Purpose and Goal of Project

The purpose and goal of this project is to advance fundamental understanding of neurodegeneration and neuroprotection in a novel and rigorous manner to identify new strategies for improving brain health. We seek to optimize cognitive function and mental health in normal aging, traumatic brain injury (TBI), and aging-related diseases of neurodegeneration, such as Alzheimer's disease (AD) and Parkinson's disease (PD).
There are 3 Aims. Aim 1 will establish the functional changes in chromatin organization that drive transition of acute TBI into chronic disease, and that drive TBl-induced increased risk of AD. These are important because even a single TBI can progress into chronic lifelong dysfunction of the brain and peripheral organs, and TBI is also the 3rd greatest risk factor for AD, behind aging and genetics, as well as the greatest known environmental cause of AD. However, the reasons are poorly understood. We are applying cutting-edge technology to examine the epigenome to define the disease mechanisms. Many diseases are driven by disruption of gene regulation and alterations to regulatory sequences contained within noncoding DNA, and these regions are not detected by traditional proteomic or transcriptomic methods. Indeed, only 1-2% of an organism's genome is profiled by state-of-the-art transcriptomic methods, and 98-99% of DNA is composed of noncoding regions that can contain gene regulatory elements such as enhancers and promoters. By profiling the epigenome, we are tackling this problem from a unique and promising direction. Aim 2 will identify the molecular targets of 3 new neuroprotective compounds that we isolated through phenotypic screening in mice, and improve their potency, efficacy and safety through medicinal chemistry and mitochondrial, cellular, and animal assays. This will identify new mechanisms of neuroprotection that will advance understanding of the fundamental processes of neurodegeneration, while simultaneously providing optimized chemical matter for drug development. This Aim will also verify protective efficacy of these and related compounds in animal models of Alzheimer’s and Parkinson’s diseases. Aim 3 will identify new small drug-like molecules and PROTACs to block the acquisition of aging-, injury-, and disease-related mediated deficits in neuroprotective autophagy.

Significance / Relevance of Project

With modern advances in medical care, people are living longer than ever before. However, progress has occurred almost entirely within the realm of aging, injured, and diseased peripheral organ systems, and the field of brain health has not kept pace. Consequently, there are no effective treatments for patients suffering from the neurodegenerative effects of aging, injury, and disease of the brain. This is dramatically
increasing the prevalence of dementia, causing widespread crippling cognitive impairment and mental health struggles. With the realization that long Covid also diminishes brain health and increases the likelihood of developing aging-related neurodegenerative diseases, the problem has intensified. Simply put, people today are living longer, but not necessarily living better. Without developing new medicines that prevent, slow, stop, or reverse neurodegeneration in the brain, there will be an epidemic
of human suffering and crippling financial cost to society. It is imperative that we advance our fundamental understanding of neurodegeneration in novel ways that facilitate discovery and development of safe and effective neuroprotective medicines.

