Nicotine treatment of mild cognitive
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
E.D. Levin, PhD
Objective: To preliminarily assess the safety and efficacy of transdermal nicotine therapy on cog-
nitive 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
nitive 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 improve-
ments 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 cogni-
tive 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 cog-
nitive 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. Neurology®2012;78:91–101
AD ? Alzheimer disease; AE ? adverse event; BMI ? body mass index; CDR ? Clinical Dementia Rating; CGIC ? Clinical
Global Impression of Change; CPT ? Continuous Performance Test; CRT ? Choice Reaction Time; MCI ? mild cognitive
impairment; OASR ? Older Adult Self Report; OABCL ? Older Adult Behavior Checklist; RT ? reaction time.
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 dementia1–3and represents a transi-
tional state between the cognition of normal aging and mild dementia.4CNS nicotinic acetyl-
choline 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, ?4?2 and
?7, have both been found to be important for cognitive function.5Nicotinic receptor loss has
been demonstrated in patients with Alzheimer disease (AD)6and is linked to the hallmark
plaques and tangles7and cognitive impairment.8–10
From the Clinical Neuroscience Research Unit, Department of Psychiatry (P.N., E.C., A.P., H.W.), and Center for Clinical and Translational Science
(D.H.), University of Vermont College of Medicine, Burlington; Center for Cognitive Medicine (P.N.), Department of Psychiatry, Vanderbilt
University School of Medicine, Nashville, TN; Department of Pharmacology (K.K.), Georgetown University School of Medicine, Washington, DC;
Department of Neuroscience (P.A.), University of California San Diego School of Medicine, San Diego; Departments of Medicine (H.W.) and
Psychiatry and Behavioral Sciences (E.D.L.), Duke University School of Medicine, Durham, NC; and United BioSource Incorporated (K.W.), Chevy
Study funding: Supported by the NIH/NIA R01AG22462 and NIGMS M01 RR00109. Pfizer Inc provided the transdermal nicotine patches.
Disclosure: Author disclosures are provided at the end of the article.
Correspondence & reprint
requests to Dr. Newhouse:
Copyright © 2012 by AAN Enterprises, Inc.
Cognitive improvement is one of the best-
established therapeutic effects of nicotine.11In
human studies, nicotine improves perfor-
mance in smokers on cognitively demanding
attentional tasks.12–14In clinical studies, mem-
ory improvement was initially seen with IV
nicotine in subjects with AD.15Others have
also found nicotine administration by subcu-
taneous injection or transdermal patch to im-
prove cognitive function in AD.16–19MCI
may be the optimal diagnosis for which to test
the efficacy of nicotinic therapy with rela-
tively large numbers of preserved nicotinic re-
ceptors, and only modest declines of cognitive
The primary goals of this trial were to eval-
uate the safety of sustained nicotine treatment
in nonsmoking older patients and to deter-
mine whether nicotine would improve cogni-
tive performance, as measured by objective
tests and clinical ratings.
METHODS Study population. One hundred subjects
were recruited from 2004 through 2007 at 3 sites. Individuals
screened for this study either carried a diagnosis of MCI or had
been identified through community memory screening pro-
grams or community clinics.
MCI diagnosis utilized the generally accepted criteria for am-
nestic MCI4: age 55?; memory complaints and memory diffi-
culties verified by an informant; abnormal memory function
documented by scoring below the education-adjusted cutoff on
the Logical Memory II subscale (Delayed Paragraph Recall) from
the Wechsler Memory Scale–Revised as used in prior MCI tri-
als20; Mini-Mental State Examination score between 24 and 30
(inclusive); Clinical Dementia Rating (CDR)21of 0.5 with a
memory box score of 0.5 or 1.0. Exclusion criteria included any
significant current or prior medical or neurologic disease, head
injury, or significant structural brain abnormalities, Axis I psy-
chiatric illness or substance abuse within the last 2 years, chronic
use of medications with centrally active cholinergic or anticho-
linergic properties, and current tobacco or nicotine use. No sub-
jects were taking any cognitive enhancing medications or
acetylcholinesterase inhibitors. Behavioral screening consisted of
a partial Diagnostic Interview Schedule,22the Beck Depression
Rating Scale,23and the structured Hamilton Depression Rating
Standard protocol approvals, registrations, and patient
consents. This study was approved by the institutional review
board at each institution. Subjects received an oral and a written
explanation of the purposes, procedures, and potential hazards of
this study and provided informed consent (separate consent for
APOE genotyping). This study was registered with the NIH clin-
ical trials database (Clinicaltrials.gov), NCT00091468.
Study design/randomization. The study was a double-
blind, parallel-group, placebo-controlled, randomized clinical
trial (figure 1) with a 6-month double-blind period with ran-
domization to either transdermal nicotine or placebo on a one-
to-one basis. The randomization and treatment allocation
sequence (generated by the study statistician, D.H.) was per-
formed within gender, age (?75 and 75?), and center. Subjects,
informants, local site PIs, and local study coordinators were
blinded to treatment assignment. The second phase was open-
label transdermal nicotine for additional 6 months which was
offered to all subjects who completed the double-blind (will be
reported separately). Subjects who met criteria for AD during
the study were removed by predetermined protocol criteria and
were offered treatment with standard approved agents.
