Chronic Stress as Risk Factor for Alzheimer’s Disease

Stress is inherent in every human being. It is the way we respond to a real or imaginary threat.  It is the fight-or-flight mechanism which enables our bodies to initiate the chain of biochemical reactions in response to a hazard, whether real or perceived. While your mind and emotions develop through the learning experience of life, instincts were given to you as a survival protection tool.

What is stress?

Stress is a normal physical response to events that make you feel threatened or upset your balance in some way. When you sense danger – whether it’s real or imagined – the body's defenses kick into high gear in a rapid, automatic process known as the “fight-or-flight” reaction, or the stress response.

When you perceive a threat, your nervous system responds by releasing a flood of stress hormones, including adrenaline and cortisol. These hormones rouse the body for emergency action.

Your heart pounds faster, muscles tighten, blood pressure rises, breath quickens, and your senses become sharper. These physical changes increase your strength and stamina, speed your reaction time, and enhance your focus – preparing you to either fight or flee from the danger at hand.

The stress response is the body’s way of protecting you. When working properly, it helps you stay focused, energetic, and alert. In emergency situations, stress can save your life – giving you extra strength to defend yourself, for example, or spurring you to slam on the brakes to avoid an accident.

The stress response also helps you rise to meet challenges. Stress is what keeps you on your toes during a presentation at work, sharpens your concentration when you’re attempting the game-winning free throw, or drives you to study for an exam when you'd rather be watching TV.

But beyond a certain point, stress stops being helpful and starts causing major damage to your health, your mood, your productivity, your relationships, and your quality of life.

Chronic Stress Danger

What happens with chronic stress then? If we are chronically stressed and experience chronic distress as a result, then we are constantly releasing cortisol. Like red wine, too much of a good thing can be bad. Chronically high cortisol has been shown to cause brain cell dysfunction, to kill brain cells, and to cause atrophy of the brain.

With aging, something additional happens. Biological systems become deregulated. Our ability to shut down biological systems once they are turned on becomes impaired with aging. Cortisol levels go up, but they stay up longer and go down slower. We become more prone to the psychological effects of stress if we are distressed, and the effects last longer. More brain cells may dysfunction and more may be killed.

Over the course of a lifetime, the effects of chronic stress can accumulate and become a risk factor for cognitive decline and Alzheimer's disease. Several studies have shown that stress, and particularly one's individual way of reacting to stress (the propensity to become distressed often found in neurotic people for example), increases the risk for Alzheimer's disease.

Clinical Research – Stress as Risk Factor for Alzheimer’s Disease

UC San Diego Study, 2010

In 2010, a research group led by Mark Tuszynski at the University of California, San Diego, performed a study on monkeys to see how different environments affect the development of Alzheimer’s disease. Some monkeys were put in very small cages when they were young, while others were in larger cages. The monkeys in the small cages were unable to get enough exercise and released larger amounts of stress hormones. These stress hormones can reduce the number of nerve synapses. Upon study of the monkeys’ brains, it was confirmed that monkeys raised in smaller cages had, on average, a higher density of plaques and lower number of synapses, the same brain pathology seen postmortem in Alzheimer’s patients.

University of Houston, 2010

In another study in March, 2010, Karim Alkadhi at the University of Houston led a research team to study the effects of stress on rodents in a water maze. Some rats were injected with amyloid peptides, while other rats were subjected to stress by placing an intruder rat in their home cage. The rats were divided into 4 groups to see the effects of the amyloid proteins and stress singly and combined.

The study results showed that only one group of students had difficulty learning the new task, reflecting substantial memory impairment - the animals that received both the amyloid dose and were regularly stressed out.”

Utah State University, 2010

Chronic psychological stress throughout a lifespan might increase an individual's risk for Alzheimer's and dementia later in life, according to research from the Emma Eccles Jones College of Education and Human Services at Utah State University.

The research, led by Maria Norton, Ph.D., built off the recently completed 15-year Cache County Memory Study (CCMS) and used that data to focus on the role psychological stress has on dementia. The findings are consistent with the hypothesis that chronic stress can expose an individual to long-term levels of stress-related hormones, which results in chronically high levels of glucocorticoids, a natural chemical, shown in both animal and human studies to increase the rate of neuronal cell death with long-term exposure.

