Arches. Photo by Daniel Chia
Jun
26
2010

Stress and Huntington’s Disease

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Stress-and-HD

Because of the hustle and bustle of everyday life, everyone is familiar with the concept of stress. We can easily recognize when we are feeling stressed because of the various physical sensations that arise from it. Some of the symptoms of stress include shortness of breath, heart palpitations, headache, and fatigue. However, stress can also have much more significant and long-lasting effects. Throughout the last few decades, scientists have investigated the connection between stress and disease. Although stress does not play a direct role in the onset and development of Huntington´s disease (HD) itself, it does have an influence on the course of the disease. The leading causes of death in people with HD are not due to HD directly, but result from complications such as pneumonia and heart disease, both of which are known to be mediated by stress. (For more information on Complications of HD, click here.) It is important to know that stress can lead to complications and the worsening of symptoms in people with HD.

How do our bodies deal with stress? How can stress be harmful over the long term? How can we combat stress? This chapter discusses the answers to each of these questions.

A Brief Overview of the Stress Response^

Our body’s response mechanisms are well adapted for dealing with short-term physical emergencies. If a lion suddenly pops out in front of us, our bodies undergo a series of physiological changes that prepare us to either stay and fight the lion or run away from it – what is commonly known as the “fight or flight response.” These life-threatening situations are exactly why these changes, collectively called the stress response, evolved in humans and other animals. When we sit around and worry about stressful things such as deadlines, taxes, or family problems, we turn on the same physiological responses, which can be a problem when provoked all the time. Stress causes a variety of physical symptoms primarily because we constantly activate a physiological system that was only designed for responding to emergencies.

To understand how stress affects the body, it is important to understand the concept of homeostasis. In order for the body to function at its best, it must maintain a constant internal environment. Homeostasis is the process that maintains all biological processes within a certain range. Numerous physiological measures in the body such as oxygen levels, acidity, temperature, etc. must be kept at certain levels in order for the body to function properly. A stressor is anything that throws the body out of this balance by changing one or more of its essential factors from an optimal level to a non-optimal level. Stressors can include injury, illness, exposure to extreme heat or cold, or mental/emotional trauma. The stress response is the body´s attempt to restore homeostasis, or bring things back to normal.

In order to restore homeostasis, the body typically requires energy. Energy is normally stored in various parts of the body until it is needed. The stress response begins when the different sources of energy are quickly brought out of storage and no further energy is stored. Glucose and simple forms of proteins and fats come streaming out of the fat cells and liver into the bloodstream so that they can be taken up by the muscles and other organs that need them. Heart rate, blood pressure, and breathing rate also increase so that nutrients and oxygen can be transported to the most important organs at a greater rate. In addition, under the influence of a stressor, the body halts many non-essential long-term processes. If we need to run away from a lion, we don´t have time to wait for the energy that comes out of the slow digestion process – our last meal can wait to be digested until we are safe from that lion! Similarly, long-term building projects such as growth and reproductive processes are also inhibited during stress because these processes aren´t necessary for immediate survival. Even the immune system is inhibited because when dealing with a stressor, it simply does not make sense for our bodies to fight infections and waste energy when the lion that is chasing us may kill us in a few seconds. Once again, we can delay fighting infections until after we escape that lion!

The stress response works extremely well when there is an immediate physical stressor, such as a dangerous predator, because the body can react and then quickly return to normal once the situation is dealt with. However, the stress response has not evolved to deal with the long-term stressors of everyday modern life. We can now trigger the same physiological response that prepares us to run from a lion just by worrying about a stressful situation. In these mentally-induced cases of the stress response, the chemicals and energy reserves that are involved in the stress response are not used as efficiently as they would be if there were actually a lion to fight or run from. Thus, these chemicals and energy reserves have nowhere to go and end up accumulating in the body. Eventually, this buildup takes its toll on the body, which wears down and becomes more prone to a variety of diseases.

