Dear Chew Nee Kong

Thank you for your response. I need to point out that I did not write this
article as so many of the responses I got to my posting seem to imply. Nor
can I take credit or blame for the many othero articles I post. If I
comment on a post I usually sign it "Ray" and I try to include the author(s)
as often as possible. I get most all my posts from Diane Wyshak and I
"plain text" them or clean them up of graphics, photos, ads, etc., so you
can read them without having to go to a website. During this process I have
inadvertently omitted sources.
I need to go back and read this one.

Ray

Rayilyn Brown
Director AZNPF
Arizona Chapter National Parkinson Foundation
[log in to unmask]
----- Original Message -----
From: "chew nee kong" <[log in to unmask]>
To: <[log in to unmask]>
Sent: Friday, August 15, 2008 9:08 PM
Subject: Re: Neglected side of PD


Dear Ray

That is an excellent summary of Parkinson's. I have personally found that
Parkinson's is the most complicated medical illness - in addition to the
motor and non-motor problems, the psychiatric complications are very common
in Parkinson's. Nowadays I have even considered the psychiatric problems as
part of Parkinson's itself. With the improved efficacy of the Parkinson's
medications, the the motor problems is less difficult to treat nowadays. In
fact, I find it much more difficult to manage the psychiatric part of PD.
Unfortunately, in my country, the psychiatric part of PD is always
neglected.

I am happy that there is a lot of research and health activities for
Parkinson's patients in your country. Over here in Malaysia, we have just
started to "wake up".

Recently, I wrote a book (a biography) on Mr. Lloyd Tan, the founding father
of the Malaysian Parkinson's support group. In this book "Selfless Warrior",
I also highlighted the neglect of the Malaysian Parkinson's community
(www.lloydtan-trust.com).

Well, let's work together for a better future for the world Parkinson's
community.

Dr Chew Nee Kong, Kuala Lumpur, Malaysia
   > Date: Sun, 3 Aug 2008 19:13:40 -0700> From: [log in to unmask]>
Subject: Neglected side of PD> To: [log in to unmask]> > The
Neglected Side of Parkinson's Disease> Posted on: Sunday, 3 August 2008,
03:00 CDT> 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 > 42).> 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 > writings.> 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 >
disease.> 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 > condition.> 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> Rayilyn Brown> Director AZNPF> Arizona Chapter National
Parkinson Foundation> [log in to unmask] >
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