DOCSLIB.ORG

DEMENTIA SCREENING and CARE out of the Shadows and Into the Light

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
DEMENTIA SCREENING and CARE out of the Shadows and Into the Light DEMENTIA SCREENING AND CARE Out of the Shadows and Into the Light Wendy Ostlind, RN, MSN Louisa Crosby, AGACNP-BC In Wyoming… ■ 9,400 people currently living with Alzheimer’s Disease – Does not include those living with other types of dementia ■ 28,000 unpaid caregivers (3:1 ratio) supporting those living with Alzheimer’s. – This number indicates a great need for community involvement. ■ By 2025 - 13,000 people will have Alzheimer’s Disease – 39% increase, the 9th highest in the U.S. – 70% of all of those living with dementia continue to live in the community (not in institutions) – One in seven of those lives alone 9/28/2018 http://www.dfwsheridan.org/statistics 2 ■ Currently –Alzheimer's5.7 million Disease Projections Americans w/ National Alzheimer’s 20 ■ Alzheimer’s is 6th leading cause of death in Public Health US Crisis ■ Total annual cost of dementia in US in13.8 2013 11.6 ) – $203 billion (not including unpaid r Currently – 5.7 million Americans w/ s e n b 10 o i l caregivers) l m Alzheimer’s i 8.4 u m N ( th Alzheimer’s is 6 leading cause of 5.8 death in US Total annual cost of dementia in US in 2013 - $203 billion (not including 0 unpaid caregivers) 2020 2030 2040 2050 Year Alzheimer’s Association Report 2018 Alzheimer’s disease facts and figures Alzheimer’s Association https://www.alzheimersanddementia.com/article/S1552-5260(18)30041-4/pdf 9/28/2018 3 National Public Health Crisis… ■ Early diagnosis of AD could have important personal and financial benefits. A mathematical model estimates that early and accurate diagnosis could save up to $7.9 trillion in medical and care costs. Alzheimer’s Association Report 2018 Alzheimer’s disease facts and figures Alzheimer’s Association https://www.alzheimersanddementia.com/article/S1552- 9/28/2018 5260(18)30041-4/pdf 4 Dementia Screening and Care – Out of the Shadows and Into the Light ■ Objectives: – Identify the barriers to as well as the importance of early diagnosis of cognitive decline. – Identify Treatment and Management Strategies. – Visualize a comprehensive continuum of care for those experiencing cognitive decline, as well as their families and care-givers. 9/28/2018 5 OBJECTIVE 1: Identify the barriers to as well as the importance of early diagnosis of cognitive decline. 9/28/2018 6 What happens when you have Alzheimer’s…. ■ https://www.youtube.com/watch?v=8Nna8ZWr720 9/28/2018 7 Out of the Darkness…Identify the barriers to early diagnosis of cognitive decline. ■ Fear – “dread reflects the kind of life that our care system has created for people who receive the diagnosis [of dementia]” as much or more than fear of disease itself. Powers, A. (2010). Dementia Beyond Drugs. ■ Misunderstanding ■ Hopelessness ■ In video, mentioned “relief….” 9/28/2018 8 Out of the Darkness…Identify the barriers to early diagnosis of cognitive decline. ■ Medical Management can only mitigate symptoms at this time – Limited beneficial effects – Side effects (especially the cholinergics) 9/28/2018 9 Out of the Darkness…Identify the importance of early diagnosis of cognitive decline. ■ Optimize current medical management ■ Relief gained from better understanding ■ Maximize decision-making autonomy ■ Access to services ■ Risk reduction ■ Plan for the future ■ Improve clinical outcomes ■ Avoid or reduce future costs ■ Diagnosis as a human right 9/28/2018 10 A Screening Tool – a portal to care ■ Screening for dementia can bring the topic into the light… – We screen for many physiologic parameters: we check weight to get a sense of metabolic functions, blood pressure and pulse for cardiovascular function and respiratory rate and quality for respiratory function. Shouldn’t we be screening for cognitive function? – Screening can normalize conversations about cognitive decline and act as a portal to care. – We are proposing the use of the Mini-Cog to screen for cognitive decline. 9/28/2018 11 The Mini-Cog ■ The Mini-Cog©; is a 3-minute instrument that can increase detection of cognitive impairment in older adults. It can be used effectively after brief training in both healthcare and community settings. ■ It consists of two components, a 3-item recall test for memory and a simply scored clock drawing test. ■ As a screening test, however, it does not substitute for a complete diagnostic workup. 