TOBACCO AND NEURODEGENERATIVE DISEASES Mini-Lecture 3 Module :Tobacco and the Nervous System

Objectives of the Mini Lecture Goals of Mini Lecture: Provide students with knowledge about the effect of smoking on risk of developing neurodegenerative diseases. Learning Objectives of Mini Lecture: Students will be able to: Describe the effect of smoking on the risk of developing multiple sclerosis and its progression. Describe the effect of smoking on Alzheimer’s disease. Describe the effect of smoking on Parkinson’s disease. Explain why smoking cessation is important.

Contents Core Slides: Smoking and Multiple Sclerosis Risk Smoking and MS Progression Secondhand Smoke and MS Smoking and Alzheimer’s Disease Smoking and Parkinson’s Disease Discussion: Smoking vs. Quitting Optional Slides: Smoking and MS: Mechanisms (1–2)

CORE SLIDES Tobacco and Neurodegenerative Disease Mini Lecture 3 Module: Tobacco and The Nervous System

Smoking and Multiple Sclerosis Risk Increased risk of developing multiple sclerosis (MS)1,2 Increased risk among active smokers2 Incidence of MS increased with cumulative exposure to smoking2 Notes:   Smoking is a significant risk factor for subsequent development of MS.1,2 No single environmental factor has been consistently identified as a causal factor in Multiple Sclerosis (MS), but a few have been reproducibly identified as associated with MS in epidemiological studies. One of these factors is smoking: smokers were found to have a 40–80% higher risk of MS than non-smokers in epidemiological studies. Several cohort studies have reported an increase in the risk of MS among active smokers.2 The Nurses’ Health Study and the Nurses’ Health Study II reported a pooled incidence rate of MS in women who were current smokers 1.6 (95% CI = 1.2–2.1) times higher than that in women who had never smoked. The incidence of MS increased with cumulative exposure to smoking in these studies. In the general population, the risk of incident MS among current and past smokers was 1.81 (95% CI = 1.1–2.9) times higher than that in subjects who had never smoked. In the Oxford Family Planning Association Study, the incidence of MS in women who smoked more than 15 cigarettes per day was 1.8 (95% CI 0.8–3.6) times higher than that in women who had never smoked. In the Royal College of General Practitioners’ Oral Contraception Study, the incidence of MS in women who smoked more than 15 cigarettes per day was 1.4 (95% CI = 0.9–2.2) times higher than that in women who had never smoked.2 References: Hawkes CH. Smoking is a risk factor for multiple sclerosis: a metanalysis. Mult Scler. 2007; 13:610-15. Mikaeloff Y, Caridade G, Tardieu M, Suissa S on behalf of the KIDSEP study group. Parental smoking at home and the risk of childhood-onset multiple sclerosis in children. Brain. 2007; 130:2589-95:1-7. http://www.elements4health.com/images/stories/conditions/multiple-sclerosis.jpg 1. Hawkes 2007; 2. Mikaeloff 2007

Smoking and MS Progression Relapsing-remitting MS patients continuing to smoke: increased risk of entering secondary progressive phase of disease1 Increased risk of severe disease 2 Notes:   Patients with relapsing-remitting disease who continue to smoke are more likely to enter the secondary progressive phase of the disease.1 An Israeli study including 241 prevalent MS cases (92% of all the cases identified in the country in 1960) and randomly selected population controls found that the proportion of smokers before the age at onset was significantly higher among cases than among controls (44% versus 36%, P = 0.02).2 Another important issue is the association between passive smoking and a severe course of the disease. One study in adults has reported an increase in the risk of clinical MS progression associated with cigarette smoking.2 References: Hawkes CH. Smoking is a risk factor for multiple sclerosis: a metanalysis. Mult Scler. 2007; 13:610–15. Mikaeloff Y, Caridade G, Tardieu M, Suissa S on behalf of the KIDSEP study group. Parental smoking at home and the risk of childhood-onset multiple sclerosis in children. Brain. 2007; 130:2589-95:1–7. http://www.knowledgebase-script.com/demo/admin/attachments/multiple-sclerosis.jpg 1. Hawkes 2007; 2. Mikaeloff 2007

