Parkinson's Disease Psychosis Research Articles

A survey into the influence of dopaminergic drug exposure on ‘sense of presence’ symptoms in patients with parkinson's disease

AimsThe first objective was to estimate prevalence of sense of presence (SoP) experiences in patients with Parkinson's Disease (PD), including whether onset was prior to or after commencing dopaminergic medication. The second objective was to explore the relationship between frequency of SoP experiences and dopaminergic drug, drug dosage and length of drug exposure. The experimental hypothesis was that SoP symptoms in PD would present more frequently in patients treated longer and with higher dopaminergic drug doses.BackgroundPD is a debilitating neurodegenerative disorder. Psychiatric symptoms are common and associated with impaired quality of life and higher treatment costs. PD psychosis often starts with ‘minor hallucinations’, the most common being a false ‘sense of presence’ (SoP), the vivid sensation that someone else is nearby when nobody is there. SoP symptoms typically do not cause significant distress but may act as a prognostic marker for future severe psychosis and may prompt alteration of treatment or reduction in dopaminergic drug dosage. This study aimed to extend prior research by characterizing SoP further and investigating the link with dopaminergic medication.MethodThis was a retrospective, cross-sectional study. Twenty-one patients diagnosed with PD completed a questionnaire to identify presence of SoP symptoms, duration of symptoms, timing of onset related to dopaminergic treatment and the frequency of symptoms in relation to current levodopa equivalent dose (LED). Descriptive frequencies were compared using a two-tailed t-test. Multiple regression analysis was conducted to assess the relationship between frequency of SP experiences, levodopa equivalent dose and length of drug exposure.ResultSixteen of twenty-one patients reported experiencing SoP symptoms. Patients who had not experienced SoP symptoms had a significantly lower LED than those who had experienced these symptoms. There were no other significant differences between the groups. No statistical significance was shown on regression analysis; however our study was not adequately powered for the regression analysis as the number of participants was too low.ConclusionThis study confirms that SoP symptoms are common among patients with PD and supports a correlation between the total daily equivalent dose of levodopa and SoP symptoms. It does not provide evidence for a temporal relationship between onset of SoP symptoms and duration of dopaminergic treatment. The study was insufficiently powered and a larger study is required to investigate further.

Comparative pharmacovigilance assessment of mortality with pimavanserin in Parkinson disease-related psychosis.

