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ORIGINAL CONTRIBUTION
Assessment of -Amyloid in a Frontal
Cortical Brain Biopsy Specimen and
by Positron Emission Tomography With
Carbon 11–Labeled Pittsburgh Compound B
Ville Leinonen, MD, PhD; Irina Alafuzoff, MD, PhD; Sargo Aalto, MSc; Timo Suotunen, BM;
Sakari Savolainen, MD, PhD; Kjell Na˚gren, PhD; Tero Tapiola, MD, PhD; Tuula Pirttilä, MD, PhD;
Jaakko Rinne, MD, PhD; Juha E. Jääskeläinen, MD, PhD; Hilkka Soininen, MD, PhD; Juha O. Rinne, MD, PhD
Objective:To compare carbon 11–labeled Pittsburgh
Compound B ([11C]PiB) positron emission tomography
(PET) findings in patients with and without Alzheimer
disease lesions in frontal cortical biopsy specimens.
Design:Cross-sectional study of [11C]PiB PET find-
ings in patients with or without -amyloid (A) aggre-
gates in frontal cortical biopsy specimens.
Setting:Two university hospitals in Finland.
Patients:Ten patients who had undergone intraven-
tricular pressure monitoring with a frontal cortical bi-
opsy (evaluated for Aaggregates and hyperphosphory-
lated tau) for suspected normal-pressure hydrocephalus.
Interventions:[11C]PiB PET and evaluation for cogni-
tive impairment using a battery of neuropsychological tests.
Main Outcome Measures:Immunohistochemical evalu-
ation for Aaggregates and hyperphosphorylated tau in
the frontal cortical biopsy specimen and [11C]PiB PET.
Results:In patients with Aaggregates in the frontal
cortical biopsy specimen, PET imaging revealed higher
[11C]PiB uptake (P⬍.05) in the frontal, parietal, and lat-
eral temporal cortices and in the striatum as compared
with the patients without frontal Adeposits.
Conclusions:Our study supports the use of noninva-
sive [11C]PiB PET in the assessment of Adeposition in
the brain. Large prospective studies are required to verify
whether [11C]PiB PET will be a diagnostic aid, particu-
larly in early Alzheimer disease.
Arch Neurol . 2008;65(10):(doi:10.1001/archneur.65.10.noc80013)
AGGREGATES OF -AMYLOID
(A) in the neuropil to-
gether with hyperphos-
phorylated tau (HP) seen
in neurons and neuronal
processes are considered diagnostic hall-
mark lesions of Alzheimer disease (AD).1
Based on current knowledge, at the first
phase presumably Adeposits in neocor-
tical regions; at the second phase, in the
allocortex; at the third phase, addition-
ally in the diencephalic nuclei and stria-
tum; at the fourth phase, additionally in
distinct brainstem nuclei; and, finally, at
the fifth phase, also in the cerebellum and
additional brainstem nuclei.2Variation in
this pattern of deposition has been re-
ported in subjects carrying the presenilin
1 mutation.3So far, the only confident
method to assess Aaggregates and HP
in the brain is the histological analysis of
tissue samples obtained either during life
or at autopsy,1,2 a major methodological
obstacle considering clinical drug trials of
early AD.
Imaging of Aaggregates by Pittsburgh
Compound B (PiB) positron emission to-
mography (PET) seems a promising method
for noninvasive evaluation of patients with
suspected AD.3-8 A case report described that
a patient with dementia with Lewy bodies
showed a positive correlation between car-
bon 11–labeled (11C) PiB PET findings dur-
ing life and postmortem assessment of A
aggregates 3 months later.9
Cognitive impairment, the leading symp-
tom of AD, is also included in the clinical
triad of normal-pressure hydrocephalus
(NPH).10 In NPH, the diagnostic accuracy
is increased by intracranial pressure (ICP)
monitoring,11 and a tiny cortical biopsy
specimen can be obtained through the bur
hole for differential diagnosis. The risk of
complications associated with this inva-
sive procedure has been low. In fact, 22%
to 42% of the patients with symptoms sug-
gestive of NPH showed AD pathological le-
sions in frontal cortical samples.12-14
In this study, our objectives were to as-
sess Aaggregates both applying nonin-
Author Affiliations:
Departments of Neurosurgery
(Drs Leinonen, Savolainen,
J. Rinne, and Jääskeläinen) and
Neurology (Drs Tapiola, Pirttilä,
and Soininen), Kuopio
University Hospital and Unit of
Pathology and Neurology,
Department of Clinical
Medicine (Dr Alafuzoff), and
Unit of Neurology, Institute of
Clinical Medicine (Drs Pirttilä
and Soininen), University of
Kuopio, Kuopio and Turku PET
Centre, University of Turku,
Turku (Drs Na˚gren and
J. O. Rinne and Messrs Aalto
and Suotunen), Finland.
