The Pittsburgh Compound-B (PIB) ligand is one of the most promising diagnostic tools for Alzheimer disease (AD). But even as PIB-based positron emission tomography (PET) in humans has blossomed around the globe, it has also been plagued by a downside. PIB-PET imaging has been unable to distinguish normal mouse brains from those laden with amyloid plaques—something researchers and drug developers would clearly like. In the October 10 Journal of Neuroscience, researchers led by Makoto Higuchi at the National Institute of Radiological Sciences, Chiba, Japan, report solving that dilemma. The researchers have generated a carbon 11 form of PIB with much higher radioactivity than has been achieved before. With this super hot PIB, they not only managed to image amyloid plaques in transgenic mice, but track amyloid reduction in response to anti-Aβ treatment as well. The study has drawn praise from Bill Klunk and Chet Mathis at the University of Pittsburgh, who developed PIB (see comment below).

Klunk and colleagues had suggested that the inability to detect mouse plaques with PIB is due to a dearth of high-affinity PIB binding sites in mouse amyloid (Klunk et al., 2005; see ARF related news story). One potential solution to that, Klunk told ARF via e-mail, is to use PIB with higher specific radioactivity. The hotter the molecule, the fewer of them are needed to get the same radioactivity, and fewer molecules means less background and better sensitivity. This is just the approach taken by the Japanese researchers. First author Jun Maeda and colleagues synthesized C-11 PIB that is around an order of magnitude hotter than that used in previous studies of transgenic mice.

Using the hotter tracer, Maeda and colleagues were able to detect amyloid plaques in APP23 mice by PET. In keeping with the known pathology in this model, they found that the PIB signal was detectable by 17 months, and grew more intense as the animals aged (up to 29 months). They also were able to use PIB to monitor a passive immunization protocol. One and 2 weeks after injecting anti-Aβ antibodies into one side of the animals’ hippocampi, the researchers detected a decrease in PIB retention in the same side. They also detected a concomitant increase in signal from a PET ligand, [18F]-FE-DAA1106, that binds to the peripheral benzodiazepine receptor, a marker of glial cell activation. Wild-type mice retained little [18F]-FE-DAA1106 after passive immunization, suggesting the glial response was due to the presence of amyloid.

The difficulty in using PIB in mice suggests that there may be something qualitatively different about mouse and human amyloid deposits, but what? That’s a key question, according to Klunk. “Per unit volume, mice have as many or more plaques than human AD, and per mg brain, Tg mice have 10-20 times more insoluble Aβ than in human AD brain. But, each mole of that mouse Aβ only contains 1/500th the number of PiB binding sites,” Klunk wrote to ARF. To find out what that qualitative difference between human and mouse amyloid might be, Maeda and colleagues measured PIB binding to a variety of Aβ subtypes. They found that, in both human and mouse brain, PIB retention correlated with levels of an N-terminal, pyroglutamate derivative of Aβ (see ARF related news story) and that this AβN3-pyroglutamate had much higher affinity for PIB in vitro. Because the formation of AβN3-pyroglutamate is a slow enzymatic process, the researchers suggest that accelerated production of Aβ in transgenic mice does not promote development of “AD-like” plaques, which are enriched in the pyroglutamate derivative.

The Pacific Rim has produced other recent advances on PIB. Researchers led by Christopher Rowe at the Centre for PET, Austin Health, Heidelberg, Australia, report in the October 10 Brain online that the ligand labels amyloid deposits in elderly people who, to all intents and purposes, appeared cognitively normal. On closer inspection, it turned out that those people have poor episodic memory. The finding supports the idea that amyloid deposition occurs long before any clinical signs of AD, but more importantly, perhaps, suggests that PIB binding portends full-blown AD.

First author Kerryn Pike and colleagues (including Klunk), measured PIB signals in 31 AD patients, 33 patients with mild cognitive impairment (MCI), and 32 healthy older adults (mean age 71.6 years, MMSE score 29.2 +/- 0.9). Not surprisingly, they found increased cortical PIB binding in 97 and 61 percent of AD and MCI patients, respectively. But they also found that 22 percent of the controls had increased PIB binding. Pike and colleagues found that those PIB-positive controls performed worse in a test of episodic memory than PIB-negative controls. They also found a correlation between episodic memory and PIB binding. This correlation was much stronger in the MCI and control groups.

