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Parkinson's Disease NIH Intramural Researchers' Biography

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Craig Blackstone, M.D., Ph.D.
Research efforts in the laboratory of Dr. Craig Blackstone (CNU, NINDS, DIR) focus on elucidating the molecular mechanisms underlying a number of neurodegenerative disorders, particularly movement disorders such as Parkinson's disease and dystonia. Current studies are emphasizing a family of proteins related to the GTPase dynamin, which acts a "molecular pinchase" during endocystosis. These dynamin-like GTPases include: (1) Drp1, which interacts with the Mohr-Tranebjaerg deafness-dystonia gene product DDP; (2) OPA1, which is mutated in autosomal-dominant optic atrophy type 1; (3) Atlastin, which is mutated in hereditary spastic paraplegia Type 3A; and (4) MxA, which is a protein component of Lewy bodies, the pathological hallmark of Parkinson's disease. Studies are primarily aimed at understanding these disorders at the structural, biochemical and cell biology levels.

David S. Goldstein, M.D., Ph.D.
Research about Parkinson's disease has focused on mechanisms and treatment of the movement disorder; however, the patients often have other problems that at first glance would seem independent of movement, such as lightheadedness upon standing or after a large meal, easy fatigue and shortness of breath during exercise, constipation, urinary incontinence, and heat or cold intolerance. Recent research by our group has by now established that these problems are not a byproduct of aging, physical deconditioning, or treatment but are part of the disease itself. We found that virtually all patients with Parkinson's disease have evidence for a loss of a particular type of "automatic" nerves, called sympathetic nerves. Sympathetic nerves are responsible for the increases in the force and rate of the heartbeat during exercise, sweating and skin temperature changes during exposure to heat, tightening of blood vessels and regulation of blood pressure when a person stands up, and many other functions. The main chemical messenger of the sympathetic nerves is norepinephrine. Norepinephrine is closely related to dopamine-they are like son and father in a small chemical family. Loss of dopamine in a particular brain pathway causes the movement disorder in Parkinson's disease. The same disease process that causes the loss of the dopamine-producing cells in the brain appears to cause the loss of the norepinephrine-producing cells outside the brain. This means that Parkinson's is not just a brain disease but a disease involving many body organs. It is possible that chemicals produced as part of the ongoing metabolic breakdown of norepinephrine and dopamine make the cells susceptible to injury and death. Identifying the causes of the "automatic" problems in Parkinson's disease should improve the health of the patients and may also provide key clues about the basis for the entire disease.
For a listing of most recent publications

Katrina Gwinn-Hardy, M.D.
The major goal of the Familial Parkinson's Disease (PD) Unit is to identify genetic causes of PD. Although most cases of PD do not appear to be hereditary, valuable insights into the etiology of the disease can be gained by studying families that appear to have a strong genetic predisposition to PD. This is done by systematically collecting familial, clinical, and genetic (blood sample) information on people with PD and their relatives. We interview people about their family members; valuable information includes name, date of birth (and death, if deceased), any diagnosis (for example, of Parkinson's disease, dementia, tremor, including essential tremor, and other disorders), and the age of disease onset. In our quest to learn why one person in a family might fall ill while others are spared, we also need to interview and examine spouses, children, brothers, sisters, parents, and cousins. Once we know families are committed to help, the research team will travel wherever necessary to try to examine distant relatives and obtain critical blood samples for the genetic work. A second goal of the Unit is to study the pre-clinical stages of PD in families that appear to have a strong genetic predisposition to the disease. Neurodegenerative processes begin before symptoms appear. Pre-symptomatic markers can predict the development of disease, which will allow interventional strategies to impact disease before disability ensues. Longitudinal evaluations including neuropsychometric testing, smell testing, PET scanning, serial MRI scanning, and sleep testing will be done in those with genetic risk of developing disease. This will allow the development of pre-clinical biological and clinical markers of disease. Included in this pre-symptomatic study is a family called the "Iowa Kindred," which has been followed by Dr. Gwinn-Hardy since the mid-1990's and by other colleagues since the 1930's. Through a technique called "positional cloning," Dr. Gwinn-Hardy and colleagues have found that somewhere within the region of chromosome 4p lies the disease causing culprit in the family. It is our hope to evaluate members of this family and others over the lifespan to try and predict who is at risk so that interventions can be applied as early as possible.
For a listing of most recent publications

Mark Hallett, M.D.
The goal of the Section is to understand the physiology of normal movement and the pathophysiology of disordered movement in different movement disorders such as Parkinson's disease. Work over the years has evaluated bradykinesia, akinesia, tremor, rigidity and balance disorder. Future plans call for investigations of (1) bradyphrenia (possible slowness of thinking), (2) the ability to make simultaneous movements, and (3) automaticity of movement. We also have plans to study the possible therapeutic effect of repetitive transcranial magnetic stimulation (rTMS) on balance and gait in patients.
For a listing of most recent publications

