Amyloid plaque imaging in vivo: current achievement and future prospects. Eur J Nucl Med Mol Imaging 35(Suppl 1):S46-S50

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DOI: 10.1007/s00259-007-0700-2 · Source: PubMed
Abstract
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 decades. Despite a probable whole cascade of events in the brain leading to impairment of cognition, amyloid is still the target for diagnosis and treatment. 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 high (11)C-PIB retention in brain at prodromal stages of AD and a possibility to discriminate AD from other dementia disorders by (11)C-PIB. Ongoing studies are focussing to understand the relationship between brain and CSF amyloid processes and cognitive processes. In vivo imaging of amyloid will be important for early diagnosis and evaluation of new anti-amyloid therapies in AD.
Amyloid plaque imaging in vivo: current achievement
and future prospects
Agneta Nordberg
#
Springer-Verlag 2007
Abstract
Introduction Alzheimers 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 imp airment 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
high
11
C-PIB retention in brain at prodromal stages of AD
and a possibil ity to discriminate AD from other dementia
disorders by
11
C-PIB. Ongoing studies are focussing to
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.
Keywords Positron emission tomography(PET)
.
Amyloid
.
PIB
.
Alzheimers disease
.
Diagnostic marker
Introduction
Alzheimers 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 $ [1]. New data suggest
that the number of AD worldwide will increase from
26.6 million in 2006 to 106.8 million in 2050 [2]. 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 future.
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 probl ems might show a sign of
AD neuropathology at autopsy. Beta amyloid (Aβ 142)
has been suggested as the primary cause of AD [5 ], 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 [6].
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.
Amyloid imaging
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
DOI 10.1007/s00259-007-0700-2
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
e-mail: Agneta.K.Nordberg@ki.se
A. Nordberg
Department of Geriatric Medicine,
Karolinska University Hospital Huddinge,
Stockholm, Sweden
tissue homogenates from mice or human autopsy brain 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 [7].
The small molecular strategy turned out to be most prom-
ising. Four amyloid positron emission tomography (PET)
ligands, namely [
18
F] 1,1-dicyano-2-[6-(dimethylamino)-2-
naphtalenyl] propene or
18
F-FDDNP [8], N-methyl [
11
C] 2-
(4-methylaminophenyl)-6-hydroxy-benzothiasole or
11
C-PIB
[9], 4-N-methylamino-4-hydroxystilbene or
11
C-SB13 [10]
and 2-(2-[-dimethylaminothizol-5-yl] ethenyl)-6-(2-[fluoro]
benzoxazole) or
11
C-BF-227 [11] have so far been applied
in PET studies to AD patients. In vitro binding studies showed
that FDDNP ligand bound to synthetic Aβ
140
with two
binding sites, a high affinity site (0.12 nM) and a low-affinity
site (1.9 nM), while binding studies with
18
F-FDDP in post-
mortem AD homogenates showed a B
max
value of 144 nM
with K
d
value of 0.75 nM [12, 13].
18
F-FDDNP has also
been found to bind to neurofibrillary tangles in human
autopsy brain tissue [14].
11
C-PIB showed two binding sites
in human autopsy brain tissue, a high affinity binding site
with B
max
of 1,407 pmol/g and K
d
value of 2.5 nM and a
low-affinity binding site with B
max
of 13 nM and K
d
of
250 nM, respectively [15].
3
H-SB-13 binding studies showed
a B
max
value of 1445 pmol/mg protein with a K
d
of 2.4 nM
[16], while BF-227 demonstrated a K
i
value of 4.3 nM to Aβ
142 fibrils [11].
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. [18]
were able to elegantly show a similar regional binding of
11
C-
PIB in transgenic mice brain sections as in autopsy brain
slices from AD patients. The
11
C-PIB binding was also by
found immunostaining to be colocalized with Aβ 40 and Aβ
42 [17].
Amyloid imaging in Alzheimers 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, K arolinska I nstitutet and Up psala
University, Sweden. Sixteen mild AD patients recruited
at Karolinska Institutet, Karolinska University Hospital
Huddinge, Stockholm, underwent imaging with
11
C-PIB
and showed significantly higher PIB retention in the frontal,
temporal, parietal and occipital cortices and the striatum
(1.91.5 times differences) compared to healthy controls
[9]. The retention of
11
C-PIB was low and simil ar in the
pons and cerebellum of both groups [9]. An inverse
significant correlation was observed between
11
C-PIB and
cerebral glucose metabolism (
18
F-FDG) [9]. The findings
with
11
C-PIB have later been confirmed by several research
groups [1923]. It is estimated that more than 500 subjects
now have been scanned with the PET amyloid imaging
ligand worldwide. Figure 1 illustrates the high
11
C-PIB
retention and the regional impairment in cerebral glucose
metabolism (
18
F-FDG) in two mild AD patients compared
to a healthy control.
