Bridging the Gap with Galantamine

Galantamine Benefits Both
Alzheimer’s Disease and
Vascular Dementia

Study provides evidence that the two diseases have more
in common than was previously thought
By Will Block

n the building trades, there has always been a friendly rivalry among carpenters, plumbers, electricians, and others regarding whose work is more important or challenging. Carpenters, of course, build the basic structure of a house—its skeleton—without which the others would have nothing to do. Plumbers install the “vascular system” to bring necessary fluids (water and gas) into the house and to eliminate the waste products. And electricians install the “nervous system” to provide the electrical circuits needed for energizing the house’s vital functions.

Even if you’re not in the building trades, it’s easy to imagine how the jokes fly among these groups, each one trying to put the others down. It’s not much different in the medical profession, where rivalries among specialists are as old as the specialties and have spawned many a great doctor joke. Like the one about the dermatologist, the gynecologist, and the psychiatrist . . . oh, you’ve heard that one, you say? OK, then let’s move on.

Plumbers vs. Electricians—An Affair of the Heart

All jokes aside (darn it), such rivalries often underlie profoundly important differences in approach to medical problems, such as the origin and nature of degenerative heart disease. Over the past century, there have been two major schools of thought among research cardiologists, and it’s worth having a quick look at them to illuminate the theme of this article, which is about dementia.

One school—the “plumbers,” who dominate in the United States—holds that the problems are largely vascular in nature, having to do primarily with hemodynamics (blood circulation) and its impairment via hypertension and atherosclerosis. Heart attacks, in this scenario, are caused by obstructions in the coronary arteries: they interrupt the blood flow to a portion of the heart tissue, killing it (and, often, its owner).

The other school—the “electricians,” who prevail in Europe—holds that the problems are largely of neuroendocrine origin, i.e., they involve the damage done when the functional relationships between the nervous system (which is governed by electrochemistry) and the endocrine system (which is all about hormonal biochemistry) go awry in various ways. The principal “actors” in this scenario are catecholamines, corticosteroids, and electrolytes, whose dysfunctional interplay causes many heart attacks that involve no obstructions at all.

Great Contributions from Both Schools

Naturally, the dichotomy described above is an oversimplification, and there is considerable overlap between the two schools of thought, both of which have made great contributions to our understanding of heart disease. But the schism is real and is, alas, an impediment to more rapid progress in combating heart disease.

We’re all familiar with the plumbers’ approach, not just because we live in the United States but also because its basic principles are easy to understand, even for laymen. It’s unfortunate that the principles of the electricians’ approach, which is the more fundamental of the two, are complex and difficult to understand, even for scientists; it’s no wonder that laymen hear virtually nothing about that school of thought.

Dementia Requires Different Approaches

A situation that’s curiously similar, yet also appreciably different, exists in the field of dementia research, where the different types of disease require different approaches—up to a point, as we’ll soon see. One type of dementia—by far the most common type—is Alzheimer’s disease, which seems to be mainly the result of dysfunctions in the brain’s neural circuitry. Understanding this disease requires high-level “electricians.”

Another dementia, one whose name is a dead giveaway to its origin, is vascular dementia (the third most common type).* It’s caused by dysfunctions of the cerebrovascular system—which is, of course, a part of the overall cardiovascular system. Clearly, understanding this disease requires sophisticated “plumbers.”


*The second most common type is Lewy body dementia (LBD), which is similar to Alzheimer’s and certain other dementias. For more on LBD and why it’s #2, see “Galantamine’s Antidementia Action Expands—Sort Of” in the March 2004 issue.


Confusion: A Tale of Three Hands

The two types of researchers can happily pursue their work without having to take flak from each other, because the diseases in question are so different, right? Of course not—that would be way too easy. In fact, Alzheimer’s disease (AD) and vascular dementia (VaD) have much in common in terms of their physiological mechanisms, their neuropathology, and their behavioral manifestations.

These similarities can obscure the otherwise markedly different characteristics of AD and VaD, and they make it difficult to distinguish between the two—a difficulty compounded by the fact that the diseases often coexist, with overlapping symptoms, in the same patient.

On the other hand, modern diagnostic techniques, including brain imaging and exotic laboratory tests, are making it ever easier to untangle the diagnostic knots and to detect the brain abnormalities while the patient is still alive rather than having to wait for an autopsy.

But on the other hand (OK, that’s three hands, but don’t quibble), the power of these diagnostic techniques has produced evidence indicating that AD and VaD have even more in common than had previously been thought, so it’s becoming harder all over again to draw a clear line between them. Considering that the human brain is the most complex object in the known universe, it’s understandable that almost everything about it is devilishly difficult to understand.

Down with the Traditional View of Alzheimer’s!

Traditionally, AD has been thought of primarily in neurological, not vascular, terms. Its chief hallmarks are the formation of harmful neuritic plaques and neurofibrillary tangles in certain regions of the brain. These pathologies contribute to a gradual deterioration of the brain’s cholinergic system—those neural circuits whose function depends on acetylcholine as the neurotransmitter. The end result is the progressive destruction of cholinergic neurons, leaving holes where brain tissue once was.

Even though Dr. Alzheimer himself, in his famous paper of 1907, discussed the fact that cerebral blood vessels were affected by the disease he was formally introducing to the world, clinicians have long viewed vascular damage as being outside the diagnostic criteria for AD. That situation, however, is changing. In a paper published recently by a group of German researchers, the authors stated,1

Recently, more and more evidence has accumulated supporting the idea that neurovascular dysfunction substantially contributes to cognitive decline and neurodegeneration in AD, thus altering the traditional neurocentric view.