BACKGROUND: Pimavanserin is approved for treatment of Parkinson disease (PD)-related psychosis, but its use has been associated with an increased risk of death during clinical trials, as well as during postmarketing surveillance. Previous reports on the association between pimavanserin and mortality have not taken into account limitations of data sources nor included comparable populations or comparisons to relevant treatment alternatives. OBJECTIVE: To conduct a comparative pharmacovigilance assessment of pimavanserin vs treatment alternatives and by restricting surveillance data to more representative populations. METHODS: This was a retrospective analysis of adverse event case reports submitted to the FDA's Adverse Event Reporting System (FAERS) from 2016 through 2019 quarter 3 (Q3). FAERS data are collected from the full population, were further restricted to only those with PD, and were based on PD medication use. Reports were assessed for exposure to pimavanserin, clozapine, quetiapine, haloperidol, and other atypical antipsychotics. The outcome of interest was all-cause death. A proportional reporting ratio (PRR) and 95% confidence limits were calculated for each 2 by 2 contingency of outcome (death) and exposure (pimavanserin and others). For each outcome/exposure pair, the baseline population was altered to include the full FAERS sample, only reports with PD, reports with PD treated with levodopa, and reports with PD treated with multiple PD medications. The sample was also stratified by time period before April 2018 and after September 2018 to capture periods of public knowledge and federal response. A lower 95% CI (Lower95CI) ≥ 2 for the PRR was considered as the accepted threshold for a drug safety signal. RESULTS: As of 2019 Q3, there were 2,287 reports of death associated with pimavanserin. Compared within the full FAERS base population, pimavanserin yielded a PRR Lower95CI = 2.08 but was smaller when restricted to comparison among only a base population with PD (Lower95CI = 1.09), PD treated with levodopa (Lower95CI = 1.15), or PD treated with multiple PD medications (Lower95CI = 1.63). Metrics for quetiapine, clozapine, and other atypical antipsychotics were similar in magnitude. Stratification by time showed a possible reporting bias associated with pimavanserin, since no safety signal was detected before April 2018; however, a signal was present thereafter. CONCLUSIONS: Compared in context with treatment alternatives for patients with PD, pimavanserin was not associated with excess reports of death in the FAERS data. This information should be used in shared decision making between physicians and PD patients to balance the risks and benefits of pimavanserin and other treatments for PD psychosis. DISCLOSURES: No outside funding supported this study. The authors report no disclosures or conflicts of interest relevant to this study. Armstrong receives research support from the NIA (P30AG047266, R01AG068128) and the Florida Department of Health (grant 20A08). She is the local principal investigator of a Lewy Body Dementia Association Research Center of Excellence. She also receives compensation from the American Academy of Neurology for work as an evidence-based medicine methodology consultant. She is on the level of evidence editorial board for Neurology and related publications (uncompensated), receives publishing royalties for Parkinson's Disease: Improving Patient Care (Oxford University Press, 2014), and has received an honorarium for presenting for Medscape CME in 2018. Okun serves as a consultant for the Parkinson's Foundation and has received research grants from NIH, Parkinson's Foundation, the Michael J. Fox Foundation, the Parkinson Alliance, Smallwood Foundation, the Bachmann-Strauss Foundation, the Tourette Syndrome Association, and the UF Foundation. Okun has participated as a site principal investigator and/or co-investigator for several NIH-, foundation-, and industry-sponsored trials over the years but has not received honoraria. Malaty has participated in research funded by the Parkinson Foundation, Tourette Association, Dystonia Coalition, Abbvie, Boston Scientific, Eli Lilly, Neuroderm, Pfizer, Revance, and Teva. She has received travel compensation and/or honoraria from the Tourette Association of America, NeuroChallenge Foundation and NIH/Neurobiology of Disease in Children, Parkinson Foundation, Medscape, International Association of Parkinsonism and Related Disorders, and Cleveland Clinic, and royalties from Robert Rose publishers. The other authors have no disclosures.

Further characterisation of psychosis-like behaviours induced by L-DOPA in the MPTP-lesioned marmoset.

Parkinson's disease (PD) psychosis afflicts over half of patients and poses a significant burden on quality of life. The aetiology of PD psychosis is multifactorial and likely arises from the complex interaction between dopamine replacement therapy and disease state. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset is a validated model to predict the efficacy of therapeutic compounds for treatment-related complications, including PD psychosis. In this model, psychosis-like behaviours (PLBs) encompass stereotypies that are idiosyncratic in nature and reproducible with each L-3,4-dihydroxyphenylanaline (L-DOPA) administration. In the present study, we sought to expand upon the existing repertoire of PLBs through the characterisation of novel stereotypical behaviours that appear dependent on the environment. We then discuss our findings in the context of clinical reports on stereotypical behaviours termed "punding" in subjects with PD, which consists of stereotypical repetitive and senseless behaviours. The poor understanding of the pathophysiology governing punding and consequent lack of effective therapies stand to benefit from enhanced characterisation of these stereotypical behaviours in a validated pre-clinical model. We hope that further characterisation of PLBs in the MPTP-lesioned marmoset will be helpful in the evaluation of interventions that seek to alleviate PD psychosis symptoms.