Time course of amyloid load in AD brain as studied
by PET
What is the time course of amyloid deposition in AD
brains? A 2-year follow-up study using
11
C-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 [24]. 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 high
11
C-PIB retention in mild cognitive
impairment (MCI) patients [2527]. 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 [26]. The difference in
11
C-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.
18
F-FDDNP PET studies
in MCI patients have also shown intermediate binding
compared with AD patients and healthy controls [28]. It is
known from histopathological studies that amyloid plaques
can be present in the cerebral cortex of cognitive normal
older subjects [29]. It was recently estimated that amyloid
plaque could be visualized in 10% of normal elderly
subjects [22]. Whether these normal elderly subjects will
develop in AD has to be systematically investigated [23].
Interestingly, high
11
C-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
group [30].
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 c ortical
11
C-PIB retention in MCI
and AD patients [24, 26, 27]. Pike et al. [27] reported a
strong correlation between episodic memory and
11
C-PIB
binding for MCI patients, while the same correlation was
weak for AD patients [27]. The latter finding might explain
the often found poor correlation between reported clinical
cognitive status and A β 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 [31]. What is
the correlation between amyloid measured in cerebrospinal
fluid (CSF) an d amyloid measured with PET in living AD
patients? In a longitudinal follow-up of CSF biomarkers in
Fig. 1 Cerebral glucose metab-
olism (
18
F-FDG) and
11
C-PIB
amyloid imaging in two AD
patients and one healthy control.
The PET scans show
18
F-FDG
and
11
C-PIB at a saggital sec-
tion. Red indicates high, yellow
medium, blue low
11
C-PIB re-
tention. MMSE Mini-Mental-
State-Examination, ys. years.
Courtesy of Uppsala PET centre/
Imanet and Karolinska Univer-
sity Hospital Huddinge
Fig. 2
11
C-PIB retention in one
MCI converter and one MCI
non-converter compared with an
AD patient and healthy control.
The PET scans show
11
C-PIB
retention at sagittal and longitu-
dinal sections at the level of the
basal ganglia. Red indicates
high, yellow medium, blue low
11
C-PIB retention. Adapted from
[26]
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. [32] observed higher
11
C-PIB retention in
subjects with low levels of CSF A β 142, while individuals
with low PIB retention showed high CSF Aβ 142 levels
[32]. A significant negative correlation has been observed
between cortical PIB retention and CSF Aβ 142, while a
positive correlation was observed between PIB retention
and CSF tau in MCI patients [26]. 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,
11
C-PIB has been used in studies of patients
with frontotemporal dementia (FTD). Rabinovici et al. [33]
investigated 12 FTD patients with
11
C-PIB. Eight of the
12 FTD patients showed negative PIB scans, while four
showed positive scans [33]. Two out of four patients with
positive PIB scans showed FDG images consistent with AD
[33]. Similarly Engler et al. [34] observed negative PIB
scans in eight out of ten FTD patients investigated with
11
C-PIB, while two patients showed high PIB retentions.
The FDG scans were consistent with the hypometabolism
pattern seen in FDT patients [34]. Drzezga et al. [35]
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 [3335]. 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. [36] observed that patients
with Parkinsons disease and normal cognition showed neg-
ative
11
C-PIB scans [36]. 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 [37]. A high
cortical PIB retention has been found in patients with Lewy
body dementia [23]. In vitro binding studies with
11
C-PIB
showed a binding to Aβ plaques and not to the Lewy
bodies in the brain tissue [38]. High
11
C-PIB retention has
also recently been reported in cognitively normal patients
with advanced cerebral amyloid angiopathy (CAA) [39].
The retention of
11
C-PIB in the occipital cortex of CAA
was interestingly enough greater than in AD patients [39].
As far as the authors know, no
11
C-PIB studies have been
performed in vascular dementia.
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 [ 40 ]. Surprisingly, MRI showed re-
duced brain volumes in immunized AD patients compared
to placebo treated [41]. Post-mortem studies of immunized
patients have sh own redu ced Aβ patholo gy w ith un-
changed tau pathology [42, 43]. A reduced in vitro binding
of
3
H-PIB was recently demonstrated in homogenates from
autopsy tissue of immunized AD patient compared to un-
treated subjects [44]. 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 of
11
C-PIB retention during
ongoing treatment allow detection of decrease in insoluble
Aβ load in brain. Mathis et al. [44] suggested that a two-
fold decrease in the testretest variability, thus 1020%,
should be sufficient to detect a reduced Aβ load. Interestingly
enough, a decreased
11
C-PIB retention in such range was
observed after treatment with phenserine, an inhibitor of the
formation of β-APP [45]. Immunization t herapies are
presently ongoing, where
11
C-PIB retention is measured
both prior and during immunization. These studies will
provide further understanding of the underlying mechanisms
for anti-amyloid therapy.
