Scope of Galantamine's Benefits Widens
Attention in Alzheimer's
Assessments by physicians, caregivers, and
patients themselves point to consistent benefits
By Will Block
ay attention! Remember that? When we were children, it was often hard to stay focused on the task at hand, whether it was listening to a teacher droning on about some subject of no earthly interest or to an exasperated parent lecturing on the evils of whatever we had just done, or were about to do next. Paying attention was not one of our strong points. Our minds tended to wander—to the Arabian Nights, to the Wild West, to fairytale castles, to the moon and stars, to worlds unimagined by stuffy old grownups. In childhood, we were unencumbered by much knowledge of the real world, and our imaginations were free to soar. Wasn't it wonderful?
Sad to say, 12 or more years of schooling, not to mention real-life experiences, can pretty much beat that otherworldly imagination out of most kids, paving the way toward responsible adulthood and its typical afflictions: taxes and mortgages, traffic jams and telemarketers, lawyers and politicians, etc. But at least they learned to pay attention, because to get by in the real world, that's a must. Whether it's holding down a job, holding up a bank, or holding a marriage together, focus matters—success depends on our ability to keep our attention on the task at hand.
Are You Still Reading?
So we soldier on through life, paying attention to the thousand and one things that are important to us while cherishing the memories of the good times and anticipating those yet to come. As the great arc of life turns downward, however, the minds of some people begin to wander again—but not, alas, in the exuberant ways of their childhood. Instead of having exciting adventures in a bright and shining city on a hill, they stumble aimlessly through a fog of confusion, not sure what they were doing only moments ago, or why they were doing it.
It begins with little things: losing track of where you were in a conversation, perhaps, or of what line you were supposed to go back to on Form 1040. But it gets worse: getting sidetracked while dinner is cooking—then burning—on the stove, or driving the wrong way on a one-way street.
We're talking, of course, about Alzheimer's disease, and dementia in general. The hallmark symptom of Alzheimer's is loss of memory function, but that's not the same as loss of attention. The latter undermines people's ability to react appropriately to their surroundings and to interact meaningfully with those around them. It also impairs their ability to manage the ordinary activities of daily living and to perform attention-demanding skills, such as following a recipe or driving a car.
Does Galantamine Help with Attention?
Naturally, scientists want to stop Alzheimer's in its tracks. Although that is not yet possible, the disease's progress can be slowed down by means of various agents, of which perhaps the most effective is galantamine, an alkaloid extracted from certain flowers. Galantamine is sold as the prescription drug Razadyne™ (formerly Reminyl), but it has a long history of use as—and is still available as—a nutritional supplement. That is something to be grateful for.
Numerous studies have demonstrated galantamine's positive effects on four factors of particular relevance to patients with Alzheimer's disease: cognitive function (including, of course, memory), behavior, activities of daily living, and global condition (an overall assessment of the patient's state of well-being, made by the physician, by the caregiver, or, in some cases, by the patient). Notably absent from these studies—except, in a few cases, as a secondary outcome of the study—was attention, the ability to stay focused on a task or activity.
European Researchers Focus on the Problem
That omission has now been rectified, in a large-scale study in which the primary outcomes of interest were galantamine's effect on attention and the effects that such changes would have on caregivers. A team of researchers from France, Portugal, Germany, Belgium, and the United Kingdom conducted galantamine trials on 373 Alzheimer's patients at 67 centers in seven European countries. All of the elderly patients (average age 75 at baseline; 62% of them were women) had been diagnosed with mild to moderate Alzheimer's. All were community-dwelling, i.e., not institutionalized.
The average age of the caregivers was 59; 94% of these individuals were partners or relatives of the patient, and 66% of them lived with the patient. As with memory loss or the other functional deficits associated with Alzheimer's, loss of attention may diminish the patient's ability to live independently and may therefore add significantly to the caregiver's burden. This burden can become overwhelming, with major negative impacts on health and lifespan (see
"Galantamine Eases the Burden on Alzheimer's Caregivers" in the July 2004 issue).
For 12 weeks, all the patients received galantamine twice daily, with breakfast and dinner. The regimen began with 8 mg/day for the first 4 weeks, followed by 16 mg/day for the next 4 weeks. At that point, each patient's physician decided whether to keep the daily dosage at 16 mg for the last 4 weeks or increase it to 24 mg (the latter amount is the one most widely recommended for general use). The great majority of patients were taking psychotropic medications, including antidepressants and antipsychotics but not antidementia drugs.
Improvements with Galantamine Were Seen Consistently . . .
The researchers decided to evaluate the patients both objectively, via simple computerized tests of attention, and subjectively, based on assessments of the patients' condition by physicians, caregivers, and the patients themselves. Either of these approaches could have been used alone, but it's preferable to use different approaches and see if the results are in substantial agreement. If they are, it gives the study that much more credibility; if they're not, it's back to the old drawing board.
