The ability to visualize fibrillar Aβ deposits in the brains of living people has been hailed as a breakthrough for Alzheimer’s disease research and differential diagnosis. Now, as the first of a suite of positron emission tomography (PET) β amyloid imaging agents stands poised to receive a ruling from the Food and Drug Administration, seven scientists are questioning the validity of this technology. Led by Abass Alavi, a nuclear medicine professor at the University of Pennsylvania, Philadelphia, they penned an editorial that appeared online October 19, 2011, in the European Journal of Nuclear Medicine and Molecular Imaging. In it, they dispute the ability of any amyloid imaging agents, including the original Pittsburgh Compound B (PIB), to accurately label Aβ deposits. Joint first authors Mateen Moghbel and Babak Saboury, also at UPenn, and colleagues claim that none of the newer fluorine-18-labeled tracers deserve regulatory approval. This editorial has become the most downloaded article in the journal’s recent history, with around 1,200 downloads in the past 90 days. Based on it, the Washington-based consumer advocacy group Public Citizen has sent a letter to the FDA, urging the agency to reject Eli Lilly and Company’s pending application for florbetapir (see ARF related news story).

Scientists in the AD imaging field have fired back. In an 11-page rebuttal published in the same journal on January 5, 2012, they collectively challenged the claims made by Alavi and colleagues, detailing neuropathological evidence and basic PET physics that substantiate the reliability of amyloid imaging technology. Their editorial, signed by 24 leading AD and amyloid PET experts from around the world, is freely downloadable and will run in print in the February issue. It has racked up more than 1,000 downloads since it appeared. First author Victor Villemagne at Austin Health, Heidelberg, Australia, and colleagues in Japan, the U.S., and Europe argue that Moghbel et al. misunderstand the current state of knowledge in the AD field, and base their conclusions on misleading and inaccurate data. Villemagne et al. stress the importance of amyloid imaging for shedding light on AD processes, as it gives researchers a glimpse into the progression of the underlying pathology. The authors of the rebuttal editorial disclose that many of them consult for companies developing amyloid tracers, or have received research grant support from these companies. The authors of Moghbel et al. do not disclose conflicts.

Why the push for 18F-labeled tracers? Although carbon-11-labeled Pittsburgh Compound B (PIB) is the current gold standard for β amyloid imaging, its 20-minute half-life limits its use to state-of-the-art facilities that can synthesize the compound on site. As an alternative, several companies are developing 18F-labeled compounds, which have a 110-minute half-life and are expected to open up the use of the technology to many more centers. Florbetapir (trade name Amyvid®), first developed by Avid Radiopharmaceuticals, is the furthest along; others in the pipeline include florbetaben at Bayer Healthcare, flutemetamol at GE Healthcare (see ARF related news story and ARF update), and AZD4694 by AstraZeneca (see ARF related news story).

Lilly reported Phase 3 results for florbetapir (see ARF related news story), but the FDA initially denied approval, citing inter-reader variability in how scans are interpreted (see ARF related news story). Public Citizen had also picked up this issue in a previous letter to the FDA on February 21, 2011. Since then, Avid has developed and tested a reader training program as requested by the agency. It was presented at the Human Amyloid Imaging conference held 12-13 January 2012 in Miami, Florida. The agency’s ruling on the resubmitted application is expected this spring.

Alavi, who is a nuclear medicine physician, states technical and philosophical objections. In an interview with ARF, Alavi said that the AD community is going down the wrong path by developing β amyloid imaging agents. Alavi claimed that the physics of imaging precludes this technology from working, particularly in cases of mild cognitive impairment (MCI) and early AD. Alavi noted he is preparing another editorial in response to Villemagne et al., which he intends to write in collaboration with physicists. He questioned whether current agents bind to β amyloid in vivo, suggesting they are detecting non-specific proteins. Furthermore, Alavi told ARF he fears that the widespread use of β amyloid imaging would ultimately lead to clinical trials in presymptomatic people with amyloid deposits. He believes such trials would not be in patients’ best interests due to potential drug side effects.

