Galantamine’s Antidementia Action Expands

Galantamine Helps Clear the Fog

Galantamine’s Antidementia
Action Expands—Sort Of

Its impressive versatility is now seen to encompass Lewy body dementia
By Will Block


f that title seems confusing, you’re not alone. Neuroscientists are a bit confused too, regarding the various types of dementia: how to define them, how to diagnose them, and how to treat them. One of the biggest problems with dementia, from a doctor’s point of view, is that a definitive diagnosis is usually impossible except by microscopic examination of the patient’s brain tissue—and even demented patients are reluctant to have their heads cut open so someone can poke around inside.

So the definitive diagnosis must wait until autopsy. At that point, researchers can backtrack through the patient’s medical history and try to correlate the recorded symptoms of dementia with the neuropathological findings. As more and more correlations are compared and contrasted over time, the profiles for the different types of dementia gradually become sharper, and symptom-based diagnoses become more reliable. That’s important, of course, because the more accurate the diagnosis, the better able the doctor is to choose the best treatment.

Lewy Body Dementia Is Common, but Rare

Through this painstaking process, scientists have recently come to the conclusion that a formerly obscure type of dementia, known as Lewy body dementia, is far more prevalent than had been thought.1* Lewy body dementia (LBD) is now regarded, in fact, as the second most common type of dementia, after Alzheimer’s disease. Although reliable data are hard to come by, it seems that Alzheimer’s accounts for about 60–70% of all dementia cases, and LBD accounts for about 10–20%. Vascular dementia (the former #2) comes next, followed by numerous dementias associated with various diseases, such as Parkinson’s disease, Huntington’s chorea, AIDS, Pick’s disease, and Creutzfeldt-Jakob disease.


*Lewy body dementia is also often called dementia with Lewy bodies, diffuse Lewy body disease, cortical Lewy body disease, or senile dementia of Lewy type. By whatever name, it’s a dreadful disease.


Complicating the picture is the fact that LBD is similar to Alzheimer’s disease in some respects, and it is also similar to the dementia associated with Parkinson’s disease (Parkinson’s is not itself a dementia, but most of its victims do eventually become demented). Pure Lewy body dementia is actually quite rare, because most cases are associated to some degree with concomitant Alzheimer’s or Parkinson’s pathology. All Parkinson’s patients have Lewy bodies, and so do up to 40% of Alzheimer’s patients. (The sidebars explain what Lewy bodies and Lewy body dementia are.)

What the Heck Is a Lewy Body?

Are you sitting down? OK, here goes: a Lewy body is a rounded eosinophilic intracytoplasmic neuronal inclusion. Perhaps some rock band would like to adopt that as its name. Or not. Although those words are English, let’s translate them from jargon to plain talk, taking them in reverse order.

In science, an inclusion is a small mass of some substance that’s embedded within a larger mass, like a raisin in a bun. In this case, the larger mass is a neuron (brain cell), hence the term neuronal. That the inclusions are intracytoplasmic means that they’re within the neurons’ cytoplasm—the complex, semifluid, translucent substance that constitutes the entire living interior of the cell except for the nucleus.


Eosin-stained Lewy body in a neuron of the cerebral cortex from a patient with Lewy body disease.
Eosinophilic refers to the fact that Lewy bodies can be stained with a red dye called eosin. Staining is a common laboratory technique in biology to enable certain kinds of microorganisms, cells, or components of cells to be visibly differentiated from their surroundings (when they selectively absorb the stain). This also provides some information about their composition, based on which stains will or will not work for a given type of object. (Eosin, by the way, is also used in textile dyeing and ink manufacturing and in coloring gasoline.)

Finally, there is rounded, a technical term meaning, uh, kind of round. So—a Lewy body is kind of a round thingy that’s embedded in the goopy interior of a brain cell and that can be stained red. (Wasn’t that easy?) But what does it consist of? Proteins, mostly—especially a protein called alpha-synuclein, whose function is unknown.