Because memory loss is one of the earliest and most predictive changes associated with AD, the authors suggest that Aβ gets deposited early in the pathological process. This is compatible with postmortem data showing that people who reported memory complaints but were clinically non-AD had some AD pathology on autopsy (see ARF related news story).

Last but not least, another Australian team, this one by Victor Villemagne at the University of Melbourne, report in the September 26 Journal of Neuroscience that though PIB does bind α-synuclein fibrils, PIB-PET signals in dementia with Lewy bodies (DLB) are due almost entirely to amyloid plaques. The finding could have diagnostic ramifications.

First author Michelle Fodero-Tavoletti and colleagues compared binding of tritiated PIB with synthetic α-synuclein fibrils and synthetic Aβ fibrils. They found that both fibrils had high- and low-affinity binding sites for PIB, but the high-affinity Aβ site bound more than 10 times tighter to the ligand than α-synuclein’s high-affinity site. Next, the researchers measured PIB binding in amyloid-positive and amyloid-negative tissue taken postmortem from DLB patients. They found that while PIB bound tightly to the amyloid-positive tissue, it failed to bind to amyloid-negative samples.

The finding indicates that PIB can be used to detect purely Aβ amyloid, and that signals will not be complicated by contributions from α-synuclein or tau aggregates (previous work showed that PIB does not significantly bind to neurofibrillary tangles, see Klunk et al., 2003). Of course, the downside, as the authors point out, is that because of the overlapping pathology between DLB and AD, PIB will be incapable of differentiating between the two without additional clinical diagnosis.—Tom Fagan


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Comments on News and Primary Papers

  1. This paper raises the interesting question of the relationship between PIB PET and the Aβ oligomers that have been shown to affect synapses and behavior.

    View all comments by Paul Coleman
  2. Most scientists have had the experience of reading a manuscript and thinking, “Wow! I wish I had written that.” The paper by Maeda et al. contains three separate studies, all of which generated that response in me. It is, in my mind, the most impressive study of amyloid imaging agents in animals yet published.

    The first part of the study by Maeda et al. involves the vexing transgenic (Tg) mouse problem reported by our lab (Klunk et al., 2005) and that of Toyama et al. (Toyama et al., 2005). The problem lies in the fact that although the amyloid imaging agent, Pittsburgh Compound-B (PiB), shows high signal-to-noise in human brain areas known to contain high loads of amyloid-β (Aβ) plaques, almost no such signal could be detected in microPET studies using transgenic (Tg) mouse models of amyloid deposition at an age when the Aβ plaque load in these mice is several-fold higher than anything seen in human brain. We had suggested that this was based on the fact that, like synthetic Aβ aggregated in vitro, Tg mouse brain contained 1/500th the number of PiB binding sites per mole of Aβ compared to homogenates of human AD brain (Klunk et al., 2005). That is, there is something physically different about Aβ fibrils aggregated in the test tube (over days) or in Tg mouse brain (over months) compared to that aggregated in human brain (over a decade). We found that the small number of PiB binding sites in Tg mouse brain did not yield a sufficient signal-to-noise level to allow detection using the typical [11C]PiB preparations we employ for animal studies (specific activity of ~20-30 GBq/μmol).

    Maeda et al. succeeded in reliably detecting a microPET PiB signal in 20-22-month-old APP23 mice, by taking great pains to prepare and employ [11C]PiB with 10-fold higher specific activity (~300 GBq/μmol). They also showed the expected age-related increase in PiB retention from 17 to 29 months in these mice. In retrospect, this makes perfect sense, and a quick check of predicted binding signal as a function of tracer-specific activity calculated with standard receptor binding equations shows that increasing the specific activity of PiB from 30 to 300 GBq/μmol would result in the signal-to-noise ratio in Tg mouse brain microPET studies going from basically undetectable (~1.0-1.1) up to the ~1.5 range reported by Maeda and colleagues.

    The natural question, then, becomes, if we can improve amyloid imaging in mice by increasing the specific activity of [11C]PiB, can we obtain similar gains in human PiB PET? The answer to this—using the same equations mentioned above—is “no” if there is significant amyloid present. That is, with the amount of amyloid we currently detect in AD patients, “amyloid-positive” MCI patients and even “amyloid-positive” controls, [11C]PiB binding is already maximal at specific activities lower than 30 GBq/μmol. Further increases in specific activity would not be predicted to show significant increases in the signal-to-noise ratio.