In response to a question from a reporter about what the field would do without Aβ imaging, Alavi said, “If I were the community, I would stick with fluorodeoxyglucose (FDG) PET.” FDG PET measures glucose metabolism in the brain; Alavi was among the pioneers of its use in AD patients in the 1970s. FDG PET is a tool widely used in AD research as an indirect measure of synaptic function. There is broad consensus among researchers in the AD field that it is not specific to the AD pathogenic process, whereas amyloid PET is being developed to visualize and quantify one of the two hallmark pathologies of Alzheimer’s disease. Alavi coauthored a Journal of Nuclear Medicine meeting abstract, which reported that florbetapir has superior sensitivity and specificity to FDG (around 95 percent for florbetapir, compared to high 80s for FDG) for distinguishing AD patients from controls.

Most of Alavi’s publications are in the areas of cancer research, infection, the effects of aging on peripheral systems, or studies of brain activity using FDG PET. Most of the coauthors are radiologists and faculty at UPenn. Curiously, coauthor Bengt Långström at Uppsala University, Sweden, is also a coauthor on some 20 papers on amyloid PET, beginning with the first reports on the technology in 2003 and 2004 (see also ARF related news story), and continuing with three papers to date in 2012. From 2002 up until three years ago, Långström was Chief Scientific Officer of GE Healthcare/Imanet, which develops flutemetamol. When contacted by ARF, Långström said he joined the editorial because he believes scientific issues regarding how β amyloid tracers work need to be resolved before taking the technology to the clinic. “I do hope that this discussion will bring the issue back to science, and the business [side] will have to wait,” he wrote to ARF (see full Q&A below).

Two of the 18F-labeled tracers, florbetapir and florbetaben, were originally developed by Hank Kung, a chemist in the Department of Radiology at UPenn. Kung chairs Avid’s scientific advisory board. In an interview with Alzforum, Kung said that Alavi is “motivated by professional jealousy. It’s unfortunate that we are being distracted by this.” Kung contends that Alavi’s objections to β amyloid imaging technology are not scientifically sound. He noted that the reasoning of Moghbel et al. would apply to any nuclear medicine procedure, many of which are used routinely in clinics around the world with great success. “What they are essentially saying is that all nuclear medicine procedures are not valid,” Kung said.

Alavi said he is concerned that β amyloid plaques cannot be imaged, based on physics principles. In their editorial, Moghbel et al. emphasize that PET gives poor spatial resolution, on the order of 5 mm, making it useless for visualizing amyloid plaques with an average size of 50 μM. Villemagne et al. counter that this claim is based on faulty logic. PET imaging of all sorts reflects the average signal from a brain region. It does not try to resolve small structures, they note. For example, FDG PET is based on cell uptake proportional to its glucose utilization, and the involved enzymes are smaller than plaques. Receptor imaging with PET is predicated on the tracer attaching to structures several orders of magnitude smaller than plaques. In general, the PET signal is derived from the tissue concentration of binding sites, not the size of the tracer’s target structure. In the case of amyloid PET, “Millions of fibrillar Aβ deposits produce a signal that is easily detectable in Aβ-laden parts of gray matter,” Villemagne et al. write.

Moghbel et al. further charge that the β amyloid burden in MCI would be too low to be detected. Their editorial notes that Aβ load in late-stage AD has been shown in histopathology slices to be around 6 percent of total brain area (see Clark et al., 2011; Bussière et al., 2002). The authors speculate that the load would be about 60 times less in people with MCI. No references are cited for this number; in answer to a question from Alzforum, Alavi said he heard the figure of 0.1 percent load in MCI in conversations with neuropathologists.

