As part of National Parkinson’s Disease Awareness Month,
Demetrius Maraganore, MD, Chairman of Neurology at NorthShore, shared some of the findings of his ongoing research into the genetic factors that influence Parkinson’s disease progression and outcomes. He also tells us why research like this is so important
for Parkinson’s disease patients and their families:
Why is funding for and research into Parkinson’s disease so important?
It’s important because the treatments that we have available don’t prevent Parkinson’s disease (PD) or slow or halt its progression. PD is characterized by progressive motor and cognitive impairment. PD patients have a seven-fold increased risk of
nursing home placement and a two-fold increased risk of death. The annual cost of PD in the U.S. exceeds $23 billion. Presently 2% of people will develop PD during their lifetime, and the prevalence of PD is expected to double by 2030. The cumulative burden
of PD to society is and will be staggering. Our patients and their families deserve methods to predict, prevent and halt PD and those will only come through research.
How long have you been conducting research into Parkinson’s disease?
My research in Parkinson’s disease (PD) started in 1989, when I was an honorary clinical and research fellow to the late Professor C. David Marsden at the National Hospital for Neurology and Neurosurgery in London, England. Dr. Marsden was the founder of the
international Movement Disorders Society and its official journal, Movement Disorders. His associate, Professor Anita Harding, was a pioneer in the field of neurogenetics. Together, we launched the first genetic studies of Parkinson’s disease.
That has remained the focus of my research, including for 20 years on the faculty of the Mayo Clinic in Rochester, MN, and in the four years that I have been Chairman of Neurology at NorthShore. While my research at Mayo focused on identifying genetic factors
that contribute to the cause of PD, my research at NorthShore has focused on understanding how those genetic factors influence disease progression and outcomes. Our research aims to develop methods to predict outcomes in PD, and to use that information to
improve neurological health.
Why have you focused the bulk of your career on the study and treatment of Parkinson’s?
As a clinician, it’s very gratifying that there are many treatments that we can employ in the first many years to reduce the burden of the disease on patients and families. However, I recognize that the benefits of the existing treatments wane with
time, and I’m driven by the sense of urgency to identify the factors that contribute to the progression of Parkinson's disease. Our goal is to target those factors so that every individual patient can have the best possible outcome.
For more information on the NorthShore Neurological Institute and the research being done at NorthShore, click
April is National Parkinson’s Disease Awareness Month. All this month, we will feature a series of posts addressing Parkinson’s disease symptoms, genetics, treatment options and more from NorthShore neurologists—Demetrius Maraganore,
MD, Aikaterini Markopoulou, MD, and Ashvini Premkumar, MD— to raise awareness about this common and often disabling neurological disorder.
Demetrius Maraganore, MD, and
Ashvini Premkumar, MD
Is it possible to detect PD before symptoms begin?
There is no established method of detecting Parkinson’s disease before symptoms begin. Because patients with Parkinson’s disease may lose their sense of smell decades before the onset of their movement disorder, some investigators have explored the use of
smell testing as a method of detecting Parkinson’s disease in at-risk subjects (e.g., persons who carry a rare gene mutation known to cause Parkinson’s disease). Persons can lose their sense of smell for many unrelated reasons though (e.g., following an upper
respiratory infection, head trauma, or if they smoke). Loss of smell can precede other brain degenerations such as Alzheimer’s disease, so smell testing lacks the specificity needed for a predictive test.
A more promising approach is brain imaging using a radiopharmaceutical called
DATSCAN. This is a compound that is injected into a vein and that binds to the endings of dopamine nerve cells in the brain. In Parkinson’s disease, dopamine nerve cells degenerate; hence, there is less binding of DATSCAN. The uptake and binding of DATSCAN
can be measured using a single photon emission computerized tomogram or “SPECT” camera. We are currently conducting a study at NorthShore to determine if persons with mild to moderate traumatic brain injury, who are at an 11-fold increased risk for Parkinson’s
disease, have lower DATSCAN binding than persons without a history of brain injury. This study would demonstrate that it’s possible to detect Parkinson’s disease in at-risk subjects before symptoms begin.
