Galantamine Broadens Its Horizons
Memory in MCI
Just as we thought, it helps patients with mild
cognitive impairment, a precursor to Alzheimer’s
By Will Block
t has been said that chance favors the prepared mind. In the same vein, it could be said that going out on a limb favors those who have a good feel for limbs. The last thing you want to hear when you’re out there is an ominous cracking sound behind you—but that’s not likely if the limb is as sound (pardon the pun) as you thought it was. What you really want is for a tree surgeon to come by and tell you, “The limb is strong—you were safe all along.”
In a manner of speaking, that is what occurred recently at Life Enhancement Products. For the past few years, we had been speculating—quite reasonably, in our view—that the natural plant alkaloid galantamine, whose efficacy in treating mild to moderate Alzheimer’s disease has been thoroughly proved, would also be useful in treating and perhaps helping to prevent mild cognitive impairment (MCI), the age-related condition that usually leads to Alzheimer’s disease.* The problem was that there was no actual clinical evidence to support this view, because no studies on the use of galantamine for treating MCI had been undertaken. So we were out on a limb—but we had little doubt that the limb was stout.
Two Birds for the Price of One
Still, we kept hoping that a “tree surgeon” would show up and confirm what we believed. Just in time for Christmas, he did. “He” was actually a multidisciplinary team of researchers at the VU University Medical Center in Amsterdam, the Netherlands, in collaboration with a colleague at Johnson & Johnson Pharmaceutical Research and Development in New Jersey. They published a paper in the journal NeuroImage detailing a study demonstrating that galantamine is effective against MCI, i.e., that our conceptual limb was indeed strong.
Paradoxically, however, demonstrating galantamine’s efficacy was not the purpose of their study. On the contrary, they simply assumed that galantamine was effective against MCI, as we had done, and they used that premise as the basis for demonstrating something else, namely, that a certain high-tech imaging technique is useful for detecting the brain’s response to the administration of memory-enhancing agents in elderly patients with MCI. Since their assumption about galantamine appears to have been correct, one might say that they killed two birds with one stone—or, to put it in a nicer way, they fed two birds with one seed.
Figure 1. fMRI images (in pairs) of a human brain engaged in mental tasks. The ADG column depicts baseline condition (no galantamine); the BEH column depicts single-dose galantamine; the CFI column depicts steady-state galantamine (see text for further details). Top row: episodic memory task (face recognition)—no significant galantamine effect. Middle row: low-level working memory task (letter sequences)—no significant galantamine effect. Bottom row: higher-level working memory task (letter sequences)—significant galantamine effect at steady state (I) but not single dose (H). From Ref. 1.
What Does a Working Brain Look Like?
The imaging technique in question is functional magnetic resonance imaging, or fMRI (see the sidebar regarding this and other brain-scan techniques). It enables researchers not just to “see” inside the brain but also to observe certain types of brain activity in real time (i.e., while they’re occurring). Evidence of the activity in question is revealed in the guise of characteristic colors in the images; the colors are not real, of course, but artifacts designed to reflect different levels of signal strength in the scanner’s output (see Figure 1). In this way, the researchers can sometimes tell whether or not (and where) a certain chemical agent, such as a drug or nutrient, is having the desired effect. In automotive terms, it’s like enabling a diagnostic technician to look inside the cylinders of an engine while it’s running and see the effects of a particular fuel additive on the power cycle.
Better Than X-Ray Vision
Magnetic resonance imaging (MRI) is a noninvasive technique that has greatly improved medical diagnostic practice by providing amazingly detailed images of virtually all the internal organs of the body. It is especially useful for looking inside structures that are surrounded by bone, notably the brain and spinal cord. Functional MRI (fMRI) goes standard MRI one better by revealing vital information about metabolism, i.e., how a particular organ or part of an organ is functioning while the scan is being conducted.
