- Email: [email protected]
Smoking, nicotine and dementia
Maturitas 72 (2012) 4–5
Contents lists available at SciVerse ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Editorial
Smoking, nicotine and dementia
Keywords: Dementia MCI Alzheimer’s disease Nicotine Prevention Treatment
Twenty to thirty years ago cross-sectional studies reported the intriguing possibility that smoking was actually beneficial in dementia and Alzheimer’s disease [1]. Such findings shone as an encouraging exception in the gloom of the grim and growing catalogue of harm that smoking causes. However, it subsequently became clear that, as with cancers and heart disease, smoking is harmful to cognitive health and is associated with an increase in dementia [2]. But some neurochemists and clinicians detected a signal in the evidence that, whatever harms smoking may cause, nicotine itself might benefit cognition in general and Alzheimer’s disease in particular [3]. Such findings have led to clinical trials investigating this exciting possibility and Dr Newhouse and colleagues have now reported a randomised study [4] in mild cognitive impairment (MCI), a pre-dementia condition. 1. A randomised study of nicotine patches in pre-dementia (MCI) The trial was designed to assess the safety and efficacy of transdermal nicotine therapy on cognitive performance and clinical status in subjects with MCI. It had a conventional double-blind randomised, parallel group, design and compared transdermal nicotine to placebo on a 1:1 basis. Subjects recruited were nonsmokers who met standard (Peterson’s) criteria for MCI and scored between 24 and 30 on the mini-mental state examination and 0.5–1.0 on the clinical dementia rating scale. Subjects were all aged 55 or over at time of recruitment and were excluded if they had any significant medical or neurological conditions, previous head trauma or significant structural brain abnormalities or any severe psychiatric illness in the last 2 years, e.g. major depression or schizophrenia. They were also excluded if they were taking anticholinergic medication or were current smokers. Subjects were randomly allocated to either transdermal nicotine patches or placebo patches. The primary cognitive outcome measure was attentional improvement as assessed by Connors continuous performance test (CPT), which is a measure of visuomotor functioning. Other primary outcome measures were clinical improvement as measured by clinician rated global improvement (CGIC) and safety measures. Secondary outcome measures included performance on 0378-5122/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2012.01.020
computerised cognitive testing and patient and observer rating scales. All of the patient’s who entered the trial were accounted for at completion of the study. 74 subjects were eligible for entry into the study, of whom 39 were randomised to nicotine and 35 to placebo. 67 subjects completed the study (34 nicotine and 33 placebo). In the nicotine group 4 subjects withdrew because of adverse effects and 1 was withdrawn, diagnosed with Alzheimer’s disease. In the placebo group 2 subjects withdrew because of adverse effects. Primary analysis was performed on all 74 randomised subjects on an intention to treat basis. Secondary analysis was performed on the 67 completed subjects. The groups were well matched for age, gender, level of education, baseline cognitive scores, MMSE, Hamilton anxiety and depression rating scores and nutritional status. No clinical or baseline variables were significantly different between the treatment groups. Aside from the drug intervention the two groups were treated equally. The groups underwent safety assessments at days 0, 7, 28, 91 and 182 and cognitive assessment at days 0, 91 and 182. The study showed that nicotine improved reaction time on the Connor’s CPT (p = 0.03) but there were no significant treatment related effects on errors (omissions or commissions) or overall hit rate or overall reaction time variance. The nicotine treatment effect size was 0.78 (Cohen d) at the end of the study (week 26). Several secondary cognitive measures showed significant nicotine-induced improvements including psychomotor speed and attention on several tasks as well as significant effects on long-term memory seen in the paragraph recall and computerised word recall test. The primary clinical outcome, the clinical global impression by clinicians did not show any significant improvement. There was no statistically significant difference between treatment groups when rated by clinicians on the CGIC (p = 0.13). The majority of adverse events were mild and there was no significant difference in the proportion of adverse events within the different severity classes between treatments. More nicotine treated subjects discontinued treatment because of adverse effects than placebo treated subjects (p = 0.05). Perhaps more importantly the nicotine treatment was also associated with a modest but significant reduction in systolic blood pressure (4 mmHg) and a significant reduction in body weight (−1.3 kg). Thus in summary, this trial reported that nicotine treatment improved reaction times, improved a few other cognitive tests but such benefits were not detectable by clinicians, as indicated by the failure to identify differences on the CGIC.
