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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