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08-04-2008, 11:43 AM
The Neglected Side of Parkinson's Disease
By Rothstein, Ted L , Olanow, C Warren

Shaking and slowness of movement may be the most obvious symptoms, but they
are often not the most debilitating ones Parkinson's disease may not be an
epidemic, but it's more common than you might think. Approximately 1,000,000
Americans suffer from the illness, with 60,000 new cases appearing each year
in the United States alone. This neurodegenerative disorder, which is both
progressive and incurable, usually begins around age 60, so neurologists
believe that its prevalence is likely to increase dramatically with the
graying of the nation's population. But Parkinson's disease shouldn't be
thought of only as an affliction of old age; it can also strike considerably
earlier in life, a fact that has become well known through such prominent
examples as Michael J. Fox (diagnosed at age 30) and Muhammad Ali (at age
For decades, researchers have understood that such classic symptoms of the
disease as shaking, slowness of movement and problems with balance result
from the loss of dapaminergic nerve cells (so named because they use the
chemical dopamine as a neurotransmitter) in a part of the brain stem called
the substantiel nigra pars compacta. One of the greatest success stories of
modern medicine came when neuroscientists recognized that there was a
dopamine deficiency in the brains of patients with Parkinson's disease and
used this knowledge to develop treatments designed to boost levels of this
important brain chemical. This strategy has now benefited millions of
people, enabling patients who once would have been crippled by the illness
to live relatively normal lives.
There are, however, aspects of the disease that do not respond to this
treatment. Unfortunately, many physicians are not particularly familiar with
these nondopaminergic manifestations. Such features, which include sleep
disorders, dementia and difficulty walking, are very important for the
clinician to address, both because they are common and because they
frequently represent the main source of disability for patients. They are
also interesting to study because they may provide investigators with clues
to why cells degenerate in Parkinson's disease, which in turn may help
researchers to develop more effective therapies. What's more, there is
mounting evidence that certain nondopaminergic symptoms may antedate the
development of the classic motor features of the disorder and thus may
permit early diagnosis.
By recognizing these early warning signs, physicians might even be able to
treat patients preemptively. The hope is that doing so could delay or
perhaps even arrest the disease before the more typical problems emerge and
the damage wrought by Parkinson's becomes irreversible. Before considering
such promising opportunities for the future, it is worthwhile to review how
the disease has been understood in the past.

