Marcia H. Ratner

Boston University | BU · Department of Pharmacology Physiology and Biophysics

The level of serum alanine aminotransferase (ALT) activity reflects damage to hepatocytes and is considered to be a highly sensitive and fairly specific preclinical and clinical biomarker of hepatotoxicity. However, an increase in serum ALT activity level has also been associated with other organ toxicities, thus, indicating that the enzyme has spe...

An earlier age at onset of Parkinson’s disease (PD) has been reported to be associated with occupational exposures to manganese and hydrocarbon solvents suggesting that exposure to neurotoxic chemicals may hasten the progression of idiopathic PD. In this study the role of occupational exposure to metals and pesticides in the progression of idiopath...

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...

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 chronica...

There is a well-recognized relationship between a person's body burden of essential trace elements such as copper and their neurological function in which both deficiencies and exposures to excessive concentrations are associated with adverse clinical outcomes. Preclinical studies indicate chronic excess copper exposure is associated with altered m...

Hypertension onset with aging is of widespread clinical significance, predominantly in males, yet the neural circuitry underpinnings for hypertension associated memory dysfunction remains unknown. Sprague Dawley (SD) male but not female rats develop age dependent increases in mean arterial blood pressure (MAP) by 16 months of age. We sought to inte...

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 assessment for drugs a...

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 mon...

Occupational and environmental medicine (OEM) specialists often encounter patients who present with a history of occupational or environmental exposure to one or more neurotoxic chemicals. The diagnosis of these patients is complicated by the fact that the clinical manifestations of neurotoxic disease often closely resemble those of idiopathic neur...

Despite improvements in occupational and environmental safety CO poisoning continues to be a significant cause of morbidity and mortality. While some patients present in the emergency room, occupational and environmental medicine providers are frequently called upon to assist in the diagnosing and treating CO exposure. Many patients exposed to CO e...

Hippocampal hyperactivity is a hallmark of memory dysfunction associated with age related mild cognitive impairment (aMCI) and Alzheimer's disease, leading to the hypothesis that hippocampal trisynaptic circuit hyperactivity impairs memory function. As a test of this hypothesis, we sought to pharmacologically recapitulate hyperactivity in young adu...

Background Despite significant investment into treatments for AD, little progress has been made in bringing new therapeutics to market. Recent failure of monoclonal antibodies targeting Ab plaques to slow disease progression in phase 3 clinical trials, suggests now more than ever it is imperative to identify early disease signatures before symptom...

A better understanding of the changes in neural activity that contribute to the prodromal progression and onset of overt symptoms of Alzheimer’s disease (AD) is essential to the discovery of e!ective therapeutics. These experiments explore prodromal neural network dysfunction in the hippocampal trisynaptic circuit by using an orally bioavailable es...

Hippocampal hyperactivity is a hallmark of amnestic mild cognitive impairment (aMCI) in aging and memory dysfunction in Alzheimer’s disease, leading to the hypothesis that hyperactivity in the hippocampal trisynaptic circuit impairs memory. As a test of this hypothesis, we sought to recapitulate hyperactivity in young adults by attenuating tonic in...

Inhibition α5GABAA-R Alzheimer's TgF344-AD A B S T R A C T 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...

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 as a selective negative modulator of...

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 typically of the postural/intention...

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 work...

Objectives: The objective of this report is to inform readers about the possibility of late onset schizophrenia masquerading as manganese psychosis in workers at risk for occupational exposure to heavy metals. Methods: We report a case of late onset schizophrenia complicated by single elevated urine manganese level in a 40-year-old man who was sel...

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-exi...

This review looks at the complex relationship between neurotoxicant exposure, chemical metabolism, genetics and age 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 rol...

Paracelsus is famous for saying “Poison is in everything, and no thing is without poison. The dosage makes it either a poison or a remedy.” The report in this issue of Neurology® by Racette et al.¹ titled “Dose-dependent progression of parkinsonism in manganese-exposed welders” provides evidence for a dose-response relationship between ongoing expo...

