Memorcise in the Context of Parkinson’s Disease
We have a limited understanding of the role of exercise on memory function among those with Parkinson’s disease (PD). This review discusses the mechanisms influencing PD, examines the extent and mechanisms through which exercise can reduce the risk of developing PD, details the extent and mechanisms through which exercise is associated with memory function among PD, and indicates the effects of exercise on various non-memory outcomes among PD patients. A narrative and systematic review approach was employed. We specifically highlight the role of dopamine in PD; indicate the protective effect of exercise in reducing PD risk, which may occur from exercise-induced alterations in dopamine levels, inflammation, oxidative stress, and neurotrophic factor levels; detail the literature (in human and animal models) demonstrating that exercise can enhance memory function among PD patients, which may occur from exercise-induced changes in dopamine and modulation of mechanisms associated with memory (e.g., AMPA and NMDA receptor expression); and demonstrate that regular exercise engagement (including various exercise modalities) among PD patients can improve motor function, psychological function, and prevent early mortality. Exercise may be a putative strategy to help prevent PD and treat the memory impairment associated with PD. Recommendations for future research are discussed.
KeywordsCognition Episodic memory Epidemiology Exercise
The term “memorcise” (Loprinzi et al. 2018; Loprinzi et al. 2017c) has recently been coined as a paradigm in which memory may be influenced by exercise. In this brief review, we discuss this paradigm in the context of Parkinson’s disease (PD). Specifically, the purpose of this brief review is fourfold: (1) discuss the mechanisms influencing PD and their implications in memory function; (2) examine the extent and mechanisms through which exercise can reduce the risk of developing PD; (3) examine the extent and mechanisms through which exercise is associated with memory function among PD; and (4) provide exercise recommendations for those with PD. Other review papers (Chiaravalloti et al. 2014; Garraux 2008; Hanagasi et al. 2017; Inskip et al. 2016; Kramberger et al. 2010; Loprinzi et al. 2013; Marchant 2016; Mattson 2015; Morrin et al. 2017; Murray et al. 2014; Naismith et al. 2013; Paillard et al. 2015; Rosenthal and Dorsey 2013) have examined some of these individual aims, but no paper, to our knowledge, has discussed each of these four aims. Thus, this brief review will provide a useful guide to clinicians to help them better understand the extent to which exercise may help to prevent and treat PD, and its memory-related sequela. Herein, we specifically focus on memory function as this is our lab’s expertise and, as discussed hereafter, is an important cognition that may be impaired from PD and may be influenced by exercise.
Aim 1: Mechanisms Influencing Parkinson’s Disease and Its Memory Sequela
A hallmark characteristic of PD is dopamine loss in the basal ganglia, which is positioned at the base of the forebrain (Galvan and Wichmann 2008). In addition to the classic behavioral characteristics of PD, including bradykinesia (slowness of movement), tremor, rigidity, and postural instability (Calne 1993), later-onset symptomology of PD may include memory-related impairment (Huber et al. 1986). In a systematic review, the prevalence of dementia in PD was 24–31% (Aarsland et al. 2005). The 4-year prevalence of dementia in PD is approximately three times higher than those without PD (Aarsland et al. 2003). The cumulative incidence of dementia has been shown to increase to 83% 20 years after PD diagnosis (Hely et al. 2008). Memory may be impaired in PD (Chiaravalloti et al. 2014) from PD-related hippocampal atrophy (Bouchard et al. 2008; Bruck et al. 2004; Jokinen et al. 2009) and medial temporal lobe atrophy (Tam et al. 2005).
PD-related dopamine loss in the basal ganglia influences several morphological changes, including a reduction in the density of dendritic spines (Villalba et al. 2009). This reduction in spine density may occur, for example, via reduced transcription levels of growth proteins, as the dopamine neurotransmitter may activate transcription factors (e.g., CREB-1) via dopamine receptor activation followed by activation of the cAMP and PKA pathways (Delghandi et al. 2005). Reduced spine density may negatively influence memory (Mahmmoud et al. 2015). A potential molecular mechanism of memory is long-term potentiation (Poo et al. 2016), which is the functional connection between pre- and post-synaptic neurons, and is influenced, in part, from increases in dendritic spine density (Wosiski-Kuhn and Stranahan 2012). Further, hippocampal long-term potentiation may lead to the formation of additional synapses and/or strengthen existing neural connections, important requisites for optimal memory functioning.
