Videos by Marcia Ratner, PhD, DABT
So, everybody’s hearing about CTE now in the news with the football players and of course the Her... more So, everybody’s hearing about CTE now in the news with the football players and of course the Hernandez story, you know right near a Patriot player, so people have come to be aware of chronic traumatic encephalopathy which occurs when someone get hits repeatedly in the head as a football player would do and, but there’s another acronym for CTE which is "chronic toxic encephalopathy" and we can think of toxic chemicals almost like little football players that come along and beat up our brains. I’m very interested in how those hits to the head, those chemical hits to the head, influence our risk for injury, direct injury to the brain and how those interact with our risk for age related neurodegenerative diseases such as Alzheimer’s.
Link to full length video on youtube
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In this video blog I discuss the differences between Parkinson's disease and parkinsonism due to ... more In this video blog I discuss the differences between Parkinson's disease and parkinsonism due to exposures to chemicals such as manganese. 16 views
Dr. Marcia Ratner of the Department of Pharmacology and Experimental Therapeutics at the Boston U... more Dr. Marcia Ratner of the Department of Pharmacology and Experimental Therapeutics at the Boston University School of Medicine and Dr. James Hendrix of LuMind IDSC were recently interviewed by Dr. Hackie Reitman of DifferentBrains about the state of the art in Alzheimer's disease research as it specifically pertains to the treatment of persons with Down syndrome.
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Articles and Book Chapters by Marcia Ratner, PhD, DABT
Pharmacol Rev, 2024
Animals and animal models have been invaluable for our current understanding of human and animal ... more Animals and animal models have been invaluable for our current understanding of human and animal biology, including physiology, pharmacology, biochemistry, and disease pathology. However, there are increasing concerns with continued use of animals in basic biomedical, pharmacological, and regulatory research to provide safety assessments for drugs and chemicals. There are concerns that animals do not provide sufficient information on toxicity and/or efficacy to protect the target population, so scientists are utilizing the principles of replacement, reduction, and refinement (the 3Rs) and increasing the development and application of new approach methods (NAMs). NAMs are any technology, methodology, approach, or assay used to understand the effects and mechanisms of drugs or chemicals, with specific focus on applying the 3Rs. Although progress has been made in several areas with NAMs, complete replacement of animal models with NAMs is not yet attainable. The road to NAMs requires additional development, increased use, and, for regulatory decision making, usually formal validation. Moreover, it is likely that replacement of animal models with NAMs will require multiple assays to ensure sufficient biologic coverage. The purpose of this manuscript is to provide a balanced view of the current state of the use of animal models and NAMs as approaches to development, safety, efficacy, and toxicity testing of drugs and chemicals. Animals do not provide all needed information nor do NAMs, but each can elucidate key pieces of the puzzle of human and animal biology and contribute to the goal of protecting human and animal health. SIGNIFICANCE STATEMENT: Data from traditional animal studies have predominantly been used to inform human health safety and efficacy. Although it is unlikely that all animal studies will be able to be replaced, with the continued advancement in new approach methods (NAMs), it is possible that sometime in the future, NAMs will likely be an important component by which the discovery, efficacy, and toxicity testing of drugs and chemicals is conducted and regulatory decisions are made.
Neuroimmunology Reports, 2022
Background
The Food and Drug Administration (FDA) has determined that certain groups including pe... more Background
The Food and Drug Administration (FDA) has determined that certain groups including people with Multiple Sclerosis (MS) are at greater risk for potential harmful effects of mercury (Hg) vapor released from dental amalgams.
Objectives
This case report explores the potential harmful effects of Hg vapor released from dental amalgams in monozygotic twin brothers discordant MS.
Methods
The patient and his twin brother both underwent testing for Epstein-Barr virus (EBV) to rule this out as an environmental trigger, neuroimaging and neurofilament light chain (NfL) to confirm the diagnosis of MS, and genetic testing to confirm monozygosity.
Results
Only the twin with Hg amalgam fillings developed MS. Both twins tested positive for EBV. Axial T2-FLAIR magnetic resonance images of the twin exposed to Hg revealed multiple periventricular white matter lesions. The twin diagnosed with MS was also found to have elevated serum NfL.
