Parkinson's Disease: Symptoms and Progression

Thursday, April 25, 2013 11:32 AM comments (0)

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.

by Demetrius Maraganore, MD, and Ashvini Premkumar, MD

symptomsIs 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 and safe. 

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.

Parkinson's Disease: Genetic Risk Factors, Family History and Research

Thursday, April 04, 2013 11:47 AM comments (0)

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.

by Demetrius Maraganore, MD:


laboratoryAre 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 Hospitals’ Gala

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