The effects of dopamine on memory has been detailed elsewhere (Gonzalez-Burgos and Feria-Velasco 2008). In addition to dopamine influencing memory via dopamine receptor/cAMP/PKA/CREB pathways, dopamine may also influence memory via an interaction effect with NMDA receptors (Bethus et al. 2010). For example, D1 receptor activation may induce NMDA potentiation via PKA activation (Cepeda et al. 2009; Snyder et al. 1998). NMDA receptor activation plays a critical role in long-term potentiation (Luscher and Malenka 2012), particularly late-phase long-term potentiation. NMDA activation increases intracellular Ca2+ levels, which, for example, help to phosphorylate (via PKA, for example) various transcription factors (e.g., CREB-1) subserving synaptic plasticity. Indeed, empirical work demonstrates that dopamine influences memory function among PD patients (Mohr et al. 1989). In addition to PD-related functional changes in the medial temporal lobe, PD may also influence prefrontal cortex function (e.g., prefrontal dopamine signaling), which may influence other types of memory, such as working memory capacity (Narayanan et al. 2013).
Various memory types have been shown to be influenced by PD, including verbal memory (Fama et al. 2000; Martin et al. 2009), non-verbal memory (Pereira et al. 2009), procedural memory (Muslimovic et al. 2007), semantic memory (Beatty et al. 1989; Salmazo-Silva et al. 2017), and working memory (Tamura et al. 2003). Although not exclusively restricted to certain brain regions, distinct neural structures may subserve these memory types, such as the medial temporal lobe (contextual episodic memory), parietal and occipital lobes (non-verbal memory), basal ganglia (procedural memory), and prefrontal cortex (working memory).
Aim 2: Potential Protective Effects of Exercise on Parkinson’s Disease
Xu et al. (2010) examined the prospective association of physical activity on PD incidence in the NIH-AARP Diet and Health Study cohort. They demonstrated that, compared to low active adults, high active adults had a 35–38% reduced risk of developing PD, and those who were consistently active over several years had a 40% reduced risk of PD. Other related epidemiological studies also provide support that regular participation in physical activity may help to prevent PD (Chen et al. 2005; Logroscino et al. 2006; Thacker et al. 2008).
Various biological parameters, including oxidative stress, inflammation, and neurotrophic proteins, are related to PD (Blesa et al. 2015; Sampaio et al. 2017; Tufekci et al. 2012). The potential mechanisms through which exercise may help to prevent PD are multifold, which may include, for example, exercise-induced alterations in dopamine levels, inflammation, oxidative stress, and neurotrophic factor levels. The narrative that follows will briefly discuss how each of these parameters influences PD and, in turn, how exercise may modulate these parameters.
The role of dopamine loss in PD was addressed in aim 1. The role of exercise in modulating dopamine levels and receptors is discussed below in aim 3. Regarding inflammation, elevated markers of inflammation directly influence dopamine levels by reducing D1 (excitatory dopamine receptor) mRNA expression and increasing D2 (inhibitory dopamine receptor) expression (Coffeen et al. 2010). As detailed elsewhere (Felger 2017), administration of inflammatory cytokines (e.g., IFN-α; interferon-α) has been shown to reduce striatal dopamine release, but can be reversed with levodopa (l-DOPA) administration. Inflammatory markers may influence dopamine neurotransmission via several mechanisms, including decreasing the synthesis of dopamine, impairing packaging and release, and influencing the reuptake of dopamine. Regarding dopamine synthesis, the rate-limiting enzyme for the conversion of tyrosine to l-DOPA is tyrosine hydroxylase (TH). The enzyme, TH, requires the enzyme cofactor tetrahydrobiopterin (BH4), and inflammatory cytokines can decrease BH4 availability (Neurauter et al. 2008). Further, inflammatory cytokines may influence the function of vesicular monoamine transporter 2 (VMAT2), which, within the neuron, transports the dopamine vesicle to the end of the terminal (Felger 2017). Inflammation may also influence the function of the dopamine transporter (DAT), which is described in more detail in aim 3.
In addition to inflammation, oxidative stress plays a contributory role in influencing PD (Dias et al. 2013). The production of reactive oxygen species (ROS) requires the activation of molecular oxygen. Examples of neural and glial cell-damaging ROS include superoxide anion radical, hydroxyl radical, and hydrogen peroxide (Dias et al. 2013). ROS can be produced in the brain from various sources, including both neurons and glia, with the electron transport chain being a major contributor. Another major ROS source includes the enzyme monoamine oxidase (MAO). Dopamine can be catalyzed by metals, oxygen, or enzymes, and as an example, MAO has been shown to influence the metabolism of dopamine (Dias et al. 2013).
