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ScienceWeek
SCIENCEWEEK
ScienceWeek
February 14, 2003
Vol. 7 Number 7
An Online Digest of Research in the Sciences
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Here is a biologist examining a culture of nerve cells in a
small dish. One set of nerve cells examining another set of
nerve cells. Not quite a trivial scenario. -- Anonymous
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Section 1
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Thematic Issue: Parkinson's Disease
1. Introduction
2. Some Historical Notes
3. Etiology of Parkinson's Disease
4. Neurobiology of Parkinson's Disease
5. Diagnosis and Treatment of Parkinson's Disease
6. Stem Cells and Parkinson's Disease
Notices and Subscription Information
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Section 2
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1. INTRODUCTION
Parkinson's disease (also called Parkinson disease) is a slowly
progressive degenerative central nervous system disorder
characterized by decreased movement, muscular rigidity, resting
tremor, and postural instability. The disease was first described
by James Parkinson in 1817 and is now known to be associated with
degeneration of one or more specific regions of the brain
(dopaminergic neuron groups) and resultant loss of neural
connections (projections) from these groups to several important
brain centers. Dopaminergic neurons are nerve cells that use
*dopamine as a *neurotransmitter substance. Dopamine is found in
several major areas of the brain, and it is the degeneration of
so-called dopamine neurons that is apparently involved in
Parkinson's disease.
One must distinguish "parkinsonism" from Parkinson's disease.
Parkinsonism is a syndrome (a complex of symptoms; in this
context, a complex of various movement symptoms) that may be
caused by Parkinson's disease, but which may also be caused by
infectious, vascular, pharmacological, toxic, metabolic,
structural, and various degenerative disorders. In other words,
not every individual with parkinsonism has Parkinson's disease.
The major differentiating characteristic is the response to the
drug "*levodopa", which is converted by the body into dopamine.
Individuals with parkinsonism who respond to levodopa treatment
receive a diagnosis of Parkinson's disease. At the present time,
Parkinson's disease is the 4th most common neurodegenerative
disease of the elderly. It affects approximately 1 percent of
people older than 65 years, and 0.4 percent of people between 40
and 65 years.
The disease has an early-onset form (age =< 50 years), and a
childhood form (juvenile Parkinson's disease), but most cases are
adult onset, with incidence increasing markedly past age 50
years.
The causes of Parkinson's disease are largely unknown, but there
is evidence that the disease has a genetic component. In a few
large families with early onset Parkinson's disease or juvenile
Parkinson's disease, the disease is transmitted as an autosomal
dominant or recessive trait resulting from mutations in the genes
encoding the proteins alpha-synuclein and parkin, respectively.
However, in the majority of families affected by Parkinson's
disease, the disease appears to skip generations, irrespective of
the age of onset. Therefore, this disease is considered a
complex, multifactorial disease resulting from interaction
between one or more genes and the environment.
Notes:
... ... *dopamine: Dopamine is an important neurotransmitter in
the human brain, and it has been implicated in several serious
behavioral pathologies. There is a dopamine hypothesis of
depression, a dopamine hypothesis of schizophrenia, and dopamine
has also been implicated in the reinforcing effects of
psychostimulant drugs of abuse such as cocaine and amphetamine.
... ... *neurotransmitter substance: Neurotransmitters are
chemical substances released at the terminals of nerve axons in
response to the propagation of an impulse to the end of that
axon. The neurotransmitter substance diffuses into the synapse,
the junction between the presynaptic nerve ending and the
postsynaptic neuron, and at the membrane of the postsynaptic
neuron the transmitter substance interacts with a receptor.
Depending on the type of receptor, the result may be an
excitatory or an inhibitory effect on the postsynaptic nerve
cell.
... ... *levodopa: (L-dopa) The biologically active form of
"dopa", which is converted into dopamine. Dopamine = 3,4-
dihydroxyphenylethylamine. Dopa = 3,4-dihydroxypheynylalanine.
PARKINSON'S DISEASE: AN OPPORTUNITY FOR NOVEL THERAPEUTIC
APPROACHES.
"Parkinson's disease is one of the major degenerative diseases of
the nervous system. Described by James Parkinson in 1817, this
disorder is characterized by tremor at rest, slowness of movement
(bradykinesia), rigidity of the extremities and neck, and minimal
facial expressions. Walking entails short steps, stooped posture,
and a paucity of associated movements (e. g., arm swinging). To
make matters worse, in some patients these abnormalities of motor
function are associated with dementia. Following a gradual onset
between the ages of 50 and 70, the disease progresses slowly and
culminates in death 10 to 20 years later. The defects in motor
function are due to the progressive loss of dopaminergic neurons
in the substantia nigra pars compacta, a population that projects
to and innervates neurons in the caudate and putamen. The cause
of the progressive deterioration of these dopaminergic neurons is
not known. In contrast to other neurodegenerative diseases such
as Alzheimer's disease or amyotrophic lateral sclerosis, in
Parkinson's disease the spatial distribution of the degenerating
neurons is largely restricted to the substantia nigra pars
Compacta. This spatial restriction, combined with the defined and
relatively homogeneous phenotype of the degenerating neurons (i.
e., dopaminergic neurons), has provided an opportunity for novel
therapeutic approaches to this disorder."
D. Purves et al: Neuroscience. Sinauer Associates 2001, p.403.
DOPAMINE AND DOPAMINE RECEPTORS
"Dopamine, a catecholamine, is synthesized in the terminals of
dopaminergic neurons from tyrosine, which is transported across
the blood-brain barrier by an active process. The rate-limiting
step in the synthesis of dopamine is the conversion of L-tyrosine
to L-dihydroxy-phenylalanine (L-DOPA), catalyzed by the enzyme
tyrosine hydroxylase which is present within catecholaminergic
neurons. L-DOPA is converted rapidly to dopamine by aromatic L-
amino acid decarboxylase. In dopaminergic nerve terminals,
dopamine is taken up into vesicles by a transporter protein; this
process is blocked by reserpine, which leads to depletion of
dopamine. Release of dopamine from nerve terminals occurs through
exocytosis of presynaptic vesicles, a process that is triggered
by depolarization leading to entry of Ca(++). Once dopamine is in
the synaptic cleft, its actions may be terminated by re-uptake
through a membrane carrier protein, a process antagonized by
drugs such as cocaine. Alternatively, dopamine can be degraded by
the sequential actions of monoamine oxidase (MAO) and catechol-O-
methyl transferase (COMT) to yield two metabolic products, 3,4-
dihydroxyphenylacetic acid (DOPAC) and 3-methoxy-4-
hydroxyphenylacetic acid (HVA). In human beings, HVA is the
primary product of the metabolism of dopamine.
"The actions of dopamine in the brain are mediated by a family of
dopamine receptor proteins. Two types of dopamine receptors were
identified in the mammalian brain using pharmacological
techniques: Dl receptors, which stimulate the synthesis of the
intracellular second messenger cyclic AMP, and D2 receptors,
which inhibit cyclic AMP synthesis. The recent application of
molecular genetics to the study of dopamine receptors has
provided a wealth of information regarding the structures of
these proteins and has revealed a more complex receptor situation
than originally envisioned. At present, five distinct dopamine
receptors are known to exist. The dopamine receptors share
several structural features, including the presence of seven
alpha-helical segments capable of spanning the cell membrane.
This structure identifies the dopamine receptors as members of
the larger superfamily of seven-transmembrane-region receptor
proteins, which includes other important neural receptors such as
beta-adrenergic receptors, olfactory receptors, and the visual
pigment rhodopsin. All members of this superfamily act through
guanine nucleotide-binding proteins."
J.G. Hardman et al: Goodman & Gilman's The Pharmacological Basis
of Therapeutics 9th Ed. McGraw-Hill 1996, p.506.
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2. SOME HISTORICAL NOTES
Note 1:
"In 1817, James Parkinson [1755-1824], a British physician,
reported on several patients with a condition now recognized as
Parkinson's disease. In his monograph titled "An Essay On The
Shaking Palsy" he gave an account of the major symptoms of the
disease that would later bear his name. Over the next one hundred
years, there was little advancement in the understanding of this
disease, although the prominent French neurologist Jean Martin
Charcot [1825-1893] elaborated on Parkinson's clinical report and
actually named the disease after James Parkinson. In the early
1900s, the pathology of the disease was identified, but it was
not until the mid 1950s that a scientific breakthrough emerged
with the suggestion by the Swedish neuroscientist, Arvid Carlsson
[winner of the Nobel Prize in Physiology or Medicine in 2000]
that patients with Parkinson's disease suffered a deficiency of
dopamine in a certain region of the brain called the striatum.
