Introduction
An aging population has challenged researchers, clinicians, and policy makers to develop strategies to promote successful aging (26,37). Successful aging is synonymous with a healthy lifestyle (23) that promotes physical activity not only to preserve functional independence and quality of life (4) but also to reduce the risk of chronic diseases, including dementia (24,60).
It is well documented that by following a healthy lifestyle, physical and cognitive function can be well preserved for individuals below the age of 60 years (1,74). After this age, the number of adults participating in regular exercise dramatically declines (62) while the prevalence of chronic diseases and associated risk factors, including cardiovascular disease (CVD) and hypertension (47), rise in concert with cognitive decline and dementia (1,46). Age-related reductions in exercise participation and cardiovascular and cognitive health coincide with structural and functional changes in cortical and subcortical regions of the brain — including the hippocampus, the temporal and parietal cortices, as well as the prefrontal cortex (PFC) (50). These structural and functional impairments manifest as a result of periventricular white matter hyperintensities or white matter lesions within the PFC, which are observed commonly in individuals with (63) or without major CVD risk (11), and have been associated with reduced executive functioning (i.e., a set of cognitive skills required to organize, coordinate, and sequence goal-directed behaviors, including abstract thinking, planning, coordination, cognitive flexibility, and working memory (17)) in older adults (40). High blood pressure contributes to progressive vascular stiffening in aging (39), and both of these factors have been identified as primary risk factors associated with age-related reductions in cerebral perfusion and the development of white matter lesions in the elderly (12,63). The incidence of these age-related neural pathologies tends to increase with each decade (11), and their occurrence has been associated highly with CVD risk factors (26), memory impairment, executive dysfunction (40), and dementia (58). Nonetheless the specific mechanisms associated with the development of these lesions in healthy older adults remain to be fully understood (11).
Current Burden of Declining Cognitive Health and Dementia
An estimated 5.4 million Americans currently are living with Alzheimer’s disease (AD) or a related dementia, with approximately 463,700 new diagnoses each year (1). In 2012, a new case of AD is diagnosed every 68 s in the United States; however, this trend will exacerbate over the following decades, reaching approximately every 33 s by 2050 (1). Additionally, in recent years, the incidence of individuals in the United States currently exhibiting some form of progressive cognitive impairment but not having met the diagnostic criteria for dementia (i.e., mild cognitive impairment (MCI), or cognitive impairment, but not dementia (CIND)) has doubled (46). With the “baby-boomer” generation aging, the prevalence and incidence of various dementias and CIND are expected to reach all-time highs in the United States and worldwide. This will impose a significant burden on societal and economic resources, resulting in an estimated $148 billion and $94 billion burden on direct and informal health care services, respectively (1,2).
As the burden of dementia and related cognitive impairment is expected to climb (1,46), it is imperative to identify tolerable, feasible, effective, and scalable interventions that are aimed at mitigating the burden of age-related chronic disease risk and cognitive decline. Identifying interventions that could produce modest delays in the onset of cognitive decline could significantly reduce this economic and societal burden; specifically, a 5-year delay in the onset of cognitive decline could translate to a 50% reduction in the incidence of dementia after several decades (8,9). The incorporation of a regular exercise regimen into daily life has been shown to promote cognitive well-being and proven useful for chronic disease management (21). The further development of cognition-oriented exercise prescriptions may prove to be an irreplaceable method for the preservation of cognitive health in older adults and mitigating the burden of dementia. Therefore identifying the potential impact that simple yet effective interventions have on the prevention of cognitive impairment is of significant importance.
Exercise and Cognitive Health in Older Adults — The Current State of the Evidence
In this review, we will present the current state of the evidence for exercise as a mitigating factor for cognitive decline and the prevention of dementia in aging populations. We will review the literature examining the relationship between cognition and aerobically based exercise, resistance-based exercise, or cognitive training. We will then discuss novel exercise modalities, with emphasis on dual-task training (Table 1). Lastly we will critically discuss the current state of the evidence and suggest future directions for research (Table 2).
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Table 1:
Key features of the reviewed studies that included neurological outcomes.
Table 2:
Limitations within the current literature and recommendations for future research.
Although many exercise modalities exist, all other forms of exercise or physical training are beyond the scope of this article and are not examined herein (e.g., yoga, tai chi, qui gong, and combined exercise programs). In general, the evidence to support these other forms of exercise is lacking, unclear, or equivocal.