A Closer Look at the Stress Pathways^

The stress response begins in both the nervous system (which reacts almost immediately) and the endocrine system (which reacts more slowly). The two major stress response systems are the sympathetic-adrenal medullary (SAM) system (the nervous system’s response) and the hypothalamic-pituitary-adrenal (HPA) axis (the endocrine system’s response). These two systems function to create a precise homeostatic balance. The problem with chronic stress lies in the fact that the SAM system and HPA axis are not isolated systems and they impact numerous biological functions. Thus, they have the potential to protect or harm other parts of the body such as the immune system, the reproductive system, the digestive system (also known as the gastrointestinal (GI) tract), the heart, and even the brain.

The SAM System^

The SAM system is commonly referred to as the “fight or flight” response because it prepares the body to run away from a stressor or stay and fight it. When the SAM system is activated, the brain sends a message down the spinal cord to a part of the body called the adrenal medulla, signaling it to release a chemical messenger called epinephrine. Epinephrine circulates throughout the bloodstream and ensures that all the cells of the body are equally stimulated. This is why the stress response is non-specific. In addition, a chemical messenger called norepinephrine is released by nerve cells onto particular glands and muscles. In this way, the SAM system contributes to several changes in the body’s physiology. It quickens the heartbeat, raises the blood pressure, dilates the pupils, inhibits the GI tract, and increases metabolism. These changes allow energy to be used in the most immediately important way – more energy is taken up by muscles, which is what we need if we want to be able to run away from a ferocious lion.

The HPA Axis^

The HPA axis is mainly involved in the long-term stress response. The purpose of the HPA axis is to increase the amount of usable energy in the body and direct it to the places it is most needed. The HPA axis begins in the hypothalamus, which is located at the base of the brain and carries out its job throughout the body using a variety of hormones. The hypothalamus communicates with other parts of the brain and body, and produces hormones that either stimulate or inhibit the release of other hormones from another region of the brain called the anterior pituitary. When the brain detects a stressor, the hypothalamus releases adrenocorticotropin hormone (ACTH). ACTH goes on to stimulate a part of the body located just above the kidneys called the adrenal cortex to synthesize and release chemicals known as glucocorticoids. Glucocorticoids are a class of steroid hormones that includes cortisone, cortisol, and corticosterone. For more information on cortisol, click here.

Fig AN-1: Hypothalamic-Pituitary-Adrenal (HPA) Axis

Glucocorticoids regulate blood pressure and cardiovascular function, as well as the body’s use of proteins, carbohydrates, and fats. Glucocorticoid release increases in response to any type of stressor (physical or emotional) and causes the breakdown of stored nutrients into usable forms of energy. Fat, protein, and glycogen are broken down into different products so that they can be used by the body. Triglycerides (the main component of fat) are broken down in the fat cells, causing free fatty acids to pour into the bloodstream. Glycogen is degraded to its usable form, glucose, in cells throughout the body and eventually enters the bloodstream as well. Protein is converted back to its building blocks of individual amino acids. These amino acids are then used by the liver to make sugar (glucose) for energy. This raises the level of energy resources in the blood so they can be used to feed the brain and other essential organs. Glucocorticoids also inhibit non-essential functions such as growth, reproduction, and inflammation. (For more information on glucocorticoids and inflammation, click here.) Basically, the long-term stress response ensures that the brain and other organs essential to the stress response have adequate energy sources and that non-essential organs and processes don´t drain these energy sources.

Fig AN-2: The Provision Of Energy By Glucocorticoid Release

Harmful Effects of the Stress Response^

Stress can be summarized by the following paradox: It protects under critical conditions, but when activated chronically it can cause damage and accelerate disease. If we experience every day as an emergency, we will pay the price. If we constantly mobilize energy instead of storing it, we will never have any surplus energy and this will eventually lead to fatigue. If our blood pressure rises every time we think about paying the mortgage or meeting a deadline, then we greatly increase the risk of developing cardiovascular disease. This is especially important because heart disease is the leading cause of death for people with HD. If we constantly turn off long-term building projects, then nothing ends up getting repaired. If our immune system is suppressed, we are less likely to resist a variety of diseases. Let´s look into each of the negative effects of stress in more detail.