Conclusions
Based on the findings presented in this case report and, the latest FDA advisory about the risk of potential harmful effects of Hg vapor released from dental amalgams we recommend extending the advisory against the use of Hg amalgam fillings in persons with MS to include asymptomatic monozygotic twins of a patients diagnosed with MS
Frontiers in Toxicology, 2022
Adverse effects of drugs on the human nervous system are rarely possible to anticipate based on p... more Adverse effects of drugs on the human nervous system are rarely possible to anticipate based on preclinical neurotoxicity data, thus propagating the centuries long single most important obstacle to drug discovery and development for disorders of the nervous system. An emerging body of evidence indicates that in vivo electrophysiology using chronically implanted high-density electrodes (ciHDE) in freely moving animals is a rigorous method with enhanced potential for use in translational research. In particular, the structure and function of the hippocampal trisynaptic circuit (HTC) is conserved from rodents to primates, including Homo sapiens, suggesting that the effects of therapeutic agents and other potential neurologically active agents, whether beneficial or adverse, are likely to translate across species when interrogated using a conserved neural circuitry platform. This review explores science advances in the rapidly moving field of in vivo ciHDE in animal models of learning and memory. For this reason we focus on the HTC, where substantial research has investigated neural circuitry level responses and specific behaviors that reflect memory permitting a test of the ground truth validity of the findings. Examples of changes in neural network activity induced by endogenous neurotoxicants associated with neurodegenerative diseases, as well as exogenous therapeutics, drugs, and neurotoxicants are presented. Several illustrative examples of relevant findings that involve longer range neural circuitry outside of the HTC are discussed. Lastly, the limitations of in vivo ciHDE as applied to preclinical neurotoxicology are discussed with a view toward leveraging circuitry level actions to enhance our ability to project the specificity of in vitro target engagement with the desired psychopharmacological or neurological outcome. At the same time, the goal of reducing or eliminating significant neurotoxic adverse events in human is the desired endpoint. We believe that this approach will lead to enhanced discovery of high value neuroactive therapeutics that target neural circuitry domains as their primary mechanism of action, thus enhancing their ultimate contribution toward discovery of precision therapeutics.
Heliyon, 2021
Decades of research attempting to slow the onset of Alzheimer's disease (AD) indicates that a bet... more Decades of research attempting to slow the onset of Alzheimer's disease (AD) indicates that a better understanding of memory will be key to the discovery of effective therapeutic approaches. Here, we ask whether prodromal neural network dysfunction might occur in the hippocampal trisynaptic circuit by using α5IA (an established memory enhancer and selective negative allosteric modulator of extrasynaptic tonically active α5GABA-A receptors) as a probe drug in TgF344-AD transgenic rats, a model for β-amyloid induced early onset AD. The results demonstrate that orally bioavailable α5IA increases CA1 pyramidal cell mean firing rates during foraging and peak ripple amplitude during wakeful immobility in wild type F344 rats in a familiar environment. We further demonstrate that CA1 ripples in TgF344-AD rats are nonresponsive to α5IA by 9 months of age, prior to the onset of AD-like pathology and memory dysfunction. TgF344-AD rats express human β-amyloid precursor protein (with the Swedish mutation) and human presenilin-1 (with a Δ exon 9 mutation) and we found high serum Aβ42 and Aβ40 levels by 3 months of age. When taken together, this demonstrates, to the best of our knowledge, the first evidence for prodromal α5GABA-A receptor dysfunction in the ripple-generating hippocampal trisynaptic circuit of AD-like transgenic rats. As α5GABA-A receptors are found at extrasynaptic and synaptic contacts, we posit that negative modulation of α5GABA-A receptor mediated tonic as well as phasic inhibition augments CA1 ripples and memory consolidation but that this modulatory mechanism is lost at an early stage of AD onset.
American Journal of Industrial Medicine, 2021
Parkinsonism and encephalopathy are frequently seen in patients who survive carbon monoxide (CO) ... more Parkinsonism and encephalopathy are frequently seen in patients who survive carbon monoxide (CO) poisoning. Neurological findings associated with CO poisoning can emerge immediately after cessation of exposure or following a brief period of pseudo‐recovery. When present, the tremor associated with CO poisoning is typical of the postural/intention type. Here, we report on a rare case of toxic encephalopathy with a dominant‐hand Holmes‐type tremor, characterized by resting, as well as postural and kinetic/intentional components, in a previously healthy 53‐year‐old man exposed to CO while actively engaged in the process of performing a physically demanding skilled labor task. The unique neuropathological and functional changes that give rise to Holmes‐type tremor and how this relates to the selective vulnerability of the inhibitory indirect pathway of the basal ganglia to glutamatergic excitotoxicity mediated by tissue hypoxia are discussed.
Toxicology Communications, 2020
Here we report a rare case of reversible neurological symptoms due to chronic ethanol vapor and m... more Here we report a rare case of reversible neurological symptoms due to chronic ethanol vapor and mist exposure in a 50-year-old machinist who intentionally used undiluted 200 proof etha-nol as a cutting fluid while turning metal machine parts on a toolroom lathe for a period of 3 years. Shortly after switching to ethanol as a cutting fluid, the worker began to experience central nervous system symptoms including headaches, fatigue, ataxia, and concentration and memory problems. Clinical neuropsychological assessment revealed mild deficits on tests of attention, executive function, and memory. The worker was subsequently advised to stop using ethanol as a cutting fluid. At follow-up after cessation of exposure the worker reported that his symptoms were remarkably improved.