In other words, plumbers as well as electricians are needed to map out the difficult terrain of AD. The evidence for this need has been building for over a decade, and a number of specific mechanisms of vascular involvement in AD have been proposed. These ideas gained additional credence when epidemiological studies indicated that the risk factors for AD and VaD are largely the same; they include poor diet, lack of exercise, diabetes, hypertension, high cholesterol levels, high homocysteine levels, and the presence of a gene, APOE-ε4, that is linked to an increased risk for dementia.

How Are Your Arteries Doing?

Experimental studies have verified that in AD there are, indeed, changes in both the tissue structure and the function of large and small cerebral blood vessels. To add to the growing body of evidence, the German team reported the results of their study, the objective of which was twofold:

  1. To assess (using noninvasive techniques that are too complex to describe here) the vasomotor reactivity of cerebral arteries in “patients with probable AD and patients with possible VaD,” the diagnoses in question being based on standardized criteria. Vasomotor reactivity (VMR) refers to the arteries’ ability to dilate or contract appropriately in response to the brain’s needs, thereby regulating cerebral blood pressure and blood flow to brain tissues.

  2. To assess the effect of the plant alkaloid galantamine on VMR in the cerebral arteries in the tests involved in #1. Galantamine is widely used in the treatment of mild to moderate AD because of its proven beneficial effects on the cholinergic system. It has also been found to be helpful in VaD—an indication that cholinergic dysfunction is an element of VaD as well as AD.

Alzheimer’s Disease Involves Arteries Too

The results for experiment #1 showed that Alzheimer’s disease is associated with severely impaired VMR in the two middle cerebral arteries (and probably in all the rest), confirming the hypothesis that AD has a vascular as well as a neurological component. The degree of impairment was similar, in fact, to that observed in the vascular dementia patients, in whom it was to be expected by the very definition of that disease.

Lest we start suspecting that AD and VaD are actually pretty much the same, it should be noted that measurements of oxygenated hemoglobin levels in the brain’s frontal cortex showed striking differences between the two groups of patients: the levels were normal in AD and severely reduced in VaD. There’s no question that these are different diseases.

Galantamine Improves Arterial Function

To test the hypothesis that the cholinergic deficits (an electrical problem) that characterize AD might be responsible for the impairment of vasomotor reactivity (a plumbing problem), the researchers retested the subjects after giving them galantamine for 5 weeks (8 mg/day for 2 weeks, then 16 mg/day for another 3 weeks). The results showed significant improvement on the VMR of the middle cerebral arteries in all the patients: those with AD and those with VaD.

Overall, the results observed with galantamine provided further support for two propositions regarding the dementias in question: (1) vascular pathology is more important in AD than had previously been thought; and (2) cholinergic dysfunction is more important in VaD than had previously been thought.

Thus, in order to understand better what’s really going on in the labyrinth of neurons and blood vessels that we call the brain, the electricians will need to become better plumbers, and the plumbers will need to become better electricians. Let’s give them all a big hand—with special thanks to galantamine for its role in helping to bridge the gap.

Reference

  1. Bär KJ, Boettger MK, Seidler N, Mentzel HJ, Terborg C, Sauer H. Influence of galantamine on vasomotor reactivity in Alzheimer’s disease and vascular dementia due to cerebral microangiopathy. Stroke 2007;38. Online preprint, doi:10.1161/STROKEAHA.107.492033.

Lithium Can Treat Alzheimer’s Disease

Dementia is a depressing subject, but lithium, it turns out, can lighten the symptoms. Lithium, the lightest of all metals, has been used for half a century in the treatment of depression, particularly the severe kind that occurs in bipolar disorder, aka manic-depressive illness.

In recent years, however, researchers have discovered other beneficial effects of lithium on the central nervous system, especially in terms of neuroprotection (enhancing the survivability of neurons) and the vital process of neurogenesis (the formation of new neurons in the adult brain). Yes, neurogenesis does occur, throughout our entire lives, and its impairment underlies most neurodegenerative diseases, in which there are massive losses of mature neurons.

The evidence for lithium’s benefits has been obtained in laboratory experiments and animal studies and in a few human clinical trials as well.* Much of it suggests that lithium’s benefits are due in large measure to its inhibition of an enzyme, GSK-3 (glycogen synthase kinase-3), that is implicated in the development of the infamous plaques and tangles with which the Alzheimer’s brain becomes clogged. *See “Can Lithium Benefit Brain Health?” (June 2004), “Lithium Promotes the Formation of New Brain Cells” March 2006), and the sidebar “Lithium’s Pharmacologic Bonus” in the article “Galantamine May Lighten Caregivers’ Load” (June 2007).

This evidence and various hypotheses regarding the biochemical mechanisms involved in lithium’s actions were reviewed recently by two researchers at the Indiana University School of Medicine.1 They concluded,

It is highly likely that lithium can achieve good clinical efficacy in treating AD . . . In the authors’ view, the future for effective AD therapies may come from understanding the mechanisms of GSK-3 deregulation in AD patients.

Reference

  1. Zhong J, Lee WH. Lithium: a novel treatment for Alzheimer’s disease? Expert Opin Drug Saf 2007;6(4):375-83.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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