Stress and cardiovascular disease^

In stressful situations such as running away from a lion, we change cardiovascular function to divert more blood to our muscles. In this case, the blood that gets to the muscles carries enough energy resources to meet the muscles´ energy demand. However, when we are sitting in traffic worrying about being late we still divert more blood to the muscles because of the same stress response. This causes the blood vessels to work very hard. If we do this on a regular basis, the inner lining of the vessels begins to tear and pit. Once this layer is damaged, the fatty acids and glucose that are released into our blood by the stress response start to work their way beneath the inner lining and stick there. There is also evidence that during stress, red blood cells are more likely to clump together underneath the torn lining. Eventually, blood flow through the vessels decreases so much that it causes plaques to accumulate underneath the lining of blood vessels, a condition known as atherosclerosis. Another way that the stress response leads to heart disease is through the release of a protein called fibrinogen, which speeds up the clotting process. Clotting helps us in an emergency by keeping bleeding to a minimum if we are injured so that we can still escape. However, activating this response repeatedly can be very dangerous because a high level of fibrinogen is a risk factor for increased blood clotting and heart attack or stroke.

Stress and the immune system^

The stress response leads to a suppression of the immune system. The immune system is restrained because when we are running away from a lion, it doesn´t make sense to use energy to fight against diseases that will take a lot longer to kill us than the lion will. Our bodies are really smart; they focus on what is most important at the present moment. However, if we activate the stress response unnecessarily for prolonged periods of time, our health will eventually pay the price. With the immune system not running at full capacity, we are not being able to rally the necessary antibodies to fight off infections and diseases. The main way that the immune system is suppressed is through glucocorticoids. Glucocorticoids shrink the thymus gland, which is located in the chest under the breastbone and is critically important in the body´s response to disease invasion. In addition, glucocorticoids stop making and reduce the responsiveness of lymphocytes (also known as white blood cells). Lymphocytes are incredibly important specialized cells that fight infections. Amazingly, glucocorticoids can actually enter a lymphocyte and kill it by causing it to make a protein that destroys its own DNA.

Stress and the Brain^

The nerve cells that are affected by Huntington´s disease are distinct from the nerve cells that are affected by stress. HD causes degeneration of nerve cells in the basal ganglia and other areas of the brain, whereas stress mainly causes degeneration of nerve cells in the part of the brain called the hippocampus. Although not directly related to HD, stress is nevertheless related to the progression of the disease because it adds to the neurodegeneration that is already taking place.

Chronic stress can alter nerve cells, brain structure, and brain function. Normal nerve cells are like miniature trees with a lot of branches. These “branches” are called dendrites, and they are the structures that connect one nerve cell to many other nerve cells. Each of these connections is separated by a very short space called a synapse. One nerve cell communicates with another nerve cell by sending a chemical signal called a neurotransmitter across the synapse and onto the receiving nerve cell´s dendrites. (For more on nerve cell structure and function, click here.)

As we have already discussed, stress causes the release of glucocorticoids. Glucorticoids go on to cause the branches of the dendrites to become shorter and less widespread, which means that the affected nerve cell cannot connect to as many other nerve cells as it used to. With fewer connections, it does not receive as much information as it should. This “de-branching” occurs mainly in the hippocampus, which is very important for learning and memory. The hippocampus normally contains a lot of glucocorticoids. However, in the case of chronic stress, having too many glucocorticoids leads to the de-branching of nerve cell dendrites and interferes with nerve cell communication. (For more information on neuroplasticity and the significance of shortened branches, click here.)

Additionally, glucocorticoids make it difficult for nerve cells in the hippocampus to get enough glucose. Not having enough glucose makes these nerve cells more vulnerable to other insults, such as a lack of oxygen or loss of blood supply. As we have discussed above, excess glucocorticoids cause the nerve cells to lose their connections to other nerve cells. This phenomena, combined with their heightened vulnerability, causes nerve cells to eventually lose their function and die. This process occurs in people with Cushing´s syndrome. These patients produce massive amounts of glucocorticoids, which makes them a good example of how an overreactive stress response affects the brain. Studies have revealed that individuals with Cushing´s syndrome have a small hippocampus resulting in memory problems.

