Atrial Fibrillation and Dementia: What is the Link?

2 January 2018

Regarding atrial fibrillation (AF), post-stroke cognitive impairment (PSCI), and post-stroke dementia (PSD), a recently published article in October 2017 by Chander and colleagues [1] reported that AF is a significant and independent risk factor for PSCI even after correction of other risk factors and that we should do follow up for patients with AF regardless of infarction type. This agrees with a meta-analysis done in 2012 [2]. Also in a systemic review done in 2017 [3], stroke patients with AF have a risk of dementia which is 1.68 times compared with patients without AF. AF was found to cause hippocampal atrophy and cognitive impairment even in patients without symptomatic stroke or with silent infarctions [4]. However, cognitive impairment sometimes may be associated with increasing age in AF patients and age-related pathologies as the prevalence of AF doubles every decade of life after the age of 50 years and reaches 10–20% in patients over the age of 80 years [5].

Another meta-analysis showed that although the risk is higher in stroke patients, there is association between AF and cognitive impairment or dementia, irrespective of occurrence of stroke [6]. This may be related to other mechanisms mentioned by Chander and colleagues as hypoperfusion, endothelial dysfunction, and neuroinflammation. We should not forget the role of brain resilience in PSCI; including cognitive reserve and brain reserve. Cognitive reserve refers to the brain capacity to maintain the same level of cognitive function despite having brain pathology; it is largely affected by age, educational level, and the performance of exercise and recreational activities [7]. The Stroke Registry Investigating Cognitive Decline (STRIDE) study showed that people who performed regular intellectual and leisure activities such as reading a newspaper and/or stretching physical exercise before stroke had a lower risk of early-onset PSD, after controlling for other factors [8]. Brain reserve refers to variation between individuals in brain size and number of neurons and synapses available, and is capable of resisting brain injury or pathologies [9]. This includes amyloid plaques, neurofibrillary tangles, and white matter hyperintensities. Although they are sometimes subclinical, they decrease brain reserve and resilience and increase the possibility of PSCI with vascular insults [10].

Last, I would like to highlight the Rotterdam study, in which AF was shown to be more likely associated with Alzheimer’s dementia with cerebrovascular disease than vascular dementia [11]. What is the possible mechanism? And is the relation between AF and dementia or AF and PSCI partially explained by Alzheimer’s pathology, being accelerated with stroke? Future prospective studies are needed to ensure the possible mechanisms responsible for cognitive impairment in AF patients, the relation between AF and Alzheimer’s disease and to identify the best treatment approach if possible for preventing or delaying the progression to dementia in patients with or without stroke.

Heba Mohamed Tawfik, MD
Lecturer and consultant of Geriatrics and Gerontology
Faculty of Medicine, Ain-Shams University
Cairo, Egypt
201005621272
hmt_82@yahoo.com

References
[1] Chander RJ, Lim L, Handa S, Hiu S, Choong A, Lin X, Singh R, Oh D, Kandiah N (2017) Atrial fibrillation is independently associated with cognitive impairment after ischemic stroke. J Alzheimers Dis 60, 867-875.
[2] Santangeli P, Di Biase L, Bai R, Mohanty S, Pump A, Cereceda Brantes M, Horton R, Burkhardt JD, Lakkireddy D, Reddy YM, Casella M, Dello Russo A, Tondo C, Natale A (2012) Atrial fibrillation and the risk of incident dementia: a meta-analysis. Heart Rhythm 9, 1761-1768.
[3] Surawan J, Areemit S, Tiamkao S, Sirithanawuthichai T, Saensak S (2017) Risk factors associated with post-stroke dementia: a systematic review and meta-analysis. Neurol Int 9, 7216.
[4] Knecht S, Oelschläger C, Duning T (2008) Atrial fibrillation in stroke-free patients is associated with memory impairment and hippocampal atrophy. Eur Heart J 29, 2125-2132.
[5] Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D’agostino RB, Massaro JM, Beiser A, Wolf PA, Benjamin EJ (2004) Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 110, 042–1046.
[6] Kalantarian S, Stern TA, Mansour M, Ruskin JN (2013) Cognitive impairment associated with atrial fibrillation: a meta-analysis. Ann Intern Med 158 (5 pt 1), 338–346.
[7] Pendlebury ST, Rothwell PM (2009) Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and metaanalysis. Lancet Neurol 8, 1006–1018.
[8] Wong A, Lau AY, Lo E, Tang M, Wang Z, Liu W, Tanner N, Chau N, Law L, Shi L, Chu WC, Yang J, Xiong YY, Lam BY, Au L, Chan AY, Soo Y, Leung TW, Wong LK, Lam LC, Mok VC (2016) Relations between recent past leisure activities with risks of dementia and cognitive functions after stroke. PLoS One 11, e0159952.
[9] Stern, Y (2012) Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol 11, 1006–1012.
[10] Pendlebury ST (2012) Dementia in patients hospitalized with stroke: rates, time course, and clinico-pathologic factors. Int J Stroke 7, 570–581.
[11] Ott A, Breteler MM, de Bruyne MC, van Harskamp F, Grobbee DE, Hofman A (1997) Atrial fibrillation and dementia in a population-based study. The Rotterdam Study. Stroke 28, 316–321.

