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Cognitive reserve hypothesis Pittsburgh Compound B and fluorodeoxyglucose positron emission tomography in relation to education in mild Alzheimer's disease.

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Cognitive Reserve Hypothesis: Pittsburgh
Compound B and Fluorodeoxyglucose
Positron Emission Tomography in Relation
to Education in Mild Alzheimer’s Disease
Nina M. Kemppainen, MD,1,2 Sargo Aalto, MSc,1,3 Mira Karrasch, PhD,3 Kjell Någren, PhD,1
Nina Savisto, MSc,1 Vesa Oikonen, MSc,1 Matti Viitanen, MD,4,5 Riitta Parkkola, MD,6
and Juha O. Rinne, MD1
Objective: The reduced risk for Alzheimer’s disease (AD) in high-educated individuals has been proposed to reflect brain
cognitive reserve, which would provide more efficient compensatory mechanisms against the underlying pathology, and thus
delayed clinical expression. Our aim was to find possible differences in brain amyloid ligand 11C-labeled Pittsburgh Compound
B ([11C]PIB) uptake and glucose metabolism in high- and low-educated patients with mild AD.
Methods: Twelve high-educated and 13 low-educated patients with the same degree of cognitive deterioration were studied
with PET using [11C]PIB and 18F-fluorodeoxyglucose as ligands. The between-group differences were analyzed with voxel-based
statistical method, and quantitative data were obtained with automated region-of-interest analysis.
Results: High-educated patients showed increased [11C]PIB uptake in the lateral frontal cortex compared with low-educated
patients. Moreover, high-educated patients had significantly lower glucose metabolic rate in the temporoparietal cortical regions
compared with low-educated patients.
Interpretation: Our results suggesting more advanced pathological and functional brain changes in high-educated patients with
mild AD are in accordance with the brain cognitive reserve hypothesis and point out the importance of development of reliable
markers of underlying AD pathology for early AD diagnostics.
Ann Neurol 2008;63:112–118
Several epidemiological studies have found a lower incidence of Alzheimer’s disease (AD) in high-educated
populations, suggesting that education provides protection against the disease.1 This reduced risk for AD
in high-educated individuals is proposed to reflect
brain cognitive reserve that provides greater brain capacity to compensate for disruption caused by disease
pathology, and thus delays the clinical expression of
AD.2 At a particular level of AD pathology, highly
educated individuals are less likely to manifest clinical
symptoms of dementia as compared with less educated individuals.3 After the diagnosis of AD, higheducated individuals show more rapid progression of
dementia and lower survival compared with loweducated AD patients.4 – 6 The different course of the
disease between these groups has been hypothesized
to reflect a more advanced AD pathology at the time
of diagnosis in high-educated patients, and a rapid
cognitive deterioration after the compensatory capacity becomes insufficient.
The association of educational level with the severity of brain damage in AD has been evaluated in vivo
with positron emission tomography (PET) and singlephoton emission computed tomography by using the
brain glucose metabolism or cerebral blood flow as
measures of brain functional changes.7–12 These studies have shown an inverse relation between the level
of education and brain glucose metabolism or blood
flow after adjusted for the dementia severity. This relation was evident especially in brain regions typically
affected in AD, such as temporal and parietal cortices.
The effect of education on the relation between brain
From the 1Turku Positron Emission Tomography Centre, University of Turku; 2Department of Neurology, Turku University Central Hospital; 3Department of Psychology, Åbo Akademi University;
Turku City Hospital, Turku, Finland; 5Clinical Geriatrics, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; and 6Department of Clinical Radiology, Turku University
Central Hospital, Turku, Finland.
Published online Nov 19, 2007 in Wiley InterScience
( DOI: 10.1002/ana.21212
Address correspondence to Dr Rinne, Turku PET Centre, University of Turku, P. O. Box 52, FIN-20521 Turku, Finland.
Received Apr 8, 2007, and in revised form Jun 14. Accepted for
publication Jul 16, 2007.
© 2007 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
AD pathology (ie, amyloid plaques and neurofibrillary tangles) and cognitive level has been evaluated in
two postmortem studies.13,14 In these studies, education was found to modify the relation of amyloid, but
not tangle load, to cognitive performance, suggesting
that brain cognitive reserve can partly compensate the
effects of amyloid accumulation on cognition but fail
to modify the effect of tangle pathology.