Aerobic Exercise Training and Cognitive Health
Adopting physical exercise or maintaining a physically active lifestyle may be an important strategy to prevent or slow the progression of AD (7,56). However a recent National Institute of Health consensus report concluded that a larger volume of high-quality research is required to determine the relationship between the primary modifiable risk factors for cognitive decline, including physical activity modifications like exercise, and its effects on maintaining or improving cognitive health in older adults (16). Observational studies have demonstrated that individuals who are more physically active (7,49,60,69) and walk more frequently (68) are less likely to experience cognitive decline and dementia in later life compared to their sedentary age-matched peers. Aerobic exercise (AE) interventions (e.g., walking, jogging, running, cycling, and swimming) have been the primary form of exercise-based interventions and have provided the most robust evidence for the influence of exercise on cognitive health in older adults.
Colcombe and Kramer (14) conducted a meta-analysis of 18 intervention studies and found a significant effect of AE on cognitive function in older adults (55 to 80 years), with the largest effects on executive function. Furthermore Colcombe et al. (15) compared the effects of progressive AE on the attentional networks of the brain during the Flanker task (i.e., participants respond to a central arrow cue embedded in an array of five congruent (<<<<<) or incongruent (<<><<) arrows that are pointed either to the right or the left) in older adults with undisclosed cognitive health status. After 6 months of moderate-intensity (40% to 70% of their heart rate reserve) AE, participants showed greater task-related activity in the PFC and regions of the parietal cortex when compared to participants in a stretching/toning control group.
More recently, Colcombe et al. (13) investigated the effects of a 6-month moderate-intensity (40% to 70% of their heart rate reserve) AE intervention on regional brain volume in previously sedentary, cognitively healthy (mini-mental state examination (MMSE) score >27) older adults. This intervention produced significant increases in regional brain volume that were localized primarily within areas of the PFC and temporal cortex. Furthermore those within the AE group experienced average reduction in the risk of brain volume loss, reaching magnitudes between 27% and 42%. Lautenschlager et al. (33) observed improved cognitive scores on the cognitive portion of the Alzheimer’s Disease Assessment Scale in a group of older adults with subjective memory complaints and in a subgroup of participants with MCI following an individualized, 6-month (50 min·d−1, three times per week) home-based program of moderately intense physical activity when compared to a usual care group. Williamson et al. (70) observed significant improvements in psychomotor speed and information processing (Digit Symbol Substitution Test) that were correlated with improved physical fitness in previously sedentary, mildly impaired to cognitively healthy (MMSE ≥21) older adults following a 12-month, individualized (accumulation of 150 min·wk−1), and AE-based exercise program. Baker et al. (5) also found that older adults with MCI had significantly better executive functioning (i.e., faster completion of Trail Making Test Part B) following a 6-month, high-intensity AE program (75% to 85% of their maximum heart rate, 45 to 60 min·d−1, 4 d·wk−1) when compared to those in a stretching program. Furthermore Uemura et al. (61) found that a 12-month supervised, moderate-intensity (60% of their maximum heart rate) AE-based training program (90 min·d−1, 2 d·wk−1, for 80 sessions) led to significant reductions in a number of circulating vascular risk factors associated with cognitive decline and the development of AD (34) in older adults with MCI. Voelcker-Rehage et al. (66) observed improvements in perceptual speed (Visual Search Task) and executive function (modified Flanker task), which were associated with improved cerebral oxygenation (via functional magnetic resonance imaging (fMRI)) following 12 months of AE or coordination training (60 min·d−1, 3 d·wk−1) in cognitively healthy (MMSE ≥27) older adults. Lastly Erickson et al. (19) found that 12 months of moderate-intensity AE produced significant increases in the volume of the anterior hippocampus, which were associated with higher serum concentrations of brain-derived neurotropic factor and improved spatial memory in previously sedentary older adults with MCI (modified MMSE ≥51) compared to an age-matched stretching control group.
