The gut-brain relationship is real. Stomach or intestinal distress can lead to anxiety or depression. However, those gut-brain connections go much further: evidence from recent studies strongly suggest a link between the gut (the gastrointestinal system) and Parkinson’s disease (PD).

In the PD research field, the Braak Hypothesis states that the earliest signs of Parkinson's are found in the enteric nervous system (known as the brain in the gut). This theory is supported by evidence that in PD, non-motor symptoms, such as constipation, may appear before motor symptoms. Braak hypothesized that abnormal alpha-synuclein can spread from the gut via the vagus nerve to the midbrain, where it selectively kills dopamine neurons.

Published in Neuron, a 2019 study titled, “Transneuronal Propagation of Pathologic alpha-Synuclein from the Gut to the Brain Models Parkinson's Disease" (Kim et al., 2019) a group of scientists tested Braak’s hypotheses, mimicking the spread of abnormal alpha-synuclein observed in PD, scientists injected both normal mice and knock-out mice (mice with no alpha-synuclein) with misfolded alpha-synuclein directly into the stomach opening and part of the small intestine ― which are packed with vagus nerve branches.

To monitor the injected abnormal alpha-synuclein, scientists used a stain to observe the progression, if any, from the gut to the brain over several months. They also tested severing the vagus nerve in the mice, to see whether it might prevent the spread of the abnormal alpha-synuclein to the brain. Additionally, throughout the study, several tests were conducted on the mice to measure motor and non-motor symptoms.

Results
In normal mice:

• Injecting abnormal alpha-synuclein into the gut did get taken by the vagus nerve and successfully traveled into the brain, causing the normal alpha-synuclein to transform into abnormal, misfolded alpha-synuclein.
• This transformation process traveled from cell-to-cell, forming more Lewy body clumps. Remember, misfolded alpha-synuclein is the main component of Lewy bodies.   
• Injecting abnormal alpha-synuclein into their gut resulted in significant dopamine loss.

In the mice with no alpha-synuclein:

• Injecting abnormal alpha-synuclein into their gut successfully made it into the brain, but nothing happened. Since there was no normal alpha-synuclein, it was not able to start the clumping.

Motor and Non-Motor Findings

Seven months after injecting abnormal alpha-synuclein into the gut of normal mice:

• There was a significant loss of dopamine in the brain.
• There were non-motor cognitive impairments, including memory and social deficits, anxiety, depression and olfactory and gastrointestinal dysfunction.
• Motor deficits included a loss of grip strength and agility.
• Those mice that had their vagus nerve severed prevented the loss of grip strength and agility shortfalls.

What Does This Mean?
The major findings of this study support that abnormal alpha-synuclein is capable of spreading from the gastrointestinal tract (the gut) through the vagus nerve into the brain, leading to a loss of dopamine.

Further, the Kim et al. (2019) study also revealed that the misfolded alpha-synuclein in the brain causes the normal alpha-synuclein to misfold; and those misfolds form into clumps, resulting in Lewy bodies, which in turn, result in Parkinsonian symptoms. In terms of potential therapeutic applications, if this gut-brain PD connection via the vagus nerve works the same way in people, it may be possible to interfere with this trafficking to prevent PD symptom progression before it reaches the brain.

Learn More
The Parkinson’s Foundation believes in empowering the Parkinson’s community through education. Learn more about the Parkinson’s and LID in the below Parkinson’s Foundation resources or by calling our free Helpline at 1-800-4PD-INFO (473-4636).

• Protein May Hold Clues to Development of Parkinson’s

A lot of excitement has been generated in the Parkinson’s disease (PD) scientific community about the LRRK2 gene. While several genes are linked to developing PD, a LRRK2 gene mutation is one of the most common forms of genetic Parkinson’s. In fact, there are several pharmaceutical companies currently looking to find ways to prevent LRRK2 activation as a potential PD treatment. 

However, is it wise to completely disable the LRRK2 gene? What if this gene plays an important role in other important functions? For example, mutations in the LRRK2 gene have been associated with an increased sensitivity to bacterial infections, as well as other immune-related disorders, such as inflammatory bowel disease. 

Further, dysfunction in the mitochondria (the powerhouse of the cell) in the LRRK2 gene has also been linked to PD. Indeed, keeping mitochondria stable and healthy is essential for providing life-saving energy to dopamine-producing cells. Which begs the question, what if the LRRK2 gene is also involved in how well our immune system works? 

Catherine Weindel, a Parkinson’s Foundation postdoctoral fellow, recently published a LRRK2 study in the journal eLife, titled, “LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis” (Weindel et al., 2020). The study investigated whether developing drugs that shut down LRRK2 might unintentionally negatively impact a person’s ability to fight infection. 

Researchers infected normal mice with mycobacterium tuberculosis – the bacterium that causes tuberculosis (TB). As a control, they also infected mice that had the LRRK2 gene removed (known as knockout mice) with TB. Next, they compared the two mice groups’ immune system reactions. They did this by measuring a signaling protein (known as a type I interferon) that is triggered when a cell is infected with a virus to let the immune system know it’s in trouble. 

