Study Finds Widespread Sympathetic Nerve Damage In Parkinson's Disease

Physicians have long known that patients with PD often have incontinence and other symptoms of autonomic nervous system function, and previous studies have found evidence of sympathetic nerve damage in PD patients' hearts. The sympathetic nervous system is one component of the autonomic nervous system. However, this study is the first to show that the disease affects sympathetic nerve endings in the thyroid gland and the kidney, says David S. Goldstein, M.D., Ph.D., of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, who led the study. It also shows that this damage is unrelated to treatment with the most commonly used Parkinson’s drug, levodopa. The study appears in the April 23, 2002, issue of 'Neurology'*.

Many people with PD develop a problem called orthostatic hypotension (OH), in which blood pressure falls suddenly when a person stands up. This condition can lead to dizziness, lightheadedness, and fainting. OH increases the risk of falls and other types of accidents, which can be disabling or even life-threatening. Patients with PD frequently have other symptoms of sympathetic nervous system failure, including intolerance to heat or cold and sexual dysfunction. However, the underlying cause of these problems has been unclear.

In the study, the researchers examined 18 patients with PD and OH, 23 patients with PD only, and 16 normal volunteers. The participants were given positron emission tomography (PET) scans of the heart, kidney, and several other organs using a chemical (fluorodopamine) that highlights sympathetic nerve endings. The researchers also measured levels of the sympathetic nerve signaling chemical norepinephrine in the blood coming from the heart and studied blood pressure responses to the Valsalva maneuver, a common test of sympathetic nervous system function in which patients blow into a tube against a resistance. The Valsalva maneuver causes a temporary decrease in the amount of blood pumped by the heart. People with a fully functioning sympathetic nervous system are able to compensate for the decrease in blood output by the heart because the brain responds by signaling the sympathetic nervous system to constrict the blood vessels. If the sympathetic nervous system is damaged, however, the blood vessels do not constrict and blood pressure progressively decreases.

The researchers found that all of the patients with PD and OH had abnormal blood pressure responses to the Valsalva maneuver and significant loss of sympathetic nerve endings in the left side of the heart. About 75 percent of the patients without OH also had lost sympathetic nerve endings in one or more areas of the heart, and six of the patients without OH had an abnormal Valsalva response. The abnormal blood pressure response to the Valsalva maneuver and loss of fluorodopamine-derived radioactivity in the heart were not seen in any age-matched normal volunteers. These findings suggest that most PD patients have at least some loss of sympathetic nerves, even if they do not develop OH, says Dr. Goldstein. In the patients who have OH, the loss of sympathetic nerves seems more widespread in the body.

The study also found that patients with PD had fewer sympathetic nerve endings in the thyroid and kidneys than the normal volunteers. PET scans of the PD patients showed normal numbers of nerve endings in the liver, spleen, and several other organs. However, patients with both PD and OH had lower norepinephrine levels in their blood than patients with PD alone, suggesting that they had a widespread loss of sympathetic nerve endings.

For years, neurologists have believed that OH in PD was due to treatment with the drug levodopa. However, several of the patients in this study who had OH had never taken levodopa, and blood levels of levodopa were the same inpatients with and without OH. This shows that the development of OH is unrelated to treatment with levodopa, although it is possible that the levodopa may cause the blood vessel walls to dilate, making the OH worse, Dr. Goldstein says. Since significant loss of sympathetic nerve endings in the heart was found in all the patients with OH, the study suggests that OH in PD is due to the loss of these nerve endings.

"One implication of this finding is that if we can understand what causes the sympathetic nerve loss, we maybe able to identify the cause of the entire disease," says Dr. Goldstein. Since norepinephrine and dopamine are part of the same family of chemicals, called catecholamines, the findings suggest that whatever causes the loss of dopamine-producing nerve fibers in the brain also causes the loss of sympathetic nerve endings in other parts of the body. The pattern of sympathetic nerve fiber loss in the heart suggests that these fibers gradually die back over time, Dr. Goldstein notes. However, more study is needed to determine what causes the fibers to die.

The NINDS is a component of the National Institutes of Health in Bethesda, Maryland, and is the nation's primary supporter of biomedical research on the brain and nervous system.

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*Goldstein DS, Holmes CS, Dendi R, Bruce SR, Li S-T. "Orthostatic Hypotension from Sympathetic Denervation in Parkinson's Disease." 'Neurology', April 23, 2002, Vol.58, No. 8., pp. 1247-1255.

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