Journal of Occupational and Environmental Medicine, 2019
to unmask latent disease and thereby contribute to a younger age at onset of PD in susceptible in... more to unmask latent disease and thereby contribute to a younger age at onset of PD in susceptible individuals. Thus, it is our opinion based on our review of the literature and our own observations in welders and welders helpers that future studies employing serum exosomal a-synuclein as a biomarker of Mn effect should be designed to assess for the interactions between age at onset of PD and exposure to Mn.
Frontiers in Endocrinology, 2019
Memory dysfunction is a symptomatic feature of many neurologic and neuropsychiatric disorders; ho... more Memory dysfunction is a symptomatic feature of many neurologic and neuropsychiatric disorders; however, the basic underlying mechanisms of memory and altered states of circuitry function associated with disorders of memory remain a vast unexplored territory. The initial discovery of endogenous neurosteroids triggered a quest to elucidate their role as neuromodulators in normal and diseased brain function. In this review, based on the perspective of our own research, the advances leading to the discovery of positive and negative neurosteroid allosteric modulators of GABA type-A (GABAA), NMDA, and non-NMDA type glutamate receptors are brought together in a historical and conceptual framework. We extend the analysis toward a state-of-the art view of how neurosteroid modulation of neural circuitry function may affect memory and memory deficits. By aggregating the results from multiple laboratories using both animal models for disease and human clinical research on neuropsychiatric and age-related neurodegenerative disorders, elements of a circuitry level view begins to emerge. Lastly, the effects of both endogenously active and exogenously administered neurosteroids on neural networks across the life span of women and men point to a possible underlying pharmacological connectome by which these neuromodulators might act to modulate memory across diverse altered states of mind.
Journal of Occupational and Environmental Medicine. , 2018
American Journal of Industrial Medicine, 2018
Unmasking of latent neurodegenerative disease has been reported following exposure to chemicals t... more Unmasking of latent neurodegenerative disease has been reported following exposure to chemicals that share one or more mechanisms of action in common with those implicated in the specific disease. For example, unmasking of latent Parkinson's disease (PD) has been associated with exposure to anti-dopaminergic agents, while the progression of pre-existing mild cognitive impairment and unmasking of latent Alzheimer's disease has been associated with exposure to general anesthetic agents which promote Aβ protein aggregation. This literature review and clinical case report about a 45-year-old man with no family history of motor neuron disease who developed overt symptoms of a neuromuscular disorder in close temporal association with his unwitting occupational exposure to volatile organic compounds (VOCs) puts forth the hypothesis that exposure to VOCs such as toluene, which disrupt motor function and increase oxidative stress, can unmask latent ALS type neuromuscular disorder in susceptible individuals.
This review looks at the complex interrelationship between neurotoxicant exposure, chemical metab... more This review looks at the complex interrelationship between neurotoxicant exposure, chemical metabolism, genetics and age at onset of Parkinson's disease (PD), Alzheimer's disease (AD) and Amyotrophic Lateral Sclerosis (ALS). While the major factors influencing the onset of these age-related neurodegenerative diseases remain genetics and age per se, the role of neurotoxicant exposure as a disease modifying factor is increasingly difficult to ignore. The magnitude and duration of the exposure are the two most important factors that must be considered when investigating the relationship between neurotoxicant exposure and age at onset of neurodegenerative disease. Exposures to high concentrations readily overwhelm the ability of the body to detoxify and eliminate neurotoxicants, while chronic exposures to lower concentrations are associated with insidious cumulative effects on nervous system function. This relationship is further modified by genetic polymorphisms and factors that regulate induction of metabolic enzyme synthesis implicated in the detoxification process. With these thoughts in mind, this review explores the interactions between neurotoxicant exposure and those genetic factors that have the inherent ability to modify chemical metabolism and interaction with mechanisms implicated in the subclinical progression and age at onset of neurodegenerative disease. This review of the literature suggests that there is sufficient evidence, based on data from numerous reliable sources, to conclude that age at onset and lifetime risk for developing overt symptoms of neurodegenerative disease are modified by exposure to chemicals including neurotoxicants found in the workplace and environment and, that this relationship is further altered by genetic factors that influence pharmacokinetic and pharmacodynamics processes implicated in these diseases.