Hence, it would appear that AE training could maintain or improve cognitive health and functioning in older adults with or without cognitive impairment. The preserving effects of AE on cognition are related likely to some combination of an exercise-induced reduction in CVD risk-factor profiles (61) or increased cerebral perfusion (48,66), elevations in circulating neural and vascular growth factors (35), improved neurotransmission, or the maintenance of PFC or subcortical structural or functional integrity (13,15). Although there is a large evidence base supporting the association between previous or current AE level and maintained or improved cognitive function, issues related to differences in exercise program prescription, small sample sizes, lack of control groups, short study durations without follow-up assessments, lack of participant adherence reports, and lack of consensus on which standardized measures represent clinically meaningful outcomes, and which outcomes should be used to monitor the effectiveness of an intervention (16,32,57,64) remain. The effects of exercise on cognitive health have been studied primarily in the form of AE; however evidence suggests that these benefits can also extend to those exposed to other forms of training, including resistance-based exercise training (RT).
Resistance Exercise Training and Cognitive Health
For older adults who may not be functionally capable of participating in AE, the cognitive benefits of habitual physical activity have the potential to extend to RT. Due to the relatively recent nature of scientific inquiry into the matter, the available literature is sparse but promising.
Perrig-Chiello et al. (42) observed significant improvements in memory (i.e., immediate and delayed free recall and recognition) in older adults with undisclosed cognitive health status following a progressive, 2-month RT program (a 10-min warm-up followed by 8 machine-based resistance exercises focusing on large muscle groups, 1 d·wk−1 for 8 wk). Of particular interest, the improvements in memory following completion of the RT program were evident up to 1 year later. Lachman et al. (31) extended this notion, investigating the effects of a 6-month, home-based RT program on working memory in previously sedentary, community-dwelling older adults with undisclosed cognitive health status. Changes in individual resistance level throughout the intervention were found to be a significant predictor of changes in memory performance in the RT group; however the directionality of these findings was inconclusive.
The implementation of multiple exercise training methods often is required in order to determine the most effective modality; this may be relevant for the effects of RT on cognitive health in older adults. Cassilhas et al. (10) investigated the cognitive effects associated with performing a 6-month progressive, moderate-intensity (50% one-repetition maximum (1RM)) or high-intensity (80% 1RM) RT program (60 min·d−1, 3 d·wk−1) in previously sedentary, cognitively healthy (MMSE ≥24) older men. Improvements in cognitive functioning among this male cohort were selective for aspects of memory and verbal concept formation, coupled with comparable elevations in insulin-like growth factor 1(IGF-1) and muscular strength for participants exercising at both intensities. IGF-1 mediates exercise-induced neurogenesis within the hippocampus (35), a region of the brain that is involved intimately with memory processes. Taken together, these observations suggest that moderate- to high-intensity RT can provide the appropriate physiological stimulus, by means of modifications in circulating growth factor profiles, to initiate improvements in cognitive performance.
Liu-Ambrose et al. (36) attempted to delineate further the requirements of a cognitively beneficial RT program by employing a 12-month, single-blinded, randomized controlled trial examining the differential effect of a varied frequency (60 min·d−1, once or twice weekly), progressive, high-intensity RT program on executive function in a group of cognitively healthy (MMSE >24), community-dwelling older women. Improvements in executive function (i.e., selective attention and conflict resolution via the Stroop task) were observed at magnitudes of 12.6% and 10.9% following once- and twice-weekly RT, respectively, when compared to a balance and toning control group; however, these improvements were found only to have occurred during the final 6 months of the intervention period. Collectively these 2 pivotal studies (10,36) demonstrate that the beneficial effects of RT on cognitive health in older adults are possible following moderate- to high-intensity (50% to 80% 1RM) RT, if performed at least once per week for 6 months.
Further research is needed to determine the optimal duration of the training period required to mediate cognitive benefits in response to RT. Anderson-Hanley et al. (3) observed significant improvements in specific measures of executive function (i.e., improved digit span backward and Stroop task C performance) compared to nonexercising controls following a 4-wk community-based, low-intensity RT program (e.g., chair exercises with small weights) in community-dwelling older adults with undisclosed cognitive health status. Improvements in executive function were specific for verbal measures of neuropsychological performance rather than global executive functioning, suggesting that certain aspects of executive function may be affected differentially by exercise modality. Yerokhin et al. (71) furthered this notion, observing that improved verbal memory (Fuld Object Memory Evaluation) was correlated with improvements in resting frontal lobe neurophysiology (electroencephalographic reduction in N200A and increase in delta asymmetry) following a 10-wk progressive, low-intensity RT program in older adults with MCI as determined by a resident physician. Although this relatively short-duration RT program did not produce improvements in executive function, the authors speculated that the changes in neurophysiological mechanisms might occur quicker than neuropsychological measures of executive function in response to exercise. Taken together, these observations (3,10,36,71) suggest that aspects of cognitive functioning differ in how they may be affected by RT on different time scales and in response to different training intensities and modalities in older adults. Furthermore the cognitive benefits provided through RT may be selective and sex specific; specifically, improved memory and verbal concept formation may be more pronounced in men (10,71), while improved executive function may be more likely to occur in women (3,36).