In this case, the objective and subjective evaluations were in accord, and the various types of subjective evaluations were remarkably similar. Lets summarize the results:
- The scores on an objective test called Choice Reaction Time, which measures the speed and accuracy of responses to visual stimuli on a computer screen, improved steadily over the 12-week period. By the end of that period, the average reaction time had decreased by 6.4%. The accuracy scores improved by 1.1% (which isn't much, but the result was deemed statistically significant).
- In terms of global (overall) condition, the physicians rated 67% of the patients as improved, 28% as unchanged, and 5% as worse. The caregivers' ratings, based on standardized questionnaires, were similar: 57% improved, 37% unchanged, and 6% worse.
. . . our findings suggest that, after
3 months of treatment, the patients
who received galantamine were
about 30% closer to being normal for
their age than they would have been
had they remained untreated.
- In terms of attention, the caregivers' impressions were the same as their ratings of global condition: 57% improved, 37% unchanged, and 6% worse.
- According to the caregivers, the ability of their patients to interact well with them and with others was improved in 51% of cases, unchanged in 44%, and worse in 5%.
- According to the patients themselves, their global condition was improved in 62% of cases, unchanged in 36%, and worse in 2%.
- The reported levels of stress involved in caring for their patients improved for 34% of the caregivers, remained unchanged for 57%, and worsened for 9%. The total amount of time spent caring for their patients daily was reduced by an average of one-quarter of an hour.
. . . And Were Deemed Meaningful
The study was open-label, i.e., not placebo-controlled. This was an obvious weakness, as the authors admitted, but they pointed out that previous studies with galantamine had not shown a marked placebo effect at 3 months. They stated,
The similar patterns of improvement observed in the objective computer test results and the impressions of clinicians, caregivers, and patients suggest that the detected improvements in attention were meaningful. These findings were also consistent across several different countries in which caregivers and doctors may have different traditions and, therefore, different expectations. . . . our findings suggest that, after 3 months of treatment, the patients who received galantamine were about 30% closer to being normal for their age than they would have been had they remained untreated.
If you've read this far, you must have been, well, paying attention. Thank you for that, and congratulations on your ability to do so. It may sound odd to be congratulated for something you've taken for granted all your life, but now you know that attention, like memory and countless other aspects of health and well-being, should not be taken for granted. Everything that is precious is capable of being lost, so we must safeguard it as best we can. In the supplements arena, galantamine stands tall as a guardian of the very thing that enables us to understand that: our brain.
- Vellas B, Cunha L, Gertz H-J, De Deyn PP, Wesnes K, Hammond G, Schwalen S, on behalf of the GAL-INT-28 Study Group. Early onset effects of galantamine treatment on attention in patients with Alzheimer's disease. Curr Med Res Opin 2005;21(9):1423-9.
Galantamine Helps in Schizophrenia-Like Psychosis
Although schizophrenia is very different from dementia, the two have some things in common. Patients with one type of disorder sometimes show symptoms of the other, which can make both the diagnosis and the therapy somewhat tricky. The usual treatment for schizophrenia is with antipsychotic drugs, but it has been found that some patients are also helped by procholinergic agents. Procholinergic means enhancing cholinergic function, and that is what galantamine does for patients with Alzheimer's, a disease of cholinergic dysfunction.
Last year in this magazine, we saw a review of scientific evidence for the potential role of galantamine in schizophrenia ("Galantamine May Help in Schizophrenia," October 2004). Earlier we had seen two case histories of men whose schizophrenia was dramatically improved when galantamine was added to their treatment with the antipsychotic drug risperidone, which was not working very well (see the sidebar
Can Galantamine Help in Schizophrenia? in the article "Remember Galantamine? (How Could You Forget?)" in the September 2002 issue).
A new report describes the case of a young woman from Cameroon who was committed to a psychiatric hospital in France after she stabbed her boyfriend in the stomach as he slept. Eight years earlier, at age 20, she had suffered severe brain injury when she was hit by a bus in Paris. This resulted in cognitive deficits and behavioral disturbances that disrupted her previously successful social and professional life. After the stabbing incident, she was diagnosed with schizophrenia-like psychosis and was treated with risperidone.
It did not work well. The patient had a host of problems, including apathy, asociality, memory impairment, and persecutory delusions. After 3 weeks, galantamine (8 mg/day) was added to her treatment, and for the next 5 weeks she improved noticeably. Then the galantamine was withdrawn because of side effects (gas and heartburn), and for the next 4 weeks, her condition deteriorated again: she became aggressive and slovenly, and her persecutory delusions increased. Finally, galantamine therapy was resumed (with no further side effects), and her condition again improved and became relatively stable. She remained on risperidone throughout.
- Bennouna M, Greene VB, Defranoux L. Adjuvant galantamine to risperidone improves negative and cognitive symptoms in a patient presenting with schizophrenia-like psychosis after traumatic brain injury. J Clin Psychopharmacol 2005;25(5):505-7.