Secondhand Smoke and MS Parental smoking at home: increased risk of first episode of MS in children (2.12 times).1 Significantly associated with prolonged duration of exposure in older cases. Notes:   Parental smoking at home was associated with a significant increase in the risk of a first episode of MS in children. After adjustment for a family history of MS or of another autoimmune disease and for the socio-professional status of the head of the family, the adjusted RR of a first episode of MS associated with exposure to parental smoking at home was 2.12 (95% CI = 1.43–3.15). Stratification for age showed that this increase in risk was significantly associated with a longer duration of exposure in older cases (over the age of 10 years at the index date): RR 2.49 (1.53–4.08), than in younger cases. The increase in risk was not associated with sex, socio-professional status or place of residence. Reference: Mikaeloff Y, Caridade G, Tardieu M, Suissa S on behalf of the KIDSEP study group. Parental smoking at home and the risk of childhood-onset multiple sclerosis in children. Brain 2007;130:2589-95:1–7 http://www.elements4health.com/images/stories/conditions/myelin-sheath.jpg 1. Mikaeloff 2007

Smoking and Alzheimer’s Disease Most studies show inverse association between smoking and Alzheimer's disease (AD), i.e. protective.1 However, Rotterdam study shows twice the risk of AD among smokers.2 Protective association restricted to patients with family history of dementia.1 Notes:   A negative trend for smoking was observed when comparing patients with Alzheimer's disease and controls: the risk of Alzheimer's disease decreased as the number of cigarettes smoked daily increased. There is some evidence that nicotine may improve information processing and attention in patients with Alzheimer's disease, which suggests that nicotine may have a protective role in Alzheimer's disease.1 The protective association between smoking and Alzheimer’s disease was restricted to patients with a family history of dementia and was independent of cardiovascular history and potential confounding variables such as age, sex, and alcohol consumption. Within families in which Alzheimer's disease was apparently inherited as an autosomal dominant disorder, it was observed that the onset of Alzheimer's disease was later in smoking patients than in nonsmoking patients.1 The lack of association in patients with sporadic Alzheimer's disease suggests that smoking may be involved only in a mechanism of primarily genetic origin. These findings suggest heterogeneity between familial and sporadic Alzheimer's disease.1 The finding of an inverse association between smoking and Alzheimer's disease should be interpreted with caution as it is not confirmed by prospective studies. Although the association is compatible with a protective effect of smoking for familial Alzheimer's disease, it has no relevance for prevention of Alzheimer's disease because of the adverse health effects of smoking.1 However, a recent study shows that smokers are more than twice as likely to develop Alzheimer's Disease as people who have never smoked. The study - the largest ever of its kind and the first major research to look at people before they develop Alzheimer's - followed 6,870 men and women aged 55 and over. None of the people had Alzheimer's, the most common form of dementia, before the study by the Erasmus Medical School in Rotterdam began.3 Over a two-year period, any who developed signs of dementia were assessed and, where possible, given a brain scan. A total of 146 people developed dementia during the course of the study, with 105 being diagnosed as having Alzheimer's. People who smoked were found to be 2.3 times more likely to develop Alzheimer's than those who had never smoked. They were also more likely to get Alzheimer's at a younger age.3 However, the researchers found that smoking does not increase the risk of developing Alzheimer's for people with a gene linked to the disease. Indeed, they believe smoking may offer protection against the disease for people with the gene - APOE epsilon 4.3 The study looked at the relationship between cigarette smoking and Alzheimer's disease (AD) in a prospective community-based study in Manhattan. The authors examined data from a community-based longitudinal study of local elders residing in Manhattan to determine whether tobacco use increases or decreases the risk of AD. The relative risk (RR) of AD among former smokers was 0.7 (95% CI, 0.5 to 1.1). The RR among current smokers was 1.9 (95% CI, 1.2 to 3.0). Smokers without an APOE-epsilon 4 allele had the highest risk of AD (RR = 2.1; 95% CI, 2.1 to 3.7) compared with those with an APOE-epsilon 4 allele (RR = 1.4; 95% CI, 0.6 to 3.3). However, they also found that among previous smokers who quit smoking, there may be a slight reduction in the risk of AD.2 References: van Duijn CM, Hofman A. Relation between nicotine intake and Alzheimer's disease. BMJ. 1991; 302:1491–4. Merchant C, Tang MX, Albert S, Manly J, Stern Y, Mayeux R. The influence of smoking on the risk of Alzheimer's disease. Neurology. 1999; 52:1408–12. Smoking may double the risk of Alzheimer’s. Available at: http://news.bbc.co.uk/2/hi/health/115829.stm 1. van Duijn et al. 1991; 2. Merchant et al. 1999

