PET imaging of cortical 11C-nicotine binding correlates with the cognitive function of attention in Alzheimer's disease.

Abstract

Patients suffering from Alzheimer's disease (AD) experience a marked reduction in cortical nicotinic acetylcholine receptors (nAChRs). In particular, selective loss of the alpha4beta2 nAChR subtype was observed in postmortem AD brain tissue. The alpha4 and alpha7 nAChR subunits were suggested to play an important role in cognitive function. Positron emission tomography (PET) has so far been used to visualize neuronal nAChRs in vivo by 11C-nicotine binding.
To investigate the relationship between measures of cognitive function and in vivo 11C-nicotine binding in mild AD brain as assessed by PET.
Twenty-seven patients with mild AD were recruited in this study. A dual tracer model with administration of 15O-water for regional cerebral blood flow and (S)(-)11C-nicotine was used to assess nicotine binding sites in the brain by PET. Cognitive function was assessed using neuropsychological tests of global cognition, episodic memory, attention, and visuospatial ability.
Mean cortical 11C-nicotine binding significantly correlated with the results of attention tests [Digit Symbol test (r = -0.44 and p = 0.02) and Trail Making Test A (TMT-A) (r = 0.42 and p = 0.03)]. No significant correlation was observed between 11C-nicotine binding and the results of tests of episodic memory or visuospatial ability. Regional analysis showed that 11C-nicotine binding in the frontal and parietal cortex, which are the main areas for attention, correlated significantly with the Digit Symbol test and TMT-A results.
Cortical nicotinic receptors in vivo in mild AD patients are robustly associated with the cognitive function of attention.

Full text

Page 1

ORIGINAL INVESTIGATION
PET imaging of cortical11C-nicotine binding correlates
with the cognitive function of attention
in Alzheimer’s disease
Ahmadul Kadir & Ove Almkvist & Anders Wall &
Bengt Långström & Agneta Nordberg
Received: 10 February 2006 /Accepted: 24 May 2006 / Published online: 11 July 2006
# Springer-Verlag 2006
Abstract
Rationale Patients suffering from Alzheimer’s disease
(AD) experience a marked reduction in cortical nicotinic
acetylcholine receptors (nAChRs). In particular, selective
loss of the α4β2 nAChR subtype was observed in
postmortem AD brain tissue. The α4 and α7 nAChR
subunits were suggested to play an important role in
cognitive function. Positron emission tomography (PET)
has so far been used to visualize neuronal nAChRs in vivo
by11C-nicotine binding.
Objectives To investigate the relationship between mea-
sures of cognitive function and in vivo11C-nicotine binding
in mild AD brain as assessed by PET.
Materials and methods Twenty-seven patients with mild
AD were recruited in this study. A dual tracer model with
administration of
flow and (S)(−)11C-nicotine was used to assess nicotine
binding sites in the brain by PET. Cognitive function was
assessed using neuropsychological tests of global cognition,
episodic memory, attention, and visuospatial ability.
Results Mean cortical
correlated with the results of attention tests [Digit Symbol
test (r=−0.44 and p=0.02) and Trail Making Test A (TMT-
A) (r=0.42 and p=0.03)]. No significant correlation was
observed between11C-nicotine binding and the results of
tests of episodic memory or visuospatial ability. Regional
analysis showed that11C-nicotine binding in the frontal and
parietal cortex, which are the main areas for attention,
correlated significantly with the Digit Symbol test and
TMT-A results.
Conclusion Cortical nicotinic receptors in vivo in mild AD
patients are robustly associated with the cognitive function
of attention.
15O-water for regional cerebral blood
11C-nicotine binding significantly
Keywords Alzheimer’sdisease(AD).Nicotinic
acetylcholinereceptors(nAChRs).Positronemission
tomography(PET).11C-nicotine binding.Cognition.
Attention
Introduction
Alzheimer’s disease (AD) is a common form of dementia,
characterized by degeneration of basal forebrain cholinergic
neurons innervating the cortex, amygdala, and hippocam-
Psychopharmacology (2006) 188:509–520
DOI 10.1007/s00213-006-0447-7
A. Kadir:A. Nordberg (*)
Department of Neurobiology, Care Sciences and Society,
Division of Molecular Neuropharmacology,
Karolinska Institutet, Karolinska University Hospital Huddinge,
Novum Floor-5,
Stockholm 141 86, Sweden
e-mail: Agneta.K.Nordberg@ki.se
O. Almkvist
Department of Neurobiology, Care Sciences and Society,
Karolinska Institutet, Karolinska University Hospital Huddinge,
Novum Floor-5,
Stockholm 141 86, Sweden
O. Almkvist:A. Nordberg
Department of Geriatric Medicine,
Karolinska University Hospital Huddinge,
Stockholm, Sweden
O. Almkvist
Department of Psychology,
Stockholm University,
Stockholm, Sweden
A. Wall:B. Långström
Uppsala Imanet,
Uppsala, Sweden