Unknown to most patients is that “magnetic resonance imaging” is a euphemism coined for the benefit of those who are easily (and irrationally) frightened by the word nuclear. Based on Nobel Prize-winning discoveries by nuclear physicists in the 1940s, the technique was originally called nuclear magnetic resonance (NMR), a name that better reflects its actual scientific roots. It is still called NMR by chemists and physicists, who have been using it for half a century in the laboratory to study the structures and interactions of molecules.
Three advantages of MRI over computerized tomography (CT) are: (1) MRI uses diagnostic radiation that is harmless (a radio-frequency field coupled with a strong magnetic field) rather than x-rays, which can damage the tissues they penetrate; (2) MRI can “see” soft tissues more clearly than CT can; and (3) MRI can distinguish between healthy and diseased tissues better than CT can. Nonetheless, CT is still a valuable imaging technique, as are various others, each of which has special strengths.
A useful variant of CT is electron beam computed tomography (EBCT), in which, yes, electron beams are used instead of x-rays. (For an example of the use of EBCT in heart disease, see
“Is There Too Much Calcium in Your Arteries?” in the November 2004 issue.)
Another powerful modern imaging technique is positron emission tomography (PET), in which a radioactive compound with an affinity for a particular part of the body—usually the brain or heart—is injected into the bloodstream. As the radioactive atoms in the compound decay, they emit subatomic particles called positrons (positively charged electrons), whose interactions with other particles release gamma radiation. This radiation is recorded to build up an image of the part of the body in question.
A landmark in neurological research is the recent development of a radioactive imaging compound (a type of dye) that will selectively attach itself to the gunky, proteinaceous deposits called amyloid plaques in the brains of Alzheimer’s victims. This makes the plaques visible via a PET scan of the living patient, whereas previously the only way to see the plaques was at autopsy.
When the new technique, which is still in the research stage, enters clinical practice several years from now (assuming that all goes well in the necessary clinical trials and the regulatory maze), it will enable doctors, for the first time, to obtain hard evidence of this type of brain damage in Alzheimer’s disease relatively early in the game and to monitor the efficacy of whatever treatment is prescribed. Stay tuned.
- Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 2004;55:306-19.
With any significant level of cognitive impairment—whether in MCI or in any type of dementia, such as Alzheimer’s disease—researchers (and, of course, doctors) want to know, as early as possible, how the brain is responding to a given therapeutic agent, because this will help them decide whether it makes sense to continue using that agent. Ideally, they want to be able to use brain imaging to detect early evidence of cognitive impairment, so that they will have an objective basis for prescribing preventive or therapeutic agents much sooner than they do now. As is always true in medicine, the earlier the better.
Alzheimer’s and MCI Have Cholinergic Dysfunction in Common
The principal neurological hallmark of Alzheimer’s disease is a severe deficit in cholinergic function, i.e., those aspects of brain activity that depend on the neurotransmitter acetylcholine. Since acetylcholine levels are low in Alzheimer’s, the main therapeutic objective is to raise them. Galantamine does this (usually at dosages of from 16 to 32 mg/day) by inhibiting the action of the enzyme acetylcholinesterase, which destroys acetylcholine molecules. In addition—and unlike other anti-Alzheimer’s agents—galantamine boosts the activity of acetylcholine by beneficially modulating the function of the brain’s nicotinic acetylcholine receptors.
It’s reasonable to think that cholinergic dysfunction (probably of a less severe degree than in Alzheimer’s) underlies the Alzheimer’s precursor disease, mild cognitive impairment, and evidence supporting this belief has recently been published. Based on that work, and making the reasonable assumption that galantamine should be effective against MCI too, the Dutch researchers used the fMRI technique to scan the brains of 28 otherwise healthy elderly MCI patients, aged 54 to 89 (average 74), to see whether fMRI would be useful for evaluating the therapeutic efficacy of pharmacological agents.
When the brain images were obtained
and the data were analyzed, it was
seen that galantamine had resulted in
a significant increase in brain
activation in certain regions.
