Amyloid plaque imaging in vivo: current achievement
and future prospects
# Springer-Verlag 2007
Introduction Alzheimer’s disease (AD) is a very complex
neurodegenerative disorder, the exact cause of which is still
not known. The major histopathological features, amyloid
plaques and neurofibrillary tangles, already described by
Alois Alzheimer, have been the focus in research for de-
cades. Despite a probable whole cascade of events in the
brain leading to impairment of cognition, amyloid is still
the target for diagnosis and treatment.
Discussion The rapid development of molecular imaging
techniques now allows imaging of amyloid plaques in vivo
in Alzheimer patients by PET amyloid ligands such as
Pittsburgh compound B (PIB). Studies so far have revealed
high11C-PIB retention in brain at prodromal stages of AD
and a possibility to discriminate AD from other dementia
understand the relationship between brain and CSF amyloid
processes and cognitive processes.
Conclusion In vivo imaging of amyloid will be important
for early diagnosis and evaluation of new anti-amyloid
therapies in AD.
11C-PIB. Ongoing studies are focussing to
Alzheimer’s disease (AD) is presently considered as the
most devastating neurodegenerative disorder. The present
cost of dementia for 29.3 million patients worldwide is
estimated to be 315.4 billion US $ . New data suggest
that the number of AD worldwide will increase from
26.6 million in 2006 to 106.8 million in 2050 . To tackle
both the increasing societal costs and the burden on the
patients and their families, great efforts are presently made
to develop early diagnostic markers of AD. This will enable
early drug intervention and hopefully find a cure of AD in
The appearance of the neuropathological hallmarks of
AD, senile plaque and neurofibrillary tangles, probably oc-
cur many years before the clinical symptoms of AD [3, 4].
As a consequence, within the aging population, subjects
with no history of cognitive problems might show a sign of
AD neuropathology at autopsy. Beta amyloid (Aβ 1–42)
has been suggested as the primary cause of AD , but
other ongoing processes, including oxidative stress, inflam-
matory reactions, microglia activations, tau phosphorylation
and neurotransmitter impairment, to some extent, play a
crucial role in the AD pathology .
The present study will focus on the recent attempts to
develop in vivo amyloid imaging methods to understand
the evolution of amyloid, which will be important for the
development of early diagnostic markers and anti-amyloid
treatment strategies in AD.
More than 10 years ago, the development of amyloid ligands
started, and the studies went from in vitro binding studies in
Eur J Nucl Med Mol Imaging
A. Nordberg (*)
Karolinska Institutet, Department of Neurobiology,
Care Sciences and Society, Division of Alzheimer Neurobiology,
Karolinska University Hospital Huddinge,
Novum 5th floor,
141 86 Stockholm, Sweden
Department of Geriatric Medicine,
Karolinska University Hospital Huddinge,
tissue homogenates from mice or human autopsybrain tissue
to in vivo imaging studies in mice, monkey and humans.
Many substances failed because of high unspecific binding
and poor distribution to brain in experiment animals .
The small molecular strategy turned out to be most prom-
ising. Four amyloid positron emission tomography (PET)
ligands, namely [18F] 1,1-dicyano-2-[6-(dimethylamino)-2-
naphtalenyl] propene or18F-FDDNP , N-methyl [11C] 2-
, 4-N-methylamino-4′-hydroxystilbene or11C-SB13 
and 2-(2-[-dimethylaminothizol-5-yl] ethenyl)-6-(2-[fluoro]
benzoxazole) or11C-BF-227  have so far been applied
inPETstudies toADpatients.Invitrobinding studies showed
that FDDNP ligand bound to synthetic Aβ1–40 with two
binding sites, a high affinity site (0.12 nM) and a low-affinity
site (1.9 nM), while binding studies with18F-FDDP in post-
mortem AD homogenates showed a Bmaxvalue of 144 nM
with Kdvalue of 0.75 nM [12, 13].18F-FDDNP has also
been found to bind to neurofibrillary tangles in human
autopsy brain tissue .11C-PIB showed two binding sites
in human autopsy brain tissue, a high affinity binding site
with Bmaxof 1,407 pmol/g and Kdvalue of 2.5 nM and a
low-affinity binding site with Bmaxof 13 nM and Kdof
250 nM, respectively .3H-SB-13 binding studies showed
a Bmaxvalue of 14–45 pmol/mg protein with a Kdof 2.4 nM
, while BF-227 demonstrated a Kivalue of 4.3 nM to Aβ
1–42 fibrils .