The Dopamine Revolution
One can find many references to the symptoms of Parkinson's disease
throughout history. The Greeks, and in particular the noted physician Galen,
wrote about them, and they are described in ancient Chinese medical
The first detailed account of Parkinson's disease came in 1817, when the
English physician James Parkinson published a monograph titled "An Essay on
the Shaking Palsy." Parkinson provided a clear description of the major
clinical features of this disorder, and his portrayal has withstood nearly
200 years of observation. Interestingly, Parkinson's monograph was based on
his analysis of just six patients. In recognition of this seminal
contribution, in the late 19th century the great French neurologist Jean
Martin Charcot coined the term "Parkinson's disease."
Parkinson described various clinical findings: tremor or trembling
movements, particularly while at rest; stiffness or rigidity of muscles;
slowness of movement, which is also known as bradykinesia; and difficulty
with walking and maintaining balance. Patients with Parkinson's disease also
frequently demonstrate a masklike facial appearance, reduced blinking, small
handwriting, loss of speech volume and melody, and a flexed posture with
tilting of the body. These motor symptoms progress gradually over the years
and were the main cause of disability in the era before effective drug
treatment became available.
Whereas James Parkinson defined in the early 19th century the classic motor
features of the disease that bears his name, it was not until the beginning
of the 20th century that scientists began to get an idea of what was going
on inside the nervous systems of people with this condition. At that time,
autopsy studies showed that the disease is associated with a loss of
pigmented dopaminergic nerve cells in the substantia nigra pars compacta.
(Substantia nigra means, literally, "black substance"; researchers now
understand that these cells gain their dark coloration from the oxidation of
dopamine to form the black pigment neuromelanin.) In addition, some of the
remaining nigral nerve cells contain abnormal protein inclusions known as
Lewy bodies, named in honor of Freidrich H. Lewy, who first described them
in 1912.
The significance of Lewy bodies is still not known, and there is debate as
to whether they are toxic and contribute to nerve-cell death or reflect a
protective mechanism that arises in response to the accumulation of abnormal
proteins. Lewy bodies turn up in postmortem studies of some individuals who
did not evidence any neurological impairment during life. So it seems
possible that these individuals had a preclinical form of Parkinson's
The importance of dopamine in Parkinson's disease first became apparent in
the 1950s when the Swedish scientist Arvid Carlsson found that reserpine, a
drug that blocks dopamine uptake into storage vesicles within cells, caused
rabbits to develop pronounced slowness and a syndrome resembling Parkinson's
disease. Carlsson further showed that this effect could be reversed by the
restoration of dopamine. For this seminal work, he was awarded the 2000
Nobel Prize in Physiology or Medicine.
In 1960, the biochemist Oleh Hornykiewicz at the University of Vienna
discovered that the disease is accompanied by dramatically reduced levels
(80 to 90 percent) of dopamine in the striatum, a part of the brain that is
connected to nerve cells in the substantia nigra pars compacta by what is
known as the nigrostriatal tract. The striatum and substantia nigra are part
of a group of deep nuclei within the brain called the basal ganglia, which
control and facilitate normal movement. Experimentally, damage to the
substantia nigra pars compacta, which can be induced with certain
neurotoxins, reproduces in animals the classic features of the illness.
Once clinicians figured out the importance of dopamine in the development
and progression of Parkinson's disease, they sought ways to replace this
crucial chemical. Dopamine itself is not effective as a drug because it does
not cross the blood-brain barrier, an obstacle that prevents most chemicals
from entering the brain. However, levodopa, a naturally occurring amino acid
found in many foods (for example, fava beans), can be transported by large
carrier molecules into the brain where it can then be converted to dopamine
by the decarboxylase enzyme.
In 1961, Hornykiewicz and his colleague Walter Birkmayer reported dramatic
benefits to a few patients with Parkinson's disease following small doses of
levodopa, but it was not until 1967 that George C. Cotzias and colleagues at
Brookhaven National Laboratory demonstrated that levodopa could consistently
ameliorate the debilitating motor symptoms, thus revolutionizing the
treatment of Parkinson's disease. Levodopa is typically administered in
combination with a drug that prevents it from being metabolized to dopamine
outside the brain-either carbidopa or benserazide hydrochloride. In the 40
years since its development, levodopa has helped millions of patients
throughout the world. Indeed, it remains the most effective treatment for
Parkinson's disease and is the "gold standard" against which new drugs must
be compared.