    However, what about in those brains in which the amyloid load is at or just below current detection limits? In these cases, increasing the specific activity could increase the sensitivity and decrease the detection threshold for amyloid. This has several implications. It is difficult to routinely produce [11C]PiB with a specific activity of 300 GBq/μmol for human studies. In contrast, fluorine-18-labeled tracers can be produced at this level of specific activity more easily in most cases. Thus, in addition to making amyloid imaging more widely available, the development of an F-18 analogue of PiB may carry additional importance. One such F-18 PiB analogue has already shown promise in preliminary human studies (Mathis et al., 2007). The present observation by Maeda et al. could prove extremely important, and could have stood alone to make an excellent contribution to the literature.

    The second part of the study by Maeda et al. is equally able to stand alone as an important contribution to the field. In this series of experiments, Maeda et al. show that their PiB microPET protocol can be used to follow the removal of amyloid in vivo over the course of 2 weeks after intrahippocampal injection of an anti-Aβ antibody. In addition, they use the activated microglial marker [18F]FE-DAA1106 to show a corresponding increase in glial markers/neuroinflammation around the injection site. They show that this microglial response is dependent on the presence of amyloid since the injection of the anti-Aβ antibody into wild-type mice did not result in increased [18F]FE-DAA1106 retention. This series of experiments certainly has implications for the monitoring of human immunotherapy trials and actually mirrors protocols being contemplated by several pharmaceutical companies.

    The third set of experiments in the Maeda et al. paper addresses the closely related issues of why PiB binds so poorly to Tg mouse brain and what is the molecular substrate of PiB binding in human brain. The authors present evidence to suggest that C-terminal heterogeneity is not a particularly important determinant of PiB binding. PiB binds to both Aβ40 and Aβ42 plaques and probably to plaques with other C-termini as well. In exploring the contribution of N-terminal heterogeneity to PiB binding, they discovered that the levels of AβN3-pyroglutamate or “N3(pE)” were much more closely tied to PiB binding than were levels of Aβ isoforms starting at the aspartate at position-1 or “N1D.” In vitro experiments using aggregated, synthetic AβN1D-42 and AβN3(pE)-42 showed that the N3(pE) form bound PiB ~fivefold better than the N1D form. However, this experiment cannot fully explain the contribution of AβN3(pE) because this form of synthetic fibril still has less than 1/100th the number of PiB binding sites per mole of Aβ than that observed per mole of Aβ in human brain (Klunk et al., 2005). This is likely due to the artificial aggregation conditions affecting the final fibril structure. Despite this, AβN3(pE) is still an attractive candidate for an important PiB binding substrate in vivo.

    Maeda et al. point out that AβN3(pE) isoforms are abundant in AD brain. Previous reports have suggested AβN3(pE)42 may account for >25 percent of the total Aβ in human plaques and appears to aggregate more readily and produce greater toxicity than N1D forms of Aβ (Saido et al., 1995; Harigaya et al., 2000; Russo et al., 2002; Guntert et al., 2006). This finding may explain a large part of the low PiB binding in Tg mouse brain, because Tg mouse brain contains very little AβN3(pE) (Guntert et al., 2006). Saido et al. have previously stressed the importance of the AβN3(pE) isoform by noting that plaques containing AβN3(pE) are “present in equivalent or greater densities than those composed of standard Aβ…” and “because deposition of the former species [i.e., AβN3(pE)] appears to precede deposition of the latter [i.e., AβN1D], as confirmed with specimens from Down syndrome patients, the processes involved in AβN3(pE) production and retention may play an early and critical role in senile plaque formation” (Saido et al., 1995). Thus, the N3(pE) form of Aβ may play a significant role in the pathogenesis of AD and be a prime binding site for PiB. This preliminary finding will require further study before its full significance can be determined, but if true, this could imply that PiB has some specificity for an Aβ isoform that has special pathological relevance.

    In summary, the paper by Maeda et al. represents a very important set of three contributions to the literature of AD and amyloid imaging:

    1. this paper shows that amyloid deposition in Tg mice can be detected in vivo by using high specific activity PiB, and this may have implications for decreasing the detection threshold in humans;

    2. this paper shows amyloid imaging can detect the therapeutic effect of anti-amyloid immunotherapy and the reciprocal nature of neuroinflammation associated with amyloid removal; and

    3. the N3(pE) isoform of Aβ may have special pathological significance; relative differences in the abundance of AβN3(pE) in human and Tg mouse brain may explain some of the poor PiB binding in Tg mice; and N3(pE) may be a specific target of PiB in vivo.