Efficacy results of pimavanserin from a multi-center, open-label extension study in Parkinson's disease psychosis patients

IntroductionPimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved for hallucinations and delusions associated with Parkinson's disease psychosis (PDP). We present durability of response with pimavanserin in patients with PDP for an additional 4 weeks of treatment. MethodsThis was an open-label extension (OLE) study in patients previously completing one of three double-blind, placebo-controlled (Core) studies. All patients received pimavanserin 34 mg once daily. Efficacy assessments included the Scale for the Assessment of Positive Symptoms (SAPS) PD and H + D scales, Clinical Global Impression (CGI) Improvement and Severity scales and Caregiver Burden Scale (CBS), through 4 weeks in the OLE. Safety assessments were conducted at each visit. ResultsOf 459 patients, 424 (92.4%) had a Week 4 efficacy assessment. At Week 4 (10 weeks total treatment), SAPS-PD mean (standard deviation) change from OLE baseline was −1.8 (5.5) and for SAPS-H + D was −2.1 (6.2) with pimavanserin 34 mg. Patients receiving placebo during the Core studies had greater improvements (SAPS-PD -2.9 [5.6]; SAPS-H + D −3.5 [6.3]) during the OLE. For participants treated with pimavanserin 8.5 or 17 mg during the Core studies, further improvement was observed during the OLE with pimavanserin 34 mg. The mean change from Core Study baseline for SAPS-PD score was similar among prior pimavanserin 34 mg and prior placebo-treated participants (−7.1 vs. −7.0). The CGI-I response rate (score of 1 or 2) at Week 4 was 51.4%. Adverse events were reported by 215 (46.8%) patients during the first 4 weeks of OLE. The most common AEs were fall (5.9%), hallucination (3.7%), urinary tract infection (2.8%), insomnia (2.4%), and peripheral edema (2.2%) ConclusionsPatients previously on pimavanserin 34 mg during three blinded core studies had durability of efficacy during the subsequent 4 week OLE SAPS-PD assessment. Patients previously on blinded placebo improved after 4 weeks of OL pimavanserin treatment. These results in over 400 patients from 14 countries support the efficacy of pimavanserin for treating PDP.

Will Artificial Intelligence Outperform the Clinical Neurologist in the Near Future? No.

Will Artificial Intelligence Outperform the Clinical Neurologist in the Near Future? No.

Pilot Study to Evaluate Pimavanserin for the Treatment of Motor and Behavioral Symptoms of Tourette Syndrome.

Pimavanserin is a serotonin 2A receptor inverse agonist and antagonist used for the treatment of hallucinations and delusions in Parkinson's disease psychosis. Numerous studies support a modulatory role of serotonin in Tourette syndrome (TS). To determine whether or not pimavanserin affects TS symptoms. In this open-label study of TS adult patients, pimavanserin was titrated to 34 mg/day over 1 week and continued for an additional 7 weeks followed by a 2-week washout. Tic severity, the primary outcome measure, was assessed by the Yale Global Tic Severity Scale Total Tic Severity score (YGTSS-TTS). Secondary outcome measures included changes in the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the Tourette Syndrome Clinical Global Impression of Change (TS-CGIC), the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII), and the Gilles de la Tourette Syndrome - Quality of Life scale (GTS-QOL). We enrolled 12 patients, but 2 dropped out after week 2 due to non-serious side effects. In the 10 patients, mean (standard deviation (SD)) age 34 (12.9) who completed the study the mean (SD) baseline YGTSS-TTS was 34 (9.3). This decreased by 3.6 (4.9) points at week 8, a 12% reduction in tic severity (P= 0.03). This improvement is small and may not be clinically important. Significant improvement was noted in the TS-CGIC, TS-PGII and GTS-QO. No serious adverse events were reported. The results of this study suggest that pimavanserin is safe and associated with improvement in motor and non-motor TS symptoms. These findings warrant further study by a larger, placebo-controlled, trial.