"Using this objective data, such as death records, medical information, and the cognitive evaluations from the CCMS, we were able to see that people who experienced particularly stressful life events, such as a parent's death during one's childhood, death of a child or spouse, or living with a spouse who is afflicted with dementia is associated with significantly higher rates of dementia later in life," Norton said.

Norton also found that there were some factors that were associated with lower rates of depression and stress, such as individuals who had high levels of religious involvement, thus indicating that the ability to cope with psychological adversity might reduce the risk of Alzheimer's.

University of South California, 2011

While there were multiple studies, which confirmed the causal relationship between chronic stress and Alzheimer’s Disease development, scientists at the University of Southern California (USC) have now found an scientifically backed up mechanism: chronic stress (physical or mental) causes over expression of the RCAN1 gene, in turn leading to neurodegenerative disease.

The mechanism involves the following steps:

1. In a healthy person, the RCAN1 gene helps cells cope with stress. However, chronic overproduction of RCAN1 causes hyperphosphorylation of tau proteins in the brain.
2. Tau proteins stabilize microtubules, which are like scaffolding, used to build the brain’s neurons. Previous research has shown that when the tau protein binds too much phosphate (hyperphosphorylation), it forms snarls that prevent the brain’s signals from effectively traveling.
3. These neurofibrillary tangles eventually choke the life out of neurons, killing off brain function a tiny piece at a time in what is outwardly recognized as degenerative brain disease.

The researchers suggests that overexpression of RCAN1 is also connected to Amyloid beta (overproduction of the Amyloid beta peptide), a competing theory of neurodegeneration.

Further supporting the RCAN1 role are observations that it has been also shown to be chronically overexpressed from birth in the brains of patients with Down syndrome. These patients develop neurofibrillary tangles and typically start to experience the onset of Alzheimer’s disease around age 40.

Sources and Additional Information:

http://www.myinnerchi.com/health_managing_stress.html

http://helpguide.org/mental/stress_signs.htm

http://www.psychologytoday.com/blog/alzheimers-hope-the-horizon/201003/stress-the-brain-aging-and-alzheimers-disease

http://www.alzheimersreadingroom.com/2011/02/can-stress-cause-alzheimers-disease.html

http://www.kurzweilai.net/how-chronic-stress-causes-alzheimers-other-brain-diseases

http://www.news-medical.net/news/20110728/Chronic-psychological-stress-linked-to-increased-risk-of-Alzheimers.aspx

Cold Sores (Herpes Simplex Virus Type 1) – strong risk factor for Alzheimer's disease

Viruses and Alzheimer’s

For almost twenty years, Dr. Ruth Itzhaki, Professor of Molecular Neurobiology at the University of Manchester in England, has been exploring possible links between viruses and Alzheimer’s. Viruses are tiny infectious particles that attach themselves to and penetrate cells, then use the capabilities of those cells to reproduce. They can cause diseases like colds, flu and AIDS, or they can just sit there, remaining dormant or latent for long periods of time. A latent virus can become active when triggered by stress, other infections or environmental factors.

For a virus to contribute to the development of Alzheimer’s, Dr. Itzhaki reasoned, it would have to be very common in humans. And because Alzheimer’s appears to develop over a long period of time, it would make sense to look for a virus that has long periods of latency, but could periodically be reactivated and cause damage.

One family of viruses fits her criteria: herpes. There are over 100 types of herpes, of which eight infect humans, causing diseases ranging from chickenpox and shingles to cold sores and mononucleosis. Most people have some type of herpes, even though they may have no symptoms.

We will review one type of herpes which is particularly suspected in having tight causal links with Alzheimer’s in more details.

About Herpes Simplex Virus1

Herpes Simplex Virus Type 1 (HSV1) is especially common in humans. It is also regularly referred to as cold sores, fever blisters, oral herpes or herpes labialis. It is a viral infection of the skin that may occur once or return again and again. This happens when the virus is cleared from the skin by the immune system it hides in the nerves and is never completely removed from the body. Herpes outbreak infections are very common. It is estimated that nine out of ten people have been exposed to herpes outbreaks and many of these don't even know they have it. Those who carry herpes can spread the disease without even knowing it.