Villemagne et al. write that this 0.1 percent figure is a “surprising and unsupported assumption.” They note that a milestone study of 79 postmortem brains, using quantitative enzyme-linked immunosorbent assays (ELISA) to measure Aβ, found that people who die at the MCI stage have about half the typical amyloid burden of people with AD (see ARF related news story on Näslund et al., 2000). Villemagne et al. point to a recent paper coauthored by Bengt Långström that demonstrated ample binding sites available for PIB in postmortem brain tissue. The paper concludes, “This radiotracer is, therefore, very suitable in the early diagnosis of AD” (see Svedberg et al., 2009).

Moghbel et al. draw attention to the finding that the brain’s white matter retains β amyloid tracers even though it contains no Aβ plaques. This nonspecific signal may spill over into nearby gray matter and overwhelm the Aβ signal, the authors speculate. In answer, Villemagne et al. acknowledge that the nonspecific signal from white matter is a limitation of all β amyloid radiotracers, probably due to a slower rate of clearance from white matter. However, they note, this nonspecific binding does not differ between AD patients and controls. Villemagne et al. charge that Figure 2 of Moghbel et al. is misleading. It uses data from FDG PET images of lung tissue (see Hickeson et al., 2002), where differences in uptake by various tissue types are huge, to represent the differential tracer uptake by white and gray matter of the brain. In a typical brain containing amyloid, the signal intensity from gray matter is threefold that from white matter, Villemagne et al. write, and white matter spillover does not interfere with the ability to read the gray matter signal.

Alavi and colleagues cast doubt on the specificity of radiotracer binding. As evidence, they point out that all existing β amyloid tracers produce a high signal from the frontal lobes, claiming that this contradicts neuropathology studies showing that Aβ deposits are highest in the occipital and temporal lobes, and lowest in the frontal lobes (see Arnold et al., 1991; Braak and Braak, 1997). “Clearly, there is something else that this agent is binding to that is heavily concentrated in the frontal lobes,” Alavi told ARF.

Villemagne et al. respond that the statement about frontal lobes containing little Aβ “is inconsistent with the current state of knowledge regarding the neuropathology of AD.” They write that it is contradicted by numerous more current studies by many of the same authors, which show early, heavy AD deposition in the frontal lobes (e.g., Thal et al., 2002; Arnold et al., 2000, and even the paper by Braak and Braak, 1997 cited by Moghbel et al.). A recent paper describes good correlation between amyloid tracer uptake and Aβ load in the frontal cortex, as determined by histopathology (see ARF related news story on Wolk et al., 2011). In addition, the quantitative study by Näslund et al. reported that frontal lobes, in fact, contain two- to fourfold higher concentrations of Aβ than do other brain regions.

Villemagne et al. point out that different forms of AD show different patterns of tracer retention (see, e.g., ARF related news story on Klunk et al., 2007), which would argue against nonspecific binding. They cite nine neuropathology studies that show strong correlations between quantitative measurements of Aβ and Aβ radiotracer retention. At the January 2012 HAI meeting, four additional studies were presented, all showing the same strong neuropathology correlation. Villemagne et al. conclude, “The functionality, sensitivity, and specificity of Aβ plaque imaging agents has by now been demonstrated in a level of detail and reliability that has not been required or provided for most other imaging tracers clinically used today.”

More globally, Moghbel et al. raise concerns about how β amyloid imaging might be used. They refer to a positive scan in a cognitively healthy person as a “false positive,” and suggest that a high rate of this finding would diminish the value of the technology for diagnosis and clinical practice. Villemagne et al. disagree, noting that this idea reflects a “conceptual misunderstanding.” Mismatches between neuropathology and symptomatic expression of AD do not reflect a problem with the imaging technology, which visualizes pathology, but instead highlight the slow progression of AD, where amyloid deposition is widely thought to precede dementia by about a decade, they write. In support of this, several studies have shown that MCI patients with Aβ deposits are more likely to continue to decline cognitively than are their peers with amyloid-negative scans (see, e.g., Forsberg et al., 2008; Okello et al., 2009). On this issue, too, ongoing longitudinal cohorts in the U.S. and Australia continue to add evidence that MCI patients with brain amyloid have a higher risk of progressing to AD dementia within the next few years.