Setting up a clozapine service for Parkinson's psychosis

SUMMARYParkinson's psychosis can be very challenging to manage, with limited treatment options available. There is a good evidence base to support the use of clozapine, but practical obstacles often prevent its use. There is a drive nationally to set up services so that people with Parkinson's psychosis can access treatment with clozapine in a timely manner and, where possible, with initiation in the community. The authors describe their experiences in setting up clozapine services specifically for this patient group in England and offer a practical approach to the assessment of Parkinson's psychosis. They also outline the evidence base in relation to treatment options and share their experiences of prescribing clozapine for Parkinson's psychosis.

The experience of care partners of patients with Parkinson's disease psychosis.

BackgroundParkinson’s disease psychosis (PDP) has a major impact on quality of life and care partner burden; however, little is known about the lived experiences of care partners in managing PDP.ObjectiveTo understand how care partners of individuals with PDP experience their role and articulate their needs related to psychosis.MethodsThis was a qualitative study of semi-structured telephone interviews. Recruitment was conducted online via the clinical study matching tool, Fox Trial Finder; study activities took place remotely via telephone interviews. Transcripts of the phone interviews were analyzed by grounded theory methods, and a codebook of key themes that emerged from the analysis was developed.ResultsNine care partners (all female) were interviewed. Discussion topics in the codebook included (1) care partner burden and guilt; (2) communication with medical professionals; (3) coping strategies; (4) emotional reactions of the care partner to psychosis; (5) sources of knowledge about PD psychosis; (6) attitudes towards medications for PDP; (7) strategies to care for loved ones with psychosis; (8) psychosis triggers.ConclusionsThis qualitative analysis uncovers important aspects of the care partner experience, including challenges in navigating the medical system and communicating with professionals. Providers treating patients with PDP should be aware of these constraints and provide added support for strained care partners.

Pimavanserin for the Treatment of Psychosis in Alzheimer's Disease: A Literature Review

<h3>Introduction</h3> Alzheimer's disease (AD) is among the most prevalent forms of dementia in the world. Approximately 25%-50% of individuals with AD develop psychotic symptoms sometime during their illness. The presence of psychosis in AD worsens outcomes. Currently, there are no FDA-approved medications for the treatment of psychosis in AD. Pimavanserin, a novel atypical antipsychotic medication, was approved by the FDA for the treatment of hallucinations and delusions associated with psychosis in Parkinson disease. Pimavanserin is also currently in clinical trials for the treatment of psychosis in AD. The purpose of this literature review is to evaluate the existing literature regarding the use of pimavanserin for treating psychosis in individuals with AD. <h3>Methods</h3> A literature review of clinical studies of pimavanserin treatment for psychosis in individuals with AD was performed using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Trials were identified by systematically searching PubMed, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus through October 2019. The 5-point JADAD scoring system was used to assess the methodologic quality of randomized placebo-controlled trials (RCT). <h3>Results</h3> A total of 499 citations were retrieved and pooled. After de-duplication, two separate screeners evaluated the titles, abstracts, and full text of the remaining 258 citations. Two publications from 1 RCT were included in the final analysis. The quality of evidence was assessed to be of good methodologic quality, scoring 4 out of 5 using the 5-point JADAD questionnaire with the JADAD Scoring calculation. This systematic review found only one RCT that evaluated the use of pimavanserin for the treatment of psychosis among individuals with AD. This phase 2 trial resulted in two publications, the second of which was a subgroup analysis from the original study. The evidence from these two publications indicated that pimavanserin improves psychotic symptoms among individuals with AD when compared to placebo at the week 6 checkpoint. <h3>Conclusions</h3> Pimavanserin may be a pharmacologic consideration for the treatment for psychosis in AD. Additional RCTs are needed to assess the evidence of effectiveness before pimavanserin is considered a standard treatment. <h3>Funding</h3> This research received no funding agency in the public, commercial, or not-for-profit sectors.

Knowledge, Responsibilities, and Peer Advice From Care Partners of Patients With Parkinson Disease Psychosis.

