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Oct 1, 2003
ORIGINS OF DEMENTIA,
On May 29, 2003, the Mount Sinai School of Medicine in New York hosted an important conference on early-life environmental origins of late-life neurodegenerative disorders, including Parkinson's and Alzheimer's disease. Presided over by the redoubtable Philip Landrigan, M.D. -- a National Academy of Sciences physician who has advised the White House on matters ranging from lead poisoning in children to Gulf War Syndrome -- this gathering drew together leading researchers from around the nation. Among the presenters were neurologists, physicists, toxicologists, pediatricians, epidemiologists, obstetricians, and geneticists.
In Rachel's #776, we examined the conceptual rationale for approaching late-life dementias from an environmental vantage point, which was the focus of several of the conference presentations. This week we examine the evidence itself. But first, let's look more closely at the Barker Hypothesis, which is emerging as an important paradigm of disease causation.
In a series of studies, British epidemiologist David Barker has revealed the ways in which stresses encountered in early life can predispose an individual to the development of certain disease in elder life. He did so by painstakingly reconstructing the medical histories of 16,000 individuals, from birth through old age. What he found was an impressive connection between birth weight and subsequent risk of heart disease, stroke, and diabetes. The smaller the body at birth, the larger the risk of these disorders in late life. He further determined that grossly inadequate nutrition during pregnancy, rather than premature birth, was the source of the developmental stress that raises the risk of subsequent disease.
Barker has also elucidated the anatomical and physiological mechanisms by which disease susceptibility is created. For example, undernourished fetuses increase blood flow to the brain and decrease blood flow through the descending aorta. This diversion spares the developing brain from damage when calories and nutrients are in short supply. If fetal blood is thus directed at the time when elastin deposition takes place, the baby will be born with less pliable blood vessels. (The protein elastin makes artery walls stretchy.) In addition, the rerouting of blood away from the trunk and toward the brain causes the ventricles of the heart to grow larger than they otherwise would. And it causes the resting pulse rate to be set higher than it otherwise would. High resting pulse rate, enlarged ventricles, and less-elastic arteries are all risk factors for high blood pressure and stroke in late life.
Thus, the Barker Hypothesis posits that human fetuses, quite apart from their genetic inheritance, are "programmed" by the early environments in which they find themselves in ways that can predict risk for late-onset diseases.
For some organ systems, this period of environmental programming extends well into childhood. Consider sweat glands. As is well known, the human ability to adapt to warm climates is a widely variable trait. Some like it hot. And some like it cold. Studies show that differences in heat tolerance among individuals is related to the number of functioning sweat glands they possess. No surprise there. People with more sweat glands cool down faster. However, genes do not account for this variability: at birth, all humans have similar numbers of sweat glands, and none of them work. During the first three years of life, a proportion of these glands become activated. As documented by Japanese physiologists, their recruitment depends on the temperature to which the child is exposed. The hotter the climate, the greater the number of sweat glands that become functional. After three years, the programming is fixed, and no further alterations in ambient temperature affect the number of functional sweat glands that individuals carry with them for the rest of their lives.
What does the Barker Hypothesis predict about late-life neurodegenerative disorders, such as Parkinson's Disease and Alzheimer's? This question, which conference participants took up in earnest, is difficult to answer. Schizophrenia, a psychiatric disease of young adulthood, almost certainly has roots in the environment of fetal life. By contrast, Parkinson's and Alzheimer's cannot even be diagnosed definitively unless an autopsy is performed after death. And some forms of dementia are not yet uniformly classified as distinct disease entities. Dementia with Lewy bodies, for example, is the second most frequent type of dementia after Alzheimer's. It is characterized by frequent delusions and hallucinations.) And yet in spite of its prevalence, clinicians do not agree on its diagnostic criteria. Lewy-body dementia is considered by some clinicians as a variant of Parkinson's Disease, by others as a form of Alzheimer's, and by some as a unique disease entity. These kinds of uncertainties in ascertainment frustrate epidemiological investigations of the kind practiced by Barker. (Dementia with Lewy bodies is the tentative diagnosis given to my own father.)
Nevertheless, an emerging body of evidence suggests that environmental exposures, in the form of toxic chemicals, can cause or at least increase the risk of late-life neurodegenerative diseases. Let's look at Parkinson's Disease first.
Neurologically speaking, Parkinson's Disease is the opposite of schizophrenia. In schizophrenia, psychiatric problems are created by an oversupply of a brain chemical called dopamine. In Parkinson's, the problem is lack of dopamine. The reason for the deficit is the premature death of dopamine-producing nerve cells in a part of the brain called the substantia nigra. Because dopamine is a chemical messenger that helps coordinate muscular activity, physical symptoms of Parkinson's Disease include tremor, rigidity, slow movement, and a shuffling, stooped-over gait. (The uncontrolled writhing seen in Parkinson's patients is a side effect of the medications used to treat the disease.) Other hallmark symptoms include small handwriting and low volume of speech. Age of onset is usually between 50 and 70 years.
