Parkinson’s Disease

What Causes Parkinson’s Disease?

Researchers have not yet discovered the causes of PD. Scientists think PD arises from a complex interplay of genetic and environmental factors. No single factor likely causes PD on its own.

Although we still don’t know precisely what causes the disease, some factors increase an individual’s risk of developing Parkinson’s disease. Risk factors include:

• The disorder is diagnosed mainly in people over the age of 60. The single most significant risk factor for PD is advancing age.
• Men are more likely than women to develop the disorder. PD usually begins with slow or rigid movement in men, while tremor is usually the dominant symptom in women.
• Genetic factors include a mutation in specific genes — LRRK2 and GBA — that raises the risk of developing PD. Several other gene variants have been linked to PD. Mutations in the mitochondria, the parts of your cells that generate energy, may also play a role in PD.
• Environmental triggers include toxic chemicals. Low-level exposure to some agricultural pesticides may be related to PD.
• Brain inflammation may play a crucial role in the development of PD.
• Head injuries increase the risk of PD.

Is Parkinson’s Disease Hereditary?

PD can strike one or more family members, but it is rarely inherited directly. Only about 2% of PD cases appear to be related to an inherited mutation. However, people of specific ethnic backgrounds — Ashkenazi Jews, North Africans, and Basques — are more likely to suffer from PD.

Changes in the LRRK2 gene (a mutation known as G2019S) account for 15-20% of cases in Ashkenazi Jews and 40% of cases in North African Arab-Berbers. Other changes in LRRK2 that raise the risk of PD have been found in people of Chinese descent.

How is Parkinson’s Disease Detected?

Early detection is vital to delaying the progression of the disorder. Some of the first warning signs of Parkinson’s disease include:

• Tremors (often in the hand or the chin)
• Changes in handwriting
• Stiffness or trouble walking
• Sleep disruptions
• Changes in voice
• Changes in posture
• Constipation
• Dizziness or fainting
• Loss of sense of smell
• Changes in facial expressions

How is Parkinson’s Disease Diagnosed?

There is no one specific laboratory test that can confirm a diagnosis of Parkinson’s disease. If your doctor suspects PD, he or she will likely order a combination of tests, exams, and treatments to rule out other sources of your symptoms and narrow in on a PD diagnosis.

Diagnostic steps may include:

• Medical history interviews to look for a pattern of symptoms or risk factors
• Physical and neurological exams to identify specific symptoms. The doctor will primarily look for evidence of slowed movement (bradykinesia).
• Blood or laboratory tests to rule out other possible causes of symptoms
• Imaging exams (MRI, CT, or PET scans) to rule out other disorders. These scans do not directly detect PD
• SPECT imaging (DaTscan) exam. This scan looks at the brain’s level of dopamine and may be used in conjunction with other tests to see if the problem is more likely to be PD.
• Administration of a medication called carbidopa-levodopa. If your symptoms respond to this medication, a diagnosis of PD is likely.

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How is Parkinson’s Disease Treated?

There is no cure for Parkinson’s disease, but several medications and therapies can effectively treat and manage the disease’s symptoms. Some treatments often become less effective over time, and different treatment approaches will probably be required as PD progresses.

Medications

Most of the medications used to treat PD manage, in one way or another, the level of dopamine in the brain. By doing so, the medications are generally effective at improving the ability to walk, move, and control tremors. Drugs commonly used include:

• Carbidopa-levodopa works by converting naturally to dopamine in the brain.
• Carbidopa-levodopa infusion is delivered directly to the intestine. This approach is often used when orally administered carbidopa-levodopa loses its effectiveness.
• Dopamine agonists such as pramipexole, ropinirole, rotigotine, and apomorphine. These medications work by simulating the effects of dopamine in the brain.
• MAO B inhibitors such as selegiline, rasagiline, and safinamide. These medications help prevent the breakdown of naturally occurring dopamine in the brain.
• Catechol O-methyltransferase (COMT) inhibitors such as entacapone. These medications can be used to boost the effectiveness of levodopa.
• Anticholinergics such as benztropine or trihexyphenidyl can be used to help control tremors.

Deep Brain Stimulation

Deep brain stimulation (DBS) is a surgical procedure in which electrodes are implanted in the brain. These electrodes deliver electrical pulses controlled by a pacemaker-likely device implanted under the skin of the chest to the parts of the brain affected by PD. The electrical pulses block the abnormal nerve signals that cause PD symptoms.

DBS is most effective at controlling PD’s tremors and movement symptoms when used in conjunction with levodopa. It is most often used in the late stages of the disease when the patient’s response to medications alone is no longer consistently effective.