Introduction: Care partners (CPs) of individuals with Parkinson disease psychosis (PDP) experience increased strain and rely on informal support networks. The objective of this study was to characterize CP responsibilities, sources of support, and peer advice.Methods: This was a mixed-methods cross-sectional study. The sample was recruited from the online Fox Insight study cohort. CPs who indicated their care recipient suffered hallucinations and/or delusions were administered a questionnaire regarding their caregiving experience to person with PDP. A free-text question asked CPs to give advice to a hypothetical peer CP. Responses to multiple-choice questions were tabulated; responses to the free-text question were grouped into advice categories.Results: 145 CP of individuals with PDP were included in this analysis, mean age (standard deviation, SD) 66.4 (9.4) years; 110 (75.9%) were women. Most (115, 79.3%) provided caregiving on a daily basis, with a range of responsibilities. Only 16 (11%) learned about PDP from a physician; communication challenges included perceived embarrassment or having to prioritize other issues in a limited appointment time. The most common peer advice was to alert the care recipient's neurologist (n = 38, 30.4%); only 8 (6.4%) suggested medication changes.Conclusion: CPs face challenges with clinician communication and learn about psychosis from a variety of informal sources. Few CPs advocate for medications to control PDP, instead preferring non-pharmacological management strategies. Peer advice favored alerting the care recipient's physician, suggesting that CPs do desire more information from the medical team.

Treatment Patterns With Antipsychotics in Long-Term Care Patients With Parkinson's Disease Psychosis.

This study assessed treatment change patterns in Parkinson's disease psychosis (PDP) residents receiving antipsychotic (AP) therapies in U.S. long-term care (LTC) facilities. Residents with PDP in LTC between 01/01/13 and 06/30/16 were identified with ≥1 claim of psychosis, hallucinations, or delusions after PD diagnosis. Treatment patterns were evaluated during the 12 months post index. We identified 864 PDP residents: 408 (47.2%) on AP therapy and 456 (52.8%) on no AP therapy. A total of 335 residents (82.1%) continued, 13 (3.2%) discontinued, 11 (2.7%) switched, and 49 (12.0%) augmented (used ≥2 APs) their index AP therapy. Based on the multivariate regression analysis, younger age, male gender, anemia, anxiolytic use or anxiety, sedatives/hypnotic use, bladder disorders including urinary tract infections, coronary conditions, diabetes, hypertension, and dementia were associated with a higher likelihood of treatment change. Understanding the factors associated with treatment change may inform ways to improve management of PDP in the U.S. LTC setting.

Pimavanserin, a 5HT2A receptor inverse agonist, rapidly suppresses Aβ production and related pathology in a mouse model of Alzheimer's disease.

Amyloid-β (Aβ) peptide aggregation into soluble oligomers and insoluble plaques is a precipitating event in the pathogenesis of Alzheimer's disease (AD). Given that synaptic activity can regulate Aβ generation, we postulated that 5HT2A -Rs may regulate Aβ as well. We treated APP/PS1 transgenic mice with the selective 5HT2A inverse agonists M100907 or Pimavanserin systemically and measured brain interstitial fluid (ISF) Aβ levels in real-time using in vivo microdialysis. Both compounds reduced ISF Aβ levels by almost 50% within hours, but had no effect on Aβ levels in 5HT2A -R knock-out mice. The Aβ-lowering effects of Pimavanserin were blocked by extracellular-regulated kinase (ERK) and NMDA receptor inhibitors. Chronic administration of Pimavanserin by subcutaneous osmotic pump to aged APP/PS1 mice significantly reduced CSF Aβ levels and Aβ pathology and improved cognitive function in these mice. Pimavanserin is FDA-approved to treat Parkinson's disease psychosis, and also has been shown to reduce psychosis in a variety of other dementia subtypes including Alzheimer's disease. These data demonstrate that Pimavanserin may have disease-modifying benefits in addition to its efficacy against neuropsychiatric symptoms of Alzheimer's disease. Read the Editorial Highlight for this article on page 560.