Cognitive Training and Cognitive Health
The participation in cognitive training or cognitively challenging activities requires the organization and direction of a significant number of neurological processes, such as attention, perception, memory, and executive function, and also has been found to benefit intellectual wellness in aging (28). The potential therefore exists for cognitive training to influence cognitive health and functioning in older adults.
It is well understood that years of formal education has a direct correlation with cognitive functioning in older age. Observational studies have demonstrated that the participation in multiple forms of cognitively stimulating activities has the potential to maintain or improve cognitive functioning in late life (65,67). In a recent review, Plassman et al. (45) found those individuals who have at least 12 years of formal education exhibit stronger cognitive functioning and a reduced risk of AD in later life. However recent work by Lachman et al. (30) suggests that the influence of less education on cognitive functioning, specifically episodic memory, can be compensated for in later life through the participation in cognitively stimulating activities (e.g., reading, solving word games or puzzles, attending educational lectures or courses, and writing) at least once per week across adulthood and into old age. Taken together, these observations suggest that the association between lower educational status and poor memory in later life can be moderated by participating in various forms of cognitive training.
The cognitive benefits associated with the participation in cognitively engaging activities also extend to musical aptitude. A recent cross-sectional examination by Hanna-Pladdy and Mackay (25) identified previous musical performance across the lifespan (>10 years) as a significant predictor for preserved cognitive functioning (i.e., verbal, visuospatial, and executive function) in advancing age. Furthermore the age-related reductions in PFC volume are attenuated in middle-aged professional musicians (55). These observations suggest that musical performance at any time throughout one’s life might be a potent, modifiable factor that can contribute to successful aging through its influence on neuroplasticity and cortical structure in aging.
Cognitive function also has been shown to improve following cognitive training interventions. Klusmann et al. (27) found that a 6-month standardized cognitive or physical activity program (90 min per session, 3 times per week) could improve or maintain episodic memory (i.e., Rivermead Behavioral Memory Test immediate and delayed recall), working memory, and executive function (i.e., Trail Making Test B divided by A) in older women with mild to moderate cognitive impairment (MMSE ≥20). Furthermore the improvements in episodic memory occurred to a similar degree following both the cognitive and physical training interventions, suggesting that a 6-month cognitive training intervention holds the potential to improve or maintain cognitive functioning and reduce the risk of developing dementia in a comparable fashion to AE in older women. These observations support the use of cognitive training in older adults to prevent or reduce the rate of cognitive decline and suggest that the effect of this type of training on cognitive health may be similar to that seen following participation in habitual exercise training. Therefore investigating the combined effects of exercise and cognitive training is warranted.
Novel Exercise Modalities and Cognitive Health: Dual Tasking
Dual-task training is a multidimensional type of intervention that combines simultaneous cognitive and motor tasks and may improve physical function in healthy older adults and people with neurological impairments (44). According to task coordination and management theory, single-task training has fewer processing demands compared with dual-task training, since single-task training does not require a participant to practice the coordination of two tasks performed concurrently. In contrast, dual-task training allows for the practice and efficient integration of dual-task coordination (29), such as walking while talking. Dual-task training reflects the demands often experienced during daily living and can provide valuable insight into the functional capacities of older adults while providing an appropriate platform for training effects to be carried over to daily life (72). The cognitive demands of dual tasking relates to the cognitive demands of the dual-task exercise and the cognitive capacity of a given individual; if the demands of performing two tasks simultaneously exceeds the cognitive capacity, performance in either one or both tasks is reduced (72).
