Dementia And Physical Activity (DAPA) trial of moderate to high intensity exercise training for people with dementia: randomised controlled trialBMJ 2018; 361 doi: https://doi.org/10.1136/bmj.k1675 (Published 16 May 2018) Cite this as: BMJ 2018;361:k1675
All rapid responses
To the Editor,
In a recent article, Lamb and colleagues (1) concluded that a moderate to high intensity aerobic and strength exercise training program does not slow cognitive impairment in people with mild to moderate dementia and cannot be recommended as a treatment option for cognitive impairment in dementia. Although the study design has been conducted according to well-designed methodological parameters (randomized, controlled and investigator masked) and the authors recruited a large sample size, there are several misunderstandings in the author’s recommendations and conclusions.
First of all, the authors are not able to conclude about the effect of moderate to high intensity exercise in cognition, since they did not evaluate after the 4-month intervention. Although they conducted a 4-month supervised exercise program, the assessments only happened 6 and 12 months after randomization. A gap of 8-months without any supervised exercise may have changed the results of the 4-months intervention. To answer these questions properly, the authors should have assessed patients immediately after the end of the 4-month intervention. Although Lamb and colleagues had oriented their patients to engage in home-based physical activities, there was no control on whether these activities were met. Besides, telephone contact is not enough to ensure compliance with the home-based program. In addition, the authors did not mention whether home-based physical activities met all items of the FITT principle (frequency, intensity, time and type of exercise) (2). Therefore, we emphasize that Lamb and her colleagues did not investigate the effect of physical exercise for dementia patients, but the effect of 4-months supervised physical intervention plus 2-months and 8-months of unsupervised physical activities. In this sense, there was no difference between groups after 4-months plus 2-months of unsupervised training, only after 8-months.
Another problem that needs to be considered is the outcome. At the point of trial registration, the primary outcome was the MMSE. However, before beginning the trial, they changed to the ADAS-cog, the only outcome that showed a significant effect size after 4-month intervention plus 8 months of unsupervised physical activity. However, recent metanalyses aimed to evaluate the effect of physical exercise on cognitive function in patients with Dementia analyzed data from MMSE because the majority of clinical trials have used this measure to assess cognition (3). A meta-analyses study by Strohle et al (4) found a large (SMCR=0.83, 95% CI 0.59 to 1.07) and small (SMCR=0.20, 95% CI 0.11 to 0.28) improvement on cognition of AD and mild cognitive impaired individuals, respectively, showing better effects of physical exercise than drug therapy. Another recent meta-analysis (5) showed that exercise promotes moderate to large effects on cognition of AD patients (SMD = 2.1, confidence interval [CI]: 0.44–3.8). ADAs-cog was used only in two of the six studies included in these meta-analyses (in the section of physical activity) which in turn analyzed MMSE results as primary outcome. However, Lamb and colleagues (1) did not show the ADAS-cog and MMSE after 4-month supervised physical intervention.
It is also important to discuss the exercise prescription. The authors structured their aerobic prescription based on a test validated by Luxton et al (6). However, Luxton and colleagues validated their test for patients with chronic obstructive pulmonary disease (COPD) (6). Therefore, it is not possible to ensure that aerobic intensity was realistic for dementia patients. Moreover, Lamb and her colleagues analyzed compliers and non-compliers in the same group to compare with controls (usual care). According to Table 2 in their article, non-compliers ranged from 0 to 22 sessions of supervised exercise. In other words, there were patients who did not really exercise. On the other hand, in the compliers group there were patients who did not lift any weight (kg) during strength training. In addition, patients in both groups (compliers and non-compliers) stayed the majority of time (mean of 210.5 and 131.5 minutes, respectively) cycling in low intensity. For example, a median of 0 minute of high intensity aerobic cycling for non-compliers is displayed in the aforementioned table. Nonetheless, the authors conclude that moderate to high intensity exercise is harmful for dementia patients. It is important to highlight that the non-compliers (patients who attended less than 75% of classes) should be excluded, as expected in RCT with intervention with physical exercise. However, these patients (almost 35%) were included in the analyses.
Another factor that may have influenced cognitive decline in the patients assessed by Lamb and colleagues is the interruption of the supervised training. As stated by the authors in the discussion section (lines 27-30), affective and social disruption due to withdrawal of supervised exercise may have led patients to deteriorate cognition in the 8-month follow-up.
