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Dementia And Physical Activity (DAPA) trial of moderate to high intensity exercise training for people with dementia: randomised controlled trial

BMJ 2018; 361 doi: https://doi.org/10.1136/bmj.k1675 (Published 16 May 2018) Cite this as: BMJ 2018;361:k1675 Visual abstract, showing the study population, design and primary outcomes.

Banging the brain-train drum; exercise is preventative not curative

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!

References
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.
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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

29 May 2018
Damian M Bailey
Professor and Royal Society Wolfson Research Fellow
Christopher J. Marley, Thomas A. Calverley
University of South Wales
Neurovascular Research Laboratory, Alfred Russell Wallace Building, Faculty of Life Sciences and Education