Besides Lewy body dementia, Lewy bodies are present in a number of other neurological diseases—most notably Parkinson’s. They were first described in 1912 by the distinguished German-American neurologist Friedrich Lewy, who, early in his career, worked in the laboratory of Alois Alzheimer, along with Hans Creutzfeldt and Alfons Jakob, the discoverers of the human version of mad cow disease that now bears their names: Creutzfeldt-Jakob disease. What a collection of brainy brain scientists under one roof!

What Is Lewy Body Dementia?

Lewy body dementia (LBD) is a severe form of dementia, of unknown origin, that is associated with the presence of Lewy bodies in certain regions of the brain, including the cortex. It is an incurable disease of late middle age and old age (its age of onset is usually after 60 but can be as low as 40, which is much younger than with Alzheimer’s or Parkinson’s), and it is slightly more common in men than women. It is relentless in destroying brain function and is more rapidly fatal (about 7 years, on average) than Alzheimer’s disease, to which it is similar in terms of cognitive deficits and behavioral abnormalities. Often, but not always, the patient’s initial complaint is memory impairment or depression.

Unlike Alzheimer’s, however, in which the mental decline is steady, LBD is characterized (for reasons unknown) by striking fluctuations in cognitive function on a day-to-day basis, at least in the early stages of the disease. This is especially true with regard to attention and alertness. Thus the patients have alternating good days and bad days, a feature that is one of the three major hallmarks of the disease.

The second hallmark is detailed visual hallucinations (usually pleasant ones), which often occur early in the development of the disease. These may be accompanied by disturbances such as paranoia and delusions (usually unpleasant ones), which are uncharacteristic of Alzheimer’s but which do occur with Parkinson’s disease dementia.

The third hallmark is the occurrence, usually in the later stages of the disease, of Parkinson-like motor disturbances, notably muscular rigidity and impaired mobility and balance. Lewy bodies are classically associated with Parkinson’s disease (for which they are a diagnostic feature), but their distribution throughout the brain is not the same in the two diseases.

There are no specific diagnostic tests for LBD, but any one of these three hallmarks is sufficient for a possible diagnosis, and any two are sufficient for a probable diagnosis. Features that would support such a diagnosis include frequent falls, fainting spells, motor disturbances during REM (rapid eye movement) sleep, and hypersensitivity to conventional antipsychotic drugs.

From the above, it sounds as though a diagnosis of LBD shouldn’t be too difficult. It often is, however, because the spectrum and severity of the symptoms can vary widely, and the patient may be suffering from more than one type of dementia concurrently. Thus the potential for diagnostic confusion is great. Treatment can be difficult, because some of the drugs used against certain symptoms can make other symptoms worse—sometimes much worse, as in fatal.

The ultimate proof of LBD—the presence of Lewy bodies in the brain—can be confirmed only at autopsy, which reveals both similarities and differences between LBD brains and the brains of Alzheimer’s or Parkinson’s patients. Typically, the regions in which LBD brain tissue was shrunk or destroyed are different from those of Alzheimer’s brains, but the damage in LBD brains is similar to that in brains from victims of Parkinson’s disease dementia (PDD).

Furthermore, anyone who has Alzheimer’s, Parkinson’s, or LBD can also have vascular dementia, which makes the diagnosis that much more difficult and the best treatment that much less certain. And vascular dementia, although its origins in deterioration within the cerebrovascular system are pretty clear, can also manifest some of the neuropathological symptoms of Alzheimer’s disease. All in all, the word confounding hardly does justice to this situation, especially when one considers that the psychological attributes upon which a specific diagnosis of dementia must be made are largely subjective to begin with.

Galantamine Has Been Treating LBD All Along

Lest we give up in despair, however, let’s hear some good news. It’s about galantamine, a natural nutritional supplement that has already proved itself as a remarkably effective anti-Alzheimer’s agent and that appears to be effective against vascular dementia and Parkinson’s disease dementia (PDD) as well.* It now appears that galantamine is also effective against Lewy body dementia. This is not too surprising, though, considering that LBD seems to embody elements of both Alzheimer’s and PDD.