    View all comments by William Klunk
  3. Besides the interesting issues already discussed at length and in depth, the data bring to mind the problem of why N-terminally directed antibodies—and particularly those against the EFRH epitope as demonstrated by Beka Solomon and coworkers—are most efficient in passive vaccination. The explanation is that the N-terminal is "dangling" outside the amyloid fibers and thereby accessible.

    Then I wonder about antibodies that react about two orders of magnitude less well with pE-Aβ (i.e., Aβ3-42 peptide, starting with pyroglutamyl at residue Glu-3), than with wt-Aβ (Gardberg et al., 2007). Are these acting not or less well on pE-Aβ in human brain and thereby explaining differences in efficacy of passive vaccination in mouse models and human patients?


    . Molecular basis for passive immunotherapy of Alzheimer's disease. Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15659-64. PubMed.

  4. This report provides first evidence for a direct correlation of PiB (Pittsburgh Compound-B) retention analyzed by PET imaging in living APP transgenic mice. This is a very important paper, because it describes the temporal and spatial distribution of plaque deposition after intravenous injection of PiB, a compound applied in Alzheimer disease (AD) patients. The authors were able to show that passive immunization against human Aβ peptide reduced PiB retention, correlating well with an increase in glia radiotracer signaling. It is at present, however, unclear, whether the observed increase in gliosis is directly involved in Aβ phagocytosis and clearance. In any case, the passive immunization clearly shows that it has an effect on PiB retention and amyloidosis in vivo. Of special interest, the PiB binding best correlated with plaques positive for N-terminally truncated and modified Aβ, Aβ-N3-pyroglutamate (AβN3[pE]) in AD brain and three different APP transgenic mouse models.

    The existence of N-terminal truncated or “ragged” variants of Aβ has been known for some time (see, e.g., Masters et al., 1985; Roher et al., 1993). The seminal paper by Takaomi Saido and coworkers (Saido et al., 1995) showed for the first time that Aβ3(pE) represents a dominant fraction of Aβ peptides in AD brain. N-terminal deletions in general enhance aggregation of β-amyloid peptides in vitro (Pike et al., 1995). Aβ3(pE) has a higher aggregation propensity (He and Barrow, 1999; Schilling et al., 2006), and stability (Kuo et al., 1998), and shows an increased toxicity compared to full-length Aβ (Russo et al., 2002). Schilling et al. have demonstrated that pyroglutamate-modified peptides display an up to 250-fold acceleration rate in the initial formation of Aβ aggregates (Schilling et al., 2006). Inhibition of enzymatic QC activity leads to significantly reduced Aβ3(pE) formation in vitro (Cynis et al., 2006).

    Maeda et al. have demonstrated that APP transgenic mouse models exhibit Aβ3(pE) levels to a different degree. Previously it has been shown that APP/PS1KI mice generate very high levels of Aβ3(pE) studied by 2D-gel electrophoresis (Casas et al., 2004) and immunostaining (Wirths et al., 2007a). Interestingly, this model elicits 50 percent CA1 neuron loss, axonopathy in brain and spinal cord (Wirths et al., 2007a), correlating well with the observed robust working memory and motor impairment (Wirths et al., 2007b).

    Overall, Maeda et al. have provided striking evidence that PiB retention is a consequence of Aβ3(pE) plaque deposition. This supports the notion that Aβ3(pE) is a major player in amyloid-driven pathology, which in my view deserves more attention in the future.

    View all comments by Thomas Bayer
  5. This is a highly interesting study on specific binding behavior of 6-OH-BTA-1, aka Pittsburgh compound B (PIB). Modern molecular imaging tracers such as PIB open the possibility to characterize neurodegenerative disorders on the basis of underlying pathology rather than on clinical symptoms alone. Labeled with the positron emitter C-11, PIB has been recently established as a most successful tracer for positron emission tomography (PET) imaging of cerebral β amlyoid pathology, in particular amyloid plaques in vivo. Amyloid plaques are considered a hallmark pathology in Alzheimer disease and, correspondingly, in a number of studies significantly higher cerebral binding of [11C]PIB has been demonstrated in the brain of AD patients, compared to healthy controls (1-3).