How does Parkinson’s Disease Progress?

Most people with PD respond well to medications, often for many years. Over time, medication response — especially to levodopa — may fluctuate. As the disease progresses, medications gradually become less effective. Disabling side effects can develop as medications lose their effectiveness.

Advanced symptoms of PD include:

• Slowed movement (bradykinesia) that makes walking difficult and time-consuming
• Impaired posture and balance problems make people appear stooped and lead to falls.
• Rigid and stiff muscles are painful and make walking difficult.
• Thinking and memory problems, ranging from mild to severe, occur over the long term. Cognitive difficulties and dementia affect approximately 40% of people with PD.
• Dyskinesia, an abnormal fidgeting, wriggling, or other involuntary movements
• Painful muscle contractions or spasms (dystonia). Approximately 40% of people living with PD experience dystonia.
• Psychotic symptoms occur in 20-40% of people treated with medications for PD. The underlying cause is poorly understood. Medications can trigger psychosis in people with cognitive problems. Visual hallucinations (seeing things that are not real) are the most common symptoms of psychosis in PD. As the disease progresses, hallucinations become more frequent and severe.
• Mood disorders such as depression and anxiety may become more frequent as PD progresses.
• Sleep disorders. Daytime sleepiness affects up to 75% of people with PD.
• Loss of automatic movements reduces unconscious movements, including blinking, smiling, or swinging the arms while walking.
• Speech changes include slurring, hesitation, or other difficulties.
• Painful stabbing, burning, or tingling sensations are common.

How is Parkinson’s Disease Prevented?

No prevention strategy has been proven to stave off PD. However, several risk factors have been identified. Head injury and pesticide exposure have been associated with higher rates of PD. Drinking coffee (and black tea) is associated with lower incidence. While further research is necessary to confirm the connection, several extensive studies have linked high caffeine intake with reduced risk of developing PD.

Parkinson’s Disease Caregiver Tips

Parkinson’s disease affects every aspect of daily life. That can be immensely frustrating and demoralizing for both the sufferer and the people who care for them. Maintaining a safe, supportive environment is the best thing that a caregiver can do for someone coping with PD.

Tips to help your loved one and yourself:

• Educate yourself about the disease, its effects, and the side effects of medications used to treat it. For example, people taking levodopa are at risk for compulsive gambling, shopping, and impulsive behaviors. PD patients are also at higher risk of developing depression and anxiety. Be on the lookout for the warning signs of these conditions.
• Encourage a healthy lifestyle. There is no cure for PD, but there are ways to manage symptoms and maintain a good quality of life for as long as possible. Facilitate your loved one’s eating a healthy diet and getting as much exercise as possible. You may also explore alternative therapies and activities such as meditation, yoga, tai chi, or massage.
• Join a support group for caregivers. Caregivers are at risk of developing physical and mental health issues, too. So take time for yourself, and get the help you need when you feel overwhelmed.

Many people with Parkinson’s disease also suffer from other brain and mental health-related issues, a situation called co-morbidity. Here are a few of the disorders commonly associated with PD:

• About a third of people with PD suffer from depression.
• More than a quarter of people with PD have an anxiety disorder such as generalized anxiety disorder, agoraphobia, social anxiety disorder, or panic disorder. Many people with PD have more than one anxiety disorder.
• People with PD often exhibit impulse-control symptoms similar to compulsive gambling, shopping, or eating disorders.
• Psychotic symptoms such as delusions or hallucinations are common in PD. Visual hallucinations are the most common of these symptoms.
• People with PD often exhibit a loss of interest in daily activities (apathy) that seems to be separate from symptoms of depression or anxiety.

Parkinson’s Disease Brain Science

PD results from a lack of dopamine in the brain. PD destroys a part of the brain stem known as the substantia nigra. Over time, dopamine-producing nerve cells in this area die, and the resulting decrease in dopamine levels leads to tremors, rigidity, and difficulty with motor skills. Researchers are trying to find ways to prevent or reverse the damage. Their work is coming at the problem from many different angles; areas of current research include:

• Inflammatory reactions. Any damage in the brain triggers a flood of inflammatory chemicals to repel the intruder. Chronic inflammation kills off neurons and allows a rogue protein to accumulate in the neurons. Deposits of this protein, called “Lewy bodies,” disrupt thinking and behavior and are a factor in Parkinson’s-related dementia.
• Gut microbiome. Researchers now suspect that the earliest stages of Parkinson’s disease occur in the gastrointestinal tract. Lewy bodies that accumulate in the brain are also found in the gastrointestinal nervous system. Beneficial bacteria and other gut microbes, if they can be identified, could potentially open new avenues for treatment.
• Immune response. The immune system is responsible for fighting infections in the body, but sometimes immune-system responses go wrong, causing the body to attack its own cells. Some scientists suspect that abnormal proteins may trigger the immune system to destroy dopamine-rich neurons in the brain.
• Gene therapy. No gene therapy has yet received FDA approval for the treatment of PD, although research is ongoing. This research could result in personalized medicine and targeted therapies to treat PD’s specific mechanism in individual patients.
• Stem cells. Early-stage clinical trials involving stem cell-derived therapies are driving pioneering research. “Pluripotent” stem cells — grown from the patient’s own skin — can generate into any cell type in the body. The most promising approach to reverse PD involves using these cells to replace the dopamine-producing neurons that have been lost.
• Pharmaceutical Research. The new science of proteins within cells—called proteomics—is driving pioneering research into targeted medications. Researchers hope to develop drugs that target specific molecules at the cellular level.

Parkinson’s Disease Research

Title: Memory impairment in PD

Stage: Enrolling patients, treatment pilot trial

Principal investigator: Gregory Pontone, MD, MHS

Johns Hopkins University School of Medicine

Baltimore, MD

Dr. Pontone and Arnold Bakker, PhD, focus on the non-motor aspects of Parkinson’s disease and related disorders in adults age 65 or older.

PD is more than just a disabling movement disorder. It also causes changes in thinking, perception, and mood regulation. As a result, more than half of persons with Parkinson’s disease suffer from dementia, anxiety, depression, and hallucinations at some point during the course of the illness.

Dr. Pontone’s research aims to gain a better understanding of how PD injures a vital part of the brain called the hippocampus. Damage to networks in this area of the brain raises the risk for memory impairment, anxiety, depression, and psychosis.

Loss of dopamine-producing neurons in the substantia nigra causes the movement symptoms of PD. However, the cause of the non-movement symptoms, such as dementia, anxiety, depression, and psychosis, is not well understood. It likely involves a complex network of structures in the brain.

New treatments for non-movement symptoms require a better understanding of the brain circuits involved in causing dementia, anxiety, depression, and psychosis in PD. Dr. Pontone is studying the brain with advanced techniques in functional magnetic imaging (fMRI) [a high-tech tool that measures blood flow in the brain].

Pilot data show that hyperactivity in the hippocampus is associated with memory impairment in PD. Dr. Pontone’s research team believes that returning the hippocampus to a normal level of activation will restore memory and may also slow or prevent progression to dementia.

Dr. Pontone and Dr. Bakker are seeking funding to extend the project by:

• Enrolling additional participants to increase statistical power for their preliminary finding that hippocampal hyperactivity is associated with memory impairment in Parkinson’s disease.
• Testing whether anxiety, depression, or psychosis are also associated with hippocampal hyperactivity.
• Performing a pilot trial to determine the safety and tolerability of an experimental treatment. Some participants will be given low-dose Levetiracetam®, an anti-seizure drug. The initial trial—in which both the researchers and participants know who is taking the drug—must be done before applying for a grant for a larger placebo-controlled trial. The goal is to determine the effect of the drug on hippocampal hyperactivity and memory dysfunction in PD.

If successful, this would be the first treatment for mild cognitive impairment in Parkinson’s disease and could lead to new treatments for neuropsychiatric disorders.

Title: Gut Microbes and Parkinson’s Disease

Stage: Early research, mouse model

Principal investigator: Sarkis K. Mazmanian, PhD

California Institute of Technology (Caltech)

Pasadena, CA

Scientists at Caltech have discovered a link between microbes in the intestines and PD. Working with mice, Dr. Mazmanian showed that changes in gut bacteria are linked to symptoms of PD. When germ-free mice received transplants from the gut of a mouse with PD, the healthy mice began to show symptoms of PD.

The researchers used mice that develop Parkinson’s symptoms because they overproduce alpha-synuclein in their brains. One experiment showed that mice born in a germ-free environment did not develop Parkinson’s symptoms, despite having deposits of alpha-synuclein clogging their brains. Mice raised in an environment of normal gut bacteria did develop symptoms of PD.

Researchers at Caltech said studies have shown that microorganisms in the guts of humans with Parkinson’s differ from those of people without PD. Certain classes of bacteria are missing or depleted in people with PD, in comparison with healthy populations.

Caltech scientists studying inflammation and motor problems in mice believe their research will someday lead to clinical trials in people. Treating the bacteria in the gut would be a much easier task than delivering medications to the brain.