In addition to killing nerve cells, glucocorticoids can cause even more problems in the hippocampus because the hippocampus itself helps to run the glucocorticoid negative feedback cycle. In a negative feedback cycle, one chemical is released that stops the production of the main chemical when there is enough of it in the body. In the glucocorticoid negative feedback cycle, the hippocampus helps stop the release of glucocorticoids when there is enough of it in the body. When the hippocampus shrinks due to nerve cell death, it becomes less able to shut off the release of glucocorticoids. In this devastating cycle, called the glucocorticoid degenerative cascade, glucocorticoids damage the hippocampus and impair its ability to stop further production of glucocorticoids. This leads to the production of more glucocorticoids which, in addition to its other harmful effects, damages the hippocampus even further.

Why do we even have glucocorticoids?^

All of this information makes it sound like glucocorticoids are nothing but trouble. You might be thinking, “If they do so much damage, then why do we even have them in our bodies?” And why in the world would doctors prescribe them to certain patients? Glucocorticoids are actually essential to the body and we would not be able to survive the rigors of daily life without them. In studies of rats that are unable to secrete glucocorticoids, normal inflammatory responses (which are part of the immune system´s response to infection) spiral out of control. Thus, a certain amount of glucocorticoids is necessary for health, and certain amounts can be prescribed to patients to treat inflammation. (For more information on inflammation, click here.) Taken in low doses, glucocorticoids are fairly safe. However, if they are taken in large doses, or are constantly mobilized during chronic stress, they can begin many of the harmful processes that we just talked about.

Stress and HD^

It is now evident that stress is capable of causing a range of complications. While all of these complications are not necessarily directly related to the progression of HD, they nonetheless have an effect on the overall health of the individual. It is very likely that a person with HD is also affected by different kinds of daily stress. Based upon the findings in this section, one could predict that if there are two identical twins who both have HD, then the twin with lower stress will probably be in much better general health and live longer than the twin with higher stress, given that all other things are equal. It is important to keep stress to a minimum, regardless of whether or not one has HD.

Stress Management^

We are not able to ward off all of life´s stressors, nor can we simply flip a switch to bring our heart rate down when we want to stay calm. Given the severity of Huntington´s disease, it is quite likely that many people with HD or people at risk for inheriting HD suffer from chronic stress. With all the information about the effects of stress on heart disease, the immune system, and brain cell loss, this may seem a bit depressing. However, there is hope. Preserving our health in a crisis – even in an ongoing state of crisis – is well within our grasp. Despite the many ways that stress can wreak havoc on our bodies, we do not all collapse or fall victim to stress-related diseases. Given the same stressors, we vary considerably in how our bodies and minds cope. The power of the physiological stress response often depends on how the individual perceives the stressor. In one study, two rats received an identical series of shocks at the same intensity. One, however, had a bar of wood in its cage to gnaw on after the shock. Given this outlet, the rat with the wood had far less of a physiological response despite experiencing the same physical stressor. Other studies on rats show the protective effects of a warning light that precedes the stressor, a lever to press that gives the rat an illusion of control, and the presence of another rat for comfort. Critical factors that intensify psychological stress include loss of control, lack of predictability, lack of outlets for frustration, and a perception of things worsening. While these studies were done on rats, the findings do translate somewhat to humans. Below are some of the steps that people can take to help counteract the effects of stressors:

Exercise^

Exercise strengthens nearly every aspect of the body. Numerous studies have shown that simple walking can prevent heart disease. In a study of 2,500 elderly men, heart disease risk went down depending on the distance that they walked. This is because walking reduces stress and when the stress response is lowered, smaller amounts of fatty acids, glucose and stress response chemicals like glucocorticoids are released into the bloodstream. With fewer stress response chemicals in the blood stream the blood vessels don´t get clogged as easily. Exercise can also improve depression and anxiety. Many studies have shown a relationship between exercise and mood. Exercise promotes wakefulness and relaxation, and improves quality of sleep. Being well rested helps the body recover from the stress response.

Relaxation^

Relaxation through meditation, yoga, visualization, and a variety of other activities can help reduce the stress response. Participating in relaxing activities promotes lower blood pressure, slower breathing, reduced metabolism and decreased muscle tension. All of these changes in the body counteract the negative effects of stress.