In vivo PET studies have shown an increased uptake of amyloid ligand 11C-labeled Pittsburgh Compound B ([11C]PIB) in AD and mild cognitive impairment patients, especially in the frontal, parietal,
and temporal cortices and in the posterior cingulate,
which indicates an increased amyloid accumulation in
these areas.15–17 There are no previous studies on the
association between education and [11C]PIB uptake
in AD. Our objective was to study [11C]PIB uptake
in high- and low-educated patients with mild AD using a voxel-based statistical analysis and to evaluate
possible differences in amyloid pathology between
these groups. Furthermore, as an indicator of brain
functional changes, possible differences in 18Ffluorodeoxyglucose ([18F]FDG) uptake between the
groups were also evaluated. Our hypothesis was that
high-educated patients with mild AD have greater
[11C]PIB uptake and lower [18F]FDG uptake, indicating more marked pathological and functional brain
changes compared with low-educated patients with
the same clinical disease stage.
lated Disorders Association criteria. All patients had progressive disease with impairment of memory and at least one
additional field of cognitive function. The patients were cognitively assessed using a comprehensive neuropsychological
test battery that included Consortium to Establish a Registry
for Alzheimer’s Disease, Wechsler Memory Scale–Revised,
parts of Wechsler Adult Intelligence Scale–Revised, Trail
Making Test and Stroop or Alzheimer’s Disease Assessment
Scale Cognitive subscale, Trail Making Test, clock drawing,
copy of modified complex figure, digit span forward, Boston
Naming Test, and fluency. The tests showed typical impairment in memory functions and in at least one separate cognitive function compared with age-appropriate norms and
estimated premorbid levels. Results from central neuropsychological tests are presented in Table 1. We studied 13 lowand 12 high-educated AD patients. The 13 (4 men, 9
women) low-educated (elementary school, 6 years of formal
education) patients with mild AD had a mean age of 71.0
(standard deviation, [SD] 7.0; range, 55– 80) years. The
mean Mini-Mental State Examination (MMSE) score in
these patients was 25.0 (SD, 2.1; range, 22–29). Five patients were receiving cholinesterase inhibitor treatment (one
rivastigmine, two galantamine, and two donepezil) at the
time of the study, and one patient also received memantine.
Eight patients in the low-educated group had never received
AD medication, and cholinesterase inhibitor treatment was
initiated after the PET studies. Apolipoprotein E genotype
was analyzed in 12 of 13 low-educated patients with 10 apolipoprotein E ε4 carriers (83%). Furthermore, 12 (9 men, 3
women) high-educated (academic degree, at least 15 years of
formal education) patients with mild AD with a mean age of
73.0 (SD, 3.6; range, 64 –77) years were studied. In the
high-educated group, five patients were receiving cholinesterase inhibitor treatment (three rivastigmine, two donepezil).
The remaining patients had never received AD medication,
and cholinesterase inhibitor treatment was initiated after the
study. The mean MMSE score of the high-educated group
was 26.0 (SD, 1.3; range, 24 –28). There was no difference
Patients and Methods
All patients were diagnosed by an experienced neurologist
(J.O.R.) according to the National Institute of Neurological
and Communication Disorders-Alzheimer’s Disease and Re-
Table 1. Neuropsychological Test Performances in the High- and Low-Educated Groups
General cognitive functioning scores
CERAD total score corrected17
Memory scores
WMS-R logical memory I
WMS-R logical memory II
Verbal function scores
Category fluency
WAIS-R: similarities
Visuoconstructive function score
WAIS-R: block design
High-Educated Group
Low-Educated Group
Mean (SD, range)
(SD, range)
26.2 (1.3, 24-28)
89.4 (12.7, 69-112)
25.0 (2.1, 22-29)
80.8 (9.5, 65-95)
17.1 (7.8, 7-33)
12.5 (9.7, 0-31)
12.9 (4.6, 7-23)
4.9 (4.5, 0-13)
21.4 (9.4, 10-36)
30.6 (2.4, 27-33)
17.8 (4.2, 9-26)
23.8 (4.4, 18-31)
20.5 (10.9, 6-42)
19.1 (7.5, 11-36)
SD ⫽ standard deviation; MMSE ⫽ Mini-Mental State Examination; CERAD ⫽ Consortium to Establish a Registry for Alzheimer’s
Disease; WMS-R ⫽ Wechsler Memory Scale–Revised; WAIS-R ⫽ Wechsler Adult Intelligence Scale–Revised.
Kemppainen et al: PIB, FDG-PET and Education in AD
in the mean MMSE score ( p ⫽ 0.23) or in the mean age
between the low- and high-educated groups ( p ⫽ 0.32).