Power. The study sample size was calculated based on data
from a previous 4-week nicotine patch trial in patients with
AD.18Using an ? level of 0.05, a SD of 3 errors at baseline and at
week 26, and a correlation between baseline and week 26 errors
of 0.5, we calculated that with 60 subjects, we had 80% power to
detect the difference in the average change score in the CPT task
between groups of 1 SD. Anticipating dropouts of up to 20%,
the planned sample size was 75 subjects (25 per center).
Study hypotheses/classification of evidence. We pro-
posed 3 hypotheses: transdermal nicotine treatment 1) would
improve cognitive performance in patients with MCI as mani-
fested by improvements in sustained attention, learning, and
memory compared to placebo treatment; 2) would improve
global ratings of cognitive and functional abilities; and 3) would
be tolerable and safe over 6 months of continuous treatment.
This study provides Class I evidence that 6 months of transder-
mal nicotine (15 mg/day) improves cognitive test performance,
but not clinical global impression of change, in nonsmoking sub-
jects with amnestic MCI.
Medication. Transdermal nicotine was begun utilizing a 5 mg
Nicotrol®patch (Pharmacia/Pfizer) transdermal delivery system,
in sizes of 10, 20, and 30 cm2each containing 0.83 mg/cm2of
nicotine, releasing 5 mg, 10 mg, and 15 mg, respectively, over 16
hours or matching placebo. Treatment (active or placebo) was
titrated to 15 mg by day 21. Subjects were contacted by phone
during the first week and returned after 7 and 28 days to moni-
tor side effects and medication compliance.
Assessment. Performance/behavioral testing was done at 0, 91,
and 182 days. The primary cognitive outcome measure was the
reaction time standard error performance on the Connors Con-
tinuous Performance Test (CPT)25,26as improvement in reaction
time standard error performance over varying intervals is a strong
indication of overall attentional performance and nicotine effects
in AD.18Secondary cognitive measures included the Cognitive
Drug Research computerized battery.14,27–29In addition, subjects
completed the Immediate and Delayed Paragraph Recall Test
(NYU version) and the Digit Symbol Substitution Task. The
Clinical Global Impression of Change30(MCI-CGIC) was used
as the primary clinical outcome measure.
Behavioral/functional assessments. Assessments included
the structured Hamilton Depression Rating Scale,24the Alzhei-
mer’s Disease Cooperative Study–Activities of Daily Living,31
the Mini Nutritional Assessment32for grading the nutritional
state of subjects, the CDR, and the Older Adult Self Report
(OASR) and Behavior Checklist (OABCL).33
Safety assessment. In addition to collecting adverse event re-
ports, vital signs were measured at all clinical visits and a repeat
of the screening laboratory tests was performed at the end of the
study. Tolerability and safety were determined by counting spe-
cific adverse events and counting dropouts due to adverse events.
Neurology 78 January 10, 2012
Statistical analyses. Primary data analysis focused on the ran-
was conducted for the first 6 months. Cognitive, clinical, and safety
variables were assessed both in subjects who received at least 1 dose
of treatment (intent to treat) as well as subjects who completed the
double-blind. Data are presented as mean ? SE unless indicated.
Cognitive performance. Mixed models repeated-measures
vs placebo as a between-subjects factor and efficacy testing time
point (0, 91, 182 days) as the categorical within-subjects factor.
Global ratings. Analysis of the MCI-CGIC compared global
ratings for nicotine and placebo utilizing ordered polychoto-
mous logistic regression and the CGIC rating at the end of
double-blind treatment (182 days). Site and gender were in-
cluded in the model as covariates.
Safety outcome. Differences for rates of adverse events or
other safety abnormalities between groups were assessed using ?2
RESULTS Of the 100 subjects screened for the
study, 74 subjects passed screening criteria and were
Figure 1 Study design, subject allocation, and subject course
AD ? Alzheimer disease; AE ? adverse event.
Neurology 78 January 10, 2012
randomized to treatment, 45 male and 29 female (ta-
ble 1). Forty subjects reported being former cigarette
smokers (?100 cigarettes lifetime) and 34 were
never smokers. At least 1 APOE4 allele was present in
30 of 70 subjects with 18 being present in the pla-
cebo group (51%) and 14 in the nicotine-treated
group (38%) (p ? 0.25). Thirty-nine subjects were
randomized to nicotine treatment (34 completers)
and 35 subjects were randomized to placebo treat-
ment (33 completers) (figure 1). The mean ages
for the nicotine-treated and placebo-treated sub-
jects were 76.2 ? 1.4 and 75.7 ? 1.1, respec-
tively. No clinical or baseline variables were
significantly different between treatment groups
or sites. The target dose was 15 mg daily and
73/74 subjects received this dose for the double-
blind phase following titration.
Primary efficacy measures. Cognitive performance. CPT.
Cognitive performance is detailed in table 2. Hit re-
action time (RT) standard error over interstimulus
interval (the primary outcome measure) showed a
significant (F1,57? 4.89, p ? 0.031) main effect of
nicotine treatment with the variability in RT over the
varying interstimulus intervals being significantly
improved (reduced) on nicotine treatment compared
to placebo (figure 2A) by days 91 and 182 (p ?