DATSCAN could prove useful as a method to develop asymptomatic Parkinson’s disease in at-risk subjects who could then be prescribed treatments or lifestyle changes that might delay or possibly even prevent the onset of Parkinson’s disease symptoms. My research
associate Dr. Ying Wu is also exploring the use of automated MRI brain measurements in the same brain injury population to see whether MRI may prove effective in detecting preclinical Parkinson’s disease changes in at-risk subjects.
Are PD symptoms or outcomes different between men and women? Between races?
My research collaborators and I have conducted several studies of gender differences in Parkinson’s disease. At every age men are 1.5 times more likely to develop Parkinson’s disease than women. We observed no convincing difference in survival for men and women
with Parkinson’s disease. While there was no difference in motor outcomes, we observed that the risk for dementia was greater in men than in women with Parkinson’s disease. It's possible that estrogen protects against dementia in women.
My collaborators and I observed no important differences in the rates of Parkinson’s disease worldwide, and I’m not aware of any convincing data to suggest that symptoms of Parkinson’s disease or its outcomes differ according to race or ethnicity.
What are some of the later complications of Parkinson’s disease?
Typically we associate Parkinson’s disease with movement disorders. As the disease progresses, patients may develop balance difficulties that result in falls. As a result, patients become increasingly dependent on assistance in walking. For example, they may
need a cane or a walker or someone to walk with them. As the movement disorder progresses more, patients may be entirely unable to stand or walk even with assistance
Parkinson’s disease is not just a movement disorder though. About one in three patients develop a significant decline in memory and mental faculties, or what we call dementia. Both falls and dementia are dreaded late complications of Parkinson’s disease because
they are resistant to medical or surgical treatments and because they carry an increased risk for nursing home placement and even death. Predicting falls and dementia as late complications of Parkinson’s disease is a research priority of the Department of
Neurology at NorthShore and a current focus of my research.
Is there a way to slow or halt the progression of PD?
There is no proven method of slowing or halting the progression of Parkinson's disease. Treatments that have been studied and that failed to provide evidence of neuroprotection are: selegiline, vitamins E and C, pramipexole, ropinerole, and COQ10. There is
some statistical evidence that carbidopa/levodopa therapy may slow motor progression in Parkinson's disease, but the benefits are trivial.
Azilect is being promoted as a neuroprotective agent, but it’s dubious because the beneficial effects were observed at smaller and not higher doses. The drug is also very expensive and prone to multiple drug-diet and drug-drug interactions. At best, the benefits
are nominal. A recent medical advisory panel to the FDA voted 17 to 0 that Azilect should not be approved as a neuroprotective therapy in Parkinson's disease.
Inosine dietary supplementation, to increase blood uric acid levels, may be neuroprotective; however, it may also increase the risk for heart disease, stroke or dementia. There is some evidence that vitamin D deficiency is a risk factor for Parkinson's disease;
however, there are no clinical trials to suggest that vitamin D therapy slows the progression of Parkinson's disease. Similarly, observational studies have suggested that non-steroidal anti-inflammatory drugs (NSAIDs) or cholesterol lowering medications (statins)
are associated with a reduced risk for Parkinson’s disease, but clinical trials evidence of neuroprotection is lacking. There are some early clinical trials of the calcium channel blocker isradipine, which may have neuroprotective effects in animal models
of Parkinson's disease. Though, the animal models of Parkinson's disease are not always informative, and some calcium channel blockers can actually cause reversible parkinsonism.
One big hope on the near horizon is therapies targeting the alpha-synuclein protein in Parkinson's disease, including a vaccine that is in early phase clinical trials. However, while genetic studies have indicated that alpha-synuclein is neurotoxic prior to
the onset of Parkinson’s disease symptoms, my research team recently provided genetic evidence that alpha-synuclein may be neuroprotective late in the disease process. So it’s unclear if therapies targeting alpha-synuclein in Parkinson’s disease will be effective
Recent studies have suggested that exercise might slow the progression of Parkinson’s disease. Apart from exercise, I have no recommendations regarding neuroprotection at this time.
Once dementia starts is there anything that can be done to reduce the loss of memory?
