HAI Chicago: PIB in Healthy People

24 Apr 2008

Many studies using Pittsburgh Compound-B (PIB) to probe amyloid deposits in the brains of MCI and AD patients have also found a fair percentage of normal elderly walking around with heads full of amyloid. While some wonder how these folks’ plaque-laden minds remain sound, others propose that the plaques may be a very early warning sign of AD—the window through which researchers can now see the “sleeping giant” long before people show symptoms of dementia. In any case, it will be important to determine if these PIB-positive healthy people have thrown a wrench into the field’s longstanding amyloid hypothesis, which claims that amyloid buildup is the primary driver of AD pathology. As discussed at the Human Amyloid Imaging meeting, held 11 April 2008 in Chicago, finding ways to reliably distinguish true controls from amyloid-positive controls has therefore become a key challenge for ongoing and future studies.

Bill Klunk of the University of Pittsburgh, Pennsylvania, who co-developed PIB with colleague Chester Mathis, opened the first session with a talk describing several objective methods for detecting amyloid positivity at the earliest stages of amyloid pathology. In one approach, mild outliers are removed from a set of PIB retention values (measured as DVRs, or distribution volume ratios) for a given brain region displayed in a standard box-and-whisker plot. Repeating the outlier removal process leaves behind the amyloid-negative group. The second method selects amyloid-negative subjects by identifying breakpoints in the distribution of a parameter calculated from the magnitude and variability of PIB uptake. From a pool of 60 non-demented controls, both methods pulled out an almost identical set of 16 amyloid-positive individuals. These objective approaches seemed to detect amyloid positivity as well or even better than did visual reads of the PIB-PET images by trained readers, but Klunk cautioned that zones of uncertainty will remain. “Amyloid deposition and PIB retention are continuous variables,” he said. “No cutoff will be perfect.” That said, the data he presented suggest it is possible to devise objective, generalizable methods for finding amyloid-positive individuals within groups of otherwise normal subjects.

In fact, it may even be reasonable to define a cutoff using one approach and apply it to an independent sample, according to new work presented by Elizabeth Mormino, a graduate student in William Jagust’s lab at the University of California, Berkeley, and winner of the first annual HAI Young Investigator Award. Using MRI and PIB-PET data from 20 healthy seniors (mean age 72.3) and 20 with AD (mean age 64.3), the researchers determined average PIB counts from the prefrontal cortex, cingulate, and parietal and lateral temporal areas. PIB cutoff values were selected based on receiver-operator characteristic (ROC) curves applied to three region-of-interest (ROI) methods: 1) ROI approach: mean PIB value from a single ROI; 2) cortical index approach: average of three ROI means extracted in method 1; 3) highest ROI approach: highest mean from ROIs used in method 1.

Optimal cutoffs determined from these curves were applied to an independent sample from the database of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a national effort to coordinate the reams of data from MRI, PET, and other biological and clinical measures to better detect AD and monitor its progression. The researchers then looked to see whether the AD-like ADNI control participants showed signs of AD in other ways—namely, age, hippocampus volume, and episodic memory. The answer was yes, at least according to the first two measures: the high-PIB group was older and had greater hippocampus atrophy. Longitudinal follow-up will determine whether any of the high-PIB folks convert to AD.

For the HAI audience, perhaps the biggest surprise from Mormino’s talk was the finding that more than 41 percent (7 of 17) of the ADNI normal controls were classified as PIB-positive, compared with just 2 of 20 Berkeley controls. In response to concern about this observation raised in the post-session Q&A, Mormino noted that the ADNI group was five to six years older and significantly less educated than the Berkeley cohort.

