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Recent Advances – Smoking and Cognitive Functioning: The Dilemma

Understanding the effect of cigarette smoke on the brain is a global imperative since smoking continues to rise in developing countries at a rate of more than 3% per year. While tobacco smoking rates in the United States have gone down overall, the highest use is among those with lower education and income. The World Health Organization (WHO) predicts that 1.5 to 1.9 billion people worldwide will be smokers in 2025.

Cigarette smoke consists of thousands of compounds, including nicotine. Many of these compounds have known toxicity to the brain, cardiovascular, and pulmonary systems. Nicotine, in contrast, has positive effects on certain cognitive domains. Nicotine is structurally similar to acetylcholine and has been shown to improve cognitive functioning, possibly through stimulation of both α4β2 and α7 nicotinic receptors, which are essential for memory functioning. Decreased nicotinic activity in the hippocampus and amygdala may impair memory function. Additionally, a number of studies have found that nicotine can improve attention following both chronic and acute administration. The improvement may be attributed to a number of factors including nicotine stimulation of dopamine in the striatum or stimulation of nicotinic neurons in the thalamus or other brain regions associated with attention or arousal, such as anterior cingulate cortex. Clinically, nicotinic treatments (e.g. nicotine patch) are being evaluated as therapeutic treatment for cognitive impairment. Several initial studies have reported positive therapeutic effects on cognitive disorders, such as Alzheimer’s disease and age-related memory deficits.

On the other hand, there is growing evidence that cognitive impairment and dementia is associated with cigarette smoking. In a recent meta-analysis of 19 prospective studies, each with 12 months or more of follow-up, current smokers had an increased risk of dementia including Alzheimer’s disease, vascular dementia, and any dementia and had greater declines in mental state testing compared to subjects who have never smoked. These findings suggest that cigarette smoke has neurotoxic effects and is associated with an increased risk of dementia. To date, however, there are relatively few studies assessing the association between secondhand smoke and cognitive dysfunction.

Secondhand smoke, defined as tobacco smoke inhaled by individuals who do not smoke, contains a greater concentration of toxic and carcinogenic chemicals than the smoke inhaled by tobacco smokers. The U.S. Centers for Disease Control and Prevention reported that almost 50,000 deaths per year can be ascribed to secondhand smoke. The mechanisms by which active smoking and secondhand tobacco smoke exposure induce their ill effects may include systemic inflammation, pro-inflammatory cytokine induction, and endothelial dysfunction. Each of these mechanisms has been independently associated with cognitive impairment and dementia.

A cross-sectional analysis of 4,809 non-smoking adults aged 50 years or more from the English Longitudinal Study of Aging (Llewellyn et al.) was carried out to examine the relationship between secondhand smoke exposure and cognitive functioning. The study used levels of salivary cotinine (ng/ml) as a biomarker for recent secondhand smoke exposure. The results showed that participants with high levels of salivary cotinine (0.8-13.5 ng/ml) were more likely to perform in the lowest 10% of scores on a battery of neuropsychological tests than those with low levels of salivary cotinine (0.0-0.1 ng/ml). The authors, therefore, suggested that high levels of secondhand smoke exposure might be related to increased odds of cognitive impairment. Similarly, using the Geriatric Mental State Examination as an assessment of dementia syndromes, a research team in China interviewed 5,921 individuals aged 60 or above and characterized their secondhand smoke exposure. The researchers found that dementia syndromes were significantly associated with exposure to secondhand smoke. It was reported that the more severe the dementia syndrome, the stronger the relationship with secondhand smoke exposure. Another study by Orsitto et al., conducted in Paradiso Hospital, Italy, found that patients with a diagnosis of mild cognitive impairment reported a significantly higher frequency of secondhand smoke compared to those with normal cognition.

While the cardiovascular and cancer risks associated with tobacco smoking are clear, the cognitive risks are complicated. Nicotinic stimulation may improve cognition but the effects of smoking may be toxic to the brain and cognitive function. Further, the effects may be experienced by those who never smoked due to second hand exposure. Other forms of nicotine delivery, including trans-dermal patch, are under investigation for cognitive benefits and indeed are worthy of study given how few agents are available to improve cognitive performance. Further studies are also needed to investigate the relationship between secondhand tobacco smoke and increased risk of cognitive disorders. Establishing that exposure to cigarette smoke may contribute to cognitive loss and dementia could provide additional motivation for smoking cessation and improve compliance with withdrawal and abstention.

References:
1. Anstey, K.J., von Sanden, C., Salim, A., O’Kearney, R. Smoking as a risk factor for dementia and cognitive decline: a meta-analysis of prospective studies. American Journal of Epidemiology 2007 Aug 15; 166: 367-78.
2. Barnes, D.E., Haight, T.J., Mehta, K.M., Carlson, M.C., Kuller, L.H., Tager, I.B. Secondhand smoke, vascular disease, and dementia incidence: findings from the cardiovascular health cognition study. American Journal of Epidemiology 2010 Feb 1; 171(3): 292-302.
3. Chen, R., Wilson, K., Chen, Y., Zhang, D., Qin, X., He, M., Hu, Z., Ma, Y., Copeland, J.R. Association between environmental tobacco smoke exposure and dementia syndromes. Occupational and Environmental Medicine 2013 Jan; 70(1): 63-9.
4. Levin, E.D., McClernon, F.J., Rezvani, A.H. Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berl) 2006 Mar; 184(3-4): 523-39.
5. Llewellyn, D.J., Lang, I.A., Langa, K.M., Naughton, F., Matthews, F.E. Exposure to secondhand smoke and cognitive impairment in non-smokers: national cross sectional study with cotinine measurement. British Medical Journal 2009 Feb 12; 338: b462.
6. Orsitto, G., Turi, V., Venezia, A., Fulvio, F., Manca, C. Relation of secondhand smoking to mild cognitive impairment in older inpatients. Scientific World Journal 2012; 2012: 726948.
7. http://www.who.int/mediacentre/factsheets/fs339/en/

Clara Li, Ph.D

Excerpted article as reprinted from IPA’s newsletter, the IPA Bulletin, Volume 30, Number 6

Acknowledgements

Acadia Pharmaceuticals Axsome Cambridge University Press Cerevel Lundbeck Otsuka