Amyloid deposition does not equate to a clinical diagnosis, Villemagne et al. stress, nor is it intended to. Instead, it is a tool for increasing the understanding of AD pathology and progression, and could be combined with clinical and fluid biomarkers to improve the diagnosis. In fact, amyloid imaging may clarify some cases of clinically diagnosed Alzheimer’s as not being due to AD but to something else when the patient turns out to have a negative amyloid scan.

“Aβ imaging has been repeatedly held up as one of the major successes of the past decade in the fight against AD,” the rebuttal notes. “The inability to obtain the information provided by Aβ imaging would most certainly slow down the urgently needed progress in understanding the basics of neurodegeneration and in the development of new approaches aiming to treat these devastating disorders.”—Madolyn Bowman Rogers

Q&A With Bengt Långström. Questions by Madolyn Rogers.

Q: What motivated you to coauthor the first editorial?

A: The reason for me to join the editorial in the first place was based on the following points:

  • Development and validation of a PET tracer molecule is a long and tedious journey. In this case, I believe that there is value in having an amyloid biomarker available in such a way that we could use a tracer molecule which could perform an in-vivo visualization of the brain pathology, giving similar information as that obtained by a pathologist who is performing various staining techniques at autopsy for the same subject.
  • The first human PIB study—in which I was involved—started actually with another compound, PIA, but was based on our previous experience of how good in-vivo PET tracers behaved. PIB was selected for the human study because this change in the molecular structure resulted in similar characteristics as several of our best PET tracers had. So we used a similar paradigm for the selection of the tracer as we had been using when developing tools for receptor expression or enzyme function.
  • The PIB story also contained another paradigm: the microdose concept which allowed human applications at microdose even with limited toxicology information. That was the main reason why we were not able to carry out a PIB study using a dose escalation, or as an alternative, a competition displacement study, in order to determine if the binding was changed due to mass dose effects, or whether binding was similar in various brain structures, or changed in various patients and healthy aging controls.
  • This is a fundamental problem with the existing "amyloid tracers": We don't know if the binding in various patients and aging healthy controls really is of the same type, that is, whether binding is the result of brain amyloid loads. That information might have been sorted out if we had carried out the dose/binding investigation. This is something which definitely should be carried out before moving this into clinical trials. The various amyloid tracers give somewhat different results, which also could be an indication that they are binding to various tissue targets.

In my estimation, this is a missing factor. The paper by Sabbagh et al., 2011 emphasizes that pathology staining might not always be in correlation with the in-vivo method which we now are discussing.

There are also other parameters which we should explore in more detail before we perform clinical trials with the intention to commercialize these tracers. It would be very important to explore in detail the impact of blood flow on the in-vivo amyloid imaging. That may increase the potential to perform quantification. Furthermore it would be valuable to understand what type of amyloid aggregates, or whether other tissue targets (e.g., enzymes) are targeted in vivo by these PET tracers. Such work is in progress.

Q: Do you believe that β amyloid imaging agents such as PIB and the new 18F-labeled tracers are specific and reliable?

A: There is literature evidence that some of them are not specific for ”amyloid aggregates.” I don’t know if this is entirely true in humans, but I certainly would like to see that we—as a scientific community—focus on performing rigorous scientific investigations to answer these questions before this is taken over by business.

In studies with a large number of patients, we see patterns. However, there are fundamental differences between the amyloid tracers compared with other structural tracers targeting functional tissue proteins, because amyloid aggregates are what I would claim is a residual (garbage) protein.

Q: Do they accurately reflect Aβ deposits in the brain?

A: Again, I don't know, but we certainly need to perform more scientific, unbiased, and professional studies to validate what the imaging observations may indicate. There is a huge need for these kind of studies, and I do hope that these will be made by the whole scientific community.

Q: What do you think of the rebuttal editorial by Villemagne and colleagues?