0.005). The 67 completers showed significant
nicotine-induced improved performance on this
measure (F1,54? 14.96, p ? 0.0003) compared to
placebo treatment. There were no significant
treatment-related changes in errors (Omission, Com-
mission), overall hit RT, or overall RT variance. The
nicotine treatment effect size was 0.78 at week 26
Global measure. CGIC. There was no statistical dif-
ference between treatment groups in the distribution
of subjects rated improved or not improved (p ?
0.13) (figure 2B). Reducing the outcomes into just 3
categories (any improvement, no change, any wors-
ening) revealed that 3 subjects in the placebo group
were rated as improved (9.1%) vs 8 subjects (23.5%,
p ? 0.12) after nicotine treatment.
Secondary efficacy measures. Cognitive measures. Para-
graph recall. Cognitive measures are detailed in table 2.
Examining change from baseline (days 91, 182) for
the 67 completers showed a significant (F1,60?
6.19, p ? 0.02) main effect with the placebo-treated
group showing greater immediate recall (but not de-
layed recall) of story units over time compared to the
nicotine-treated group. Analysis of forgetting be-
tween immediate and delayed trials showed a signifi-
cant (F1,60? 4.42, p ? 0.04) effect of nicotine
treatment showing reduced loss of information com-
pared to the placebo-treated group (figure 3A).
Digit Symbol Substitution Task. There was a trend (p ?
0.13) for nicotine-treated subjects to show improved
accuracy by day 182.
Computerized cognitive battery. Memory. Delayed
word recall accuracy (table 1) showed a significant
effect of treatment (F1,70? 5.92, p ? 0.018) with
Table 1 Subject demographics, baseline
cognitive assessment, and APOE
(n ? 39)
(n ? 35)
Gender, n (%)
Male (n ? 45)
25 (64) 20 (57)
Female (n ? 29)
14 (36)15 (43)
76.9 (15.7) 73.9 (14.7)
15.6 (2.9)16.2 (2.4)
Sum of boxes
1.4 (0.7) 1.5 (0.8)
2 (0.2)2 (0.2)
2.7 (2.5) 3.7 (3.6)
27.4 (1.9)27.5 (2.1)
0.92 (1.13) 0.88 (1.01)b
13.2 (1.2) 13.3 (1.0)
7.4 (3.6) 7.5 (3.8)
4.4 (3.2) 4.7 (3.8)
112 (11) 113 (13)
108 (8)111 (7)
112 (10) 114 (11)
109 (7)111 (9)
112 (9)114 (11)
Genetics, n (%)
(n ? 70)
(n ? 30)
14 (38) 18 (51)
(n ? 40)
23 (62)17 (49)
Abbreviations: CDR ? Clinical Dementia Rating; DRS ? De-
mentia Rating Scale; GDS ? Global Deterioration Scale;
Ham-D ? Hamilton Depression Rating Scale; MMSE ?
Mini-Mental State Examination; MNA ? Mini-Nutritional In-
ventory; WAIS ? Wechsler Adult Intelligence Scale; WMS ?
Wechsler Memory Scale; WTAR ? Wechsler Test of Adult
aThere were no significant differences on measures be-
tween treatment groups. Data are mean (SD) or n (%).
bData missing for 1 patient.
cData missing for 2 subjects.
Neurology 78January 10, 2012
Table 2 Continuous Performance Task, paragraph recall, and Cognitive Drug Research Battery individual
scores (adjusted means and standard errors) for all subjects (74)
Day 0Day 7 Day 21 Day 91Day 182
No. of omissions
20.2 (8.3) 13.7 (5.1) 22.2 (9.9)12.2 (3.7) 19.7 (9.3)
8.97 (1.75) 15.97 (9.92)14.44 (6.23) 17.03 (9.88)22.27 (10.65)
Percent of omissions
6.3 (2.6) 4.3 (1.6)6.9 (3.1) 3.8 (1.2)6.1 (2.9)
2.8 (0.5)4.9 (3.1)4.5 (1.9) 5.3 (3.1)6.9 (3.3)
No. of commissions
10.9 (0.9) 11.1 (0.8)9.5 (1.0) 9.1 (0.7)9.5 (0.8)
12.4 (1.1) 11.3 (1.2)11 (1.3) 10.9 (1.2)10.9 (1.4)
Percent of commissions
30.4 (2.4)31.0 (2.2)26.4 (2.8)25.3 (2.1) 26.4 (2.2)
34.6 (3.0) 31.3 (3.4) 30.6 (3.6)10.9 (1.2)10.9 (1.4)
Hit reaction time
487 (26) 454 (10)452 (10) 453 (10)454 (11)
468 (13)470 (16)463 (13) 482 (19) 475 (13)
5.3 (0.4)3.4 (0.4) 4.4 (0.4)4.0 (0.4) 3.8 (0.4)
4.9 (0.4) 4.1 (0.4)4.6 (0.4) 5.4 (0.4)4.4 (0.4)
4.0 (0.5)3.2 (0.5) 3.3 (0.5) 4.3 (0.5)3.8 (0.5)
4.1 (0.5) 3.2 (0.5) 3.2 (0.5)4.8 (0.5)3.8 (0.5)
Cognitive Drug Research Battery
individual item scores
Simple reaction time
350 (10)355 (9)353 (11) 370 (15) 370 (12)
378 (19) 366 (13) 376 (18)377 (18) 373 (16)
Choice reaction time
552 (13) 532 (10)541 (13)529 (11) 543 (14)
556 (19) 560 (22)552 (21)567 (21)566 (22)
Delayed picture recognition
0.55 (0.03)0.56 (0.03)0.57 (0.03) 0.59 (0.04)0.60 (0.04)
0.57 (0.04)0.56 (0.03)0.63 (0.04)0.56 (0.04)0.54 (0.05)
Delayed word recognition