9/28/2018 12 Mini-Cog Improves Physician Recognition *** 100 *** 80 60 *** Mini-Cog 40 Patient’s own % Correct % physician 20 *** p < 0 .001 CDR Stage 0.5 1 2 3 MCI Mild Mod Sev Borson S et al. Int J Geriatr Psychiatry 2006; 21: 349 9/28/2018 13 The Mini-cog – a Screening Tool that is… ■ Simple – Easy to administer; throws a wide loop – Not meant to tell you anything ABOUT cognitive decline, but IS meant to pick up cognitive decline EARLY. – Further testing then can lead to early diagnosis, proactive, patient directed planning. ■ Objective – Subjective assessments often miss cues that indicate there may be a problem ■ Reliable – studies have show that this simple test is as good as more complex assessments at identifying the need for further assessment – Good with varying levels of education as well as those who speak English as a second language. 9/28/2018 14 Cognitive Screening and follow up… 9/28/2018 15 www.actonalz.org/sites/default/files /documents/Mini-Cog_.pdf 9/28/2018 16 Clock #1 9/28/2018 17 Clock #2 9/28/2018 18 Clock #3 9/28/2018 19 Clock #4 9/28/2018 20 Clock #5 9/28/2018 21 Clock #6 9/28/2018 22 Clock #7 9/28/2018 23 A word about interpretation pitfalls ■ Do not interpret low scores without context – make note of significant context ■ Do not skimp on history taking ■ Do not interpret education or ethnicity as impairment ■ Keep in mind that this only a snapshot in time ■ Do not fall prey to confirmatory bias ■ The absence of evidence is not evidence of absence – if someone has concerns they should be assessed further 9/28/2018 24 Summary - Identify the barriers to as well as the importance of early diagnosis of cognitive decline. ■ Fear and misunderstanding can be addressed through education ■ The fact that we have no medical treatments to change the course of illness feels hopeless; education about the non-medical support and management is crucial. ■ Caregiver, family and community support are essential to successful disease management ■ A simple, objective, reliable screen brings cognitive health out of the shadows. ■ Subjective evaluation does not identify cognitive decline until late in the course of decline. ■ Early diagnosis defines the prognosis and facilitates planning enabling the person experiencing cognitive decline to be the master of their own fate. ■ It is not the years in your life that count, but the life in those years…………………. 9/28/2018 25 OBJECTIVE 2: Identify Treatment and Management Strategies 9/28/2018 26 Two-step approach The Workup 1. Determine if MCI or Dementia is present 2. Identify underlying disease(s) ■ History ■ Review of Systems ■ Medical history ■ Social history ■ Family history ■ Physical and neurologic examination – Cognitive screening ■ Labs ■ Imaging ■ Consultations – geriatrician, neurology?, palliative/hospice 9/28/2018 27 General Management Considerations ■ Fixing vs. Supporting – Partnership: patient, caregiver, clinician – Goals: mitigating symptoms vs. living with disease at all costs – Side effects of medications (especially cholinergics) ■ FDA-approved medications may help improve or maintain cognitive and functional status, for a time…. – Medical management can only mitigate symptoms – Families/caregivers are helped by treatments that improve behavioral and psychological symptoms ■ Non-pharm strategies may help compensate for cognitive loss 9/28/2018 28 General Management Considerations • De-prescribe as able / refer to BEERs list • Anti-hyperglycemics and hypertensives • Anticholinergics - benadryl, antispasmodics, etc. • Anticoagulation for atrial fibrillation vs. WATCHMAN • Statins • Vitamins/minerals • In-appropriate uses of anti-psychotics, hypnotics, narcotics, benzos • Create plan with care team • Family plan for managing meds • Med management aids (pill boxes, alarms) • Create & review medication log 9/28/2018 29 Non-Pharm Treatment ■ External memory aids – Calendars, lists, whiteboards - keep in the same place ■ Learning habits with procedural memory can help in middle/moderate stages ■ Pictures are easier to remember than spoken/written words ■ Art and Music ■ Aerobic exercise – Stimulates new neurons in the hippocampus and has positive effects on cardiovascular health and mood ■ Social and cognitively stimulating activities help improve function ■ Structured environments / routine schedule ■ Annual hearing/vision evaluation 9/28/2018 30 Strategies for Prevention • Physical Interventions to