A: To join the first editorial was, for me, a must, since I have at many occasions been making the point that there is a need for more fundamental studies which we should perform before making precipitous conclusions about the value of these "amyloid tracers." I do hope that this discussion will bring the issue back to science and the business will have to wait.


  1. This story gives a fair and correct account of this battle. I personally believe that Alavi et al. are wrong with most of their statements, while Villemagne et al. are right with most of their rebuttal. The interview with Bengt Långström points to the remaining core of uncertainty about our understanding of amyloid imaging—he is probably right, but I would see the remaining uncertainty as a minor point. I have published my view on clinical amyloid imaging in a recent short review for Lancet Neurology (Herholz and Ebmeier, 2011).

    This debate is probably just "the tip of the iceberg" with respect to a much larger debate: whether it makes sense to test healthy individuals (or people with just some moderate memory deficit) for amyloid, assuming that a positive scan indicates that they already have an early stage of Alzheimer's disease and that we should aim for prevention of dementia in these subjects. PET is the obvious tool for doing this—thus, we now have the debate on PET, but it is not really the imaging science that is being discussed; it is the aim and implications of what it is going to be used for. This has potentially huge societal implications. Obviously, an effective strategy for early diagnosis and intervention to prevent dementia will need industry to pursue it with appropriate clinical trials, but with industry, big money and conflicts of interest also get involved quite heavily. Both we academics and patients need the pharmaceutical industry (just like they are needed to combat cancer), even though we don't love them. We need to be careful that things are being done right when engaging in early diagnosis of Alzheimer's disease.


    . Clinical amyloid imaging in Alzheimer's disease. Lancet Neurol. 2011 Jul;10(7):667-70. PubMed.

  2. This is an interesting and necessary debate. Interesting because things have been going so quickly: It took more than 20 years for hippocampal atrophy to be included as part of the Alzheimer’s disease diagnostic workup, while Aβ PET started being considered in revised diagnostic guidelines only a few years after the first PIB publication. Necessary, because the conflict of interest that inevitably accompanies the considerable economic dimension of this technique raises questions in the community’s mind. Some may have been wondering if this remarkable speed is because Aβ imaging truly represents a revolution in our field or because of its economic aspect. We need such debates to think about the use of this technique and its ethical aspects before its release, so that we can help prevent any abusive use or negative consequences. Debates such as this remind us of our duty, as scientists and clinicians, to be prudent.

    This provocative editorial, although some of its arguments were clumsy, is worth talking about. Let’s take the time to defuse some of the potential serious ethical issues that may be associated with Aβ imaging. Let’s make clear what Aβ imaging does and what it does not allow. That is how I interpret the spirit behind the paper by Moghbel et al., though I would personally not have used the same arguments. For example, we should acknowledge the limitation of Aβ imaging in that it only binds to fibrillar but not the soluble form of Aβ, but I don’t think we can question the ability of Aβ imaging to visualize plaque or refute that Aβ imaging is a revolution in the field of AD research. It fills the gap between neuropathologists and neuroimagers; it fills the gap between molecular, cellular, or ex-vivo experimentation and human in-vivo “macroscopic” research. It provides the most direct neuroimaging measure to date for a neuropathological hallmark of AD.

    This is very exciting. In spite of this, we clinician-scientists have the responsibility to proceed thoughtfully. I don’t agree with the arguments by Moghbel et al., but I salute their initiative, because it may calm down the industry race and because it gives Victor Villemagne and coauthors the opportunity to argue, answer, detail, explain, justify several critical points related to Aβ imaging. And they did that extremely well. They provide a systematic, objective, and documented answer to each of the issues raised by Moghbel et al. This enlightenment is extremely useful and was crucial.