0.50 (0.05)0.51 (0.04) 0.55 (0.03) 0.52 (0.03)0.54 (0.03)
0.56 (0.04) 0.49 (0.04)0.53 (0.04) 0.55 (0.05)0.53 (0.04)
Spatial memory reaction time
1436 (70)1159 (143) 1225 (49) 1153 (49)1396 (80)
1617 (194)983.5 (57)1252 (91)1342 (133) 1535 (168)
Spatial memory sensitivity
0.75 (0.04) 0.78 (0.05)0.75 (0.04) 0.86 (0.03) 0.75 (0.04)
0.68 (0.06) 0.89 (0.04) 0.77 (0.04)0.75 (0.07) 0.66 (0.06)
Digital vigilance accuracy
96.2 (0.6) 97.1 (0.6)96.0 (1.2) 96.5 (0.8)94.51 (1.3)
97.5 (0.7)97.4 (0.5)97.1 (0.6) 95.8 (0.9)95.6 (1.0)
Neurology 78January 10, 2012
the nicotine-treated group showing a significant
improvement over time compared to the placebo
group (figure 3B). Analysis of the 67 completers
demonstrated that the nicotine-treated group had
a significant (F1,61? 5.37, p ? 0.02) improve-
ment compared to the placebo-treated subjects.
The spatial memory and delayed picture recogni-
tion sensitivity revealed trends (p ? 0.10 and p ?
0.12, respectively) favoring the nicotine-treated
group with improvement over baseline at both
Attention/response speed. The speed of memory sum-
mary measure (table e-1 on the Neurology®Web site
at www.neurology.org) showed a strong trend (F3,70?
2.56, p ? 0.06) in the intent-to-treat sample for a
treatment-by-time interaction with the nicotine-
treated group showing improved overall memory
speed by day 91. RT variability (a measure of atten-
tional fluctuation) showed a strong trend for im-
provement with nicotine (F1,66? 3.34, p ? 0.07).
In the Choice Reaction Time task (CRT), there was
a main effect of treatment (F1,66? 4.44, p ? 0.04)
on accuracy performance with nicotine treatment as-
sociated with greater accuracy over time (also seen in
completers, p ? 0.06) (table 1). Continuity of atten-
tion (table e-1) showed a trend (F1,61? 2.96, p ?
0.09) for a positive effect of nicotine treatment as did
the picture recognition task (F1,70? 3.62, p ?
0.061) and delayed word recognition (F1,70? 2.88,
p ? 0.09).
For the power of attention summary measure (ta-
ble e-1), there was an interaction between treatment
and APOE genotype (p ? 0.047) such that the
APOE4 double allele subgroup had a significant
(p ? 0.019) improvement with nicotine treatment
but the E4/E3 and E3/E3 groups did not. Com-
pleters showed a significant treatment-by-genotype
interaction (F2,50? 3.26, p ? 0.047) with nicotine
improving the double allele group only (t ? 2.39,
p ? 0.021). For the Digit Vigilance Task, speed
showed a similar significant (p ? 0.01) advantage for
nicotine treatment in the APOE4 double allele group
compared to the other groups.
Safety. Body weight. Change in body weight (figure
e-1) showed that there was a significant treatment-
by-day interaction (F3,71? 5.55, p ? 0.002) with
the nicotine-treated group showing a decline in body
weight by day 91 compared to placebo: ?1.3 kg for
the nicotine-treated group (range ?6.9 to ?1.6 kg)
vs ?0.12 kg for the placebo-treated subjects (range
?4.4 to ?4.1 kg). A significant treatment effect was
also seen for body mass index (BMI) by day 91.
However, by day 182, mean BMI values remained in
the normal range and were similar between treatment
groups: 25.9 ? 3.6 for placebo and 25.8 ? 4.2 for
Vital signs. There was a significant nicotine treat-
ment effect (F1,71? 9.01, p ? 0.004) with a signifi-
cant reduction in systolic blood pressure compared
to placebo (figure e-2). By day 182, the placebo
group showed an average increase of 9.6 mm Hg in
systolic blood pressure (range ?30 to ?38 mm Hg)
compared to a reduction of 4 mm Hg (range ?30 to
?47 mm Hg) in the nicotine-treated group. There
was no effect of treatment on diastolic blood pres-
sure, pulse, or oral temperature. There was a signifi-
cant (F1,70? 5.16, p ? 0.03) nicotine-associated
reduction in respirations.
Adverse events. Total adverse events (AEs) for the
double-blind treatment period were 82 for nicotine
vs 52 for placebo (?2 ? 3.92, p ? 0.05). How-
ever, the majority of AEs were mild and there was no
statistically significant difference in the proportion of
adverse events within the different severity classifica-
tions between treatments (Mann-Whitney test p ?