Outside the Realm of Dopamine
Unfortunately, levodopa therapy doesn't satisfactorily control many clinical
aspects of Parkinson's disease, presumably because they result from
degeneration of nondopaminergic parts of the nervous system.
Researchers are discovering that the pathology of the disease is far more
extensive than their predecessors initially appreciated and is not
restricted to dopaminergic nerve cells in the substantia nigra pars
compacta. Indeed, they have identified signs of neurodegeneration with the
development of Lewy bodies in nondopaminergic regions of the brain, the
spinal cord and the peripheral nervous system, which use a variety of
different neurotransmitters (such as serotonin, norepinephrine and
acetylcholine). Strangely, some regions of the brain can suffer profound
nerve-cell loss with Lewy-body formation, while neighboring areas are
completely spared, indicating that some asyet-unknown factors make only
certain nerve cells vulnerable to degeneration in Parkinson's disease.
Although nondopaminergic symptoms are common, doctors may not think to ask
about them and thus may not realize that they are causing problems for their
patients. And both patients and doctors often do not appreciate that
nondopaminergic parts of the disease frequently constitute a significant
source of disability. This phenomenon is illustrated by the Sydney
multicenter study, which followed more than 100 Parkinson's disease patients
for 15 years. One third of them survived; of those, four-fifths displayed
gait impairment with falls (leading to leg fracture in one-fifth of the
subjects evaluated), and about the same fraction demonstrated cognitive
impairment (with half of those meeting standard criteria for dementia).
Other nondopaminergic symptoms that the researchers described in this
population were choking, difficulty with swallowing, urinary problems and
severe constipation. In virtually all instances, severe nondopaminergic
difficulties (such as dementia), not the classic motor features of the
disease, were ultimately responsible for placement of the patient in a
nursing home. Asking Patients
The frequency and importance of nondopaminergic problems in Parkinson's
disease are also readily apparent in the results of a study that one of us
(Olanow) recently conducted in collaboration with several colleagues. We
developed a questionnaire and raring scale focusing on these nondopaminergic
symptoms and found that they occur in patients with Parkinson's disease far
more often than they do in otherwise healthy people of similar age. This
research also showed that the frequency and severity of these
nondopaminergic manifestations increase along with the progression of the
classic motor impairments of Parkinson's disease.
Sadly, people with this condition have to cope with even more than what is
on the list of common symptoms. With advancing disease, many also begin to
have a stooped posture, shuffle as they walk, have difficulty making a turn
and lose control of their balance so that they find themselves involuntarily
running forward or backward to stay upright. In addition, patients may
experience "freezing episodes" during which they have difficulty starting to
walk, or they may suddenly stop for several seconds or even minutes in the
middle of walking, particularly as they pass through a doorway or encounter
a curb. As a result, patients are at increased risk of falling and breaking
bones, and frequently they must rely on a walking aid or wheelchair to
maintain mobility. The precise site in the brain that is responsible for
this gait impairment is not known, although a region in the upper brain stem
known as the pedunculopontine nucleus has recently been implicated.
Dementia, a progressive decline in cognitive function sufficient to
interfere with one's usual daily activities, is another important feature of
Parkinson's disease that does not respond to, and may in fact be worsened
by, dopamine-replacement therapy. Studies suggest that dementia eventually
develops in 40 to 80 percent of patients with Parkinson's disease-more than
six times the rate expected in the general population. The dementia of
Parkinson's disease primarily affects what are known as executive functions,
such as the ability to focus one's attention, make coherent decisions, plan
and organize, and visualize the spatial arrangement of objects. This mental
handicap differs from the dementia of Alzheimer's disease, which primarily
affects higher cortical functions, such as memory, calculations and
language. People with Parkinson's dementia also commonly experience visual
hallucinations, which can be the first indication of dementia. Autopsy
studies of patients with dementia from Parkinson's disease often reveal
Lewy-body inclusions throughout the cerebral cortex, a region of the brain
where thought processes take place. And these tissues also show Alzheimer
pathology at an unusually high frequency.
Patients with Parkinson's disease experience many other ailments that do not
stem directly from depleted dopamine-depression, for example, is present in
approximately half of these people. Researchers have debated whether
depression is an inherent part of the disease, possibly related to
alterations in the brain's serotonin levels. Others contend that it develops
as a consequence of patients having to live with the knowledge that they
have a progressive neurodegenerative disorder.
Disturbed sleep is another aspect of Parkinson's disease that does not
respond to, and may even be aggravated by, dopamine therapies. As many as 70
percent of patients with this disease have some sort of sleep disorder. The
lack of restorative nighttime sleep causes them to experience excessive
daytime drowsiness-some have even fallen asleep while driving. Another
problem that is also frequently seen is Rapid Eye Movement (REM) behavior
disorder, where the "sleep paralysis" that normally prevents us from acting
out our dreams during REM sleep fails to occur. The resultant thrashing can
cause serious injury to the patient or to his or her bed companion. People
with Parkinson's disease may also experience restless-leg syndrome, a
condition in which there is an inexplicable urge to move one's legs,
particularly when lying down at night.
Other nondopaminergic difficulties can include a drop in blood pressure on
standing, slowed gastrointestinal transit with resulting constipation,
increased urinary frequency and incontinence, and erectile dysfunction. It
also appears that the nerves serving the heart may be compromised in some
patients with Parkinson's disease, perhaps contributing to complaints of
light-headedness and fatigue.
Although many of the symptoms of Parkinson's disease can be readily
classified as dopaminergic or nondopaminergic, others don't seem to fit this
simple categorization. Recently, physicians have noticed that treatment with
levodopa and other dopaminergic drugs renders some patients susceptible to
impulse-control disorders, including pathologic gambling, hypersexuality,
compulsive shopping and eating, and a tendency to perform useless tasks
compulsively and repetitively, a behavior neurologists call punding. Because
dopamine is a key part of the brain's reward system, these disorders are
thought to be related to a dopamine imbalance, which probably results from
there being too much dopamine in some parts of the brain (from the
medications) and too little in other parts (from the underlying disease).
Investigators are focusing intense scrutiny on this issue, which may one day
provide insight, not only into Parkinson's disease, but also into the nature
of addiction.