Prevent Cognitive Decline Insufficient evidence to support physical activity interventions in preventing cognitive decline Low strength evidence that supports multimodal approach (diet, physical activity, cognitive training) in preventing cognitive decline • Vitamins/Minerals Daily folic acid/B12 - some evidence to improve performance on cog evals Vit E - moderate evidence showing no benefit on cognition Omega 3, MVT, Vit C, Vit D + Ca, beta carotene, folic acid alone, soy, ginkgo biloba - limited or low strength evidence to support benefit in preventing cognitive decline • Pioglitazone Diabetes patients - protective effect for developing dementia with long term/high dose exposure 9/28/2018 31 Strategies for Treatment ■ FDA Approved Cholinesterase Inhibitors: Donepezil, Galantamine, Rivastigmine NMDA Receptor Antagonist: Memantine ■ Forthcoming
Load more

Recommended publications
  • Shexiang Baoxin Pill, a Traditional Chinese Herbal Formula, Rescues the Cognitive Impairments in APP/ PS1 Transgenic Mice
    ORIGINAL RESEARCH published: 14 July 2020 doi: 10.3389/fphar.2020.01045 Shexiang Baoxin Pill, a Traditional Chinese Herbal Formula, Rescues the Cognitive Impairments in APP/ PS1 Transgenic Mice † † Wei-Hui Hu 1,2,3 , Shing-Hung Mak 1,2 , Zhong-Yu Zheng 1,2, Ying-Jie Xia 1,2, Miranda Li Xu 1,2, Ran Duan 1,2,3, Tina Ting-Xia Dong 1,2,3, Shao-Ping Li 4, Chang-Sen Zhan 5,6, Xiao-Hui Shang 5,6 and Karl Wah-Keung Tsim 1,2,3* 1 Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Shenzhen, China, 2 Division of Life Science and Center for Chinese Medicine and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, Hong Kong, 3 Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, China, 4 Institute of Chinese Medical Sciences, University of Macau, Macau, Macau, 5 Shanghai Edited by: Engineering Research Center for Innovation of Solid Preparation of TCM, Shanghai, China, 6 Shanghai Hutchison Qiaobing Huang, Pharmaceuticals Ltd., Shanghai, China Southern Medical University, China Reviewed by: Background: Shexiang Baoxin Pill (SBP), a formulated traditional Chinese medicine Bing-Xing Pan, Nanchang University, China (TCM), has been widely used to treat cardiovascular diseases for years. This herbal Wenda Xue, mixture has been shown to promote differentiation of cultured neuronal cells. Here, we Nanjing University of Chinese aimed to investigate the effects of SBP in attenuating cognitive impairment in APP/PS1 Medicine, China *Correspondence: transgenic mice.
    [Show full text]
  • The “Rights” of Precision Drug Development for Alzheimer's Disease
    Cummings et al. Alzheimer's Research & Therapy (2019) 11:76 https://doi.org/10.1186/s13195-019-0529-5 REVIEW Open Access The “rights” of precision drug development for Alzheimer’s disease Jeffrey Cummings1*, Howard H. Feldman2 and Philip Scheltens3 Abstract There is a high rate of failure in Alzheimer’s disease (AD) drug development with 99% of trials showing no drug- placebo difference. This low rate of success delays new treatments for patients and discourages investment in AD drug development. Studies across drug development programs in multiple disorders have identified important strategies for decreasing the risk and increasing the likelihood of success in drug development programs. These experiences provide guidance for the optimization of AD drug development. The “rights” of AD drug development include the right target, right drug, right biomarker, right participant, and right trial. The right target identifies the appropriate biologic process for an AD therapeutic intervention. The right drug must have well-understood pharmacokinetic and pharmacodynamic features, ability to penetrate the blood-brain barrier, efficacy demonstrated in animals, maximum tolerated dose established in phase I, and acceptable toxicity. The right biomarkers include participant selection biomarkers, target engagement biomarkers, biomarkers supportive of disease modification, and biomarkers for side effect monitoring. The right participant hinges on the identification of the phase of AD (preclinical, prodromal, dementia). Severity of disease and drug mechanism both have a role in defining the right participant. The right trial is a well-conducted trial with appropriate clinical and biomarker outcomes collected over an appropriate period of time, powered to detect a clinically meaningful drug-placebo difference, and anticipating variability introduced by globalization.