0.97). No severe AEs were classified as related to
drug treatment in either treatment group. Adverse
event rates by body systems (figure e-3) were gener-
ally comparable, with the exception of gastrointesti-
nal and neurologic, for which there were more AEs
reported in the nicotine-treated group. More
nicotine-treated subjects (4) discontinued treatment
Table 2 Continued
Day 0Day 7Day 21 Day 91Day 182
Digital vigilance reaction time
464 (9) 461 (9) 458 (9) 464 (9) 473 (11)
465 (8) 460 (7)462 (7)477 (8)479 (8)
Immediate word recall
3.54 (0.25) 3.64 (0.27)3.68 (0.32) 3.53 (0.33)3.56 (0.32)
3.77 (0.39)3.71 (0.30)3.74 (0.35)3.77 (0.36) 3.75 (0.35)
Delayed word recall
1.03 (0.21)1.33 (0.24)1.62 (0.29)1.61 (0.32)1.69 (0.30)
1.35 (0.37)1.35 (0.25)1.52 (0.34)1.68 (0.33)1.59 (0.38)
Neurology 78January 10, 2012
for adverse events than placebo-treated subjects (0)
(?2 ? 3.79; p ? 0.05). No withdrawal symptoms
were reported by subjects or informants nor were any
subjects reported to be continuing to use nicotine
after the study was completed.
Subject- and informant-completed behavioral mea-
sures. OASR and OABCL. The self-rated Worries and
Anxiety subscales showed significant (F2,86? 3.48,
p ? 0.04 and F2,86? 3.14, p ? 0.05) interactions
with the nicotine-treated group showing improved
scores by day 182. There was a strong trend (F2,86?
2.74, p ? 0.07) for nicotine to improve scores in the
DSM-oriented dementia subscale (consisting of
items from the OASR commonly associated with a
DSM dementia diagnosis). The informant-completed
OABCL showed lower ratings on the Anxiety/De-
pression subscale (F2,90? 5.00, p ? 0.009) for pla-
cebo treatment. The Beck Depression Inventory
showed no significant treatment effect (p ? 0.72) or
interactions (p ? 0.50).
DISCUSSION This study demonstrated that trans-
dermal nicotine treatment for 6 months improved
cognitive performance in subjects with amnestic
MCI. The primary cognitive outcome (Connors
CPT) showed a significant nicotine-induced im-
provement with an effect size of 0.78 which com-
pares favorably to a previous study of nicotine in
AAMI34in which the effect size was 0.53 at 4 weeks
on the same measure. Several secondary cognitive
measures showed significant nicotine-induced im-
provement including psychomotor speed and atten-
Figure 2 Primary efficacy variables
(A) Continuous Performance Task: hit reaction time standard error change over interstimulus intervals, change from base-
line (n ? 67). Nicotine treatment significantly improved performance on this measure (F1,57? 14.96, p ? 0.0003) com-
pared to placebo treatment. (B) Clinical Global Impression of Change (CGIC). CGIC all categories (n ? 67): there was no
statistical difference between treatments in the distribution of subjects rated improved or not improved (p ? 0.13).
Neurology 78 January 10, 2012
tion on several tasks as well as significant effects on
long-term memory seen in both the paragraph recall
task and computerized word recall task (e.g., figure
3B). This is consistent with prior studies of nicotinic
stimulation in AD, where we saw more robust effects
on long-term recall than short-term recall,15,35and
suggests that this is a specific effect on patients with
memory impairment, as studies have indicated that
nicotine does not generally improve performance un-
less subjects are impaired.36There were trends for
improvements in a number of other cognitive mea-
sures. Whether these trends would become statisti-
cally significant with larger sample sizes is unclear
and will require further study to assess the overall
impact of nicotinic stimulation. There was no evi-
dence for loss of cognitive effects over time. The
primary clinical outcome, the Clinical Global Im-
pression by the clinician, did not show significant
improvement; however, patients and their infor-
mants did report nicotine-induced improvements.
Nicotine was well-tolerated with few subjects
withdrawing because of medication side effects. All
but one subject tolerated the highest administered
dose. Transdermal administration method probably
contributed to improved tolerability, particularly re-
ducing the incidence of potential gastrointestinal side
effects. Nicotine treatment was associated with a
modest reduction in systolic blood pressure. The re-
duction in weight (approximately 2.5 kg by day 182)
is not unexpected considering the mild anorectic ef-
fects of nicotine. No significant medical conse-
quences related to the loss of weight occurred in the
nicotine-treated subjects and no subject developed a
clinically low BMI (?18.5) over the course of the
trial. However, further study will be necessary to
confirm that there are no long-term negative conse-
Figure 3Secondary verbal memory cognitive performance variables
(A) Paragraph recall: immediate recall minus delay recall; change from baseline (n ? 67). Note that negative score indicates
improvement (less forgetting from immediate to delay trials). Nicotine treatment produced a significant (F1,60? 4.42, p ?
0.04) effect showing reduced loss of information between the immediate and delayed trials compared to the placebo-
treated group. (B) Delayed word recall accuracy, Cognitive Drug Research Battery. Change from baseline (n ? 67). There
was a significant effect of nicotine treatment (F1,70? 5.92, p ? 0.018) with the nicotine-treated group showing a signifi-
cant improvement over time in delayed word recall accuracy compared to the placebo group.
