After decades of helplessly watching Alzheimer's, Huntington's and other diseases ravage the brain, medical science is striking back with a potent weapon -- the brain's newly discovered power to heal itself.
Enlightened by the insights of molecular biology, scientists now know that Mother Nature equips the brain with a kind of fountain of youth -- hormones and other chemicals that nurture and
sustain brain cells. But when the fountain begins to dry up, as it sometimes does with age and some mental disorders, brain cells wither and die.
Memory loss, Alzheimer's, Parkinson's, Huntington's and other degenerative diseases are now believed to be the biological desert created when these rejuvenating chemicals vanish. If we can measure when our brain-nurturing chemicals start to decline and restore them to youthful levels, we may be able to cure or prevent many of the things that go wrong with the brain.
Hormones -- estrogen, progesterone, testosterone and growth hormone -- play key roles in maintaining many types of brain cells, researchers now believe. Some of these hormones, which may become the first effective drugs to prevent Alzheimer's disease and memory loss, already have produced promising preliminary results.
"We have to think of the brain in terms of a system in balance," said neurobiochemist Dr. Eugene Roberts of the City of Hope's Beckman Research Institute in Duarte, Calif.
"When a part of the system changes -- like a decline in estrogen, growth factors or other hormones -- the balance is upset and that's when the trouble starts," said Dr. Roberts, who has shown that he can improve memory in aging animals with a brain hormone called DHEA. Dr. Roberts is now testing the precursor of DHEA, a basic hormone called pregnenolone, in human beings to determine whether it improves their memories.
Fortunately, most brains work well throughout life, diminishing only slightly in memory power with age. For many who do forget easily, the problem may simply be a matter of disuse -- in effect, they allow their brains to rust.
For those who have more fundamental problems with their memories -- the chemical and electrical circuits that make people who they are -- researchers are learning which chemicals need to increased. One of their biggest surprises is the discovery that estrogen has an ability to nourish many types of crucial brain cells.
Estrogen was once thought to be solely a female sex hormone involved in reproduction. But the hormone, a small, almost indestructible molecule with a biological passport to enter most cells, is turning out to be an important rejuvenator of female and male brains.
"People, and this is true for most doctors, are not aware of the fact that the brain is a major target of estrogen," said cell biologist Dominique Toran-Allerand of Columbia University.
Because of estrogen's ability to carry all sorts of biological messages, it has played a dominant role throughout evolution as a communications superhighway between the brain and the rest of the body in most living things. That becomes most obvious in women just before menopause, usually around age 50, when the ovaries drastically decrease their production of estrogen.
AThe brain itself appears to suffer when estrogen levels drop; the risk of Alzheimer's disease, for instance, increases in women after menopause. According to some estimates, postmenopausal women have 5 to 10 percent more Alzheimer's than men, whose estrogen levels do not plummet as rapidly. Several studies suggest that women who take estrogen supplements after menopause can significantly reduce their risk of Alzheimer's.
The male brain also is bathed in estrogen, a component of the male sex hormone testosterone.
Columbia's Dr. Toran-Allerand recently showed that estrogen stimulates the production of nerve growth factor, which is essential for the survivability of many types of brain cells, especially those involved in learning and memory.
Brain-cell connections
Estrogen also increases the sprouting of connections between brain cells, which determine the brain's power to produce thoughts and learn new things. Animal studies in Bruce McEwen's neuroscience laboratory at Rockefeller University showed that by increasing estrogen, more of these connections were formed. When estrogen was reduced, connections broke off and retracted. Finally, estrogen prevents a decline in acetylcholine, the chemical messenger that orders new memories to be imprinted in various parts of the brain. Alzheimer's patients suffer increasingly severe losses of acetylcholine, which first robs them of their short-term memory and eventually of long-term memory.
"Whatever it is that makes women and men at risk for Alzheimer's disease, if the brain is deprived of a necessary molecule [estrogen], then it may make those neurons [brain cells] more vulnerable to the disease," Dr. Toran-Allerand said.
Barbara Sherwin, a psychologist at McGill University in Montreal, gave estrogen replacements to women whose ovaries were removed during hysterectomies, thus eliminating their major source of estrogen. She found that the brains of the women who got estrogen supplements could think and remember more effectively than the women not given estrogen.
Some women resist
Yet, some women resist hormone replacement on the ground that menopause is a natural event, Dr. Sherwin said.
"It may have been natural in 1850 when women lived to be 50 and very few outlived menopause and its consequent problems of osteoporosis, heart disease and other degenerative disorders," Dr. Sherwin said. "Now that North American women live to the average age of 78, these disorders have become huge problems."
Some women shy away from estrogen replacement because of concerns that it may increase their risk of breast cancer.
Studies attempting to link estrogen to a breast cancer risk are inconclusive, and some experts believe there is no clear evidence for such a risk.
While there is some evidence for a potential link between estrogen replacement and uterine cancer, many medical authorities consider the risk small. They also note that uterine cancer can be detected early and is curable.
Nobuyoshi Hagino of the University of Texas Health Sciences Center in San Antonio is giving female Alzheimer's patients 0.625 mg. of estrogen, the same amount routinely given to women after menopause because it is thought to be safe.
Significant improvement
Dr. Hagino's study, which involves 15 women in Japan, found that two-thirds of the women improved significantly, and their improvement has continued for up to five years so far.
"They can remember in space and time what happened the day before," he said. "They can communicate with their families and take care of themselves. Patients who wouldn't eat even when food was placed before them in bed, now go to the cafeteria, get their food, eat it and put their trays on the counter."
CAs tantalizing as estrogen's role as a brain-saver appears, not all scientists are convinced.
"I think estrogen may have some protective effect but I'm skeptical whether it's as big as everyone thinks," said Dr. Elizabeth Barrett-Connor, head of family and preventive medicine at the University of California at San Diego.
Her study of 800 highly educated women living in Rancho Bernardo in Southern California failed to find any significant memory benefit among those taking estrogen. The women, whose average age was 77, were basically normal and healthy and were tested for memory impairment associated with aging.
Scientists also are racing to test other chemicals from the brain's fountain of youth. The National Institutes of Health is supporting studies at eight centers to find out whether, by restoring to youthful levels three hormones that decline with age -- estrogen, testosterone and growth hormone -- aging can be retarded.
The answer, according to early results, appears to be affirmative, supporting the pioneering work of the late Dr. Daniel Rudman of the Medical College of Wisconsin. Dr. Rudman, who reported in 1989 the first evidence that growth hormone increased muscle mass and decreased fat deposits in elderly men, described the age-related decline of testosterone and growth hormone as the "male menopause."
And, like estrogen, testosterone and growth hormone supplements appear to make the brain run better.
"There seems to be a beneficial effect of testosterone supplementation on spacial cognition, which is the ability to interpret one's surroundings in a three-dimensional framework," said Dr. Eric S. Orwoll, chief of endocrinology and metabolism at the Portland Veterans Administration Medical Center.
Dr. Orwoll, who is also at the Oregon Health Sciences University in Portland, is treating 100 elderly men with testosterone supplements. So far no side effects have been found.
Early results from other research show that growth hormone, which until recently was thought to be active only in childhood, has a profound effect on brain operations throughout life.
More than 100 adults who have growth hormone deficiencies because of pituitary tumors are being given supplements of the hormone in a study by Dr. Bengt-Ake Bengtsson, chief of endocrinology at the Sahlgrenska Hospital in Goteborg, Sweden.
"The most important thing is the effect of growth hormone on the brain," he said, improving "energy, vitality, sleep patterns, memory, concentration, all those things."