Archive for December, 2008

A form of vitamin B3 named nicotinamide prevents transgenic mice from getting Alzheimer’s pathology. But will it work in humans?

If humans were like transgenic mice, than a miracle cure for Alzheimer’s disease has been found. Nicotinamide (also called niacinamide) works to decrease levels of phosphorylated tau which one of the key neuropathological hallmarks of Alzheimer’s disease. Tau is involved in the formation of mircotubules which can be thought of as the train tracks (or key transportation system) along the length of the cell. Without it, both intra- and extracellular communication can’t occur. It also increases the stability of this transportation system via other mechanisms, and works to increase p25, a protein which has been linked to improved learning and memory.

The transgenic mice that were used had 2 of the most important key pathological hallmarks of Alzheimer’s disease (Abeta plaques and tangles) and memory loss as well which begins at 4 months in these mice. Thus scientist Kim Green and colleagues fed the mice pharmacological doses of nicotinamide in their drinking water at age 4 month until they were 8 months old. They found that the mice did just as well in many measures in the Morris Water Maze (used to test memory) as normal control mice. Much of the typical neuropathology expected in the mice never appeared.

So does nioctinamide show promise for preventing or reversing Alzheimer’s in humans? No and yes.

Because of disappointing outcomes from previous human trials with other substances in those with Alzheimer’s, current trials are targeting early stages of the disease to prevent further decline. Thus, like the mice who were just at the beginning stages of showing pathology when the experiment began, Green who is starting a phase 2 trial at UC Irvine is looking for patients who are in the early stages of the disease.

While vitamin B3 is easily found in meat, fish, beans, potatoes and cereals, equivalent doses for humans would be far more than what we’d normally get in our diet. Investigators are starting a phase 2 trial in humans at UC Irvine, and will be giving subjects 1,500 mg twice a day. Normally a multivitamin only contains 10mg, and the standard recommended daily dose is 16mg for men and 14mg for women. Doses at pharmacological levels could induce liver toxicity and other side effects, and more information on safety will be available with the completion of phase 2 and 3 clinical trials.

However, there is an observational prospective study conducted by Martha. C. Morris at Rush University that shows in their Chicago population of 3718 subjects that those who consumed more niacin (a precursor to nicotinamide) over a 5.5 yr period had substantially less cognitive decline. This same study showed in a smaller subset that those who consumed more niacin also had a 70% lower risk of Alzheimer’s disease.

So while a reversal of Alzheimer’s disease is unlikely, nicotinamide or niacin shows great promise of slowing the cognitive decline associated with the disease, and or decreasing the risk of the disease. While it’s too early to take pharmacologic doses of vitamin B3, you might want to keep your eye on your B3 intake, and to stay tuned for more news in the future with regards to this vitamin.

For more information:

http://www.sciencedaily.com/releases/2008/11/081104180926.htm

http://www.alzforum.org/new/detail.asp?id=1962

http://www.npr.org/templates/story/story.php?storyId=96747179

References:

Green KN, Steffan JS, Martinez-Coria H, SunX, Schreiber SS, Thompson LM, LaFerla FM. Nicotinamide Restores Cognition in Alzheimer’s Disease Transgenic Mice Via a Mechanism Involving Sirtuin Inhibition and Selective Reduction of Thr231-Phosphotau. Journal of Neuroscience. 2008 Nov 28(45):11500-11510.

Morris MC, Evans DA, Bienias JL, Scherr PA, Tangney CC, Hebert LE, Bennett DA, Wilson RS, Aggarwal N. Dietary niacin and the risk of incident Alzheimer’s disease and of cognitive decline. J Neurol Neurosurg Psychiatry. 2004 Aug;75(8):1093-9.

A Miracle Drug

I am not one to normally sing praises to any drug. Many drugs have untoward side effects, and at a gut level, I’m uncomfortable with idea of developing new compounds in the laboratory to address our health issues. I like the idea of using ingredients and solutions that are derivative from more natural environments. And I’m a big fan of prevention where possible. That being said, last month I heard about a drug that made me do more than sit up and take note. As you can see, I’ve been inspired to write a blog about it.