A Sign of Things to Come
Considerable evidence now suggests that the earliest symptoms of Parkinson's
disease may be nondopaminergic ones. Support for this possibility comes from
the work of Heiko Braak at the Johann Wolfgang Goethe University in
Frankfurt. In 2003 he and his colleagues carried out postmortem examinations
of the brains of elderly people to determine the distribution of Lewy bodies
and Lewy neurites (abnormal protein aggregates found in the slender
extensions that radiate from the body of a nerve cell). Based on his results
he believed that the pathological changes in brains of patients with
Parkinson's disease begin in the olfactory regions and the lower brain stem
(two nondopaminergic areas) and then spread to involve the more classic
dopaminergic areas in the midbrain (for example, the substantia nigra pars
compacta). In the final stage, pathologic changes are found diffusely
throughout the cerebral cortex, likely accounting for the dementia that so
frequently accompanies motor impairments. That is, he argued that
nondopaminergic regions are affected before dopaminergic ones.
Unfortunately, Braak's study did not include clinical assessments, so one
can't really be sure whether his staging scheme is completely correct.
Nonetheless, his results raise the interesting possibility that the lower
brain stem and olfactory regions may be the first sites of neural damage. If
so, it makes sense that certain nondopaminergic symptoms might precede the
development of the classic motor difficulties, an observation that may allow
physicians to better predict the course of the disease.
Clinical findings seem to support this argument. One is the observation that
a loss in the sense of smell is a common feature in Parkinson's disease.
This impairment may exist for many years before motor difficulties appear.
Studies of asymptomatic relatives of patients with Parkinson's disease show
that those with a compromised sense of smell are more likely than ones with
a normal sense of smell to have reduced dopaminergic activity (as evidenced
by brain- imaging studies) and to go on to develop the hallmark motor
deficits of Parkinson's disease.
This tendency was demonstrated in a 2004 study. A group of researchers in
Amsterdam led by Henk W. Berendse of the Vrije Universiteit Medical Center
examined more than 300 asymptomatic relatives of patients with Parkinson's
disease and identified 40 with a diminished sense of smell. Over the course
of the next two years, the classic motor symptoms developed in four of them,
who were thus diagnosed as having Parkinson's disease. Within those two
years, Parkinson's disease developed in half of those who had displayed both
an abnormal sense of smell and reduced dopaminergic activity. Yet during
this same period, none of the relatives with a normal sense of smell were
diagnosed with the disease.
A weakened sense of smell is not the only possible manifestation of early
Parkinson's disease. People with REM behavior disorder frequently have
reduced dopaminergic activity in the striatum, and their brain tissues often
show mild Parkinson's pathology in postmortem studies. What's more, about
half of the people with REM behavior disorder and no other neurological
symptoms will eventually go on to experience the classic motor impairments
of Parkinson's disease.
Constipation may also be an early warning sign. Autopsy studies have
revealed Lewy bodies in the networks of cells that innervate the colon in
patients with Parkinson's disease as well as in individuals who hadn't
displayed any neurological deficits before they died. This finding raises
the possibility that the latter group may, in fact, have had early
Parkinson's disease and, had they not died of other causes, may have gone on
to develop the classic motor impairments. Epidemiologic studies provide
further support for this notion. During the course of the Honolulu Heart
Study, which followed 8,000 men of Japanese ancestry for 31 years to assess
risk factors for heart disease, 96 subjects developed Parkinson's disease. A
look back at information collected years earlier revealed that Parkinson's
disease was 2.7 to 4.5 times more likely to develop in patients who had less
than one bowel movement per day than in those who had one or two movements
per day. And those with Parkinson's disease were more likely to have had
chronic constipation at an earlier age, again suggesting that this seemingly
minor problem could be an early harbinger of a devastating neurological

