Your Brain with
Improve Myelin Integrity
Thinking outside the box leads neurologist to a
new view of developmental and degenerative brain disorders
By Will Block
Few people think more than two or three times a year;
I have made an international reputation for myself by
thinking once or twice a week.
— George Bernard Shaw
f you asked an electrician to rewire your house with wire that had multiple breaks in its insulation, he would
be . . . shocked. You might as well set your house on fire now and be done with it. But the most complex electrical circuitry in the known universe—the human brain—entails the use of “wires” with broken insulation! How can that be? Are our brains defective and therefore possibly subject to recall by some government agency? (But their recall decision would have to be made with their brains, which would be defective too, so . . .)
We’ll get to that matter of broken insulation. First, however, let’s consider a provocative idea put forth recently by Dr. George Bartzokis, a neurologist at UCLA’s David Geffen School of Medicine, who stepped outside the box to have a fresh look at something important to all of us: our brain function and how it deteriorates with age. The box in question encompasses our thinking about the use of acetylcholinesterase inhibitors (AChEIs) for the treatment of neurodegenerative diseases, particularly Alzheimer’s disease, the greatest scourge of them all.
Bartzokis believes that the indisputable benefits of AChEIs may be due in large measure to something other than what we’ve thought all along. To put his view into perspective, let’s have a quick look inside the box he broke out of. It’s not that there’s anything wrong in there—there certainly isn’t, as he’s quick to point out—but rather that the box is too small to encompass the larger picture he sees.
Cholinergic Function—Key to Cognition
Our learning, memory, and other cognitive functions depend critically on the actions of the neurotransmitter acetylcholine (ACh), which facilitates the propagation of neural signals (nerve impulses) across the synapses (gaps) between neurons in certain regions of the brain. Brain activity that depends on ACh as the neurotransmitter is called cholinergic function. In Alzheimer’s disease, ACh levels decline markedly, degrading cholinergic function and, therefore, our cognitive functions, especially memory.
ACh levels are regulated in part by the enzyme acetylcholinesterase (AChE), which destroys excess ACh molecules as part of a necessary biochemical balancing act to maintain proper cholinergic function. As ACh levels decline sharply in Alzheimer’s disease, however, it becomes desirable to inhibit the action of this enzyme so as to maintain healthy ACh levels and, therefore, normal cognitive function, for as long as possible. That’s what acetylcholinesterase inhibitors do.
Galantamine—Potent and Versatile
It has long been known that AChEIs, such as the plant alkaloid galantamine, are effective in alleviating the symptoms of Alzheimer’s disease (AD) and slowing its inevitable course, usually for a period of about 6 months to a year, before the decline resumes in earnest. (There is still no cure for AD, which is ultimately fatal.) Some AChEIs, such as donepezil and rivastigmine, are prescription drugs. Galantamine too is sold by prescription, but, unlike the others, it’s also available as a nutritional supplement, owing to its use as such for many years before the FDA approved it as a “drug” in 2001.
In addition to being an acetylcholinesterase inhibitor, galantamine has another mode of action that the other AChEIs do not. Galantamine is a potent allosteric modulator of nicotinic acetylcholine receptors, a fancy way of saying that it improves the receptivity of neurons to acetylcholine molecules that are trying to transmit a nerve impulse across a synaptic junction.
In other words, galantamine not only enhances the availability of ACh molecules (as do the other AChEIs), but it also makes them more effective in accomplishing their appointed task. Abundant evidence suggests that galantamine’s exceptional efficacy as a treatment for mild to moderate Alzheimer’s disease rests mainly on its protection and stimulation of nicotinic acetylcholine receptors.
Much additional research has indicated that galantamine is also effective, to varying degrees, against other dementias, such as Lewy body dementia, vascular dementia, and the dementia of Parkinson’s disease. It has even shown some benefit against schizophrenia, which is not a dementia.*
A Startling Idea from Outside the Box
Because AChEIs are effective in treating the symptoms of AD even while the degenerative process continues seemingly unabated, it has become easy to assume that that’s all they do. Enter Dr. Bartzokis—or rather, exit Dr. Bartzokis from that particular conceptual box, to do some original thinking. He has suggested that: (1) there may be a neurophysiological dimension to Alzheimer’s disease that has not been adequately explored, and (2) the beneficial effects of AChEIs may be attributable in part to their operation in this hitherto underappreciated domain.*
The premise of his theory is that improving cholinergic function at neuronal synapses is not the sole mode of action of AChEIs, as has generally been assumed. In particular, the premise is that such neuronal synaptic effects may not even be the principal mode of action underlying the disease-modifying or -delaying effects of the AChEIs—a startling idea from the viewpoint of conventional wisdom (the box) in this arena.