    I fully agree with what I consider the most important point of the reply (as it is the most important confusion with regard to Aβ imaging). That is, we should not ask Aβ imaging to do what it is not supposed to do. It is not a tool to diagnose AD, but it is a tool to visualize Aβ deposition. As such, it is immediately a considerable breakthrough to further our understanding of AD pathology and progression. As for the clinical application, it would certainly be useful for diagnosis. My opinion is that we probably need to know a bit more about what information Aβ imaging provides, and what is the relative risk associated with an amyloid-positive scan (and, inversely, the percent chance of developing AD when someone has a negative scan). There are not enough studies to make firm conclusions about this yet. And we should think about the ethical issue. Absent a treatment, what do we do with the information provided by the amyloid scan? What information should be released to the patient?

    In my opinion, the real question at this point in time is not whether Aβ imaging is valid to visualize amyloid, but, What do we do with the information it provides beyond the evident interest for research?

  3. I disagree with Moghbel et al. It is well established that PIB has been a very useful diagnostic tool, and most likely other experimental compounds, including those seeking FDA approval, are, too. The specificity of binding to amyloid fibrils issue may be relevant for early detection of Alzheimer's disease when smaller aggregates are predominantly present; however, additional experimental studies should be able to address this issue instead of asking for radical dismissal of the entire trace compound approach. I don't believe the radiotracers or dye tracers currently in development are fake. These compounds have very promising potential and are rather highly useful for AD diagnostics.

  4. The recent editorial by Moghbel et al. has the merit of bringing to light a number of valid concerns that have permeated the interpretation of "amyloid imaging" scans for too long already. The purported amyloid specificity of these probes has been predicated on the basis of in vitro determinations certainly suitable for staining of fibrillar neuroaggregates, but not appropriate for identification of other tissue targets. Now we know that amyloid probes structurally related to the 6-hydroxybenzothiazole (and related) family (e.g., PIB, flutemetamol or 3’-fluoroPIB and others) are not amyloid-specific but are also targeted in vivo in brain by estrogen sulfotransferase (SULT1E1) (Cole et al., 2010), a labile low abundance cytosolic enzyme, first thought to be absent in the human brain (Mathis et al., 2004) As expected, the enzyme is present in all human tissues and also is extensively expressed in other animal species (Miki et al., 2002). What this means is that these amyloid PET probes can be retained in brain in vivo as their 6-O-sulfate, similar to the tissue retention of FDG as FDG 6-phosphate (the basis of the concept of metabolic trapping of PET probes), and not as a result of the presence of amyloid aggregates. This possibility has been demonstrated in rodent brain (Cole et al, 2010) and suggested already as a likely explanation for the multiple inconsistencies reported in the literature between positive PET scans and neuropathology localization in humans (Shin et al., 2011; Phelps and Barrio, 2011).

    We do not yet know what these purported amyloid probes detect in vivo: for instance, the PIB family of probes were first considered specific for neuritic plaques and insensitive to diffuse amyloid (Cairns et al., 2009; Reiman et al., 2009); later it was reported that PET positive signals were correlated with diffuse amyloid and not neuritic plaques (Kantarci et al., 2010), following reports that PIB binding correlated to total insoluble Abeta (Abeta40 plus Abeta42) (Ikonomovic et al., 2008). Most recently however it was reported that the PIB PET signal in a PIB(-) case was only correlated to Abeta42, and not Abeta40 plaques or diffuse amyloid, (Ikonomovic et al., 2012) but in a PIB(+) case it was correlated to both Abeta42 and Abeta40 plaques.

    Equally confusing is the report that Florbetapir PET amyloid positive imaging matches with autopsy cortical neuropathologic findings of frequent neuritic and diffuse plaques, as well as frequent amyloid angiopathy, in neocortex but not with frequent neuropathologically demonstrated diffuse plaques and amyloid angiopathy in cerebellum (Sabbagh et al., 2011). Then, what is it? What do these probes label in vivo in brain? It is probably none of the above.