This speculation was quickly confirmed by two Viennese
neuroscientists, leading to the first of several trials of the
dopamine precursor levodopa, the active ingredient in Sinemet,
one of the most effective drugs used to treat the disease."
Author unknown:
http://www.parkinsonsinstitute.org/movement_disorders/parkinsons
.html
Note 2:
Lauren White discusses Pierre Marie Charcot (1825-1893), the
author making the following points:
1) Charcot worked with Parkinson's disease from 1860 to 1890 at
the Salpetriere clinic in Paris. He related the disease to
depression, catatonia, and hysteria, and called Parkinson's
Disease a 'neurosis'. He saw the final futile outcome of the
struggle between the patient and Parkinson's disease as the
tremor, rigidity, and akinesia of his patients. It was Charcot
that coined the term 'la maladie de Parkinson'. With his
colleague Edme Felix Alfred Vulpian [1826-1887], Charcot studied
multiple sclerosis and employed a sphygmograph to distinguish
between multiple sclerosis and Parkinson's disease. Charcot
noted that tremors were seen in multiple sclerosis during
voluntary movements, while in Parkinson's disease tremors were
seen during involuntary movements. He described these observation
in the first volume of his 'Lectures on the Nervous System',
published in 1872.
2) Charcot observed the rigidity associated with Parkinson's
disease and wondered why Parkinson had not reported it. Charcot
also noted the blank stare and postural changes associated with
an advanced course of the disease. In regard to hand movements,
Charcot wrote, 'At this stage of the disease... we occasionally
find the rhythmical and involuntary oscillations of the different
parts of the hand recalling the appearance of certain coordinated
movements. Thus in some patients, the thumb moves over the
fingers, as when a pencil or paper ball is rolled between them;
in others, the movements are more complicated and resemble what
takes place when crumbling a piece of bread.' Charcot also
observed the propulsions, or forward running movements, of his
less progressed patients, as well as their tendency to jerk
backward. Charcot also noticed subtle behavioral changes such as
how they spoke between their teeth and changes in handwriting.
3) Charcot also devised several novel treatments for Parkinson's
disease, although most of his inventions were more creative than
therapeutic. He built a trembling armchair for patients after he
observed that his patients seemed to tremble less after traveling
long distances in shaky carriages. He also devised a harness
that bounced his patients into the air. In addition to his work
on multiple sclerosis and Parkinson's disease, Charcot studied
amyotropic lateral sclerosis, cerebral localization, Gilles de la
Tourette's syndrome, hysteria, and Charcot-Marie tooth disease
before his death in 1893. Charcot was apparently one of the most
prolific clinical scientists in history, a physician especially
talented in observations of medical conditions.
Lauren White: http://www.geocities.com/smithie24/charcot.html
Note 3:
Robert A. Fink discusses the history of Parkinson's disease, the
author making the following points:
1) James Parkinson was more known for his unpopular views of
social reform than for the disease that bears his name. Parkinson
was anti-war, anti-military, believed in what today would be
called socialism, supported civil disobedience, and did as much
work with his hobbies, geology and paleontology, as he did with
medicine. He was even implicated in a plot to assassinate King
George III with a poisoned dart fired from a popgun, but he was
later cleared of that charge. He studied Latin and Greek as a
young man, and came to medicine by taking over his father's
vocation as a general practitioner in a suburb of London. He
wrote a little known paper on 'The Nature and Cure of Gout' in
1805, and this was followed, in 1817 by his classical "Essay on
the Shaking Palsy", which attached his name forever to that
illness. However, he was never honored for his astute
observations of Parkinson's disease, and there is not even a
likeness of James Parkinson currently available.
2) While observing people on the streets of London, Parkinson
noted that some suffered from a tremor which, along with muscle
weakness, worsened with time. The Latin name for this condition
was "paralysis agitans", or the "shaking palsy"; but with no
standardized neurological examination available in the 19th
century, the symptom complex, which is well-known today, was not
understood. Despite the lack of a standardized method of
diagnosis, however, one of the main features of the detection of
this condition was established early in the history of medicine:
a careful observation of the patient.
3) It was not until the late 19th century that physicians had
some understanding of the anatomy and physiology of the nervous
system. Pioneering work by such researchers in anatomy and
physiology as [Santiago] Ramon y Cajal [1852-1934] (from Spain)
and [Charles] Sherrington [1857-1952] (Britain) revealed the fine
anatomy of the brain, and when studies were made of the brains of
patients who had died with Parkinson's disease, it was learned
that certain areas of the brains of these patients were
apparently affected by the disease. These areas, including such
structures as the substantia nigra (so named because the tissue
is black with pigment), globus pallidus, and parts of the
thalamus, were all joined together in a generic description as
the "basal ganglia", or collections of nerve cells at the base of
the brain. The term "basal ganglia" refers to these multiple
areas, many of which play a role in other illnesses that are
different from Parkinson's disease but which are also associated
with similar symptoms. As knowledge grew and the physiology of
the nervous system began to be understood, it became apparent
that Parkinson's disease was a disease of both muscle weakness
and abnormal movement. The tremor of Parkinson's disease is
usually described as a typical "pill-rolling" tremor, low in
frequency (approximately 4 to 5 cycles per second). The tremor is
a "tremor at rest", i.e., it is most pronounced when the patient
is not making a voluntary movement, and it tends to decrease or
even disappear with voluntary movements.
Robert A. Fink: http://www.rafink.com/downloads/parktalk.pdf
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3. ETIOLOGY OF PARKINSON'S DISEASE
GENETICS AND ENVIRONMENT IN PARKINSON'S DISEASE
K. Steece-Collier et al (Rush Presbyterian Medical Center
Chicago, US) discuss Parkinson's disease, the authors making the
following points:
1) Idiopathic Parkinson's disease (PD) is the second most common
neurodegenerative disorder and affects more than 1 million
Americans over the age of 55. The disease selectively affects
dopaminergic neurons of the substantia nigra pars compacta,
culminating in their demise. After 50% of the dopamine neurons
and 75-80% of striatal dopamine is lost, patients start to
exhibit the classical symptoms of PD including bradykinesia,
postural reflex impairment, resting tremor, and rigidity (1,2).
Although there are several treatments that are effective for a
number of years, their usefulness wanes over time and is
accompanied by unacceptable side effects. New therapies are
clearly needed for this disorder.
2) Despite many years of focused research, the causes of this
disease remain to be elucidated. Understanding the cause of PD is
critical as that knowledge could lead to directed research that
will develop new and potent therapies. The relative contributions
of genetic versus environmental factors regarding the cause of PD
have been hotly debated. In an attempt to define a cause for this
disease, early epidemiological studies examining twins suggested
an absence of genetic factors (3). However, these studies were
not definitive and could never account for differences in disease
progression between twin pairs that could account for discordance
in diagnosis.
3) The discovery that the protoxin n-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP) causes parkinsonism in both humans and
nonhumans further strengthened the hypothesis that PD had an
environmental etiology. Other environmental toxins have been
shown to induce a parkinsonian state as well, supporting this
view (4). However, the recent discovery of inherited forms of PD
shifted the emphasis back to genetic factors. Among the different
genetic forms of PD, mutations in the gene encoding for alpha-
synuclein have received the most attention. Mutations in this
gene cause rare forms of PD. Furthermore, alpha-synuclein is also
present in the Lewy bodies that are the pathoneumonic feature of
PD.(5)
References (abridged):
1. Fearnley, J. M. & Lees, A. J. (1991) Brain 114, 2283-2301.
2. Marsden, C. D. (1994) Clin. Neuropharmacol. 17, Suppl. 2, S32-
S44.
3. Piccini, P. , Burn, D. J. , Ceravolo, R. , Maraganore, D. &
Brooks, D. J. (1999) Ann. Neurol. 45, 577-582.
4. McCormack, A. L. , Thiruchelvam, M. , Manning-Bog, A. B. ,
Thiffault, C. , Langston, J. W. , Cory-Slechta, D. A. & Di Monte,
D. A. (2002) Neurobiol. Dis. 10, 119-127.
5. Dauer, W. , Kholodilov, N. , Vila, M. , Trillat, A.-C. ,
Goodchild, R. , Larsen, K. E. , Staal, R. , Tieu, K. , Schmitz,
Y. , Yuan, C. A. , et al. (2002) Proc. Natl. Acad. Sci. USA 99,
14524-14529.