Finally, the authors justified their findings hypothesizing that impaired reoxygenation and augmented inflammation promoted by short-term exercise could be implicated on cognitive deterioration. Both statements of authors are based on two unsuitable references (7, 8). Valenzuela et al. (8) did not mention anything about exercise or physical activity and their relationship with inflammation. Cipryan et al. (7) investigated acute high intensity interval training (HIIT) on diverse physiological parameters of endurance and sprint athletes, which does not provide any substantial data to compare with dementia patients. To address these misconceptions, we cited a Position Statement published in the Exercise Immunology Reviews (9) which clarifies the effects of exercise on inflammation. Acute and chronic exercises have different results on inflammation depending on the intensity.
In summary, exercise with moderate intensity can diminish inflammatory cytokine synthesis chronically (e. g. IL-1, IL-6, and TNF-α) while augments those anti-inflammatory (IL-1ra, IL-10) due to different mechanisms such as macrophage phenotype alteration. Moreover, the statement indicates that exercise prevents many diseases including dementia. Therefore, the study published by Lamb and colleagues has several important limitations and the experimental design did not properly investigate the effect of moderate-high intensity exercise. They did not investigate cognitive function after the 4-month intervention, so they cannot conclude about this type of intervention. Moreover, cognitive impairment is one of the symptoms of Dementia. Independence in Activities of Daily Living is also important for patients with Dementia and the evidence in literature, based on recent meta-analyses, recommends physical exercise to improve clinical response, as well as strength, gait, aerobic resistance, and physical health. Until now, we have more reasons to indicate physical exercise to patients than not. The DAPA article received so much attention in the media and, as Dr Paul W Franks said: “the damage is done”. We need to be more careful with the messages that we send to society.
1. Lamb SE, Sheehan B, Atherton N, Nichols V, Collins H, Mistry D, et al. Dementia And Physical Activity (DAPA) trial of moderate to high intensity exercise training for people with dementia: randomised controlled trial. BMJ. 2018;361:k1675.
2. Oberg E. Physical activity prescription: our best medicine. Integrative Medicine. 2007;6(5):18-22.
3. Groot C, Hooghiemstra AM, Raijmakers PG, van Berckel BN, Scheltens P, Scherder EJ, et al. The effect of physical activity on cognitive function in patients with dementia: A meta-analysis of randomized control trials. Ageing Res Rev. 2016;25:13-23.
4. Ströhle A, Schmidt DK, Schultz F, Fricke N, Staden T, Hellweg R, et al. Drug and Exercise Treatment of Alzheimer Disease and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis of Effects on Cognition in Randomized Controlled Trials. Am J Geriatr Psychiatry. 2015;23(12):1234-49.
5. Liang JH, Xu Y, Lin L, Jia RX, Zhang HB, Hang L. Comparison of multiple interventions for older adults with Alzheimer disease or mild cognitive impairment: A PRISMA-compliant network meta-analysis. Medicine (Baltimore). 2018;97(20):e10744.
6. Luxton N, Alison JA, Wu J, Mackey MG. Relationship between field walking tests and incremental cycle ergometry in COPD. Respirology. 2008;13(6):856-62.
7. Cipryan L, Tschakert G, Hofmann P. Acute and Post-Exercise Physiological Responses to High-Intensity Interval Training in Endurance and Sprint Athletes. J Sports Sci Med. 2017;16(2):219-29.
8. Valenzuela M, Brayne C, Sachdev P, Wilcock G, Matthews F, Study MRCCFaA. Cognitive lifestyle and long-term risk of dementia and survival after diagnosis in a multicenter population-based cohort. Am J Epidemiol. 2011;173(9):1004-12.
9. Walsh NP, Gleeson M, Shephard RJ, Woods JA, Bishop NC, Fleshner M, et al. Position statement. Part one: Immune function and exercise. Exerc Immunol Rev. 2011;17:6-63.
Competing interests: No competing interests
Mobilizing reserves: why does physical activity appear to be not beneficial, or even detrimental, in advanced stages of neurodegeneration?
Lamb et al. report potentially negative results of exercise interventions on cognition in patients with mild to moderate dementia. This appears counterintuitive, considering the beneficial effects of physical activity in a broad range of diseases, including various chronic diseases and neurodegenerative diseases. To better understand the risks and benefits of physical activity, more systematic studies are necessary. These studies should assess the impact of different types of exercises and take into account the heterogeneity of dementia and the individuals’ tolerance to exercise interventions.
Physical exercise benefits health and brain function, by processes at least partially mediated via preconditioning tissues, organs or organisms to later insults. In preconditioning, a stimulus below the threshold of damage induces a tolerance against subsequent similar or different harmful stimuli.