Acknowledgement The financial support of the Swedish Research
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.
Conflict of interest statement There are no conflicts of interest for
the author.
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    • "This was supported by reports of non-demented individuals presenting with significant plaque load upon autopsy (Wischik et al., 2010). Live molecular imaging techniques have since confirmed the presence of plaques in the brains' of cognitively normal individuals in vivo (Nordberg, 2008; Villemagne et al., 2008). These findings suggest that plaques are not necessarily causative of memory deficits, indicating flaws in the Amyloid Cascade Hypothesis. "
    Article · Feb 2014
    • "The pattern of the trends observed, however, resembles the pattern typically observed in patients with AD in positron emission tomography (PET) studies (Minoshima et al., 1997; Mosconi et al., 2007 Mosconi et al., , 2008 Mosconi, 2005) and in other fMRI studies (Greicius et al., 2004; Rombouts et al., 2009; Sorg et al., 2007) where a typical pattern of progress, starting with pathology in the temporomesial cortex with further spread through the cingulate cortex, parietal lobes, and later on, the frontal lobes was described. Furthermore, the regions with diminished activity within the DMN are the same as those identified with high amyloid load in AD patients by neuropathology and neuroimaging studies (Braak and Braak, 1991; Buckner et al., 2005; Nordberg, 2004 Nordberg, , 2008). Despite these factors, simple VOI measurements of activity within the DMN in ICA maps performed poorly as a diagnostic tool (sensitivity 53.3%, specificity 71.4% for activity within the DMN in the anterior cingulate), owing to the high variability of values in different subjects. "
    [Show abstract] [Hide abstract] ABSTRACT: Functional magnetic resonance imaging (fMRI) of default mode network (DMN) brain activity during resting is recently gaining attention as a potential noninvasive biomarker to diagnose incipient Alzheimer's disease. The aim of this study was to determine which method of data processing provides highest diagnostic power and to define metrics to further optimize the diagnostic value. fMRI was acquired in 21 healthy subjects, 17 subjects with mild cognitive impairment and 15 patients with Alzheimer's disease (AD) and data evaluated both with volumes of interest (VOI)-based signal time course evaluations and independent component analyses (ICA). The first approach determines the amount of DMN region interconnectivity (as expressed with correlation coefficients); the second method determines the magnitude of DMN coactivation. Apolipoprotein E (ApoE) genotyping was available in 41 of the subjects examined. Diagnostic power (expressed as accuracy) of data of a single DMN region in independent component analyses was 64%, that of a single correlation of time courses between 2 DMN regions was 71%, respectively. With multivariate analyses combining both methods of analysis and data from various regions, accuracy could be increased to 97% (sensitivity 100%, specificity 95%). In nondemented subjects, no significant differences in activity within DMN could be detected comparing ApoE ε4 allele carriers and ApoE ε4 allele noncarriers. However, there were some indications that fMRI might yield useful information given a larger sample. Time course correlation analyses seem to outperform independent component analyses in the identification of patients with Alzheimer's disease. However, multivariate analyses combining both methods of analysis by considering the activity of various parts of the DMN as well as the interconnectivity between these regions are required to achieve optimal and clinically acceptable diagnostic power.
    Full-text · Article · Mar 2012
    • "The pattern of the trends observed, however, resembles the pattern typically observed in patients with AD in positron emission tomography (PET) studies (Minoshima et al., 1997; Mosconi et al., 2007 Mosconi et al., , 2008 Mosconi, 2005) and in other fMRI studies (Greicius et al., 2004; Rombouts et al., 2009; Sorg et al., 2007) where a typical pattern of progress, starting with pathology in the temporomesial cortex with further spread through the cingulate cortex, parietal lobes, and later on, the frontal lobes was described. Furthermore, the regions with diminished activity within the DMN are the same as those identified with high amyloid load in AD patients by neuropathology and neuroimaging studies (Braak and Braak, 1991; Buckner et al., 2005; Nordberg, 2004 Nordberg, , 2008). Despite these factors, simple VOI measurements of activity within the DMN in ICA maps performed poorly as a diagnostic tool (sensitivity 53.3%, specificity 71.4% for activity within the DMN in the anterior cingulate), owing to the high variability of values in different subjects. "
    Article · Jan 2012 · Neurobiology of aging
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