    [Show full text]
  • Current Research Efforts in the Prevention and Treatment of Alzheimer’S Disease (AD) and Related Dementias
    Current Research efforts in the prevention and treatment of Alzheimer’s Disease (AD) and Related Dementias What’s new? 1. New and More effective Biomarkers 2. New Diagnostic Framework : • New “A/T/N” Framework • New Framework conceptualizes AD as a continuum from pathophysiological, biomarker and clinical perspectives. 3. LATE (Limbic-predominant, Age-related, TDP-43 Encephalopathy) looks like Alzheimer’s disease 4. Alzheimer’s pathophysiology starts decades prior to clinical disease! 1. New and More Effective Biomarkers AD Pathology • Alzheimer’s Disease consists of two main features: • Senile plaques (β-amyloid)- earliest pathological event! • Neurofibrillary tangles (hyperphosphorylated tau)- primary culprit in cells death • Mechanism: • β-amyloid hyperphosphorylated tau tau spreads throughout the brain from neuron to neuron (Pooler et al, 2013). Cell Death Biomarkers Budson & Solomon, Practical Neurology 2012;12:88–96 PET Amyloid Imaging was approved since 2012 • Use when knowing that AD pathology is present in symptomatic patient would change management. • May detect amyloid plaques in asymptomatic patients who may not develop disease for 10-15+ years • Not paid for by Medicare or other insurance companies • Can obtain through Veterans Affairs hospitals, clinical trials/research studies, and self-pay. • Will have broader use when disease modifying therapies are available. Alzheimer’s Disease Non-AD dementia 65 year old MoCA 21 From Budson & Solomon, 2016 PET tau imaging : FDA approved May 2020 • Use when knowing that AD pathology is present in symptomatic patient would change management. • Will detect AD tau tangles in symptomatic patients and should correlate with symptoms • May detect other types of tau tangles in other dementias (not yet clear) • Not paid for by Medicare or other insurance companies • Can obtain through Veterans Affairs hospitals, clinical trials/research studies, and self-pay.
    [Show full text]
  • Drug Candidates in Clinical Trials for Alzheimer's Disease
    Hung and Fu Journal of Biomedical Science (2017) 24:47 DOI 10.1186/s12929-017-0355-7 REVIEW Open Access Drug candidates in clinical trials for Alzheimer’s disease Shih-Ya Hung1,2 and Wen-Mei Fu3* Abstract Alzheimer’s disease (AD) is a major form of senile dementia, characterized by progressive memory and neuronal loss combined with cognitive impairment. AD is the most common neurodegenerative disease worldwide, affecting one-fifth of those aged over 85 years. Recent therapeutic approaches have been strongly influenced by five neuropathological hallmarks of AD: acetylcholine deficiency, glutamate excitotoxicity, extracellular deposition of amyloid-β (Aβ plague), formation of intraneuronal neurofibrillary tangles (NTFs), and neuroinflammation. The lowered concentrations of acetylcholine (ACh) in AD result in a progressive and significant loss of cognitive and behavioral function. Current AD medications, memantine and acetylcholinesterase inhibitors (AChEIs) alleviate some of these symptoms by enhancing cholinergic signaling, but they are not curative. Since 2003, no new drugs have been approved for the treatment of AD. This article focuses on the current research in clinical trials targeting the neuropathological findings of AD including acetylcholine response, glutamate transmission, Aβ clearance, tau protein deposits, and neuroinflammation. These investigations include acetylcholinesterase inhibitors, agonists and antagonists of neurotransmitter receptors, β-secretase (BACE) or γ-secretase inhibitors, vaccines or antibodies targeting Aβ clearance or tau protein, as well as anti-inflammation compounds. Ongoing Phase III clinical trials via passive immunotherapy against Aβ peptides (crenezumab, gantenerumab, and aducanumab) seem to be promising. Using small molecules blocking 5-HT6 serotonin receptor (intepirdine), inhibiting BACE activity (E2609, AZD3293, and verubecestat), or reducing tau aggregation (TRx0237) are also currently in Phase III clinical trials.