In the next session, Chet Mathis of the University of Pittsburgh, Pennsylvania, presented more evidence for greater-than-expected amyloid positivity among control subjects. He summarized PIB-PET data from 78 baseline studies at 12 ADNI sites collected as of February 2008. (PIB-PET scans were added to the ADNI study in 2007.) In this preliminary analysis of 17 controls (mean age 79), 46 people with MCI (mean age 74), and 15 with AD (mean age 73), the general trends were not surprising: the control group had lower PIB retention than did the MCI group, which had lower PIB uptake than did the AD group. However, the average PIB value across the control group was somewhat high, and when the iterative mild outlier approach (described in Klunk’s talk) was applied to the data, 11 of 17 controls met the cutoff for PIB positivity (as did 40/46 MCI and 14/15 AD subjects). In the control group, the precuneus was the brain area that contributed most to the high PIB values.

Distinguishing true controls from PIB-positive controls can be tricky, as shown in the mean PIB images from this study of 43 normal controls. Though PIB-positive controls tend to have lower levels of PIB retention than do AD patients, their regional distribution of high PIB uptake can be quite similar. Image credit: University of Pittsburgh Amyloid Imaging Group

In side-by-side comparisons with Pittsburgh PIB-PET data, both ADNI control and MCI subjects had higher PIB uptake than did their Pittsburgh counterparts, consistent with the trend in the Berkeley-ADNI comparisons reported by Mormino. But there were also differences—one of which Mathis mentioned in post-meeting e-mail correspondence with ARF. Illustrating how conclusions can vary based on cutoff definitions, Mathis noted that different methods used by the Pittsburgh and Berkeley teams to define amyloid positivity may explain why the groups identified different proportions of the ADNI controls as PIB-positive (11/17 and 7/17, respectively). The Berkeley researchers used an average of four cortical regions and the ROC method to define controls above a cutoff value. The Pittsburgh group set a lower bar for PIB positivity: subjects whose PIB uptake in just one of seven cortical areas that was significantly greater than a regional cutoff were defined as PIB-positive.

During Q&A, several people wondered whether the ADNI controls might be skewed by people who volunteer for the study out of concern for their (or their spouse’s) cognitive health. Chris Rowe, director of the Centre for PET at Austin Health in Melbourne, mentioned that the PIB positivity rate in Australia’s version of ADNI (the Australian Imaging, Biomarkers and Lifestyle study of aging (AIBL) is near 30 percent.

Though it was not the major focus of the research, a high percentage of PIB-positive normal controls was also reported on a poster by Stephen Gomperts of Keith Johnson’s group at Massachusetts General Hospital, Boston. In this study looking at whether amyloid detection using PIB could distinguish dementia with Lewy bodies (DLB) from Parkinson disease dementia (PDD), Gomperts and colleagues found that 51 percent (19 of 37) of the normal controls used in the PDD analysis had brain amyloid levels in the PIB-positive range.

Along similar lines, consider this interesting tidbit shared between HAI talk sessions by Agneta Nordberg of the Karolinska Institute, Stockholm, Sweden: an 83-year-old healthy man, who was PIB-positive when the first European human PIB trials began in 2002 at her Stockholm clinic, is still doing well today—more than six years later.

On the flip side, a poster by Gil Rabinovici and colleagues (including Mormino and Jagust) at UC Berkeley and UCSF presented data suggesting that PIB might not be sensitive enough to pick up the very earliest amyloid changes. In their study of a 58-year-old with familial frontotemporal lobar degeneration with motor-neuron disease (FTLD-MND), the researchers found control-range PIB uptake on PET, yet saw a moderate degree of immature diffuse plaques at the patient’s autopsy 11 months later.

Pondering these various cases, scientists may wonder, on one hand, just how long normal people can remain under the PIB radar (if half of controls can appear PIB-positive with no cognitive decline) and yet, at the same time, whether PIB requires some threshold of amyloid buildup before it picks up anything at all. Determining the clinical relevance of PIB-based amyloid readouts will likely require coordinated analysis of data from PIB-PET data other brain imaging techniques as well as biological and neuropsychological tests.—Esther Landhuis.

This is Part 1 of a four-part series. See Part 2.

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HAI Chicago: Can PIB Predict Cognitive Decline?