Transgenic mice models overexpressing human mutant
amyloid protein (APP) and amyloid pathology are valuable
in AD research. PIB binding, however, was initially
demonstrated in brain of APP transgenic mice [15, 17]. By
increasing the specific activity of PIB, Maeda et al. 
were able to elegantly show a similar regional binding of11C-
PIB in transgenic mice brain sections as in autopsy brain
slices from AD patients. The11C-PIB binding was also by
found immunostaining to be colocalized with Aβ 40 and Aβ
Amyloid imaging in Alzheimer’s disease
The first studies in humans with the PIB were performed
in Uppsala, Sweden in 2002. The PIB compound was
developed by William Klunk and Chester Matties at the
Pittsburgh University. The first PET PIB imaging studies
were performed in collaboration between the Pittsburgh
University, USA, Karolinska Institutet and Uppsala
University, Sweden. Sixteen mild AD patients recruited
at Karolinska Institutet, Karolinska University Hospital
Huddinge, Stockholm, underwent imaging with
and showed significantly higher PIB retention in the frontal,
temporal, parietal and occipital cortices and the striatum
(1.9–1.5 times differences) compared to healthy controls
. The retention of11C-PIB was low and similar in the
pons and cerebellum of both groups . An inverse
significant correlation was observed between11C-PIB and
cerebral glucose metabolism (18F-FDG) . The findings
with11C-PIB have later been confirmed by several research
groups [19–23]. It is estimated that more than 500 subjects
now have been scanned with the PET amyloid imaging
ligand worldwide. Figure 1 illustrates the high
retention and the regional impairment in cerebral glucose
metabolism (18F-FDG) in two mild AD patients compared
to a healthy control.
Time course of amyloid load in AD brain as studied
What is the time course of amyloid deposition in AD
brains? A 2-year follow-up study using11C-PIB showed no
significant change in the PIB retention compared to base-
line, although a decline in cerebral glucose metabolism was
observed in all patients and especially in those who had
deteriorated in cognitive function by more than 3 points on
the MMSE during the follow-up period . This finding
was of course somewhat unexpected, because it had been
assumed that the amyloid load would continuously increase
in the brain during the progression of AD. The unchanged
PIB retention at the 2-year follow-up suggests a different
time course for the amyloid load compared to changes in
the functional activity in the brain. It is possible that a
maximum amyloid load in brain is reached almost in the
prodromal stage of AD disease. This assumption is also
supported by the high11C-PIB retention in mild cognitive
impairment (MCI) patients [25–27]. Seven MCI patients
who subsequently converted to AD showed high PIB re-
tention in brain by PET at baseline, whereas none of the
ten MCI patients with low PIB retention converted to AD
after the 2-year follow-up . The difference in11C-PIB
retention between MCI converters and non-converters is
illustrated in Fig. 2. The finding that MCI patients showed
less impairment in cerebral glucose metabolism in compar-
ison to PIB retention supports the assumption that amyloid
represents an earlier event in the time course of AD pa-
thology than metabolic changes.18F-FDDNP PET studies
in MCI patients have also shown intermediate binding
compared with AD patients and healthy controls . It is
known from histopathological studies that amyloid plaques
can be present in the cerebral cortex of cognitive normal
older subjects . It was recently estimated that amyloid
plaque could be visualized in 10% of normal elderly
subjects . Whether these normal elderly subjects will
develop in AD has to be systematically investigated .
