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Anticholinergic drugs and risk of dementia: case-control study

BMJ 2018; 361 doi: https://doi.org/10.1136/bmj.k1315 (Published 25 April 2018) Cite this as: BMJ 2018;361:k1315

Rapid Response:

Drugs for dementia; exercise is medicine!

To the Editor,
We would like to congratulate the authors on their comprehensive study highlighting the proposed dangers of anticholinergic drug use and its association with the onset of dementia1. While we appreciate that this research took an epidemiological approach, it is important to direct some attention towards the mechanistic adaptations that may underlie the reported association. In turn, this will allow for health services to gain a comprehensive understanding of how to improve the likelihood of delaying if not indeed preventing the onset of dementia in the future.
The authors correctly allude to neurodegeneration as the pathological process precipitating dementia. However, it is important to focus on cerebrovascular changes that occur as a result of neurodegeneration. This is especially relevant given recent evidence suggesting that cerebral hypoperfusion is associated with cognitive impairment and dementia2. Furthermore, research has demonstrated that anticholinergic drug use decreases regional cerebral blood flow (CBF) in patients with Parkinson’s disease3. This can likely be attributed to a reduction in the circulating bioavailability of the primary vasodilator, nitric oxide following acetylcholine inhibition4. Thus, it is plausible that a reduction in CBF contributed to the increased risk of dementia, given the association between anticholinergic drugs administered to treat Parkinson’s disease and dementia risk observed by Richardson et al.1. This possible explanation is certainly concerning to healthcare professionals and Parkinson’s disease patients alike.
Fortunately, the inexorable decline in CBF can be attenuated by physical activity. Bailey et al.5 demonstrated that participants who exercised throughout the lifespan exhibited increased CBF compared to age-matched sedentary controls. With this in mind, the neuroprotective benefits associated with exercise may serve as a countermeasure to neurodegeneration, and thus we advocate the use of exercise as an intervention should clinicians deem it necessary to prescribe anticholinergic drugs. However, as a result of the aforementioned findings it was unfortunate that the authors did not consider exercise as an important covariate.
On a final note, we agree with the authors for recognising that the brain is susceptible to neurodegeneration long before the symptoms of dementia appear. However, it is equally apparent that the brain presents sufficient plasticity during middle age to adapt to external stimuli, such as physical activity. In fact, recent findings suggests that the brain can still benefit from exercise-induced improvements in cognitive function in fifty year olds subsequent to NO-mediated vascular adaptation6. These data advocate the need to maintain exercise levels throughout the lifespan and this now appears especially pertinent for patients prescribed anticholinergic drugs.

Financial disclosure
No competing financial interests exist.

Funding
D.M. Bailey is a Royal Society Wolfson Research Fellow (#WM170007).

References
1. Richardson K, Fox C, Maidment I, et al. Anticholinergic drugs and risk of dementia: case-control study. BMJ 2018;361:k1315. doi: 10.1136/bmj.k1315
2. Wolters FJ, Zonneveld HI, Hofman A, et al. Cerebral Perfusion and the Risk of Dementia: A Population-Based Study. Circulation 2017;136(8):719-28. doi: 10.1161/CIRCULATIONAHA.117.027448
3. Takahashi S, Tohgi H, Yonezawa H, et al. The effect of trihexyphenidyl, an anticholinergic agent, on regional cerebral blood flow and oxygen metabolism in patients with Parkinson’s disease. Journal of the neurological sciences 1999;167(1):56-61.
4. Toda N, Ayajiki K, Okamura T. Cerebral blood flow regulation by nitric oxide: recent advances. Pharmacological reviews 2009;61(1):62-97.
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):3235-38.
6. Northey JM, Cherbuin N, Pumpa KL, et al. Exercise interventions for cognitive function in adults older than 50: a systematic review with meta-analysis. Br J Sports Med 2017:bjsports-2016-096587.

Competing interests: No competing interests

05 May 2018
Damian M. Bailey
Royal Society Wolfson Research Professor
Thomas A. Calverley, Robin Corkill
University of South Wales
Neurovascular Research Laboratory, Alfred Russel Wallace Building, Faculty of Life Sciences and Education, University of South Wales, UK CF37 4AT