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 d...

Learning and memory deficits associated with age-related mild cognitive impairment have long been attributed to impaired processing within the hippocampus. Hyperactivity within the hippocampal CA3 region that is associated with aging is mediated in part by a loss of functional inhibitory interneurons and thought to underlie impaired performance in...

The use of high density chronically implanted electrodes to monitor systems level in vivo electrophysiological responses to therapeutic agents is emerging as a powerful tool for the validation of targets and targeted drugs. In this study we sought to determine whether the spatial learning and memory enhancing effects of the α5GABAA receptor selecti...

Anxiety disorders are a major public health concern. Here, we examine the familiar area of anxiolysis in the context of a systems-level understanding that will hopefully lead to revealing an underlying pharmacological connectome. The introduction of benzodiazepines nearly half a century ago markedly improved the treatment of anxiety disorders. Thes...

Memory deficits associated with normal aging have long been attributed to impaired processing within the hippocampus, perhaps due in part to a decrease in its ability to perform pattern separation- the creation of distinct representations for separate but overlapping experiences. Non-demented older adults and patients with amnestic mild cognitive i...

The discovery of a nonaddictive therapeutic that diminishes relapse of cocaine-seeking behavior would be a major advance in the treatment of cocaine addiction. Glutamate receptor activation mediates reinstatement of cocaine-seeking behavior in rats. Here, we asked whether pregnanolone hemisuccinate (3α5βHS), a synthetic negatively charged neuroacti...

Glutamate receptors within the nucleus accumbens (NAc) play an important role in relapse following withdrawal in cocaine addiction. Animal studies indicate that inhibition of AMPA receptors in the NAc inhibits reinstatement of cocaine seeking (Cornish and Kalivas, 2000), while selective inhibition of NMDA receptors induces reinstatement (Park et al...

The prevention of relapse is among the greatest challenges in the treatment of cocaine addiction. Research has shown that activation of glutamate receptors in the nucleus accumbens is involved in reinstatement of cocaine seeking behavior in rats (Cornish and Kalivas, 2000). While inhibition of NMDA receptors has been shown to induce reinstatement (...

This document was prepared at the request of the WSIB to elaborate on materials discussed in the book Parkinson’s Disease (CRC Press, 2004). The aim of this document is to: 1) facilitate differentiating idiopathic Parkinson’s disease (PD) from parkinsonism; and 2) assist in recognizing and differentiating those cases of idiopathic PD that have been...

The adverse effects of exposure to neurotoxic chemicals on the brain manifest themselves behaviorally as changes in mood and in cognitive function. Neuropsychological testing has emerged as a means of documenting and measuring these changes. This methodology has several advantages for use in both the clinical diagnosis of chemically induced disorde...

Background: N,N-Diethyl-m-toluamide (DEET) is a widely used topical insect repellent known to produce central nervous system effects by an unknown mechanism. Consumer products contain 10-30% DEET in an alcohol base. DEET is absorbed through the intact skin. Elimination of a single dose of DEET is complete within 2-3 days in animals. Excretion of DE...

Metals are ubiquitous. Exposure to metals has been associated with producing acute and chronic effects on the human nervous system ranging from disabling neuropathies to life-threatening encephalopathies. Many metals produce constellations of symptoms that strongly resemble those of idiopathic neurodegenerative diseases. Metals have been hypothesiz...

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...

This paper describes symptoms and findings in a 57-year-old painter who had been exposed to various organic solvents for over 30 years. He began to work as a painter at 16 years of age, frequently working in poorly ventilated areas; he used solvents to remove paint from the skin of his arms and hands at the end of each work shift. The patient and h...

This article provides the neurologist with simple methods that can be applied to all clinical neurologic evaluations, regardless of the future potential for litigation. This article defines the appropriate application and interpretation of conventional neurologic, neurophysiologic, neuropsychological, and biochemical diagnostic tests that are sensi...