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vasive [11C]PiB PET and invasive surgery. We com-
pared [11C]PiB PET results in 10 patients with known
histopathological features (ie, the presence or absence of
Aaggregates and HPin frontal cortical samples ob-
tained during ICP monitoring).
METHODS
BASIC SERIES
Altogether, 125 patients underwent ICP monitoring with fron-
tal cortical biopsy for suspected NPH at the Department of Neu-
rosurgery, Kuopio University Hospital, between January 2004
and February 2007.
PRESENT SERIES
Medical records of the patients, who were 75 years or younger,
were first screened according to the medical history by an in-
dependent neurologist. Exclusion criteria included poor gen-
eral health, severe dementia, or severe concomitant diseases af-
fecting the ability to cooperate in the PET examination or
contraindication for magnetic resonance imaging. Approxi-
mately 50 patients fulfilled the study criteria. These patients
were contacted by telephone and only 10 patients agreed to par-
ticipate in the [11C]PiB PET study (Table 1). Based on the neu-
ropathological findings in the frontal cortical biopsy speci-
men, patients were divided into 2 groups. Six patients had A
(3 of them had also HP) pathological lesions in the biopsy speci-
men, whereas 4 patients had no AD-related pathological le-
sions in the biopsy specimen (Table 1). Close to the PET in-
vestigation, the patients were evaluated for cognitive impairment
using the Clinical Dementia Rating Scale (CDR),16 CDR sum
of boxes, Mini-Mental State Examination,17 Consortium to Es-
tablish a Registry for Alzheimer’s Disease (CERAD) neuropsy-
chological test battery,18 and total score of CERAD con-
structed as suggested by Chandler and colleagues.15
ICP MONITORING AND FRONTAL
CORTICAL BIOPSY
A right frontal 12-mm bur hole was made under local anes-
thesia. The standard site was 2 cm right from the midline
ahead of the coronary suture. Prior to insertion of the intra-
ventricular monitoring catheter, cylindrical cortical brain
biopsy specimens of 2 to 5 mm in diameter and 3 to 7 mm in
length were obtained through the bur hole. The samples were
placed in buffered formalin and, after overnight fixation, were
embedded in paraffin.
HISTOCHEMICAL AND
IMMUNOHISTOCHEMICAL STAINING
Consecutive 7-µm-thick sections were stained with hematoxylin-
eosin, Bielschowsky silver impregnation technique, and im-
munohistochemical (IHC) methods. Briefly, deparaffinized sec-
tions were manually immunostained with antibodies directed
to HPand A(Table 2). -amyloid antibodies included both
6F/3D (reactive to amino acid residue 10-15), labeling both pa-
renchymal aggregates (ie, plaques) as well as cerebral amyloid
angiopathy, and 4G8 (residue 18-22), labeling primarily pa-
renchymal Aaggregates and especially fleecy and diffuse ag-
gregates seen at early stages. The labeled streptavidin-biotin
method (Histostain-Plus Kit; Zymed, San Francisco, Califor-
Table 1. Case Characteristics and IHC Findings of Frontal Cortical Biopsy Specimens
Case/Sex/
Age at Biopsy, y
Score
NPHb
Time From
Biopsy to PET,
mo HP
No. of
Amyloid 
Aggregatesc
(4G8)
No. of
Diffuse/Neuritic
Plaquesd
(Bielschowsky
Silver Stain)CDR
CDR
SOB
CERAD
TotalaMMSE
1/F/68 0.5 0.5 78 30 ⫹36 − 0 0/0
2/F/75 0 1 73 26 ⫹23 − 0 0/0
3/M/70 0 0.5 82 29 ⫹15 − 0 0/0
4/F/72 1 6 53 22 − 2 − 0 0/0
5/F/72 1 2.5 67 24 ⫹5 − 1 (only fleecy) 0/0
6/F/72 1 5.5 62 19 ⫹20 − 39 0/1
7/F/71 1 3.5 57 28 ⫹12 − 42 2/0
8/F/75 0.5 1 60 27 ⫹26 ⫹45 11/2
9/F/66 2 9.0 49 22 − 27 ⫹66 20/3
10/M/70 1 5 74 23 − 28 ⫹80 20/0
Abbreviations: CDR, Clinical Dementia Rating Scale; CDR SOB, CDR sum of boxes; CERAD, Consortium to Establish a Registry for Alzheimer’s Disease;
HP, hyperphosphorylated tau; ICP, intracranial pressure; IHC, immunohistochemical; MMSE, Mini-Mental State Examination; NPH, normal-pressure
hydrocephalus; PET, positron emission tomography; ⫹, present; −, absent.
