| by Sandra Steingraber, Ph.D.* [Here we continue exploring early-life events that may lead to
late-life dementia. See Rachel's #776.] (published
October 1, 2003) 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.[1] 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.[2] 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.[2] 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.[3]
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.[4]) 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.[5] Neurologically speaking, Parkinson's Disease is the opposite of
schizophrenia.[6] 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.[6] (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.[7] 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.[7] 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.[8] 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.[9] 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.[10] 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.[10] 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.[11]
A recent French study found links between risk of Alzheimer's and
occupational exposures to pesticides among men -- but not women.[12] By
contrast, a recent Canadian study found no risk of Alzheimer's with
exposure to pesticides.[13] 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. =========================================== *Sandra Steingraber, Ph.D., 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.
Unless otherwise noted, all citations refer to presentations made at
the Mt. Sinai School of Medicine conference, "Early Environmental Origins
of Neurodegenerative Disease in Later Life: Research and Risk Assessment"
(New York Academy of Medicine, May 16, 2003). Conference proceedings are
currently in preparation for publication. [1] A description of the conference, along with a complete list of
presenters, can be found at the web site of the Mt. Sinai Center for
Children's Health and the Environment: http://www.childenvironment.org/conferences.htm.
[2] C. Osmond and D.J.P. Barker, "Fetal, Infant, and Childhood Growth
Are Predictors of Coronary Heart Disease, Diabetes, and Hypertension in
Adult Men and Women," Environmental Health Perspectives Vol. 108
Supplement 3 (2000), pgs. 545-553. See also http://www.som.soton.ac.uk/research/foad/barker.asp.
[3] A.S. Brown and E.S. Susser, "In Utero Infection and Adult
Schizophrenia," Mental Retardation and Developmental Disabilities Research
Review Vol. 8 (2002), pgs. 51-57. [4] E.K. Doubleday et al., "Qualitative Performance Characteristics
Differentiate Dementia with Lewy Bodies and Alzheimer's Disease," Journal
of Neurology, Neurosurgery, and Psychiatry Vol. 72 (2002), pgs. 602-07.
[5] See also Rachel's #635 (Jan. 28, 1999). [6] Frederick Marshall, M.D., University of Rochester, "Parkinson's
Disease: Remembering to Recognize and Treat It," presentation at the
Ithaca College Gerontology Institute conference, "Meeting the Challenge of
Dementia," May 29, 2003. [7] C. Warren Olanow, Mount Sinai Medical Center, "New Research in
Parkinson's Disease." [8] Giancarlo Logroscino, Harvard School of Public Health, "The
Epidemiology of Parkinson's Disease." [9] Deborah Cory-Slechta, University of Rochester, "Animal Models of
Parkinson's Disease." [10] John Morrison, Mount Sinai School of Medicine, "Neurobiology of
Aging and Dementia." [11] Alan Lockwood, University of Buffalo, "The Epidemiology of
Neurodegenerative Disease." [12] I. Baldi and others, "Neurodegenerative Diseases and Exposures to
Pesticides in the Elderly," American Journal of Epidemiology Vol. 157
(2003), pgs. 409-414. [13] E. Gauthier and others, "Environmental Pesticide Exposure as a
Risk Factor for Alzheimer's Disease: A Case-Control Study," Environmental
Research Vol. 86 (2001), pgs. 37-45.
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