Page 2

pus, which manifests itself through difficulties in maintain-
ing and sustaining attention and profound cognitive impair-
ments, such as loss of memory and learning ability (Aubert
et al. 1992; Coyle et al. 1983). A major loss of cholinergic
neurons in the nucleus basalis of Meynert suggested the
possible involvement of cholinergic receptors in AD.
Numerous preclinical and clinical studies provided evi-
dence implicating the nicotinic system in AD (Aubert et al.
1992; Paterson and Nordberg 2000).
Patients suffering from AD experience a marked
reduction in cortical nicotinic acetylcholine receptor
(nAChR) binding (Nordberg and Winblad 1986; Perry et
al. 2000). Selective loss of the α4β2nAChR subtype was
observed in vitro in postmortem brain tissue from patients
suffering from AD (Warpman and Nordberg 1995).
Although reduction of α7 nAChR subtype levels was
observed in the frontal cortex (Wevers et al. 1999), no
significant loss was detected in the temporal cortex of
patients with AD (Guan et al. 2000). A significant increase
in the total number of astrocytes and of astrocytes
expressing the α7nAChR subunit, along with significant
decreases in the level of α7and α4nAChR subunits on
neurons was observed in the hippocampus and temporal
cortex in vitro in AD brain tissue (Yu et al. 2005).
The use of positron emission tomography (PET) for
assessing the longitudinal progression in the brains of AD
patients is known to be a sensitive method (Nordberg 1999).
Use of PET to visualize neuronal nAChRs in vivo has so far
been used by11C-nicotine binding. An earlier PET study has
demonstrated that the uptake of11C-nicotine binding is lower
in the brains of patients with AD compared with that in
control subjects, reflecting losses in high and low affinity
nicotinic receptor sites (Nordberg et al. 1990). In addition,
significantly lower11C-nicotine binding was observed in the
frontal cortex, temporal cortex, and hippocampus of AD
patients compared with controls (Nordberg et al. 1995).
Neuronal nAChRs are involved in cognitive processes in the
brain where both α4and α7subunits were suggested to play
an important role in cognitive function (Nordberg 2001). A
significant correlation between the reduction of11C-nicotine
binding and cognitive impairment of AD patients was
reported (Nordberg et al. 1995). When nicotinic receptors
were blocked with antagonist drugs in healthy humans, the
most prominent effect on cognition was concerned with
attention rather than memory (Lawrence and Sahakian 1995;
Robbins et al. 1997). Attention may thus be associated with
nAChRs, which represent one of the main targets in
cholinergic replacement therapy (Nordberg 1999). Outcomes
of treatment with the cholinesterase inhibitor (ChEI) tacrine
in AD patients showed that the cognitive parameters of
attention and executive functions improved more after
treatment than did mnemonic functions (Alhainen et al.
1993; Almkvist et al. 2001; Sahakian et al. 1993). In a recent
study, it was shown that galantamine especially improved
attention in patients with AD and this effect may be a
consequence of the potentiating action of galantamine at
nicotinic receptors (Vellas et al. 2005). In the present study,
we wanted to investigate the relationship between measures
of cognitive function and
assessed by PET to better understand the effect of nicotinic
receptors as regards cognitive syndrome in mild AD. Scores
of global cognition [mini-mental state examination (MMSE)],
episodic memory, attention, and visuospatial ability were
chosen in this study as a standardized cognitive battery in the
diagnosis of AD.
11C-nicotine binding in vivo as
Materials and methods
Patients and HCs
Twenty-seven patients (11 women and 16 men) with mild
AD (MMSE score ≥21) were recruited from the Department
of Geriatric Medicine, Karolinska University Hospital Hud-
dinge, Stockholm, Sweden. All subjects for memory disorder
assessments had undergone a thorough clinical investigation,
including medical history, cognitive (MMSE score), physical,
and neurological examination, laboratory blood tests, apoli-
poprotein E genotyping, psychometric investigation, lumbar
puncture to analyze the level of tau and beta amyloid, and
magnetic resonance imaging/computed tomography scans.
The diagnosis of mild AD was made by exclusion of other
dementia diseases, in accordance with guidelines from the
National Institute of Neurological and Communication
Disorders and Stroke–Alzheimer’s Disease and Related
Disorders Association (NINCDS-ADRDA) (McKhann et al.
1984). In the present study, no subjects were taking any
anticholinesterase drugs. The patients later participated in a
PET study involving treatment with rivastigmine and galant-
amine. The results of these treatment studies are reported
elsewhere (Kadir et al. 2006a,b, in preparation).
In this study, we also used neuropsychology data from
36 healthy controls (HCs). These subjects had no history of
neurological, psychiatric or major medical disease, and had
normal neurological examination results at the time of the
study.
The present study was conducted according to the
declaration of Helsinki and subsequent revisions and was
approved by the Ethics Committee of Karolinska University
Hospital Huddinge, Stockholm and the Faculty of Medicine
and Isotope Committee of Uppsala University, Sweden.
PET studies
PET studies were performed on all mild AD patients at the
Uppsala PET Centre, Uppsala. The tracers
15O-water for
510Psychopharmacology (2006) 188:509–520

Page 3

regional cerebral blood flow (rCBF) and (S)-[11C]methyl
nicotine (11C-nicotine) were synthesized according to a
standard manufacturing procedure for each tracer, following
the guidelines in radiopharmaceutical preparations (D125)
and local QC procedures.
PET was performed using one of the two Siemens ECAT
HR+cameras with an axial field of view of 155 mm,
providing 63 contiguous 2.46 mm slices with 5.6 mm
transaxial and 5.4 mm axial resolution. The orbitomeatal
line was used to center the subjects so that the first slice
corresponded to the lowest level of the cerebellum.
Tracers were given as intravenous bolus injections. With
PET the time course of the regional radioactivity concen-
tration was measured in the brain. The following tracer
doses and predetermined scanning protocols were used:
22 MBq/kg of bodyweight of [15O]water (frames of 17×5
and 2×20 s during 125 s in 2D mode); and approximately
5 MBq/kg of [11C]nicotine (frames of 20×6, 6×30, and
1×120 s during 7 min in 3D mode).
Attenuation correction was based on a 10-min windowed
transmission scan with rotating
administration of the tracer. The emission data were
normalized and corrected for random coincidences, dead
time, and for scatter using a method devised by Watson et
al. (1997). Images were reconstructed with the standard
software supplied with the scanner (ECAT 7.1 CTI PET
systems, Knoxville TN, USA) using Fourier rebinning
followed by two-dimensional filtered back projection
applying a 5-mm Hanning filter. In a subsequent step,
image data were converted from Siemens/CTI format to
Scanditronix/General Electric format with in-house devel-
oped software. The 63 slices were resampled to 30 slices
with a slice thickness of 5 mm because the local procedures
for PET image analysis utilize tools based on the image
analysis software IDA from Scanditronix/General Electric.
A computerized reorientation procedure was used to align
consecutive PET studies for accurate intra- and interindi-
vidual comparisons, and to correct for movements within
the PET scans (Anderson 1995).
Continuous blood sampling with online registration of
radioactivity in blood from the arteria radialis, report rate of
1 sample/s, was used during the [15O]water and [11C]
nicotine scans. Blood sampling was started simultaneously
with the tracer injection; 3 ml/min were withdrawn during
145 and 300 s for the [15O]water and the [11C]nicotine
scans, respectively. Discrete arterial samples (4 ml/sample)
were withdrawn at 6 and 7 min after [11C]nicotine injection.
68Ge rod sources before
Analysis of the PET data
Regions of interest (ROIs) were drawn on a11C-nicotine
image where the brain anatomy was seen most clearly.
Most of the ROIs were delineated in several consecutive
slices and were linked, i.e., summed up to a volume of
interest (VOI). The defined regions were checked to ensure
that they were inside the realigned volume for every PET
scan. The regions delineated were putamen, thalamus,
parietotemporal cortex, and the whole brain at the level of
basal ganglia in one slice per region; pons, sensorimotor
cortex, primary visual cortex, cerebellum, and frontal
association cortex were drawn in two consecutive slices;
frontal cortex and anterior cingulate cortex in four
consecutive slices; and the parietal cortex in six consecutive
slices. The regions for the temporal cortex were drawn in
six consecutive coronal slices and the medial temporal lobe
in two coronal slices with a slice thickness of 8 mm. The
VOIs were subsequently used to generate time activity
(TACT) data or for measurements of rCBF. Mean cortical
value was calculated as a composite score from anterior
cingulate cortex, frontal cortex, frontal association cortex,
parietal cortex, parietotemporal cortex, and temporal cortex,
considering the areas most susceptible to disease progres-
sion (Herholz et al. 1990). Because we did not have the
complete data from the medial temporal lobe of all patients
(18 out of 27 patients were available), we could not include
the medial temporal lobe in the mean cortical value.
Figure 1 illustrates ROIs placement in PET images.
k2* model for11C-nicotine binding
A dual tracer model with administration of15O-water and
11C-nicotine in close succession was used to assess nicotine
binding sites in the brain. The parameter k2for11C-nicotine
is highly flow-dependent, hence, a flow-compensated
parameter (k2*) was calculated as k2for nicotine divided
by rCBF (Lundqvist et al. 1998). In this model, a low (k2*)
value corresponds to high11C-nicotine binding in the brain.
The TACT data for VOIs and the blood TACT data were
the input functions in the two-compartment model used to
calculate k2for11C-nicotine. Five parameters were included
in the model: k1=rate constant of radioactivity transport
from blood to tissue, k2=rate constant of radioactivity
transport from tissue to blood, td=time delay in the input
function due to the transport time in the arterial catheter,
k (min−1)=blood dispersion constant, and ɛ=blood volume.
During the modeling, k1and k2were fitted independently.
Radioactivity in the whole brain was fitted with the
parameter-free dispersion. Dispersion for the whole brain
region was subsequently used as a fixed constant to model
k2for the other VOIs. Data from the first 5 min of the
investigation were used for the calculation of k2. For a full
description of the compartment model, see (Lundqvist et al.
1998).
Regional CBF was measured from parametric blood
flow images generated according to the method described
by Herscovitch et al. (1983) and Raichle et al. (1983). The
Psychopharmacology (2006) 188:509–520511