Bartzokis proposes that improving cholinergic function can, in addition to enhancing synaptic neurotransmission, have beneficial nonsynaptic effects, by improving certain of the brain’s lifelong developmental processes. His focus is on those processes that involve myelin, the white, fatty material that acts as an electrical insulator—the myelin sheath—on most of the brain’s neuronal axons. (The brain’s white matter is white because of myelin.) If you’re not familiar with the structure and function of neurons, now would be a good time to bone up (brain up?) on this subject by reading the sidebar “Of Axons, Myelin, and Really Big Numbers.”
Of Axons, Myelin, and Really Big Numbers
Do you like mind-boggling numbers? Here are some to wrap your brain around. Your brain contains roughly 100 billion neurons (nerve cells) and about 1 to 10 trillion glial cells, which support the function of the all-important neurons in numerous ways.
Each neuron has a soma (the cell body), where the nucleus and the other organelles are found. Attached to the soma are many dendrites—long, thin, highly branched, protoplasmic projections that receive electrical signals (nerve impulses) from other neurons and conduct them into the soma. Dendrites are rarely more than 1½ mm long (about the thickness of a penny), but that’s enormous compared with the diameter of the soma (a few micrometers). A typical neuron has thousands of them, and there are as many as several hundred thousand on some cortical neurons.
Also projecting from the soma is one axon, a long, taillike nerve fiber that conducts the inbound nerve impulses away from the soma. It ends in a branched structure of axon terminals (nerve endings), to which the impulses travel. At these terminals, neurotransmitters, such as acetylcholine, are released to carry the impulses across the synaptic junctions (about 20 nanometers, or about one-millionth of an inch) to the dendrites of other neurons.*
And so the electrochemical process continues. Since each neuron has about 10,000 synaptic junctions, on average, the number of possible connections among the 100 billion neurons is about 1 quadrillion (which, in easy-to-grasp terms, is 1 million billion). The number of possible neural pathways among all these connections is truly unimaginable, being incomparably greater than the number of elementary particles in the known universe.
Axons are anywhere from about 0.25 to 10 μm (micrometers) in diameter. They can be as short as dendrites, or they can be amazingly long—as much as 1 meter, i.e., roughly a million times as long as they are thick. (With those proportions, a 2-mm-diameter piece of spaghetti would be about 2 km, or 1¼ miles, long.) These superlong axons are found, however, only in the peripheral nervous system, not the central nervous system. It has been estimated that the combined length of all the brain’s nerve fibers is about 4 million miles, or almost 9 round trips to the moon.
Is your brain spinning? Have you OD’d on the numbers? (How many of your neural pathways got fried?) OK, then, let’s turn to something more mundane, namely, myelin, which is a soft, white, fatty material consisting of lipids and lipoproteins. In the form of the myelin sheath found on most axons, this material acts as an electrical insulator, like the plastic sheath on a copper wire, to minimize signal loss.
The myelin sheath looks like a chain of minuscule white sausage links, because at frequent intervals along its length, it’s broken—there are narrow constrictions where a tiny segment of the axon is laid bare. These are called the nodes of Ranvier after Louis-Antoine Ranvier, the French histologist who discovered the myelin sheath in 1878. (Myelin itself had been discovered in 1854 by the great German pathologist Rudolf Virchow.)
Far from degrading the axon’s performance in transmitting nerve impulses, however, the nodes of Ranvier improve its performance, by facilitating an electrochemical mechanism that boosts the signal from node to node. In that sense, the nodes are somewhat like the voltage-boosting regulators placed at intervals in electric power distribution networks to offset line losses. The myelin sheath, with its nodes of Ranvier, greatly increases the axon’s capacity to carry nerve impulses at high speeds and high repetition rates (neuronal “firing” rates).
In meters per second, nerve impulses travel at speeds of 0.5 to 120, which, in miles per hour, is about 1.1 to 270—quite a range! Some neurons are like turtles, while others, thanks to the myelin sheath, are like rabbits on steroids and can fire up to 1000 times per second.
The Myelin Model of the Human Brain
In his paper, Bartzokis outlines what he calls the myelin model of the human brain, which he has been developing over the last several years (in numerous published papers). It involves the fact that the myelination of axons in the human brain is not fully developed at birth, but develops gradually throughout the first four decades of life, peaking at around age 45; thereafter, the brain’s myelin content declines gradually for the rest of our lives, as the myelin sheaths degrade. From the myelin perspective, these two broad phases in the life of the brain—a development phase (myelination) and a degeneration phase (demyelination) represent a curved trajectory, as seen below.
The approximate myelination trajectory of the frontal lobe of normal human brains (there are large individual variations). Adapted from Ref. 1.