Dual-task coordination is controlled by executive functions (72), and research suggests that executive control processes and their underlying brain regions are plastic and can be modified by training. For instance, Erickson et al. (18) demonstrated a dual-task training-related “shift” in the location of dual-task-related brain activity in younger adults and suggest that this may represent a training-induced reorganization of the cortical areas involved in dual tasking, resulting in more efficient task performance. You et al. (73) observed improvements in memory recall following a preliminary investigation of the effects of a 6-wk dual-task cognitive-gait training intervention that involved the simultaneous completion of motor (walking) and cognitive (memory recall) tasks (30 min·d−1, 5 d·wk−1) in cognitively healthy (MMSE >24) older adults with a history of falls. Silsupadol et al. (52,53) compared the effects of a 1-month single-task, fixed-priority dual-task, or variable-priority dual-task balance training program in cognitively healthy (MMSE >24) older adults with balance impairment. The dual-task programs required participants to respond to cognitively challenging questions (e.g., counting backward) while performing balance activities, focusing attention on both activities simultaneously (fixed priority), or each activity separately (variable priority), whereas the single-task program solely required participants to complete the balance exercises. Results indicated that older adults who received dual-task balance training improved their dual tasking (i.e., faster gait speed) (53) and cognitive performance (52) compared to those receiving single-task balance training. Although both dual-task training groups experienced acute improvements in cognitive function, only those in the variable-priority dual-task training program retained the associated benefits 12 wk after the cessation of the program, suggesting that the associated benefits of dual-task training can be optimized when attention is focused variably between the two tasks rather than constantly dividing attention between the two tasks. Pichierri et al. (43) observed significant improvements in single- and dual-task motor performance following a 3-month randomized controlled strength (e.g., walking, standing up from a chair, sitting down, and stair climbing), balance (using air-filled balance cushions and grip balls), and cognitive-motor (Dance Dance Revolution™) training program (2 d·wk−1) in older adults with normal cognitive health or MCI (MMSE ≥22), who were residing in care homes. Although neuropsychological outcomes were not obtained in this study, since higher levels of functioning during dual-task motor performance have been associated previously with higher executive function in older adults (72), this suggests that this short duration, combined intervention may positively impact executive function and cognitive health in older adults living in care facilities. Lastly Forte et al. (22) furthered this notion, observing improved executive functioning that was specific for inhibitory control processes in previously sedentary, community-dwelling older adults with undisclosed cognitive health status following a 3-month multicomponent exercise intervention which incorporated specific cognitive challenges into neuromuscular coordination, balance, and agility exercises in order to engage higher-level cognitive and executive control processes.
The impact of dual-task exercise also has been investigated in older adults with further progressed cognitive impairment. Schwenk et al. (51) randomized patients with confirmed dementia to receive 3-months of dual-task exercise training (e.g., balance exercises with concurrent cognitive tasks), or unspecified low-intensity exercise. Following the intervention, improvements in dual-task performance were observed through reductions in the dual-tasking cost on gait speed (i.e., while walking and counting backward by 3’s) for those in the dual-task training group. These results suggest that patients with dementia can improve executive function in the form of attention-related dual-task performance to levels comparable to cognitively intact older adults following dual-task training.
These studies have provided an exciting foundation for the inclusion of dual-task training in cognitive rehabilitation and other exercise programs for older adults, particularly those at-risk for future cognitive decline and mobility limitations.
Future Directions Investigating Cognitive Health and Exercise
Although the influence of exercise on cognitive health in older adults appears beneficial and promising, the current knowledge base must be criticized carefully in order to develop definitive exercise recommendations for the elderly (16). Addressing the current limitations within the literature will help develop future research strategies to solidify the use of exercise interventions for the maintenance of cognitive function. For instance, the use of alternate forms of commonly employed neuropsychological tests should be promoted in order to avoid potential practice effects involved with serial testing (71). Due to the inconsistency of several observations concerning critical cognitive outcomes in the elderly, the inclusion of additional neurophysiological and morphological outcome measures should be incorporated within exercise intervention trials (3,71). Novel imaging techniques (e.g., perfusion computed tomography (CT), transcranial Doppler, and fMRI) hold the potential to link changes in neuropsychological performance to cerebral structure and function in aging, and could be used to further define the mechanisms underlying the relationship of exercise and cognitive health. Furthermore assessments that are deemed appropriate for evaluating domains of cognitive health in older adults must be standardized widely in order to allow for the direct comparison of outcomes across multiple studies (16).