aCERAD total score was constructed as suggested by Chandler and colleagues.15
b⫹Indicates NPH according to clinical symptoms and ICP monitoring and the patient has a shunt.
cCount of diffuse and dense aggregates independent of size in a visual field (3.14 mm2) in magnification ⫻100.
dCount of diffuse and neuritic plaques in a visual field (3.14 mm2) in magnification ⫻100. None of the neuritic plaques were labeled with HP.
Table 2. Antibodies Used in IHC Evaluation of Frontal Cortical Samples
Antigen Pretreatment Type Clone Code Company Dilution
-amyloid 80% formic acid 1 h Monoclonal 6F/3D M0872 Dako (Glostrup, Denmark) 1:100
Monoclonal 4G8 9220 Signet Laboratories (Dedham, Massachusetts) 1:2000
HPNone Monoclonal AT8 3Br-3 Innogenetics (Gent, Belgium) 1:30
Abbreviations: HP, hyperphosphorylated tau; IHC, immunohistochemical.
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nia) was used with romulin 3-amino-9-ethylcarbazole chro-
mogen (Biocare Medical, Walnut Creek, California). The sec-
tions were counterstained with Harris hematoxylin (Merck,
Darmstadt, Germany), dehydrated, and mounted in DePex (BDH
Laboratory Supplies, Poole, England). Omission of primary an-
tibodies revealed no detectable staining.
HISTOLOGICAL EXAMINATION
The assessment of stained sections was carried out under light
microscopy at magnifications ⫻100 to ⫻200. Cellular or neu-
ritic HPstructures were sought and rated as negative or posi-
tive. In Bielschowsky silver–stained and in A-IHC–stained sec-
tions, fleecy, diffuse, and dense plaques were counted in
magnification ⫻100 within the whole visual field (3.14 mm2)
composed of gray matter.
[11C]PiB PET IMAGING
PET Imaging
[11C]PiB was produced by the reaction of 6-OH-BTA-0 and
[11C]methyl triflate, as reported earlier.7The radiochemical pu-
rity of the tracer was more than 98% in all [11C]PiB studies. Mean
(SD) 442.8 million (90.1 million) Bq (range, 255-530 million
Bq) (to convert to curies, multiply by 2.7⫻10−11)of[
11C]PiB was
injected intravenously as a bolus and all patients underwent a
90-minute dynamic PET scan with a GE Advance PET scanner
(General Electric Medical Systems, Milwaukee, Wisconsin) in
the 3-dimensional scanning mode, as described earlier.7Posi-
tron emission tomography imaging was performed without the
knowledge of the neuropathological data of the patient.