The presence of an intact myelin sheath, with its nodes of Ranvier (see the sidebar), boosts not only the speed of nerve impulses (10-fold) but also their frequency (34-fold) over those of unmyelinated axons. Thus, in Bartzokis’s analysis, maximal myelination can produce up to a 340-fold increase in effective bandwidth for information transfer along neural pathways in the human brain, an organ that is unique even among primates in the extensive and pervasive myelination of its axons (most animals have little or no myelination).* He believes that our brains’ huge capacity for information processing depends in large measure on myelination. He states (literature citations omitted),
From the perspective of this model, the development and maintenance/repair of myelin’s functional integrity over our lifespan is the single most critical element for acquiring and maintaining normal human cognition and behavior. In short, myelin represents the “Achilles’ heel” of brain development as well as degeneration. . . .
In adulthood, healthy individuals who myelinated normally go on to lose up to 45% of their myelinated fiber length in the degenerative phase of their myelination trajectory. The degenerative process of myelin breakdown recapitulates the myelination process in reverse, with the most vulnerable later-myelinated regions and functions succumbing first. This age-related myelin breakdown underlies the . . . [pattern of] . . . cellular changes that define the highly prevalent age-related degenerative dementing diseases, such as AD.
He goes on to say that in cases of dementia, demyelination begins early in the disease process, before a diagnosis of dementia or even its common precursor, mild cognitive impairment (MCI), can be made. It can be detected in living humans even before the fifth decade.
Where’s the Evidence? (Patience . . .)
So much for the myelin model of the human brain, which is certainly intriguing. But where’s the evidence that improving cholinergic function with acetylcholinesterase inhibitors, such as galantamine, can have the kind of nonsynaptic effects associated with the myelination trajectory that underlies this model?
There is no direct evidence yet, but it could be forthcoming soon because, Bartzokis points out, noninvasive brain-imaging technologies now make it possible to assess the trajectory of myelin development and its subsequent degradation in the brains of living humans, as well as to observe certain physical changes in the brain associated with changes in cholinergic function.
AChEIs Benefit Brain Disorders in Young and Old
OK, but what are the reasons for believing that such evidence will be forthcoming? To that central question, Bartzokis devotes several pages of detailed analysis; we’ll summarize the highlights.
The principal reason is that recent clinical trials have shown AChEIs to be effective against a remarkably broad spectrum of neuropsychiatric disorders—not just those, such as various dementias, that afflict the elderly, but also several that afflict primarily younger people, during the development phase of their myelination trajectory. These disorders include multiple sclerosis, autism, attention deficit hyperactivity disorder (ADHD), schizophrenia, and addiction, and they are not normally associated with synaptic cholinergic deficits. Significantly, brain disorders on both sides of the myelination trajectory demonstrate myelin deficits.
Dr. George Bartzokis
Furthermore, recent evidence suggests that the brain’s nicotinic acetylcholine receptors—cellular receptors that are activated by acetylcholine (and by nicotine; hence the name)—are found not just on neurons but also on other, nonneuronal cells, especially of a type called oligodendrocytes (which are one of the four types of glial cells). That’s significant because oligodendrocytes are the source of the brain’s myelin—these sheetlike glia wrap themselves around axons in multiple turns, and that is what constitutes each segment of the myelin sheath in the central nervous system. (In the peripheral nervous system, the myelin sheath comes from a different type of cell, called Schwann cells.)
AChEIs—Your Myelin Sheaths’ Friends
Thus, there appears to be a direct connection between cholinergic function—and therefore, presumably, the action of AChEIs, such as galantamine—and the myelin sheath. Supporting this idea is the fact that in healthy older individuals, there are age-related declines in both myelin and nicotinic acetylcholine receptors, and both of these declines are exacerbated in multiple degenerative brain disorders.
It’s not unreasonable to suppose that maintaining healthy cholinergic function throughout life is important for maintaining, as much as possible, the integrity of axonal myelination in the brain. Indeed, AChEI treatments have demonstrated efficacy in both developmental and degenerative brain disorders, as noted above, and they have also demonstrated preventive effects, according to Bartzokis.
It’s noteworthy that AChEIs can improve cognitive function in patients with MCI and that such treatments delay the progression of MCI to AD. It’s hard to explain the benefits to MCI patients on the basis of synaptic cholinergic deficits, because cholinergic function tends to be normal or elevated in these patients (and even in early AD patients), according to the results of several postmortem studies from several research groups. To Bartzokis, these findings suggest that the short-term memory deficits seen in MCI are caused not by cholinergic deficits but by some other, nonsynaptic mechanism—probably myelin degradation.
So, how does your brain feel after reading all that? Well-myelinated, we hope. And if not, there’s always galantamine, which may help preserve and protect those precious myelin sheaths, “broken” as they may be by the nodes of Ranvier.
It’s frustrating to have to wait and see whether the kinds of evidence discussed above will, in fact, be forthcoming, but at least we have plenty of new food for thought—
always a good thing. We don’t want to be like the people Bertrand Russell was talking about when he said, “Most people would die sooner than think; in fact, they do.”
- Bartzokis G. Acetylcholinesterase inhibitors may improve myelin integrity. Biol Psychiatry 2007;62:294-301.
Will Block is the publisher and editorial director of Life Enhancement magazine.