Unmet Needs
Clearly, Parkinson's disease is more than just a dopaminergic illness.
Further study of the nondopaminergic features may help physicians to
identify and develop new therapies-and new strategies are sorely needed.
Although levodopa is able to correct some of the most debilitating symptoms,
eventually disability develops that this drug cannot control. What these
people really need is a treatment that addresses the underlying cause of the
affliction. Such a neuroprotective therapy would slow or, ideally, stop the
disease in its tracks.
Of course, researchers would have much better results designing therapies to
delay progression of the disease if they understood what caused it in the
first place. Cell death in Parkinson's disease has been linked to several
different factors, including accumulation of free radicals (molecules with
unpaired electrons that are consequently highly reactive and can damage
neighboring molecules), malfunctioning mitochondria (the energy powerhouses
for cells), excitotoxicity (a pathological process by which excess levels of
the neurotransmitter glutamate cause an influx of calcium ions that then
kill or damage the cells), inflammation, apoptosis (programmed cell death)
and the deficiency of certain cell-growth factors. In addition, recent
research has indicated that the death of these neurons may be connected to
an impairment in the cell's capacity to clear abnormal and misfolded
proteins. This concept may provide an explanation for the presence of Lewy
bodies, which may be the vehicle by which a nerve cell tries to remove, or
at least segregate, these unwanted proteins. It is not immediately obvious,
however, how all these different processes interact and whether they are
necessarily the same from person to person. So although researchers may
design neuroprotective strategies to target specific problem areas, a given
approach may work for only a subset of patients-if it works at all.
Thus far, investigators have tested a number of candidate agents, including
antioxidants that clear free radicals, bioenergetics that enhance
mitochondrial function and antiapoptotics that interfere with the proteins
that signal the cell to commit suicide. However, to date no drug has
demonstrated the ability to slow the degeneration of neurons.
One of the main challenges lies in the design of clinical trials that can
accurately assess the effect of a given substance on the underlying disease.
None of the end points that have been used thus far have proved to be good
yardsticks for measuring the rate of disease progression. Even if
considerable improvement is seen during testing, it remains difficult for
physicians to determine whether the putative neuroprotective agent actually
slowed the death of brain cells or merely ameliorated symptoms in a way that
masks their ongoing loss. And one can't simply wait for the drug to wear off
to make that judgment, because that might require weeks or months-far too
long for patients to go without treatment. Until researchers are able to
address these problems, efforts to develop neuroprotective drugs will likely
remain unsuccessful.
The nondopaminergic features of Parkinson's disease may, however, provide a
way out of this conundrum. These symptoms do not respond to current drug
therapies and, indeed, progress despite them. So if a drug introduced early
in a patient's treatment results in a delay in the emergence of the
nondopaminergic problems, this result would be consistent with the agent
being truly neuroprotective. And even if the drug's effect were only to
alleviate symptoms, the discovery would still be momentous, because no drug
is currently known to be able to help with the nondopaminergic aspects of
the disease. For these reasons, the major trial sponsored by the National
Institutes of Health (NIH Exploratory Trials in Parkinson's Disease, or
"NET- PD") will use nondopaminergic features as primary endpoints.
Because some nondopaminergic features manifest themselves years before the
classic motor symptoms of the disease first appear, physicians may be able
to identify people who are in the earliest stages of the illness. These
individuals could be ideal candidates for testing an experimental
neuroprotective therapy. Indeed, it may be essential to introduce such
agents at this stage, when the disease is not so far advanced, if the
intervention is to slow the natural progression of the illness in a
significant way. The hope is that such early treatment might entirely
prevent the emergence of the motor impairments.
Ironically, the current interest in the nondopaminergic symptoms comes as a
direct result of the widespread success of levodopa therapy, without which
physicians would have continued to focus on the more dramatic motor features
of Parkinson's disease. Our current challenge is to develop new treatments
that can ameliorate, or better yet prevent, the development of all aspects
of this debilitating illness.
For relevant Web links, consult this issue of American Scientist Online:
http://www.americanscientist.org/ Issue TOC/issue/1081