Biosketch of Principal Investigator

Andrew A. Pieper earned his B.A. from Earlham College in Richmond, Indiana with a double major in Biology and Chemistry. At Earlham, he was awarded College Honors, Biology Departmental Honors, Chemistry Departmental Honors, membership in Phi Beta Kappa, and the Russel L. Malcom Premedical Award. He then enrolled at Johns Hopkins University for MD / PhD training. He earned his PhD in Neuroscience in the laboratory of Dr. Solomon H. Snyder, a world-renowned psychiatrist-neuroscientist and founder of the Johns Hopkins University Solomon H. Snyder Department of Neuroscience. Here, Pieper pioneered work on intracellular calcium signaling and the role of tissue regional differences in basal energy metabolism as a risk factor for pathological cell death. He additionally showed that pharmacologically preserving cellular energy levels in living mice exerted potent protective efficacy in preclinical models of stroke, traumatic brain injury, myocardial infarction, and diabetes. After earning his MD and PhD degrees, Pieper completed Medicine internship and Psychiatry residency training at Johns Hopkins Hospital, where he worked with Dr. Glenn Treisman to advance the understanding and treatment of the unique mental health issues
facing HIV-infected patients. Next, he conducted his postdoctoral training in the Biochemistry Laboratory of Dr. Steven McKnight at UT Southwestern Medical Center in Dallas, where he discovered that the primary role of a genetic transcription factor known to be mutated in patients with schizophrenia was to control survival of newborn
hippocampal neurons in the hippocampus, an essential brain region for learning, memory, and mood regulation. He extended this work as Assistant Professor of Psychiatry and Biochemistry at UT Southwestern Medical Center, where he also dedicated 15% of his professional time as an Attending Psychiatrist in the Parkland Hospital Psychiatry Emergency Department. Pieper then moved to the University of Iowa where he was promoted to Full Professor, serving 5 years as the Director of Translational Neuroscience in the Department of Psychiatry. In Iowa, he devoted 20% of his professional time as an Attending Psychiatrist for the inpatient unit at the University of Iowa VA Medical Center. He then moved to Cleveland, Ohio, where he has since served as a psychiatrist and neuroscientist as Professor in the Departments of Psychiatry, Neurosciences, and Pathology at Case Western Reserve University (CWRU) and University Hospitals (UH) Cleveland Medical Center. He also serves as Director of the Brain Health Medicines Center at the Harrington Discovery Institute, which is focused on drug development in the field of Alzheimer’s disease and dementia. He additionally serves as Associate Director of the CWRU Medical Scientist Training Program, the CWRU Rebecca E. Barchas, M.D.,
Professor in Translational Psychiatry, and the UH Morley Mather Chair in
Neuropsychiatry. In addition to his laboratory and administrative duties, Pieper also treats patients in the Geriatric Psychiatry Outpatient Clinic for one day a week as a Psychiatrist at the Louis Stokes Cleveland VA Medical Center. Pieper’s goals are to use his scientific and clinical skills to understand and investigate human neurodegenerative disorders with the ultimate goal of fostering development of new treatments that will prevent, slow, stop, or reverse neurodegenerative disease in patients. He is deeply committed to optimizing cognitive function and mental health through both patient care and laboratory research.

Purpose & Goal(s)

The purpose of this research project is to discover drugs that inhibit the accumulation of misfolded proteins and advance them as therapies for neurodegenerative diseases. Alzheimer’s (AD) and Parkinson’s (PD) diseases cause devastating disorders in almost 7 million Americans. Currently, about 5.5 million Americans suffer from AD, and about 1.5 million are afflicted with PD. Each year, about 500,000 people die with AD and about 500,000 new AD cases are recorded.

The number of AD and PD cases will increase dramatically as the longevity of populations worldwide continues to rise. Age is the greatest risk factor for both diseases. At age 60, about 1% of people have AD, while at 70, about 10% of people have AD. By age 85, nearly half of the population develops AD, and the proportion continues to increase. By 2050, about 14 million Americans are estimated to have AD.

AD is a progressive degeneration of the central nervous system (CNS). The cruelty of this disorder generally manifests as a decade-long course of unrelenting, progressive mental disability. AD is a terrifying disease for many older people and their families.

Two proteins form the signature pathology of AD: amyloid beta (Abeta) and tau. Both proteins undergo a profound change in shape and assemble into aggregates. Abeta aggregates form amyloid fibrils that coalesce into plaques in the space between neurons. Tau aggregates form filaments that coalesce into tangles inside neurons. Genetic studies have identified that mutations related to Abeta cause familial AD. In contrast, mutations in the tau gene do not cause AD but do cause familial tauopathies. This genetic evidence supports the hypothesis that Abeta induces the formation of tau aggregates to initiate AD.

Another protein, alpha-synuclein, causes both PD and multiple system atrophy (MSA). Mutations in alpha-synuclein cause familial PD, while wild-type alpha-synuclein causes sporadic PD as well as MSA. In PD, alpha-synuclein accumulates within neurons to form Lewy bodies, while in MSA, alpha-synuclein builds up to form glial cytoplasmic inclusions (GCIs) within oligodendrocytes where myelin is formed in the CNS. It is now evident that the divergent presentation and course of these diseases arises from two different misfolded shapes of alpha-synuclein. We can objectively differentiate these by assay in cell culture.

We and others have demonstrated that individual conformers, or shapes, of each misfolded protein are responsible for specific diseases. We have demonstrated that small molecules can bind selectively to prions, disrupting their pathogenic propagation. In our pioneering work with alpha-synuclein prions, we have demonstrated that these small molecules can cross the blood-brain barrier and delay the onset of neurodegeneration in transgenic rodent models of disease. We enabled structure-based drug design for prion therapeutics and now seek to apply it broadly to the accelerated identification of drugs for all protein misfolding diseases.