Page 4

integration time used was 0–60 s after the bolus appeared
in the brain; blood density was set to 1.05 g/cc and the
distribution volume was set to 0.95.
Neuropsychology tests
Global cognition was assessed using the MMSE score
(Folstein et al. 1975). Episodic memory was evaluated
using two measures from the Stockholm Gerontology
Research Center test (Backman and Forsell 1994) of
memory for words: (1) the number of correct responses in
free recall of words (word recall); and (2) the d-prime value
(an integration of correct responses and false alarms
following decision theory) in recognition of words (word
recognition-d). The test procedure was as follows:
–
Twelve common and unrelated words were presented
in written format and also orally by the instructor; one
word at a time (1 word/5 s) with the instruction to
remember the words presented. The subject had to
recall as many words as possible.
For word recognition, the subject had to respond yes/
no as to whether a word had been presented previously
(12 target words mixed with 12 distractor words).
These words were also presented one at a time and in
random order.
–
It is believed that these measures of memory are related to
medial temporal brain activity in particular (Cabeza and
Nyberg 2000).
Attention was assessed using two measures: (1) the
number of correct responses in the Digit Symbol test from
the revised Wechsler Adult Intelligence Scale (Wechsler
1981); and (2) the time needed to complete the Trail
Making Test A (TMT-A) (Lezak 1995). These measures are
thought to be associated with the frontal and parietal
network of brain activity (Cabeza and Nyberg 2000).
Visuospatial ability was judged on the basis of the
number of correct responses in drawing and recogniz-
ing the clock time (Luria 1966). The latter tests were
chosen to reflect parietal lobe function (Cahn-Weiner
et al. 1999).
Statistical analysis
Data are expressed as mean±SD. Student’s unpaired t test
was used to evaluate the difference of cognitive function
between the AD and HC groups. Two-tailed Pearson’s
correlation coefficients were used in correlation analysis
between
patients with mild AD, and the data were then visualized
graphically using simple regression plots. In all instances
statistical significance was defined as p<0.05.
11C-nicotine binding and cognitive function of
Results
Patients and HCs
There were no significant differences in age between the
groups: mild AD (69.8±8.2 years) and HCs (68.8±
7.8 years; t=0.50 and p=ns). Global cognitive functions
measured by MMSE scores were significantly decreased
in mild AD (25.6±3.0) compared with the HC group
(28.7±1.0; t=−5.6 and p<0.00001).
Fig. 1 Illustration of the ROIs placement in PET images. 1 Putamen,
2 thalamus, 3 parietotemporal cortex, 4 whole brain, 5 pons, 6
sensorimotor cortex, 7 primary visual cortex, 8 cerebellum, 9 frontal
association cortex, 10 frontal cortex 11 anterior cingulate cortex, 12
parietal cortex, 13 temporal cortex, and 14 medial temporal lobe. The
vertical bar indicates11C-nicotine uptake
512Psychopharmacology (2006) 188:509–520

Page 5

Cognitive tests
The cognitive data are summarized in Table 1. Patients with
mild AD showed significantly worse performance in all
cognitive measures compared with HC subjects. The
relative differences in cognitive performance between the
two groups were greatest as regards the Digit Symbol
attention test (t=−6.2 and p<0.00001).
Correlation between11C-nicotine binding (k2*)
and cognitive function
For correlation between cognitive function and (S)(−)11C-
nicotine binding, k2* values were used. Correlation coef-
ficients between mean cortical11C-nicotine binding (k2*)
and test results of cognitive function in patients with mild
AD are shown in Table 2. The attention tests Digit Symbol
and TMT-A were the only cognitive tests that showed
significant correlations with mean cortical
binding. The correlations between mean cortical
nicotine binding and cognitive measures were further
checked by using partial correlation coefficients, i.e., the
influence of MMSE score on the relationship between
specific cognitive tests and11C-nicotine binding was sorted
out. After correction for the influence of MMSE score, the
results of the Digit Symbol test (r=−0.40 and p=0.04) and
TMT-A (r=0.37 and p=0.03, one-tailed) were also signif-
icantly associated with11C-nicotine binding.
11C-nicotine
11C-
Visual plots of mean cortical11C-nicotine binding (k2*)
and attention test data (Digit Symbol and TMT-A) from
patients with mild AD are presented in (Fig. 2a,b). The
correlation analyses demonstrated that patients with mild
AD and high cortical11C-nicotine binding (i.e., low k2*
value) performed better in attention tests than patients with
lower11C-nicotine binding.
When the regional k2* values of individual patients were
plotted against the Digit Symbol test results, significant
negative correlations were observed in the right frontal
association cortex (r=−0.49 and p=0.009), right parietal
cortex (r=−0.47 and p=0.01), left parietal cortex (r=−0.47
and p=0.01), right parietotemporal cortex (r=−0.52 and
p=0.005), and left thalamus (r=−0.37 and p=0.03, one
tailed) (Fig. 3a–d). On the other hand, when regional k2*
values of individual mild AD patients and the results of the
attention test TMT-A were compared, significant positive
correlations were observed in the right anterior cingulate
cortex (r=0.37 and p=0.03, one-tailed), right parietal cortex
(r=0.44 and p=0.02), left parietal cortex (r=0.53 and p=
0.005), right parietotemporal cortex (r=0.55 and p=0.003),
left temporal cortex (r=0.43 and p=0.03), and left thalamus
(r=0.44 and p=0.02) (Fig. 4a–d).
The correlation between regional
and visuospatial ability test data (clock drawing and clock
recognition) was as follows: There was significant correla-
tion between the clock drawing test results and11C-nicotine
binding in the left parietal cortex (r=−0.51 and p=0.007),
right temporal cortex (r=−0.40 and p=0.04), and left
temporal cortex (r=−0.39 and p=0.05).11C-nicotine bind-
ing in the right parietal cortex (r=−0.50 and p=0.008) and
left parietal cortex (r=−0.51 and p=0.007) significantly
correlated with clock recognition test results (Fig. 5a–d).
No significant correlation was observed between
nicotine binding in any of the brain regions and the
episodic memory test data. Episodic memory is a function
of the medial temporal lobe, but in this study, we found no
correlation between
temporal lobe and episodic memory results (word recall and
word recognition-d). When we analyzed cognitive data and
rCBF as measured by15O-water, we found no significant
correlation (data not shown).
11C-nicotine binding
11C-
11C-nicotine binding in the medial
Table 1 Neuropsychological test results in the mild AD and HC groups
AD (n=27)HC (n=36)t valueSignificance (p value)
Word recall (0–12)
Word recognition-d (0–4.64)
Digit Symbol (0–93)
TMT-A (0–300 s)
Clock drawing (0–15)
Clock recognition (0–15)
3.7±1.9
1.6±0.9
23.5±12.9
100.3±67.8
8.3±4.7
11.3±4.6
6.0±2.3
3.2±1.2
41.8±10.3
37.4±8.5
12.3±2.7
14.8±1.1
–4.2
–5.8
–6.2
5.5
–4.3
–4.4
<0.0001
<0.00001
<0.00001
<0.00001
<0.0001
<0.0001
Values are mean±SD
AD Alzheimer’s disease, HC healthy Control, and TMT A Trail Making Test A (a high score indicated more cognitive impairment)
Table 2 Correlation coefficients between cognitive function test
results and mean cortical11C-nicotine binding (k2*) measured by using
(S)(−)11C-nicotine adjusted for rCBF in patients with mild AD
Cognitive test Pearson’s correlation coefficient
(r)
p
value
MMSE
Word recall
Word recognition-d
Digit Symbol
Trail Making Test A (s)
Clock drawing
Clock recognition
–0.22
–0.04
–0.09
–0.44
0.42
–0.36
–0.31
ns
ns
ns
0.02
0.03
ns
ns
Psychopharmacology (2006) 188:509–520513

