Aerobic Exercise: Evidence for a Direct Brain Effect to Slow Parkinson Disease Progression

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.^{,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,}  Exercised monkeys (1 hour daily of treadmill exercise for 5 months) performed better than sedentary control monkeys.

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.^{,  ,  ,  ,} 

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 genes and synaptic proteins such as synapsin I and synaptophysin.^{,  ,  ,  ,} 

Perhaps the most studied neuroplasticity factor is brain-derived neurotrophic factor (BDNF). Many animal studies have documented significantly increased brain BDNF levels with exercise.^{,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,}  Brain insulinlike growth factor I interacts with BDNF and increases with exercise.

Glial cell line–derived neurotrophic factor (GDNF) caught the attention of PD researchers when it was recognized to promote the survival and differentiation of dopaminergic neurons in vitro. It attenuates neurotoxin-induced parkinsonism in rodents. Several studies have reported increased brain concentrations of GDNF in animals exercised long-term.^{,  ,} 

Multiple studies in rodents have reported that the parkinsonian motor deficits from unilateral nigrostriatal injection of 6-OH-DA are markedly attenuated or reversed by exercise,^{,  ,  ,  ,  ,  ,  ,}  although with 3 negative trials.^{,  ,}  In this unilateral condition, forced use of the affected limb also attenuated the deficit (cast immobilization of the unaffected limb).^,  Conversely, preventing use of the 6-OH-DA–affected limb by casting exacerbated the motor deficit. In these studies, postmortem histologic analysis documented partial restoration of histologic markers of striatal dopaminergic terminals^{,  ,  ,  ,  ,  ,  ,  ,  ,  ,}  or neurons,^{,  ,}  although not confirmed in 1 study. In controlled studies, daily exercise in 6-OH-DA animals increased striatal BDNF and GDNF levels or BDNF levels,^{,  ,}  postulated as relevant to the neuroprotective outcomes. Forced overuse of a limb before 6-OH-DA injection elevated striatal GDNF levels, attenuated the motor deficit, and reduced the striatal dopamine loss.

Mice systemically injected with MPTP develop bilateral parkinsonism due to selective neurotoxic destruction of the dopaminergic nigrostriatal system. Exercise attenuated MPTP-induced parkinsonism in 7 studies,^{,  ,  ,  ,  ,  ,}  but not in 2 others.^,  Cast immobilization exacerbated the motor deficit.

Histochemical markers of the dopaminergic nigrostriatal system were inconsistently protected in these studies. Evidence of preserved or restored (sprouted) dopaminergic terminals were found in the minority of investigations,^{,  ,  ,}  with 7 of 11 reports documenting no change in the dopaminergic terminal markers.^{,  ,  ,  ,  ,  ,}  Midbrain dopaminergic neuron counts were partially preserved with exercise in most,^{,  ,  ,}  but not all,^,  studies. A dose-effect was documented in 2 investigations,^,  with greater exercise duration and intensity associated with incremental attenuation of parkinsonism and histochemical results.

In other MPTP studies, exercise attenuated postsynaptic changes caused by loss of dopaminergic input to striatal neurons. Specifically, exercise reversed striatal neuron hyperexcitability and tended to restore glutamate (AMPA) receptors and dendritic spine density.

Brain-derived neurotrophic factor is a small molecule and crosses the blood-brain barrier.^,  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 exercise, as summarized in a recent meta-analysis.

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. In 2 other uncontrolled studies, 8 weeks of cycling exercise significantly increased serum BDNF levels.^,  Perhaps relevant is the finding that low serum BDNF concentrations were significantly associated with reduced cognitive scores in a cohort of patients with PD.

As mentioned previously herein, the neurotrophic factor GDNF protects dopaminergic neurons and promotes their survival in vitro; in vivo, it attenuates the neurotoxic effects in animal models of parkinsonism. 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 neurotrophic effects of GDNF on dopaminergic neurons were the basis for brain infusion trials in patients with PD. Because GDNF does not cross the blood-brain barrier it was administered via cannulas implanted in the brains (striata) of patients with PD.^,  Trials of these direct infusions yielded mixed results. An initial open-label trial revealed parkinsonian benefit, but this was not replicated in an RCT. The failure in the controlled trial was possibly attributed to the limited distribution or poor retrograde neuronal transport of GDNF from the striatal injection site; this large molecule diffuses poorly in brain tissue.

In a meta-analysis of prospective studies, midlife exercise conferred a significantly lower subsequent risk of developing PD. Subsequently, this outcome was similarly reported in 2 individual large cohorts^,  and in 1 cross-sectional analysis. Obviously, reverse causation cannot be excluded; ie, before PD, patients might have been less inclined to exercise due to subclinical PD-related factors.

No clinical trials have assessed whether exercise in early PD reduces later risks of dementia. This would be a difficult investigation for the reasons discussed at the beginning of this article. However, limited studies suggest 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. Again, reverse causation could have explained this finding (ie, those with more severe PD may have been disinclined to exercise).

Numerous small trials assessing 1 to 6 months of aerobic-type exercise by patients with PD have documented statistically significant cognitive improvement; however, the outcomes have been modest, limited, or inconsistent across cognitive measures. Most of these studies included a nonexercise control group,^{,  ,  ,  ,  ,}  but 2 were uncontrolled^,  and 2 others assessed only 1 or 2 patients with PD.^, 

Numerous clinical trials have assessed cognitive outcomes after several months of aerobic-type exercise in healthy adults. In the aggregate, the benefits have been modest and inconsistent. These findings may be summarized as follows.