Data Analysis
Before the voxel-based statistical analysis and automated region-
of-interest (ROI) analysis, dynamic images were first com-
puted into quantitative parametric images. Parametric images
representing [11C]PiB uptake in each pixel were calculated as
a region-to-cerebellum ratio of the radioactivity concentra-
tion over 60 to 90 minutes, as described earlier.7
Statistical Parametric Mapping Analysis
Voxel-based statistical analyses of [11C]PiB data were per-
formed using Statistical Parametric Mapping version 99 (SPM99)
and MATLAB 6.5 for Windows (MathWorks, Natick, Massa-
chusetts), using procedures described in detail earlier.7Briefly,
spatial normalization of parametric images was performed using
a ligand-specific [11C]PiB template.7The between-group com-
parison equaling 2-sample ttests and testing the difference in
ratio values was performed as an explorative analysis covering
the whole brain. Multiple comparison–corrected Pvalues ⬍.01
were considered significant.
Automated ROI Analysis
To obtain quantitative regional values of [11C]PiB uptake,
automated ROI analysis was performed, as described earlier.7
Briefly, the standardized ROIs were defined using Imadeus
software (version 1.50; Forima Inc, Turku, Finland) on the
magnetic resonance imaging template image representing
brain anatomy in accordance with MNI space (Montreal Neu-
rological Institute database). Because this method is based on
a common stereotactic space (ie, spatial normalization of the
images), the operator-induced error in defining ROIs indi-
vidually for each subject can be avoided. The ROIs were posi-
tioned bilaterally on the frontal cortex, lateral temporal cor-
tex, medial temporal lobe, inferior parietal lobe, occipital
cortex, cerebellar cortex, and subcortical white matter.8The
Case 5
Case 7
Case 9
Case 6
Case 8
Case 10
Figure 1. Immunohistochemical examination of protein aggregates in the
frontal cortex biopsy specimens using -amyloid antibody (clone 4G8). Inserts
show cytoplasmic labeling with hyperphosphorylated tau antibody (clone AT8).
Large panels, original magnification ⫻100, scale bar, 200 µm; inserts, original
magnification ⫻400, scale bar, 10 µm. In case 5, there is pale staining of fleecy
aggregates, and in cases 6 and 8, predominantly dense plaques are seen. In the
remaining cases, all types (ie, fleecy, diffuse, and dense plaques) were noted.
Cytoplasmic hyperphosphorylated tau labeling was seen in 3 cases (8, 9, and
10) and even then only in occasional neurons.
Figure 2. Visualization of the results of statistical parametric mapping
analysis. The regions with statistically significant increases (corrected P
value at cluster level ⬍.01) in carbon 11–labeled Pittsburgh Compound B
uptake in patients with -amyloid aggregates (n= 5, cases 6-10) compared
with patients without any -amyloid aggregates (n= 4, cases 1-4) in the
cortical biopsy specimen are indicated with colors.
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average regional ratio values of [11C]PiB uptake were calcu-
lated using these ROIs from spatially normalized parametric
ratio images (see “Statistical Parametric Mapping Analysis”
subsection) and subjected to statistical analysis conducted
using SPSS for Windows (release 12.0.1; SPSS Inc, Chicago,
Illinois).
The study was approved by the Kuopio University Hospi-
tal Research Ethics Board. All patients provided a written in-
formed consent prior to their participation.
RESULTS
The cognitive status of the 10 patients (Mini-Mental State
Examination score, CDR score, CDR sum of boxes, and
CERAD total score) at the time of the [11C]PiB PET scan
and the histological and IHC findings in the frontal cor-
tical biopsy specimens are presented in Table 1 and
Figure 1. Occasional cytoplasmic HPwas seen in only
3 of the 10 patients. No neuropil or plaque-associated
neurites (ie, no HP-labeled neuritic plaques) were seen.
No cerebral amyloid angiopathy was seen in any of our
subjects either.
The between-group SPM analysis (Figure 2) showed
significantly higher [11C]PiB uptake in the frontal, pari-
etal, and lateral temporal cortices (phase 1 of regional A
deposition) and striatum (phase 3) in patients with Aag-
gregates in the frontal cortex compared with those with-
out notable Aaggregates in the brain biopsy specimen.
The automated ROI analysis showed that the pa-
tients with Aaggregates had higher [11C]PiB uptake in
the lateral frontal and lateral temporal cortices (phase 1),
anterior and posterior cingulate gyri (phases 2-3), and
caudate nucleus (phase 3) than the patients without A
aggregates (Table 3). The difference did not reach sig-
nificance in the medial temporal lobe, inferior parietal
and occipital cortices (phases 1-2), or putamen and thala-
mus (phase 3). Figure 3 indicates representative trans-
axial slices of parametric [11C]PiB images.