This may be compared to a roundtable discussion about unmet medical needs in Neurology, Volume 62(1) Supplement 1, 13 January 2004, pp S1-S8

Dr. Olanow: I think it is important to appreciate that PD is not just a disorder of motor function. There are many non-motor features that can be important sources of disability for PD patients and are important to recognize and treat. These include depression, dementia, anxiety, mood disturbances, problems with sleep, sensory dysfunction, and a host of autonomic disturbances such as sexual dysfunction, bowel and bladder problems, constipation, and orthostatic hypotension. They are important because they may vary in severity in “on” and “off” stages, and may not respond at all to dopaminergic treatment. Many consider these to reflect more widespread degeneration than just the nigrostriatal system and when a neuroprotective therapy is designed it is important to appreciate that pathology in PD can be widespread and can affect neurons using multiple neurotransmitter systems.

Dr. Koller: It is interesting to consider whether non-motor or non-dopaminergic PD features could result from dopamine denervation and if they could be prevented if you provided levodopa in a more continuous and physiologic manner.

Dr. Olanow: You raise a good point. It is certainly possible that some of the features we consider non-dopaminergic may result initially from dopamine depletion. The SNc provides dopaminergic innervation throughout the basal ganglia and not just the striatum. There is also widespread dopamine innervation of the cerebral cortex, and it is intriguing to consider that a loss of dopamine may play a role in the evolution of dementia. Dopamine depletion also leads to overactivity of the subthalamic nucleus, which uses glutamate as a transmitter and could cause excitotoxic damage to target neurons. In the final analysis, however, I think you need to consider that, in sporadic PD, degeneration is more widespread than just the SNc, and this likely contributes to these other features. For example, patients with a Parkin mutation experience a relatively selective and severe SNc dopaminergic neuron loss with a young age of onset, but their subsequent course is relatively benign and they do not go on to develop non-motor features. If the problems were entirely a result of dopamine depletion, they would be expected to have a higher frequency of non-motor problems. That they do not suggests that it is the more widespread degeneration that occurs in sporadic PD that is the likely cause.

Dr. Obeso: I agree that it is important to consider non-nigral degeneration if we are to deal with the real unmet needs for PD, i.e., stopping disease progression. We see neuron degeneration and Lewy bodies in many brain areas, not just those with dopaminergic neurons. It is also interesting to consider whether PD starts in the nigra and spreads from there or if it is a multisystem process. I think it is possible that other areas degenerate first but represent clinically silent areas or are associated with clinical features that are not readily detected or not looked for.

Dr. Koller: But dementia is a later symptom in the disease. Does that not suggest that it is sequential?

Dr. Olanow: It is only a later feature because we choose to define it as such. If someone presents with dementia and develops Parkinsonism, we call it something else.


and more here (http://www.dopaction.com/textes/mppbttt.htm), read only black for english speaking ones -blue is for french translation

This is only the tiniest side of the whole neglectence, and nothing we did not know here, absolutely no reboot of thinking the underlying process, no cultural revolution, a pity indeed..............