Reference Module in Neuroscience and Biobehavioral Psychology, 2016
The field of neurobehavioral toxicology is the branch of toxicology dedicated to understanding th... more The field of neurobehavioral toxicology is the branch of toxicology dedicated to understanding the adverse effects of chemical and biological agents on the nervous system. Paracelsus, the Swiss German philosopher, physician credited as the founder of toxicology once said, “Poison is in everything, and there is no thing that is without poison. The dosage makes it either a poison or a remedy.” Unfortunately many chemicals intended to improve the quality of our lives also have the potential to cause acute and permanent changes in our behavior. This article reviews these behavioral manifestations in terms of the acute and persistent chemical induced changes in brain function and how behavioral testing is used in conjunction with clinical neurological, neurophysiological, and neuroimaging studies to make the differential diagnosis of toxic encephalopathy, toxic neuropathy and neurotoxicant-induced parkinsonism.
Encyclopedia of the Human Brain. , 2002
GLOSSARY cognitive domain Various modalities of behavior as expressed by the terms attention, exe... more GLOSSARY cognitive domain Various modalities of behavior as expressed by the terms attention, executive function, memory (short-term and remote), visuospatial ability, motor function, and mood and affect.
In: Pfeiffer, R.F., and Ebadi M. (eds): Parkinson’s Disease. Boca Raton, CRC Press, Chapter 6, pp 51-62, 2005., 2005
The role of environmental and occupational exposures to neurotoxicants in the pathogenesis of neu... more The role of environmental and occupational exposures to neurotoxicants in the pathogenesis of neurodegenerative disease has not been fully elucidated. Recent published research on whether genetic polymorphisms contribute to individual susceptibility to develop neurodegenerative diseases such as Parkinson's disease have been equivocal at best. This review relates putative mechanisms of neurotoxicant-induced cell damage to polymorphisms in the genes that encode for the enzymes involved in the metabolism of neurotoxicants. The effects that genetically induced alterations in enzyme functioning have on neurotoxicant metabolism and how this relates to the risk of neurotoxic effects among exposed individuals are reviewed. A pragmatic approach to future research in the area of neurodegenerative disease is developed on the basis of the interrelationship between known routes of neurotoxicant metabolism and human genetics.
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Videos by Marcia Ratner, PhD, DABT
Link to full length video on youtube
https://www.youtube.com/watch?v=ZciwM0woJdA
Link to full length video on YouTube
https://www.youtube.com/watch?v=sNy-NHLGJnE
Articles and Book Chapters by Marcia Ratner, PhD, DABT
The Food and Drug Administration (FDA) has determined that certain groups including people with Multiple Sclerosis (MS) are at greater risk for potential harmful effects of mercury (Hg) vapor released from dental amalgams.
Objectives
This case report explores the potential harmful effects of Hg vapor released from dental amalgams in monozygotic twin brothers discordant MS.
Methods
The patient and his twin brother both underwent testing for Epstein-Barr virus (EBV) to rule this out as an environmental trigger, neuroimaging and neurofilament light chain (NfL) to confirm the diagnosis of MS, and genetic testing to confirm monozygosity.
Results
Only the twin with Hg amalgam fillings developed MS. Both twins tested positive for EBV. Axial T2-FLAIR magnetic resonance images of the twin exposed to Hg revealed multiple periventricular white matter lesions. The twin diagnosed with MS was also found to have elevated serum NfL.
Conclusions
Based on the findings presented in this case report and, the latest FDA advisory about the risk of potential harmful effects of Hg vapor released from dental amalgams we recommend extending the advisory against the use of Hg amalgam fillings in persons with MS to include asymptomatic monozygotic twins of a patients diagnosed with MS
Link to full length video on youtube
https://www.youtube.com/watch?v=ZciwM0woJdA
Link to full length video on YouTube
https://www.youtube.com/watch?v=sNy-NHLGJnE
The Food and Drug Administration (FDA) has determined that certain groups including people with Multiple Sclerosis (MS) are at greater risk for potential harmful effects of mercury (Hg) vapor released from dental amalgams.
Objectives
This case report explores the potential harmful effects of Hg vapor released from dental amalgams in monozygotic twin brothers discordant MS.
Methods
The patient and his twin brother both underwent testing for Epstein-Barr virus (EBV) to rule this out as an environmental trigger, neuroimaging and neurofilament light chain (NfL) to confirm the diagnosis of MS, and genetic testing to confirm monozygosity.
Results
Only the twin with Hg amalgam fillings developed MS. Both twins tested positive for EBV. Axial T2-FLAIR magnetic resonance images of the twin exposed to Hg revealed multiple periventricular white matter lesions. The twin diagnosed with MS was also found to have elevated serum NfL.
Conclusions
Based on the findings presented in this case report and, the latest FDA advisory about the risk of potential harmful effects of Hg vapor released from dental amalgams we recommend extending the advisory against the use of Hg amalgam fillings in persons with MS to include asymptomatic monozygotic twins of a patients diagnosed with MS