Smelling trouble


by Quinn Eastman

The earliest harbingers of Parkinson's disease may be those we cannot see.

Doctors first told John McCune that he had lost his sense of smell because of sinus blockages, but surgery to allow his sinuses to drain failed to help. He next tried large doses of zinc, but with no apparent benefit. Then several years passed before any visible sign of trouble arrived.

“Both my wife and my daughter noticed that my left arm didn’t move while I was walking, and I had started to shuffle a bit,” McCune says.

He was diagnosed with Parkinson’s disease in 2006, more than a decade after first noticing that his sense of smell was weakening.

Today neurologists are recognizing that the loss of the sense of smell is one of a group of “non-motor” symptoms associated with Parkinson’s disease. They include sleep disturbances, constipation, blood pressure changes, depression, and as the disease becomes more advanced, hallucinations and confusion.

These symptoms are like proverbial canaries in a coal mine, warning of danger years before classic signs of the disease such as tremors and stiffness.

  canary in coal mine  

Like proverbial canaries in a coal mine, today neurologists are recognizing that the loss of the sense of smell is one of a group of “non-motor” symptoms associated with Parkinson’s disease. They include sleep disturbances, constipation, blood pressure changes, depression, and as the disease becomes more advanced, hallucinations and confusion.


Several Emory researchers are investigating these non-motor features of Parkinson’s, ranging from degeneration of the nerves that regulate the digestive system to subtle changes in memory and decision-making. They are working both in Emory’s clinics and with animal models developed to simulate the non-motor symptoms seen in humans.

“The field is moving in this direction because doctors realize that we have to address the effects of the disease in a more systemic way,” says Emory neurologist James Greene, who is comparing digestive problems in animal models of Parkinson’s. “Non-motor symptoms significantly affect patients’ quality of life.”

In addition, non-motor symptoms demonstrate that Parkinson’s can cause damage to more than one part of the brain and more than one variety of brain cell. They provide clues to how the disease develops and how it might be delayed or prevented.

Getting to this point

The recent emphasis on non-motor symptoms reflects the history of treatment for Parkinson’s, says Emory neurologist Mahlon DeLong, who has spent decades researching the disease and developing better treatments for patients.

We’ve known about non-motor symptoms for a while,” he says. “But they’ve remained in the background because of the considerable progress in treating motor symptoms.”

In the 1960s, researchers discovered that the drug L-dopa had a dramatic effect on motor symptoms in people with Parkinson’s. However, over time, L-dopa can lose its effectiveness.

Neurologists believe motor symptoms arise from loss of cells that make dopamine, especially in the part of the brain called the basal ganglia, which plays a critical role in regulating movement. Surgery with deep brain stimulation (DBS), which DeLong and others pioneered, targets specific areas of the basal ganglia in an effort to regulate them with electric current.

Several medications available to treat the motor symptoms of Parkinson’s have built on the success of L-dopa. However, these drugs have little effect on many non-motor symptoms, such as constipation and sleep disruption.

When Parkinson’s affects the part of the brain that prevents people from acting out their dreams, for example, it leads to REM sleep behavior disorder, which in turn can lead to falls or other injuries. One Emory patient awoke in a closet after a nightmare.

Another patient, a retired bank executive, is unable to sleep at night and consequently nods off throughout the day. Not being able to get regular sleep “definitely makes the motor symptoms worse,” he says.

Recent studies also indicate that the majority of hospitalizations for Parkinson’s patients come from non-motor symptoms. “What drives Parkinson’s patients into the hospital are things like hallucinations and confusion, or problems with balance, which can lead to severe injuries,” DeLong says. “These can’t be treated with L-dopa.

Although hallucinations can be addressed with antipsychotics, adding drug upon drug can create new problems, says DeLong.

  mary louise brown jewell

In memory

“What was most noticeable was that Worley lost his voice. He always had a strong voice.”