The drug is alemtuzumab. It is normally prescribed for leukemia, and it targets CD52 (a receptor on lymphocytes). In a phase II clinical trail for multiple sclerosis (MS), it actually reversed disability normally caused by the disease. In this trial 111 people received the standard treatment (Interferon beta-1a), and 223 received alemtuzumab. Those who received the drug had a 74% reduced risk of relapse, and a 71% reduction in what would otherwise be a progressive path of disability. The most striking finding is that while the disability score of patients who took Interferon beta-1a increased (the higher the score, the more disabled), the disability score of the patients who took alemtuzumab went down! Brain volumes increased for those with the drug, and decreased for those with Interferon beta-1a, and those with alemtuzumab had less brain inflammation.

The quote from Dr. Alasdair Cole, a co-author on the study is “This is unprecedented”. I agree. It’s not only significant for the field of MS, but I can’t think of one drug for any neurodegenerative disease that has shown such a powerful and clear cut effect. Neurodegenerative diseases by definition are diseases where over time, one’s brain slowly degenerates. It’s always accompanied by increases in inflammation, oxidative stress and often times there are deposits such as plaques. Then there are the functional losses. Over my decade of research in Alzheimer’s disease, I’ve never once believed that there would be a drug that could not only slow down the disability, but that would restore abilities. While I’m still skeptical that there maybe one for Alzheimer’s disease, the results of the alemtuzumab trial are loosening my once firmly held convictions.

For more information:

http://www.sciencedaily.com/releases/2008/10/081022211030.htm

http://content.nejm.org/cgi/content/short/359/17/1786?rss=1&query=current

New Years Resolutions: How to Succeed with Change Without Really Failing

New Years is a comin’ around the corner, and if you are like millions of other American’s, you’ll come up with one or more New Year’s resolutions, and then a few months later, you’ll find yourself consumed with other responsibilities. Sigh. Why is change so hard? Is there anyway to increase our likelihood of success? Yes! But we can’t expect it to be easy.

Deciding to change requires a cost benefit analysis. Many of our vices, whether they be overeating, smoking, gambling, shopping, or watching too much TV, have benefited us in the short term in some way. We may either find some pleasure in our habits, or they may serve to ease our anxiety about our present moment or situation. They may sooth us due to their familiarity, and may feel hopelessly ingrained. We may have received plenty of advice on how to change, and the steps look easy enough, so why haven’t we been able to implement them? Our doctors/therapists/mothers/experts have told us why we need to drop those pesky habits and/or embrace healthy ones. We’ve been told how it will affect our health, and we know that we aren’t doing ourselves any good by continuing with the status quo. So what is holding us back?

According to Hal. Arkowitz and Scott. O. Lilienfeld in the article “Why don’t people change?” in a 2007 issue of Scientific American Mind, there are four major forces that block change. 1.) The status quo feels like home. Its comfortable and familiar. Change is scary and unpredictable. 2.) People are concerned if they fail, they’ll just feel worse. 3.) Faulty beliefs. For example people might consider themselves a failure unless they’ve completely eliminated the problem. Or recommendations to change by family or authoritative figures are taken as an imposition against personal freedom, and thus we rebel. 4.) Our habits may be our best solution for dealing with distress or anxiety.

So with all these mental blocks to changing our habits, its no wonder that many of the tips we are given (ie. portion control, cutting up credit cards, etc), don’t do us much good unless we are ready and committed to change.

