Robert E. Becker*, Nigel H. Greig, Debomoy K. Lahiri, Joseph Bledsoe, Sarah Majercik, Clive Ballard, Dag Aarsland, Lon S. Schneider, Douglas Flanagan, Ramprakash Govindarajan, Mary Sano, Luigi Ferrucci and Dimitrios Kapogiannis Pages 883 - 891 ( 9 )
Background: Concussion (mild) and other moderate traumatic brain injury (TBI) and Alzheimer's disease (AD) share overlapping neuropathologies, including neuronal pre-programmed cell death (PPCD), and clinical impairments and disabilities. Multiple clinical trials targeting mechanisms based on the Amyloid Hypothesis of AD have so far failed, indicating that it is prudent for new drug developments to also pursue mechanisms independent of the Amyloid Hypothesis. To address these issues, we have proposed the use of an animal model of concussion/TBI as a supplement to AD transgenic mice to provide an indication of an AD drug candidate’s potential for preventing PPCD and resulting progression towards dementia in AD.
Methods: We searched PubMed/Medline and the references of identified articles for background on the neuropathological progression of AD and its implications for drug target identification, for AD clinical trial criteria used to assess disease modification outcomes, for plasma biomarkers associated with AD and concussion/TBI, neuropathologies and especially PPCD, and for methodological critiques of AD and other neuropsychiatric clinical trial methods.
Results: We identified and address seven issues and highlight the Thal-Sano AD ‘Time to Onset of Impairment' Design for possible applications in our clinical trials. Diverse and significant pathological cascades and indications of self-induced neuronal PPCD were found in concussion/TBI, anoxia, and AD animal models. To address the dearth of peripheral markers of AD and concussion/TBI brain pathologies and PPCD we evaluated Extracellular Vesicles (EVs) enriched for neuronal origin, including exosomes. In our concussion/TBI, anoxia and AD animal models we found evidence consistent with the presence of time-dependent PPCD and (-)-phenserine suppression of neuronal self-induced PPCD. We hence developed an extended controlled release formulation of (-)-phenserine to provide individualized dosing and stable therapeutic brain concentrations, to pharmacologically interrogate PPCD as a drug development target. To address the identified problems potentially putting any clinical trial at risk of failure, we developed exploratory AD and concussion/TBI clinical trial designs.
Conclusions: Our findings inform the biomarker indication of progression of pathological targets in neurodegenerations and propose a novel approach to these conditions through neuronal protection against self-induced PPCD.
Alzheimer's disease, traumatic brain injury, concussion, extracellular vesicle biomarkers, pre-programmed cell death, (-)-phenserine, neurodegeneration, neurodegenerative disorder clinical trial design, exosomes, apoptosis.
Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, Baltimore, MD 21224, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, Baltimore, MD 21224, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, Surgery-Emergency Medicine, Stanford Medicine and Department of Emergency Medicine, Intermountain Medical Center, Murray, UT 84157, Trauma and Surgical Critical Care, Intermountain Medical Center, Salt Lake City, UT 84107, Medical School, University of Exeter, Exeter, EX1 2LU, Department of Old Age Psychiatry, Institute of Psychiatry, Psychology, & Neuroscience, King’s College London, London SE5 8AF, Departments of Psychiatry, Neurology, and Gerontology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, College of Pharmacy, University of Iowa, Iowa City, IA 52242, College of Pharmacy, University of Iowa, Iowa City, IA 52242, Department of Psychiatry and Alzheimer`s Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, Baltimore, MD 21224, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Baltimore MD, 21224