This concept however, implies the necessity of a certain reserve capacity. The smaller this reserve, the more likely the preconditioning stimulus exceeds the threshold, resulting in direct damage rather than increasing tolerance. We propose that such buffering reserves may be reduced in the brain of patients suffering from neurodegenerative diseases, like Alzheimer’s disease, and should be considered when designing exercise-based intervention strategies.
Interestingly, several physiological parameters that are positively affected by regular physical activity are compromised in neurodegenerative diseases: e.g. mitochondrial function, the antioxidative defense systems, neuroinflammation and neuronal proteostasis[4 5]. We argue that loss of buffering capacities in dementia patients (such as tolerance to oxidative stress, a well-documented event in early dementia and importantly affected by exercise) might have been responsible for the negative effects on cognition after an intense exercise challenge as applied by Lamb et al.
The study by Lamb et al. highlights important limitations of exercise interventions in patients already affected by dementia and contributes valuable information on the effects of physical activity on dementia patients. But the approach is lacking stratification on the basis of parameters linked to tolerance to physical exercise or consideration of individual threshold levels. Given the small, albeit statistically significant, difference observed in this study, we believe it is crucial to systematically assess to what extent the intensity and type of exercise regimen and individual reserve capacity influence the effect of physical exercise on brain function at different stages of disease progression. Accordingly, submaximal (below the reserve threshold) personalized exercising routines should not be excluded as useful interventions for neurodegeneration patients, in particular if combined with other novel approaches to enhance reserve capacities in controlled ways, for instance by intermittent hypoxic-hyperoxic training.
Please find a supporting figure here: https://imgur.com/a/jFdA3AE
1. Lamb SE, Sheehan B, Atherton N, et al. Dementia And Physical Activity (DAPA) trial of moderate to high intensity exercise training for people with dementia: randomised controlled trial. BMJ (Clinical research ed.) 2018;361:k1675 doi: 10.1136/bmj.k1675[published Online First: Epub Date]|.
2. Kujala UM. Benefits of exercise therapy for chronic diseases. British journal of sports medicine 2006;40(1):3-4 doi: 10.1136/bjsm.2005.021717[published Online First: Epub Date]|.
3. Hoffmann K, Sobol NA, Frederiksen KS, et al. Moderate-to-High Intensity Physical Exercise in Patients with Alzheimer's Disease: A Randomized Controlled Trial. Journal of Alzheimer's disease : JAD 2016;50(2):443-53 doi: 10.3233/jad-150817[published Online First: Epub Date]|.
4. Dirnagl U, Becker K, Meisel A. Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use. The Lancet. Neurology 2009;8(4):398-412 doi: 10.1016/s1474-4422(09)70054-7[published Online First: Epub Date]|.
5. Lawler JM, Rodriguez DA, Hord JM. Mitochondria in the middle: exercise preconditioning protection of striated muscle. The Journal of physiology 2016;594(18):5161-83 doi: 10.1113/jp270656[published Online First: Epub Date]|.
6. Nunomura A, Perry G, Aliev G, et al. Oxidative damage is the earliest event in Alzheimer disease. Journal of neuropathology and experimental neurology 2001;60(8):759-67
7. Radak Z, Chung HY, Goto S. Systemic adaptation to oxidative challenge induced by regular exercise. Free radical biology & medicine 2008;44(2):153-9 doi: 10.1016/j.freeradbiomed.2007.01.029[published Online First: Epub Date]|.
8. Bayer U, Likar R, Pinter G, et al. Intermittent hypoxic-hyperoxic training on cognitive performance in geriatric patients. Alzheimer's & dementia (New York, N. Y.) 2017;3(1):114-22 doi: 10.1016/j.trci.2017.01.002[published Online First: Epub Date]|.
Competing interests: No competing interests
To the Editor,
By 2050, it is estimated that more than 100 million people worldwide will be living with dementia1 and thus it is vital that we continue to investigate potential therapeutic treatments to help those living with the disease. Lamb and colleagues (2018)2 are to be commended for the design and implementation of the large-scale Dementia And Physical Activity (DAPA) trial that investigated to what extent, or indeed not, exercise training attenuates the inexorable decline in cognitive function observed in these patients.
DAPA was a 4-month randomised control trial combining two supervised group-based gym sessions per week that included both aerobic and strength-based exercise of a moderate-high intensity for up to 60-90 minutes, with one home-based exercise session for an additional hour per week. The trial found that exercise fails to slow cognitive impairment in people living with mild to moderate dementia2, though this may prove somewhat unsurprising given the findings of the most recent Cochrane review on this topic3. The authors further suggested that exercise may have impaired cognition compared to the control. Whilst this should not be cast aside and warrants further investigation, we must ensure that the message outlining the preventitive benefits of regular exercise is not misconstrued. Particularly since physical activity is an established modifiable risk factor that can provide neuroprotective benefits across the adult lifespan and help prevent the onset of dementia4 5.