The first of several meta-analyses assessed 16 prospective RCTs of 1 to 18 months of aerobic-type exercise and documented significant, but modest cognitive benefit in healthy adults (some seniors). In contrast, 2 subsequent meta-analyses of prospective RCTs of long-term exercise in healthy seniors revealed no aggregate benefit.^,  Subsequently, 6 of 8 individual RCTs assessing long-term aerobic-type exercise documented significant cognitive improvement^{,  ,  ,  ,  ,}  ; the 2 negative studies assessed 1 to 2 years of regular walking.^,  Complicating interpretation of these findings is uncertain exercise engagement in the exercise group. Even when attendance is monitored, there is no assurance that vigorous and persistent exercise is performed. Moreover, off-protocol exercise in the sedentary control groups is never monitored.

Recent cross-sectional exercise studies in seniors have also generated inconsistent cognitive findings. On the one hand, better cognitive scores were associated with greater physical activity, either questionnaire based^,  or tabulated by a 6-day accelerometer assessment. In contrast, 2 decades of high-effort endurance exercise reported by older adults documented no cognitive differences compared with a nonsedentary control group of similar age.

Some of the limitations of the prospective exercise trials may be better addressed when the independent variable is fitness, which is the intended outcome of aerobic exercise. Fitness can be physiologically defined by the measured oxygen uptake during maximum exercise. There is a voluminous literature relating to fitness and cognition, with compelling evidence favoring fitness.

Several large studies measured fitness at baseline and assessed later cognitive outcomes. The largest of these studied 1.2 million Swedish men aged 18 years inducted into the military. Fitness was measured at the time of induction, revealing highly significant positive correlations between cardiovascular fitness and cognitive test scores; the findings were similar when the assessment was confined to the 1432 monozygotic twins among their inductees. Also, in this cohort, fitness at age 18 years predicted educational outcomes 10 to 36 years later, whereas lower fitness was associated with a greater risk of dementia, with follow-up to 42 years. Similar outcomes were documented in 2 community-based studies. In the first study, baseline fitness predicted cognition 25 years later; in the other, baseline fitness was associated with slower cognitive decline over decades of aging. In a cohort of military veterans, better baseline fitness predicted a significantly lower risk of cognitive impairment at mean follow-up of 10 years. Several cross-sectional studies have reported that better fitness was concurrently associated with better cognitive scores,^{,  ,  ,  ,}  although in another study, this was found only in seniors and not in young adults. Masters athletes performed significantly better on 2 of 4 cognitive tests than sedentary control subjects.

One recent publication cautions about reverse causation in these fitness studies, arguing that early socioeconomic or inherited advantages may confer both healthier lifestyles and better cognition; or, that those with better cognition tend to choose healthier lifestyles.

Meta-analyses of midlife-documented exercise/physical activity found a significantly reduced frequency of later cognitive decline and dementia. More recent similar prospective studies have reported similar significant outcomes,^{,  ,  ,}  although this trend in 1 other study was only marginally significant. Midlife vigorous leisure activity (ie, more vigorous than walking) was associated with a significantly lower risk of a death certificate diagnosis of dementia at 29 years of follow-up.

Cross-sectional studies found midlife fitness to be associated with a reduced risk of later dementia, and higher reported lifetime physical activity was associated with better cognitive scores. Multiple studies have found midlife exercise to be linked to a reduced risk of later mild cognitive impairment,^{,  ,  ,  ,  ,  ,  ,  ,}  which is recognized to be a frequent prelude to dementia.

Among those already cognitively impaired, most prospective exercise trials documented significant cognitive benefits^{,  ,  ,  ,  ,  ,  ,  ,  ,}  ; however, a few reported only modest outcomes,^{,  ,}  with 1 negative study. The most recent meta-analysis assessing RCTs of aerobic exercise in demented patients reported significant positive effects on cognition. Although 2 earlier meta-analyses of long-term exercise in demented patients were negative, they included numerous trials using nonaerobic interventions.^, 

The hippocampus is a crucial component of brain memory circuits. Hippocampal atrophy is not only a marker of Alzheimer disease but also is found in PD with dementia.^,  In cross-sectional analyses controlling for relevant variables, larger hippocampal volumes were significantly associated with cardiovascular fitness.^,  The volume of the entorhinal cortex (which encompasses the hippocampus) was similarly correlated with fitness, at least on 1 side.

In prospective RCTs, hippocampal volumes increased with 1 to 2 years of aerobic exercise.^,  Likewise, in a shorter treadmill exercise RCT (3 months), hippocampal volumes were significantly larger in proportion to the measured change in fitness.

In the Framingham Heart Study, poor fitness at age 40 years was associated with a smaller overall brain volume 20 years later. Several studies documented that physically fit seniors have significantly less age-related cortical volume loss.^{,  ,  ,} 

Prospective 6-month RCTs of exercise documented increased neocortical volumes in 2 studies,^,  but not in 1 walking exercise trial. Reported physical activity has concurrently been associated with greater gray matter volumes,^,  whereas reported walking distances prospectively correlated with cortical volumes 9 years later.