    Apart from amyloid plaques, many different types of pathologic protein aggregations in the brain have been associated with neurodegenerative disorders. Thus, to be valuable for scientific and clinical application, a tracer detecting cerebral molecular pathology should be as specific as possible. For example, in AD, besides amyloid deposits, neurofibrillary tangles (NFT) constituted of tau protein represent another characteristic pathologic entity. The binding of PIB to NFTs has been previously evaluated and is currently regarded to be negligible (4,5). This corresponds well to results of studies that were able to demonstrate a lack of binding of [11C]PIB in frontotemporal dementia, which is primarily characterized by tau and/or ubiquitin pathology and underlines the potential value of this tracer for differential diagnosis of dementia (3) .

    So far, binding of PIB to Lewy bodies has not been systematically addressed. The term “Lewy bodies” describes intracellular aggregations mainly of the α-synuclein peptide in cerebral neurons, named according to Friedrich H. Lewy (a neurologist who also worked with Alois Alzheimer in Munich) (6). These Lewy bodies have originally been associated with Parkinson disease, where they can be found consistently in the brain stem but also in other brain regions. Dementia with Lewy bodies (DLB) probably represents the third most frequent causality of dementia (following AD and vascular dementia) and may account for up to 20 percent of all cases of dementia (but not 20 percent of all elderly patients as accidentally mentioned in the current manuscript) (7). DLB is characterized by the presence of Lewy bodies throughout the neocortex and the limbic system. DLB shares many characteristics (regarding clinical, neuropathological, and imaging findings) with the so-called Parkinson-associated dementia, or PDD, which patients with Parkinson disease may eventually develop in later disease stages. Thus, recently it has been speculated that both disorders may represent different expressions of a disease spectrum. There is also considerable overlap of pathologies between AD and DLB. In many DLB cases, amyloid plaque deposits can be detected, and it has even been discussed that clinical diagnosis of DLB is associated with the presence of Alzheimer pathology rather than on Lewy body distribution (8). It appears that both cases with (DLB/AD) and without amyloid pathology (pure DLB) occur. Also, in AD the presence of Lewy bodies has been described. Nevertheless, AD and DLB are regarded nosologically differently (9).

    Increasing evidence is collected indicating that various pathologies may be present in different types of neurodegeneration, and only differ in their extent and localization. Regarding this confusing overlap of pathologies, it appears particularly relevant to have suitable specific imaging tools at hand to assess the contribution of single abnormalities to different disorders in vivo. Some of the authors of the current study also contributed to a recent work which has demonstrated relevant [11C]PIB-retention in a group of patients with DLB in similar extent and pattern as described in AD (1). These results strongly suggested that one evaluate if Lewy body pathology eventually contributes to the binding of [11C]PIB.

    In the current study, the authors applied modern in-vitro measurement techniques to assess the binding of PIB to α-synuclein-containing Lewy bodies in comparison to binding to β amyloid aggregation pathology. They were able to demonstrate that PIB binds to α-synuclein fibrils only with low affinity and that any contribution of Lewy bodies to the [11C]PIB signal would be negligible. This underlines the high specificity of [11C]PIB for amyloid plaque pathology. Furthermore, it indicates that the detected binding of [11C]PIB in Lewy body patients is actually due to amyloid pathology and not to Lewy bodies. In light of these results, it is plausible that a recent study was able to demonstrate a lack of significant [11C]PIB retention in a small group of patients with cognitively intact Parkinson disease in early stages, corresponding to the idea that Lewy bodies but no amyloid plaques may be present in these patients (10).

    A recent different study demonstrated that PIB may have limited specificity regarding the detection of classical amyloid plaques but appears to bind to Aβ peptide related pathology in general (such as diffuse plaques and cerebrovascular amyloid pathology) (5). However, the current study underlines that the tracer [11C]PIB may indeed open the possibility to specifically assess the extent to which amyloid pathology contributes to different clinical entities, and it may help to identify subtypes of neurodegeneration (e.g., DLB with/without amyloid plaque pathology) which may be of interest for classification, prognosis, and therapy selection in patients suffering from neurodegenerative disorders.

    The significance of the current study is only limited by a few methodological restrictions: results from in-vitro studies never allow absolute conclusions on the behavior of a PET tracer in vivo. Many confounding variables such as blood-brain barrier permeability, metabolism, and reaction of the tracer in the living tissue potentially affect in vivo tracer kinetics. These questions should be a matter of future studies and can only be addressed with the help of suitable animal models and postmortem studies.

    See also:
    Forster E, Lewy FH. Paralysis agitans. Berlin: Springer Verlag 1912;Pathologische Anatomie. Handbuch der Neurologie (edited by M. Lewandowsky):920-933.