2. A new treatment to prevent dementia For those working in the field of dementia it is pleasing to see a report of a clinical trial, which has a positive outcome. Over the
Editorial / Maturitas 72 (2012) 4–5
last few years there have been a series of phase II and III studies, which have failed to demonstrate benefits from a range of anti-Alzheimer’s disease treatments, with most of these not being reported outside conferences. The target group (people with MCI) is an appropriate one for novel dementia treatments because it is widely recognised that early interventions are needed which modify the Alzheimer’s disease process and thus prevent or reduce the rate at which people develop dementia. Previous studies have shown that transdermal patches and nicotine administered by other routes can have a mild beneficial effect on attention and cognition in people including those who have Alzheimer’s disease. White and Levin [5] reported results from a small-scale trial over a 4-week period, which showed that transdermal nicotine improved attention and reaction times in subjects with age-associated cognitive decline; Howe and Price [6] also reported that transdermal nicotine improved performance on cognitive tests including verbal learning and delayed recall in individuals “at risk” of developing dementia; Sahakian et al. [7] reported that nicotine improved the performance of individuals with Alzheimer’s disease on tests of attention and information processing. There have also been numerous trials investigating the effects of nicotine on cognitive performance in individuals with other psychiatric disorders, such as schizophrenia [8]. These too have shown that nicotine improves concentration and attentional processing. Thus in context this trial is another example adding to the evidence that nicotine can have a beneficial effect on cognition in the short-term; however the long term benefits of nicotine on cognition are unknown. And more importantly at present there has been very little research into the crucial question of whether nicotine treatment can delay the conversion of MCI or similar predementia syndromes to dementia. The expected conversion rates for MCI to dementia are reported to be between 10 and 15% per year [9]. In the current trial only one subject converted to AD over the course of the study period (6 months). However, the study was not designed and so was underpowered to detect conversion rates to dementia and did not follow up the subjects for a long enough time period to determine whether nicotine reduced progression of MCI. 3. Conclusion The authors of this study are suitably cautious about its implications acknowledging the study shows statistically significant results but that these are not clearly clinical important in that they may not translate into significant benefit to individuals in “the real world”. The unsupervised use of nicotine (either nicotine patches or smoking) is not without potential problems. Nicotine is an addictive drug with many possible side-effects and associated withdrawal effects if used over long periods of time. High-doses of nicotine can also be toxic to the body. Certainly the established health risks of smoking outweigh any potential benefits in terms of cognition. At present it is too early to advocate the use of nicotine patches or other methods of nicotine administration, such as e-cigarettes, by older people for cognitive benefit although this is certainly an important area for future research.
5
Contributors Both authors contributed equally to this manuscript. Funding None was secured for the writing of this manuscript. Competing interest None declared. Provenance and peer review Commissioned, not externally peer reviewed. References [1] Graves AB, van Duijn CM, Chandra v, et al. Alcohol and tobacco consumption as risk factors for Alzheimer’s disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group. International Journal of Epidemiology 1991;20(Suppl 2):S48–57. [2] Ott A, Slooter AJ, Hofman A, et al. Smoking and risk of dementia and Alzheimer’s disease in a population-based cohort study: the Rotterdam study. Lancet 1998;351(9119):1840–3. [3] Hellstrom-Lindahl E, Court J, Keverne J, et al. Nicotine reduces A beta in the brain and cerebral vessels of APPsw mice. European Journal of Neuroscience 2004;19(10):2703–10. [4] Newhouse P, Kellar K, Aisen P, et al. Nicotine treatment of mild cognitive impairment: a 6-month double-blind pilot clinical trial. Neurology 2012;78(2): 91–101. [5] White HK, Levin ED. Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer’s disease. Psychopharmacology 1999;143(2):158–65. [6] Howe MN, Price IR. Effects of transdermal nicotine on learning, memory, verbal fluency, concentration, and general health in a healthy sample at risk for dementia. International Psychogeriatrics 2001;13(4): 465–75. [7] Sahakian B, Jones G, Levy R, et al. The effects of nicotine on attention, information processing, and short-term memory in patients with dementia of the Alzheimer type. British Journal of Psychiatry 1989;154:797–800. [8] Barr RS, Culhane MA, Jubelt LE, et al. The effects of transdermal nicotine on cognition in non-smokers with schizophrenia and non-psychiatric controls. Neuropsychopharmacology 2008;33(3):480–90. [9] Bruscoli M, Lovestone S. Is MCI really just early dementia? A systematic review of conversion studies. International Psychogeriatrics 2004;16(2): 129–40.