Pimavanserin Treatment for Parkinson's Disease Psychosis in Clinical Practice.

Background Parkinson's disease psychosis (PDP) is a common, nonmotor symptom of Parkinson's disease (PD), which may affect up to 60% of patients and is associated with impaired quality of life, increased healthcare costs, and nursing home placement, among other adverse outcomes. Characteristic symptoms of PDP include illusions; visual, auditory, tactile, and olfactory hallucinations; and delusions. PDP symptoms typically progress over its course from being mild, infrequent, and often untroubling to complex, sometimes constant, and potentially highly disturbing. PDP has traditionally been treated with atypical antipsychotics (e.g., clozapine and quetiapine) although these are not approved for this indication and clozapine requires frequent white blood cell count monitoring due to the risk of agranulocytosis. Pimavanserin is a newer atypical antipsychotic with highly selective binding to serotonergic receptors, no evidence for worsening motor symptoms in PD, and no need for white blood cell count monitoring. It is currently the only approved medication indicated for PDP treatment. However, because it was approved relatively recently (2016), clinical experience with pimavanserin is limited. Case Presentations. A wide variety of representative clinical scenarios are presented, each with distinct variables and complications. Issues addressed include distinguishing PDP from similar symptoms caused by other disorders such as dementia, coordinating pimavanserin with other PD medications and with deep brain stimulation, adapting pimavanserin dosing for optimal benefit and tolerability, and recognizing variability of PDP symptoms due to patients' changing life circumstances. Conclusions These scenarios provide multiple insights regarding PDP management and the role of pimavanserin. Effective treatment of PDP may reduce disturbing symptoms of psychosis, thus improving patient function and quality of life. In addition, effective pharmacotherapy for PDP may also facilitate the use of other medications needed to treat neurological symptoms of PD (e.g., tremor, bradykinesia, and dyskinesia), although they may also have adverse effects that contribute to symptoms of PDP.

Effect of the mGlu2 positive allosteric modulator CBiPES on dyskinesia, psychosis-like behaviours and parkinsonism in the MPTP-lesioned marmoset.

Advanced Parkinson's disease (PD) is often complicated by the occurrence of dyskinesia, motor fluctuations and psychosis. To this day, few treatment options are available for each of these phenomena, and they are at times not effective or elicit adverse events, leaving some patients short of therapeutic options. We have recently shown that positive allosteric modulation of metabotropic 2 (mGlu2) receptors with the prototypical positive allosteric modulator (PAM) LY-487,379 is efficacious at alleviating both dyskinesia and psychosis-like behaviours (PLBs), while simultaneously enhancing the anti-parkinsonian action of L-3,4-dihydroxyphenylalanine (L-DOPA), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we assessed the effects of CBiPES, a mGlu2 PAM derived from LY-487,379, but with improved pharmacokinetic properties. Six MPTP-lesioned marmosets with reproducible dyskinesia and PLBs were administered L-DOPA in combination with vehicle or CBiPES (0.1, 1 and 10mg/kg), after which their behaviour was rated. CBiPES 10mg/kg reduced global dyskinesia by 60% (P < 0.0001), while peak dose dyskinesia was reduced by 66% (P < 0.001), compared to L-DOPA/vehicle. CBiPES 10mg/kg also diminished global PLBs by 56% (P < 0.0001), while peak dose PLBs were reduced by 64% (P < 0.001), compared to L-DOPA/vehicle. Lastly, CBiPES enhanced the anti-parkinsonian action of L-DOPA, by reducing global parkinsonian disability by 43% (P < 0.01), compared to L-DOPA/vehicle. Our results provide further evidence that mGlu2 positive allosteric modulation may be an approach that could be efficacious for the treatment of dyskinesia, psychosis and motor fluctuations in PD.