    View all comments by Alexander Drzezga
  6. The elegant report by Maeda and colleagues [1] shows that in vivo amyloid imaging with 11C-PIB in transgenic (Tg) mice is possible. After the initial in vivo studies with multiphoton microscopy showing binding of PIB to plaques in Tg mice [2], it was reported that 11C-PIB did not significantly bind to aggregated Aβ in Tg mice [3].

    The key to this groundbreaking report is the ability to inject mice with very high specific activity (SA) 11C-PIB. As Bill Klunk points out, what seems critical is not the amount of Aβ or the number of plaques but rather the amount of available binding sites, and their relative affinity, reflected in image contrast and the amount of non-specific binding. The 11C-PIB SA reported by Maeda were in excess of 7.9 Ci/μmol (or 5.4 Ci/μmol at the time of injection), much higher than the ones reported by Toyama (1.1-3.2 Ci/μmol) [3], or Klunk (>1 Ci/μmol) [4]. Not too many PET centers can achieve such high SA. To our knowledge, the only other group that has been able to show quantifiable images of 11C-PIB in Tg mice is the group led by Alexander Drzezga in Munich [5].

    On the other hand, a quick review of the PIB literature reveals that SA does not seem to be that crucial in 11C-PIB PET studies in Alzheimer patients or age-matched controls, with reported SA ranging from 0.68 Ci/μmol [6] to 4.3-4.5 Ci/μmol [7,8]. Nevertheless, a more detailed evaluation of the effects of high and low SA on 11C-PIB PET studies, as Maeda and colleagues suggest, may be warranted. The use of high SA 11C-PIB might also help better characterize Aβ deposition in asymptomatic control subjects [7,9].

    This study also sheds light into the kind of Aβ species bound by 11C-PIB in senile plaques, showing that it preferably binds to the N-terminal truncated Aβ species, more specifically the one truncated at position 3 (Aβ3[pE]). This is relevant because the accelerated formation of plaques seems to be associated with this Aβ3(pE)1-42(43) species. [10,11] The present study shows that 11C-PIB binding colocalized with Aβ3(pE)1-42(43), displaying a fivefold higher affinity than for Aβ1-42(43).

    Maeda and colleagues also evaluated the Aβ deposition in the mouse brain over time but, more importantly, the effect of intrahippocampal administration of passive anti-Aβ immunization, assessed by both 11C-PIB and 18F-fluoroethyl-DAA1106, a microglial activation radioligand, demonstrating the usefulness of this approach to evaluate and screen the effects of anti-Aβ treatment over time.

    This report highlights the need of using high SA 11C-PIB for microPET mice studies. On the other hand, these requirements might not be achievable in every PET center, precluding the application of this important approach to investigate the spatial and temporal pattern of Aβ deposition and monitor the effectiveness of novel anti-Aβ therapy.

    View all comments by Victor L. Villemagne


News Citations

  1. Translational Biomarkers in Alzheimer Disease Research, Part 4
  2. Salzburg: Aβ’s N-terminal Shenanigans
  3. Subtle Forgetfulness in Cognitively Normal Elderly—A Foreshadowing of AD?

Paper Citations

  1. . Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-beta in Alzheimer's disease brain but not in transgenic mouse brain. J Neurosci. 2005 Nov 16;25(46):10598-606. PubMed.
  2. . The binding of 2-(4'-methylaminophenyl)benzothiazole to postmortem brain homogenates is dominated by the amyloid component. J Neurosci. 2003 Mar 15;23(6):2086-92. PubMed.

Other Citations

  1. APP23

Further Reading


  1. . In vivo amyloid imaging with PET in frontotemporal dementia. Eur J Nucl Med Mol Imaging. 2008 Jan;35(1):100-6. PubMed.
  2. . [(11)C]-PIB imaging in patients with Parkinson's disease: preliminary results. Parkinsonism Relat Disord. 2008;14(4):345-7. PubMed.

Primary Papers

  1. . Longitudinal, quantitative assessment of amyloid, neuroinflammation, and anti-amyloid treatment in a living mouse model of Alzheimer's disease enabled by positron emission tomography. J Neurosci. 2007 Oct 10;27(41):10957-68. PubMed.
  2. . Beta-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer's disease. Brain. 2007 Nov;130(Pt 11):2837-44. PubMed.
  3. . In vitro characterization of Pittsburgh compound-B binding to Lewy bodies. J Neurosci. 2007 Sep 26;27(39):10365-71. PubMed.