25 Apr 2008

One of the big surprises at this year’s Human Amyloid Imaging meeting, held 11 April 2008 in Chicago, was the finding that a significant proportion of healthy controls are PIB-positive. In a study that directly addresses the frequency of amyloid positivity among normal seniors, Mark Mintun and colleagues at Washington University, St. Louis, Missouri, are using PIB-PET imaging to look for high PIB retention in normal elderly and determine whether any pattern predicts dementia down the road. Here is what they have learned thus far. Of the 203 non-demented subjects who have submitted to PIB-PET scanning as part of this longitudinal study, 7.3 percent of people in their fifties had elevated PIB retention, followed by 14.9 percent of sixty-somethings and 30 percent of those in their seventies. Between ages 50 and 80, PIB uptake basically doubled each decade. Curiously, only 28 percent of subjects in the 80- to 90-year-old group had high PIB uptake, but it was suggested during the Q&A that this could reflect a survivor effect among those in the study who have reached their eighties without yet succumbing to dementia. Mintun noted that all subjects have agreed to return for further evaluation, which should help determine PIB’s ability to forecast conversions to dementia. The data thus far, which show particularly high PIB uptake in the precuneus and pregenual anterior cingulate, support the notion that amyloid gums up the brain well before cognitive deficits appear.

In Chicago, Mintun also reported results of a newer study, led by Washington University colleague Alison Goate, which addressed whether amyloid patterns revealed by PIB-PET imaging are a heritable phenotype. In this study of healthy volunteers from more than 25 local “sibships” consisting of 70- to 75-year-olds with at least one other sibling within five years of age, the answer seems to be yes. Nearly a third of the participants had elevated PIB retention, and the heritability estimate was calculated to be 0.72 (heritability of 1 indicates perfect genetic linkage).

Questions about a possible relationship between amyloid buildup and genetic predisposition to AD were at the root of new work presented by Eric Reiman, executive director of the Banner Alzheimer's Institute in Phoenix, Arizona. As apolipoprotein E4 (ApoE4) is a well-known risk factor for AD, this study involved eight cognitively normal ApoE4 homozygotes and six ApoE4 non-carriers in their fifties and sixties who were already enrolled in an ongoing longitudinal study and had agreed to add PIB-PET to their battery of procedures. Fibrillar amyloid burden, as assessed by PIB retention, was found to be higher in the ApoE4 homozygote group as compared with non-carriers in all brain areas tested. The anterior cingulate, temporal cortex, and hippocampus showed the most significant differences. These preliminary findings suggest a means for subject enrichment or stratification in primary prevention trials, and support PIB’s use as a readout in human trials of amyloid-reducing agents, Reiman said.

PIB also showed promise as a predictor of cognitive decline in work presented by Victor Villemagne of the Department of Nuclear Medicine at Austin Hospital, Melbourne, Australia. In an ongoing longitudinal study of 51 subjects, three of eight PIB-positive controls and all four PIB-positive MCI subjects showed cognitive decline (to MCI or AD, respectively) in neuropsychological reassessments done almost two years after the initial PIB-PET scan. Among non-demented study participants, the researchers found a strong correlation between episodic memory and Aβ burden.

At the Turku PET Center in Finland, one of very few countries allowing human brain biopsies, work presented in Chicago by Juha Rinne suggests that PIB-PET data correlates well with Aβ deposits seen in cortical brain biopsy. For this study, researchers looked at 10 patients undergoing intraventricular pressure monitoring with a frontal cortical biopsy for suspected normal pressure hydrocephalus (NPH). NPH is a brain condition, the treatment of which involves surgical placement of a shunt to drain excess CSF from the brain into the abdomen. Some NPH patients have concomitant AD pathology, which has been shown to predict a poor response to shunting. In six patients with Aβ deposits in the frontal cortical biopsy, post-surgery PET scans showed higher PIB uptake in the frontal, parietal, and lateral temporal cortices and in the striatum compared with the four patients without frontal Aβ deposits. Follow-up evaluation is needed to determine whether a higher PIB level is correlated with progressive cognitive decline. In the Q&A, Rinne noted that of the eight NPH patients who were shunted, the only one who didn’t improve was the one who had AD pathology, as well.—Esther Landhuis.

