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RDN-929 clinical trial Therapies against motor loss and progression in Parkinson’s’ disease (PD) may need to tackle the imbalance between two neurotransmitters, dopamine and acetylcholine, instead of focusing on dopamine alone, an early study suggests. The study, “Dopamine Deficiency Reduces Striatal Cholinergic Interneuron Function in Models of Parkinson’s Disease,” was published in the journal Neuron. Motor and cognitive functions depends on the coordinated interaction in the brain of two neurotransmitters — substances produced in response to nerve signals that act as chemical messengers — called dopamine and acetylcholine. In Parkinson’s, the degeneration of motor neurons that produce dopamine in a brain region called the striatum results in difficulties with voluntary movement control. Therapies that increase dopamine or activate dopamine receptors, such as levodopa, are currently used to restore motor skills. However, these treatments are not fully effective and their benefits wear off over time. Researchers have thought that a decline in dopamine levels would increase acetylcholine production. Higher levels of acetylcholine are suggested to cause the dyskinesia — uncontrolled, involuntary movements — observed in Parkinson’s patients under long-term dopamine therapy. Researchers at Yale University questioned points in these assumptions. They investigated how dopamine affects acetylcholine by looking at a specific type of nerve cell, called striatal interneurons, that is the main source of acetylcholine in the striatum. To test the effects of dopamine loss, the team used a mouse model genetically modified to mimic Parkinson’s that has a progressive decline in dopamine levels. When motor symptoms appear in these mice, it is estimated that about 30% of dopamine is already lost, increasing to 60–80% at their death. This progressive dopamine loss, the researchers saw, was matched in the animals by an initial and smaller decrease in the production of acetylcholine by striatal interneurons, creating an imbalance. “While the concentrations of both dopamine and acetylcholine decline, the balance between these two neurotransmitters shifts to favor acetylcholine,” the researchers wrote. Subsequent release of dopamine from remaining axon terminals push an increase of acetylcholine, worsening the imbalance between both neurotransmitters. Under dopamine depleted conditions, proper motor function is dependent on adequate levels of both acetylcholine and dopamine, the study concluded. Its findings suggest that progressive dopamine deficiency reduces the activity of striatal cholinergic interneurons, resulting in progressive motor difficulties. Future treatments aiming to slow Parkinson’s progression should include those targeting the balance between acetylcholine and dopamine. “Our findings suggest that targeted cholinergic therapy [those that mimic the action of acetylcholine] has a place in the management PD and highlight the need for additional experiments that will offer therapeutic options distinct from disease prevention,” the researchers wrote. About the AuthorPatricia Inácio, PhD Patricia holds her PhD in cell biology from the University Nova de Lisboa, Portugal, and has served as an author on several research projects and fellowships, as well as major grant applications for European agencies. She also served as a PhD student research assistant in the Department of Microbiology & Immunology, Columbia University, New York, for which she was awarded a Luso-American Development Foundation (FLAD) fellowship. OverviewParkinson’s disease (PD) is a progressive disorder that affects nerve cells in the brain responsible for body movement. When dopamine-producing neurons die, symptoms such as tremor, slowness, stiffness, and balance problems occur. Treatments focus on reducing symptoms to enable a more active lifestyle and include medication, diet, exercise, and deep brain stimulation surgery. The nervous system & dopamineTo understand Parkinson's, it is helpful to understand how neurons work and how PD affects the brain (see Anatomy of the Brain). Nerve cells, or neurons, are responsible for sending and receiving nerve impulses or messages between the body and the brain. Try to picture electrical wiring in your home. An electrical circuit is made up of numerous wires connected in such a way that when a light switch is turned on, a light bulb will beam. Similarly, a neuron that is excited will transmit its energy to neurons that are next to it. Neurons have a cell body with branching arms, called dendrites, which act like antennae and pick up messages. Axons carry messages away from the cell body. Impulses travel from neuron to neuron, from the axon of one cell to the dendrites of another, by crossing over a tiny gap between the two nerve cells called a synapse. Chemical messengers called neurotransmitters allow the electrical impulse to cross the gap. Neurons talk to each other in the following manner (Fig. 1): Figure 1. Neurons communicate with each other across a tiny gap called a synapse. Incoming messages from thefigcaption-center are passed to the axon where the nerve cell is stimulated to release neurotransmitters into the synapse. The neighboring nerve cell receptors pick up these chemical messengers and effectively transmit the message onto the next nerve cell.