Interestingly, high11C-PIB retention and low cerebral glu-
cose metabolism were recently reported in highly educated
Eur J Nucl Med Mol Imaging
AD compared to low-educated AD patients as a possible
sign for a greater neuroplasticity in the highly educated
Brain amyloid imaging and cognition
It has generally been concluded from the autopsy studies in
the literature that the quantified amyloid plaque pathology
correlates less with cognitive function than neurofibrillary
tangles and neurotransmitter activity. What is the finding in
AD patients undergoing amyloid imaging with PET? A
negative correlation has been observed between episodic
memory test scores and cortical11C-PIB retention in MCI
and AD patients [24, 26, 27]. Pike et al.  reported a
strong correlation between episodic memory and11C-PIB
binding for MCI patients, while the same correlation was
weak for AD patients . The latter finding might explain
the often found poor correlation between reported clinical
cognitive status and Aβ burden in autopsy brain tissue.
Brain amyloid imaging and CSF biomarkers
In a recent autopsy study, AD patients who prospectively
had undergone magnetic resonance imaging (MRI) and
cognitive testing before death showed less correlation be-
tween brain beta amyloid burden and atrophy than between
density of neurofibrillary tangles and atrophy . What is
the correlation between amyloid measured in cerebrospinal
fluid (CSF) and amyloid measured with PET in living AD
patients? In a longitudinal follow-up of CSF biomarkers in
Fig. 1 Cerebral glucose metab-
olism (18F-FDG) and11C-PIB
amyloid imaging in two AD
patients and one healthy control.
The PET scans show18F-FDG
and11C-PIB at a saggital sec-
tion. Red indicates high, yellow
medium, blue low11C-PIB re-
tention. MMSE Mini-Mental-
State-Examination, ys. years.
Courtesy of Uppsala PETcentre/
Imanet and Karolinska Univer-
sity Hospital Huddinge
MCI converter and one MCI
non-converter compared with an
AD patient and healthy control.
The PET scans show11C-PIB
retention at sagittal and longitu-
dinal sections at the level of the
basal ganglia. Red indicates
high, yellow medium, blue low
11C-PIB retention. Adapted from
11C-PIB retention in one
Eur J Nucl Med Mol Imaging
a cohort of community-dwelling volunteers of whom some
were cognitively normal whereas one had very mild or mild
AD, Fagan et al.  observed higher11C-PIB retention in
subjects with low levels of CSFAβ 1–42, while individuals
with low PIB retention showed high CSF Aβ 1–42 levels
. A significant negative correlation has been observed
between cortical PIB retention and CSF Aβ 1–42, while a
positive correlation was observed between PIB retention
and CSF tau in MCI patients . Furthermore, systematic
studies are needed to verify how closely brain amyloid
plaque load correlates to CSF biomarkers.
Amyloid imaging in other forms of dementia
Some of the value for PIB, as future early diagnostic mark-
er in AD, depends on the possibility to discriminate by PIB
imaging between AD and other forms of dementia. In some
recent studies,11C-PIB has been used in studies of patients
with frontotemporal dementia (FTD). Rabinovici et al. 
investigated 12 FTD patients with
12 FTD patients showed negative PIB scans, while four
showed positive scans . Two out of four patients with
positive PIB scans showed FDG images consistent with AD
. Similarly Engler et al.  observed negative PIB
scans in eight out of ten FTD patients investigated with
11C-PIB, while two patients showed high PIB retentions.