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HAI Chicago: PIB and Aβ Show Regional Nuances and Sleep-Wake Rhythm

28 Apr 2008

What is going on in older folks who seem to do fine with amyloid-peppered brains? Do their brains rewire themselves to compensate for the unwelcome protein deposits? To address such questions, studies using functional magnetic resonance imaging (fMRI) have zeroed in on what’s been dubbed the “default network”—brain areas that are most active during passive daydreaming periods and typically turn off when the person engages in a focused mental task (see Lustig et al., 2003; Greicius et al., 2004; ARF related news story). Impaired default activity—in other words, failure to brush off distractions and focus on the task at hand—might help explain why people with MCI or AD have a harder time remembering things (see Buckner et al., 2005 and ARF related news story).

According to more recent studies led by Reisa Sperling, director of clinical research at the Memory Disorders Unit at Brigham and Women’s Hospital, Boston, coordinated deactivation of medial parietal lobe activity and activation of the hippocampus are required for a person to learn and remember a face-name pair (see Miller et al., 2008 and ARF related news story). Another study by Sperling and colleagues (Pihlajamaki et al., 2008) found that mild AD patients undergoing memory recall tests had abnormal increased activity in the medial temporal lobe (MTL), a larger brain area that houses the hippocampus. These results raised the possibility that MTL hyperactivation could help older people compensate for cognitive problems associated with amyloid buildup at the earliest stages of AD. To make this claim, the researchers needed to look more closely at the low-performing subjects and determine whether amyloid was in fact piling up in the brain areas with the odd network activity.

At this year’s Human Amyloid Imaging meeting, held 11 April 2008 in Chicago, Sperling presented results of this new study, which examined the relationship between fibrillar amyloid deposition detected by PIB-PET and regional brain activity during the face-name memory test as assessed by fMRI. The work was done in collaboration with Keith Johnson and Randy Buckner at Massachusetts General Hospital. In their analysis of 31 non-demented seniors (mean age 77.7; 19 with Clinical Dementia Rating (CDR) 0, 12 with CDR 0.5 who did not yet meet MCI criteria as defined in Petersen, 2004), high levels of PIB retention were associated with abnormal increased activity in the PCC (precuneus/posterior cingulate cortex) and medial frontal areas. These are part of a default network and typically “turn off” during successful memory formation—in this case, predicting the ability to remember a face-name pair 30 minutes later. Furthermore, high PIB uptake in the PCC correlated with increased hippocampal activation only when subjects recalled the face-name pair correctly but not when their memory failed.

These findings suggest that PIB-positive individuals who maintain good performance in cognitive tests might be sending their hippocampus into overdrive to do so, Sperling said. She noted in the Q&A, however, that her data do establish any causal relationships. At present, the study leaves unclear whether amyloid buildup makes the default network go awry or whether neuronal problems within the default network feed back and lead to amyloid deposition. “I don't have arrows saying that amyloid causes this dysfunction, although my bias is that it does,” Sperling said. “All I can say here is that these findings go together and that the disruption of functional activity occurs even before you have any medical symptoms.”

In a related study, neuropsychologist Dorene Rentz and colleagues (including Sperling and Johnson) at Harvard Medical School showed on a poster that normal elderly with more amyloid in the precuneus at baseline did noticeably worse on memory tests one year later. Though 15 of the 31 non-demented subjects were classified as CDR 0.5, the researchers saw the amyloid-memory correlation even in the remaining CDR 0 individuals, after adjusting neuropsychological test scores for cognitive reserve by using measures such as education and IQ. That any decline was seen after just one year, Rentz said, suggests that amyloid in the brains of apparently normal people might not be so harmless, after all.