Louise Grayson Alan J. Thomas ∗ Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, United Kingdom ∗ Corresponding
author. Tel.: +44 0191 445 5212; fax: +44 0191 445 6685. E-mail address: [email protected] (A.J. Thomas) 24 January 2012 25 January 2012
Contents lists available at SciVerse ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Editorial
Smoking, nicotine and dementia
Keywords: Dementia MCI Alzheimer’s disease Nicotine Prevention Treatment
Twenty to thirty years ago cross-sectional studies reported the intriguing possibility that smoking was actually beneficial in dementia and Alzheimer’s disease [1]. Such findings shone as an encouraging exception in the gloom of the grim and growing catalogue of harm that smoking causes. However, it subsequently became clear that, as with cancers and heart disease, smoking is harmful to cognitive health and is associated with an increase in dementia [2]. But some neurochemists and clinicians detected a signal in the evidence that, whatever harms smoking may cause, nicotine itself might benefit cognition in general and Alzheimer’s disease in particular [3]. Such findings have led to clinical trials investigating this exciting possibility and Dr Newhouse and colleagues have now reported a randomised study [4] in mild cognitive impairment (MCI), a pre-dementia condition. 1. A randomised study of nicotine patches in pre-dementia (MCI) The trial was designed to assess the safety and efficacy of transdermal nicotine therapy on cognitive performance and clinical status in subjects with MCI. It had a conventional double-blind randomised, parallel group, design and compared transdermal nicotine to placebo on a 1:1 basis. Subjects recruited were nonsmokers who met standard (Peterson’s) criteria for MCI and scored between 24 and 30 on the mini-mental state examination and 0.5–1.0 on the clinical dementia rating scale. Subjects were all aged 55 or over at time of recruitment and were excluded if they had any significant medical or neurological conditions, previous head trauma or significant structural brain abnormalities or any severe psychiatric illness in the last 2 years, e.g. major depression or schizophrenia. They were also excluded if they were taking anticholinergic medication or were current smokers. Subjects were randomly allocated to either transdermal nicotine patches or placebo patches. The primary cognitive outcome measure was attentional improvement as assessed by Connors continuous performance test (CPT), which is a measure of visuomotor functioning. Other primary outcome measures were clinical improvement as measured by clinician rated global improvement (CGIC) and safety measures. Secondary outcome measures included performance on 0378-5122/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2012.01.020
computerised cognitive testing and patient and observer rating scales. All of the patient’s who entered the trial were accounted for at completion of the study. 74 subjects were eligible for entry into the study, of whom 39 were randomised to nicotine and 35 to placebo. 67 subjects completed the study (34 nicotine and 33 placebo). In the nicotine group 4 subjects withdrew because of adverse effects and 1 was withdrawn, diagnosed with Alzheimer’s disease. In the placebo group 2 subjects withdrew because of adverse effects. Primary analysis was performed on all 74 randomised subjects on an intention to treat basis. Secondary analysis was performed on the 67 completed subjects. The groups were well matched for age, gender, level of education, baseline cognitive scores, MMSE, Hamilton anxiety and depression rating scores and nutritional status. No clinical or baseline variables were significantly different between the treatment groups. Aside from the drug intervention the two groups were treated equally. The groups underwent safety assessments at days 0, 7, 28, 91 and 182 and cognitive assessment at days 0, 91 and 182. The study showed that nicotine improved reaction time on the Connor’s CPT (p = 0.03) but there were no significant treatment related effects on errors (omissions or commissions) or overall hit rate or overall reaction time variance. The nicotine treatment effect size was 0.78 (Cohen d) at the end of the study (week 26). Several secondary cognitive measures showed significant nicotine-induced improvements including psychomotor speed and attention on several tasks as well as significant effects on long-term memory seen in the paragraph recall and computerised word recall test. The primary clinical outcome, the clinical global impression by clinicians did not show any significant improvement. There was no statistically significant difference between treatment groups when rated by clinicians on the CGIC (p = 0.13). The majority of adverse events were mild and there was no significant difference in the proportion of adverse events within the different severity classes between treatments. More nicotine treated subjects discontinued treatment because of adverse effects than placebo treated subjects (p = 0.05). Perhaps more importantly the nicotine treatment was also associated with a modest but significant reduction in systolic blood pressure (4 mmHg) and a significant reduction in body weight (−1.3 kg). Thus in summary, this trial reported that nicotine treatment improved reaction times, improved a few other cognitive tests but such benefits were not detectable by clinicians, as indicated by the failure to identify differences on the CGIC.