The FDG scans were consistent with the hypometabolism
pattern seen in FDT patients . Drzezga et al. 
investigated eight subjects with semantic dementia who all
showed negative PIB scans. It can, thus, be concluded that
although six out of 28 patients with FTD and semantic
dementia have shown high PIB retention, PIB may help to
discriminate AD from FTD [33–35]. Post-mortem studies
are needed to clarify whether PIB-positive FTD patients
represent FTD/AD pathology or AD pathology mimicking
FTD clinically. Johansson et al.  observed that patients
with Parkinson’s disease and normal cognition showed neg-
ative11C-PIB scans . Among ten Parkinson patients
who were classified as demented, eight patients showed
PIB-negative scans, while two patients showed positive PIB
scans and were considered more AD-like . A high
cortical PIB retention has been found in patients with Lewy
body dementia . In vitro binding studies with11C-PIB
showed a binding to Aβ plaques and not to the Lewy
bodies in the brain tissue . High11C-PIB retention has
also recently been reported in cognitively normal patients
with advanced cerebral amyloid angiopathy (CAA) .
The retention of11C-PIB in the occipital cortex of CAA
was interestingly enough greater than in AD patients .
As far as the authors know, no11C-PIB studies have been
performed in vascular dementia.
11C-PIB. Eight of the
Amyloid imaging for evaluation of anti-amyloid therapy
Different treatment strategies are presently tried to reduce
the amyloid load in the brain of AD patients. Active and
passive immunotherapy is in focus. The first trial (AN-1792)
using an active immunization with Aβ 42 and an immuno-
genic adjuvant was suspended because of the occurrence of
meningoencephalitis . Surprisingly, MRI showed re-
duced brain volumes in immunized AD patients compared
to placebo treated . Post-mortem studies of immunized
patients have shown reduced Aβ pathology with un-
changed tau pathology [42, 43]. A reduced in vitro binding
of3H-PIB was recently demonstrated in homogenates from
autopsy tissue of immunized AD patient compared to un-
treated subjects . A crucial question is the extent of Aβ
pathology before immunization, because all amyloid stud-
ies, so far, have dealt with post-mortem brain tissue.
In vivo imaging of amyloid in patients undergoing anti-
amyloid treatment has great potential for several reasons. In
vivo PIB imaging before start of treatment would allow
selection of patients with demonstrable high amyloid load
in the brain. Repeated studies of11C-PIB retention during
ongoing treatment allow detection of decrease in insoluble
Aβ load in brain. Mathis et al.  suggested that a two-
fold decrease in the test–retest variability, thus 10–20%,
should be sufficient to detect a reduced Aβ load. Interestingly
enough, a decreased11C-PIB retention in such range was
observed after treatment with phenserine, an inhibitor of the
formation of β-APP . Immunization therapies are
presently ongoing, where
both prior and during immunization. These studies will
provide further understanding of the underlying mechanisms
for anti-amyloid therapy.
11C-PIB retention is measured
Council (project no 05817), Stohnes foundation, Foundation of Old
Servants, KI foundations, The Alzheimer foundation in Sweden,
Swedish Brain Power, and the EC-FP5-project NCI-MCI, QLK6-CT-
2000-00502 is gratefully acknowledged.
The financial support of the Swedish Research
Conflict of interest statement
There are no conflicts of interest for
1. Wimo A, Winblad B, Jönsson L. An estimate of the total world-
wide societal cost of dementia 2005. Alzheimer & Dementia.
2. Brookmeyer R, Johnson E, Ziegler-Graha K, Arrighi HM.
Forecasting the global burden of Alzheimer’s disease. Alzheimer
& Dementia. 2007;3:186–91.
3. Braak H, Braak E. Frequency of stages of Alzheimer-related
lesions in different age categories. Neurobiol Aging. 1997;
Eur J Nucl Med Mol Imaging
4. Thal DR, Rub U, Orantoes M, Braak H. Phases of A-beta Download full-text
deposition in the human brain and its relevance for the
development of AD. Neurology. 2002;58:1791–800.
5. Hardy JA, Selkoe DJ. The amyloid hypothesis of Alzheimer’s
disease: progress and problems on the road to therapeutics.
6. Mattson MP. Pathways towards and away from Alzheimer’s
disease. Nature. 2004;430:631–9.
7. Nordberg A. PET imaging of amyloid in Alzheimer’s disease.
Lancet Neurol. 2004;3:519–27.