[11C]PiB uptake in the right frontal cortex (ROI) cor-
related (Pearson r=0.85; P=.002) with the amount of A
aggregates in the right frontal cortical biopsy specimen
(Figure 4).
COMMENT
This is, to our knowledge, the first study where living
patients were assessed regarding their Adeposition in
the brain both by means of surgery and imaging. Our re-
sults indicate that Adeposition in a frontal cortical bi-
opsy specimen obtained during life is in line with the
[11C]PiB uptake found in PET imaging, suggesting that
[11C]PiB PET reflects brain Adeposition.
In suspected NPH, we routinely monitor intraven-
tricular ICP and obtain a small right frontal cortical bi-
Table 3. Automated ROI Analysis of [11C]PiB Uptake:
Mean (SD) Region-to-Cerebellum Ratio in Patients
With or Without AAggregates in the Frontal Cortical
Biopsy Specimen
Brain Area
A
Aggregates
(n=6)
No A
Aggregates
(n=4)
P
Value
Lateral frontal cortex 1.75 (0.59) 1.01 (0.11) .03
Lateral temporal cortex 1.54 (0.45) 1.04 (0.07) .04
Medial temporal lobe 1.36 (0.22) 1.15 (0.09) .07
Inferior parietal cortex 1.57 (0.63) 1.10 (0.15) .13
Anterior cingulate 1.95 (0.69) 1.15 (0.13) .04
Posterior cingulate 2.08 (0.77) 1.19 (0.12) .04
Caudate nucleus 1.71 (0.50) 1.18 (0.10) .05
Putamen 1.78 (0.41) 1.54 (0.18) .23
Occipital cortex 1.49 (0.28) 1.35 (0.08) .29
White matter 1.93 (0.32) 1.75 (0.21) .35
Thalamus 1.45 (0.18) 1.20 (0.31) .15
Abbreviations: A,-amyloid; [11C]PiB, carbon 11–labeled Pittsburgh B
Compound; ROI, region of interest.
Case 1 Case 2 Case 3 Case 4 Case 5
Case 6 Case 7 Case 8 Case 9 Case 10
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Figure 3. Transaxial slices of parametric carbon 11–labeled Pittsburgh Compound B images. The values represent ratios to cerebellar value. The case numbers
refer to Figure 1 and Table 1.
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opsy specimen to exclude or verify a specific neurode-
generative process.11,12,14 Alzheimer disease–related lesions
(ie, HP) are primarily seen in the temporoparietal re-
gions,1whereas the deposition of Astarts from the neo-
cortex, proceeding via central structures to the subten-
torial structures.2Thus, a frontal cortical biopsy specimen
with Aaggregates without HPwould suggest early AD.2
Six of our patients displayed AD-related pathological le-
sions in the cortical biopsy specimen, but none of them
had severe dementia.
In our study, the most significant differences in [11C]PiB
uptake between patients with Aimmunoreactivity in
the frontal cortical biopsy specimen and those without
were seen in the frontal cortex (phase 1), the lateral tem-
poral cortex (phase 1), the anterior and posterior cingu-
late gyri (phases 2-3), and the caudate nucleus (phase
3). The patients with the highest Aload in the biopsy
specimen had also the highest [11C]PiB uptake in PET
imaging. The correlation and SPM analysis showed that
the [11C]PiB uptake increased with increasing Aload
in the biopsy specimen. Our findings are congruent with
the previous PET data from patients with AD4,7 or mild
cognitive impairment8,19 and from healthy controls.