Bob Innis, M.D.
Robert Innis, MD, PhD was recently recruited to head NIMH's Molecular Imaging Branch in the Intramural Research Program. The goals of this laboratory are to develop, evaluate and implement new radiotracers for the study of neuropsychiatric disorders. The primary imaging methodology will be PET (positron emission tomography), which can accurately quantify specific protein targets in the brain. Dr. Innis has a long-standing interest in neuroimaging of Parkinson's disease. He developed a radiolabeled probe for the neurons that degenerate in Parkinson's disease. That is, he developed a probe for the dopamine transporter, which is located on the terminal membrane of the dopamine neurons projecting from the substantia nigra to the striatum. Loss of these dopamine transporters is a marker for the presence and severity of the illness. In fact, the loss of the dopamine transporter may well be able to identify individual before the onset of symptoms. This tracer [123I]-FPCIT was approved in Europe to aid in the diagnosis of Parkinson's disease. It may well be the first biological test for Parkinson's disease and is certainly the first neuroreceptor agent approved for clinical use.

Dr. Innis is now working with investigators at NINDS with an improved probe for the dopamine transporter as well as new probes to assess the pathophysiology of Parkinson's disease. In collaboration with Drs. Katrina Gwinn-Hardy, Bernard Ravina, and Mark Hallett, PET tracers will be used to as assess the severity of the motor symptoms (dopamine transporter probe), depression that is commonly found in the disorder (serotonin transporter probe), and the cognitive deficits (nicotine and dopamine D1 receptor probes).
For a listing of most recent publications

Christy Ludlow, Ph.D.
The Laryngeal and Speech Section conducts research on voice, speech and swallowing disorders and new treatments for such disorders. Hypophonia and dysphagia in Parkinson's disease are not as well managed as other functions in the disease by levodopa, surgery or deep brain stimulation. Therefore, improved understanding of the speech and swallowing problems in this disease is needed. A recent study of laryngeal muscle activation in Parkinson's disease involved previously untreated patients to determine the laryngeal pathophysiology associated with hypohonia and vocal fold bowing. Increased levels of activity in the laryngeal muscles activity were correlated with vocal fold bowing and hypophonia. After a therapeutic dose of levodopa was administered, persons with the greater reductions in muscle activity had the most voice benefit. The Section is also developing a novel approach to assist patients with chronic dysphagia and aspiration. Neuromuscular stimulation is being developed to control laryngeal elevation, relaxation of the upper esophageal sphincter and closure of the glottis. The aim is to enable persons at risk for aspiration to take food orally.
For a listing of most recent publications

Ron McKay, Ph.D.
Several strategies are being pursued, by the McKay laboratory to develop new therapies for Parkinsonian patients. The major new techniques include deep brain stimulation, gene and cell therapy. The clinical use of stem cells is rapidly becoming a central part of many medical disciplines. The goal of our group at NIH on models of Parkinson's disease is to develop a stem cell that provides an unlimited supply of quality controlled midbrain dopamine neurons. Recent results suggest that we can control the birth and life of the dopamine neuron, the next logical goals are to understand the functions of this cell during life and the causes of death.

Derivation of midbrain dopaminergic neurons from stem cells in the fetal mid-brain
Transplantation of neurons is a clinically promising experimental treatment in late stage Parkinson's disease. More than 200 patients have been transplanted worldwide. Clinical improvement has been confirmed. However, the technology is still poorly defined. Transplantation therapy generally requires human fetal tissue from at least 3-5 embryos to obtain a clinically reliable improvement in the patient. This poses an enormous logistical and ethical dilemma. To address these problems we are investigating alternative sources for the neurons required. Neurons that synthesize dopamine have been generated from brain precursor cells. These precursor-derived neurons express dopamine functions in vitro and in vivo they restore behavioral deficits in a rat model of Parkinson's disease. Even though fetal midbrain tissue is a source of stem cells for use in Parkinson's research, the cell number provided by this method is caused by a switch from the production of neurons making dopamine to neurons that make other neurotransmitters.