As discussed above, ROS are produced because of oxygen metabolism. Exercise obviously increases ROS given the increased oxygen utilization during exercise (Powers et al. 2016). However, exercise can also increase levels of antioxidants that detoxify free radicals and, thus, minimize oxidative damage. This can be achieved via exercise-induced expression of transcription factors, such as NF-KB, which can elevate antioxidant enzymes (Gomez-Cabrera et al. 2005). Indeed, long-term exercise has been shown to increase levels of various antioxidants (Fisher et al. 2011; Higuchi et al. 1985; Powers et al. 1994). Even acute exercise increases antioxidant levels (Berzosa et al. 2011). Lastly, and in addition to exercise-induced modulation of dopamine, inflammation, and oxidation, exercise may indirectly influence PD risk via alterations in neurotrophic factors, such as BDNF (brain-derived neurotrophic factor). This protein (BDNF) plays an important role in the survival of neurons and in long-term potentiation, which appears to be an important cellular mechanism of memory function (Ying et al. 2002). As discussed in the model developed by Sleiman et al. (Sleiman et al. 2016), exercise increases DBHB (D-β-hydroxybutyrate) synthesis in the liver, which is transported through the circulatory system to the brain, where DBHB induces BDNF expression through HDAC (histone deacetylase) inhibition. Additionally, exercise may increase BDNF levels directly in the brain via the afferentation theory of cerebral arousal (Lanier 1997). This involves the stimulation of muscle stretch receptors (i.e., muscle afferents), producing direct cerebral stimulation (i.e., action potentials generated by the muscle afferents are transmitted by peripheral nerves directly to the brain) (Lanier et al. 1989; Lanier et al. 1994).
In addition to inflammation and oxidative stress, neurotrophic factors, such as BDNF, may not only influence the survival of neurons (via, for example, the PI3K-AKT pathways), but may also influence dopamine release. For example, mature BDNF proteins bind to Trk-B receptors, which may activate PLC-y and then IP3. This then leads to the release of intracellular Ca2+, which can trigger the release of dopamine (Neal et al. 2003).
As stated, inflammation, oxidative stress, and neurotrophic factors may influence dopamine levels and PD risk. As discussed elsewhere (Gleeson et al. 2011), exercise may have an anti-inflammatory effect via reduction in visceral fat mass (the expansion of adipose tissue increases the production of pro-inflammatory adipokines, such as IL-6). Additionally, acute exercise increases levels of IL-6, but this transient increase in IL-6 subsequently increases anti-inflammatory cytokines, such as IL-10 (produced by Treg and T helper 2 cells). IL-10 helps downregulate the expression of several pro-inflammatory cytokines and molecules (e.g., intracellular adhesion molecule 1; ICAM1) to minimize inflammation-induced tissue damage. Further, the increased IL-6 levels from exercise may increase cortisol from the adrenal cortex, which, in turn, may inhibit tumor necrosis factor (TNF) production from monocytes (Gleeson et al. 2011).
Aim 3: The Effects and Mechanisms of Exercise on Memory Function in Parkinson’s Disease
We performed a computerized search of articles in PubMed to identify studies addressing this aim, which is shown in the “Appendix.” Our search located 12 relevant articles, and among these, 4 were among human PD patients (Altmann et al. 2016; David et al. 2015; Hurwitz 1989; Nocera et al. 2013), with 8 in animal PD models (Aguiar Jr. et al. 2009; Aguiar Jr. et al. 2016; Cho et al. 2013; Fisher et al. 2004; Goes et al. 2014; Klein et al. 2016; Pothakos et al. 2009; Sung 2015). Consistent with other human-based studies examining “global” cognition (Hazamy et al. 2017), including our empirical work (Loprinzi et al. 2017a), the evaluated studies for this review demonstrated beneficial effects of exercise on memory function among PD patients. Of the 4 evaluated human studies, 3 demonstrated evidence of a beneficial effect of exercise in improving memory function (David et al. 2015; Hurwitz 1989; Nocera et al. 2013). For example, Nocera et al. (2013) demonstrated that a 16-week Tai Chi exercise program demonstrated evidence of memory improvement (via Digit Backwards test) among PD patients. Similarly, David et al. (2015) demonstrated that 24 months of progressive resistance exercise improved attention and working memory capacity among non-demented patients with mild-to-moderate severity of PD. Hurwitz (1989) showed that a home-based exercise program, over an approximate 12-month period, which involved weekly 30-min exercise sessions of head-to-toe range of motion exercises, was effective in enhancing memory. Altmann et al. (2016) employed a 16-week intervention (aerobic vs. stretch-balance), with sessions occurring three times a week, and although there were no exercise-induced improvements in memory, other cognitive functions, such as executive function, improved in the aerobic exercise group.
