Seeking Biomarkers for Parkinson's Disease


by Tom Valeo

July 13, 2011

By the time people with Parkinson’s disease develop tremors, muscle rigidity, and other familiar symptoms, they’ve already lost well over half of the brain cells that produce dopamine, the neurotransmitter vital to normal movement. At that point, the only treatment involves boosting inadequate levels of dopamine in the brain, which does not eliminate all symptoms.

But Parkinson’s, like Alzheimer’s disease, appears to simmer for years or possibly decades before overt symptoms appear. If subtle early changes could be detected, researchers would have a way to measure the effectiveness of new drugs that slow the progression of Parkinson’s, or prevent it altogether.

That’s why the search for such biomarkers has intensified, says Todd Sherer, CEO of the Michael J. Fox Foundation for Parkinson’s Research.

“Biomarkers for Parkinson’s disease would accelerate the development of therapies,” Sherer said during a recent webinar he moderated on “Early Detection of Parkinson’s Disease.” “By identifying patients at the earliest stages of the disease we could improve patient selection for clinical trials, assess the efficacy of treatments better, and monitor disease progress.”

Nearly all people who develop PD recall several early signs, such as loss of smell, constipation, sleep disturbances, changes in color vision, minor cognitive deficits, anxiety, and depression, according to a German physician, Alexandra Gaenslen. For a study published recently in Movement Disorders,1 she and her colleagues interviewed 93 PD patients and 93 people without the disease. “A total of 98.8 percent of all patients interviewed reported to have experienced prodromal symptoms prior to receiving the initial diagnosis of PD,” the researchers wrote. Some of the controls also reported such symptoms, leading Gaenslen to speculate about a “tenuous border” between normal aging and the start of neurodegeneration.

The early symptoms of Parkinson's probably result from degeneration of neurons in the olfactory bulb and the lower brainstem, says Gaenslen. That would account for loss of smell and reduced movement of the gastrointestinal tract—a cause of constipation. Some patients in the study reported constipation nearly 17 years before they received a diagnosis, and loss of smell more than 11 years before. Eventually the degeneration affects dopamine-producing cells in the substantia nigra at the top of the brain stem, causing the familiar movement disorders.

Loss of smell, or hyposmia, has long been recognized as an early symptom in PD patients. That’s why the Parkinson’s Associated Risk Study (PARS), which aims to identify biomarkers in people on the road to developing PD, first administers a smell identification test to prospective participants.

“PARS takes advantage of the fact that up to 90 percent of PD patients have olfactory deficits at the time of diagnosis,” said Andrew Siderowf a neurologist at the University of Pennsylvania School of Medicine and one of the PARS researchers.

But many people lose olfactory sensitivity as they age, so hyposmia alone (the reduced ability to smell and to detect odors) is a weak biomarker. That’s why the researchers also use a SPECT scanner that shows dopamine transporter (DAT) proteins in a subject’s brain, to measure of the amount of dopamine being produced. DAT imaging shows abnormalities in more than 95 percent of people with Parkinson’s, according to the Parkinson’s Disease Society. Combining the smell test with a DAT imaging provides a far more reliable indication of the presence of Parkinson’s pathology than hyposmia alone, says Siderowf.

“Only 1 percent of 'normals' had abnormal DAT scans,” he said. “Among hyposmics, 11 percent had an abnormal DAT scan.” By administering both tests, researchers can narrow their search for study participants by 80-90 percent.

Biomarkers also would allow PD patients to start taking potential treatments long before significant neurodegeneration occurs.

“The advantage of identifying presymptomatic individuals is that treatments probably will be more effective when there is less neuronal loss,” says Kenneth Marek of the Institute for Neurodegenerative Disorders in New Haven, Connecticut, and another PARS researcher. “We’d like to prevent the disease rather than treat it. I think neuroprotection becomes theoretically possible if we can identify who is at high risk for Parkinson’s.”

Testing the heart

Another potential biomarker of approaching Parkinson's involves heart rate variability, a normal process that displays subtle changes in people with diabetes, heart disease, and perhaps PD.

“It’s normal and healthy to have heart rate variability,” says J. William Langston of the Parkinson’s Institute. “Even when you’re just sitting around, there’s some variation. But we know that there’s denervation [loss of nerve function] in the autonomic nervous system in Parkinson’s patients. We reasoned that we might be able to pick that up on an EKG.”

In an article in a recent issue of Movement Disorders,2 Langston and his colleagues measured the heart rate variability found in 11 people with REM sleep behavior disorder, which often heralds the approach of PD. The disorder causes sleepers to thrash about in bed and vocalize as they act out unpleasant dreams. The researchers compared the EKG readings of these people with 11 control subjects who had ordinary insomnia. Those with REM sleep behavior disorder displayed significant reductions in heart rate variability, a consequence of cardiac autonomic denervation, a near-universal symptom of PD. This suggests that decreasing heart rate variability, detectable with modern EKG machines used for routine physical exams, might serve as a biomarker for approaching PD.

