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The miracle drug L-dopa, which has been prescribed
for Parkinson's disease (PD) patients for more than 30 years, may itself
be partly responsible for the cognitive deficits associated with PD, 3
independent teams of researchers reported here today at the annual conference
of the Society for Neuroscience. PD patients are also impaired at "habit"
learning, which depends on the basal ganglia, the part of the brain that
is affected by the disease. In addition to severe motor problems, scientists
have identified PD-associated affective and cognitive defects, which can
ultimately lead to a type of dementia. The cognitive aspects are very
different from those seen in patients with Alzheimer's disease (AD), however.
Rutgers University neuroscientist Mark Gluck and his colleagues developed
computational models for brain simulation, which distinguish between PD
and AD defects. AD patients with hippocampal damage have no trouble with
simple associations between cues but have trouble transferring that knowledge
to a novel task, for example. In contrast, PD patients are slow to learn
but once they master the associations, can apply their knowledge in novel
situations. To the researchers' surprise, however, PD patients taken off
medications did not have any problems with the tasks. "What is known about
cognitive deficits may be from being on the medication," Gluck said. Probably,
different levels of dopamine are required for different parts of the brain,
Gluck says. Introducing dopamine globally (as the traditional oral medications
do) may serve to "overflood the brain in certain areas." Delivering too
much dopamine may also carry a risk of causing schizophrenia-like symptoms.
Gluck's results are borne out by data from researchers led by University
of Colorado neurologist Curt Freed. Transplants of dopamine-producing
cells into the putamen region produce abonormal movements, or dyskinesias,
in some patients, mimicking the side-effects of L-dopa, Freed reported.
The abnormal movements are associated with the transplantation of excessive
amount of cells, which cause neurons in the putamen less affected by PD
to produce too much dopamine, he notes. Based on the results, Freed plans
to modify the transplantation surgery to target only those areas of the
putamen with the greatest dopamine depletion. A second strategy may be
to use dopamine agonists, rather than L-dopa, to treat the disease. Dopamine
receptors are expressed differentially in different parts of the brain.
It may be possible, therefore, to design medications that bind receptors
only in areas with dopamine depletion. While too much L-dopa seems to
trigger at least some cognitive defects, damage to the basal ganglia impairs
the kind of learning which allows an individual to perform tasks on "auto-pilot,"
says Barbara Knowlton, a cognitive neuroscientist at the University of
California in Los Angeles. This form of memory, called habit memory, is
newer to scientists than the traditional representation of memory, now
referred to as declarative memory, which is associated with the hippocampus.
Habit memory depends on the basal ganglia. Declarative memory requires
a lot of cognitive resources, Knowlton says, while habit memory, which
is acquired only after numerous trials, can be more efficient. Because
their basal ganglia is affected, PD patients, while they have good declarative
memory, cannot form habitual memories and "need more effort to get through
daily life." Using the "Rutgers Weather Prediction Task," the same task
used by Knowlton, Gluck and his colleagues found that rather than shifting
from a simple strategy to a complex strategy to solve a task, PD patients
stick to a simple strategy the entire time. By acknowledging and capitalizing
on the different strategies PD patients use, Gluck said, the results may
"lead to an array of clinical treatments that could help people with PD
overcome their cognitive deficits." |
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