What is Parkinson's disease?Parkinson’s disease (PD) is a degenerative, progressive disorder that affects nerve cells in deep parts of the brain called the basal ganglia and the substantia nigra. Nerve cells in the substantia nigra produce the neurotransmitter dopamine and are responsible for relaying messages that plan and control body movement. For reasons not yet understood, the dopamine-producing nerve cells of the substantia nigra begin to die off in some individuals. When 80 percent of dopamine is lost, PD symptoms such as tremor, slowness of movement, stiffness, and balance problems occur. Body movement is controlled by a complex chain of decisions involving inter-connected groups of nerve cells called ganglia. Information comes to a central area of the brain called the striatum, which works with the substantia nigra to send impulses back and forth from the spinal cord to the brain. The basal ganglia and cerebellum are responsible for ensuring that movement is carried out in a smooth, fluid manner (Fig. 2). Figure 2. A cross section of the brain. The impulse for body movement begins in the motor cortex of the brain. The basal ganglia are responsible for activating and inhibiting specific circuits or feedback loops.These impulses are passed from neuron to neuron, moving quickly from the brain to the spinal cord and, finally, to the muscles. When dopamine receptors in the striatum are not adequately stimulated, parts of the basal ganglia are either under- or over-stimulated. In particular, the subthalamic nucleus (STN) becomes overactive and acts as a brake on the globus pallidus interna (GPi), causing shutdown of motion and rigidity. When the GPi is overstimulated, it has an over-inhibitory effect on the thalamus, which in turn decreases thalamus output and causes tremor (Fig. 3). Figure 3. When the basal ganglia are over- or understimulated the symptoms of tremor, rigidity and slowness of movement occur.The action of dopamine is opposed by another neurotransmitter called acetylcholine. In PD the nerve cells that produce dopamine are dying. The PD symptoms of tremor and stiffness occur when the nerve cells fire and there isn't enough dopamine to transmit messages. High levels of glutamate, another neurotransmitter, also appear in PD as the body tries to compensate for the lack of dopamine. What are the symptoms?Symptoms of PD vary from person to person, as does the rate of progression. A person who has Parkinson's may experience some of these more common "hallmark" symptoms:
Other symptoms that may or may not occur:
What are the causes?The cause of Parkinson's is largely unknown. Scientists are currently investigating the role that genetics, environmental factors, and the natural process of aging have on cell death and PD. There are also secondary forms of PD that are caused by medications such as haloperidol (a drug used to treat confusion and hallucinations), reserpine (an ingredient in some anti-hypertension drugs), and metoclopramide (an anti-nausea drug). Who is affected?More than 1.5 million Americans have PD. It typically occurs in men and women around age 60. Early-onset Parkinson’s occurs around age 40. How is a diagnosis made?Because other conditions and medications mimic the symptoms of PD, getting an accurate diagnosis from a physician is important. No single test can confirm a diagnosis of PD, because the symptoms vary from person to person. A thorough history and physical exam should be enough for a diagnosis to be made. Other conditions that have Parkinson’s-like symptoms include Parkinson’s plus, essential tremor, progressive supranuclear palsy, multi-system atrophy, dystonia, and normal pressure hydrocephalus. What treatments are available?Many Parkinson's patients enjoy an active lifestyle and a normal life expectancy. Maintaining a healthy lifestyle by eating a balanced diet and staying physically active contributes to overall health and well-being. Parkinson's disease can be managed with self-care, medication, and surgery. Self care These are some practical tips patients can use:
Medications
After a time on medication, patients may notice that each dose wears off before the next dose can be taken (wearing-off effect) or erratic fluctuations in dose effect (on-off effect). Anti-Parkinson’s drugs can cause dyskinesia, which are involuntary jerking or swaying movements that typically occur at peak dosage and are caused by an overload of dopamine medication. Sometimes dyskinesia can be more troublesome than the Parkinson’s symptoms. A new method to take medication is through a drug pump that delivers a carbidopa/levodopa gel (Duopa) directly into the intestines. Surgery is required to place a small hole (stoma) in the stomach through which a tube is connected to a portable pump worn on your belt. It is designed to deliver the medicine continuously, a little at a time, to improve absorption and reduce off-times. Duopa is similar to insulin pumps used by diabetics. Surgery Figure 4. Overview of a deep brain stimulator (DBS). Electrodes are placed deep within the brain through small holes in the skull. The electrodes are connected by an extension wire to a battery-powered stimulator placed under the skin of the chest. Because the left side of the brain controls the right side of the body and vice versa, DBS is commonly performed on both sides of the brain. The patient is able to turn the stimulator off and on with a handheld controller.