8. Shoghi-Jadid K, Small D, Agdeppa ED, Kepe V, Ercoli LM, et al.
Localization of neurofibrillary tangles and beta-amyloid plaques
in the brain of living patients with Alzheimer disease. Am J
Geriatr Psychiatry. 2004;10:24–35.
9. Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in
Alzheimer’s disease with Pittsburgh compound-B. Ann Neurol.
10. Verhoeff NP, Wilson AA, Takeshita S, Trop L, Hussey D, Singh
K, et al. In vivo imaging of Alzheimer disease beta-amyloid with
[11C]SB-13 PET. Am J Geriatr Psychiatry. 2004;12:584–95.
11. Kudo Y, Okamura N, Furumoto S, et al. 2-(2-[2-Dimethylamino-
thiazol-5-yl] Ethenyl)-6-(2-[Fluoro]Ethoxy)Benzoxazole: a novel
PET agent for in vivo detection of dense amyloid plaques in
Alzheimer’s disease patients. J Nucl Med. 2006;48:553–61.
12. Agdeppa ED, Kepe V, Liu J, et al. Binding characteristics of
radiofluorinated 6-dialkylamino-2-naphtylethylidene derivatives
as positron emission tomography imaging probes for β-amyloid
plaques in Alzheimer’s disease. J Neurosci. 2001;21:1–5.
13. Agdeppa ED, Kepe V, Liu J, et al. Dialkylamino-6-acylmalonno-
nitrile substituted naphthalenes (DDNP analogs): novel diagnostic
and therapeutic tool in Alzheimer’s disease. Mol Imaging Biol.
14. Ye L, Morgenstern JL, Gee AD. Delineation of PET imaging
agent binding sites on beta-amyloid peptide fibrils. J Biol Chem.
15. Klunk WE, Lopresti BJ, Ikonomovic MD, et al. Binding of
positron emission tomography tracer Pittsburgh Compound-B
reflects the amount of amyloid-β in Alzheimer’s disease brain
but not in transgenic mice brain. J Neurosci. 2005;25:10598–606.
16. Kung M-P, Hou C, Zhuang Z-P, Skovronsky D, Kung HF.
Binding of two potential imaging agents targeting amyloid
plaques in postmortem brain tissue of patients with Alzheimer’s
disease. Brain Res. 2004;1025:98–105.
17. Toyama H, Ye D, Ichise M, et al. PET imaging of brain with the
β-amyloid probe, [11C]6-OH-BTA-1, in a transgenic mouse model
of Alzheimer’s disease. Eur J Nucl Med Mol Imaging.
18. Maeda J, Bib J, Irie T, et al. Longitudinal, quantitative assessment
of amyloid, neuroinflammation, and anti-amyloid treatment in a
living mouse model of Alzheimer’s disease enable by positron
emission tomography. J Neurosci. 2007;10:10957–68.
19. Price JC, Klunk WE, Lopresti BJ, et al. Kinetic modelling of
amyloid binding in humans using PET imaging and Pittsburgh
compound-B. J Cereb Blood Flow Metab. 2005;25:1528–47.
20. Archer HA, Edison P, Brooks DJ, et al. Amyloid load and cerebral
atrophy in Alzheimer’s disease: an 11C-PIB positron emission
tomography study. Ann Neurol. 2006;60:145–7.
21. Kemppainen NM, Aalto S, Wilson IA, et al. Voxel-based analysis
of PET amyloid ligand [11C]PIB uptake in Alzheimer disease.
22. Mintun MA, LaRosso GN, Dence CS, et al. [11C] PIB in a
nondemented population. Potentional antecendent marker of
Alzheimer’s disease. Neurology. 2006;67:446–52.
23. Rowe CC, Ng S, Ackermann U, et al. Imaging β-amyloid burden
in aging and dementia. Neurology. 2007;68:1718–25.
24. Engler H, Forsberg A, Almkvist O, et al. Two year follow-up of
amyloid deposition in patients with Alzheimer’s disease. Brain.