Page 6

Discussion
The first PET ligand applied in monkeys and humans for
visualizing nAChRs in the brain was11C-nicotine. Because
11C-nicotine is an agonist of nicotinic receptors, it is not an
ideal PET ligand, owing to a relatively high level of
nonspecific binding, short receptor interaction, and strong
dependence on cerebral blood flow (Maziere and Delforge
1995). These problems can be overcome by applying a dual
tracer method (Lundqvist et al. 1998). In several studies
(Nordberg et al. 1998; Nordberg et al. 1997; Nordberg et al.
1995), we have applied a kinetic model approach where the
rate constant k2* expresses
independent of cerebral blood flow. A low k2* rate constant
corresponds to high11C-nicotine binding in the brain. To
demonstrate the use of this kinetic model, we performed a
11C-nicotine binding and is
study in monkeys and confirmed that the calculated k2* rate
constant was blood flow-independent (Lundqvist et al.
1998). A significant increase in k2* values was observed in
the temporal and frontal cortices and hippocampus of AD
patients compared with age-matched HCs (Nordberg et al.
1997; Nordberg et al. 1995).
Recently, several other compounds were developed as
PET ligand candidates for visualizing nAChRs (Nordberg
2006). So far, only
studies in AD patients while 2-[18F]fluoro-A-85380 and 6-
[18F]fluoro-A-85380 were tested in healthy subjects (Ding
et al. 2004; Gallezot et al. 2005). It is evident from in vitro
binding studies that various PET ligands such as [76Br]Br-
A-85380 (Sihver et al. 1999), 6-[18F]fluoro-A-85380
(Gundisch et al. 2005), and 2-[18F]fluoro-A-85380 (Chefer
et al. 2003), show a very high affinity for α4 nAChR
subunits, whereas11C-nicotine also shows a high affinity
for non-α4nAChR subtypes. However, it seems plausible
that A-85380 also binds to the α6β2 nAChR subtype
(Mogg et al. 2004). A drawback of 2-[18F]fluoro-A-85380
and 6-[18F]fluoro-A-85380 as PET ligands is the very long
scanning time (hours) that is needed, while the scanning
time with11C-nicotine is 1 h or less.
In the current study, we found that the patients with mild
AD differed from HC subjects most strongly in all
measures of cognitive function. Furthermore, we observed
that mean cortical
significantly correlated with the results of tests of attention
(Digit Symbol test and TMT-A). It is interesting to note that
we did not find any significant correlation between cortical
11C-nicotine binding and memory function in our patients.
Cholinergic deficits probably do not account for the full
severity of memory loss seen in AD. Our findings are in
accordance with the results of a recent study on AD patients
showing that cortical acetylcholinesterase (AChE) activity
measured by11C-PMP PET was more robustly associated
with the cognitive functions of attention and working
memory compared with performance in primary memory
(Bohnen et al. 2005). Studies on experimental lesions in the
basal forebrain in monkeys suggest that attention, rather
than memory function, is disrupted when cortical choliner-
gic neurons are eliminated (Voytko et al. 1994). A previous
study with non-human primates also failed to show a
significant correlation between reduced cholinergic inner-
vation and memory impairment (Calhoun et al. 2004). It is
plausible that primary memory deficits in AD may be
related to microstructural changes, such as the deposition of
neurofibrillary tangles in the medial temporal lobe, causing
disruption of hippocampal pathways (Guillozet et al. 2003;
Ikonomovic et al. 2003). A different explanation for the
memory deficits in AD was described in a previous study in
which it was suggested that soluble oligomers of the
amyloid beta protein may directly interfere with synaptic
11C-nicotine was applied in clinical
11C-nicotine binding in AD patients
0
10
20
30
40
50
0.200.250.300.350.40
0
50
100
150
200
250
300
350
0.200.25 0.300.350.40
mean cortical 11C-nicotine binding (k2*)
Fig. 2 Correlation between mean cortical11C-nicotine binding (k2*)
and attention test results in patients with mild AD. a Digit Symbol
test: Higher scores indicate better cognitive function. b TMT-A (s):
Lower scores indicate better cognitive function. Lower (k2*) values
indicate more11C-nicotine binding. All values are absolute
Digit Symbol test
Trail Making Test A
r = -0.44
p = 0.02
r = 0.42
p = 0.03
(a)
(b)
514Psychopharmacology (2006) 188:509–520