Regarding the animal models of PD, there is consistent evidence that exercise has a protective and restorative effect on PD-induced memory impairment. Klein et al. (2016) showed that, after MPTP-induced PD, short-term exercise training (8 days) alleviated MPTP-induced spatial learning deficits. This exercise-induced restorative effect was thought to occur from exercise restoring precursor cell proliferation in the hippocampus and influencing dopamine transmission. This increased dopamine in the post-synaptic cleft may enhance downstream, intracellular signaling that may activate genes for the regeneration, proliferation, differentiation, and survival of neurons (Klein et al. 2016). This is in support of the work by Cho et al. (2013) who showed that 4 weeks of treadmill exercise after 6-OHDA-induced PD attenuated dopaminergic loss, alleviated short-term memory impairment, and increased cell proliferation in the dentate gyrus. In alignment with these observations, other related work demonstrates that MPTP decreases BDNF and Trk-B levels in the hippocampus, but exercise has been shown to counteract this effect by increasing levels of these parameters in MPTP-induced PD mice (Sung 2015).
From a neuroprotective effect, Aguiar Jr. et al. (2016) had mice exercise on a treadmill for 6 weeks and then were treated with MPTP to induce PD. The exercising mice had an attenuated MPTP-induced striatal dopamine turnover. Additionally, exercise also attenuated MPTP-induced procedural and working memory impairment. Other work employing a swimming protocol also demonstrated neuroprotective effects of 6-OHDA-induced PD (Goes et al. 2014). Four weeks of swimming training attenuated 6-OHDA-induced impairment of depression-like behavior, memory, and decreases in dopamine (Goes et al. 2014). 6-OHDA-induced oxidative damage to neurons and 4 weeks of swimming training protected against the neurotoxic effects of 6-OHDA by increasing oxidative enzymes, such as GST (glutathione S-transferase), GPx (glutathione peroxidase), and GR (glutathione reductase) (Goes et al. 2014). In addition to the anti-oxidative effects of exercise, the 4-week swimming regimen had a neuroprotective effect from anti-inflammatory mechanisms. Pro-inflammatory markers (e.g., IL-1β) can induce neuronal damage via the generation of free oxygen radicals as well as from direct binding to dopaminergic cell surfaces and their receptors. Goes et al. (2014) showed that 6-OHDA increased IL-1β levels in the striatum of sedentary mice, but 4 weeks of swimming training protected against this 6-OHDA-induced pro-inflammatory effect.
In a reserpinized PD model, 4 weeks of exercise prior to reserpine injection protected against social memory deficits and also attenuated motor behavior deficits (Aguiar Jr. et al. 2009). In the context of the latter (motor behavior deficits), within the basal ganglia, the biosynthesis of dopamine is influenced by the enzyme tyrosine hydroxylase (TH), with the clearance of dopamine heavily influenced by the dopamine transporter (DAT). Alterations in DAT influence the occupancy of dopamine, and factors that downregulate DAT may lead to motor-related behavioral improvements (e.g., less motor tremors) by increasing the synaptic occupancy of dopamine. Such an exercise-induced downregulation of DAT has been demonstrated in a MPTP-induced PD model (Fisher et al. 2004). Other works also support this exercise-induced restorative effect of motor behavior deficits in MPTP-induced PD (Pothakos et al. 2009). In addition to exercise-induced downregulation of DAT, which can prevent decreases in dopamine levels in PD, another mechanism through which exercise can positively influence dopamine levels is through dopamine receptor expression (Beaulieu and Gainetdinov 2011). For example, 28 days of treadmill exercise in MPTP mice increased dopamine D2 receptor expression (Fisher et al. 2004). Such an effect has also been observed in human PD patients (Fisher et al. 2013). In addition to exercise-induced dopamine receptor alterations, stimulation of dopamine receptors can also influence the surface expression of glutamate receptor (GluR1)-containing AMPA receptors (via PKA) (as well as NMDA receptors, as describe above) (Gao and Wolf 2007; Sun et al. 2005). Our previous work details the importance of both AMPA and NMDA receptors in subserving memory function, as well as the role of exercise in this context (Loprinzi et al. 2017b). Other works have also detailed the effects of exercise on dopamine neurotransmission (Petzinger et al. 2015).