Patients with severe depression, advanced dementia, or an unstable medical condition may not be candidates for surgery. Also, patients who have symptoms similar to PD but who have been diagnosed with a different disorder, such as multiple system atrophy, progressive supranuclear palsy, or cortical basal degeneration should not consider surgery. Clinical trialsClinical trials are research studies in which new treatments—drugs, diagnostics, procedures, and other therapies—are tested in people to see if they are safe and effective. Research is always being conducted to improve the standard of medical care. Information about current clinical trials, including eligibility, protocol, and locations, are found on the Web. Studies can be sponsored by the National Institutes of Health
(see Clinicaltrials.gov) as well as private industry and pharmaceutical companies (see Centerwatch.com). Sources & LinksIf you have any questions, please call Mayfield Brain & Spine at 513-221-1100 or 800-325-7787. Links Glossaryaxon: a long process of the nerve cell (neuron) that carries nerve impulses away from the cell body to other nerve cells. acetylcholine: a neurotransmitter that allows messages to be passed from neuron to neuron across a synapse; released by cholinergic nerves. basal ganglia: a mass of nerve cell bodies (gray matter) located deep within the white matter of the cerebrum. Has connections with areas that subconsciously control movement. bradykinesia: slowness of movement, impaired dexterity, decreased blinking, drooling, expressionless face. dendrite: the “arms” of a nerve cell that connect with the axons to transmit impulses toward the cell body. dopamine: a neurotransmitter that allows messages to be passed from neuron to neuron across a synapse. dystonia: a movement disorder that causes sustained muscle contraction producing repetitive movements or abnormal postures. Spasms can often be controlled with sensory tricks to suppress the movement. essential tremor: involuntary rhythmic tremors of the hands and arms. Tremors occur both at rest and during purposeful movement. Also affects the head in a “no-no” motion; often an inherited condition. globus pallidus interna (GPi): nuclei in the brain that regulate muscle tone; part of the basal ganglia. glutamate: a neurotransmitter that allows messages to be passed from neuron to neuron across a synapse. micrographia: small handwriting seen in Parkinson's Disease. neuron: basic unit of the nervous system, composed of a cell body, dendrites, and axon; also called a nerve cell. neurotransmitter: a chemical substance that allows for the transmission of electrical impulses from one nerve cell to another across synapses. progressive supranuclear palsy: a degenerative neurologic disorder that causes motor disturbances similar to Parkinson's. Notable symptom is the loss of ability to move the eyes to look downward. striatum (corpus striatum): part of the basal ganglia involved with the subconscious regulation of movement. substantia nigra: a group of cells in the brain where dopamine is produced. subthalamic nucleus (STN): a group of cells below the thalamus that is linked to the basal ganglia. synapse: the tiny gap between two nerve cells; across which impulses pass by release of neurotransmitters. thalamus: a relay station for all sensory messages that enter the brain; part of the basal ganglia. updated > 4.2018 |