    If the in vivo brain signal with these biomarkers is (totally or partially) related to estrogen sulfotransferase or other estrogen targets, then the PET positive signal could be related to inflammatory processes—well known to be involved with AD (Akiyama et al., 2000). It is also well-established that the stilbene-based Florbetapir and related probes are structurally related to estrogen analogs and alternative explanations associated with inflammation can be made for these probes also. An inflammation target would more easily explain the white matter ‘non-specific binding’ observed with these probes, or their ‘affinity for myelin’ (Stankoff et al., 2011), the 30 percent positive PET scans of controls subjects, the ‘on and off’ PET scan profile of MCIs, the negative PET scans in cases of autopsy validated AD cases (Cairns et al., 2009), the lack of cortical PET positive signal in autopsy validated familial AD cases with significant cortical neuropathology deposition (Klunk et al., 2007); the elevated signal in some brain cortices, e.g., precuneus with no more amyloid accumulation than other brain areas, including the medial temporal lobe (Nelson et al., 2009) and also the modest (if any) decline in positive-"amyloid scans" in subjects under anti-amyloid therapies. If the PET-positive signal is related to estrogen or estrogen sulfotransferase, then it is not accident that PIB accumulation would match the PET results of other markers of inflammation with the same patients, as shown in Bengt Langstrom’s recent article with C-11-L-deuteriodeprenyl as a marker of astrocytosis (Santillo et al., 2011).

    The "amyloid imaging" results need critical analyses, not a monotonic amyloid explanation pathway or consensus science justification (Barrio, 2009). The in vivo target specificity of these probes ought to be addressed, not dismissed. An ample debate is needed, not to win the argument, but to arrive at the correct scientific answer. These concerns need to be addressed because a possible erroneous interpretation of positive PET imaging, as indicative of the presence of brain amyloid particularly in asymptomatic controls, is not a mere academic issue. We would all agree that unnecessarily administering current anti-amyloid therapies to these subjects could have devastating medical consequences. Our patients, our profession and our scientific commitment in search for the truth should not permit it.


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  5. I concur with the rebuttal by Villemagne et al. It is already clear that imaging amyloid will make a significant contribution to the understanding of this devastating disease. Even if there are multiple issues which remain to be elucidated further, the progressive use of biomarkers, such as offered with these compounds, will become paramount.

    Provided that sufficient rigor is seen in the evaluation of data, I see no conflict with "business" taking over. We should welcome it.

  6. Dr. Barrio raises scientific questions regarding the precise relevance of PIB and related derivatives as a new generation of compounds in imaging diagnostics. His comment looks more like an article on its own, and answering each individual detail would go beyond the scope of this forum. I agree with some of the specificity concerns. However, that is all the more reason to continue investments in studies using these compounds, rather than shutting them down. The imaging field is not standardized experimentally for routine medical applications, and the variety of protocols performed by different groups create a variety of often conflicting results, such as contribution of inflammation, or estrogen and sulfo-enzymes, or cortical versus cerebellum specificity to the labeling probe. Therefore, more studies are needed, and yes, they should be performed with the highest ethics by all involved, particularly pharmaceutical companies. It is important to keep in mind, though, that imaging is to be used in conjunction with other diagnostic testing approaches rather than as exclusive and conclusive methodology. A number of amyloid angiopathies never even progress to AD, and certainly no one wants to see unnecessary administration of "preventive" therapies. Yet, some individual scientific articles reporting opposing results should not halt a field where a certain degree of consensus opinion has been established. When supported by creatively planned, detailed studies from different groups of investigators, which fully address all questions and provide solid answers, consensus science is tremendously useful, with or without politics.

  7. The comment above by Dr. Barrio is certainly provocative, but it is from time to time inaccurate and incomplete, and there are several major weaknesses in the argumentation. For example, Dr. Barrio argues that a positive PIB signal may be due to inflammatory processes in the brain. This immediately raises the question of why most patients with FTD or other forms of dementia show negative PIB scans, as there is involvement of inflammation in other neurodegenerative diseases as well. Furthermore, to support the claim that PIB binding reflects a neuroinflammatory response, Dr. Barrio refers to a paper by Santillo et al. (2011) that showed overlap between PIB and carbon-11-deuteriodeprenyl (DED, a PET tracer with affinity to bind to MAO-B enzymes, which are spatially related to astrocytes) in AD patients. They do not refer to Carter et al. (2012), however, who used the same tracers and found that average DED retention was highest in MCI patients, whilst PIB uptake was highest in AD patients. The dissociation between these tracers strongly argues against the author’s statement that PIB binding reflects neuroinflammation.