Neurology 78 January 10, 2012
quences of nicotine-induced weight loss in patients
with MCI and the treatment of patients with low
BMI with nicotine should be approached with cau-
tion. There was no withdrawal syndrome and no
subjects continued to use nicotine products. Thus, in
this nonsmoking population, there was no evidence
for abuse liability of transdermal nicotine. Only non-
smokers were utilized for this study to simplify dose-
ranging. As former smoking status was not a focus of
this study and the number of former smokers was
small, an analysis of prior smoking status and efficacy
was not performed. Whether these findings of cogni-
tive enhancement would apply to individuals with
substantial histories of tobacco use or active smoking
will require further study and potentially different
While strategies that attempt to mitigate directly
or indirectly the molecular pathology that leads to
synaptic loss will be important in treating/preventing
MCI and AD, it is likely that neurotransmitter-based
treatments will continue to be necessary to directly
enhance cognitive functioning, particularly in do-
mains that are relevant to the aging process and to
the loss of synaptic connectivity in MCI and AD.
Furthermore, there is strong evidence that nicotine
itself may be neuroprotective and may have a role in
amyloid processing37(although nicotine has been
shown to exacerbate tau pathology in a rodent
model38). Thus there may be an additional motiva-
tion for nicotinic treatment in patients with bio-
marker or clinical evidence for early cognitive
impairment. Treatment periods longer than 1 year
may be necessary in future studies to look for disease-
The finding that APOE genotype impacted the
response to nicotine is intriguing. A recent study in
young individuals demonstrated that nicotine had a
greater cognitive activity in APOE4-positive individ-
uals,39suggesting that the cholinergic system may be
upregulated in APOE4-positive individuals or in
MCI.40Thus it is possible that nicotinic augmenta-
tion may be a particularly appropriate choice for
Limitations in the study included a relatively
small sample size (74). Power was calculated on the
basis of a cognitive measure (CPT task), so the power
to detect effects from clinical global ratings was quite
limited. Because of the length of the study, no data
on progression could be obtained. To simplify dose-
ranging only nonsmokers were tested. Nicotine dose
titration was only performed to limit side effects.
Further clinical benefit might be achieved by titra-
tion also based on efficacy.
This study found that transdermal nicotine over 6
months is a safe treatment for nonsmoking subjects
with MCI. As this was a pilot clinical trial, we
wanted to measure a broad number of cognitive and
behavioral domains which might be influenced by
nicotinic stimulation. Thus, it is not surprising that
some measures showed no effect of treatment. How-
ever, measures of attentional, memory, and psy-
chomotor performance did show an effect of nicotine
and this finding provides strong justification for fur-
ther treatment studies of nicotine for patients with
early evidence of cognitive dysfunction.
Dr. Newhouse: designed and conceptualized the study, conducted the
study as principal investigator including supervising the coordinating cen-
ter research team, supervised analysis and interpretation of the data, and
drafted and revised the manuscript. Dr. Kellar: assisted with design and
conceptualization of the study, assisted with drafting and revising the
manuscript. Dr. Aisen: assisted with design and conceptualization of the
study, conducted the study as a site principal investigator, assisted with
drafting and revising the manuscript. Dr. White: assisted with design and
conceptualization of the study, conducted the study as a site principal
investigator, assisted with drafting and revising the manuscript. Dr.
Wesnes: developed and tested key cognitive outcome measures, per-
formed data analysis and interpretation for secondary outcome measures,
assisted with drafting and revising the manuscript. E. Coderre: supervised
the acquisition of subject data, responsible for design and implementation
of clinical databases and data analysis, assisted with drafting and revising
the manuscript. A. Pfaff: responsible for implementation of clinical data-
bases and data analysis, assisted with drafting and revising the manuscript,
conducted reanalysis of adverse event data. H. Wilkins: supervised the
acquisition of subject data, responsible for ongoing implementation of
clinical databases and data analysis, assisted with drafting and revising the
manuscript, conducted analysis of clinical trial visits and vital signs data.
D. Howard: lead statistician with responsibility for randomization, sub-
ject assignment, and data analyses as well as assistance with data interpre-
tation. Dr. Levin: co-designed and conceptualized the study, conducted
certain data analyses, assisted with drafting and revising the manuscript.
The authors thank the members of the Data and Safety Monitoring Com-
mittee (Daniel Kaufer, MD, Tony George, MD, William Pendlebury,
MD, Eric Westman, MD, Takemura Ashikaga, PhD) and Julie Dumas,
PhD, and Jenna Makarewicz for technical assistance.