[11C]PIB PET scanning was performed for all patients
and FDG for all in the low-educated group. In the higheducated group, FDG-PET was performed in 11 in 12 patients with mean age of 73.2 years and mean MMSE score of
26.1. Patients underwent a magnetic resonance imaging,
which was interpreted by an experienced neuroradiologist
(R.P.). Magnetic resonance imaging showed central or cortical atrophy, or both, and hippocampal atrophy. No findings
incompatible with the diagnosis of AD were found.
The study was approved by the Ethical Committee of
Southwest Finland Health Care District. All patients gave
their written informed consent. In cases where there was
doubt that a patient was competent to give consent, it was
obtained from the patient’s next of kin.
Positron Emission Tomography Imaging
[11C]PIB was produced by the reaction of 6-OH-BTA-0 and
[11C]methyl triflate, as reported earlier.16 The specific radioactivity of [11C]PIB at the time of administration was 32.5
(SD, 7.8) MBq/nmol. The radiochemical purity of the tracer
was more than 98 % in all [11C]PIB studies. [18F]FDG was
synthesized with an automatic apparatus by a modified
method of Hamacher and colleagues.18 The radiochemical
purity of the tracer was more than 95% in all [18F]FDG
studies. In [11C]PIB studies, all patients underwent a 90minute dynamic PET scan with a GE Advance PET scanner
(General Electric Medical Systems, Milwaukee, WI) in the
three-dimensional scanning mode as described earlier.16
[11C]PIB was injected into an antecubital vein as a bolus
with a mean dose of 449MBq (SD, 92MBq) and flushed
with saline. No blood sampling was performed during the
scan. Imaging data were reconstructed into a 128 ⫻ 128
matrix using a transaxial Hann filter with a 4.6mm cutoff
and an axial Ramp filter with an 8.5mm cutoff. In
[18F]FDG imaging, the same scanner, scanning mode, patient positioning (orbitomeatal and sagittal lines), and reconstruction matrix were used as in [11C]PIB studies. Before
scanning, two cannulas were placed in both antecubital
veins, one for injection of [18F]FDG (3.7MBq/kg) and the
other for blood sampling. Twenty-one arterialized blood
samples were drawn from the preheated arm during the 55minute study to measure plasma activity. Additional blood
samples were obtained for plasma glucose concentration
measurement before the tracer injection and 25 and 55 minutes after the beginning of the scan. The mean of these three
measurements was used in data analysis.
Data Analysis
Before the voxel-based statistical analysis and automated
region-of-interest (ROI) analysis, dynamic images were first
computed into quantitative parametric images. Parametric
images representing [11C]PIB uptake in each pixel were calculated as a region-to-cerebellum ratio of the radioactivity
concentration over 60 to 90 minutes, as described earlier.16
Cerebral glucose metabolic rate (GMR) in each pixel in
[18F]FDG images were calculated using tracer kinetic modeling and plasma activity data.19
Annals of Neurology
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Statistical Parametric Mapping Analysis
Voxel-based statistical analyses of [11C]PIB and [18F]FDG
data were performed using Statistical Parametric Mapping
version 99 (SPM99) and Matlab 6.5 for Windows (Math
Works, Natick, MA), using procedures described in detail
elsewhere.16,20 In brief, spatial normalization of parametric
images was performed using ligand-specific [11C]PIB and
[18F]FDG templates.16,20 The between-group comparison
equaling two-sample t tests and testing the difference in ratio
values was performed as an explorative analysis covering the
whole brain. Multiple-comparison corrected p values less
than 0.05 were considered significant.
Automated Region-of-Interest Analysis
To obtain quantitative regional values of [11C]PIB uptake
and GMR, we performed automated ROI analysis as described earlier.16,20 In brief, the ROIs were defined using
Imadeus software (version 1.50; Forima, Turku, Finland) bilaterally on the frontal cortex, lateral temporal cortex, inferior parietal lobe, occipital cortex, hippocampus, parahippocampal gyrus, cerebellar cortex, and subcortical white
matter.17 The average regional ratio values of [11C]PIB uptake and GMR were calculated using these ROIs from spatially normalized parametric ratio images (see earlier SPM
analyses) and subjected to statistical analysis conducted using
SPSS for Windows (1989-2001, release 12.0.1; SPSS, Chicago, IL).
Statistical Parametric Mapping Analysis
The between-group SPM analysis showed that higheducated patients with mild AD had significantly
greater [11C]PIB uptake in the ventrolateral frontal
cortex compared with low-educated patients (Fig, A).
Furthermore, SPM analysis showed that high-educated
patients had significantly lower GMR in the temporal
and parietal cortices compared with low-educated patients (see Fig, B). There was no difference in GMR in
the frontal cortex between the groups.
