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#777 - Origins of Dementia, Part 2, 03-Sep-2003

(published October 1, 2003)

by Sandra Steingraber, Ph.D.*

[Here we continue exploring early-life events that may lead to
late-life dementia. See Rachel's #776.]

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

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

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

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

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:

[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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