Results

Many sophisticated tests ranging from gene expression, RNA-sequence analyses, death receptor signaling, to qualitative and quantitative assessments were conducted. The key findings are as follows:  

• Mice with no LRRK2 gene infected with TB produced the type I interferon – alerting the immune system that an attack was commencing. 
• Mice with no LRRK2 gene not infected with TB produced the type I interferon – meaning it alerted the immune system to mount an attack when no attack was happening. 
• Mice with no LRRK2 gene experienced far more severe TB symptoms than the mice with a functioning LRRK2 gene.
• Normal LRRK2 mice infected with TB produced the appropriate response of the type I interferon, and when not infected with TB, appropriately, did not produce the type I interferon. 

What Does It Mean?

The LRRK2 gene produces a protein that is essential for maintaining healthy, stable mitochondria. Mitochondria play a crucial role in generating the energy required for brain cells (including dopamine producing cells) to survive and to do their job. 

This mouse study suggests that mutated LRRK2 genes may impair the immune responses in the brain to such an extent, it triggers the immune system to attack, even when no harm is happening. Thus, this study findings suggests that great care must be taken when creating drugs or therapies that inactivate the LRRK2 gene, as doing so may have unintended negative effects, such as triggering a chronic high alert immune response and diminishing a person’s ability to fight infection.

Learn More

The Parkinson’s Foundation believes in empowering the Parkinson’s community through education. Learn more about LRRK2 research by vising the below Parkinson’s Foundation resources or by calling our free Helpline at 1-800-4PD-INFO (473-4636) for answers to all your Parkinson’s questions.

• Genetics and Parkinson’s
• Possible New Key to Parkinson’s Treatment

Recently, worldwide Parkinson’s expert Michael Okun, MD, shared top tips from his book Living with Parkinson’s Disease: A Complete Guide for Patients and Caregivers, which is available now. 

There is so much that we can do to help people with Parkinson’s disease (PD) have great lives. Here are just some of the tips that Dr. Okun covered in his Parkinson’s Foundation Facebook Live event, Living with Parkinson's New Book Release, on August 4. 

Dance, Dance, Dance!

Exercise is like a drug and we know that it can help with rehabilitation for people with Parkinson’s greatly. We are seeing tangible benefits from exercise. There is a part of the brain that can, in certain circumstances, overcome deficits and exercise can be used as a treatment. Dance is a great option, so is Tai Chi. There are a lot of pearls in the exercise chapter of the book.

Nutrition – Can the Ketogenic Diet be helpful?

There’s not enough research to determine whether ketosis (a low carbohydrate diet that causes the body to break down fat and create an acid called ketones that fuels your body and brain) is beneficial for Parkinson’s. Is the Ketogenic (also known as Keto) diet helpful? Maybe. 

The biggest advice: be careful and follow the advice of your medical team first and foremost with nutrition. The only way we will find out if there is something to this theory is with proper studies and control groups. There are some exciting, emerging studies in nutrition and diets for Parkinson’s on the way.

The Importance of Sleep

If you don’t have a good night’s sleep, it’s all but guaranteed that you will not have a good day the next day. Many people don’t know that they are not sleeping well until they get a sleep study. This is something that we need to work on in treating Parkinson’s ― focusing on the importance of sleep as sleep problems are very common with Parkinson’s. 

If you find you are falling asleep frequently during the day, you likely have a sleep problem. There are options ― whether it’s decreasing your dosage of dopamine or looking into adding other prescriptions. Talk to your doctor about your prescription and looking into getting a sleep study ― a sleep study can really change your life! One of the chapters in Living with Parkinson’s Disease focuses on the treatment of neuropsychiatric effects and we discuss sleep specifically.

Depression and Parkinson’s

Depression is the largest unmet hurdle in Parkinson’s. What we realized in writing Living with Parkinson’s Disease was demoralization was also a huge unmet need, which can occur in one in five patients. It’s not just that you are depressed or have anxiety or even experience hallucinations, it’s that you are demoralized. There are therapies that can help greatly with demoralization. Treatment is so important ― you can have a better life! We are too stuck on the name of the depression pill and we should refocus on how we administer the treatment.

Parkinson’s and Hallucinations

Most hallucination medications block dopamine. Blocking dopamine with Parkinson’s will make symptoms worse. There are some medicines for other issues ― like for gut issues and headaches that also block dopamine and we need to be on the lookout for that. 

When we think about hallucinations, we must look for drugs that will not block dopamine ― there are drugs that do this! Before we get to medications, there needs to be a thorough physical examination to ensure other issues are treated first. Check out Chapter 8 in Living with Parkinson’s and talk to your doctor for more information. Dr. Okun also offers more advice on the Facebook Live event.

One of the last tips from the Facebook Live event comes from a viewer and is a really important message: “If you are not a fighter, learn to be one. How well you live with Parkinson’s is up to you.”

For more tips from Dr. Okun, check out the book, Living with Parkinson’s Disease: A Complete Guide for Patients and Caregivers! 

