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Neurology. 2012 Jan 10; 78(2): 91–101.
doi:  [10.1212/WNL.0b013e31823efcbb]
PMCID: PMC3466669
PMID: 22232050
Nicotine treatment of mild cognitive impairment
A 6-month double-blind pilot clinical trial
P. Newhouse, MD, K. Kellar, PhD, P. Aisen, MD, H. White, MD, K. Wesnes, PhD, E. Coderre, MSc, A. Pfaff, BA, H. Wilkins, BA, D. Howard, MS, and E.D. Levin, PhD


 Objective:
To preliminarily assess the safety and efficacy of transdermal nicotine therapy on cognitive performance and clinical status in subjects with mild cognitive impairment (MCI).
 

Methods:
Nonsmoking subjects with amnestic MCI were randomized to transdermal nicotine (15 mg per day or placebo) for 6 months. Primary outcome variables were attentional improvement assessed with Connors Continuous Performance Test (CPT), clinical improvement as measured by clinical global impression, and safety measures. Secondary measures included computerized cognitive testing and patient and observer ratings.
 

Results:
Of 74 subjects enrolled, 39 were randomized to nicotine and 35 to placebo. 67 subjects completed (34 nicotine, 33 placebo). The primary cognitive outcome measure (CPT) showed a significant nicotine-induced improvement. There was no statistically significant effect on clinician-rated global improvement. The secondary outcome measures showed significant nicotine-associated improvements in attention, memory, and psychomotor speed, and improvements were seen in patient/informant ratings of cognitive impairment. Safety and tolerability for transdermal nicotine were excellent.
 

Conclusion:
This study demonstrated that transdermal nicotine can be safely administered to nonsmoking subjects with MCI over 6 months with improvement in primary and secondary cognitive measures of attention, memory, and mental processing, but not in ratings of clinician-rated global impression. We conclude that this initial study provides evidence for nicotine-induced cognitive improvement in subjects with MCI; however, whether these effects are clinically important will require larger studies.
 

Classification of evidence:
This study provides Class I evidence that 6 months of transdermal nicotine (15 mg/day) improves cognitive test performance, but not clinical global impression of change, in nonsmoking subjects with amnestic MCI.
Mild cognitive impairment (MCI) is defined as a subjective and objective decline in cognition and function that does not meet criteria for a diagnosis of dementia1–3 and represents a transitional state between the cognition of normal aging and mild dementia.4 CNS nicotinic acetylcholine receptor stimulation may be a promising strategy to ameliorate symptoms of MCI and slow progression to dementia. The 2 most prevalent nicotinic receptors in the brain, α4β2 and α7, have both been found to be important for cognitive function.5 Nicotinic receptor loss has been demonstrated in patients with Alzheimer disease (AD)6 and is linked to the hallmark plaques and tangles7 and cognitive impairment.8–10

Cognitive improvement is one of the best-established therapeutic effects of nicotine.11 In human studies, nicotine improves performance in smokers on cognitively demanding attentional tasks.12–14 In clinical studies, memory improvement was initially seen with IV nicotine in subjects with AD.15 Others have also found nicotine administration by subcutaneous injection or transdermal patch to improve cognitive function in AD.16–19 MCI may be the optimal diagnosis for which to test the efficacy of nicotinic therapy with relatively large numbers of preserved nicotinic receptors, and only modest declines of cognitive function.

The primary goals of this trial were to evaluate the safety of sustained nicotine treatment in nonsmoking older patients and to determine whether nicotine would improve cognitive performance, as measured by objective tests and clinical ratings.