Dr. Newhouse has served as a consultant for AstraZeneca, Gerson
Lehrman Group, Guidepoint Global, Summer Street Research Partners,
and Biotechnology Value Fund, L.P.; and receives research support from
AstraZeneca, Eli Lilly and Company, Targacept, Inc., and the NIH (NIA,
NIDA, NIAMS.). Dr. Kellar holds patent(s) re: Nicotinic receptor desen-
sitizing ligands and methods for their testing and use; and receives re-
search support from the NIH (NIDA, NIMH). Dr. Aisen serves on a
scientific advisory board for NeuroPhage and Novartis; serves on the edi-
torial boards of BMC Medicine and Alzheimer’s Research & Therapy; is
listed as inventor on a patent re: DHA therapy for apolipoprotein E4
negative Alzheimer’s disease (potential royalties assigned in full to
UCSD); serves as a consultant to Elan Corporation, Wyeth, Eisai Inc.,
Schering-Plough Corp., Bristol-Myers Squibb, Eli Lilly and Company,
NeuroPhage, Merck & Co., Roche, Amgen, Genentech, Inc., Abbott,
Pfizer Inc, Novartis, Bayer Schering Pharma, Astellas Pharma Inc., Daini-
ppon Sumitomo Pharma, BioMarin Pharmaceutical Inc., Solvay Pharma-
ceuticals, Inc., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo,
AstraZeneca, Janssen, and Medivation, Inc.; receives research support
from Pfizer Inc, Bayer Schering Pharma, Baxter International Inc., and
the NIH/NIA; and has received stock options from Medivation, Inc. and
NeuroPhage. Dr. White has received research support from Merck Se-
rono; has served as a consultant for GlaxoSmithKline; participates in a
Neurology 78January 10, 2012
sanofi-aventis sponsored educational program; and her husband receives
publishing royalties for Neuroscience, Fourth Edition (Sinauer Associates,
Inc., 2008). Dr. Wesnes serves on scientific advisory boards for Bristol-
Myers Squibb, Roche, Astellas Pharma Inc., and Cephalon, Inc.; has re-
ceived funding for travel and speaker honoraria from Astellas Pharma Inc.,
Pharmaton®, and Novartis; serves as a consultant for P1vital and UCB;
was sole owner (until August 2009) of Cognitive Drug Research Ltd. and
is currently an employee (since August 2009) of United BioSource Corpo-
ration, which provides contract services to numerous pharmaceutical
companies; and holds stock and stock options in United BioSource Cor-
poration. E. Coderre, A. Pfaff, H. Wilkins, and D. Howard report no
disclosures. Dr. Levin serves on a scientific advisory board for Astellas
Pharma Inc.; serves as a Section Editor for Neurotoxicology and Teratology
and Pharmacology, Biochemistry and Behavior; holds patents re: Agonist-
antagonist combination to reduce the use of nicotine and other drugs;
receives publishing royalties for Neurotransmitter Interactions and Cognitive
Function (Birkha ¨user, 1992, 2006), Nicotinic Receptors in the Nervous System
(CRC Press, 2002), and Animal Models of Cognitive Impairment (CRC Press,
2006); serves as a consultant for Targacept, Inc., Astellas Pharma Inc., Astra-
Zeneca, and Gilead Sciences, Inc.; and receives research support from Astra-
Zeneca, Gilead Sciences, Inc., Philip Morris-USA, the NIH (NIA, NIDA,
NIEHS), the EPA, and the Wallace Research Foundation.
Received May 24, 2011. Accepted in final form August 31, 2011.
1. Crook T, Bartus T, Ferris S, Whitehouse P. Age associated
memory impairment: proposed diagnostic criteria and
measures of clinical change: report of a National Institute
of Mental Health Work Group. Dev Neurobiol 1986;2:
2. Dawe B, Procter A, Philpot M. Concepts of mild memory
impairment in the elderly and their relationship to demen-
tia: a review. Int J Geriatr Psychiatry 1992;7:473–479.
3. Petersen RC. Normal aging, mild cognitive impairment, and
early Alzheimer’s disease. Neurologist 1995;1:326–344.
4.Petersen RC, Doody R, Kurz A, et al. Current concepts in
mild cognitive impairment. Arch Neurol 2001;58:1985–
5. Levin ED. Nicotinic receptor subtypes and cognitive func-
tion. J Neurobiol 2002;53:633–640.
6. Whitehouse PJ, Martino AM, Antuono PG, et al. Nico-
tinic acetylcholine binding sites in Alzheimer’s disease.
Brain Res 1986;371:146–151.
7. Perry E. Cholinergic signaling in Alzheimer disease: thera-
peutic strategies. Alzheimer Dis Assoc Disord 1995;9:1–2.
8. Nordberg A. Imaging of nicotinic receptors in human
brain. In: Domino EF, ed. Brain Imaging of Nicotine and
Tobacco Smoking. Ann Arbor, MI: Npp Books; 1995:
9. Nordberg A. Clinical studies in Alzheimer patients with
positron emission tomography. Behav Brain Res 1993;57:
10. Nordberg A. In vivo detection of neurotransmitter changes
in Alzheimer’s disease. Ann NY Acad Sci 1993;695:27–33.
11. Heishman SJ, Kleykamp BA, Singleton EG. Meta-analysis
of the acute effects of nicotine and smoking on human
performance. Psychopharmacology 2010;210:453–469.
12.Provost SC, Woodward R. Effects of nicotine gum on re-
peated administration of the Stroop test. Psychopharma-
13. Rusted J, Graupner L, O’Connell N, Nicholls C. Does
nicotine improve cognitive function? Psychopharmacology
14. Wesnes K, Revell A. The separate and combined effects of
scopolamine and nicotine on human information process-
ing. Psychopharmacology 1984;84:5–11.
Newhouse PA, Sunderland T, Tariot PN, et al. Intrave-
nous nicotine in Alzheimer’s disease: a pilot study. Psycho-
Jones GMM, Sahakian BJ, Levy R, Warburton DM, Gray
JA. Effects of acute subcutaneous nicotine on attention,
information processing and short-term memory in Alzhei-
mer’s disease. Psychopharmacology 1992;108:485–494.