Proc. Nat. Acad. Sci. 2002 99:13972
Related Background Brief:
RECENT ADVANCES IN THE GENETICS AND PATHOGENESIS OF PARKINSON
DISEASE. The identification of three genes and several additional
loci associated with inherited forms of levodopa-responsive PD
has confirmed that this is not a single disorder. Yet, analyses
of the structure and function of these gene products point to the
critical role of protein aggregation in dopaminergic neurons of
the substantia nigra as the common mechanism leading to
neurodegeneration in all known forms of this disease. The three
specific genes identified to date -- alpha-synuclein, Parkin, and
ubiquitin C terminal hydrolase L1 -- are either closely involved
in the proper functioning of the ubiquitin-proteasome pathway or
are degraded by this protein-clearing machinery of cells.
Knowledge gained from genetically transmitted PD also has clear
implications for nonfamilial forms of the disease. Lewy bodies,
even in sporadic PD, contain these three gene products,
particularly abundant amounts of fibrillar alpha-synuclein.
Increased aggregation of alpha-synuclein by oxidative stress, as
well as oxidant-induced proteasomal dysfunction, link genetic and
potential environmental factors in the onset and progression of
the disease. The biochemical and molecular cascades elucidated
from genetic studies in PD can provide novel targets for curative
therapies. M. Maral Mouradian: Neurology 2002 58:179
Related Background Brief:
HUMAN ALPHA-SYNUCLEIN OVER-EXPRESSION INCREASES INTRACELLULAR
REACTIVE OXYGEN SPECIES LEVELS AND SUSCEPTIBILITY TO DOPAMINE.
alpha-Synuclein is a major component of Lewy bodies found in the
brains of patients with Parkinson's disease (PD). Two point
mutations in alpha-synuclein (A53T and A30P) are identified in
few families with dominantly inherited PD. Yet the mechanism by
which this protein is involved in nigral cell death remains
poorly understood. Mounting evidence suggests the importance of
oxidative stress in the pathogenesis of PD. The authors report
they investigated the effects of wild-type and two mutant forms
of alpha-synuclein on intracellular reactive oxygen species (ROS)
levels using clonal SH-SY5Y cells engineered to over-express
these proteins. All three cell lines, and particularly mutant
alpha-synuclein-expressing cells, had increased ROS levels
relative to control LacZ-engineered cells. In addition, cell
viability was significantly curtailed following the exposure of
all three alpha-synuclein-engineered cells to dopamine, but more
so with mutant alpha-synuclein. The authors suggest these results
indicate that over-expression of alpha-synuclein, and especially
its mutant forms, exaggerates the vulnerability of neurons to
dopamine-induced cell death through excess intracellular ROS
generation. Thus, these findings provide a link between mutations
or over-expression of alpha-synuclein and apoptosis of
dopaminergic neurons by lowering the threshold of these cells to
oxidative damage. E. Junn and M.M. Mouradian: Neurosci Lett 2002
320:146.
Related Background:
FACTORS IN THE ETIOLOGY OF PARKINSON'S DISEASE
W.K. Scott et al (Duke University, US) discuss the etiology of
Parkinson disease (also called Parkinson's disease), the authors
making the following points:
1) Parkinson disease is a neurodegenerative disease that affects
more than 500,000 people in the US, and the economic, social, and
emotional burden of this disease will increase as the population
ages.
2) Controversy has surrounded the etiology of Parkinson disease,
with evidence suggesting that both genetic and environmental
factors influence disease risk. Familial aggregation of Parkinson
disease has been observed for decades, and data from family
studies, including a recent large study from Iceland, have shown
that the sibling recurrence ratio ranges from 2 to 10, suggesting
that a genetic component to Parkinson disease exists. However,
twin studies have produced conflicting results concerning the
genetic contributions, suggesting that little if any genetic
contribution exists in the development of Parkinson disease.
3) The authors carried out what is apparently the largest
complete genomic screen in idiopathic Parkinson disease. The
authors suggest that the results provide strong evidence that the
parkin gene is influential in the development of early-onset
Parkinson disease, that several genes may influence the
development of late-onset Parkinson disease, and that age at
onset and levodopa response pattern may be useful discriminators
for genetic etiology. "Like many complex traits, it is likely
that Parkinson disease is caused by an interaction of genetic and
environmental risk factors, in which specific genetic templates
are more susceptible to the influences of environmental
exposures."
.J. Am. Med. Assoc. 2001 286:2239
Related Background:
THE ENVIRONMENT AND PARKINSON'S DISEASE
Bette Hileman (CEN) discusses the relation between Parkinson's
disease and the environment, the author making the following
points:
1) Parkinson's disease is a progressive and incurable disorder,
and the second most common neurodegenerative disease in the US.
The disease begins when a class of brain cells that produce
dopamine start to die, symptoms becoming apparent only when 60 to
80 percent of these cells are dead. The disease is characterized
by resting tremor, rigidity, slow movement, postural instability,
and progressively involuntary writhing movements, paralysis, and
an inability to talk or even swallow. Although the medication
levodopa, a dopamine precursor, relieves many symptoms of the
disease, the effectiveness of the medication declines as the
disease progresses.
2) Only approximately 10 percent of cases of Parkinson's disease
are familial, i.e., apparently caused by inherited dysfunction.
The remainder of cases apparently result from unknown factors
that include an interaction between genetic susceptibility and
the environment. Essentially 3 lines of evidence have led
researchers to believe that chemical exposures, particularly to
pesticides, play a role in some cases of Parkinson's disease: a)
people who live in farming areas, especially those who drink well
water, and who have a history of exposure to pesticides, are more
likely to contract the disease; b) several studies have
demonstrated that those who die of the disease have higher levels
of organochlorine pesticides in their brains than the general
population; c) in the early 1980s, a group of young people
developed Parkinson's disease after taking illegal drugs
containing a contaminant (MPTP), a substance whose metabolite is
similar to the pesticide paraquat.
Chem. & Eng. News 2001 17 Sep
Related Background:
LINK BETWEEN HOME PESTICIDE EXPOSURE AND PARKINSON'S DISEASE
Joan Stephenson (J. Amer. Med. Assoc., US) reviews a presentation
by Lorene Nelson (Stanford University) at a recent meeting of the
American Academy of Neurology, at which meeting Nelson presented
evidence of a link between home pesticide use and Parkinson's
disease. Stephenson makes the following points:
1) The study involved 496 patients diagnosed with Parkinson's
disease within the Kaiser Permanente Medical Care Program of
Northern California during the years 1994-1995, and 541 age- and
sex-matched controls from the same population. Using in-person
structured interviews, a research team collected information
about lifetime history of exposure to home pesticides
(herbicides, insecticides, and fungicides) prior to diagnosis.
2) After controlling for known risk factors such as family
history of the disorder, occupational exposure to pesticides and
herbicides, and cigarette smoking, the investigators found that
home exposure to insecticides and herbicides were associated with
an increased risk of Parkinson's disease. Fungicide exposure was
not linked with an increased risk of the disorder.
3) Individuals with high-level herbicide exposure had a 70
percent increased risk compared with those who were not exposed.
People who used insecticides in the garden showed a 50 percent
increased risk compared to those who had never been exposed to
home pesticides of any type. In-home use of insect-killing
chemicals was associated with a 70 percent increased risk of
Parkinson's disease compared with no use of pesticide.
4) In her report to the American Academy of Neurology, Lorene
Nelson, a neuroepidemiologist, pointed out that the idea that
pesticides might be linked with Parkinson's disease is
biologically plausible, since many pesticides are neurotoxic and
may affect various aspects of central nervous system function,
possibly even resulting in the death of specific nerve cells.
Previous studies have found a substantially increased rate of
Parkinson's disease among city dwellers who gardened for a hobby.
J. Am. Med. Assoc. 2000 283:3055
Related Background Brief:
ENVIRONMENTAL RISK FACTORS AND PARKINSON'S DISEASE: SELECTIVE
DEGENERATION OF NIGRAL DOPAMINERGIC NEURONS CAUSED BY THE
HERBICIDE PARAQUAT. Environmental toxicants and in particular
pesticides have been implicated as risk factors in Parkinson's
disease (PD). The authors report a study whose purpose was to
determine if selective nigrostriatal degeneration could be
reproduced by systemic exposure of mice to the widely used
herbicide paraquat. Repeated intraperitoneal paraquat injections
killed dopaminergic neurons in the substantia nigra (SN) pars
compacta, as assessed by stereological counting of tyrosine
hydroxylase (TH)-immunoreactive and Nissl-stained neurons. This
cell loss was dose- and age-dependent. Several lines of evidence
indicated selective vulnerability of dopaminergic neurons to
paraquat. The number of GABAergic cells was not decreased in the
SN pars reticulata, and counting of Nissl-stained neurons in the
hippocampus did not reveal any change in paraquat-treated mice.