Automated Region-of-Interest Analysis
The ROI analyses supported the results of the SPM
analyses and showed significant increases in [11C]PIB
uptake in the ventrolateral frontal cortex in higheducated compared with low-educated patients. In
this region, high-educated patients showed 14%
greater [11C]PIB uptake values than the low-educated
patients. High-educated patients had significantly
lower GMR in the parietal cortex and a trend toward
lower GMR in the lateral temporal cortex. Higheducated patients showed less than 85% of the GMR
in these areas compared with low-educated patients.
The mean [11C]PIB uptake values, mean GMRs, and
percentage differences in the studied brain regions are
shown in Table 2.
Fig. Visualization of the results of Statistical Parametric Mapping (SPM) analysis. Regions with statistically significant increases
(corrected p value at cluster level ⬍ 0.01) in [11C]PIB uptake (A) and decreases (corrected p value at cluster level ⬍ 0.01) in
glucose metabolic rate (GMR) (B) in high-educated compared with low-educated patients are indicated with colors. The red-yellow
scale indicates the level of statistical significance of the differences in [11C]PIB uptake (yellow indicates most significant difference).
This study demonstrates significantly increased brain
uptake of the amyloid PET ligand [11C]PIB in the
frontal cortex in high-educated patients with mild
AD compared with low-educated AD patients at the
same stage of the disease. Furthermore, high-educated
patients showed significantly lower GMR in the temporal and parietal cortices compared with loweducated patients. Both groups were clinically diagnosed as having mild AD according to National
Institute of Neurological and Communication
Disorders-Alzheimer’s Disease and Related Disorders
Association criteria, and there was no between-group
difference in the MMSE scores and Consortium to
Establish a Registry for Alzheimer’s Disease total
scores corrected for age, education, and sex.21 Despite
the lack of differences in the more global measures of
general cognitive functioning, the high-educated
group showed significantly better performances in
verbal neuropsychological tests compared with the
low-educated group. Tests of naming, verbal fluency,
and verbal memory have been shown to be affected
by educational attainment in older age,22 and thus
may also be particularly resistant to decline in higheducated AD patients. Patients with high education
may also gain an advantage by being more familiar
with the kinds of tasks used in neuropsychological assessments. However, after AD incident faster decline
in memory and executive speed is associated with
higher education.23
The lower incidence of AD in high-educated populations has been shown in several epidemiological
studies, but the protective mechanism of education
against the disease is still unclear.1 Brain reserve hypothesis relies on the theory that more efficient neural
networks may compensate the disruption caused by
pathology, and thus delay the expression of the disease.2 Moreover, one explanation for the lower risk
for AD in high-educated populations might be the
different pattern of metabolic activity, that is, lower
basal or default activity and greater specific activity in
high-educated compared with low-educated individuals.24,25 This pattern of mental activity has been hypothesized to decrease neuronal A␤ release and protect against AD because the presence of brain regions
with high basal activity has been suggested to lead to
Kemppainen et al: PIB, FDG-PET and Education in AD
Table 2. Results from Automated Region-of-Interest
Analysis of 11C-Labeled Pittsburgh Compound B
Uptake (Mean Region-to-Cerebellum Ratio at 60 –90
Minutes [SD]) and Glucose Metabolic Rate (Mean
[SD]) in High- and Low-Educated Patients with
Mild Alzheimer’s Disease and the Percentage of the
High-Educated Mean of the Low-Educated Mean
Brain Region
PIB ratio
1.66 (0.17) 1.45 (0.24) 114 0.02
14.9 (3.9)
16.9 (4.9)
88 0.53
Parietal cortex
PIB ratio
1.63 (0.28) 1.57 (0.42) 104 0.93
18.1 (3.1)
22.0 (3.9)
82 0.03
Lateral temporal
PIB ratio
1.66 (0.25) 1.60 (0.35) 104 0.86
18.4 (3.1)
21.8 (3.7)
84 0.06
Posterior cingulate
PIB ratio
2.12 (0.46) 1.96 (0.53) 108 0.64
22.5 (3.8)
24.8 (4.5)
91 0.35
Occipital cortex
PIB ratio
1.41 (0.17) 1.42 (0.26)
99 0.86
20.7 (4.6)
81 0.12
25.0 (5.6)
Mesial temporal
PIB ratio
1.28 (0.13) 1.25 (0.17) 102 0.80
13.4 (2.5)
14.2 (2.7)
94 0.64
White matter
PIB ratio
1.25 (0.14) 1.20 (0.16) 104 0.95
10.6 (1.3)
11.1 (1.9)
95 0.84
VLFC ⫽ ventrolateral frontal cortex; PIB ⫽ Pittsburgh
Compound B; GMR ⫽ glucose metabolic rate.