    [Show full text]
  • A New Analysis of the Phase II Alzheimer's
    Will the Next Five Years Witness an Innovation Wave in Medicines for Alzheimer’s? The Healthcare System Is Not Ready for New Alzheimer’s Drugs Success in drug development for Alzheimer’s disease has been elusive. Recent analysis has shown a near 100% failure rate in the past decade. Yet, each failed trial advances the science and presents the opportunity to apply new insights. As a result, there are a significant number of compounds in Phase 3, the final stage of drug development. Seventeen drugs in this final stage are likely to finish testing and could be available to people with the disease in the next five years. These findings are based on the analysis led by ResearchersAgainstAlzhei- mer’s, a global network of leading Alzheimer’s researchers at top academic institutions and corporations. Our analysis leads us to be cautiously optimistic that innovative treatments are within our reach. We need to make sure the healthcare system is ready. Understanding the Alzheimer’s Drug Development Pipeline Robust Alzheimer’s Phase 3 Drugs in Development That Could Launch in the Next Five Years Pipeline Offers Promise for Treatment – Despite 2016 2017 2018 2019 2020 2021 Recent Track Record Brexpiprazole Otsuka Pharmaceuticals, H. Lundbeck Aripiprazole Otsuka Pharmaceuticals Solanezumab Eli Lilly MORE THAN A DECADE SINCE A NOVEL Masitinib ALZHEIMER’S DRUG WAS APPROVED AB Science Namenda was approved by TRx0237 the FDA in 2003, marking the last TauRx Therapeutics time a novel Alzheimer’s therapy Idalopirdine reached the market.1 Otsuka Pharmaceuticals, H. Lundbeck RVT-101 Axovant Sodium Oligo Shanghai Greenvalley Pharmaceuticals Azeliragon vTv Therapeutics PIPELINE OUTLOOK Nilvadipine There are approximately 50 drugs Astellas Pharma, Archer Pharmaceuticals in Phase 2 trials and about a dozen 2 ALZT-0P1 drugs in Phase 2/3 trials.
    [Show full text]
  • Randomized Trial of Verubecestat for Mild-To-Moderate Alzheimer's Disease
    The new england journal of medicine Original Article Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer’s Disease Michael F. Egan, M.D., James Kost, Ph.D., Pierre N. Tariot, M.D., Paul S. Aisen, M.D., Jeffrey L. Cummings, M.D., Sc.D., Bruno Vellas, M.D., Ph.D., Cyrille Sur, Ph.D., Yuki Mukai, M.D., Tiffini Voss, M.D., Christine Furtek, B.S., Erin Mahoney, B.A., Lyn Harper Mozley, Ph.D., Rik Vandenberghe, M.D., Ph.D., Yi Mo, Ph.D., and David Michelson, M.D.​​ ABSTRACT BACKGROUND Alzheimer’s disease is characterized by the deposition of amyloid-beta (Aβ) plaques in From Merck Research Laboratories, Merck, the brain. Aβ is produced from the sequential cleavage of amyloid precursor protein Kenilworth, NJ (M.F.E., J.K., C.S., Y. Mu- kai, T.V., C.F., E.M., L.H.M., Y. Mo, D.M.); by β-site amyloid precursor protein–cleaving enzyme 1 (BACE-1) followed by Banner Alzheimer’s Institute, Phoenix, γ-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the Aβ level in the AZ (P.N.T.); University of Southern Cali- cerebrospinal fluid of patients with Alzheimer’s disease. fornia, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, METHODS Las Vegas (J.L.C.); Gerontopole, INSERM We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evalu- Unité 1027, Alzheimer’s Disease Research and Clinical Center, Toulouse University ate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in Hospital, Toulouse, France (B.V.); and patients who had a clinical diagnosis of mild-to-moderate Alzheimer’s disease.
    [Show full text]
  • Aducanumab for Alzheimer's Disease
    Aducanumab for Alzheimer’s Disease: Effectiveness and Value Draft Evidence Report May 5, 2021 Prepared for ©Institute for Clinical and Economic Review, 2021 AUTHORS: Grace A. Lin, MD Associate Professor of Medicine and Health Policy University of California, San Francisco Melanie D. Whittington, PhD, MS Associate Director of Health Economics Institute for Clinical and Economic Review Patricia G. Synnott, MS, MALD Senior Manager, CEA Registry & Global Health Initiatives Center for the Evaluation of Value and Risk in Health Avery McKenna Research Assistant II, Evidence Synthesis Institute for Clinical and Economic Review Jon Campbell, PhD, MS Senior Vice President for Health Economics Institute for Clinical and Economic Review Steven D. Pearson, MD, MSc President Institute for Clinical and Economic Review David M. Rind, MD, MSc Chief Medical Officer Institute for Clinical and Economic Review DATE OF PUBLICATION: May 5, 2021 How to cite this document: Lin GA, Whittington MD, Synnott PG, McKenna A, Campbell J, Pearson SD, Rind DM. Aducanumab for Alzheimer’s Disease: Effectiveness and Value; Draft Evidence Report. Institute for Clinical and Economic Review, May 5, 2021. https://icer.org/assessment/alzheimers- disease-2021/. Grace A. Lin served as the lead author for the report. Patricia G. Synnott led the systematic review and authorship of the comparative clinical effectiveness section in collaboration with Avery McKenna and Emily Nhan. Melanie D. Whittington was responsible for the development of the cost-effectiveness model. Jon Campbell provided oversight of the cost-effectiveness analyses and ©Institute for Clinical and Economic Review, 2021 Page i Draft Evidence Report – Aducanumab for Alzheimer’s Disease developed the budget impact model.