In the 1980’s Prochaska and Diclemente developed the Transtheoretical Model of Change, which is also called the Stages of Change model. It is used by therapists and researchers to describe what stage of change we are in. They are: 1.) the precontemplative phase: where we really aren’t interested in changing. 2.) the contemplative phase: a person may recognize at times that the behavior needs to be changed, but they aren’t ready to make the commitment to change. 3.) the preparation phase: a person may have decided to change, perhaps they’ve set a date or made small changes, but they are still not completely committed. 4.) the action phase: the person has made the commitment to change and has achieved abstinence from 1 day to 6 months. 5.) the maintenance phase: a person has changed behavior for 6 months, and is trying to prevent a relapse. Many therapeutic programs assume you are in the action phase and ready to change. But there is now plenty of research showing with a large number of addictive behaviors that if the therapy you receive doesn’t match your stage of change, that your chances of success are substantially lower. And what stage are most of us in? This probably depends on what behavior we are talking about, but its likely that most of us are in the contemplative phase with the more addictive behaviors.

Say there are 2 people who are trying to quit smoking and they’ve been abstinent for 1 or more weeks. But one of them came to the decision quickly because their friend’s father was just diagnosed with lung cancer. The other spent a lot of time weighing the pros and cons of being a non-smoker, gathered information about what it would take, and mentally prepared for any negative consequences of change (like loss of peers for example). Technically speaking, as per Janis & Mann (1977), the first person used a hypervigilant decision making process, was scared into quitting, and was motivated by a high degree of anxiety. The second used a vigilant decision making process, where she approached the decision more calmly and carefully. Research shows that people who’ve used vigilant decision making to reach the action phase are more likely to succeed. And the person who was scared into quitting has a higher chance of falling back into the contemplative phase.

So lets review. In order to successfully quit smoking, gambling, shopping, etc., we need to be in a therapeutic program that matches our stage of change. We are also more likely to succeed if we are well informed about the process, if we have thought carefully about the consequences of change, and if we prepared to address them.

So for those of us who aren’t ready to embrace change or who are good at talking ourselves out of it, there is a form of therapy called motivational interviewing that is worth a try. Motivational Interviewing is based on the concept of “I learn what I believe as I hear myself talk” (Miller, 1995, Miller & Rollnick, 1991). By asking the right questions, a therapist works to help you find your own reasons to change, and helps you think positively about the idea. The therapist needs to never be construed as being pushy or we are more likely to resist. He or she must be compassionate, and most importantly be very patient. It takes awhile to reprogram our thinking, and as we embrace action for change, we may encounter difficulties that bring us back to our original mindset. The therapist needs to help us prepare for what might happen and make sure that we are ready to handle it. And the therapist must help use set challenging and yet reasonable goals throughout the process. Thus motivational interviewing can help us use a vigilant decision making process to decide to change.

Now that we have a better understanding of what’s involved in getting rid of those vices, let’s start with some changes in how we approach our New Years resolutions. For those tough habits, success requires a lot of support. Ideally, we need a cognitive behavioral therapist who will access our readiness to change and determine what stage we are in, and who practices “motivational interviewing” as a part of their treatment. If you don’t have access to a therapist, you can start with the “Readiness the change ruler” by G.L. Zimmerman, C.G. Olsen and M.F. Bostworth in an article entitled “A ‘Stages of Change’ approach to helping patients change behavior”. It helps you determine what stage you are in, and gives you appropriate questions that match each stage of change. Its goal is to give you incentives to keep moving you forward through the process.

Changing those pesky persistent behaviors is no easy ride. It takes a considerable amount of energy to be disciplined, so the better we can relax and nurture ourselves the easier it will be to succeed. So we might consider adding yoga classes or other healthy ways of relaxing to our list of New Years Resolutions. People who succeed in major behavior change often have a great social network of support. So join group therapy, a 12 step program, or set goals with friends and family. And try to stay positive. The mantra “Yes we can” can be changed to “Yes, I can!” Embrace it folks! It could be your ticket to personal change!

References:

Arkowitz, H., Lilienfeld, S.O. Why don’t people change?. Scientific American Mind. June/July 2007: 82-83.

Janis L., Mann L. (1977). Decision making: A psychological analysis of conflict, choice and commitment. New York: Free Press.

