeting was held on December 14, 2017, in New Orleans. The program was established to increase patient access to clinical experts on Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), and to create a clinical trials-ready network. Four working groups (WG) were created to pursue the LBDA RCOE aims: (1) increase access to high-quality clinical care, (2) increase access to support for people living with LBD and their caregivers, (3) increase knowledge of LBD among medical and allied (or other) professionals, and (4) create infrastructure for a clinical trials-ready network as well as resources to advance the study of new therapeutics.

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., Competing Interests: Charbel Moussa is an inventor of several U.S. and International Georgetown University patents to use Nilotinib and other tyrosine kinase inhibitors as a treatment for neurodegenerative diseases. No other authors declare any conflict of interests with this study.

Huntington disease (HD) is an autosomal-dominant disorder resulting from CAG triplet repeats, which leads to an expanded polyglutamine sequence in the HTT (Huntingtin) protein. Accumulation of the Huntingtin protein ultimately leads to neurodegeneration and negative effects in multiple clinical domains, including motor function, cognition, and behavior. HD is a disorder governed by genetics, and the ability to quantify the CAG triplet repeats can provide important insight regarding clinical onset, severity, and disease progression. HD affects generations of family members and can typically span several decades. Understanding HD is invaluable for the advancement in therapeutics for other prevalent neurodegenerative disorders caused by the accumulation of misfolded proteins such as Parkinson disease, Alzheimer disease, and Lewy body dementia., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: We evaluated the effects of low doses of the tyrosine kinase Abelson (Abl) inhibitor Nilotinib, on safety and pharmacokinetics in Parkinson's disease dementia or dementia with Lewy bodies., Objectives: The primary outcomes of this study were safety and tolerability; pharmacokinetics and target engagement were secondary, while clinical outcomes were exploratory., Methods: Twelve subjects were randomized into 150 mg (n = 5) or 300 mg (n = 7) groups and received Nilotinib orally every day for 24 weeks., Results: This study shows that 150 mg and 300 mg doses of Nilotinib appear to be safe and tolerated in subjects with advanced Parkinson's disease. Nilotinib is detectable in the cerebrospinal fluid (CSF) and seems to engage the target Abl. Motor and cognitive outcomes suggest a possible beneficial effect on clinical outcomes. The CSF levels of homovanillic acid are significantly increased between baseline and 24 weeks of treatment. Exploratory CSF biomarkers were measured., Conclusions: This small proof-of-concept study lacks a placebo group and participants were not homogenous, resulting in baseline differences between and within groups. This limits the interpretations of the biomarker and clinical data, and any conclusions should be drawn cautiously. Nonetheless, the collective observations suggest that it is warranted to evaluate the safety and efficacy of Nilotinib in larger randomized, double-blind, placebo-controlled trials.

"Cardiac cephalgia" is a type of secondary headache disorder, usually initiated by exertion that is related to myocardial ischemia. Primary exertional headaches such as sex-, cough-, or exercise-induced headaches are typically benign. Cardiac cephalgia, on the other hand, can have life-threatening complications. Due to overlapping features and similarities in presentation, cardiac cephalgia can be misdiagnosed as a primary headache disorder such as migraine. However, the management of these conditions is unique, and treatment of cardiac cephalgia with vasoconstrictors intended for migraine can potentially worsen myocardial ischemia. Thus, it is important to make the correct diagnosis by evaluating cardiac function with an electrocardiogram and/or stress testing. In this review, we examine reported cases of cardiac cephalgia from the past 5 years to highlight the importance of this condition in the differential diagnosis of a headache in a patient with a history of cardiovascular risk factors, as well as to discuss the appropriate approach to diagnosis and the proposed pathogenic mechanisms of this condition.