    [Show full text]
  • Downloaded in PDB Format from Protein Conducted Setting the Maximum Heavy Atom RMSD Data Bank (
    Sarkar et al. Egyptian Journal of Medical Human Genetics (2021) 22:10 Egyptian Journal of Medical https://doi.org/10.1186/s43042-020-00127-8 Human Genetics RESEARCH Open Access Identification of the most potent acetylcholinesterase inhibitors from plants for possible treatment of Alzheimer’s disease: a computational approach Bishajit Sarkar1* , Sayka Alam1†, Tiluttoma Khan Rajib1†, Syed Sajidul Islam1†, Yusha Araf2 and Md. Asad Ullah1 Abstract Background: Being one of the rapidly growing dementia type diseases in the world, Alzheimer’s disease (AD) has gained much attention from researchers in the recent decades. Many hypotheses have been developed that describe different reasons for the development of AD. Among them, the cholinergic hypothesis depicts that the degradation of an important neurotransmitter, acetylcholine by the enzyme acetylcholinesterase (AChE), is responsible for the development of AD. Although, many anti-AChE drugs are already available in the market, their performance sometimes yields unexpected results. For this reason, research works are going on to find out potential anti-AChE agents both from natural and synthetic sources. In this study, 50 potential anti-AChE phytochemicals were analyzed using numerous tools of bioinformatics and in silico biology to find out the best possible anti-AChE agents among the selected 50 ligands through molecular docking, determination of the druglikeness properties, conducting the ADMET test, PASS and P450 site of metabolism prediction, and DFT calculations. Result: The predictions of this study suggested that among the selected 50 ligands, bellidifolin, naringenin, apigenin, and coptisine were the 4 best compounds with quite similar and sound performance in most of the experiments.
    [Show full text]
  • Impact of Amyloid-Beta Changes on Cognitive Outcomes in Alzheimer's
    Geerts et al. Alzheimer's Research & Therapy (2018) 10:14 DOI 10.1186/s13195-018-0343-5 RESEARCH Open Access Impact of amyloid-beta changes on cognitive outcomes in Alzheimer’s disease: analysis of clinical trials using a quantitative systems pharmacology model Hugo Geerts1,2* , Athan Spiros1 and Patrick Roberts1,3 Abstract Background: Despite a tremendous amount of information on the role of amyloid in Alzheimer’s disease (AD), almost all clinical trials testing this hypothesis have failed to generate clinically relevant cognitive effects. Methods: We present an advanced mechanism-based and biophysically realistic quantitative systems pharmacology computer model of an Alzheimer-type neuronal cortical network that has been calibrated with Alzheimer Disease Assessment Scale, cognitive subscale (ADAS-Cog) readouts from historical clinical trials and simulated the differential impact of amyloid-beta (Aβ40 and Aβ42) oligomers on glutamate and nicotinic neurotransmission. Results: Preclinical data suggest a beneficial effect of shorter Aβ forms within a limited dose range. Such a beneficial effect of Aβ40 on glutamate neurotransmission in human patients is absolutely necessary to reproduce clinical data on the ADAS-Cog in minimal cognitive impairment (MCI) patients with and without amyloid load, the effect of APOE genotype effect on the slope of the cognitive trajectory over time in placebo AD patients and higher sensitivity to cholinergic manipulation with scopolamine associated with higher Aβ in MCI subjects. We further derive a relationship between units of Aβ load in our model and the standard uptake value ratio from amyloid imaging. When introducing the documented clinical pharmacodynamic effects on Aβ levels for various amyloid-related clinical interventions in patients with low Aβ baseline, the platform predicts an overall significant worsening for passive vaccination with solanezumab, beta-secretase inhibitor verubecestat and gamma-secretase inhibitor semagacestat.