Miller, W., (1995) Increasing motivation to change. In R. Heaster & W. Miller (Eds.) Handbook of alcoholism treatment approaches: Effective alternatives (2nd ed., 89-104). Boston: Allyn & Bacon.

Miller, W., Rollnick, S., (1991) Motivational interviewing: Preparing people to change addictive behavior. New York: Guilford.

Prochaska, J. DiClemente, C., Norcross J. (1992) In search of how people change: Application to addictive behaviors. American Psychologist; 47: 1102-1114.

Ryder, D., Deciding to Change: Enhancing Client Motivation to Change Behavior. Behavior Change. Vol 16 (3): 165-174.

Zimmerman, G.L., Olsen C.G., and Bostworth, M.F., A ‘Stages of Change’ approach to helping patients change behavior. American Family Physician 61(5):15; March 1 2000

Can we effect personal change?

For those of us who’ve been watching the news, it’s obvious that change has come to Washington. The most visible sign is that we will soon have a self-described mutt (in his case half black and half white) with immediate family from 3 different continents in the White house! How did it happen? It began with the efforts of one very effective community organizer who inspired many of us to find time in our busy schedules to work for something we believed in. It took thousands of volunteers and tons of time and money. But if we want to change something in our own personal lives, does it take that much effort?

According to this month’s Scientific American Mind article “Set in Our ways”, we are constantly yearning for something new, yet we begin to loose our appetite for novelty after age 30. Why? Well the most likely explanation is that we get bogged down by the responsibilities of life. Substantial change in our lives becomes more difficult as we develop social circles (ie work, family) that we are more interdependent with. The upside is that we become more reliable and agreeable with age.

Because new experiences can bring “chaos and uncertainty”, we become creatures of habit and hold onto what is familiar. According to brain researcher Gerhard Roth at the University of Berlin, habits imbue us with “feelings of pleasure”, and “holding to the tried and true gives us a feeling of security, safety and competence while at the same time reducing our fear of the future and failure”.

A study by Kate C. McLean at the University of Toronto Mississauga found that young people were more profoundly affected by novel experiences than older people. This is in line with research from Brent W. Roberts at the University of Illinois who found that our personalities become increasingly stable till about 60, when they begin to become less stable. Interestingly, it is this time in an adult’s life where children leave home.

Some people are more open to changes than others. Psychologist Richard W. Robins of the University of CA at Davis showed in a longitudinal study that the personality trait “openness”, relative to others, is a life-long trait.

So with societal responsibilities and what appears to be an ingrained desire for stability, how can we overcome this monumental force to induce personal change?

First we need to understand that the older we get, the harder it will be to change. Second, our self-efficacy, our belief in our power to achieve a goal matters. If our self-efficacy is too high, we are more vulnerable to “false hope syndrome”, where we may fail due to overblown expectations. We may launch forward without fully appreciating the challenges we face, and thus we may fail to educate ourselves about the best way to achieve our goals. In the case of trying to change a bad habit, we need to realize that we might rebel if are feeling deprived, and that our body may be more willing to accept small and gradual changes. We also need to recognize that our brains have been wired or programmed for a long time to engage in a particular habit, and that it takes time and persistence to change that wiring. Setting more realistic goals maybe the key to success. If our self-efficacy is too low, we may be easily discouraged, and become resigned to a belief that change is out of our control. Thus for effective personal change, perhaps the first thing we should work on is self-efficacy, which can be influenced by our social interactions, having appropriate models for change, our experiences and our perceptions of our physiological responses.

There is much research that looks at factors required to influence personal behaviors, habits and addictions. Stay tune for more details in future blogs. Meanwhile, returning to the question of whether personal change takes a monumental amount of time, people and money as it did to change our leadership: I believe for our most ingrained habits, it does. But I also believe if we begin by working on our self-efficacy, as Obama did with the mantra “Yes we can”, that we are off to the right start!