Page 7

mechanisms mediating aspects of learning and memory,
including long-term potentiation (Walsh and Selkoe 2004).
To our knowledge, this is the first study in which
nAChRs visualized by PET in vivo in the brains of patients
with mild AD were correlated with measurements of
cognitive function of attention. Previous studies evaluating
the effects of acute or chronic nicotinic receptor agonist
administration on cognitive function in AD patients tend to
support enhancement of attention but not memory function.
In clinical studies, Newhouse et al. (1988) showed evidence
of improvement in cognitive function after intravenous
injection of nicotine in AD subjects. Nicotine administra-
tion by subcutaneous injection was shown to improve
attention-related task performance in AD (Jones et al. 1992;
Sahakian and Jones 1991). In AD patients, a 4-week trial of
transdermal nicotine treatment was shown to lead to
significant improvement in attention (White and Levin
1999). Furthermore, these findings are consistent with data
showing improvements of attention by means of chronic
nicotine administration in individuals with age-associated
memory impairment (White and Levin 2004). In contrast to
nicotine-induced improvements in attention, in at least three
studies no evidence was found on the improvement of
memory function by nicotine administration in AD patients
(Snaedal et al. 1996; White and Levin 1999; Wilson et al.
1995). However, despite these negative findings regarding
memory function, transdermal nicotine was shown to
improve acquisition of information in AD patients (Wilson
et al. 1995) and the nicotinic agonist ABT-418 was also
shown to improve components of both learning and
memory in AD patients (Potter et al. 1999). Rusted et al.
(1998) have suggested that nicotine might selectively
modulate processes concerned with associative memory,
either through encoding or via a consolidation advantage.
Careful separation of the cognitive domains affected by
nicotinic stimulation has led to identification of attentional
performance as the most likely candidate to be positively
influenced by nicotinic receptor activation. Positive effects
of nicotine on learning and memory might be mediated by
its effect on attentional function (Rusted et al. 2000).
Learning and memory require acquisition, encoding, stor-
age, and retrieval; however, attention is the “front end” of
this process and adequate attentional function is a primary
requirement.
Attention may reflect frontal and parietal cortical
function (Cabeza and Nyberg 2000). In the current study,
0
10
20
30
40
50
0.200.25 0.300.350.400.45 0.500.55
0
10
20
30
40
50
0.200.250.300.350.400.45 0.50
0
10
20
30
40
50
0.220.26 0.300.340.38 0.42
0
10
20
30
40
50
0.150.200.250.30 0.350.400.45
(a) Right frontal association cortex
(b) Right parietal cortex
(c) Left parietal cortex
(d) Left thalamus
11C-nicotine binding (k2*)
11C-nicotine binding (k2*)
Digit Symbol test
Digit Symbol test
Fig. 3 Correlationbetween11C-nicotine binding and results of the Digit
Symbol test, a measure of attention in patients with mild AD. a Right
frontal association cortex, b right parietal cortex, c left parietal cortex,
and d left thalamus. Lower (k2*) values indicate more11C-nicotine
binding. All values are absolute
Psychopharmacology (2006) 188:509–520515

Page 8

we observed that11C-nicotine binding in the right frontal
association cortex and the right/left parietal cortex signif-
icantly correlated with the results of the Digit Symbol test.
With the TMT-A (time) data, significant correlation with
11C-nicotine binding was found in the right anterior
cingulate cortex and the right/left parietal cortex. Signifi-
cant correlations between
frontal-parietal cortex and attentional performance were
also found in patients with mild AD treated with the ChEIs
galantamine and rivastigmine (Kadir et. al 2006a,b, in
preparation). In this study, we found that
binding in the left thalamus significantly correlated with
attention test results. Previous studies showed that the
thalamus is one of the brain regions containing a high
density of nicotinic receptors (Nordberg et al. 1992). The
α4β2 receptors are predominant on the thalamocortical
glutaminergic efferent pathway (Flores et al. 1992; Pabreza
et al. 1991) that composes parts of the frontal subcortical
circuits. As a nicotinic receptor modulator, galantamine was
shown to increase glucose metabolism in the left anterior
medial thalamus in cognitive and behavioral responders in a
11C-nicotine binding in the
11C-nicotine
group of AD patients (Mega et al. 2005). Increased11C-
nicotine binding was also found in the left thalamus of
rivastigmine-treated patients with mild AD (Kadir et al.,
2006b, in preparation). Studies indicate that the thalamus
has an important effect on attention via nicotinic receptors.
In this study, we also found that11C-nicotine binding in the
parietotemporal cortex and temporal cortex significantly
correlated with the results of attention tests. At least two
previous studies also support our finding of involvement of
the temporal cortex in attention tasks in patients with mild
AD. Bohnen et al. (2005) showed that temporal cortical
AChE activity measured by11C-PMP PET was significant-
ly associated with attention and working memory test data
(Digit Span). Another study with resting single photon
emission computed tomography (SPECT) showed that
perfusion of the superior temporal gyrus was significantly
correlated with visually sustained attention (Nobili et al.
2005). These findings may be confounded by the fact that
temporal changes are common early in the course of AD
(Alexander et al. 2002; Herholz et al. 1999). The observed
association between attentional performance and cortical
0
50
100
150
200
250
300
350
0.15 0.200.25 0.30 0.350.400.45
0
50
100
150
200
250
300
350
0.200.25 0.30 0.350.400.450.50
0
50
100
150
200
250
300
350
0.20 0.250.30 0.350.40
0
50
100
150
200
250
300
350
0.150.20 0.25 0.30 0.35 0.400.45
(a) Right anterior cingulate cortex
(b) Right parietal cortex
(c) Left parietal cortex
(d) Left thalamus
r = 0.37
p = 0.03
r = 0.44
p = 0.02
r = 0.53
p = 0.005
r = 0.44
p = 0.02
Trail Making Test A
Trail Making Test A
11C-nicotine binding (k2*)
11C-nicotine binding (k2*)
Fig. 4 Correlation between
TMT-A, a measure of attention in patients with mild AD. a Right
anterior cingulate cortex, b right parietal cortex, c left parietal
11C-nicotine binding and results of
cortex, and d left thalamus. Lower TMT A scores indicate better
performance and lower (k2*) values indicate more
binding. All values are absolute
11C-nicotine
516Psychopharmacology (2006) 188:509–520

Page 9

11C-nicotine binding in various regions in the current study
is consistent with a more topographically widespread
appearance of cholinergic alteration in AD.
In this study, significant correlation was observed
between
and right/left temporal cortex and the results of the
visuospatial ability test of clock drawing.
binding in the right/left parietal cortex in this study
significantly correlated with the results of the clock
recognition test, in spite of the fact that there was a ceiling
effect in this test. However, this ceiling effect, or restriction
of range, will result in an underestimation of the true
association, given that there is an association. In a previous
study, the results of visual–constructional function test in
AD patients correlated with the left inferior parietal lobule
as assessed by
Impairment in copying of line drawings, which correlated
with right parietal hypometabolism, was found in AD, as
measured by PET (Foster et al. 1983; Haxby et al. 1985). In
another study, visuoconstructive performance in AD
patients showed correlation with left and right temporopari-
11C-nicotine binding in the left parietal cortex
11C-nicotine
18F-FDG PET (Teipel et al. 2005).
etal hypometabolism in resting state PET (Ober et al. 1991).
A SPECT study of rCBF showed that in the left
posterolateral temporal cortex, rCBF correlated with clock
drawing test performance in AD patients (Nagahama et al.
2005). The strong correlation observed between
nicotine binding in the parietal cortex and visuospatial
ability test data in our study may, thus, at least partly, reflect
attentional deficits contributing to impaired performance in
the visuospatial ability tests in AD patients. The left inferior
parietal lobule subserves the allocation of attention to
locations in the visual field (Robertson et al. 1988).
Attentional deficits are common in AD and are recog-
nized as an important component of cognitive decline
(Lawrence and Sahakian 1995; Perry and Hodges 2000).
Loss of attention affects patients ability to respond to their
surroundings and to interact with those around them (Foldi
et al. 2002), and it also affects the ability to perform
activities of daily living (Vitaliano et al. 1984) and specific
skills (Duchek et al. 1997). Our study in patients with mild
AD demonstrates that cortical nAChRs are robustly
associated with the cognitive function of attention, suggest-
11C-
-2
0
2
4
6
8
10
12
14
16
0.200.250.300.350.40
-2
0
2
4
6
8
10
12
14
16
0.150.200.25 0.300.35 0.40
-2
0
2
4
6
8
10
12
14
16
0.200.25
11C-nicotine binding (k2*)
0.300.35 0.40 0.450.50
-2
0
2
4
6
8
10
12
14
16
0.200.25
11C-nicotine binding (k2*)
0.300.350.40
(a) Left parietal cortex
(b) Right temporal cortex
(c) Right parietal cortex (d) Left parietal cortex
Clock Drawing test
Clock Recognition test
r = -0.51
p = 0.007
r = -0.40
p = 0.04
r = -0.50
p = 0.008
r = -0.51
p = 0.007
Fig. 5 Correlation between
visuospatial ability test in patients with mild AD. a Correlation
between left parietal cortex and clock drawing, b correlation between
right temporal cortex and clock drawing, c correlation between right
11C-nicotine binding and results of the
parietal cortex and clock recognition, and d correlation between left
parietal cortex and clock recognition. Higher scores indicate better
visual spatial ability performance and lower k2* values indicate more
11C-nicotine binding. All values are absolute
Psychopharmacology (2006) 188:509–520517