There are certain “cognitive enhancing” medications that may be useful in improving cognitive symptoms and slowing the progression of dementia in patients with Parkinson’s disease. These include a class of drugs entitled cholinesterase inhibitors (rivastigmine,
galantamine, donepezil). The Exelon patch in particular was specifically studied in Parkinson’s patients and obtained FDA approval for treatment of Parkinson’s related dementia. Memantine, an NMDA receptor antagonist, has been FDA approved for treatment of
Alzheimer’s dementia; however, in clinical practice, it has also been found to be helpful in certain patients with Parkinson’s disease related dementia. In addition, nonpharmacological interventions including exercise, social stimulation, and cognitive rehabilitation
can be helpful in the treatment of dementia in Parkinson’s disease.
Apart from genes, are there any environmental risk factors for PD?
My research team was funded by the National Institute for Environmental Health Sciences for more than ten years to study both genetic and environmental risk factors for Parkinson’s disease. We found that pesticide exposure, both occupational and gardening-related,
was associated with a two-fold increased risk for Parkinson’s disease. In particular, exposure to herbicides carried an increased risk. Of the herbicides recalled by our study subjects, the one most significantly associated with Parkinson’s disease was 2,4-Dichlorophenoxyacetic
acid, a major component of Agent Orange. There have been reports that Vietnam War veterans are at an increased risk for Parkinson’s disease. Pesticides may contribute to an increased risk for Parkinson’s disease by causing the alpha-synuclein protein to misfold
and form toxic accumulations within vulnerable nerve cell regions.
My research team also observed that head trauma may be a risk factor for Parkinson’s disease. A closed head injury that produced loss of consciousness or that required hospitalization was associated with an 11-fold increased risk for Parkinson’s disease. Head
trauma may contribute to an increased risk for Parkinson’s disease by causing an acute spike in alpha-synuclein levels.
While my research team observed no evidence for an interaction of pesticide exposures and alpha-synuclein gene variants, a research team from California recently reported an interaction of head trauma and alpha-synuclein gene variants in Parkinson’s disease.
Currently, my research team at NorthShore is conducting a brain imaging study of mild traumatic brain injury to determine if there are Parkinson’s disease-like abnormalities in the brain scans of persons exposed to head trauma, even in the absence of symptoms
of Parkinson’s disease. We will also consider the interaction of traumatic brain injury and alpha-synuclein gene variations in that study.
April is National Parkinson’s Disease Awareness Month. All this month, we will feature a series of posts addressing Parkinson’s disease symptoms, genetics, treatment options and more from NorthShore neurologists—Demetrius Maraganore, MD, Aikaterini Markopoulou,
MD, and Ashvini Premkumar, MD— to raise awareness about this common and often disabling neurological disorder.
Ashvini Premkumar, MD
What are the most effective medications for the treament of Parkinson’s disease?
The most effective medications for the treatment of Parkinson’s disease are the dopaminergic medications. Carbdiopa/levodopa is by far the most effective, followed by dopamine agonists and lastly mao-b inhibitors. Non-dopaminergic medications include anticholinergics,
which are sometimes useful for treatment of tremor but have to be used with caution because of the side effect profile, particularly in elderly patients.
What are the most common side effects of carbidopa/levodopa?
The most common side effects for carbidopa/levodopa that we see clinically include: nausea/vomiting, lightheadedness, sleepiness, hallucinations, and dyskinesias.
Do you recommend the early use of carbidopa/levodopa? Delay its use?
The early vs. delayed use of carbidopa/levodopa has been debated for many years. The crux of the debate rests on the concern that early use of carbidopa/levodopa may increase one’s risk for motor complications, namely fluctuations (“on” and “off”
periods) and dyskinesias. The risk is approximately 40 percent within four to six years, particularly among young patients. Whether or not to start carbidopa/levodopa has to be highly individualized decision, which will be based on many factors, including
disease severity, age, co-existing symptoms (i.e. cognitive impairment) and occupational concerns.