In one-third of patients, for reasons not known, the disease progresses to include dementia. Like Lewy-body dementia, which Parkinson's dementia closely resembles, early symptoms include hallucinations and delusions. And, curiously enough, these often involve very particular themes. Among Parkinson's patients, spousal infidelity is the most common delusion, and visions of people or animals intruding into one's house a common hallucination. (My father suffers from both of these.)
Here is what we know so far about the environmental links to Parkinson's, as presented at the Mount Sinai conference. First, the disease was originally identified in 1817, at the beginning of the industrial revolution. There is no mention of "shaking palsy" in ancient medical writings. Second, severe Parkinson's-like symptoms have been triggered in people who took recreational drugs contaminated by a neurotoxic chemical called MPTP. This chemical has been proven to produce Parkinson's in both humans and animals. Third, occupational studies show that the metal manganese accumulates in the brain of exposed workers where it produces symptoms similar to Parkinson's.
Fourth, there appear to be links with pesticides. Rural living, drinking well water, and being employed in farming are all recognized risk factors for the disease. Some studies show that exposure to the herbicide paraquat is, all by itself, a risk factor for Parkinson's. It is known to target the dopamine-producing structures of the brain. While experimental evidence for this is equivocal, toxicologist Deborah Cory-Slechta of the University of Rochester, has demonstrated that combined exposures to paraquat and the fungicide maneb can create synergistic effects in laboratory animals. These findings are important because paraquat and maneb are often used in the same places.
Now to Alzheimer's. If Parkinson's is the opposite of schizophrenia, Alzheimer's is the opposite of cancer. Cancer is runaway cell growth. Alzheimer's is runaway cell death. Primarily affected are neurons in the cortex of the brain, which is the center for higher thought. This cascade of cell death can eventually spread out to include almost every cortical region except the primary visual cortex. Nevertheless, Alzheimer's always originates in the same place: the hippocampus, which is the seat of memory. Thus, Alzheimer's invariably begins as an isolated memory problem and then expands to affect language, judgment, personality, and behavior. No one knows exactly what causes the cortical neurons to die. Affected cells show two pathologies: they extrude plaque on the outside, and they develop tangled fibers on the inside. Which symptom is the more important one for disease progression is a matter of heated debate within the neurological community.
The evidence for an environmental link to Alzheimer's is more sketchy than for Parkinson's, but it points to some of the same culprits. Alzheimer's has been associated with exposures to glues, fertilizers, and pesticides, particularly the now-banned organochlorine pesticide dieldrin. It has a higher prevalence in rural environments than urban settings. A recent French study found links between risk of Alzheimer's and occupational exposures to pesticides among men -- but not women. By contrast, a recent Canadian study found no risk of Alzheimer's with exposure to pesticides.
For all of us who dearly love someone lost in the white-water rapids of a late-life dementia, the recent findings reviewed at this conference are hardly satisfying. But they do mark the beginning of a fresh new approach to a terrible scourge. We cannot change our genes. But we can change our environment. And in this, there is hope.
ORIGINS OF DEMENTIA, PT.
by Sandra Steingraber, Ph.D.*
Here is a sign of our times: within the publishing world, a new nonfiction subgenre has emerged -- the Alzheimer's memoir. Among the first was Elegy for Iris, written by English literary critic John Bayley about his wife, the novelist Iris Murdoch. In both the book and the movie based on it, we see the famously brilliant Murdoch descend into a mental state in which, no longer able to dress or speak, she desires only to watch the famously simple children's show, Teletubbies. More recent are The House on Beartown Road: A Memoir of Learning and Forgetting by journalist Elizabeth Cohen, which was excerpted in People magazine, and The Story of My Father by best-selling novelist Sue Miller, which was profiled in Reader's Digest.
And these include only the books in which the subject of the story is a former college professor. There are many, many others.
My own father is a former college professor, and he suffers from dementia. He now lives in a nursing home. This is hardly an unconventional situation -- half of all nursing home residents in the United States are demented -- but the decision to place him there was an extraordinary one for our family. After fifty years of marriage, my father wanted to live out his days with my mother in the house that he had built for them both when she was a young bride; my mother was devoted to caring for him there, no matter what it took. And for several years after his diagnosis she did.
But then Dad became "delusional and combative," in the language of neurology. "Delusional" meant he came to believe my mother was having an affair. He grew suspicious when the phone rang. He followed her to the mailbox, shouting accusations. He prowled the house at night looking for the other man. He stood over her while she slept. "Combative" meant that he began to relive his experiences in Italy during World War II. It was a dangerous combination.
And so, my retired college professor father -- the man who introduced me to calculus and Rachel Carson, who planted an organic garden every spring, who took up the piano in his 40s, who loved to embroider, bake bread, and make candles, who had seat belts installed in the family car before they were standard-issue -- is now institutionalized in a facility from which he regularly attempts to escape and whose staff he periodically attempts to assault. He has quite literally become an imprisoned combatant, which was his biggest fear when, sixty years ago as a teenage soldier, he sailed into the Mediterranean on a warship.