Page 10

ing that nAChRs might be a promising target of drug
treatment in AD.
Acknowledgements
Research Council (project no. 05817), Stiftelsen for Gamla
Tjänarinnor, Stohne’s Foundation, and Swedish Brain Power.
This research was supported by the Swedish
References
Alexander GE, Chen K, Pietrini P, Rapoport SI, Reiman EM (2002)
Longitudinal PET evaluation of cerebral metabolic decline in
dementia: a potential outcome measure in Alzheimer’s disease
treatment studies. Am J Psychiatry 159:738–745
Alhainen K, Helkala EL, Riekkinen P (1993) Psychometric discrim-
ination of tetrahydroaminoacridine responders in Alzheimer
patients. Dementia 4:54–58
Almkvist O, Jelic V, Amberla K, Hellstrom-Lindahl E, Meurling L,
Nordberg A (2001) Responder characteristics to a single oral
dose of cholinesterase inhibitor: a double-blind placebo-con-
trolled study with tacrine in Alzheimer patients. Dement Geriatr
Cogn Disord 12:22–32
Anderson J (1995) A rapid and accurate method to realign PET-scans
utilizing image edge information. J Nucl Med 36:657–669
Aubert I, Araujo DM, Cecyre D, Robitaille Y, Gauthier S, Quirion R
(1992) Comparative alterations of nicotinic and muscarinic
binding sites in Alzheimer’s and Parkinson’s diseases.
J Neurochem 58:529–541
Backman L, Forsell Y (1994) Episodic memory functioning in a
community-based sample of old adults with major depression:
utilization of cognitive support. J Abnorm Psychol 103:
361–370
Bohnen NI, Kaufer DI, Hendrickson R, Ivanco LS, Lopresti B, Davis
JG, Constantine G, Mathis CA, Moore RY, DeKosky ST (2005)
Cognitive correlates of alterations in acetylcholinesterase in
Alzheimer’s disease. Neurosci Lett 380:127–132
Cabeza R, Nyberg L (2000) Imaging cognition II: an empirical review
of 275 PET and fMRI studies. J Cogn Neurosci 12:1–47
Cahn-Weiner DA, Sullivan EV, Shear PK, Fama R, Lim KO,
Yesavage JA, Tinklenberg JR, Pfefferbaum A (1999) Brain
structural and cognitive correlates of clock drawing performance
in Alzheimer’s disease. J Int Neuropsychol Soc 5:502–509
Calhoun ME, Mao Y, Roberts JA, Rapp PR (2004) Reduction in
hippocampal cholinergic innervation is unrelated to recognition
memory impairment in aged rhesus monkeys. J Comp Neurol
475:238–246
Chefer SI, London ED, Koren AO, Pavlova OA, Kurian V, Kimes AS,
Horti AG, Mukhin AG (2003) Graphical analysis of 2-[18F]FA
binding to nicotinic acetylcholine receptors in rhesus monkey
brain. Synapse 48:25–34
Coyle JT, Price DL, DeLong MR (1983) Alzheimer’s disease: a
disorder of cortical cholinergic innervation. Science 219:
1184–1190
Ding YS, Fowler JS, Logan J, Wang GJ, Telang F, Garza V, Biegon A,
Pareto D, Rooney W, Shea C, Alexoff D, Volkow ND, Vocci F
(2004) 6-[18F]Fluoro-A-85380, a new PET tracer for the
nicotinic acetylcholine receptor: studies in the human brain and
in vivo demonstration of specific binding in white matter.
Synapse 53:184–189
Duchek JM, Hunt L, Ball K, Buckles V, Morris JC (1997) The role of
selective attention in driving and dementia of the Alzheimer type.
Alzheimer Dis Assoc Disord 1(Suppl 11):48–56
Flores CM, Rogers SW, Pabreza LA, Wolfe BB, Kellar KJ (1992) A
subtype of nicotinic cholinergic receptor in rat brain is composed
of alpha 4 and beta 2 subunits and is up-regulated by chronic
nicotine treatment. Mol Pharmacol 41:31–37
Foldi NS, Lobosco JJ, Schaefer LA (2002) The effect of attentional
dysfunction in Alzheimer’s disease: theoretical and practical
implications. Semin Speech Lang 23:139–150
Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A
practical method for grading the cognitive state of patients for the
clinician. J Psychiatr Res 12:189–198
Foster NL, Chase TN, Fedio P, Patronas NJ, Brooks RA, Di Chiro G
(1983) Alzheimer’s disease: focal cortical changes shown by
positron emission tomography. Neurology 33:961–965
Gallezot JD, Bottlaender M, Gregoire MC, Roumenov D, Deverre JR,
Coulon C, Ottaviani M, Dolle F, Syrota A, Valette H (2005) In
vivo imaging of human cerebral nicotinic acetylcholine receptors
with 2-18F-fluoro-A-85380 and PET. J Nucl Med 46:240–247
Guan ZZ, Zhang X, Ravid R, Nordberg A (2000) Decreased protein
levels of nicotinic receptor subunits in the hippocampus and
temporal cortex of patients with Alzheimer’s disease. J Neurochem
74:237–243
Guillozet AL, Weintraub S, Mash DC, Mesulam MM (2003)
Neurofibrillary tangles, amyloid, and memory in aging and mild
cognitive impairment. Arch Neurol 60:729–736
Gundisch D, Koren AO, Horti AG, Pavlova OA, Kimes AS, Mukhin
AG, London ED (2005) In vitro characterization of 6-[18F]
fluoro-A-85380, a high-affinity ligand for alpha4beta2* nicotinic
acetylcholine receptors. Synapse 55:89–97
Haxby JV, Duara R, Grady CL, Cutler NR, Rapoport SI (1985)
Relations between neuropsychological and cerebral metabolic
asymmetries in early Alzheimer’s disease. J Cereb Blood Flow
Metab 5:193–200
Herholz K, Adams R, Kessler J, Szelies B, Grond M, Heiss W (1990)
Criteria for the diagnosis of Alzheimer’s disease with positron
emission tomography. Dementia 1:156–164
Herholz K, Nordberg A, Salmon E, Perani D, Kessler J, Mielke R,
Halber M, Jelic V, Almkvist O, Collette F, Alberoni M, Kennedy
A, Hasselbalch S, Fazio F, Heiss WD (1999) Impairment of
neocortical metabolism predicts progression in Alzheimer’s
disease. Dement Geriatr Cogn Disord 10:494–504
Herscovitch P, Markham J, Raichle ME (1983) Brain blood flow
measured with intravenous H2(15)O. I. Theory and error
analysis. J Nucl Med 24:782–789
Ikonomovic MD, Mufson EJ, Wuu J, Cochran EJ, Bennett DA,
DeKosky ST (2003) Cholinergic plasticity in hippocampus of
individuals with mild cognitive impairment: correlation with
Alzheimer’s neuropathology. J Alzheimers Dis 5:39–48
Jones GM, Sahakian BJ, Levy R, Warburton DM, Gray JA (1992)
Effects of acute subcutaneous nicotine on attention, information
processing and short-term memory in Alzheimer’s disease.
Psychopharmacology (Berl) 108:485–494
Kadir A, Almkvist O, Wall A, Darreh-Shori T, Grut M, Strandberg B,
Ringheim A, Erikson B, Blomquist G, Långström B, Nordberg A
(2006a) PET imaging of acetylcholinesterase activity and nicotine
binding in galantamine treated AD patients. In preparation
Kadir A, Darreh-Shori T, Almkvist O, Wall A, Långström B,
Nordberg A (2006b) Changes in the brain 11C-nicotine binding
sites in mild AD patients following rivastigmine treatment as
assessed by PET. In preparation
Lawrence AD, Sahakian BJ (1995) Alzheimer disease, attention, and
the cholinergic system. Alzheimer Dis Assoc Disord 2(Suppl
9):43–49
Lezak M (1995) Neuropsychological assessment, 3rd edn. Oxford
University Press, London, UK
Lundqvist H, Nordberg A, Hartvig P, Langstrom B (1998) (S)-(−)-
[11C]nicotine binding assessed by PET: a dual tracer model
evaluated in the rhesus monkey brain. Alzheimer Dis Assoc
Disord 12:238–246
518Psychopharmacology (2006) 188:509–520