    [Show full text]
  • AVN-211, Novel and Highly Selective 5-HT6 Receptor Small Molecule Antagonist, for the Treatment of Alzheimer's Disease Alexandre V
    Subscriber access provided by University of Pennsylvania Libraries Article AVN-211, Novel and Highly Selective 5-HT6 Receptor Small Molecule Antagonist, for the Treatment of Alzheimer's Disease Alexandre V. Ivachtchenko, Yan Lavrovsky, and Yan A. Ivanenkov Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.5b00830 • Publication Date (Web): 17 Feb 2016 Downloaded from http://pubs.acs.org on February 22, 2016 Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
    [Show full text]
  • Clinical Trials of New Drugs for Alzheimer Disease Li-Kai Huang1,2†, Shu-Ping Chao1,3† and Chaur-Jong Hu1,2,4,5*
    Huang et al. Journal of Biomedical Science (2020) 27:18 https://doi.org/10.1186/s12929-019-0609-7 REVIEW Open Access Clinical trials of new drugs for Alzheimer disease Li-Kai Huang1,2†, Shu-Ping Chao1,3† and Chaur-Jong Hu1,2,4,5* Abstract Alzheimer disease (AD) accounts for 60–70% of dementia cases. Given the seriousness of the disease and continual increase in patient numbers, developing effective therapies to treat AD has become urgent. Presently, the drugs available for AD treatment, including cholinesterase inhibitors and an antagonist of the N-methyl-D-aspartate receptor, can only inhibit dementia symptoms for a limited period of time but cannot stop or reverse disease progression. On the basis of the amyloid hypothesis, many global drug companies have conducted many clinical trials on amyloid clearing therapy but without success. Thus, the amyloid hypothesis may not be completely feasible. The number of anti-amyloid trials decreased in 2019, which might be a turning point. An in-depth and comprehensive understanding of the contribution of amyloid beta and other factors of AD is crucial for developing novel pharmacotherapies. In ongoing clinical trials, researchers have developed and are testing several possible interventions aimed at various targets, including anti-amyloid and anti-tau interventions, neurotransmitter modification, anti-neuroinflammation and neuroprotection interventions, and cognitive enhancement, and interventions to relieve behavioral psychological symptoms. In this article, we present the current state of clinical trials for AD at clinicaltrials.gov.We reviewed the underlying mechanisms of these trials, tried to understand the reason why prior clinical trials failed, and analyzed the future trend of AD clinical trials.
    [Show full text]
  • Spotlight on Axovant After Lundbeck's Alzheimer's Failure
    September 23, 2016 Spotlight on Axovant after Lundbeck’s Alzheimer’s failure Madeleine Armstrong The phase III failure of Lundbeck’s idalopirdine is yet another example of just how difficult Alzheimer’s drug development is, and another nail in the coffin for the 5-HT6 antagonist class. It is therefore likely to be bad news for Lundbeck's rival Axovant, which uses the same approach with its own phase III project intepirdine. While some analysts were adamant that idalopirdine’s stumble was not a bad omen, it is hard to remain optimistic after the second late-stage collapse of a 5-HT6 antagonist this year – the other involved Pfizer’s PF-05212377, which was discontinued in February for lack of efficacy in a phase II trial. Axovant investors seemed inclined to agree: the company’s stock fell 12% yesterday. Meanwhile, Lundbeck was down as much as 15% today after yesterday's post-market release of data, and its partner Otsuka declined 3%. The analysts were in accord on one thing: this is likely the end of the road for idalopirdine, which will nevertheless limp on in two more phase III trials. These studies seem unlikely to return positive results after the Starshine trial failed to show a benefit on the primary endpoint, the ADAS-cog score, at either dose of idalopirdine – 30mg or 60mg on top of 10mg of Aricept against Aricept plus placebo. The project also failed to demonstrate an improvement on secondary endpoints. ABG Sundal Collier analysts were particularly scathing, writing: “We find nothing [in] the announcement to support any sort of optimism around idalopirdine being a potentially approvable drug.” The ongoing Starbeam study is testing idalopirdine at 10mg or 30mg on top of 10mg of Aricept, while Starbright evaluates 30mg or 60mg in combination with an unnamed acetylcholinesterase inhibitor – the same drug class as Aricept.
    [Show full text]