Thanks Rayilynlee!  This was extremely informative :-)

Regards,

Nic

On Mon, Aug 4, 2008 at 4:13 AM, rayilynlee <[log in to unmask]> wrote:

> 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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