Herpes simplex begins as a group of small red bumps that blister and preceded by itching and burning of the area. The blisters begin to dry up after a few days and form a yellow crust. The crust then falls off and the redness slowly goes away. The whole process takes about 10-14 days. Scars rarely form.

What causes Herpes Simplex Virus1?

• Cold sores are generally contracted from skin to skin contact with an infected area.
• People can catch HSV1 by sexual contact such as kissing a person with a cold sore or sharing a drinking glass or utensils
• Family members should not share towels or linen with someone who has an outbreak of herpes on the genitalia or cold sores. Herpes outbreaks can spread from person to person even when an infected individual has no outbreak or symptoms.
• Once infected with cold sores, the virus remains inside the body in a latent (sleeping) state. Throughout a person's life the virus can then become "activated" causing a cold sore recurrence.

What causes or "activates" a Cold sores or fever blisters recurrence?

If you've had cold sores before, it can be hard to tell what might make them come back. Below are some factors that may trigger it to return:

• Stress
• Sun (Exposure of the area to strong sunlight)
• Incorrect diet
• Fever
• Menstruation Cycle
• Fatigue (not getting enough rest)
• Being run-down
• Pregnancy
• Drinking a lot of alcohol
• Ultraviolet light
• Skin irritation (such as sunburn)
• Certain foods
• Temperature extremes

Herpes Simplex Virus1 and Alzheimer’s

Whilst it is not the case that everyone with herpes will indeed develop Alzheimer's, there is a fairly strong linkage. It all comes down to a particular gene which appears to damage a key part of the nervous system which is responsible for keeping Alzheimer's at bay.

What this means is that whilst herpes does not directly cause Alzheimer's, it doesn't weaken the system which Alzheimer's attacks, and therefore leaves you more vulnerable than someone who does not have the HSV1 disease.

Over the past several years, compelling evidence has surfaced linking HSV1 to Alzheimer's disease. In 2008, Canadian researchers Luc Letenneur and Karine Peres demonstrated a dramatic increase in antibodies directed against HSV1 in Alzheimer's patients compared to age-matched individuals without the disease.

University of New Mexico (UNM), Brown University, and House Ear Institute (HEI) recent study supplied even more conclusive results to support the theory of this causal relationship. “It’s no longer a matter of determining whether HSV1 is involved in cognitive decline, but rather how significant this involvement is. We’ll need to investigate anti-viral drugs used for acute herpes treatment to determine their ability to slow or prevent cognitive decline,” comments Elaine Bearer, M.D., Ph.D., Harvey Family Professor and Vice Chair for Research, Department of Pathology, UNM School of Medicine.

Professor Ruth Itzhaki has explored the relationship of HSV1 to Alzheimer's disease in great depth. In her landmark article published in 2008 entitled "Herpes Simplex Virus Type 1 in Alzheimer's disease: The Enemy Within," Dr. Itzhaki revealed that HSV1 infects the brains of 90 percent of adults. If HSV1 causes Alzheimer's, this high rate of infection would be a necessary characteristic in light of the very high prevalence of Alzheimer's disease. Further, she points out, HSV1 can remain latent in the nervous system lifelong and may undergo periodic reactivation causing persistent brain inflammation. As an example, HSV1 is the cause of recurrent fever blisters that occur when the virus gets activated in the brain. Undoubtedly the most compelling evidence linking HSV1 to Alzheimer's disease comes from her recent discovery of HSV1 DNA actually located exactly within the beta amyloid plaque, the so-called "hallmark" of the disease.

So compelling are these findings that Dr. Itzhaki has concluded, "Our present data suggest that this virus is a major cause of amyloid plaques and hence probably a significant etiological factor in Alzheimer's disease. They point to the usage of antiviral agents to treat the disease and possibly of vaccination to prevent it."

How It Happens?

One of the theories of this relationship has to do with the way that the herpes virus interacts with the receptors of lipoproteins. In partnership with the gene – Allele, the system which is responsible for motor functions is gradually degraded – not to the point where it doesn't work, but instead to the point where it is left open to developing Alzheimer's more quickly.