Page 11

Luria A (1966) Higher cortical functions in man. Basic Books, New
York
Maziere M, Delforge J (1995) PET imaging [11C]nicotine: historical
aspects. In: Domino E (ed) Brain imaging of nicotine and
tobacco smoking. NPP Books, Ann Arbor, pp 13–28
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan
EM (1984) Clinical diagnosis of Alzheimer’s disease: report of
the NINCDS-ADRDA work group under the auspices of
Department of Health and Human Services Task Force on
Alzheimer’s Disease. Neurology 34:939–944
Mega MS, Dinov ID, Porter V, Chow G, Reback E, Davoodi P,
O’Connor SM, Carter MF, Amezcua H, Cummings JL (2005)
Metabolic patterns associated with the clinical response to
galantamine therapy: a fludeoxyglucose f 18 positron emission
tomographic study. Arch Neurol 62:721–728
Mogg AJ, Jones FA, Pullar IA, Sharples CG, Wonnacott S (2004)
Functional responses and subunit composition of presynaptic
nicotinic receptor subtypes explored using the novel agonist
5-iodo-A-85380. Neuropharmacology 47:848–859
Nagahama Y, Okina T, Suzuki N, Nabatame H, Matsuda M (2005)
Neural correlates of impaired performance on the clock drawing
test in Alzheimer’s disease. Dement Geriatr Cogn Disord
19:390–396
Newhouse PA, Sunderland T, Tariot PN, Blumhardt CL, Weingartner
H, Mellow A, Murphy DL (1988) Intravenous nicotine in
Alzheimer’s disease: a pilot study. Psychopharmacology (Berl)
95:171–175
Nobili F, Brugnolo A, Calvini P, Copello F, De Leo C, Girtler N,
Morbelli S, Piccardo A, Vitali P, Rodriguez G (2005) Resting
SPECT–neuropsychology correlation in very mild Alzheimer’s
disease. Clin Neurophysiol 116:364–375
Nordberg A (1999) PETstudies and cholinergic therapy in Alzheimer’s
disease. Rev Neurol (Paris) 4(Suppl 155):S53–S63
Nordberg A (2001) Nicotinic receptor abnormalities of Alzheimer’s
disease: therapeutic implications. Biol Psychiatry 49:200–210
Nordberg A (2006) Visualization of nicotinic and muscarinic receptors
in brain by positron emission tomography. In: Ezio G, Pepeu G
(eds) The brain cholinergic system. Martin Dunitz, London
Nordberg A, Winblad B (1986) Reduced number of [3H]nicotine and
[3H]acetylcholine binding sites in the frontal cortex of Alzheimer
brains. Neurosci Lett 72:115–119
Nordberg A, Hartvig P, Lilja A, Viitanen M, Amberla K, Lundqvist H,
Andersson Y, Ulin J, Winblad B, Langstrom B (1990) Decreased
uptake and binding of 11C-nicotine in brain of Alzheimer
patients as visualized by positron emission tomography. J Neural
Transm Park Dis Dement Sect 2:215–224
Nordberg A, Alafuzoff I, Winblad B (1992) Nicotinic and muscarinic
subtypes in the human brain: changes with aging and dementia.
J Neurosci Res 31:103–111
Nordberg A, Lundqvist H, Hartvig P, Lilja A, Langstrom B (1995)
Kinetic analysis of regional (S)(−)11C-nicotine binding in
normal and Alzheimer brains—in vivo assessment using positron
emission tomography. Alzheimer Dis Assoc Disord 9:21–27
Nordberg A, Lundqvist H, Hartvig P, Andersson J, Johansson M,
Hellstrom-Lindahi E, Langstrom B (1997) Imaging of nicotinic
and muscarinic receptors in Alzheimer’s disease: effect of tacrine
treatment. Dement Geriatr Cogn Disord 8:78–84
Nordberg A, Amberla K, Shigeta M, Lundqvist H, Viitanen M,
Hellstrom-Lindahl E, Johansson M, Andersson J, Hartvig P, Lilja
A, Langstrom B, Winblad B (1998) Long-term tacrine treatment
in three mild Alzheimer patients: effects on nicotinic receptors,
cerebral blood flow, glucose metabolism, EEG, and cognitive
abilities. Alzheimer Dis Assoc Disord 12:228–237
Ober BA, Jagust WJ, Koss E, Delis DC, Friedland RP (1991)
Visuoconstructive performance and regional cerebral glucose
metabolism in Alzheimer’s disease. J Clin Exp Neuropsychol
13:752–772
Pabreza LA, Dhawan S, Kellar KJ (1991) [3H]Cytisine binding to
nicotinic cholinergic receptors in brain. Mol Pharmacol 39:9–12
Paterson D, Nordberg A (2000) Neuronal nicotinic receptors in the
human brain. Prog Neurobiol 61:75–111
Perry RJ, Hodges JR (2000) Fate of patients with questionable (very
mild) Alzheimer’s disease: longitudinal profiles of individual
subjects’ decline. Dement Geriatr Cogn Disord 11:342–349
Perry E, Martin-Ruiz C, Lee M, Griffiths M, Johnson M, Piggott M,
Haroutunian V, Buxbaum JD, Nasland J, Davis K, Gotti C,
Clementi F, Tzartos S, Cohen O, Soreq H, Jaros E, Perry R,
Ballard C, McKeith I, Court J (2000) Nicotinic receptor subtypes
in human brain ageing, Alzheimer and Lewy body diseases. Eur J
Pharmacol 393:215–222
Potter A, Corwin J, Lang J, Piasecki M, Lenox R, Newhouse PA
(1999) Acute effects of the selective cholinergic channel
activator (nicotinic agonist) ABT-418 in Alzheimer’s disease.
Psychopharmacology (Berl) 142:334–342