On the other hand, data presented by Ira Driscoll of the National Institute on Aging, Bethesda, Maryland, seem to indicate that healthy seniors can tolerate a fair amount of amyloid before brain atrophy is seen on an MRI scan. As part of the Baltimore Longitudinal Study of Aging, the research measured amyloid load in 56 well-functioning elderly (mean age 78.7, mean MMSE 28.9), with PIB-PET scans taken about a decade after the first of up to 10 MRI scans. MRI data revealed declines in whole brain volume and volumes of all regions tested (ventricular CSF; white matter (WM); gray matter (GM); hippocampus; and frontal, temporal, parietal, and occipital WM and GM); no significant association was found between PIB retention and brain atrophy rates in the clinically normal study participants. The findings are consistent with the threshold model of disease, which would predict that the brain tolerates a certain degree of amyloid pathology until a threshold is crossed. In other words, Driscoll said, amyloid load may not affect brain volume or performance within the clinically normal range of function.

This issue is still open, though. In a study combining PIB-PET with fine-tuned volumetry, Keith Johnson reported that amyloid plaques do accumulate in brain areas marked by reduced cortical thickness. The researchers examined 55 people (32 classified as CDR 0; 15 as CDR 0.5; and 8 as CDR 1) and found that, at the vertex level, both amyloid buildup and cortical thinning were significantly greater in CDR 0.5/1 individuals than in the CDR 0 group. Local amyloid deposition was correlated with cortical thinning primarily in posterior cingulate/precuneus and temporal cortices—brain regions that commonly sustain neuronal damage in AD. During the Q&A after his talk, Johnson said he and colleagues are discovering that the brain areas for which the amyloid-cortical thinning relationship holds are quite different from areas where this correlation is not seen. Future studies will take a closer look at whether and how these regions relate to memory function. For a separate, recently published study comparing PIB-PET to MRI, see Jack et al., 2008. In Chicago, Cliff Jack of the Mayo Clinic, Rochester, Minnesota, presented follow-up work to this paper but still found no consistent relationship between PIB binding and memory performance in normal controls, unlike the Melbourne group, which did (see Part 2 of this series).

Regional differences also showed up in the work of Ansgar Furst, a postdoctoral fellow in William Jagust’s lab at the University of California, Berkeley. Using structural MRI, [11C]PIB and [18F]FDG PET, Furst examined the relationship between amyloid burden and glucose metabolism in 13 patients with probable AD (mean age 63.9, mean MMSE 20.0) and 11 healthy controls (mean age 72.6, mean MMSE 29.4). Voxel-wise, atrophy-corrected analyses showed that increased amyloid load in temporo-parietal regions (including the precuneus) and the anterior and posterior cingulate was associated with lower glucose use in these areas, whereas even whopping amounts of amyloid in the frontal lobes, striatum, and thalamus were not coupled with similar metabolic drops. These data support the idea that amyloid plaques exert non-uniform effects across different brain areas, and they invoke again the old question of what molecular mechanisms are behind the selective vulnerabilities of different brain areas in AD.

Get Your ZZZ’s: A Connection Between Aβ and Sleep?
Why does amyloid seem to preferentially deposit in specific brain areas in the first place? This question was addressed by HAI keynote speaker David Holtzman of Washington University, St. Louis. Holtzman first reviewed published data that make the case for CSF Aβ42 and tau as antecedent biomarkers for AD. In particular, the combination of amyloid imaging and CSF markers offers strong predictors for future AD (Fagan et al., 2006). He then described work first author John Cirrito and colleagues reported this month in Neuron showing that synaptic activity and Aβ levels are linked via the endocytic pathway (Cirrito et al., 2008 and ARF related news story). Holtzman concluded with intriguing new data on a connection between sleep and Aβ levels.