Amyloid Plaque: Another Notch in EGCG's Belt?
Readers of this magazine are well aware that one of the biggest guns in Mother Nature's arsenal of therapeutic compounds is EGCG (epigallocatechin gallate), an antioxidant bioflavonoid found in green tea. EGCG is found to a lesser extent in oolong tea, and to a much lesser extent in black tea, because the fermentation process that takes tea from green to oolong to black destroys it.
EGCG is the most abundant, and the most potent, of a group of related green-tea compounds called catechins (pronounced CAT-eh-kins). In addition to being among the most effective natural anticancer agents known to science (among many other health benefits), EGCG is believed to be the principal reason why green tea helps protect against Alzheimer's disease—in test tubes and laboratory mice, at any rate (see
"Green Tea May Help Prevent Alzheimer's" in the January 2005 issue).
Now comes word from a team of American and Japanese researchers that EGCG inhibits the formation of amyloid-beta, the proteinaceous gunk that constitutes the senile plaques found in the brains of Alzheimer's victims. In this case, the victims were mice that had been genetically engineered to develop an Alzheimer's-like neurodegenerative disease. Daily treatment with EGCG for 2 months reduced the amount of amyloid-beta in their brains by up to 54%.
That's remarkable. Also remarkable—and perplexing—was the finding that various other green tea catechins, with documented health benefits similar to those of EGCG, tended to inhibit the action of EGCG when they were administered along with it. This suggests that EGCG alone, rather than a green tea extract containing EGCG and its catechin cousins, may be preferable for combating amyloid-beta.
Jumping to that conclusion would be a mistake, however, for at least two reasons: (1) these were genetically engineered mice, not natural human beings; and (2) the EGCG was administered not orally but by injection, both intraperitoneally (into the abdominal cavity) and intracerebroventricularly (into the brain's ventricles).
You might wonder why the researchers chose injection rather than oral administration, when the latter would have been much easier and more directly relevant to human health concerns. The answer is simple: they wanted to keep the experiments as biochemically clean as possible by bypassing the messy gastrointestinal tract. This entails a tradeoff, however: although the results can be easier to interpret and the conclusions drawn can be more definitive, the conclusions are less relevant (in the worst case, irrelevant) than if the experiments had simulated real-life conditions.
When a supplement (or any food or drug) is taken orally, all of its components are subject to a rich panoply of metabolic reactions that occur in the GI tract and the liver before it even has a chance of reaching the general circulation, let alone the brain. These metabolic processes can have profound effects on the substances in question, altering their compositions and activities in myriad ways that can be either beneficial or detrimental (sometimes both simultaneously) to human health. Some compounds never make it to the bloodstream at all—only their metabolites do. Thus, the effects that we attribute to a given compound taken orally may actually be due, at the cellular level, to one or more other compounds.
With supplements, the metabolic mishmash is, in any case, usually impossible to predict, because of the complexity of the biochemistry involved and because of our ignorance of much of it. Only clinical trials on actual human beings can tell whether or not a supplement is safe and effective. This is true whether the supplement is taken orally or by any other means.
- Rezai-Zadeh K, Shytle D, Sun N, Mori T, Hou H, Jeanniton D, Ehrhart J, Townsend K, Zeng J, Morgan D, Hardy J, Town T, Tan J. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J Neurosci 2005;25(38):8807-14.
Galantamine provides a heralded dual-mode action for boosting cholinergic function: it inhibits the enzyme acetylcholinesterase, thereby boosting brain levels of acetylcholine, and it modulates the brain's nicotinic receptors so as to maintain their function. The recommended daily serving ranges from a low of 4 to 8 mg of galantamine to begin with to a maximum of 24 mg, depending on the individual's response.
For an added measure of benefit, it is a good idea to take choline, the precursor molecule to acetylcholine, as well as pantothenic acid (vitamin B5), an important cofactor for choline. Thus it is possible to cover all bases in providing the means to enhance the levels and effectiveness of your acetylcholine.
It’s also a good idea to take the following:
- Green tea polyphenols, a class of antioxidants, operating together as a system, that can also fight amyloid-beta toxicity
- Vitamin C and Vitamin E, which have been shown to work together to help protect your brain's hotbeds of free radical activity
- Turmeric curcuminoids, a system of antioxidants that helps protect your neurons from damage or death caused by amyloid-beta
- Folic acid, vitamin B6, and vitamin B12, important vitamins that help prevent damage to mitochondria (where they help repair DNA damage), cofactor the production of nitric oxide, and reduce levels of homocysteine (a neurotoxin)
- Lithium, an important brain food that is found in the bottled waters of American and European health spas ... that also lowers the toxicity of amyloid-beta while causing an increase in neurotrophic factors that help induce neurons to repair themselves when under stress ... that helps cause an increase in gray matter and helps enhance neurogenesis of hippocampal neurons
Will Block is the publisher and editorial director of Life Enhancement magazine.