Cognitive decline and dementia are characterised by an accelerated decline in vascular endothelial function that culminates in cerebral hypoperfusion6, the likely consequence of exaggerated oxidative-nitrosative-inflammatory stress7, and regionalcerebral atrophy8. However, regular physical activity has the capacity to alter redox-state and cerebral perfusion and subsequently oxygenation9 10. Moreover, it has the capacity to increase brain volume in cognition-related regions such as the prefrontal cortex, temporal lobe and hippocampus11 12. This relationship can perhaps be explained by exercise-induced elevations in brain-derived neurotrophic factor and antioxidant defence, that have the collective capacity to reduce oxidative stress13, improve neurogenesis14 and synaptogenesis15. While the precise mechanisms that underpin the neuroprotective benefits of regular physical activity remain unclear, its importance for brain health is becoming increasingly evident.
Lamb and colleagues further suggest that the high-intensity nature of the exercise may explain why cognitive function may have been further impaired, owing to increased inflammation and corresponding attenuation in cortical reoxygenation. This is an interesting proposal since high-intensity interval training (HIIT) is being increasingly used in both recreational and clinical settings, due to it being more time-efficient and stimulating superior metabolic and vascular adaptations compared to existing continuous moderate intensity exercise guidelines16. However, the impact HIIT has on brain health remains to be determined17. To date, there is no single randomised control trial that has investigated the impact HIIT may have (positive or negative) on brain health. While it is not unreasonable to hypothesise that the superior metabolic and cardiovascular adaptations observed in previous studies also translates to the cerebrovasculature, the rapid increases in blood pressure associated with this form of training remain a concern. This may beespecially relevant for dementia patients characterised by impaired cerebral autoregulation18 who are incapable of effectively buffering acute surges in blood pressure and are potentially more vulnerable to blood-brain barrier disruption subsequent to cerebral hyperperfusion. Therefore, it is imperative that randomised control trials are conducted to determine the effectiveness and safety of HIIT for brain health. Until such time, the preventative, rather than the curative neuroprotective benefits conferred by regular physical activity in line with current recommendations should be emphasised to optimise brain health and reduce the risk of dementia across the adult lifespan. We should continue to bang the brain-train drum!
1. Prince MJ. World Alzheimer Report 2015: the global impact of dementia: an analysis of prevalence, incidence, cost and trends: Alzheimer's Disease International 2015.
2. Lamb SE, Sheehan B, Atherton N, et al. Dementia And Physical Activity (DAPA) trial of moderate to high intensity exercise training for people with dementia: randomised controlled trial. BMJ 2018;361:k1675.
3. Forbes D, Thiessen EJ, Blake CM, et al. Exercise programs for people with dementia. Cochrane Database Syst Rev 2013;12:0.
4. Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer's disease prevalence. The Lancet Neurology 2011;10(9):819-28.
5. Bailey DM, Marley CJ, Brugniaux JV, et al. Elevated aerobic fitness sustained throughout the adult lifespan is associated with improved cerebral hemodynamics. Stroke 2013;44(11):3235-8. doi: 10.1161/STROKEAHA.113.002589 STROKEAHA.113.002589 [pii] [published Online First: 2013/08/22]
6. de la Torre JC. Is Alzheimer's disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. The Lancet Neurology 2004;3(3):184-90.
7. Cobley JN, Fiorello ML, Bailey DM. 13 reasons why the brain is susceptible to oxidative stress. Redox biology 2018;15:490-503.
8. Fox NC, Schott JM. Imaging cerebral atrophy: normal ageing to Alzheimer's disease. The Lancet 2004;363(9406):392-94.
9. Ainslie PN, Cotter JD, George KP, et al. Elevation in cerebral blood flow velocity with aerobic fitness throughout healthy human ageing. The Journal of physiology 2008;586(16):4005-10.
10. Bailey DM, Marley CJ, Brugniaux JV, et al. Elevated aerobic fitness sustained throughout the adult lifespan is associated with improved cerebral hemodynamics. Stroke 2013;44(11):3235-38.
11. Colcombe SJ, Erickson KI, Scalf PE, et al. Aerobic exercise training increases brain volume in aging humans. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2006;61(11):1166-70.