Interestingly, when the Allele gene is not present, there is no effect of herpes on the development of Alzheimer's, meaning that obviously the two need to be in sync with each other to have any tangible effect.

Reviewing the possible causes for the devastating HSV1 role in Alzheimer’s, Dr. Itzhaki mentioned that the complete mechanism on how HSV1 might damage the brain is still unclear. It could be via inflammation and oxidation. Oxidation is when unstable molecules called oxygen free-radicals combine with other molecules. In the same way that rusting damages metal, oxidation can damage brain cells. Dr. Itzhaki says that oxidation has been found in HSV1 infected cells in the lab and in brain cells harboring latent HSV1.

“We think inflammation must be a major factor,” she says. She lays out the hypothesized chain of events: “When HSV1 is latent (i.e. in a dormant state) in the brain, it can be activated by inflammation of the brain. The latter can occur when somebody has an infection, or is stressed, or immunosuppressed. The virus then augments the inflammation there. So other viral or bacterial infections (not necessary in the brain) can cause indirect trouble.”

Herpes Simplex Virus1 Treatment

Currently, there are no cures or vaccines for the herpes simplex virus. However, avoiding precipitating factors, such as sunburn and stress, can help prevent additional outbreaks. There are established treatments available to help decrease healing time, reduce pain associated with the lesion, and in specific cases, suppress the recurrence of the virus.

Nondrug therapy

Frequent hand washing will help reduce the spread of the virus to other parts of the body or to other people. Also, applying cool, moist compresses to the lesion may decrease pain and keep the lesion from drying and cracking.

Some recommendations on how to minimize the risk:

- Replace your toothbrush because it can harbor the virus for days and re-infect you with another cold sore. Don't keep your toothbrush in the bathroom. The moisture in the bathroom prolongs the life of the virus causing cold sore in your toothbrush. In short, keep your toothbrush dry.

- Avoid excessive arginine-rich food such as chocolate, cola, peas, grain cereals, peanuts, gelatin, cashew and beer.

- Supplement your daily diets with good food sources of lysine such as dairy products, potatoes and brewer's yeast.

- Lemon has been used to stop fever blisters or cold sores over decades in Europe. You can cut a small slice of lemon and place it either on your cold sore and leave it there as long as you can. Change it as often as possible with a fresh slice.

- Apple cider vinegar is one of the oldest home remedies for cold sores, herpes and wounds. It should not be used pure on open sores because it can sting a lot. Pour a few drops on a cotton ball and apply it on your cold sore or blister. You can also mix it with lemon juice to increase its potential.

- Garlic is a broad-spectrum antibiotic, killing bacteria, fungus, yeast, viruses and parasites. A scientific study has confirmed that garlic can destroy several virus types on contact including herpes type 1.

- Ice cubes are a great way to ease the pain associated with a cold sore. Simply rub an ice cube directly onto the cold sore for a few minutes when it first begins to appear. Repeat this every 10 minutes for about an hour or so.

- The juice from an aloe plant can help ease the pain from a cold sore. Simply rub aloe juice directly onto the infected area for some fast relief. Aloe gels can also be used instead of fresh aloe juice.

- Use petroleum-based products all over the infected area. This will help prevent any secondary infection from bacteria as well as expedite healing.

- An effective remedy is to apply tea bags to the affected area. This facilitates the tannic acid in the tea to act against the virus and prevent its further development. Another effective method is to press a warm tea bag on the cold sore. A five-day application will make the sores disappear.

- If powered common salt is applied to the affected area by a moistened index finger, it’ll make cold sores disappear in two to three days.

- Herbs like herbal sage, tea tree oil and the herbal sedative violet have been used as treatments for cold sores. Sage leaf tea with a small ginger root piece or ginger powder is effective against this condition.

- Avoid physical contact with the cold sore area. Touching, rubbing, and scratching cold sores can not only increase bacterial infection but also unwittingly spread the virus to other areas of the face and possibly infect other persons.

- Clean the cold sore with a washcloth, soap, and warm water. This will minimize itching as well as prevent the virus from spreading.

- Avoid salty and acidic foods like lemon and potato chips as these will aggravate cold sores and become more painful.