Significance of Research:

Neurodegenerative diseases (NDs) inflict incalculable suffering and anguish on patients and their families worldwide. The economic costs are also profound. In the U.S. alone, the two most prevalent NDs rob Americans of over $400 billion annually, including medical costs and uncompensated caregiving (https://www.fightchronicdisease.org/resources/us-burden-neurodegenerative-disease); this is equal to about half the annual budget of the U.S. military or all U.S. K-12 schools. Despite this overwhelming societal need, no effective treatment for either Alzheimer’s (AD) and Parkinson’s (PD) diseases has been developed. Recently, patients and health care providers alike have been confused by controversial, limited FDA approvals of anti-AD antibody therapies that provide marginal benefits at best. This situation underscores the fact that safe and broadly effective anti-AD treatments do not exist.

We are committed to discovering drugs that stop AD and PD. To this end, we discovered that these NDs feature self-propagating misfolded proteins called prions; notably, the discovery of prions eventually led to the Nobel Prize being awarded to Stanley Prusiner in 1997. After identifying the intrinsic pathogen driving NDs, our laboratories have been dedicated to identifying a cure. In the process, we have discovered a fundamentally new mode of action for drugs that modify the activity of repeating beta-sheet structures. Among NDs, multiple system atrophy (MSA) rapidly emerged as the most tractable test case: it was amenable to propagation in cell culture and transgenic mice and its relatively rapid course in patients promises for a swift and meaningful outcome in clinical studies. The techniques established using MSA should be immediately applicable to other prion diseases.

Biosketch of Principal Investigator

Stanley B. Prusiner is Director of the Institute for Neurodegenerative Diseases and Professor of Neurology and Biochemistry at the University of California San Francisco (UCSF). He received his B.A. in Chemistry in 1964 and his M.D. in 1968 from the University of Pennsylvania. After completing his military service as a lieutenant commander in the U.S. Public Health Service at the National Institutes of Health and his neurology residency training at UCSF, he joined the UCSF faculty in 1974 and set up a laboratory to study brain diseases.

Prusiner discovered an unprecedented class of pathogens that he named prions. Prions are proteins that acquire an alternative shape that becomes self-propagating. As prions accumulate, they cause neurodegenerative diseases in animals and humans. Prusiner’s discovery led him to develop a novel disease paradigm: prions cause disorders such as Creutzfeldt-Jakob disease (CJD) in humans that manifest as (1) sporadic, (2) inherited, and (3) infectious illnesses. When proposed, many scientists considered Prusiner’s concept of “infectious proteins” as well as his proposal that a single protein could possess multiple biologically active shapes or conformations to be heretical. Based on his seminal discovery that prions can assemble into amyloid fibrils, Prusiner proposed that the more common neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases may be caused by prions. Remarkably, a wealth of evidence continues to accumulate arguing that prions cause not only these common degenerative diseases, but also the frontotemporal dementias (FTDs), chronic traumatic encephalopathy (CTE), MSA, and dementia with Lewy bodies (DLB). Much of Prusiner’s current research focuses on developing therapeutics that reduce the levels of the specific prions responsible for MSA, DLB, and some FTDs, as well as CTE.

Prusiner’s contributions to scientific research have been internationally recognized: He is a member of the National Academy of Sciences, the National Academy of Medicine, the American Academy of Arts and Sciences, and the American Philosophical Society, and he is a foreign member of the Royal Society, London. He is the recipient of numerous prizes, including the Potamkin Prize for Alzheimer’s Disease Research from the American Academy of Neurology (1991); the Richard Lounsbery Award for Extraordinary Scientific Research in Biology and Medicine from the National Academy of Sciences (1993); the Gairdner Foundation International Award (1993); the Albert Lasker Award for Basic Medical Research (1994); the Wolf Prize in Medicine from the State of Israel (1996); the Nobel Prize in Physiology or Medicine (1997); and the United States Presidential National Medal of Science (2009).

Prusiner is the author of over 550 scientific research articles and 300 review articles and is the editor of 13 books on diseases caused by prions. Prusiner’s single-author book Madness and Memory, which chronicles his discovery of prions, received wide acclaim. He holds 50 issued or allowed United States patents, all of which are assigned to the University of California. He has delivered over 150 honorary and over 750 invited lectures.