“I don’t think it’s diagnostic by itself, but if you detected heart rate variability and something else—loss of smell, for example—that would bump up concern about pre-motor Parkinson’s, and the patient could be referred for a dopamine scan to see if dopamine is decreasing,” says Langston.

Testing the breath

A simple “breath print” may soon help to strengthen the suspicion that a person is developing Parkinson's. At the recent meeting of the American Academy of Neurology, Israeli physician Ilana Schlesinger reported on a clinical trial 3 involving 35 PD patients and 15 healthy controls whose breath was analyzed by an artificial olfactory system, or electronic “nose,” already used to detect compounds found in the breath of people with certain types of cancer. They identified 10 molecular markers that appear in different ratios in PD patients. “We had few patients in our study, so we want to check in a larger sample size,” said Schlesinger. “After that, we’ll see where we can go.”

Hossam Haick, an associate professor at Technion School of Chemical Engineering in Haifa, who helped to develop the AOS for cancer detection, said no single marker for PD has been verified, despite much research, “but there is growing evidence that relatively subtle metabolic disturbances are associated with PD,” he said. “We could trace statistically relevant changes in the relative concentrations of seven volatile organic compounds in the breath.”

In people developing PD, these compounds might have been produced by cell wall breakdown, or by cell death in general, says Haick. “We believe that a PD breath print could provide a robust, inexpensive PD biomarker that could be easily traced. Our sensor array proved to be a highly accurate and reliable tool for ‘smelling’ the PD breath print.”

Since Parkinson's seems to be a consequence of changes in the protein alpha-synuclein, researchers at the University of Washington School of Medicine are trying to determine if alpha-synuclein found in saliva might serve as another biomarker of the disease. In a recent article in Brain, 4 the researchers assert that a decrease in alpha-synuclein and an increase in DJ-1, another protein associated with PD, could serve as reliable biomarkers for the disease. Other researchers in Sweden think that antibodies created by the immune system against forms of alpha-synuclein provide a valid biomarker for early PD. 5

People who develop PD also tend to carry certain genes that apparently contribute to the disease somehow. One of the most tantalizing is GBA1, carried by 8-20 percent of PD patients. The gene appears to elevate levels of alpha-synuclein.

“The more alpha-synuclein you produce, the more likely you are to get PD and related problems,” said Michael Schlossmacher of the University of Ottowa, who is studying genes linked to PD. “GBA1 is a very important biomarker that can be considered a reliable surrogate for the process of synucleinopathy in the brain. If we had a drug likely to work in subjects with a GBA1 mutation and PD, then this marker would help to select the right cohort for the clinical trial.”

Ultimately, biomarkers will lead the way to new treatments for PD, and possibly control of the disease.

“Prevention is the ultimate goal in Parkinson’s disease,” said Siderowf. “Biomarkers have an obvious role since, at time of screening, there are no signs of clinical disease. Biomarkers may be the only underlying  manifestation of pathology.”

In the meantime, perhaps the best protection involves regular exercise. In a PBS Frontline documentary on Parkinson’s disease titled “My Father, My Brother, and Me,” Judith L. Cameron of the Oregon Health & Science University in Portland, describes research 6 in which rhesus monkeys that walked regularly on a treadmill were unaffected by a drug that induced severe Parkinson’s symptoms in sedentary monkeys.

“It makes us think that exercise somehow protects (the brain) against damage,” she says. “When we exercise the monkeys on the treadmill for the amount of exercise that clinicians would recommend that middle-aged people undertake, their brain is less likely to be damaged when there’s an insult.”

References:

1 Gaenslen A, Swid I, Liepelt-Scarfone I, Godau J, Berg D. Patients’ Perception of Prodromal Symptoms Before the Initial Diagnosis of Parkinson’s Disease. Movement Disorders 2011; 26(4):653-658.

2 Langston JW et al. Exploring the Electrocardiogram as a Potential Tool to Screen for Premotor Parkinson’s Disease. Movement Disorders 2010;25(14):2296-2303.

3 Exloratory Study Using Nanotechnology to Detect Biomarkers of Parkinson’s Disease From Exhaled Breath http://clinicaltrials.gov/ct2/show/NCT01246336

4 Devic I, Zhang J, et al. Salilvary α-synuclein and DJ-1: potential biomarkers for Parkinson’s disease. Brain 2011, Epub ahead of print February 24, 2011.

5 Yanamandra K, Morozova-Roche LA, et al. α-Synuclein Reactive Antibodies as Diagnostic Biomarkers in Blood Sera of Parkinson’s Disease Patients. PLoS One 2011;6(4):e18513.

6 Zigmond MJ, Cameron JL, Leak RK, Mirnics K, Russell VA, Smeyne RJ, Smith AD. Triggering endogenous neuroprotective processes through exercise in models of dopamine deficiency. Parkinsonism & Related Disorders. 2009 Dec;15 Suppl 3:S42-5.