Larger sample sizes are required in order to determine whether other neurological effects have been overlooked due to a lack of statistical power (16). Moreover multiple large-scale interventions would allow for the identification of the most beneficial frequency, intensity, time, and type of exercise for the maintenance or improvement of cognitive functioning, and the influence of comorbidities on neuropsychological performance in older adults with or without cognitive impairment (3,71). Dropout rate is highest among the older cohort of elderly adults in exercise programs (41), suggesting that the development of exercise programs that are focused on the prevention of cognitive decline rather than improvements in cognitive functioning or those designed to keep the oldest participants engaged in the exercise program might be the most effective strategies. Older adults also experience increased motivation to participate and autonomously perform home-based exercises through the use of a novel, mobile app-based interventions, suggesting that the use of new technologies in exercise programs may promote greater adherence within the notoriously noncompliant population of older adults (54). If prevention is the goal of the intervention, longitudinal studies incorporating extended follow-up periods may be required to determine the beneficial effects of an exercise program on the basis of when impaired cognitive functioning is identified (6,41). Thom and Clare (59) suggested that older adults with declining physical function may be able to sustain the associated benefits of a brief exercise intervention (≥3 months) for longer durations if booster sessions are performed at regular intervals; however the nature and frequency of these booster sessions have to be defined yet.
Lastly the majority of available literature is focused on examining the effects of exercise on cognitive health in ethnically uniform older adults who are relatively healthy (3,10,13,15,19,20,22,27,31,36,41,42,70). Although investigations focusing on less fit older adults with some form of cognitive impairment do exist (5,32,33,43,61,71), future studies should aim to include ethnically diverse populations with lower levels of physical and cognitive health in order to further elucidate the effects of exercise training programs on cognitive outcomes in the population of older adults who may stand to achieve the greatest benefits. Progress in this area has begun, with a recent announcement by the National Institutes of Health to fund a new, large-scale, and long-term AE trial in sedentary older adults with MCI (38). However multiple longitudinal studies incorporating the use of novel imaging techniques and the assessment of growth factors or other neurotropic mechanisms that are coupled also with standardized neuropsychological assessment batteries should be undertaken. Collectively these studies would have the potential to determine the effects of exercise interventions on cognitive performance and functioning in older adults over time and illuminate the possible mechanisms linking exercise with improved cognitive functioning.
Conclusions
Leading a physically active and cognitively engaged lifestyle can have a beneficial influence on cognitive health as individuals advance in age. Multiple modalities of exercise are relatively inexpensive and have proven to be well tolerated and safe for older adults, and are thus readily accessible to the majority of seniors. Identifying interventions that could effectively delay the onset cognitive decline in older adults at risk for future cognitive decline would lead to significant reductions in the incidence of dementia after several decades, and approximately 1 million fewer cases by 2050 (8,9). Therefore furthering our understanding of the potential impact that physical exercise and cognitive training interventions have on the incidence and prevention of cognitive impairment is of significant importance. The cardiovascular benefits of physical activity and the cognitively demanding requirements of cognitive training have been proposed as the driving factors influencing the mechanisms by which cognition can be preserved or improved in old age. While recent evidence suggests that motor tasks combined with a cognitive stressor (i.e., dual-task training) can provide additive beneficial effects on cognitive functioning in older adults with or without cognitive impairment, a specific exercise program aimed at preserving cognitive health yet has to be endorsed by the scientific community. Nonetheless it appears that exercise-induced cognitive benefits, in the form of improved memory and executive function, have the potential to be maximized in older adults with or without cognitive impairment when coupling individualized or progressive, moderate-to-high AE-based exercise with dual-task training over a period of 1 to 12 months. Furthermore although the evidence supporting the use of RT programs is promising, future research is required to determine the effectiveness of RT as a stand-alone treatment or a component within combination training programs for the maintenance of cognitive health in older adults. However further investigations into the combined benefit of physical exercise and dual-task training involving comprehensive neurophysiological and neuropsychological assessments may provide the best avenue for examining how exercise can impact the lives of older adults and the mechanisms by which cognitive functioning may be preserved in advancing age.
This work was funded in part by the following grants: St. Joseph’s Health Care Foundation, St. Joseph’s Health Care Foundation Parkwood Research-Specific Endowments, and CIHR grant no. 201713. The authors declare no conflicts of interest.
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