Raichle ME, Martin WR, Herscovitch P, Mintun MA, Markham J
(1983) Brain blood flow measured with intravenous H2(15)O. II.
Implementation and validation. J Nucl Med 24:790–798
Robbins TW, McAlonan G, Muir JL, Everitt BJ (1997) Cognitive
enhancers in theory and practice: studies of the cholinergic
hypothesis of cognitive deficits in Alzheimer’s disease. Behav
Brain Res 83:15–23
Robertson LC, Lamb MR, Knight RT (1988) Effects of lesions of
temporal-parietal junction on perceptual and attentional process-
ing in humans. J Neurosci 8:3757–3769
Rusted JM, Graupner L, Tennant A, Warburton DM (1998) Effortful
processing is a requirement for nicotine-induced improvements in
memory. Psychopharmacology (Berl) 138:362–368
Rusted JM, Newhouse PA, Levin ED (2000) Nicotinic treatment for
degenerative neuropsychiatric disorders such as Alzheimer’s
disease and Parkinson’s disease. Behav Brain Res 113:
121–129
Sahakian BJ, Jones GM (1991) The effects of nicotine on attention,
information processing, and working memory in patients with
dementia of the Alzheimer type. In: Adlkofer F, Thruau K (eds)
Effects of nicotine on biological system. Birkhauser Verlag,
Basel
Sahakian BJ, Owen AM, Morant NJ, Eagger SA, Boddington S,
Crayton L, Crockford HA, Crooks M, Hill K, Levy R (1993)
Further analysis of the cognitive effects of tetrahydroaminoacri-
dine (THA) in Alzheimer’s disease: assessment of attentional and
mnemonic function using CANTAB. Psychopharmacology (Berl)
110:395–401
Sihver W, Fasth KJ, Horti AG, Koren AO, Bergstrom M, Lu L,
Hagberg G, Lundqvist H, Dannals RF, London ED, Nordberg A,
Langstrom B (1999) Synthesis and characterization of binding of
5-[76Br]bromo-3-[[2(S)-azetidinyl]methoxy]pyridine, a novel
nicotinic acetylcholine receptor ligand, in rat brain. J Neurochem
73:1264–1272
Snaedal J, Johannesson T, Jonsson JE, Gylfadottir G (1996) The
effects of nicotine in dermal plaster on cognitive functions in
patients with Alzheimer’s disease. Dementia 7:47–52
Teipel SJ, Willoch F, Ishii K, Burger K, Drzezga A, Engel R,
Bartenstein P, Moller HJ, Schwaiger M, Hampel H (2005)
Resting state glucose utilization and the CERAD cognitive
battery in patients with Alzheimer’s disease. Neurobiol Aging
27(5):681–690
Vellas B, Cunha L, Gertz HJ, De Deyn PP, Wesnes K, Hammond G,
Schwalen S (2005) Early onset effects of galantamine treatment
on attention in patients with Alzheimer’s disease. Curr Med Res
Opin 21:1423–1429
Psychopharmacology (2006) 188:509–520519

Page 12

Vitaliano PP, Breen AR, Albert MS, Russo J, Prinz PN (1984)
Memory, attention, and functional status in community-residing
Alzheimer type dementia patients and optimally healthy aged
individuals. J Gerontol 39:58–64
Voytko ML, Olton DS, Richardson RT, Gorman LK, Tobin JR, Price
DL (1994) Basal forebrain lesions in monkeys disrupt attention
but not learning and memory. J Neurosci 14:167–186
Walsh DM, Selkoe DJ (2004) Deciphering the molecular basis
of memory failure in Alzheimer’s disease. Neuron 44:
181–193
Warpman U, Nordberg A (1995) Epibatidine and ABT 418 reveal
selective losses of alpha 4 beta 2 nicotinic receptors in Alzheimer
brains. Neuroreport 6:2419–2423
Watson CCND, Casey ME et al (1997) Evaluation of simulation based
scatter correction for 3D PET cardiac imaging. IEEE Trans Nucl
Sci 21:136–144
Wechsler D (1981) Wechsler Adult Intelligence Scale—revised
manual. Psychological Corporation, New York
Wevers A, Monteggia L, Nowacki S, Bloch W, Schutz U, Lindstrom
J, Pereira EF, Eisenberg H, Giacobini E, de Vos RA, Steur EN,
Maelicke A, Albuquerque EX, Schroder H (1999) Expression of
nicotinic acetylcholine receptor subunits in the cerebral cortex in
Alzheimer’s disease: histotopographical correlation with amyloid
plaques and hyperphosphorylated-tau protein. Eur J Neurosci
11:2551–2565
White HK, Levin ED (1999) Four-week nicotine skin patch treatment
effects on cognitive performance in Alzheimer’s disease.
Psychopharmacology (Berl) 143:158–165
White HK, Levin ED (2004) Chronic transdermal nicotine patch
treatment effects on cognitive performance in age-associated
memory impairment. Psychopharmacology (Berl) 171:465–471
Wilson AL, Langley LK, Monley J, Bauer T, Rottunda S, McFalls E,
Kovera C, McCarten JR (1995) Nicotine patches in Alzheimer’s
disease: pilot study on learning, memory, and safety. Pharmacol
Biochem Behav 51:509–514
Yu WF, Guan ZZ, Bogdanovic N, Nordberg A (2005) High selective
expression of alpha7 nicotinic receptors on astrocytes in the
brains of patients with sporadic Alzheimer’s disease and patients
carrying Swedish APP 670/671 mutation: a possible association
with neuritic plaques. Exp Neurol 192:215–225
520Psychopharmacology (2006) 188:509–520