Smoking and Parkinson’s Disease1 Patients with Parkinson's disease (PD) observed to smoke less than control subjects Most studies of cigarette smoking and PD have reported a protective effect of smoking Notes:   In most studies of Parkinson's disease, patients have been observed to smoke less than control subjects. Most studies of cigarette smoking and Parkinson's disease have also reported a protective effect of smoking. Reference: van Duijn CM, Hofman A. Relation between nicotine intake and Alzheimer's disease. BMJ. 1991; 302:1491–4. http://www.about-dementia.com/images/ParkinsonsDopamine.jpg 1. van Duijn et al. 1991

Discussion: Smoking vs. Quitting Data on protective effect of smoking on AD and PD is inconclusive. Moreover, smoking is a known risk factor for many major diseases like stroke, heart disease, etc. No overall advantage in smoking. Notes:   Available data on protective effect of smoking on certain neurodegenerative disorders is controversial and inconclusive. In such a scenario, the overall benefit lies in quitting as the harmful/causative effects of smoking on many other major diseases and conditions like stroke and heart disease have been established beyond any doubt.

OPTIONAL SLIDES Tobacco and Neurodegenerative Disease Mini Lecture 3 Module: Tobacco and The Nervous System

Smoking and MS: Mechanisms (1) Immune stimulation or suppression1 Direct effect of cigarette smoke components1,2: increased blood-brain permeability Induces deficiency of interferon gamma producing cells in adenoids of children2 Notes:   A variety of mechanisms have been suggested to explain the association between smoking and multiple sclerosis either by immune stimulation or suppression. Smoking is claimed to be linked to autoimmune disease, such as rheumatoid arthritis, systemic lupus erythematosis, Grave’s disease and Crohn’s disease.1 The underlying mechanism may involve a direct effect of cigarette smoke components on the blood–brain barrier or a nicotine effect on microvascular blood flow in the brain.2 Nicotine may increase blood-brain permeability to allow entry of abnormal T cells, or tobacco smoke may poison the central myelin, as it does in tobacco amblyopia, possibly by elevation of blood levels of its metabolite, thiocyanate.1 It was also recently demonstrated that exposure to passive smoking could induce a deficiency of interferon gamma producing cells in adenoids of children.2 References: Hawkes CH. Smoking is a risk factor for multiple sclerosis: a metanalysis. Mult Scler. 2007; 13:610–15. Mikaeloff Y, Caridade G, Tardieu M, Suissa S on behalf of the KIDSEP study group. Parental smoking at home and the risk of childhood-onset multiple sclerosis in children. Brain. 2007; 130:2589-95:1–7. http://2getherwewill.com/yahoo_site_admin/assets/images/mscleros.32502053_std.gif 1. Hawkes 2007; 2. Mikaeloff et al. 2007

Smoking and MS: Mechanisms (2) Direct toxic effects on the central nervous system1: Demyelination by cyanide (cigarette smoke)1 Axonal degeneration due to nitric oxide2 Notes:   Some components of cigarette smoke may have direct toxic effects on the central nervous system. Serum concentrations of cyanide, a component of cigarette smoke, and its main metabolite, thiocyanate, are strongly correlated with the level of tobacco consumption. The administration of high doses, as in adults who actively smoke, has been shown to cause demyelination in the central nervous system of animals, but similar effects were also observed at lower doses, equivalent to those resulting from passive smoking in children.1 An alternative mechanism might be through axonal exposure to nitric oxide (NO). Smoking is claimed to elevate NO levels in plasma, conceivably leading to an increase of NO levels at the site of demyelinated axons. Physiologically active or demyelinated neurons are particularly susceptible to NO exposure, and this, in turn, could result in axonal degeneration or conduction block. This theory provides a mechanism for both initiation of MS and the accelerated progression of disability.2 Smoking may also increase the risk of MS by increasing the frequency and persistence of respiratory infections.1 References: Mikaeloff Y, Caridade G, Tardieu M, Suissa S on behalf of the KIDSEP study group. Parental smoking at home and the risk of childhood-onset multiple sclerosis in children. Brain. 2007; 130:2589-95:1–7. Hawkes CH. Smoking is a risk factor for multiple sclerosis: a metanalysis. Mult Scler. 2007; 13:610–15. http://repairstemcell.files.wordpress.com/2009/02/ww5r308_big.jpg 1. Mikaeloff et al. 2007; 2. Hawkes 2007

The most important health message a doctor can give to patients is to quit smoking.