Derivation of functional midbrain dopaminergic neurons from embryonic stem cells
In contrast to precursor cells in the fetal brain, embryonic stem (ES) cells can proliferate indefinitely and maintain the ability to make all the cells in the body. Human cells with ES properties have recently been isolated. Our group has played a leading role in showing that we can control the production of brain cells from ES. In particular, we have developed methods to generate dopaminergic neurons from ES cells. This is the only current method that can provide unlimited numbers of these neurons that are central to use of stem cell techniques Parkinson's disease. We have developed methods that increase the proportion of the neurons that synthesize dopamine from 5% to >85%. The remaining neurons are predominantly of a single type synthesizing the neurotransmiter serotonin. We can also demonstrate that the precursors to these neurons express genes characteristic of the mid-brain.
The neurons derived from ES cells express the dopamine transporter, that is characteristic of mature dopamine neurons. The maturation of the neurons has also been demonstrated by direct electrophysiological analysis in tissue culture. In these experiments we show that ES derived dopamine neurons make synapses with neurons in their normal target region, the striatum. In addition, transplanted ES derived neurons control the motor behavior of animal models of Parkinson's disease. These are important statements because we can now say for the first time that we have an unlimited supply of mid-brain, functional dopaminergic neurons.

Can adult stem cells substitute for ES and fetal cells?
Adult stem cells have great clinical potential and we were recently part of a collaborative effort showing that bone marrow derived stem cells could regenerate the injured heart. There are many good reasons to find an adult source of dopamine neurons. Our group has characterized stem cells in the adult brain and although there is no current adult source that will efficiently generate mid-brain-dopamine neurons, we are actively pursuing this goal.

Detmar Plenz, Ph.D.
Research in the laboratory of Dr. Dietmar Plenz (NNP, LSN, NIMH, DIR) focuses on the function of dopamine in the basal ganglia. Long-term organotypic slice cultures are used to reconstruct neuronal circuits of cortex and basal ganglia in vitro and neuronal activity patterns that emerge in these cultured neuronal networks are analyzed using electrophysiological recordings and calcium imaging. His recent discovery demonstrated that the subthalamic nucleus and globus pallidus form a central pacemaker in the absence of dopamine. This finding has spurred new research in the understanding of tremor generation in Parkinson's Disease and the beneficial effect of deep brain stimulation. His latest research focuses on the control of spike transmission within and between neurons in the striatum by dopamine.
For a listing of most recent publications

David R. Sibley, Ph.D.
The research focus of the Molecular Neuropharmacology Section is the characterization of neurotransmitter receptor-mediated information transduction, and its regulation, across neuronal membranes. The primary model systems under investigation are those receptors linked to their signal transduction pathways via guanine nucleotide binding regulatory proteins (GPCRs) with emphasis on dopamine receptor subtypes. Specific G proteins link these receptors to the activation and inhibition of various nucleotide cyclases, phospholipases, and several ion channels. In order to characterize these receptors at the molecular level and study their regulation, there are several interrelated lines of research that are ongoing. These include investigations of receptor structure/function/pharmacology relationships, receptor-effector coupling mechanisms, G protein interactions, and biochemical mechanisms of receptor desensitization and intracellular trafficking. Additional projects involve the identification of proteins that interact with dopamine receptor subtypes, site-directed mutagenesis and receptor chimera studies, analysis and characterization of gene structure, and regulation of receptor expression in both normal and pathophysiological states. Transgenic and receptor knockout mouse projects are also in progress. Since dopamine is the transmitter lost during the development of Parkinson's disease, and since the most effective drugs currently used to treat Parkinson's disease are known to directly activate dopamine receptors, more knowledge about the structure, function and regulation of dopamine receptors may result in the development of better drugs to treat this disease. We are currently examining the interactions of several novel agonists with specific dopamine receptor subtypes to determine their potency and efficacy for receptor activation.
For a listing of most recent publications

Judith R. Walters, Ph.D.
Research in the Neurophysiological Pharmacology Section, led by Judith R, Walters, Ph.D., is directed toward elucidating the function of dopamine in regulating information processing in the basal ganglia. The goal is to gain insight into why this neurotransmitter system is critical to appropriate neuronal transmission in this brain region and to identify mechanisms which could be manipulated to prevent, correct, and/or compensate for dysfunction occurring in these systems as a result of dopamine cell loss in Parkinson's disease. Neurophysiological techniques, in conjunction with biochemical and anatomical approaches, are utilized to investigate the role of specific dopamine receptor subtypes in modulating the operations of the basal ganglia and the potential for modulating basal ganglia function with drugs and other interventions. Areas of current interest include: a) the role of specific dopamine receptor subtypes in mediating behavioral, neurophysiological and molecular alterations in basal ganglia function, b) functional roles of tonic, phasic and oscillatory firing patterns of neurons within the basal ganglia and its associated areas, and c) processes regulating alterations in these functions in dopamine_depleted states.
For a listing of most recent publications

Last updated September 05, 2007