Why sleep? Having established that synaptic activity regulates Aβ levels in the brain’s interstitial fluid (ISF), the researchers wondered whether ISF Aβ is dynamically modulated over the course of a day, and whether drugs that modulate synaptic activity and Aβ might therefore have therapeutic potential. Using EEG electrodes to track brain activity in mice over several days, Jae Eun Kang, a graduate student in the Holtzman lab, observed that the animals’ Aβ levels are higher at night (when rodents tend to be more awake) and lower during the day (when rodents sleep more). The amount of wakefulness (minutes awake per hour) was significantly correlated with ISF Aβ levels, she found. Holtzman noted that Randy Bateman, also at Washington University, is assessing human CSF Aβ levels over time and has data to suggest that similar trends may be occurring in people, as well.

When the mice were sleep-deprived, their Aβ levels remained higher than they otherwise would have been during a period where sleep is more common, Holtzman said, suggesting that something associated with wakefulness is boosting Aβ. In rodents who were put on the sleep-enhancing drug diazepam, baseline Aβ levels dropped by about 30-40 percent. When given modafinil, a wake-promoting agent, the mice had increased Aβ levels. These findings support the idea that the Aβ fluctuations during sleep-wake cycles might stem from changes in synaptic activity, Holtzman said, but this connection has not been proven. Asked whether the new data suggest that certain anticonvulsants could be candidates for AD prevention, Holtzman mentioned a possible scenario in which drugs that regulate synaptic activity in specific ways without affecting cognition might be able to modulate Aβ levels, which ultimately determine whether Aβ aggregation occurs. The drug effects would likely be brain region-dependent, he said. His group is starting to do regional microdialysis experiments to look more closely at specific brain regions—for instance, those involved in the default network—to see whether Aβ levels correlate with localized synaptic activity.—Esther Landhuis.

This is Part 3 of a four-part series. See also Part 1, Part 2.

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References

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Paper Citations

Lustig C, Snyder AZ, Bhakta M, O'Brien KC, McAvoy M, Raichle ME, Morris JC, Buckner RL. Functional deactivations: change with age and dementia of the Alzheimer type. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14504-9. PubMed.
Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, Sheline YI, Klunk WE, Mathis CA, Morris JC, Mintun MA. Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci. 2005 Aug 24;25(34):7709-17. PubMed.
Miller SL, Celone K, DePeau K, Diamond E, Dickerson BC, Rentz D, Pihlajamäki M, Sperling RA. Age-related memory impairment associated with loss of parietal deactivation but preserved hippocampal activation. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2181-6. PubMed.
Pihlajamäki M, Depeau KM, Blacker D, Sperling RA. Impaired medial temporal repetition suppression is related to failure of parietal deactivation in Alzheimer disease. Am J Geriatr Psychiatry. 2008 Apr;16(4):283-92. PubMed.
Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004 Sep;256(3):183-94. PubMed.
Jack CR, Lowe VJ, Senjem ML, Weigand SD, Kemp BJ, Shiung MM, Knopman DS, Boeve BF, Klunk WE, Mathis CA, Petersen RC. 11C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment. Brain. 2008 Mar;131(Pt 3):665-80. PubMed.
Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, Shah AR, Larossa GN, Spinner ML, Klunk WE, Mathis CA, Dekosky ST, Morris JC, Holtzman DM. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol. 2006 Mar;59(3):512-9. PubMed.
Cirrito JR, Kang JE, Lee J, Stewart FR, Verges DK, Silverio LM, Bu G, Mennerick S, Holtzman DM. Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron. 2008 Apr 10;58(1):42-51. PubMed.

External Citations

HAI Chicago: Not Just PIB—Other PET Tracers in Clinical Pipeline

29 Apr 2008

A large body of research has established that amyloid plaques and neurofibrillary tau tangles—the pathological hallmarks of AD—often crop up years before a patient realizes something is awry. But the road to reliable preclinical AD biomarkers has proven long and difficult. The PET tracer Pittsburgh Compound-B (PIB) is perhaps furthest along in the journey, but the short half-life of its original radioisotope has restricted its use to academic medical centers with on-site cyclotrons and highly specialized personnel. The Human Amyloid Imaging conference, held 11 April 2008 in Chicago, offered glimpses of a handful of newer compounds being developed for broader clinical application.