12. Erickson KI, Voss MW, Prakash RS, et al. Exercise training increases size of hippocampus and improves memory. Proceedings of the National Academy of Sciences 2011;108(7):3017-22.
13. Spina MB, Squinto SP, Miller J, et al. Brain‐derived neurotrophic factor protects dopamine neurons against 6‐hydroxydopamine and N‐methyl‐4‐phenylpyridinium ion toxicity: involvement of the glutathione system. Journal of neurochemistry 1992;59(1):99-106.
14. Van Praag H, Christie BR, Sejnowski TJ, et al. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proceedings of the National Academy of Sciences 1999;96(23):13427-31.
15. Christie BR, Eadie BD, Kannangara TS, et al. Exercising our brains: how physical activity impacts synaptic plasticity in the dentate gyrus. Neuromolecular medicine 2008;10(2):47.
16. Weston KS, Wisløff U, Coombes JS. High-intensity interval training in patients with lifestyle-induced cardiometabolic disease: a systematic review and meta-analysis. Br J Sports Med 2014;48(16):1227-34.
17. Lucas SJ, Cotter JD, Brassard P, et al. High-intensity interval exercise and cerebrovascular health: curiosity, cause, and consequence. Journal of Cerebral Blood Flow & Metabolism 2015;35(6):902-11.
18. Brickman AM, Guzman VA, Gonzalez-Castellon M, et al. Cerebral autoregulation, beta amyloid, and white matter hyperintensities are interrelated. Neuroscience letters 2015;592:54-58.
Competing interests: No competing interests
Re: Dementia And Physical Activity (DAPA) trial of moderate to high intensity exercise training for people with dementia: randomised controlled trial
Lamb and colleagues conducted a randomized controlled trial to test the important question of whether structured exercise training affects dementia (1). The authors concluded that dementia may have been exacerbated by the exercise intervention. Unsurprisingly, this controversial conclusion has generated intense media publicity, with headlines emphasizing the potentially detrimental nature of exercise.
Scientists, clinicians and no doubt many members of the public perceive randomized controlled trials as the optimal design to test causal relationships. However, in trials where intervention assignment cannot be concealed from the study participants, such as is the case with exercise interventions, compensatory behaviours should be expected.
The exercise intervention in Lamb et al’s trial totalled about four-hours each week of structured, group-based exercise or home-based physical activities, accounting for about 2% of the total time in a week. The remaining 98% of the time allows ample opportunity for compensatory behaviours to occur that could counter the effects of the intervention. In a study of similar aged adults (58–78 years old) who underwent a similar exercise intervention to Lamb et al’s, energy expenditure was objectively assessed using gold standard methods (doubly labeled water and respiratory gas analysis) (2). The authors found that during the trial, exercise energy expenditure increased by 150 kcal/day on average; however, energy expended through other means (non-exercise energy expenditure) decreased proportionately and no overall change in total energy expenditure occurred. This makes sense, as engaging in structured exercise sessions might encourage the avoidance of other forms on non-structured exercise owing to fatigue or reward, particularly in populations unaccustomed to regular exercise. One might also expect compensatory changes in diet for similar reasons, not to mention contrasting lifestyle adaptations in control participants owing to Hawthorn effect. The use of objective assessment techniques to monitor changes in physical activity and diet in both arms of Lamb et al’s trial would have helped address some of these limitations.
Lamb et al cite improvements in fitness (assessed through a six-minute walk test) as evidence that the exercise intervention worked. Importantly, this way of assessing fitness is susceptible to bias owing to the impact that the exercise intervention may have, not only on fitness, but also on exercise-related self-efficacy (3). Moreover, no comparable data was available in the control arm, making it impossible to determine whether similar increases in walking distance would have occurred in control participants. The authors dismiss this possibility in their paper.
Given these caveats, it is concerning that this study has generated so much negative publicity around the role of physical activity in dementia. Sadly, letters like this that highlight the limitations of high-profile studies rarely garner much attention in the media - the damage is done.
1. Lamb SE, Sheehan B, Atherton N, Nichols V, Collins H, Mistry D, Dosanjh S, Slowther AM, Khan I, Petrou S, Lall R and Investigators DT. Dementia And Physical Activity (DAPA) trial of moderate to high intensity exercise training for people with dementia: randomised controlled trial. BMJ. 2018;361:k1675.
2. Goran MI and Poehlman ET. Endurance training does not enhance total energy expenditure in healthy elderly persons. Am J Physiol. 1992;263:E950-7.
3. Biddle SJ and Mutrie N. Psychology of physical activity: determinants, well-being, and interventions. London: Routledge; 2007.
Competing interests: No competing interests