Dear Ray
 
Well, whoever wrote the articles, one thing for sure is they are a good collection of articles.
 
Dr Chew> Date: Sun, 17 Aug 2008 18:39:22 -0700> From: [log in to unmask]> Subject: Re: Neglected side of PD> To: [log in to unmask]> > 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] > > > ----------------------------------------------------------------------> To > sign-off Parkinsn send a message to: mailto:[log in to unmask]> > In the body of the message put: signoff parkinsn> _________________________________________________________________> Easily publish your photos to your Spaces with Photo Gallery.> http://get.live.com/photogallery/overview> ----------------------------------------------------------------------> To sign-off Parkinsn send a message to: mailto:[log in to unmask]> In the body of the message put: signoff parkinsn > > ----------------------------------------------------------------------> To sign-off Parkinsn send a message to: mailto:[log in to unmask]> In the body of the message put: signoff parkinsn
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