Please discuss Neupro transdermal therapy
Neupro transdermal therapy, or the rotigotine patch, is dopamine agonist that is FDA approved for the treatment of Parkinson’s disease. It can be used in early Parkinson’s disease. It also can be used as an adjunctive medication in advanced Parkinson’s
disease as it was shown in studies to reduce “off” time by roughly one hour a day. It has also been approved in the treatment of moderate to severe restless legs. The side effects include: nausea/vomiting, somnolence (sleep attacks), reactions at application
site, dizziness, anorexia and compulsive behavior. The specific benefit of Neupro, like other extended-release dopamine agonists, is that it maintains as constant a level of drug as possible throughout the day.
Some say that exercise eases Parkinson's diease symptoms. What exercises or physical activities are recommended for people with Parkinson’s disease?
We recommend an exercise program that combines aerobic activity and core muscle strengthening. And this should preferably be complemented by exercises aimed at balance and stretching (i.e. yoga and Tai Chi).
Is it safe to ride a bicycle with PD?
This question needs to be routinely addressed by the patient’s treating neurologist. In general, in the early stages of PD, where balance is not significantly affected, it’s considered safe. However, once postural instability becomes noted, either
by reported falls or upon routine examination, then it would be advisable to ride only stationary bicycles.
How can I prevent falls if I have PD?
Prevention of falls should be emphasized at each clinic visit with one’s treating neurologist. The best way to prevent falls is to be educated as to what causes falls in Parkinson’s disease and then to take every precaution to avoid those “missteps.”
Aikaterini Markopoulou, MD
What is DBS?
Deep brain stimulation is a type of surgical treatment for Parkinson’s disease. It involves the insertion of electrodes into specific areas of the brain that control movement. The electrodes are connected to a battery that is placed under the skin in the upper
part of the chest. Electrical current that passes through the electrode stimulates these brain areas on one side of the brain. This stimulation results in improvement of tremor and slowness or stiffness on the other side of the body.
Who is a good candidate for DBS?
To be a candidate for DBS surgery a number of conditions have to be met:
Is DBS covered by Medicare?
Yes, DBS is covered by Medicare.
When a patient has bilateral DBS is it necessary to have two stimulators, or will one suffice?
In the majority of Parkinson’s cases, symptoms affect both sides of the body; therefore, electrodes are inserted in both sides of the brain. In some cases where the symptoms affect mostly one side, the electrode can be inserted only in the opposite site of
If you have DBS, how does it affect your ability to get through airport checks, metal detectors, etc.?
Each patient is provided with an identification card that includes information about the implanted stimulator. The TSA agent should offer a private screening or screening with a manual wand instead of the patient walking through a metal detector.
What percentage of DBS surgeries result in complications? What complications might a patient encounter?
The DBS surgery may result in complications both during the implantation and after surgery, which include bleeding at the electrode insertion site that can be fatal, hardware malfunctioning, and infection and symptom worsening. In a large multicenter clinical
trial, 7.5% of patients developed intracranial hemorrhage, 10.6% device-related infection and 8.1% one-sided weakness.
How long is DBS effective?
Studies that have followed patients for ten years have been published and the DBS remained effective throughout the ten-year interval.
Are there any long term risks associated with DBS?
DBS therapy remains a safe treatment option for Parkinson’s patients for at least ten years.
Demetrius Maraganore, MD:
Are the children of a parent with Parkinson’s disease likely to inherit the disease? Is there a greater risk
if the father or the mother has the disease?
My research team conducted family studies that defined the risk of inheriting Parkinson’s disease. The children of Parkinson’s disease patients carry a two-fold risk for Parkinson’s disease. They are twice as likely to get Parkinson’s disease compared to the
children of persons without Parkinson’s disease. However, one needs to consider that the lifetime risk for Parkinson’s disease in the general population is 2%, so the risk of Parkinson’s disease for the children of a patient is 4%, or twice the baseline risk
for the general population. That’s a pretty low risk and I wouldn't recommend any specific lifestyle changes or preventive therapies for the children of patients with Parkinson’s disease.
That said, about 5% of Parkinson’s disease cases are due to an inherited gene abnormality (mutation). In families where multiple members have Parkinson’s disease, the risk may be as great as 50% to the children of an affected person. When there are multiple
family members with Parkinson’s disease, I refer patients for genetic counseling and in some instances we also perform genetic testing.