In the Alzheimer's wing of the nursing home where he lives a detailed description of each resident is posted on the door to their room. It's a way of helping the patients remember where their beds are located. These biographies also remind my mother, my sister, and me that Dad is part of a much bigger tribe. The dementia-sufferers there include former teachers, former farmers, former entrepreneurs, former church ministers, former world travelers, former ballroom dancers. Each has a life history, a family, an identity.
And this small, rural nursing home is itself part of a larger collective story. In the United States, about 4.5 million people suffer from Alzheimer's disease, and another 1.5 million from other forms of dementia. Because the risk of developing a dementing illness rises sharply with age (ten percent of those over 65 years old are afflicted with Alzheimer's, while 40 percent of those over 85 are) and because the population itself is aging rapidly (the first baby boomers turn 65 in 2011), we are standing on the cusp of a slow-motion epidemic.[3,4] A disease for which there is no cure, Alzheimer's has already risen from the 12th leading cause of death to the 8th. By the year 2050, 10-15 million Americans are projected to have Alzheimer's -- more than double the number we have now.
The economic implications of these statistics are equally sobering. (And, as an accounting professor, my father would have found them compelling.) Alzheimer's patients live, on average, eight years after diagnosis. During this time, they require, on average, $213,000 in medical care. This makes Alzheimer's the third most expensive disease in the United States. (Cancer and heart disease still take the top two slots.) Yes, someone has done the math: the current economic burden of Alzheimer's, in medical treatment costs alone, is about $100 billion each year. One researcher has estimated that annual costs could rise to $700 billion by 2050. These figures do not include the one-third of neurodegenerative dementias that are non-Alzheimer's in origin. The prevalence of Lewy-body dementia (which is the second most common form of dementia) and Parkinson's disease (which leads to dementia in one third of all cases) is also expected to increase sharply as the population ages.
All these diseases are officially classified as "idiopathic disorders of unknown pathogenesis," which is another way of saying that no one knows what causes them. Thus, in addition to presenting overwhelming personal challenges to those afflicted and to their caregivers, neurodegenerative dementia brings with it four other miserable characteristics: it has no known cause; it has no known cure; it is becoming increasingly common; and it costs considerably more than an average home mortgage to care for each person diagnosed.
Clearly, then, addressing the question of dementia's causality should be a national priority. Some medical researchers are indeed working feverishly to understand the genesis of dementia, and, while their efforts have not yet taken on the coordinated urgency that has characterized, say, the atomic bomb program in the 1940s or the space program in the 1960s, there are signs of an emerging new framework for inquiry.
In May 2003, the Mount Sinai School Center for Children's Health and the Environment organized an important conference at the New York Academy of Medicine entitled "Early Environmental Origins of Neurodegenerative Disease in Later Life." In Rachel's #777, we will take a close look at the evidence for an environmental connection to Alzheimer's and Parkinson's disease. Here we will examine the conceptual rationale for pursuing early-life environmental links to late-life dementias, as presented at this ground-breaking conference.
The chain of logic goes as follows. First, inheritance alone appears to play little direct role in the risk of developing dementia. (Heredity explains only five percent of Parkinson's disease, for example.) This means we need to look toward the environment, possibly in concert with genetics and lifestyle factors, to understand dementia's root causes.
Second, many neurodegenerative diseases are thought to arise through a series of stages that require many years or even many decades to progress. The cascade of neuronal changes leading to Alzheimer's may already be evident in one's 20s or 30s. This means toxic exposures early in life -- even prenatal exposures -- may be more relevant to late-life dementias than equivalent exposures encountered later.
Third, many cognitive disorders known to be caused by exposure to toxic chemicals have decades-long latent effects. Dupont workers exposed to high levels of lead on the job showed more rapid cognitive declines during their retirements than coworkers exposed to lower lead levels, even though neither group had been exposed to any lead for almost twenty years. Similar findings come from South Korea.
Fourth, animal studies show that early-life exposures to certain neurotoxic chemicals can create subtle but permanent changes in the brain that produce no functional deficits until the effects of these "silent toxicities" are unmasked by later challenges. This means early-life exposures to neurotoxic chemicals can enhance susceptibility to late-life exposures.
Fifth, neurotoxic chemicals, in the form of pesticides, persistent organochlorines, and heavy metals, are widely distributed in the U.S. environment.
Sixth, human studies of non-dementing illnesses show that certain factors encountered early in life can predispose an individual to the development of disease in their elder years. For example, studies in England show that babies born small because they were denied adequate nutrition in the womb develop into adults who are, in advanced age, at higher risk of hypertension, stroke, diabetes, and breast or prostate cancer. The results of these studies suggest that infants are "programmed" by environmental insults that take place at a critical period of development in ways that have lifelong consequences. This idea is known as the Barker Hypothesis. In Rachel's #777, we shall explore the relevance of the Barker Hypothesis for Alzheimer's and Parkinson's Disease.
*Sandra Steingraber is a biologist and author (see Rachel's #565). She is currently a Distinguished Visiting Scholar in the Interdisciplinary Studies Program at Ithaca College in Ithaca, New York.
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