Degenerating cell bodies were observed by silver staining, but
only in the SN pars compacta, and glial response was present in
the ventral mesencephalon but not in the frontal cortex and
cerebellum. No significant depletion of striatal dopamine
followed paraquat administration. On the other hand, enhanced
dopamine synthesis was suggested by an increase in TH activity.
These findings unequivocally show that selective dopaminergic
degeneration, one of the pathological hallmarks of PD, is also a
characteristic of paraquat neurotoxicity. The apparent
discrepancy between pathological (i.e., neurodegeneration) and
neurochemical (i.e., lack of significant dopamine loss) effects
represents another important feature of this paraquat model and
is probably a reflection of compensatory mechanisms by which
neurons that survive damage are capable of restoring
neurotransmitter tissue levels. A.L. McCormack et al: Neurobiol
Dis 2002 10:119.
Related Background:
GENETIC COMPONENTS IN PARKINSON'S DISEASE
S. Sveinbjoernsdoettir et al (9 authors at 2 installations, IS
US) report a study of familial aggregation of Parkinson's disease
in Iceland, the authors making the following points:
1) The authors reviewed the medical records and confirmed the
diagnosis of Parkinson's disease in 772 living and deceased
patients in whom the disease had been diagnosed during the
previous 50 years in Iceland. With the use of an extensive
computerized database containing genealogical information on
610,920 people in Iceland during the past 11 centuries, several
analyses were conducted to determine whether the patients were
more related to each other than random members of the population
(the control subjects).
2) Patients with Parkinson's disease, including a subgroup of 560
patients with late-onset disease, were significantly more related
to each other than were subjects in matched groups of controls,
and this relatedness extended beyond the nuclear family. The risk
ratio for Parkinson's disease was 6.7 for siblings, 3.2 for
offspring, and 2.7 for nephews and nieces of patients with late-
onset Parkinson's disease.
3) In summary, the authors suggest late-onset Parkinson's disease
has a genetic component as well as an environmental component.
The authors conclude: "There has been a recent trend to discount
the possibility that genetic factors contribute to the late-onset
form of the disease, which represents the majority of cases of
Parkinson's disease. Although the search for environmental
factors contributing to late-onset Parkinson's disease is
important and should continue, our data suggest that the search
to discover its genetic basis should also continue."
New Engl. J. Med. 2000 343:1765
Related Background Brief:
THE ROLE OF INHERITANCE IN SPORADIC PARKINSON'S DISEASE: EVIDENCE
FROM A LONGITUDINAL STUDY OF DOPAMINERGIC FUNCTION IN TWINS.
Despite the major finding of a genetic defect being responsible
for the Parkinson's disease (PD) phenotype in some kindreds with
dominantly transmitted PD, the role of inheritance in the cause
of the more widespread sporadic form of the disease is still
unclear. Twin studies are a classic tool for assessing the
influence of hereditary factors in diseases; however, the
application of this approach to late-onset illnesses, like PD,
poses some problems because of the identification of subclinical
cases. The authors report that in the present longitudinal study
they have used [18F]dopa and positron emission tomography to
study dopaminergic function in twin pairs at baseline clinically
discordant for PD. At baseline, the concordance for subclinical
striatal dopaminergic dysfunction was found to be significantly
higher in 18 monozygotic than in 16 dizygotic twin pairs (55% vs
18%, respectively). The asymptomatic monozygotic co-twins all
showed progressive loss of dopaminergic function over 7 years and
4 developed clinical PD. None of the dizygotic twin pairs became
clinically concordant. At follow-up, the combined concordance
levels for subclinical dopaminergic dysfunction and clinical PD
were 75% in the 12 monozygotic and 22% in the 9 dizygotic twin
pairs evaluated twice. The authors suggest their findings
indicate a substantial role for inheritance in sporadic PD. P.
Piccini et al: Ann Neurol 2000 47:682.
Related Background Brief:
ETIOLOGY AND PATHOGENESIS OF PARKINSON'S DISEASE. Parkinson's
disease (PD) is an age-related neurodegenerative disorder that
affects approximately 1 million persons in the United States. It
is characterized by resting tremor, rigidity, bradykinesia or
slowness, gait disturbance, and postural instability.
Pathological features include degeneration of dopaminergic
neurons in the substantia nigra pars compacta coupled with
intracytoplasmic inclusions known as Lewy bodies.
Neurodegeneration and Lewy bodies can also be found in the locus
ceruleus, nucleus basalis, hypothalamus, cerebral cortex, cranial
nerve motor nuclei, and central and peripheral components of the
autonomic nervous system. Current treatment consists of a
dopamine replacement strategy using primarily the dopamine
precursor levodopa. While levodopa provides benefit to virtually
all PD patients, after 5 10 years of treatment the majority of
patients develop adverse events in the form of dyskinesia
(involuntary movements) and fluctuations in motor response.
Further, disease progression is associated with the development
of dementia, autonomic dysfunction, and postural instability,
which do not respond to levodopa therapy. Accordingly, research
efforts have been directed toward understanding the etiology and
pathogenesis of PD in the hope of developing a more effective
therapy that will slow or halt the natural progression of PD. C.
W. Olanow and W. G. Tatton: Annu. Rev. Neurosci. 1999 22:123.
Related Background:
PERSONALITY TRAITS IN PARKINSON'S DISEASE
V. Kaasinen et al (University of Turku, FI) discuss personality
traits in Parkinson's disease, the authors making the following
points:
1) For nearly a century, it has been suggested that Parkinson's
disease could be associated with a specific personality type. The
"parkinsonian personality" has been described as compulsive,
industrious, introverted, morally rigid, punctual, serious,
stoic, and quiet. There are studies that have indicated that
Parkinson's disease patients score lower than controls on a
personality trait called "novelty-seeking", which, according to
the theory of Cloninger (1987), is the temperament trait
primarily modulated by dopamine. The description of the low
novelty-seeking personality type is similar to the description of
the parkinsonian personality type in the literature, and it has
thus been hypothesized that when people approach novel stimuli,
the normal pleasurable rewarding increase in dopamine is not
possible in patients with Parkinson's disease and the result is
less novelty-seeking -- the parkinsonian personality.
2) Because the risk factors for Parkinson's disease are unclear,
the possibility of a distinctive parkinsonian personality is
intriguing and of clinical importance. If there is indeed a
premorbid, dopamine-related, low-novelty-seeking personality type
in Parkinson's disease, relatively simple personality screenings
could be used to evaluate individual risk for the disease.
3) To test the hypothesis that Parkinson's disease is associated
with a specific dopamine-related personality type, the authors
investigated the personality structures of 61 unmedicated
Parkinson's disease patients and 45 healthy controls. In
addition, in 47 Parkinson's disease patients, radioisotope
dopamine distribution in the brain was directly measured with
positron emission tomography and magnetic resonance imaging.
4) The authors report that although the results of this study are
not in disagreement with the concept of a low-novelty-seeking
personality type in Parkinson's disease, this personality type
does not appear to be dopamine dependent. The authors suggest
that the observed correlation between the personality trait of
harm avoidance and dopamine distribution may reflect a specific
feedback circuitry of neurotransmitters associated with negative
emotionality in Parkinson's disease.
Proc. Nat. Acad. Sci. 2001 98:13272
Related Background Brief:
AGING AND PARKINSON'S DISEASE: SUBSTANTIA NIGRA REGIONAL
SELECTIVITY. The authors report that the micro-architecture of
the substantia nigra was studied in control cases of varying age
and patients with parkinsonism. A single 7 micron section stained
with hematoxylin and eosin was examined at a specific level
within the caudal nigra using strict criteria. The pars compacta
was divided into a ventral and a dorsal tier, and each tier was
further subdivided into 3 regions. In 36 control cases there was
a linear fallout of pigmented neurons with advancing age in the
pars compacta of the caudal substantia nigra at a rate of 4.7%
per decade. Regionally, the lateral ventral tier was relatively
spared (2.1% loss per decade) compared with the medial ventral
tier (5.4%) and the dorsal tier (6.9%). In 20 Parkinson's disease
(PD) cases of varying disease duration there was an exponential
loss of pigmented neurons with a 45% loss in the first decade.
