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
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