Social support^

Social contacts, friends, and family relationships can also help people live less stressful lives. One study showed that people who are forced to give a public speech have a less dramatic cardiovascular response (it was easier to breathe and their hearts didn´t beat as fast) when they have a supportive friend in the audience. Another study found that male baboons with more playmates and grooming buddies have lower glucocorticoid levels than males with fewer attachments. Social support is incredibly helpful when coping with disease. In a study of men who were infected with HIV but did not have the advanced symptoms of AIDS, the infection progressed more quickly in those men who reported less satisfaction with social support. In the famous Alameda county study, the findings showed that people who lacked social and community ties were more likely to die in the follow-up period than people with extensive contacts. This implies that people with HD can benefit greatly from the love and support of family and friends.

Maintain a Healthy Lifestyle^

Poor lifestyle choices can affect the HPA axis and increase levels of glucocorticoids, even if we aren´t actually stressing about something. Therefore, it is important that we do not worsen the stress response by drinking or smoking excessively or by eating unhealthy foods. A study found that stressed individuals eat more sweet, fatty foods than non-stressed individuals, although it is difficult to determine which came first, the lifestyle or stress. This is important because fatty foods can accelerate the development of heart disease, which is one of the leading causes of death among people with HD. Maintaining a healthy diet is one way that we can keep the stress response from spiraling out of control. Stress weakens the immune system, making it harder to fight off infection. Smoking is incredibly hazardous to the lungs, making it more likely that someone under added stress (such as a person with HD) would get a respiratory disease. Furthermore, smoking may cause respiratory complications to appear earlier in the disease process. Since respiratory diseases are one of the leading causes of death among people with HD, it is especially unwise for people with HD to smoke.

Gain Control^

Stress is often related to the anxiety caused by a feeling of being out of control. Sometimes, the processes in our bodies that result in disease are inevitable (as is the case with HD) and it is important not to feel guilty or discouraged by this. It is also important for people with HD to understand as much as they can about their health and health problems – stress-related and otherwise – and take measures to bolster their well-being, while working with doctors and following approved treatment plans.

For further reading^

  1. A.A. Hakiim et al. “Effects of walking on coronary heart disease in elderly men: The Honolulu Heart Program.” Circulation 100 (1999): 9-13.
    This is a fairly easy to read study that showed the beneficial effects of walking.
  2. Berkman, L.F. “Social networks, host resistance and mortality: a nine-year follow-up study of Alameda county residents.” American Journal of Epidemiology 109 (1979): 186-204.
    This article goes into depth about the methodology and results of the Alameda study.
  3. Esch T, Stefano GB, Fricchione GL, Benson H. “The role of stress in neurodegenerative diseases and mental disorders.” Neuroendocrinology Letters 23 (2002): 199-208. Online.
    This is a paper that explains how stress affects various neurodegenerative diseases. It does not address Huntington´s disease specifically and is of medium difficulty.
  4. Gerin, W. et al. “Social support in social interaction: A moderator of cardiovascular activity.” Psychosomatic Medicine 54 (1992): 324.
    This is a very interesting study that showed that people become less stressed when giving a public speech if they have a friend or loved one in the audience. It is fairly easy to read.
  5. Leserman, J. et al. “Impact of stressful life events, depression, social support, coping, and cortisol on progression to AIDS.” American Journal of Psychiatry. 157 (2000): 1221-1228.
    This is a study that examined whether or not social support influenced the onset of AIDS. It is of medium difficulty.
  6. Oliver, G. et al. “Stress and food choice: A laboratory study,” Psychosomatic Medicine. 62 (2000): 853-865.
    This is a laboratory study that investigated whether acute stress influenced food choice during a meal. It is of medium-difficulty.
  7. Sapolsky, Robert. Stress, the Aging Brain, and the Mechanisms of Neuron Death. Cambridge: A Bradford Book, 1992.
    This is a highly informative book that details exactly what stress does to nerve cells in the brain. It is fairly difficult reading.
  8. Sapolsky, Robert. Why Zebras Don´t Get Ulcers. New York: WH Freeman and Company, 1994.
    This is very enjoyable book that can help the layperson understand the mechanisms behind the stress response.

-D. McGee, 04/18/05; recorded by B. Tatum 8/21/12