The vast majority of published PET amyloid imaging studies have used [11C]PIB, a super-hot molecule with a high signal-to-noise ratio. Despite its robust performance, what keeps it from widespread use is the fact that it must be synthesized on-site and used for PET scanning within a half hour. However, compounds labeled with 18F, an isotope widely used in cancer imaging, are stable for up to six to eight hours after production, which would greatly extend their clinical access.

The only 18F amyloid PET tracers with published results at this point are 18F BAY94-9172 and FDDNP. 18F BAY94-9172 (also known as AV-1/ZK) was invented by Avid Radiopharmaceuticals, Philadelphia, Pennsylvania, and sublicensed to Bayer Schering Pharma; Chris Rowe of Austin Health, Melbourne, Australia, leads clinical studies of this compound (Rowe et al., 2008 and ARF related news story). FDDNP is an 18F-labeled PET tracer that labels both amyloid plaques and tau tangles in brain slices in vitro (Agdeppa et al., 2001) and can distinguish normal controls from subjects with MCI or AD (ARF related news story). Gary Small of the University of California, Los Angeles, provided an update on studies with FDDNP, as described later in this story.

Side-by-side comparisons of PET scans using [11C]PIB and 18F BAY94-9172 in the same subjects have not been formally published. But in historical comparisons of the two compounds using the same measuring technique, Rowe wrote via e-mail after the meeting that the mean cortical uptake of BAY94-9172 was 55 percent higher in AD patients than in healthy controls, compared with an 80 percent increase using [11C]PIB. Despite its lower signal relative to [11C]PIB, BAY94-9172 reliably distinguishes AD from frontotemporal dementia (FTD) and healthy controls, Rowe said, and only requires a 20-minute scan that produces easy-to-read images, so it has good potential clinically. Later this year, Bayer Schering Pharma will conduct multicenter Phase 2 trials with BAY94-9172 at sites in the U.S., Australia, Europe, and Japan.

Data on another Avid 18F amyloid tracer, AV-45, will be presented publicly for the first time by Dean Wong of Johns Hopkins University, Baltimore, Maryland, at the Society of Nuclear Medicine meeting in June, with another presentation to follow at ICAD in July. AV-45 is a pyridinyl analog of AV-1/BAY94-9172. Neither is a PIB derivative.

Meanwhile, a group led by Rik Vandenberghe of the Catholic University of Leuven, Belgium, has just completed the first Phase 1 studies of an 18F-labeled PIB derivative. 18F AH110690, a 3’ F-PIB analog dubbed 18F 3’-F-PIB, comes from the makers of [11C]PIB, i.e., Bill Klunk, Chet Mathis, and colleagues at the University of Pittsburgh. GE Healthcare is developing it for commercial use. In preliminary studies described by the Pittsburgh team in an abstract for the 2007 Society of Nuclear Medicine meeting, the new compound did nearly as well as [11C]PIB (standardized uptake values within 10 percent) at detecting amyloid in the precuneus and frontal cortex. It showed about 20 percent higher non-specific binding in white matter, but Klunk said that this does not preclude its ability to quantify cortical Aβ deposits.

Results from the single-center, non-randomized study of 18F 3’-F-PIB in Belgium were presented on a poster at the HAI meeting in Chicago. The first step of the study, which involved dynamic, whole-body PET scans on six healthy volunteers ages 51-73, established the compound’s effective dose (33.8mSv/MBq +/- 3.4 SD), showed it was safe, and set the injected activity to 185 MBq for the next stage of the study. This step aimed at optimizing the imaging procedure, and toward this goal performed dynamic brain PET scanning on three normal volunteers and three AD patients. All AD subjects showed higher specific binding in cortical regions—particularly in the frontal and lateral temporal cortex and posterior cingulate—relative to the healthy controls. Other brain areas, including the occipital cortex, had lower relative uptake ratios. Uptake ratios and distribution volume ratios (DVRs; see Part 1 in this series) were similar in white matter across all patients. Ongoing studies with an additional 10 participants (five AD, five normal) will be presented at ICAD in July, and Phase 2 trials are scheduled to start in June at three European sites.