Aim 4: Exercise Recommendations for Those with Parkinson’s Disease
Research demonstrates that PD patients may have cognitive and mobility limitations during dual-tasking (e.g., completing a cognitive task while walking) (Bell et al. 2017; de Souza Fortaleza et al. 2017; Gao et al. 2017; Nieuwhof et al. 2017; Salazar et al. 2017; Strouwen et al. 2017; Whitfield and Goberman 2017). Thus, careful prescription of exercise in PD patients is needed. In a systematic review of 13 randomized controlled trials (Ramazzina et al. 2017), strength training has been shown to improve gait function, balance, and quality of life in PD patients. This review highlights the need for additional research examining the effects of strength training on freezing events. Other systematic reviews also provide support for strength training in improving mobility and performance parameters in PD patients (Brienesse and Emerson 2013). Not all strength training studies, however, demonstrate greater effects when compared to other physical training programs or usual activities (Saltychev et al. 2016).
In addition to resistance exercise, aerobic exercise has many benefits among PD patients. In a review of 18 randomized controlled trials (Shu et al. 2014), aerobic exercise has been shown to improve balance and gait function in PD patients. Although beneficial effects of exercise on motor function in PD patients have been observed, these effects may be challenging to observe and sustain in clinical practice given the extensive time requirement and training needed to observe such effects (Allen et al. 2012). Encouragingly, however, intensive exercise therapy of strength training and endurance training appear to be safe and feasible in PD patients (Uhrbrand et al. 2015).
There is a need, however, to evaluate other exercise modalities, one of which is aquatic exercise, which shows some encouraging beneficial results in this population (Methajarunon et al. 2016; Perez and Cancela 2014). Other modalities of exercise have also started to be investigated. Nordic walking (moderate-to-high intensity; minimum of 12 sessions of 60 min in a period of 6–24 weeks) has been shown to improve motor and psychological function among PD patients (da Silva et al. 2016). Similarly, a 10-week high-challenging balance program (three times per week, 60 min per session, over a 10-week period) has been shown to improve balance and cognition in PD (Conradsson et al. 2015). In addition to these relatively shorter-term effects, regular exercise participation among PD patients may have survival effects. Exercise has been shown to prevent early mortality among PD patients (Kuroda et al. 1992), which is important as mortality is higher among PD patients with memory impairment compared to PD patients without memory impairment (Steenland et al. 2010).
This brief, yet comprehensive review discusses the mechanisms influencing PD, examines the extent and mechanisms through which exercise can reduce the risk of developing PD, details the extent and mechanisms through which exercise is associated with memory function among PD, and indicates the effects of exercise on various non-memory outcomes among PD patients. We specifically highlight the role of dopamine in PD; indicate the protective effect of exercise in reducing PD risk, which may occur from exercise-induced alterations in dopamine levels, inflammation, oxidative stress, and neurotrophic factor levels; detail the literature (in human and animal models) demonstrating that exercise can enhance memory function among PD patients, which may occur from exercise-induced changes in dopamine and modulation of mechanisms associated with memory (e.g., AMPA and NMDA receptor expression); and demonstrate that regular exercise engagement (including various exercise modalities) among PD patients can improve motor function, psychological function, and prevent early mortality. Future research is encouraged to investigate whether an optimal intensity, frequency, and dose of exercise, and what progression of these parameters, exist to maximize the benefits of exercise in PD. It is uncertain has to whether a differential exercise intensity, duration, and modality is needed for different PD-related outcomes (e.g., memory function, motor function). At the present moment, for example, there is evidence that 16 weeks of Tai Chi exercise can improve memory function in PD (Nocera et al. 2013), 24 weeks of progressive resistance exercise can improve working memory capacity among non-demented patients with mild-to-moderate severity of PD (David et al. 2015), and 10 weeks of balance training can improve balance and cognitive function among PD patients (Conradsson et al. 2015). Encouragingly, even shorter periods (e.g., 6 weeks) of exercise, specifically Nordic walking, can improve motor and psychological functioning in PD (da Silva et al. 2016). Taken together, these findings provide clinicians with a host of viable exercise opportunities to improve primary and secondary features of PD.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflicts of interest.
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