Regionally, the pattern was opposite to ageing. Loss was greatest
in the lateral ventral tier (average loss 91%) followed by the
medial ventral tier (71%) and the dorsal tier (56%). The
presymptomatic phase of PD from the onset of neuronal loss was
estimated to be about 5 yrs. This phase is represented by
incidental Lewy body cases: individuals who die without clinical
signs of PD or dementia, but who are found to have Lewy bodies at
post-mortem. In 7 cases cell loss was confined to the lateral
ventral tier (average loss 52%) congruent with the lateral
ventral selectivity of symptomatic PD. It was calculated that at
the onset of symptoms there was a 68% cell loss in the lateral
ventral tier and a 48% loss in the caudal nigra as a whole. The
regional selectivity of PD is relatively specific. In 15 cases of
striatonigral degeneration the distribution of cell loss was
similar, but the loss in the dorsal tier was greater than PD by
21%. In 14 cases of Steele-Richardson-Olszewski syndrome (SRO)
there was no predilection for the lateral ventral tier, but a
tendency to involve the medial nigra and spare the lateral. These
findings suggest that age-related attrition of pigmented nigral
cells is not an important factor in the pathogenesis of PD. J.M.
Fearnley and A.J. Lees: Brain 1991 114:2283.
Related Background:
THE ETIOLOGY OF IDIOPATHIC PARKINSON'S DISEASE
D.B. Ramsden et al (University of Birmingham, UK) discuss the
etiology of Parkinson's disease, the authors making the following
points:
1) Idiopathic Parkinson's disease (i.e., Parkinson's disease of
unknown cause) appears not to be a single entity but rather a
spectrum of conditions resulting from the death of the pigmented
dopaminergic neurons of the substantia nigra, pars compacta,
which ultimately leads to the one single, fatal endpoint. As
such, this spectrum is unlikely to have a single cause. Despite
an intense research effort over many years, these causes still
await elucidation. Various factors contribute to the difficulties
in the search. Some obvious ones are the long period between the
initiation of the disease process and the manifestation of
clinical symptoms, the lack of any distinctive blood biochemistry
with which to trace the disease process, and the inadequacy of
current animal models.
2) Quite when idiopathic Parkinson's disease begins is uncertain.
Based on the premise that clinical symptoms appear when
approximately 50% of pigmented dopaminergic neurons are dead and
the surviving ones can supply the striatum with only about 20 30%
of its dopamine demand, mathematical models of neuronal death
rates suggest that there may be as small a gap as three years or
as large a one as 20. However, beyond the strictly mathematical,
clinical case histories of twins suggest the presence of a
"parkinsonian" personality that, in hindsight, was present in
very early life. Whether such a personality exists and, if so,
whether it implies the presence of the disease process so early
in life remain obscure.
3) Nevertheless, the concept that early life events might be of
crucial importance has been moved from the realms of fancy with
the recognition of the role of specific transcription factors in
brain development, particularly the proteins Nurr 1 (and its
related subfamily members), Lmx1b, and Ptx-3. These are
transcription factors that are involved in determining
neurogenesis in the basal ganglia. It has been hypothesized that
immature neurons die by apoptosis because of neurotrophic factor
deprivation, as a result of failing to make adequate contacts in
their target sites, whereas mature neurons die because of toxic
insult. However, the quality of contact and/or degree of
neurotrophic support in early life may be of importance in
determining the length of survival. In addition, these proteins
are expressed throughout life in the basal ganglia, which
suggests that they have roles in maintaining the continuing
health of specific neurons and makes them worthy of consideration
in terms of the etiology of idiopathic Parkinson's disease.
J Clin Pathol: Mol Pathol 2001 54:369
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4. NEUROBIOLOGY OF PARKINSON'S DISEASE
A DROSOPHILA MODEL OF PARKINSON'S DISEASE
M.B. Feany and W.W. Bender (Harvard University, US) discuss a
model of Parkinson't disease, the authors making the following
points:
1) It is unclear how mutations in alpha-synuclein, an abundant
neuronal protein of unknown function, produce neurodegeneration
in familial cases of Parkinson's disease. However, the dominant
inheritance pattern and production of insoluble protein
aggregates indicate a toxic dominant mechanism, perhaps relating
to abnormal protein accumulation. Expression of human alpha-
synuclein in Drosophila might therefore model Parkinson's
disease. The authors report they have produced transgenic fly
lines that produce normal human alpha-synuclein and separate
lines with each of the two mutant proteins linked to familial
Parkinson's disease, A30P and A53T alpha-synuclein.
2) The authors use a bipartite expression system that relies on
transcriptional activation by the yeast protein GAL4 to express
normal and mutant alpha-synuclein in flies. Normal and mutant
human alpha-synuclein complementary DNA constructs are placed
downstream of multiple binding sites for GAL4. Transgenic animals
carrying the GAL4-responsive constructs are then crossed to a
number of well characterized lines that express the yeast
activator in a variety of tissue- and cell-type-specific patterns
(the 'drivers'). Development of neuronal and non-neuronal tissues
proceeds normally in the presence of human alpha-synuclein, as
indicated by appropriate external morphology, histological
appearance, viability and behavior of newly eclosed flies. To
confirm appropriate activity of the drivers, the authors
expressed an unrelated toxic protein, mutant ataxin-1, in the
same developmental and tissue-specific patterns. In contrast to
alpha-synuclein, mutant ataxin-1 produces marked defects during
development. Other laboratories have also induced phenotypes with
these driver lines.
3) In summary: Parkinson's disease is a common neurodegenerative
syndrome characterized by loss of dopaminergic neurons in the
substantia nigra, formation of filamentous intraneuronal
inclusions (Lewy bodies) and an extrapyramidal movement disorder.
Mutations in the alpha-synuclein gene are linked to familial
Parkinson's disease(1,2) and alpha-synuclein accumulates in Lewy
bodies and Lewy neurites(3-5). The authors report they express
normal and mutant forms of alpha-synuclein in the fruit fly
Drosophila and produce adult-onset loss of dopaminergic neurons,
filamentous intraneuronal inclusions containing alpha-synuclein
and locomotor dysfunction. This Drosophila model thus
recapitulates the essential features of the human disorder, and
makes possible a powerful genetic approach to Parkinson's
disease.
References (abridged):
1. Polymeropoulos, M. H. et al. Mutation in the -synuclein gene
identified in families with Parkinson's disease. Science 276,
2045-2047 (1997).
2. Krger, R. et al. Ala30Pro mutation in the gene encoding
alpha-synuclein in Parkinson's disease. Nature Genet. 18, 106-108
(1998).
3. Spillantini, M. G., Schmidt, M. L., Lee, V. M. -Y. &
Trojanowski, J. Q. Alpha-synuclein in Lewy bodies. Nature 388,
839-840 (1997).
4. Spillantini, M. G., Crowther, R. A., Jakes, R., Hasegawa, M. &
Goedert, M. Alpha-synuclein in filamentous inclusions of Lewy
bodies from Parkinson's disease and dementia with Lewy bodies.
Proc. Natl Acad. Sci. USA 95, 6469-6473 (1998).
5. Baba, M. et al. Aggregation of alpha-synuclein in Lewy bodies
of sporadic Parkinson's disease and dementia with Lewy bodies.
Am. J. Pathol. 152, 879-884 (1998).
Nature 2000 404:394
Related Background Brief:
STRESS-INDUCED PARKINSON'S DISEASE: A WORKING HYPOTHESIS. Some
cases of Parkinson's disease (PD) can be attributed to genetic
mutations, others to specific environmental factors; yet the
cause of a great majority of cases is unknown. Physical and
emotional traumas were once briefly considered as factors in the
pathophysiology of this disorder. With increasing evidence that
stress can indeed increase neuronal loss in some brain regions,
this hypothesis deserves to be reexamined. Stress increases the
extracellular availability of glucocorticoids (GCs), dopamine
(DA), and glutamate in the striatum as well as other brain
regions. These factors undoubtedly can serve to enhance the
functions of the striatum. However, each also has the capacity to
be neurotoxic. Moreover, they can act synergistically to promote
neuronal loss. Thus, the authors propose that stress might,
indeed, be a key factor in the loss of dopaminergic neurons that
underlies PD. A.D. Smith et al: Physiol Behav 2002 77:527.
Related Background Brief:
DEEP BRAIN STIMULATION OF THE SUBTHALAMIC NUCLEUS DOES NOT
INCREASE THE STRIATAL DOPAMINE CONCENTRATION IN PARKINSONIAN
HUMANS. Deep brain stimulation of the subthalamic nucleus (STN-
DBS) has become an effective treatment option in advanced
Parkinson's disease (PD). Recent animal studies showed an
increase of neuronal firing in dopaminergic neurons under
effective STN-DBS. Increased striatal dopamine levels may also
contribute to the stimulation's mechanism of action in humans.
The authors report they investigated the striatal dopamine
release in 6 patients with advanced PD under effective bilateral
STN-DBS with positron emission tomography (PET) of the reversible
dopamine-D2/3-receptor ligand [(11)C]raclopride (RACLO). Although
STN-DBS proved to be a highly effective treatment in these
subjects, the authors found no significant difference of the
striatal RACLO binding between the STN-DBS-on and -off condition.