The study groups with or without frontal cortical A
aggregates were similar in age, sex, and time from the
cortical biopsy to PET imaging. Thus, the patients were
suitable for the main objective of the study: method-
ological comparison of the [11C]PiB PET imaging find-
ings and cortical biopsy specimen to indicate Adepo-
sition in the brain independently from the cognitive status
of the patients. Case 5 was excluded from the SPM analy-
sis because there was only 1 fleecy plaque in the biopsy
specimen, and the presence or absence of that case did
not change the result. The interval between the surgery
and imaging (Table 1) might to some extent skew the
interpretation of our results. In parallel with the in-
crease of IHC/Alabeling, an increase in the plaque count
was noted while using silver stain. The surgically ob-
tained cortical biopsy sample was small and thus false-
negative results are possible, and the absence of Aag-
gregates in the frontal cortex does not securely reflect the
Adeposition in other isocortical brain regions. Also, the
false-positive result of sampling of a very small area of
high plaque load is possible. To validate the clinical sig-
nificance of the surgically obtained frontal cortical bi-
opsy specimen in diagnosing brain amyloidosis, further
systematic assessment, preferably by postmortem veri-
fication of brain pathological lesions in subjects in whom
a biopsy specimen has been taken during life, needs to
be carried out. However, all the patients with normal bi-
opsy results also had negative PiB results in spite of the
interval between biopsy and PET imaging. On the other
hand, along with the potential technical errors of PET
imaging and labeling of the histological samples, case 6
(IHC positive but PiB negative) emphasizes the poten-
tial that there might be types of Adeposits that PiB does
not detect. Diagnosis of NPH was based on clinical symp-
toms and intraventricular ICP monitoring. Four of the
7 patients with NPH also had concomitant AD-related
lesions (A) in the cortical biopsy specimen. This is in
line with the previous findings of notable comorbidity
of NPH and AD-related pathological lesions.12-14
This study supports the use of [11C]PiB PET in the evalu-
ation of Adeposition in, for example, mild cognitive im-
pairment, AD, or NPH. Large and prospective studies are
required to verify whether [11C]PiB PET will become a
tool in diagnosing AD. Another potential use of [11C]PiB
would be the quantitative monitoring of Adeposits in
the brain in subjects under treatment in pharmaceutical
trials of early AD targeting amyloid accumulation.
Accepted for Publication: February 5, 2008.
Published Online: August 11, 2008 (doi:10.1001/
archneur.65.10.noc80013).
Correspondence: Ville Leinonen, MD, PhD, Department
of Neurosurgery, Kuopio University Hospital, PO Box 1777,
70211 Kuopio, Finland (ville.leinonen@kuh.fi).
Author Contributions: Study concept and design: Alafuzoff,
Savolainen, Tapiola, Pirttilä, J. Rinne, Jääskeläinen,
Soininen, and J. O. Rinne. Acquisition of data: Leinonen,
Alafuzoff, Suotunen, Savolainen, Na˚gren, and Soininen.
Analysis and interpretation of data: Leinonen, Alafuzoff,
Aalto, Pirttilä, and J. O. Rinne. Drafting of the manu-
script: Leinonen and Aalto. Critical revision of the manu-
script for important intellectual content: Alafuzoff, Aalto,
Suotunen, Savolainen, Na˚gren, Tapiola, Pirttilä, J. Rinne,
Jääskeläinen, Soininen, and J. O. Rinne. Statistical analy-
sis: Aalto. Obtained funding: Soininen and J. O. Rinne. Ad-
ministrative, technical, and material support: Alafuzoff,
Aalto, J. Rinne, Jääskeläinen, and Soininen. Study super-
vision: Savolainen, Pirttilä, J. Rinne, Jääskeläinen, Soin-
inen, and J. O. Rinne.
Financial Disclosure: None reported.
Funding/Support: The study was supported by grant
5772720 from the Kuopio University Hospital, the Acad-
emy of Finland (project 205954), and the Sigrid Juselius
Foundation.
2.4
1.8
2.1
1.5
1.2
0.9
0
3
41
5
2
6
8
9
710
20 40 60 80
No. of Aβ Aggregates
PiB
Figure 4. Scatterplot of carbon 11–labeled Pittsburgh Compound B
([11C]PiB) uptake (region of interest) in the right frontal cortex. Aindicates
the number of -amyloid (clone 4G8) aggregates in the right frontal cortical
biopsy specimen (count of diffuse and dense aggregates independent of size
in a visual field). The diamonds are labeled by case numbers indicated in
Figure 1 and Figure 3 and Table 1.
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