Sahakian BJ, Jones GMM. The effects of nicotine on
attention, information processing, and working mem-
ory in patients with dementia of the Alzheimer type. In:
Adlkofer F, Thruau K, eds. Effects of Nicotine on Bio-
logical Systems. Basel: Birkhauser Verlag; 1991:623–
White HK, Levin ED. Four-week nicotine skin patch
treatment effects on cognitive performance in Alzheimer’s
disease. Psychopharmacology 1999;143:158–165.
Wilson AL, Langley LK, Monley J, et al. Nicotine
patches in Alzheimer’s disease: pilot study on learning,
memory, and safety. Pharmacol Biochem Behav 1995;
Petersen RC, Thomas RG, Grundman M, et al. Vitamin E
and donepezil for the treatment of mild cognitive impair-
ment. N Engl J Med 2005;352:2379–2388.
Berg L. Clinical Dementia Rating (CDR). Psychopharma-
col Bull 1988;24:637–639.
Robins LN, Helzer JE, Croughan J, Ratcliff KS. National
Institute of Mental Health Diagnostic Interview Schedule:
history, diagnostics, and validity. Arch Gen Psychiatry
Gallagher D, Nies G, Thompson LW. Reliability of the
Beck Depression Inventory with older adults. J Consult
Clin Psychol 1982;50:152–153.
Williams JBW. A structured interview guide for the Ham-
ilton depression rating scale. Arch Gen Psychiatry 1988;
Conners CK. The Continuous Performance Test (CPT):
Use as a Diagnostic Tool and Measure of Treatment Out-
come. Los Angeles, CA: 1994.
Conners CK, ed. The Continuous Performance Test, V30.
Toronto: Multi-Health Systems; 1995.
Wesnes K, Warburton DM. The effects of cigarette smok-
ing and nicotine tablets upon human attention. In: Thorn-
ton RE, ed. Smoking Behaviour: Physiological and
Psychological Influences. London: Churchill-Livingstone;
Wesnes K, Warburton DM. The effects of cigarettes of
varying yield on rapid information processing perfor-
mance. Psychopharmacology 1984;82:338–342.
Wesnes K, Simpson PM, Christmas L. Puff by puff pro-
files of performance, mood and acceptability in low and
non-low tar smokers. In: Rand MJ, Thurau K, eds. The
Pharmacology of Nicotine. Oxford: IRL Press; 1988:406–
Schneider LS, Olin JT, Doody RS, et al. Validity and reli-
ability of the Alzheimer’s Disease Cooperative Study–
Clinical Global Impression of Change: The Alzheimer’s
Disease Cooperative Study. Alzheimer Dis Assoc Disord
Galasko D, Bennett D, Sano M, et al. An inventory to
assess activities of daily living for clinical trials in Alzhei-
Neurology 78 January 10, 2012
mer’s disease: The Alzheimer’s Disease Cooperative Study.
Alzheimer Dis Assoc Disord 1997;2(11 suppl):S33–S39.
Guigoz Y, Vellas B, Garry PJ. Mini Nutritional Assess-
ment: A Practical Assessment Tool for Grading the Nutri-
tional State of Elderly Patients. Paris: Serdi Publishing
Brigidi BD, Achenbach TM, Dumenci L, Newhouse PA.
Broad spectrum assessment of psychopathology and adap-
tive functioning with the Older Adult Behavior Checklist:
a validation and diagnostic discrimination study. Int J
Geriatr Psychiatry 2010;25:1177–1185.
White HK, Levin ED. Chronic transdermal nicotine patch
treatment effects on cognitive performance in age-
associated memory impairment. Psychopharmacology
Potter A, Corwin J, Lang J, Piasecki M, Lenox R, New-
house P. Acute effects of the selective cholinergic channel
activator (nicotinic agonist) ABT-418 in Alzheimer’s dis-
ease. Psychopharmacology 1999;142:334–342.
36. Newhouse PA, Potter A, Singh A. Effects of nicotinic stim-
ulation on cognitive performance. Curr Opin Pharmacol
Kihara T, Shimohama S, Sawada H, et al. ?7 nicotinic
receptor transduces signals to phosphatidylinositol
3-kinase to block a ?-amyloid-induced neurotoxicity.
J Biol Chem 2001;276:13541–13546.
Deng J, Shen C, Wang YJ, et al. Nicotine exacerbates tau
phosphorylation and cognitive impairment induced by
amyloid-beta 25–35 in rats. Eur J Pharmacol 2010;637:
Marchant NL, King SL, Tabet N, Rusted JM. Positive
effects of cholinergic stimulation favor young APOE
[epsiv]4 carriers. Neuropsychopharmacology 2010;35:
DeKosky ST, Ikonomovic MD, Styren SD, et al. Upregu-
lation of choline acetyltransferase activity in hippocampus
and frontal cortex of elderly subjects with mild cognitive
impairment. Ann Neurol 2002;51:145–155.
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Share New Tools to Spot Sports Concussion with
High School Coaches and Athletes
Neurologists are urged to reach out to all high school coaches, athletes, and parents to learn the signs
of sports concussion and to know when a player must leave the game. The AAN’s website includes
links to two free 20-minute online safety courses for high school and youth coaches that were
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Neurology 78 January 10, 2012