What are the most important genetic risk factors for Parkinson’s disease?
There are two types of genetic factors that are important to Parkinson’s disease: 1) genes that rarely cause familial Parkinson’s disease (multiple affected members in the same kindred), and 2) genes that are not causal but that slightly increase the risk for
Parkinson’s disease in populations worldwide (susceptibility genes). About a dozen genes have been identified as rare causes of familial Parkinson’s disease, and about a dozen genes have been identified as common risk factors in populations worldwide. The
causal gene mutations are rare, accounting for less than 5% of all Parkinson’s disease cases. The susceptibility gene variants are common—e.g., occurring in 25% of persons in the general population—but they have small effects (no more than doubling the risk
for Parkinson’s disease).
Of all of the Parkinson’s disease genes, the most important is alpha-synuclein because it is both a causal gene in some families and also a susceptibility gene in populations worldwide. In other words, rare variants (mutations) cause Parkinson’s disease in
rare families, while common variations (polymorphisms) increase the risk for Parkinson’s disease worldwide.
The alpha-synuclein gene holds the code for making the protein alpha-synuclein. The protein alpha-synuclein accumulates abnormally in the brain cells of every patient with Parkinson’s disease regardless of the causes. Many scientists believe that it holds the
key to understanding and curing Parkinson’s disease. Our research team at NorthShore has led many of the most important studies of alpha-synuclein and Parkinson’s disease, including studies in families and in populations worldwide. We were also amongst the
first to study the interaction of alpha-synuclein with other genes or environmental factors, or to study the association of the alpha-synuclein gene with motor and cognitive outcomes in Parkinson’s disease.
Are there genetic research studies of Parkinson’s disease at NorthShore? How can I participate?
At NorthShore we are conducting a genetic study called the DodoNA Project. We aim to discover genetic factors that predict how neurological diseases progress in severity and that predict disease outcomes. We aim to use this information to individualize the
care of our patients and to halt the progression of neurological diseases. One of the diseases we are studying is Parkinson’s disease.
We will enroll at least 1,000 Parkinson’s disease patients into the study, and follow them at least annually for several years. To be eligible for the study you need to be new to our Movement Disorders practice within the past year, a resident of Cook or Lake
County and willing to provide a blood sample for DNA extraction and storage. We also require your permission to compare your genetic code with the information that we collect in your medical record.
If you wish to participate, the best thing to do is to request an appointment to be seen as a patient in the Department of Neurology at NorthShore. We can then enroll you into the study after your office visit. You can also support the DodoNA project by joining
forces with NorthShore’s Auxiliary and by supporting the
In Parkinson’s disease (PD) low levels of dopamine in the brain lead to the symptoms of tremor, slowness, stiffness and difficulty walking. There is an easy way to replace dopamine with Sinemet tablets. The levodopa in these tablets is converted to dopamine
in the brain and helps relieve the symptoms. Why then should we consider a surgical treatment for PD?
Over time, patients on PD show a fluctuating response to medications. A dose that would last four to six hours now lasts for two or three hours. In between doses, the symptoms return with a vengeance. In addition there may be involuntary movements called dyskinesias
or a severe tremor not controlled despite increasing doses of medications.
Deep brain stimulation (DBS) surgery is a way out of this predicament. While not a cure, it can set the clock back on the severity of the disease. Some patients can reduce medication doses thereby reducing the side effects. Tremor, dyskinesias and muscle rigidity
are symptoms that improve the most. Patients show a longer duration of action of medications following surgery.
The surgery is a three-part process that involves placing an electrode in the brain connected to a pacemaker device placed under the skin in the chest. The first part maps the brain using MRI techniques. To further improve the accuracy of the electrode placement,
the NorthShore DBS team uses a sophisticated brain mapping technique called microelectrode recording. The third part involves placing the pacemaker and connecting it to the brain electrode. Patients typically return home in 2-3 days after surgery.
The NorthShore DBS team has over 15 years of experience with DBS surgery.
Dr. Dalvi has been involved with training neurologists nationally on managing the DBS pacemaker settings following surgery. When medications for PD fail it is time to consider DBS surgery.