A Preliminary Investigation of the Views of People With Parkinson's (With and Without Psychosis) and Caregivers on Participating in Clinical Trials During the Covid-19 Pandemic: An Online Survey.

Background: The coronavirus pandemic is having a profound impact on non-COVID-19 related research, including the delivery of clinical trials for patients with Parkinson's disease.Objectives: A preliminary investigation to explore the views of Parkinson's disease (PD) patients, with and without experience of psychosis symptoms, and carers on the resumption of clinical research and adaptations to trials in light of COVID-19.Methods: An anonymous self-administered online survey was completed by 30 PD patients and six family members/carers via the Parkinson's UK Research Support Network to explore current perceptions on taking part in PD research and how a planned clinical trial for psychosis in PD may be adapted so participants feel safe.Results: Ninety-one percent of respondents were enthusiastic about the continuation of non-COVID-19 related research as long as certain safety measures were in place. Ninety-four percent stated that they would be happy to complete assessments virtually. However, they noted that care should be taken to ensure that this does not exclude participants, particularly those with more advanced PD who may require assistance using portable electronic devices. Regular and supportive communication from the research team was also seen as important for maintaining the psychological well-being of participants while taking part in the trial.Conclusions: In the era of COVID-19 pandemic, standard approaches will have to be modified and rapid adoption of virtual assessments will be critical for the continuation of clinical research. It is important that alongside the traditional methods, new tools are developed, and older ones validated for virtual assessments, to allow safe and comprehensive assessments vital for ongoing research in people with Parkinson's.

Psychosis-Like Behavior and Hyperdopaminergic Dysregulation in Human α-Synuclein BAC Transgenic Rats.

Parkinson's disease psychosis is a prevalent yet underreported and understudied nonmotor manifestation of Parkinson's disease and, arguably, the most debilitating. It is unknown if α-synuclein plays a role in psychosis, and if so, this endophenotype may be crucial for elucidating the neurodegenerative process. We sought to dissect the underlying neurobiology of novelty-induced hyperactivity, reminiscent of psychosis-like behavior, in human α-synuclein BAC rats. Herein, we demonstrate a prodromal psychosis-like phenotype, including late-onset sensorimotor gating disruption, striatal hyperdopaminergic signaling, and persistent novelty-induced hyperactivity (up to 18 months), albeit reduced baseline locomotor activity, that is augmented by d-amphetamine and reversed by classical and atypical antipsychotics. MicroRNA-mediated α-synuclein downregulation in the ventral midbrain rescues the hyperactive phenotype and restores striatal dopamine levels. This phenotype is accompanied by an abundance of age-, brain region- and gene dose-dependent aberrant α-synuclein, including hyperphosphorylation, C-terminal truncation, aggregation pathology, and mild nigral neurodegeneration (27%). Our findings demonstrate a potential role of α-synuclein in Parkinson's disease psychosis and provide evidence of region-specific perturbations prior to neurodegeneration phenoconversion. The reported phenotype coincides with the latest clinical findings that suggest a premotor hyperdopaminergic state may occur, while at the same time, premotor psychotic symptoms are increasingly being recognized. © 2020 International Parkinson and Movement Disorder Society.

Evaluating rates of reporting symptoms of Parkinson’s disease psychosis: provider versus targeted questionnaire

Purpose/aim A targeted questionnaire may help increase rates of reporting Parkinson’s disease psychosis (PDP) symptoms. Despite the need for a rapid patient- and/or caregiver-administered screening tool for PDP symptoms, an appropriate tool is not yet available. This study developed a targeted PDP questionnaire and examined rates of reporting psychosis symptoms in response to the questionnaire compared to rates of reporting symptoms to healthcare providers during a routine visit. Materials and methods This was a single-center, cross-sectional observational study of patients at an outpatient neurology practice. Medical charts were screened for eligibility, and patients were contacted by telephone for informed consent. Results A total of 25 patients (24%, N = 104) newly reported PDP symptoms in response to the targeted questionnaire. The frequency of reporting new symptoms in response to the questionnaire was statistically significantly greater compared to frequency of reporting symptoms without use of a targeted questionnaire (p < 0.0001). Conclusions A targeted questionnaire increases rates of reporting PDP symptoms, and based on frequency, severity, and distress ratings, may allow for capture of PDP symptoms earlier in the course of the disease. By using a questionnaire, patients reported symptom onset an average of 1.4 years earlier than patients who reported symptoms to their providers according to patient medical records.