Purpose, Goals & Objectives
To Convert 2nd floor of Neuropsychiatric Center (NPC) in collaboration with Harris Health System to a dual diagnosis inpatient treatment & stabilization unit with a one-time build up cost of 2 million (in year one). Harris Health system has agreed to provide the space for this inpatient short stay unit. This will decrease ER boarding time, which currently is over 24-48 hours in some cases for alcohol and substance use related cases. Additionally, it will not only provide better, but a safer and appropriate environment to these patients at a reduced overall cost of care.

With an operational cost of 3 million divided equally in 3 years we plan to support Addiction Psychiatrist, case managers/social work, and a post-doctoral fellow to run this unit. Harris Health will help with the operational cost of nursing and other related staffing. We will also work closely with Houston Recovery Center for patient disposition and care and hold an annual educational conference free for health care professionals to disseminate information.

In 2012,  the average cost to deliver drug use disorder treatment was $4,591 for 5.2 days and $3,422 for 3.7 days; alcohol use disorder treatment was $5,908 for 6.2 days and $4,147 for 3.8 days[1]. These costs are much higher a decade later. Additionally, readmission costs seem to be linked to higher cost per hospitalization episode[2]. With this dual diagnosis unit, we plan to minimize this cost and decrease boarding times in ER.

Significance/Relevance of the Project:
We hope that this project will show improvement in the lives of patients with co-occurring disorders and make integrated care the standard in Houston area. This proposal will have a teaching, research, and educational arm, in keeping with the missions and broad expertise of Baylor College of Medicine and the Harris Health System. Through collaboration with our partner agencies, we aim to create a model of care that can be replicated anywhere in the United States. We hope to improve lives of many through this project and make a difference in the lives of those who suffer from alcohol and substance use disorder and mental health, hence called dual diagnosis & Stabilization Unit.

At Harris Health System, a public hospital system serving the 4.7 million people in Harris County, behavioral health visits account for 10% of ED visits, exceeding the 8% trauma activations at this urban level-1 trauma center. Over two thirds of these mental health visits have dual diagnosis (alcohol use disorder (AUD), substance use and mental health diagnosis) and most come to ER multiple times a year, with diagnoses of Psychosis, alcohol use disorder (AUD) and substance related disorders (like Cocaine, Marijuana, Methamphetamine etc.), Depression & Bipolar Disorders. According to an economic analysis of the 2017 Healthcare Cost and Utilization Project Nationwide Emergency Department Sample and National Inpatient Sample examining more than 124 million visits, the total annual estimated attributable SUD medical cost in hospitals was $13.2 billion (all drugs/substances) including $7.6 billion for alcohol-related disorders[3]. The literature supports that integrated model is more cost-effective than standard care, and the purpose of this proposal is to establish a continuum of care integrating mental health and substance use treatments[4]. This will not only save money for the system but provide better care for the people of Harris county and city of Houston.

References:
1. Stensland, M., P.R. Watson, and K.L. Grazier, An examination of costs, charges, and payments for inpatient psychiatric treatment in community hospitals. Psychiatr Serv, 2012. 63(7): p. 666-71.
2. Lin, J., et al., Economic Burden of Treatment-Resistant Depression Among Patients Hospitalized for Major Depressive Disorder in the United States. Psychiatr Res Clin Pract, 2019. 1(2): p. 68-76.
3. Peterson, C., et al., Assessment of Annual Cost of Substance Use Disorder in US Hospitals. JAMA Network Open, 2021. 4(3): p. e210242-e210242.
4. Karapareddy, V., A Review of Integrated Care for Concurrent Disorders: Cost Effectiveness and Clinical Outcomes. Journal of Dual Diagnosis, 2019. 15(1): p. 56-66.

Cognitive impairment, often stemming from neurodegenerative or psychiatric disorders, is a leading cause of global disability. While certain conditions like hypothyroidism or vitamin deficiencies can be diagnosed and treated, many reversible causes of cognitive impairment are frequently overlooked. This proposal introduces a novel, multi-modal approach to identify and treat three lesser-known causes of reversible cognitive impairment: seronegative autoimmune encephalitis, infectious encephalitis from undetectable pathogens, and rare Mendelian genetic disorders.