- Use an anesthetic ointment to alleviate the pain.

- Recognize cold sore symptoms to prepare you for it, as well as be aware of the conditions that trigger your cold sore outbreak. Stress, weather extremes, the menstrual cycle. All these can cause an outbreak. Avoid too much exposure to direct sunlight, and use a good sunscreen.

- Get lots of rest. A well-rested person would have higher immunity against cold sores.

- Take vitamin supplements, especially those with a substantial amount of anti-oxidants and Vitamin B. Vitamin B deficiency has been found to have a direct link with cold sore outbreaks, and anti-oxidants are essential for a healthy body.

- Exercise. Not only does it bolster your immune system, it is an effective way to ward off stress, one of the common triggers of cold sores.

Over-the-counter (OTC) topical medications

Most topical OTC products provide symptomatic relief only; they do not decrease healing time. Using topical anesthetics that contain benzocaine (5%-20%), lidocaine (0.5%-4%), tetracaine (2%), or dibucaine (0.25%-1%) will help relieve burning, itching, and pain. The most commonly recommended products are Lipactin gel and Zilactin. It is important to keep in mind that these topical anesthetics have a short duration of action, usually only lasting 20-30 minutes. Skin protectants, such as allantoin, petrolatum, and dimethicone-containing products help keep the lesion moist and prevent cracking of the lesion. Sunscreen-containing lip balms may also help prevent additional outbreaks if the sun is a precipitating factor. For additional pain relief, using aspirin, ibuprofen (Advil), or acetaminophen (Tylenol) may be beneficial. These products should be used according to package directions.

Docosanol 10% cream (Abreva) is the only OTC topical product that is known to decrease healing time when applied at the first sign of recurrence (for example, the prodrome or tingling sensation). Docosanol is applied five times per day until the lesion is healed. Common side effects include rash and itching at the site of application.

Prescription-strength topical medications

Treatment with topical acyclovir (Zovirax 5% cream) or penciclovir (Denavir 1% cream) will reduce healing time by approximately half a day and decrease pain associated with the lesion. Topical treatment is limited in its effectiveness because it has poor penetration to the site of replication of the virus, and therefore is restricted in its healing ability. Acyclovir cream should be applied five times per day for four days, and penciclovir cream should be applied every two hours while awake for four days. In August 2009, the FDA approved a cream containing acyclovir and a topical steroid, which reduces healing time by approximately one day.

Oral prescription-strength medications

The current FDA-approved oral antiviral medications used in the treatment of herpes simplex virus in adults are acyclovir, valacyclovir (Valtrex), and famciclovir (Famvir). Famciclovir has not been tested in children with cold sores. These oral medications have been shown to decrease the duration of the outbreak, especially when started during the prodrome (symptom onset before the actual condition becomes fully evident). The medications are generally well tolerated with few side effects. Most common side effects include headache, nausea, and diarrhea. Treatment is only for one day with valacyclovir and famciclovir. Valacyclovir is given as 2 grams orally every 12 hours for one day, and famciclovir is given as 1,500 milligrams orally for one dose. Acyclovir is given as 400 mg orally five times per day for five days. Acyclovir, valacyclovir, and famciclovir are considered relatively safe and effective when used in pregnancy, although topical treatment would be preferred when appropriate. Acyclovir and valacyclovir have been used while breastfeeding. However, pregnant women and nursing mothers should contact their physician or pharmacist prior to using any medication.

People who have more than two outbreaks in four months, which significantly affect their daily lives, should consider chronic suppressive therapy. The FDA has approved the use of oral valacyclovir daily to prevent recurrence of the herpes simplex virus in people with normal immune systems and famciclovir in people with suppressed immune systems.

Sources and Additional Information:

http://www.tangledneuron.info/the_tangled_neuron/2007/04/herpes_simplex_.html

http://www.antiherpes.com/oral_herpes.asp

http://neurosciencenews.com/researchers-link-herpes-virus-alzheimers-disease-cold-sores-hsv1/

http://www.huffingtonpost.com/dr-david-perlmutter-md/alzheimers-herpes-could-be-a-cause_b_814047.html

http://www.medicinenet.com/herpes_simplex_infections_non-genital/page6.htm