A side note: while 18F radiolabeling methods were being worked out, GE Healthcare made an 11C-labeled version of 3’-F-PIB. This compound first went into humans two years ago in studies led by Juha Rinne at the Turku PET Centre in Finland. As presented at the HAI meeting on a poster, 11C 3’-F-PIB works well as an amyloid tracer. It shows increased uptake in the frontal, parietal, anterior cingulate, posterior cingulate, and occipital cortex of AD patients relative to healthy controls. The researchers found no significant change in 11C 3’-F-PIB uptake during AD progression over one year, consistent with previous experiments using [11C]PIB, which also show that PIB retention has plateaued by the time a person receives a clinical diagnosis of AD. The fact that 11C 3’-F-PIB did well in the Turku human studies gave GE Healthcare the go-ahead to continue working on the 18F-labeled 3’-F-PIB, the compound headed toward commercial use.

As mentioned above, the HAI audience also heard from Gary Small, who summarized recent findings and preliminary data from several studies with FDDNP, an amyloid PET tracer he co-invented. In a study of 59 non-demented ApoE4 carriers and non-carriers, his team found higher FDDNP binding in ApoE4 carriers, particularly in the medial temporal region. In a study involving patients with Down syndrome, which has been proposed as a model for studying AD, Small and colleagues observed that age and behavioral symptoms were correlated with global FDDNP signal—the older and/or more severe the behavioral symptoms, the higher the FDDNP signal. For further research on FDDNP, see Noda et al., 2008.

In a conversation with this reporter after the meeting, Klunk envisioned a day when amyloid imaging might do for AD what colonoscopy has done for colon cancer—reliably predict who will need intervention years down the road. Many studies, including those presented by keynote speaker David Bennett of Rush University Medical Center, Chicago, have converged on the idea that amyloid deposition is a very early event in the long path to AD diagnosis and that effective interventions will be needed before the MCI stage. We may not know what the future of AD treatment holds, but we do know, as Bennett reminded the audience in his talk title, that “in the beginning…there was amyloid.”—Esther Landhuis.

This story concludes our conference series. See also Part 1, Part 2, and Part 3.

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Rowe CC, Ackerman U, Browne W, Mulligan R, Pike KL, O'Keefe G, Tochon-Danguy H, Chan G, Berlangieri SU, Jones G, Dickinson-Rowe KL, Kung HP, Zhang W, Kung MP, Skovronsky D, Dyrks T, Holl G, Krause S, Friebe M, Lehman L, Lindemann S, Dinkelborg LM, Masters CL, Villemagne VL. Imaging of amyloid beta in Alzheimer's disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism. Lancet Neurol. 2008 Feb;7(2):129-35. PubMed.
Agdeppa ED, Kepe V, Liu J, Flores-Torres S, Satyamurthy N, Petric A, Cole GM, Small GW, Huang SC, Barrio JR. Binding characteristics of radiofluorinated 6-dialkylamino-2-naphthylethylidene derivatives as positron emission tomography imaging probes for beta-amyloid plaques in Alzheimer's disease. J Neurosci. 2001 Dec 15;21(24):RC189. PubMed.
Noda A, Murakami Y, Nishiyama S, Fukumoto D, Miyoshi S, Tsukada H, Nishimura S. Amyloid imaging in aged and young macaques with [11C]PIB and [18F]FDDNP. Synapse. 2008 Jun;62(6):472-5. PubMed.

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HAI Chicago: Not Just PIB—Other PET Tracers in Clinical Pipeline

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