greater A␤ release.24 –26 These results indicate a
greater amyloid pathology and more diminished brain
metabolism in high-educated compared with loweducated AD patients and led to the proposal that
education would provide cognitive reserve and later
expression of the disease rather than protection
against disease pathology. Accordingly, a functional
magnetic resonance imaging study showed that in
older adults, higher education is associated with
greater and more widespread activation of the frontal
cortex than low education, suggesting compensatory
network engaged to aid cognitive function.27 The
cross-sectional study design used in this study does
not shed light on the development of brain patholog-
Annals of Neurology
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January 2008
ical and functional changes during the presymptomatic phase of the disease. It is thus possible that the
pathological changes in the high-educated group have
started to develop earlier compared with the loweducated group, or that the brain changes in the
high-educated group have developed more rapidly.
The difference in cognitive reserve between individuals could result from genetic factors or from a lifelong
mental stimulation due to education, or both. In addition to cognitive reserve hypothesis, there are also
alternative explanations for the lower incidence of AD
among highly educated people. Higher education is
often associated with healthier lifestyle, fewer diseases,
and lower exposure to toxic factors, and this could
contribute to the differences between educational
groups, as suggested for heart disease mortality.28 The
brain reserve hypothesis implies that people with
higher education have greater reserve capacity, and
that greater pathological changes are needed for dementia to manifest itself. This reserve could be innate
and people with greater reserve would be prone to
have more education. The cognitive reserve hypothesis, however, emphasizes functional aspects such as
more efficient and flexible usage of the existing neural
Previous in vivo PET studies have shown increased
[11C]PIB uptake in anterior and posterior cingulate;
frontal, parietal, temporal and occipital cortices; and
in the striatum and thalamus in AD and mild cognitive impairment patients compared with healthy control subjects.15–17,29 Our results showed a regionally
different pattern of [11C]PIB uptake increase and
GMR decrease in high-educated compared with loweducated patients with increased [11C]PIB uptake in
the frontal cortex and decreased GMR in the temporoparietal cortical regions in the high-educated
group. These brain regions show the most prominent
changes in [11C]PIB and [18F]FDG PET studies in
AD as the greatest [11C]PIB uptake values and the
most significant between-group differences have been
reported in the frontal cortex and posterior cingulate.15,16 On the other hand, the strongest decrease in
GMR takes place in the temporoparietal cortical regions in AD patients.30 It has been suggested that regional [11C]PIB uptake indicating amyloid accumulation is not directly associated with glucose
metabolism and neuronal function in the same region. Increased [11C]PIB uptake has been demonstrated especially in the frontal cortex, which shows
preserved glucose metabolism but clearly increased
[11C]PIB uptake in AD.29 Thus, decreased metabolism and neuronal dysfunction in certain brain regions might be mediated by other factors such as formation of neurofibrillary tangles, which spreads to
frontal cortex relatively late during the disease.26
The study has certain limitations. The number of
low- and high-educated groups is relatively small, reducing the power to detect differences between the
groups. The patient groups were not perfectly matched
regarding cognitive functions because the low-educated
group did not perform as well as the high-educated
group in some of the cognitive tests. This, however,
would, if anything, underestimate the difference in
[11C]PIB and [18F]FDG uptake between low- and
high-educated groups. As an extension to this study
one could in the future perform a study to explore the
relation between education and [11C]PIB and
[18F]FDG uptake in a population that would be more
homogenous according to distribution of level of education.
Our results indicate more pronounced amyloid accumulation and neuronal dysfunction in higheducated compared with low-educated patients with
mild AD. These results are in accordance with cognitive reserve hypothesis and delayed clinical expression
of the disease in high-educated patients with marked
AD pathology. The late appearance of clinical symptoms in these patients makes it challenging to detect
the disease process in its early phase and points out
that this group of patients would especially benefit
from reliable markers of AD pathology. Possible candidates for such a marker are, for example, in vivo
PET imaging of amyloid accumulation or glucose metabolism, hippocampal magnetic resonance imaging,
biomarkers from cerebrospinal fluid, and detailed
neuropsychological assessment. This becomes increasingly important when treatments affecting the disease
progression become available.
This study was supported by Turku University Hospital (J.O.R.),
the Maud Kuistila Foundation (N.M.K.), the Sigrid Juselius Foundation (J.O.R.), and the Research Council for Health of the Academy of Finland (J.O.R.; project #205954).
We thank the staff of the Turku PET Centre for technical assistance
and GE Healthcare Medical Diagnostics for providing [11C]PIB for
this study.
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