That’s Mary Louise Brown Jewell talking about the Parkinson’s disease that took her husband’s voice, then his memory, then his life. Worley Brown, who was CEO of the Rock-Tenn Corporation, suffered from Lewy body dementia, a progressive form of Parkinson’s that affects the ability to remember as well as to reason and carry out simple actions. It also causes hallucinations.

Jewell recently pledged $2 million to establish a chair in neurology at Emory to honor her late husband and a $500,000 gift to renovate a clinical research unit at Wesley Woods. Both contributions are lead gifts for an endowment to raise funds for Parkinson’s and other movement disorders, and they are part of Campaign Emory’s $1.6 billion fund-raising initiative.

“I want there to be a cure,” says Jewell, “and through the research being performed at Emory, I believe that can be accomplished.”


Animal model for non-motor symptoms

By the time many patients consult a neurologist about classic Parkinson’s symptoms, most of their dopamine-making cells already have been lost. DeLong says research must concentrate more on preventing or forestalling Parkinson’s.

Prevention requires knowledge about the disease’s causes and mechanisms, which are highly complex in Parkinson’s, says Gary Miller, a neurotoxicologist at Emory’s Rollins School of Public Health.

A small number of cases are clearly inherited, but most probably come from a mix of genetic variation, personal history, and exposure to environmental hazards such as pesticides. Miller, Greene, and other Emory colleagues are studying how pesticides injure certain brain cells.>

Working with several Emory laboratories, Miller has developed a genetically engineered mouse that matches the pattern of non-motor symptoms seen in people with Parkinson’s and thus could be a research tool in the search for medications to treat non-motor symptoms. “These mice are very useful for studying the major non-motor symptoms of Parkinson’s because they have all of the symptoms together as a package,” he says.

The mice are deficient in an enzyme that normally packages chemicals such as dopamine, norepinephrine, and serotonin into vesicles in order to deliver them to other cells. In the altered mice, the improperly stored neurotransmitters are thought to damage brain cells.

As part of a national clinical trials network, Emory is testing several proposed neuroprotectants that may have the ability to protect brain cells from Parkinson’s damage. While some have failed to work, others seem to show early promise.

Before such a neuroprotectant could be used to help prevent or forestall Parkinson’s, however, other questions need answering. How could people who could benefit from such a drug be identified?

Early warning sentinels

Emory is participating ina national study that aims to identify relatives of people with Parkinson’s who are most at risk of developing the disease themselves. Known as PARS (Parkinson-associated risk study), it uses a mail-in scratch-and-sniff test as an initial screening device, followed by brain scans, if necessary.

With similar aims, clinicians have teamed up with neuroscientists Yoland Smith and Beth Buffalo at Yerkes National Primate Research Center at Emory. In parallel, they will use color- and shape-matching tasks to test people recently diagnosed with Parkinson’s and monkeys treated with the neurotoxin MPTP (which simulates Parkinson’s damage). The goal is to identify subtle changes in memory and attention that may help identify patients who can benefit from early treatment, Smith says.

Still, each patient’s experience with Parkinson’s and how it progresses is different. For every person who loses his or her sense of smell early on, another patient experiences classic tremors and stiffness first.

Parkinson’s is really a collection of several diseases,” says Stewart Factor, director of Emory’s Movement Disorders program at Wesley Woods Center. What they have in common, he says, is the pathology—the pattern of damage in the brain late in disease. But where that damage occurs first can vary, and many of the non-motor symptoms of Parkinson’s can blend in with signs of “normal” aging.

Teasing out which symptoms came first—motor or non-motor—can be difficult. “Part of what we face is a recall bias or hindsight problem,” Factor says. “A patient might tell me he’s had recurring constipation for 10 years, but he wouldn’t say anything to a neurologist about it until he starts having other symptoms.”

For example, Emory patient Bill Carroll’s fading sense of smell became most apparent when he couldn’t detect a gas leak in his house or an animal that had died in his car, leaving family members puzzled and concerned. “I didn’t realize it had to do with Parkinson’s disease,” he says. “I thought it was just part of me.”

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