The changes of radioligand binding did not correlate with the
patients' improvement in clinical rating scales or with the
stimulation amplitudes. Therefore, the PET data in living
parkinsonian humans do not provide evidence for an increased
striatal dopamine concentration under effective STN-DBS. The
authors conclude that the modulation of dopaminergic activity
does not seem to play a crucial role for the stimulation's
mechanisms of action in parkinsonian humans. R. Hilker et al: Mov
Disord 2003 18:41.
Related Background Brief:
EFFECTS OF ANTIOXIDANT PRETREATMENT ON THE SURVIVAL OF EMBRYONIC
DOPAMINERGIC NEURONS IN VITRO AND FOLLOWING GRAFTING IN AN ANIMAL
MODEL OF PARKINSON'S DISEASE. The effect of pretreating cell
suspensions of embryonic rat ventral mesencephala (VM) with
antioxidant combinations on the survival of dopaminergic (DA)
neurons was studied in vitro and following transplantation into
the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of
Parkinson's disease. The in vitro experiments examined the
effects of two thiol antioxidants, N-acetyl-L-cysteine (NAC) and
reduced glutathione (GSH), and a member of the lazaroid family of
21-aminosteroids, U-83836E, singly and in combination, on
survival of DA neurons derived from dissociated E14 rat VM
tissue. For in vivo studies, cell suspensions were pretreated
with combinations of NAC, GSH, and U-83836E prior to
transplanting into 6-OHDA-lesioned rats to investigate whether DA
neuron survival could be further improved. NAC, GSH, and U-83836E
individually increased DA neuron survival in vitro and a
combination of all three resulted in the greatest survival. In
vivo, pretreatment with U-83836E alone resulted in a
significantly greater reduction in amphetamine-induced rotation 6
weeks post-grafting compared with a control group receiving
nontreated graft tissue. This functional effect correlated with a
significant improvement in DA neuron survival 6 weeks post-
grafting. The thiol combination pretreatment of NAC and GSH, and
the triple combination of NAC, GSH, and U-83836E, however, failed
to improve both functional recovery and DA neuron survival when
compared with the nontreated control grafts. R.M. Love et al:
Cell Transplant 2002 11:653.
Related Background Brief:
NEURON-SPECIFIC AGE-RELATED DECREASES IN DOPAMINE RECEPTOR
SUBTYPE MRNAS. Age-related decline in dopamine receptor levels
has been observed in regional studies of animal and human brains;
however, identifying specific cellular substrates and/or
alterations in distinct neuronal populations remains elusive. The
authors report that to evaluate whether age-related decreases in
dopamine receptor subtypes are associated with specific cell
populations in the hippocampus and entorhinal cortex, antisense
RNA amplification was combined with cDNA array analysis to
examine effects of aging on D1-D5 dopamine receptor mRNA
expression levels in hippocampal CA1 pyramidal neurons and
entorhinal cortex layer II stellate cells from post-mortem human
brains (19-92 years). In CA1 pyramidal neurons, significant age-
related decline was observed for dopamine receptor mRNAs (D1-D4,
P < 0.001; D5, P < 0.05) but not for the cytoskeletal elements
beta-actin, three-repeat (3R) tau, and four-repeat (4R) tau. In
contrast, no significant changes were observed in stellate cells
across the same cohort. Thus, senescence may be a factor
responsible for cell-specific decrements in dopamine receptor
gene expression in one population of neurons within a circuit
that is critical for learning and memory. Furthermore, these
results support the hypothesis that alterations in dopaminergic
function may also be related to behavioral abnormalities, such as
psychosis, that occur with aging. S.E. Hemby et al: J Comp Neurol
2003 456:176.
Related Background Brief:
ALTERED PROTEASOMAL FUNCTION IN SPORADIC PARKINSON'S DISEASE.
Parkinson's disease (PD) is characterized pathologically by
preferential degeneration of the dopaminergic neurons in the
substantia nigra pars compacta (SNc). Nigral cell death is
accompanied by the accumulation of a wide range of poorly
degraded proteins and the formation of proteinaceous inclusions
(Lewy bodies) in dopaminergic neurons. Mutations in the genes
encoding alpha-synuclein and two enzymes of the ubiquitin-
proteasome system, parkin and ubiquitin C-terminal hydrolase L1,
are associated with neurodegeneration in some familial forms of
PD. The authors demonstrate that, in comparison to age-matched
controls, alpha-subunits (but not beta-subunits) of 26/20S
proteasomes are lost within dopaminergic neurons and 20S
proteasomal enzymatic activities are impaired in the SNc in
sporadic PD. In addition, while the levels of the PA700
proteasome activator are reduced in the SNc in PD, PA700
expression is increased in other brain regions such as the
frontal cortex and striatum. The authors also found that levels
of the PA28 proteasome activator are very low to almost
undetectable in the SNc compared to other brain areas in both
normal and PD subjects. The authors suggest these findings
indicate that failure of the ubiquitin-proteasome system to
adequately clear unwanted proteins may underlie vulnerability and
degeneration of the SNc in both sporadic and familial PD. K.
McNaught et al: Exp Neurol 2003 179:38.
Related Background Brief:
SELECTIVE PREFRONTAL CORTEX INPUTS TO DOPAMINE CELLS:
IMPLICATIONS FOR SCHIZOPHRENIA. Dopamine (DA) neurons in the
substantia nigra (SN) and ventral tegmental area (VTA) form
several projection systems with diverse functions, such as motor
planning through the striatum, reward seeking via the nucleus
accumbens (NAc), and cognitive control through the prefrontal
cortex (PFC). Disruptions in DA cell activity profoundly impair
these functions and contribute to serious clinical conditions
such as Parkinson's disease and schizophrenia. DA neurons have
been extensively investigated in studies detailing their anatomy,
physiology, and neurochemical regulation. Moreover, recordings
from behaving animals suggest that phasic changes in DA cell
firing signal expectancy or attentional shifts associated with
approach/avoidance behavior. These ideas raise interesting
questions regarding how DA neurons are regulated to produce such
phasic signals. For example, it is not yet known how different
classes of DA projection neurons are regulated by specific
inputs. In the first study of its kind within the VTA, the
laboratory of the authors recently demonstrated that excitatory
inputs from the PFC synapse selectively onto DA neurons that
project back to the PFC but not onto DA cells that project to the
NAc. The authors suggest these findings may explain some of the
unique functional properties of mesoprefrontal DA neurons.
Moreover, the results are important for understanding the
pathophysiology of mental disorders such as schizophrenia. S.R.
Sesack and D.B. Carr: Physiol Behav 2002 77:513.
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5. DIAGONOSIS AND TREATMENT OF PARKINSON'S DISEASE
PLACEBO EFFECT MECHANISM IN PARKINSON'S DISEASE
R. de la Fuente-Fernandez et al (University of British Columbia,
CA) discuss the mechanism of the placebo effect in Parkinson's
disease, the authors making the following points:
1) The simple act of receiving any treatment (active or not) may
in itself have a positive effect because of expectation of
benefit. This is the "placebo effect", a potential confounder in
assessing the efficacy of any therapeutic intervention. Placebo-
controlled studies were designed precisely to control for such an
effect, and it has been assumed that the placebo response is not
mediated directly through any physical or chemical effect of
treatment.
2) In Parkinson's disease the placebo effect can be prominent,
but little is known about its mechanism. Using positron emission
tomography with Parkinson's disease patients, the authors report
in vivo evidence for substantial release of endogenous dopamine
in the striatum (caudate nucleus and putamen) in response to
placebo. The dopamine system is involved in the regulation of
several cognitive, behavioral, and sensorimotor functions, and
particularly in reward mechanisms. These experiments, however,
did not involve a direct reward. The authors conclude that
dopamine release in the nigrostriatal system is linked to
expectation of a reward, in this case the anticipation of
therapeutic benefit. All patients were familiar with the effect
of an active drug (levodopa), and such previous experience may
have enhanced their expectation.
Science 2001 293:1164
Related Background Brief:
PROBLEMS WITH LONG-TERM LEVODOPA THERAPY FOR PARKINSON'S DISEASE.
