ARTICLE: Aerobic Exercise: Evidence for a Direct Brain Effect to Slow Parkinson Disease Progression Flashcards
(40 cards)
Although no medications are proven to slow PD progression, there is substantial evidence for vigorous ___ attenuating PD progression, which is the
specific focus of this article.
exercise
Unfortunately, a valid and reliable RCT of long-term
exercise to slow PD progression is not truly
feasible for several reasons.
First, PD progression tends to be very
slow. Reliable and valid biomarkers of PD pro
gression have yet to be developed.
Second is the physical and motivational
challenge of longer-term engagement in an
aerobic exercise program. Long-term adher
ence to a rigorous exercise protocol among
senior patients with PD is potentially
problematic.
Third, confirmation of exercise effort in
such a clinical trial is not easily assessed,
although cardiovascular fitness is an objective
outcome of long-term aerobic exercise.
there is
a very extensive and diverse literature relating
to direct exercise influences in the brain, relevant to PD.
At an elementary level, this
includes exercise-induced brain neuroplasticity, maintenance of synaptic connections,
and preservation of brain integrity. Macroscopically, exercise influences on brain integrity are now measureable with modern brain
magnetic imaging technology.
The goal of this article is to review the
evidence for long-term aerobic-type exercise
as a means for slowing PD progression.
a concerted effort was made to survey the entire pub
lished literature identified in a PubMed search
and report both positive and negative find
ings. The intent is to provide clinicians with
the evidence needed for counseling their patients with PD.
Aerobic type exercise was the focus because
a prelimi
nary reading of this literature indicated that
this is the most robust and comprehensive
component of this exercise literature. It also
allowed extension to animal studies, where
running exercise is a common experimental
variable. Although resistance exercise might
be relevant to this topic, preliminary review
of resistance exercise publications suggested
too few articles and too varied methods to reli
ably assess. Papers reporting exercise out
comes in nonrelevant disease groups were
excluded (eg, patients with diabetes, cancer,
etc). Only studies of long-term exercise were
included, excluding short-term exercise trials.
Studies using outcome measures that could
be influenced by symptomatic drug treatment
were excluded
Exercise Facilitates Neuroplasticity in Animals
Much of the early literature relevant to this
topic was from animal studies, which pro
vided the initial scientific rationale for exercise
directly enhancing brain neuroplasticity. The
term neuroplasticity implies the ongoing capac
ity of the brain to form and modify synaptic
connections. This is the basis for motor and
cognitive memory and is the fundamental
repair and maintenance process tending to
counter neurodegenerative disease and brain
aging.
neuroplasticity
implies the ongoing capacity of the brain to form and modify synaptic
connections. This is the basis for motor and
cognitive memory and is the fundamental
repair and maintenance process tending to
counter neurodegenerative disease and brain
aging
Exercised Animals Perform Better on Simple Cognitive Tests.
Controlled trials of
running exercise in rats and mice use running
wheels or treadmills. Many such studies have
documented significant exercise-related
improvement in spatial memory (maze) or
object recognition.4-17 Exercised monkeys (1
hour daily of treadmill exercise for 5 months)
performed better than sedentary control
monkeys.
Microscopic and Neurophysiologic Evidence
of Exercise-Related Neuroplasticity.
The
hippocampus is crucial to memory and is
one of the very few brain regions where new
neurons are generated: neurogenesis. Many
published studies in rats/mice have consistently documented enhanced hippocampal
neurogenesis associated with long-term
running exercise. The putative
neurophysiologic substrate of memory is hippocampal long-term-potentiation, which was
significantly enhanced by running exercise in
rodents, although only in male and not
female rats in 1 study. Learning involves
restructuring of synaptic connections, and
several rodent studies documented enhanced
dendritic length and complexity and increased
dendritic spines after long-term running
exercise.
The hippocampus is crucial to memory and is
one of the very few brain regions where new
neurons are generated
new neurons being generated = ________
neurogenesis
Many
published studies in rats/mice have consis
tently documented enhanced hippocampal
neurogenesis associated with long-term
________ exercise.
RUNNING
Exercise Facilitates Biochemical Markers of
Neuroplasticity.
Long-term running exercise
in rodents increased brain factors known to
mediate neuroplasticity, including CREB and
intracellular kinases. Long-term running exercise also enhanced the expression of synaptic plasticity genes35 and synaptic proteins such as synaptophysin, and
synapsin
I
Exercise Influences on Brain Neurotrophic
Factors
Neurotrophic factors have long been proposed
as a potential therapeutic target for neurode
generative diseases, including PD.38,39 Applied
in vitro, they enhance neuron vitality, survival,
and neuritic outgrowth; they tend to protect
neurons from biologic insults (neuro
toxins).39,40 Intuitively, enhanced brain neu
rotrophic
factor
concentrations
should
benefit neurodegenerative disease, ie, PD.
Brain Neurotrophic Factor Levels Increase
With Exercise in Animals.
Perhaps the most
studied neuroplasticity factor is brain-derived
neurotrophic factor (BDNF). Many animal
studies
have
documented significantly
increased brain BDNF levels with exercise.