2. A new treatment to prevent dementia For those working in the field of dementia it is pleasing to see a report of a clinical trial, which has a positive outcome. Over the
Editorial / Maturitas 72 (2012) 4–5
last few years there have been a series of phase II and III studies, which have failed to demonstrate benefits from a range of anti-Alzheimer’s disease treatments, with most of these not being reported outside conferences. The target group (people with MCI) is an appropriate one for novel dementia treatments because it is widely recognised that early interventions are needed which modify the Alzheimer’s disease process and thus prevent or reduce the rate at which people develop dementia. Previous studies have shown that transdermal patches and nicotine administered by other routes can have a mild beneficial effect on attention and cognition in people including those who have Alzheimer’s disease. White and Levin [5] reported results from a small-scale trial over a 4-week period, which showed that transdermal nicotine improved attention and reaction times in subjects with age-associated cognitive decline; Howe and Price [6] also reported that transdermal nicotine improved performance on cognitive tests including verbal learning and delayed recall in individuals “at risk” of developing dementia; Sahakian et al. [7] reported that nicotine improved the performance of individuals with Alzheimer’s disease on tests of attention and information processing. There have also been numerous trials investigating the effects of nicotine on cognitive performance in individuals with other psychiatric disorders, such as schizophrenia [8]. These too have shown that nicotine improves concentration and attentional processing. Thus in context this trial is another example adding to the evidence that nicotine can have a beneficial effect on cognition in the short-term; however the long term benefits of nicotine on cognition are unknown. And more importantly at present there has been very little research into the crucial question of whether nicotine treatment can delay the conversion of MCI or similar predementia syndromes to dementia. The expected conversion rates for MCI to dementia are reported to be between 10 and 15% per year [9]. In the current trial only one subject converted to AD over the course of the study period (6 months). However, the study was not designed and so was underpowered to detect conversion rates to dementia and did not follow up the subjects for a long enough time period to determine whether nicotine reduced progression of MCI. 3. Conclusion The authors of this study are suitably cautious about its implications acknowledging the study shows statistically significant results but that these are not clearly clinical important in that they may not translate into significant benefit to individuals in “the real world”. The unsupervised use of nicotine (either nicotine patches or smoking) is not without potential problems. Nicotine is an addictive drug with many possible side-effects and associated withdrawal effects if used over long periods of time. High-doses of nicotine can also be toxic to the body. Certainly the established health risks of smoking outweigh any potential benefits in terms of cognition. At present it is too early to advocate the use of nicotine patches or other methods of nicotine administration, such as e-cigarettes, by older people for cognitive benefit although this is certainly an important area for future research.
5
Contributors Both authors contributed equally to this manuscript. Funding None was secured for the writing of this manuscript. Competing interest None declared. Provenance and peer review Commissioned, not externally peer reviewed. References [1] Graves AB, van Duijn CM, Chandra v, et al. Alcohol and tobacco consumption as risk factors for Alzheimer’s disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group. International Journal of Epidemiology 1991;20(Suppl 2):S48–57. [2] Ott A, Slooter AJ, Hofman A, et al. Smoking and risk of dementia and Alzheimer’s disease in a population-based cohort study: the Rotterdam study. Lancet 1998;351(9119):1840–3. [3] Hellstrom-Lindahl E, Court J, Keverne J, et al. Nicotine reduces A beta in the brain and cerebral vessels of APPsw mice. European Journal of Neuroscience 2004;19(10):2703–10. [4] Newhouse P, Kellar K, Aisen P, et al. Nicotine treatment of mild cognitive impairment: a 6-month double-blind pilot clinical trial. Neurology 2012;78(2): 91–101. [5] White HK, Levin ED. Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer’s disease. Psychopharmacology 1999;143(2):158–65. [6] Howe MN, Price IR. Effects of transdermal nicotine on learning, memory, verbal fluency, concentration, and general health in a healthy sample at risk for dementia. International Psychogeriatrics 2001;13(4): 465–75. [7] Sahakian B, Jones G, Levy R, et al. The effects of nicotine on attention, information processing, and short-term memory in patients with dementia of the Alzheimer type. British Journal of Psychiatry 1989;154:797–800. [8] Barr RS, Culhane MA, Jubelt LE, et al. The effects of transdermal nicotine on cognition in non-smokers with schizophrenia and non-psychiatric controls. Neuropsychopharmacology 2008;33(3):480–90. [9] Bruscoli M, Lovestone S. Is MCI really just early dementia? A systematic review of conversion studies. International Psychogeriatrics 2004;16(2): 129–40.
Louise Grayson Alan J. Thomas ∗ Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, United Kingdom ∗ Corresponding
author. Tel.: +44 0191 445 5212; fax: +44 0191 445 6685. E-mail address: [email protected] (A.J. Thomas) 24 January 2012 25 January 2012