The introduction of levodopa 25 years ago revolutionized the
management of Parkinson's disease. However, it soon became
apparent that the drug offered only symptomatic relief and did
not affect the underlying pathology. Moreover, chronic use of the
drug was associated with a range of adverse effects. Current
therapeutic strategies seek to delay long-term complications of
treatment for as long as possible. However, once they appear,
most adverse effects are amenable to some form of management. A
number of therapeutic strategies are available for treatment of
Parkinson's disease. The final choice of therapy depends on the
individual circumstances and requirements of the patient and
should balance tolerance for adverse effects with the amount of
symptomatic relief required. Patients receiving long-term
levodopa therapy must contend with some adverse effects. After 5
years the majority of these patients suffer fluctuations,
dyskinesias, toxicity, or loss of efficacy. Fluctuations can be
reduced by changing the drug regimen to a combination therapy of
Sinemet and Sinemet controlled-release (CR), or by the addition
of deprenyl or a dopamine agonist. Variations in gastric emptying
and absorption of levodopa and dietary factors become important.
Dyskinesias in long-term levodopa therapy are poorly understood
and difficult to manage, although dopamine agonists can be of
some use. As the disease progresses, new disabilities appear that
are less responsive to levodopa, and its efficacy can appear to
diminish, with increased doses often leading to toxicity. C.D.
Marsden: Clin Neuropharmacol 1994 17:S32.
Related Background Brief:
NEUROPROTECTION IN IDIOPATHIC PARKINSON'S DISEASE.
Neuroprotection may be defined as measures to protect neurons
from degenerative processes by use of medication, to stop or
prolong cell death and to positively interfere with the
underlying cell death mechanism(s) in Parkinson's disease. So
far, the question whether neuroprotection exists in parkinsonian
treatment was difficult to answer because we had no objective
method to check for dopaminergic cell death. Imaging techniques
such as beta-CIT-SPECT or F-Dopa-PET are the best methods to
approach this goal. The author critically reviews the two most
recently published studies on the possible neuroprotective effect
of the dopamine agonists pramipexole and ropinirole. For the
first time, these two drugs have shown a significantly smaller
decrease in dopamine cell function when compared to levodopa.
Nonetheless, there may still be some hesitation to accept the
good correlation between imaging techniques and dopamine cell
function. For obvious reasons, neither study included a placebo
arm, since ethical reasons forbid a period of 2 to 4 years
without treatment. Thus, the question whether these two dopamine
agonists are really neuroprotective or whether levodopa increases
cell death in Parkinson's disease remains open. A rather
remarkable finding was that in both studies motor function was
slightly better in the levodopa arm, which raises the question
whether imaging techniques really reflect improvement in cell
function in those patients treated with dopamine agonists. The
search must continue for even better tools to evaluate
neuroprotection. H. Reichmann: J Neurol 2002 249:III-21.
Related Background Brief:
EARLY DIAGNOSIS OF PARKINSON'S DISEASE. In idiopathic Parkinson's
disease (IPD) approximately 60 % of the nigrostriatal neurons of
the substantia nigra (SN) are degenerated before neurologists can
establish the diagnosis according to the widely accepted clinical
diagnostic criteria. It is conceivable that neuroprotective
therapy starting at such an 'advanced stage' of the disease will
fail to stop the degenerative process. Therefore, the
identification of patients at risk and at earlier stages of the
disease appears to be essential for any successful
neuroprotection. The discovery of several genetic mutations
associated with IPD raises the possibility that these, or other
biomarkers, of the disease may help to identify persons at risk
of IPD. Transcranial ultrasound have shown susceptibility factors
for IPD related to an increased iron load of the substantia
nigra. In the early clinical phase, a number of motor and
particularly non-motor signs emerge, which can be identified by
the patients and physicians years before the diagnosis is made,
notably olfactory dysfunction, depression, or 'soft' motor signs
such as changes in handwriting, speech or reduced ambulatory arm
motion. These signs of the early, prediagnostic phase of IPD can
be detected by inexpensive and easy-to-administer tests. As one
single instrument will not be sensitive enough, a battery of
tests has to be composed measuring independent parameters of the
incipient disease. Subjects with abnormal findings in this test
battery should than be submitted to nuclear medicine examinations
to quantify the extent of dopaminergic injury and to reach the
goal of a reliable, early diagnosis. G. Becker et al: J Neurol
2002 249:III-40.
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6. STEM CELLS AND PARKINSON'S DISEASE
EMBRYONIC STEM CELLS AND PARKINSON'S DISEASE
L.M. Bjorklund et al (Harvard University, US) discuss embryonic
stem cells, the authors making the following points:
1) Parkinson's disease (PD) is a degenerative disorder
characterized by a loss of midbrain dopamine (DA) neurons with a
subsequent reduction in striatal DA (1). Pharmacological
treatment with L-DOPA works initially, but reduced efficacy and
development of motor complications requires treatment
alternatives such as deep brain stimulation and fetal DA neuron
transplantation (2). There is evidence both from animal models
and clinical investigations showing that fetal DA neurons can
produce symptomatic relief (3-5). Technical and ethical
difficulties in obtaining sufficient and appropriate donor fetal
brain tissue have limited the application of this new therapy.
2) Previous work showed that DA neurons can be produced in vitro
from ventral mesencephalic (VM) precursor cells. A problem using
expanded fetal VM precursors is the low in vivo survival rate of
3-5% of the grafted DA neurons, which eliminates the actual gain
by in vitro cell number expansion compared with fresh
(unexpanded) fetal day-12 VM.
3) Embryonic stem (ES) cells have many characteristics required
for an optimal cell source for cell-replacement therapy. ES cells
are self-renewing and multipotent cells derived from the inner
cell mass of the preimplantation blastocyst. The authors have
shown previously that mouse ES cells transplanted to normal mice
or 6-hydroxydopamine (OHDA)-lesioned rats can differentiate
spontaneously into tyrosine hydroxylase (TH)-positive and
serotonin (5HT)-positive neurons. This differentiation is likely
not caused by a specific inductive signal from the host brain,
because similar neuronal differentiation occurs after placement
in the kidney capsule. In the previous study, grafts frequently
showed heterogeneous morphology and often became very large,
disrupting the cytoarchitecture at the implantation site, which
prevented the possibility for functional integration. Because
neurons develop from ES cells even when implanted outside the
central nervous system and ectoderm develops into neural tissue
when cell-to-cell communication is disrupted by dissociation of
the cells, the authors hypothesized that dilution of ES cells
into single-cell suspensions of low ES cell concentrations would
result in neuronal development. A low cell concentration
decreases ES cell-to-cell contact and increases the influence
from the adult host striatum, which in contrast to adult
neurogenic regions may restrict cell migration and proliferation,
thus allowing default differentiation into neurons in this
paradigm.
4) In summary: Although implantation of fetal dopamine (DA)
neurons can reduce parkinsonism in patients, current methods are
rudimentary, and a reliable donor cell source is lacking. The
authors report a demonstration that transplanting low doses of
undifferentiated mouse embryonic stem (ES) cells into the rat
striatum results in a proliferation of ES cells into fully
differentiated DA neurons. ES cell-derived DA neurons caused
gradual and sustained behavioral restoration of DA-mediated motor
asymmetry. Behavioral recovery paralleled in vivo positron
emission tomography and functional magnetic resonance imaging
data demonstrating DA-mediated hemodynamic changes in the
striatum and associated brain circuitry. The authors suggest
these results demonstrate that transplanted ES cells can develop
spontaneously into DA neurons. Such DA neurons can restore
cerebral function and behavior in an animal model of Parkinson's
disease.
References (abridged):
1. Olanow, C. W. & Tatton, W. G. (2000) Annu. Rev. Neurosci. 22,
123-144
2. Olanow, C. W. & Obeso, J. A. (2000) Ann. Neurol. 47, 167-178
3. Freed, C. R. , Greene, P. E. , Breeze, R. E. , Tsai, W. Y. ,
DuMouchel, W. , Kao, R. , Dillon, S. , Winfield, H. , Culver, S.
, Trojanowski, J. Q. , Eidelberg, D. & Fahn, S. (2001) N. Engl.
J. Med. 344, 710-719
4. Hauser, R. A. , Freeman, T. B. , Snow, B. J. , Nauert, M. ,
Gauger, L. , Kordower, J. H. & Olanow, C. W. (1999) Arch. Neurol.
(Chicago) 56, 179-187
5. Piccini, P. , Brooks, D. J. , Bjorklund, A. , Gunn, R. N. ,
Grasby, P. M. , Rimoldi, O. , Brundin, P. , Hagell, P. ,
Rehncrona, S. , Widner, H. & Lindvall, O. (1999) Nat. Neurosci.