Animal Models of Neurotoxin-Induced
Parkinsonism, Attenuated by Exercise
Parkinson disease symptoms are primarily
mediated by neurodegeneration of the dopa
minergic nigrostriatal system, and dopamine
replenishment with levodopa therapy is the
most efficacious symptomatic treatment.
Exercise Increases Neurotrophic Factor
Levels and Attenuates 6-OH-DA Nigros
triatal Neurotoxicity.
Multiple studies in
rodents have reported that the parkinsonian
motor deficits from unilateral nigrostriatal in
jection of 6-OH-DA are markedly attenuated
or reversed by exercise,44,49-55 although with 3
negative trials.
Exercise Tends to Reduce MPTP Nigros
triatal
Neurotoxicity.
Mice systemically
injected with MPTP develop bilateral parkin
sonism due to selective neurotoxic destruction
of the dopaminergic nigrostriatal system. Exer
cise attenuated MPTP-induced parkinsonism
in 7 studies,48,54,63-67 but not in 2 others.68,69
Cast immobilization exacerbated the motor
deficit.70
Humans and Neurotrophic Factors
As cited previously herein, animal studies have
consistently documented increased brain
concentrations of neurotrophic factors with
long-term exercise (eg, BDNF, GDNF). Neuro
trophic factors are proposed as neuroprotec
tive for neurodegenerative disease (ie, PD).
Exercise Increases BDNF in Humans.
Brain
derived neurotrophic factor is a small molecule
and crosses the blood-brain barrier.78,79 Hence,
circulating
BDNF concentrations should
correlate with brain levels in humans. Most
studies in normal humans have documented
increased serum BDNF concentrations, both
after acute exercise and with long-term exer
cise, as summarized in a recent meta-analysis.80
Exercise Increases Serum BDNF in Patients
With PD.
Serum BDNF levels significantly
increased after 1 month of treadmill exercise
in a cohort of patients with PD; the levels
were unchanged in the unexercised control
patients with PD.81 In 2 other uncontrolled
studies, 8 weeks of cycling exercise signifi
cantly increased serum BDNF levels.82,83
Perhaps relevant is the finding that low
serum BDNF concentrations were significantly
associated with reduced cognitive scores in a
cohort of patients with PD.8
Side Story: Direct Brain Administration of
GDNF in Patients With PD.
As mentioned
previously herein, the neurotrophic factor
GDNF protects dopaminergic neurons and
promotes their survival in vitro45; in vivo, it
attenuates the neurotoxic effects in animal
models of parkinsonism.46 However, unlike
BDNF, the large GDNF molecule does not
cross the blood-brain barrier, and blood levels
are independent of brain concentrations.
Laboratory studies documenting neurotro
phic effects of GDNF on dopaminergic neu
rons were the basis for brain infusion trials
in patients with PD. Because GDNF does not
cross the blood-brain barrier it was adminis
tered via cannulas implanted in the brains
(striata) of patients with PD.38,46 Trials of
these direct infusions yielded mixed results.
An initial open-label trial revealed parkinso
nian benefit, but this was not replicated in
an RCT.85 The failure in the controlled trial
was possibly attributed to the limited distribu
tion or poor retrograde neuronal transport of
GDNFfrom the striatal injection site; this large
molecule diffuses poorly in brain tissue.38
Exercise and PD Midlife Exercise Reduces Later PD Risk.
In a meta-analysis of prospective studies,
midlife exercise conferred a significantly lower
subsequent risk of developing PD.86 Subse
quently, this outcome was similarly reported
in 2 individual large cohorts87,88 and in 1
cross-sectional analysis.89 Obviously, reverse
causation cannot be excluded; ie, before PD,
patients might have been less inclined to
exercise due to subclinical PD-related factors.
Exercise in Early PD and Later Dementia.
No clinical trials have assessed whether
exercise in early PD reduces later risks of
dementia. This would be a difficult investiga
tion for the reasons discussed at the beginning
of this article. However, limited studies sug
gest favorable trends.
In a cross-sectional study involving 2252
patients with PD, questionnaire-based regular
exercise was associated with less cognitive
decline after 1 year.90 Again, reverse causation
could have explained this finding (ie, those
with more severe PD may have been disin
clined to exercise).
Numerous small trials assessing 1 to 6
months of aerobic-type exercise by patients
with PD have documented statistically signifi
cant cognitive improvement; however, the
outcomes have been modest, limited, or
inconsistent across cognitive measures. Most
of these studies included a nonexercise control
group,91-96 but 2 were uncontrolled97,98 and
2 others assessed only 1 or 2 patients
with PD.99,10
Non-PD Human Clinical Studies: Exercise
and Cognition
Although studies addressing exercise and
cognition in PD are limited, there is a substantial literature relating to exercise influences on cognition in the general population.
Note, however, that exercise-related cognitive
enhancement in healthy adults may be limited
by a ceiling effect and may fundamentally
differ from biological mechanisms counteract
ing a very slow PD neurodegenerative process.