About the author: Michael Okun, MD, is considered a world's authority on Parkinson's disease treatment and research. He is currently Executive Director of the Fixel Institute for Neurological Diseases, Chair of Neurology at the University of Florida, a Parkinson’s Foundation Center of Excellence and the National Medical Director for the Parkinson's Foundation.

For many, it is embarrassing to bring up taboo topics with your doctor ― from sexual dysfunction to incontinence. However, when it comes to living with Parkinson’s disease (PD), sometimes these topics can be connected to the disease itself or side effects to PD medications.

No topic should be considered off limits to discuss with your healthcare team. The more we normalize and bring awareness to these issues, the less taboo they become. Scroll down to view some of these topics and their connection to Parkinson's, or click to jump straight to a specific topic.

Sexual Dysfunction

Sexual dysfunction is common in men and women with PD. The issue often goes unaddressed as patients, spouses and healthcare providers may not be comfortable discussing sex. Parkinson’s itself may cause sexual dysfunction due to the loss of dopamine. Medications, such as anti-depressants, can also contribute to sexual dysfunction. To note, most PD drugs are not associated with impotency or loss of libido.

Hypersexuality can also be linked to certain dopamine agonists. There are many ways to address PD-related sexual dysfunction, and it all starts with speaking to your doctor. Try writing your symptoms down before your next appointment and telling your doctor you have a sensitive issue you want to discuss.

Learn more

• Sexual Health and Parkinson’s
• Navigating Sexuality and Intimacy with PD

• Intimacy Issues and Parkinson’s Disease 101

Impulse Control Disorders

Dopamine medications have improved life for millions of people, but researchers believe that some people with PD on dopamine agonists or monoamine oxidase (MAO) inhibitors can develop impulse control disorders: unhealthy levels of gambling, shopping, eating or sexual activity.

If you believe that you or a loved one has an impulse control disorder, try to identify a trend in unhealthy behaviors and discuss it with your doctor. These disorders usually respond to medication changes. Your doctor can often work with you to reduce your dosage or switch to another medication.

Learn more

• Impulse Control
• New Study Examines Impulse Control, REM sleep and Dopamine

Caregiver Burnout

For many, stress can be a part of life when caring for someone with a chronic illness such as PD. However, some care partners may have a tough time coping with the fact that they need help. Care partners and their loved ones should address caregiver burnout as soon as you notice warning signs: feelings of anxiety, anger followed by guilt, bitterness towards family members and depression.

In general, 40 to 70 percent of caregivers are significantly stressed, and about half of these meet the criteria for clinical depression. While a challenge in itself, learn your limits as a care partner and find a support network that works for you. Many times, you can work with your loved one’s care team or a social worker to find additional help and resources that work best for you.

Learn more

• Balancing Life and Caregiving
• What to Expect Emotionally

Palliative Care

For many, the term palliative care is associated with fear. Think of palliative care as supportive care, defined as helping people with Parkinson’s and care partners plan for the future, address non-motor symptoms and provide an extra level of support. Palliative care can help people with PD and their families at any stage.

Palliative care is not the same as hospice care. It does include hospice, which is end-of-life palliative care, but also provides support for patients and families from the time of diagnosis.

Learn more

• Launching A Modern Supportive Care Program Across U.S. Centers of Excellence
• Advanced PD and Palliative Care in the 21st Century
• Palliative and Hospice Care

End of Life Planning

Many adults avoid the subject altogether. However, all adults, even if their health is excellent, should document their wishes and preferences should a health emergency occur. If you have a spouse, partner, children or others you care about, as your disease progresses estate planning can help you ensure that they are provided for and cared for, if necessary.

Get organized. Consider creating a binder with the following main document categories: Medical, Family, Insurance/Property and Finance. Make sure that a close family member or friend knows where to find them in case they are needed. Taking the time to make advance preparations for this inevitability is practical and necessary. Honest conversations about end-of-life planning and care may not be comfortable or easy, but they are important so you can ensure that your wishes are honored.

Learn more

• End of Life
• The Role of Hospice
• Getting Organized
• Caregiving: Preparing for Changes
• Planned Giving

Addressing Uncomfortable Topics with Your Doctor

Doctors usually wait until the end of an appointment to ask, “anything else?” How do you transition into your potentially uncomfortable topic? 

1. Remember that your doctor has heard it all. She/he wants to help you increase your quality of life.
2. Give yourself a quick pep talk. Your symptom or issue has been impeding on your quality of life. The conversation will only last a few minutes and may have a simple solution.
3. Write it down. Give yourself a natural transition in the conversation to bring up your topic. Try something like, “I wrote down some symptoms and/or issues I want to discuss, and they are sensitive in nature.”
4. Add details. Try to remember when the issue began, how long it has been a problem, when it occurs and all your symptoms.

Your doctor will work with you to address the issue and can often provide guidance or a recommendation.

For more information visit our non-movement symptoms page. You can also discuss any topic with our Helpline at 1-800-4PD-INFO (473-4636).