2, 1137-1140
Proc. Nat. Acad. Sci. 2002 99:2344
Related Background Brief:
TRANSPLANTATION OF EMBRYONIC DOPAMINE NEURONS FOR SEVERE
PARKINSON'S DISEASE. Transplantation of human embryonic dopamine
neurons into the brains of patients with Parkinson's disease has
proved beneficial in open clinical trials. However, whether this
intervention would be more effective than sham surgery in a
controlled trial is not known. The authors randomly assigned 40
patients who were 34 to 75 years of age and had severe
Parkinson's disease (mean duration, 14 years) to receive a
transplant of nerve cells or undergo sham surgery; all were to be
followed in a double-blind manner for one year. In the transplant
recipients, cultured mesencephalic tissue from four embryos was
implanted into the putamen bilaterally. In the patients who
underwent sham surgery, holes were drilled in the skull but the
dura was not penetrated. The primary outcome was a
subjective global rating of the change in the severity of
disease, scored on a scale of 3.0 to 3.0 at one year, with
negative scores indicating a worsening of symptoms and positive
scores an improvement. The mean (ñSD) scores on the global rating
scale for improvement or deterioration at one year were 0.0ñ2.1
in the transplantation group and 0.4ñ 1.7 in the sham-surgery
group. Among younger patients (60 years old or younger),
standardized tests of Parkinson's disease revealed significant
improvement in the transplantation group as compared with the
sham-surgery group when patients were tested in the morning
before receiving medication (P=0.01 for scores on the Unified
Parkinson's Disease Rating Scale; P=0.006 for the Schwab and
England score). There was no significant improvement in older
patients in the transplantation group. Fiber outgrowth from the
transplanted neurons was detected in 17 of the 20 patients in the
transplantation group, as indicated by an increase in 18F-
fluorodopa uptake on positron-emission tomography or postmortem
examination. After improvement in the first year, dystonia and
dyskinesias recurred in 15 percent of the patients who received
transplants, even after reduction or discontinuation of the dose
of levodopa. The authors conclude that human embryonic dopamine-
neuron transplants survive in patients with severe Parkinson's
disease and result in some clinical benefit in younger but not in
older patients. C.R. Freed et al: New Engl. J. Med. 2001 344:710.
Related Background:
EMBRYONIC STEM CELLS AND PARKINSON'S DISEASE
J-H. Kim et al (National Institutes of Health, US) discuss
Parkinson's disease, the authors making the following points:
1) Fetal midbrain precursors can proliferate and differentiate
into dopamine-synthesizing neurons in vitro, and transplantation
of these cells leads to recovery in a rat model of Parkinson's
disease(1,2). However, these precursor cells, which are derived
from either rodent or human midbrain, generate dopamine neurons
for only short periods in culture. Embryonic stem (ES) cells can
proliferate extensively in an undifferentiated state and may
provide an unlimited source of many cell types. A related benefit
of using ES cells is their accessibility for genetic engineering,
which will permit the isolation and functional analysis of
specific cell types. The isolation of human ES cells and the
related embryonic germ cells has stimulated interest in their
potential clinical value(3,4). Although the use of ES cells in
cell therapy is widely discussed, there are few cases showing
that ES cell technology can be successfully applied to animal
models of disease(5).
2) The authors have previously defined signals that improve the
efficiency of dopamine-neuronal differentiation from ES cells,
but this approach may still provide too few neurons for
widespread use. The purpose of the present study was to develop a
method of further increasing the efficiency of midbrain-specific
generation of dopamine neurons from ES cells, and to demonstrate
that these cells can functionally integrate into host tissue as
well as lead to recovery in a rodent model of Parkinson's
disease.
3) In summary: Parkinson's disease is a widespread condition
caused by the loss of midbrain neurons that synthesize the
neurotransmitter dopamine. Cells derived from the fetal midbrain
can modify the course of the disease, but they are an inadequate
source of dopamine-synthesizing neurons because their ability to
generate these neurons is unstable. In contrast, embryonic stem
(ES) cells proliferate extensively and can generate dopamine
neurons. If ES cells are to become the basis for cell therapies,
we must develop methods of enriching for the cell of interest and
demonstrate that these cells show functions that will assist in
treating the disease. The authors demonstrate that a highly
enriched population of midbrain neural stem cells can be derived
from mouse ES cells. The dopamine neurons generated by these stem
cells show electrophysiological and behavioral properties
expected of neurons from the midbrain. The authors suggest these
results encourage the use of ES cells in cell-replacement therapy
for Parkinson's disease.
References (abridged):
1. Studer, L., Tabar, V. & McKay, R. D. Transplantation of
expanded mesencephalic precursors leads to recovery in
parkinsonian rats. Nature Neurosci. 1, 290-295 (1998)
2. Sanchez-Pernaute, R., Studer, L., Bankiewicz, K. S., Major, E.
O. & McKay, R. D. In vitro generation and transplantation of
precursor-derived human dopamine neurons. J. Neurosci. Res. 65,
284-288 (2001)
3. Thomson, J. A. et al. Embryonic stem cell lines derived from
human blastocysts. Science 282, 1145-1147 (1998)
4. Shamblott, M. J. et al. Derivation of pluripotent stem cells
from cultured human primordial germ cells. Proc. Natl Acad. Sci.
USA 95, 13726-13731 (1998)
5. McDonald, J. W. et al. Transplanted embryonic stem cells
survive, differentiate and promote recovery in injured rat spinal
cord. Nature Med. 5, 1410-1412 (1999)
Nature 2002 418:50
Related Background Brief:
TRANSPLANTATION OF EXPANDED MESENCEPHALIC PRECURSORS LEADS TO
RECOVERY IN PARKINSONIAN RATS. In vitro expansion of central
nervous system (CNS) precursors might overcome the limited
availability of dopaminergic neurons in transplantation for
Parkinson's disease, but generating dopaminergic neurons from in
vitro dividing precursors has proven difficult. The authors
report that a three-dimensional cell differentiation system was
used to convert precursor cells derived from E12 rat ventral
mesencephalon into dopaminergic neurons. The authors demonstrate
that CNS precursor cell populations expanded in vitro can
efficiently differentiate into dopaminergic neurons, survive
intrastriatal transplantation and induce functional recovery in
hemiparkinsonian rats. The authors suggest the numerical
expansion of primary CNS precursor cells is a new approach that
could improve both the ethical and the technical outlook for the
use of human fetal tissue in clinical transplantation. L.Studer
et al: Nature Neurosci. 1998 1:537.
Related Background Brief:
IN VITRO GENERATION AND TRANSPLANTATION OF PRECURSOR- DERIVED
HUMAN DOPAMINE NEURONS. The use of in vitro expanded human CNS
precursors has the potential to overcome some of the ethical,
logistic and technical problems of fetal tissue transplantation
in Parkinson disease. Cultured rat mesencephalic precursors
proliferate in response to bFGF and upon mitogen withdrawal,
differentiate into functional dopamine neurons that alleviate
motor symptoms in Parkinsonian rats (Studer et al. [1998] Nat.
Neurosci. 1:290-295). The successful clinical application of CNS
precursor technology in Parkinson disease will depend on the
efficient in vitro generation of human dopaminergic neurons. The
authors demonstrate that human dopamine neurons can be generated
from both midbrain and cortical precursors. Transplantation of
midbrain precursor-derived dopamine neurons into Parkinsonian
rats resulted in grafts rich in tyrosine hydroxylase positive
neurons 6 weeks after transplantation. No surviving tyrosine
hydroxylase positive neurons could be detected when dopamine
neurons derived from cortical precursors were grafted. The
authors suggest their data demonstrate in vitro derivation of
human dopamine neurons from expanded CNS precursors and encourage
further studies that systematically address in vivo function and
clinical potential. R. Sanchez-Pernaute et al: J Neurosci Res
2001 65:284.
Related Background Brief:
CURRENT STATE OF STEM CELL RESEARCH FOR THE TREATMENT OF
PARKINSON'S DISEASE. Current findings suggest that multipotent
stem cells may be suitable for cell replacement therapies in the
treatment of neurodegenerative disorders. Embryonic stem (ES)
cells are pluripotent cells isolated from the inner cell mass of
the preimplantation blastocyst, which give rise to all cells in
the organism. Similarly, multipotent stem cells are also able to
regenerate, but are believed to have a more restricted potential
than ES cells, and are often defined by the organ from which they
are derived. Neural stem cells have been categorized as
multipotent stem cells derived from the nervous system with the
capacity to regenerate and to give rise to cells belonging to all
three cell lineages in the nervous system: neurons,
oligodendrocytes, and astrocytes. It is hoped that research on
stem cells may reveal methods for producing an infinite supply of
dopamine neurons for transplant into Parkinson's disease (PD)
patients. The problem is controlling cell growth and
differentiation. The authors briefly review the current state of
stem cell research and critically discuss the potential of stem
cells for the treatment of Parkinson's disease. M. Gerlach et al:
J Neurol 2002 249:III-33.
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