    . In vivo imaging of astrocytosis in Alzheimer's disease: an ¹¹C-L-deuteriodeprenyl and PIB PET study. Eur J Nucl Med Mol Imaging. 2011 Dec;38(12):2202-8. PubMed.

    . Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J Nucl Med. 2012 Jan;53(1):37-46. PubMed.

    . Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA. 2011 Jan 19;305(3):275-83. PubMed.

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  6. Pittsburgh Compound-B Zooms into View
  7. New Study Correlates Aβ Levels to Degree of Dementia
  8. F18 PET Tracers, New MRI Method to Expand Reach of Brain Imaging
  9. eFAD Research Surprise: In Mutation Carriers, Amyloid Starts in Striatum

Paper Citations

  1. . Imaging the pathology of Alzheimer's disease: amyloid-imaging with positron emission tomography. Neuroimaging Clin N Am. 2003 Nov;13(4):781-9, ix. PubMed.
  2. . Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol. 2004 Mar;55(3):306-19. PubMed.
  3. . Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA. 2011 Jan 19;305(3):275-83. PubMed.
  4. . Stereologic assessment of the total cortical volume occupied by amyloid deposits and its relationship with cognitive status in aging and Alzheimer's disease. Neuroscience. 2002;112(1):75-91. PubMed.
  5. . Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA. 2000 Mar 22-29;283(12):1571-7. PubMed.
  6. . [(11)C]PIB-amyloid binding and levels of Abeta40 and Abeta42 in postmortem brain tissue from Alzheimer patients. Neurochem Int. 2009 May-Jun;54(5-6):347-57. PubMed.
  7. . Use of a corrected standardized uptake value based on the lesion size on CT permits accurate characterization of lung nodules on FDG-PET. Eur J Nucl Med Mol Imaging. 2002 Dec;29(12):1639-47. PubMed.
  8. . The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cereb Cortex. 1991 Jan-Feb;1(1):103-16. PubMed.
  9. . Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging. 1997 Jul-Aug;18(4):351-7. PubMed.
  10. . Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002 Jun 25;58(12):1791-800. PubMed.
  11. . Quantitative neurohistological features of frontotemporal degeneration. Neurobiol Aging. 2000 Nov-Dec;21(6):913-9. PubMed.
  12. . Association between in vivo fluorine 18-labeled flutemetamol amyloid positron emission tomography imaging and in vivo cerebral cortical histopathology. Arch Neurol. 2011 Nov;68(11):1398-403. PubMed.
  13. . Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci. 2007 Jun 6;27(23):6174-84. PubMed.
  14. . PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol Aging. 2008 Oct;29(10):1456-65. PubMed.
  15. . Conversion of amyloid positive and negative MCI to AD over 3 years: an 11C-PIB PET study. Neurology. 2009 Sep 8;73(10):754-60. PubMed.
  16. . Positron emission tomography and neuropathologic estimates of fibrillar amyloid-β in a patient with Down syndrome and Alzheimer disease. Arch Neurol. 2011 Nov;68(11):1461-6. PubMed.

Other Citations

  1. See Q&A With Bengt Långström

External Citations

  1. letter
  2. previous letter
  3. meeting abstract

Further Reading

Primary Papers

  1. . Amyloid-β imaging with PET in Alzheimer's disease: is it feasible with current radiotracers and technologies?. Eur J Nucl Med Mol Imaging. 2012 Feb;39(2):202-8. PubMed.
  2. . Aβ Imaging: feasible, pertinent, and vital to progress in Alzheimer's disease. Eur J Nucl Med Mol Imaging. 2012 Feb;39(2):209-19. PubMed.