Comments

Submitted by Nagaendran Kandiah, MBBS, FRCP... on

In the letter entitled “Atrial fibrillation and dementia: what is the link?”, Dr. Tawfik addresses the findings published by our group in Journal of Alzheimer’s Disease in October 2017 [1]. The letter raises the point that while there is a connection between atrial fibrillation (AF) and post-stroke cognitive impairment (PSCI) as demonstrated by the paper, there are also other mitigating factors that can have an effect on this relationship, such as age, cognitive reserve, brain reserve, and Alzheimer’s disease (AD) pathology. Also, AF can be related to non-stroke cognitive impairment. Given this, more information is needed to further clarify the link between AF and PSCI. We thank Dr. Tawfik for his insights in this topic and for providing his comments on the matter.

We acknowledge the mitigating factors that were raised, and agree with them to be valid. In doing so, we also acknowledge the limitations of our analysis to include the lack of MRI scans of sufficient quality for volumetric analysis, and the lack of amyloid or tau imaging, as this has not allowed us to definitively characterize brain reserve and AD pathology enough to address these concerns. While we have attempted to account for the effects of underlying neurodegeneration by including global cortical atrophy scores into our modeling [odds ratio (OR) for PSCI = 1.56 (95% confidence interval; CI = 1.02 – 2.40)], we agree that more study is needed in this area. Also, while we did not have any explicit data on cognitive reserve via pre-stroke physical and intellectual activity, our results do corroborate the notion that cognitive reserve via education plays a part in PSCI. In our findings, higher education was associated with an OR of 0.86 (95% CI = 0.82 – 0.92) for PSCI. The findings also are in agreement with age being a risk factor (OR = 1.03; 95% CI = 1.00 – 1.06). That aside, it should be noted that the presence of AF was still significantly associated with a higher odds ratio for PSCI after correcting for these factors and more, demonstrating an association that has at least some effect on its own [1].

Overall, we agree with the notion put forward by Dr. Tawfik that the connection between AF and PSCI is complex, due to AF being related to cognition in the absence of stroke, and there being factors other than AF that are related to PSCI. We have discussed the generalizability of our results in our manuscript, and mentioned that the mechanisms of the link between AF and PSCI may extend beyond vascular pathologies. Such issues will be important to consider when determining treatment or prophylactic strategies appropriate for stroke survivors with AF, and if treatment plans that are vascular-centric, amyloid-centric, or both, would be most appropriate and effective.

Regardless of AF having vascular effects via infarct severity, vascular effects via chronic cerebrovascular disease, non-vascular effects, or any combination of these, it is clear that AF is significantly associated with cognitive decline, and that this effect has its own impact independent of other factors. When characterizing the risk factor profile of a stroke survivor in assessing their chances of PSCI, the question if AF has a vascular or non-vascular effect is relatively moot; its mere presence already confers onto the stroke survivor an increased risk for developing cognitive impairment, and it is this increased risk that we feel cannot be understated.

Reference:
[1] Chander RJ, Lim L, Handa S, Hiu S, Choong A, Lin X, Singh R, Oh D, Kandiah N (2017) Atrial fibrillation is independently associated with cognitive impairment after ischemic stroke. J Alzheimers Dis 60, 867-875.