*Of the many articles on galantamine previously published in Life Enhancement, see, e.g., “Galantamine Improves Both Alzheimer’s and Vascular Dementia” (July 2002) and “Galantamine Helps in Parkinson’s Disease with Dementia” (December 2003).


Perhaps the evidence of galantamine’s efficacy against LBD (see below) suggests not so much an expansion of its role in combating dementia as a confirmation of its versatility in treating different types of dementia (hence the “Sort Of” in the title of this article). Although LBD has only recently been recognized as a distinct disease,2 it has, of course, been out there all along, often misdiagnosed as either Alzheimer’s or PDD. It’s likely, therefore, that some of the “Alzheimer’s” or “PDD” patients included in clinical trials of galantamine were actually LBD patients—or that they were “hybrids” suffering simultaneously from different types of dementia.

In any case, the fact that galantamine is a potent booster of acetylcholine function—the primary therapeutic approach to Alzheimer’s disease—makes it a prime candidate for treating LBD, a disease in which deficits in acetylcholine function are even greater than they are in Alzheimer’s. The advantage that galantamine holds over other anti-Alzheimer’s agents lies in its unique dual mode of action as (1) an acetylcholinesterase inhibitor and (2) a modulator of nicotinic acetylcholine receptors in the brain. It is the latter mode—which the other agents do not possess—that gives galantamine its exceptional versatility in combating dementias. And not just in the short term (months), like the other agents, but in the longer term (years).

First Galantamine Trial on LBD

Researchers from half a dozen American medical institutions have collaborated on a study to evaluate the safety and efficacy of galantamine in patients with mild to moderate LBD.3 A 12-week interim analysis of their 24-week study has just been published, with encouraging results. The study was open-label (not placebo-controlled or blinded) and involved 25 patients diagnosed with probable LBD who did not have signs of any other type of dementia. The patients were 69 to 90 years old except for one who was 50; there were 17 males and 8 females.

The treatment consisted of galantamine taken orally twice daily, in doses of 8 mg/day for the first 4 weeks, then 16 mg/day for the next 4 weeks, then 24 mg/day for the duration of the study. At baseline and again after 12 weeks, the patients were given a wide variety of tests or interviews (with their caregivers) covering three broad areas of concern: (1) cognitive function, such as memory, attention, reaction time, and visual-spatial tasks; (2) behavior, including such things as delusions, hallucinations, apathy, and depression; and (3) global functioning, including Parkinsonism features and the ability to perform routine daily tasks.

Attention! The Results Are Promising

Overall, the interim results showed distinct improvements in all three categories of evaluation. Among the most striking effects were those seen in fluctuations in attention. Attention is known to depend strongly on cholinergic (acetylcholine-based) function in the brain and, in particular, to depend on those nicotinic receptors we mentioned above. That puts it right up galantamine’s alley, so to speak. And because fluctuation in attention is one of the core features of LBD, the improvement observed implies that galantamine may have a beneficial effect on the mechanism of the disease, not just its symptoms.

The authors reported that galantamine was generally well tolerated by the patients. We will discuss the results of this study in greater detail when they are published in final form (the full 24-week study). Meanwhile, it’s good to know that galantamine’s star continues to shine, bringing some much-needed light into the dark and confusing world of dementia. And for those who wish devoutly never to enter that world, galantamine may be a prudent choice in nutritional supplements.

References

  1. Kaufer DI. Pharmacologic treatment expectations in the management of dementia with Lewy bodies. Dement Geriatr Cogn Disord 2004;17(Suppl 1): 32-9.
  2. McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996;47:1113-24.
  3. Edwards KR, Hershey L, Wray L, Bednarczyk EM, Lichter D, Farlow M, Johnson S. Efficacy and safety of galantamine in patients with dementia with Lewy bodies: a 12-week interim analysis. Dement Geriatr Cogn Disord 2004; 17(Suppl 1):40-8.

Dual-Action Galantamine

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.

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