25. Kempainen NM, Aalto S, Wilson IA, et al. PET amyloid ligand
[11C]PIB uptake is increased in mild cognitive impairment.
26. Forsberg A, Engler H, Almkvist O, et al. PET imaging of amyloid
deposition in patients with mild cognitive impairment. Neurobiol
Aging. 2007 May 10 (in press).
27. Pike KE, Savage G, Villemagne VL, et al. β-amyloid imaging and
memory in non-demented individuals: evidence for preclinical
Alzheimer’s disease. Brain. 2007;130:2037–844.
28. Small G, Kepe V, Ercoli LM, et al. PET of brain amyloid and tau
in mild cognitive impairment. N Engl J Med 2006;355:2652–63.
29. Price JL, Morris JC. Tangles and plaques in nondemented aging
and “preclinical” Alzheimer’s disease. Ann Neurol 1999;45:358–
30. Kemppainen NM, Aalto S, Karrasch M, et al. Cognitive reserve
hypothesis: Pittsburgh compound B and fluorodeoxyglucose
positron emission tomography in relation to education in mild
Alzheimer’s disease. Ann Neurol. 2007 Nov 19 (in press).
31. Josephs KA, Whitwell JL, Ahmed Z, et al. β-amyloid burden is
not associated with rates of atrophy. Ann Neurol. 2007 Sept 25
32. Fagan AM, Roe CM, Xiong C, et al. Cerebrospinal fluid tau/β-
amyloid 42 ratio as a predictor of cognitive decline in non-
demented older adults. Neurology 2007;64:343–9.
33. Rabinovici GD, Furst AJ, O’Neil, JP, et al. 11C-PIB PET imaging
in Alzheimer disease and frontotemporal lobar degeneration.
34. Engler H, Fritzell Santillo A, Wang SX, et al. In vivo amyloid
imaging with PET in frontotemporal dementia. Eur J Nucl Mol
35. Drzezga A, Grimmer T, Henriksen G, et al. Imaging of amyloid
plaques and cerebral glucose metabolism in semantic dementia
and Alzheimer’s disease. Neuroimage. 2008;39:619–33.
36. Johansson A, Savitcheva I, Forsberg A, et al. [11C]-PIB imaging
in patients with Parkinson’s disease: preliminary results. Parkin-
sonism Relat Disord. 2007 Sept 11 (in press).
37. Maetzler W, Reimold M, Liepelt I, et al. PIB binding in
Parkinson’s disease dementia. Neuroimage. 2007 Oct 22 (in press).
38. Fodero MT, Smith DP, McLean CA, et al. In vitro characterization
of Pittsburgh compound-B binding to Lewy bodies. J Neurosci
39. Johnson KA, Gregas M, Becker JA, et al. Imaging of amyloid
burden and distribution in cerebral amyloid angiopathy. Ann
40. Gilman S, Koller M, Black RS, et al. Clinical effects of Abeta
immunization (AN1792) in patients with AD in an interrupted
trial. Neurology 2005;64:1553–62.
41. Fox NC, Black RS, Gilman S, et al. Effect of Abeta immunization
(AN1792) on MRI measures of cerebral volume in Alzheimer
disease. Neurology 2005;64:1563–72.
42. Nicoll JA, Wilkinson D, Holmes C, et al. Neuropathology of
human Alzheimer disease after immunization with amyloid-β
peptide: a case report. Nat Med 2003;9:448–52.
43. Masliah E, Hansen L, Adame A, et al. Abeta vaccination effects
on plaque pathology in the absence of encephalitis in Alzheimer
disease. Neurology 2005;64:129–31.
44. Mathis CA, Lopresti BJ, Klunk WE. Impact of amyloid imaging
on drug development in Alzheimer’s disease. Nucl Med Biol
45. Kadir A, Andreasen N, Almkvist O, et al. Effect of phenserine
treatment on brain functional activity and amyloid in AD. Ann
Neurol 2008 (in press).
Eur J Nucl Med Mol Imaging