Autoimmune encephalitis, a condition in which the immune system mistakenly attacks the brain, can lead to severe cognitive issues, and a majority of suspected cases remain undiagnosed. Here, we will establish a comprehensive autoantibody discovery pipeline to identify disease-causing autoantibodies in individuals with unexplained and atypical cognitive impairment. Infectious encephalitis, caused by various pathogens, is another significant concern, with over half of its cases remaining unidentified. Current diagnostic methods are limited and often result in false negatives. Metagenomics, or genome sequencing of pathogen’s DNA/RNA, offers a promising solution by evaluating for the presence of thousands of potential pathogens simultaneously. Lastly, over 60 Mendelian genetic disorders can lead to cognitive decline, with many being overlooked in routine clinical evaluations. Thus, we will also employ clinical whole genome sequencing to identify these rare genetic conditions. By integrating these three state-of-the-art technologies, this proposal aims to uncover new causes of cognitive impairment, provide crucial biomarkers, and pave the way for therapeutic interventions for those afflicted by these debilitating conditions.

The immediate clinical significance of this study for potential participants is substantial. At this moment, there are millions of individuals in hospitals, psychiatric institutions, prisons, and nursing homes suffering from cognitive impairment. A meaningful proportion of these individuals have been misdiagnosed with primary neurodegenerative or psychiatric disorders and are suffering from potentially curable conditions. These disorders affect individuals of all ages, causing lifelong disability and often death if not diagnosed and treated in a timely manner. Delayed or missed diagnoses also lead to millions in health care costs due to prolonged hospitalization or institutionalization.

In addition to providing a possible diagnosis for participants, this study will yield biomarkers that can be screened for in cohorts with primary neuropsychiatric disorders such as schizophrenia. Two recent studies of more than 400 individuals with schizophrenia revealed that 7.5% of participants harbored autoantibodies to two novel
neuronal antigens, NCAM1 and NRXN1a. Notably, these individuals had no abnormalities on conventional clinical testing—their only defining feature was treatment resistance to antipsychotics. Given that nearly 30% of patients with schizophrenia are treatment resistant, there is an urgent need to understand what fraction of those patients are not responding because they are suffering from curable autoimmune conditions. This question is not only relevant for schizophrenia, but for treatment resistant forms of neuropsychiatric disorders such as dementia, epilepsy, depression, OCD, tic disorders, and others that have been revealed to have treatable autoimmune mimics. We envision this study as a comprehensive first step towards shedding light on this critical question.


Dr. Zoghbi’s research is dedicated to understanding the biological basis of neuropsychiatric disorders, with the goal of translating these insights into improvements in clinical care, disease risk prediction, and novel therapeutic development. During his residency at Columbia, Dr. Zoghbi was fascinated by the clinical heterogeneity of schizophrenia. He wondered how patients with such varied symptom profiles, severity, cognitive functioning, and clinical courses could all be suffering from the same disease. Witnessing the advances in genomic technology and its impact on other medical disciplines, he turned to genetics to decipher this complexity. Under the mentorship of Dr. David Goldstein, he led a project using an "extreme phenotype sequencing" approach to study patients with severe, extremely treatment-resistant schizophrenia (SETRS) who were chronically institutionalized in the New York State hospital system. His aim was to test the hypothesis that this uniquely severe form of schizophrenia would show both a higher incidence of rare genetic variation and autoimmune causes of psychosis, such as NMDA-R encephalitis. This study, funded initially by the Chapman Perelman Foundation, provided a proof-of-concept and the preliminary data for his current NIMH K23 award, which has expanded the recruitment of this cohort.

In July 2021, Dr. Zoghbi established his research group at Baylor College of Medicine and subsequently published the results of his K23 work which revealed that individuals with SETRS carry the highest burden of rare genetic variants observed in schizophrenia to date. Furthermore, their research team identified two cases of autoimmune encephalitis among the SETRS cohort including one patient who demonstrated a remarkable response to immunosuppressive medication was discharged after 26 years of continuous hospitalization. Dr. Zoghbi currently serves as an attending on the consult-liaison service at Ben Taub, where he encounters numerous patients with unexplained, untreated neuropsychiatric symptoms and severe cognitive deficits. In this project, he aims to integrate these disparate aspects of biology—genetic, immune, infectious diseases, biomarker-based assays—to unravel the molecular mechanisms behind these challenging patient presentations. Completing the proposed work will directly impact the care of these severely disabled patients and characterize the relative contribution of genomics, autoimmunity, and infectious diseases to unexplained cognitive impairment.