For each patient, the scans were done under three test conditions, at 1-week intervals: (1) at baseline (no galantamine); (2) 3 hours after a single oral dose of 8 mg of galantamine; and (3) after a steady-state regimen of galantamine (8 mg/day) for 5 days, with this last test timed so that the patient’s plasma level of galantamine would be roughly the same as it was in test #2. The actual sequence of these tests was randomized to prevent bias from interfering with the possible effects of the galantamine.
Galantamine Produced Significant Brain Activation . . .
To make the fMRI functional, as the acronym stipulates, the scans were conducted while the patients’ brains were engaged in specific mental functions. In this case, they were performing various tasks that enabled the researchers to measure aspects of episodic memory and working memory—which, to an appreciable degree, involve different parts of the brain. Thus the researchers would be able to correlate the effects of galantamine with different brain structures and their associated memory systems under different functional circumstances.
When all the brain images were obtained and the data were analyzed (a complex task requiring great sophistication in the use of advanced statistical methods), two things seemed clear: (1) fMRI is indeed a viable technique for detecting cholinergic dysfunction in elderly patients with MCI, and (2) galantamine resulted in a significant increase in brain activation in certain regions of the brain after the steady-state regimen (but not after the single dose).* According to the authors, however, this does not mean that the single dose had no effect on brain activation, but only that “A longer period of exposure [to galantamine] may have provided more time for synaptic rearrangement of task-related networks, resulting in more activation when these networks were stimulated.”
. . . Despite the Low Dosage
The actual observed changes in brain activation after galantamine administration were “small in number, extent, and intensity,” according to the authors. They suggested a number of possible reasons for this, but they omitted one that might have been important: the low dosage of only 8 mg/day, which is generally ineffective, at least in the treatment of mild to moderate Alzheimer’s disease. Nonetheless, measurable benefits from galantamine administration were observed in the test of working memory, which involved random letter sequences. (There was no evidence of an effect of galantamine on episodic memory, involving a face-recognition task.)
In reference to the test of working memory, the authors went on to say,
Task performance data showed a highly significant effect of galantamine treatment on task accuracy scores … and a significant decrease in reaction times … indicating a clear effect of galantamine intake on neural function associated with this task.
Galantamine May Help Keep MCI at Bay
Although it’s gratifying to have been correct when we went out on that limb a few years ago, what’s really important is that we can now be quite sure that the realm of cognitive impairment in which galantamine is beneficial includes MCI. At least 4 million Americans already have Alzheimer’s disease, and experts estimate that the incidence of MCI, which is a fast track to Alzheimer’s, is about four times as great (with most cases going undiagnosed). These numbers are expected to increase dramatically in the coming years unless we employ effective interventions.
We can now be quite sure that the
realm of cognitive impairment in
which galantamine is beneficial
We can’t do anything to stop the number one risk factor for Alzheimer’s—age—but we can surely improve our diet, get more exercise, avoid smoking, and keep our minds busy with healthy challenges, such as reading, playing games, and doing puzzles. If all those things help keep Alzheimer’s at bay regardless of how old we get, they probably do so by first keeping MCI at bay. And another good way to do that, it seems, is by taking galantamine. As time goes by, we expect to see more confirming evidence supporting this belief, and we will report on it as it comes.
- Goekoop R, Rombouts SARB, Jonker C, Hibbel A, Knol DL, Truyen L, Barkhof F, Scheltens P. Challenging the cholinergic system in mild cognitive impairment: a pharmacological fMRI study. NeuroImage 2004;23:1450-9.
- DeKosky ST, Ikonomovic MD, Styren SD, Beckett L, Wisniewski S, Bennett DA, Cochran EJ, Kordower JH, Mufson EJ. Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann Neurol 2002;51:145-55.
- Loy C, Schneider L. Galantamine for Alzheimer’s disease (Cochrane Review). In: The Cochrane Library, Issue 4, 2004. John Wiley & Sons, Chichester, UK.
- DeCarli C. Mild cognitive impairment: prevalence, prognosis, aetiology, and treatment. Lancet Neurol 2003;2:15-21.
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.
Will Block is the publisher and editorial director of Life Enhancement magazine.