Repurposing Pimavanserin, an Anti-Parkinson Drug for Pancreatic Cancer Therapy

Despite major advances in cancer treatment, pancreatic cancer is still incurable and the treatment outcomes are limited. The aggressive and therapy-resistant nature of pancreatic cancer warrants the need for novel treatment options for pancreatic cancer management. Drug repurposing is emerging as an effectual strategy in the treatment of various diseases, including cancer. In the present study, we evaluated the anticancer effects of pimavanserin tartrate (PVT), an antipsychotic drug used for the treatment of Parkinson disease psychosis. PVT significantly suppressed the proliferation and induced apoptosis in various pancreatic cancer cells and gemcitabine-resistant cells with minimal effects on normal pancreatic epithelial cells and lung fibroblasts. Growth-suppressive and apoptotic effects of PVT were mediated by the inhibition of the Akt/Gli1 signaling axis. The oral administration of PVT suppressed subcutaneous and orthotopic pancreatic tumor xenografts by 51%–77%. The chronic administration of PVT did not demonstrate any general signs of toxicity or change in behavioral activity of mice. Our results indicate that pancreatic tumor growth suppression by PVT was orchestrated by the inhibition of Akt/Gli1 signaling. Since PVT is already available in the clinic with an established safety profile, our results will accelerate its clinical development for the treatment of patients with pancreatic cancer.

Managing the Burden of Dementia-Related Delusions and Hallucinations

Identify the burden experienced by patients with dementia-related delusions and hallucinations. Assess patients with dementia for the presence of delusions and hallucinations. Individualize treatment in patients with dementia-related delusions and hallucinations. Align treatment of patients with Parkinson's psychosis with current recommendations.

High γ-Aminobutyric Acid Content Within the Medial Prefrontal Cortex Is a Functional Signature of Somatic Symptoms Disorder in Patients With Parkinson's Disease.

The dysfunctional activity of the medial prefrontal cortex has been associated with the appearance of the somatic symptom disorder, a key feature of the Parkinson's disease (PD) psychosis complex. The objectives of this study were to investigate whether the basal contents of inhibitory γ-aminobutyric acid and excitatory glutamate plus glutamine neurotransmitter levels are changed in the medial prefrontal cortex of patients with PD with somatic symptom disorder and whether this alteration represents a marker of susceptibility of PD to somatic symptom disorder, thus representing a signature of psychosis complex of PD. Levels of the γ-aminobutyric acid and glutamate plus glutamine were investigated, at rest, with proton magnetic resonance spectroscopy. Total creatine was used as an internal reference. The study cohort included 23 patients with somatic symptom disorder plus PD, 19 patients with PD without somatic symptom disorder, 19 healthy control subjects, and 14 individuals with somatic symptom disorder who did not show other psychiatric or neurological disorders. We found that, compared with patients with PD without somatic symptom disorder or healthy control individuals, patients with somatic symptom disorder, with or without PD, show increased γ-aminobutyric acid/total creatine levels in the medial prefrontal cortex. The medial prefrontal cortex contents of glutamate plus glutamine/total creatine levels or γ-aminobutyric acid/glutamate plus glutamine were not different among groups. Our findings highlight a crucial pathophysiologic role played by high γ-aminobutyric acid within the medial prefrontal cortex in the production of somatic symptom disorder. This phenomenon represents a signature of psychosis complex in patients with PD. © 2020 International Parkinson and Movement Disorder Society.