06 Feb 2015

From January 14 to 16, the ninth annual Human Amyloid Imaging (HAI) conference unfolded in Miami Beach, Florida, with a record attendance of 340 scientists—and arguably a curious little identity problem. HAI began in 2007, soon after the discovery of Pittsburgh compound B (PiB), and quickly became the premier gathering for unpublished data sharing and frank, extensive discussion of the leading edge of all things amyloid PET. Truth be told, the ninth HAI meeting still was that. But the hottest ticket in Miami this time was tau. Talks and poster sessions, hallway and lunch conversations were most animated when it came to the rapid emergence of PET tracers for the live imaging of the second defining molecular pathology described by Alois Alzheimer in 1906.

HAI is co-organized by Keith Johnson of Massachusetts General Hospital, Bill Klunk and Chet Mathis at the University of Pittsburgh, and Bill Jagust at University of California, Berkeley.

This new tau PET tracer shows low uptake in controls, intermediate uptake in mild cognitive impairment, and intense tau pathology spreading across the frontal and temporal cortex in Alzheimer’s disease. [Image courtesy of Nobuyuki Okamura, Tohoku University.]

With brain imaging for both amyloid plaques and tau tangles now at hand, scientists believe they will soon crack key questions in the field. Which sequence of events in the brain leads up to Alzheimer’s disease and other tauophathies? Which molecular pathology in which brain region causes which type of symptom, and how is normal brain aging different from neurodegenerative disease?

In AD in particular, scientists were excited about the notion that they will finally be able to understand how amyloid and tau pathology, as described for decades from postmortem brains, relate to each other during a person’s lifetime. The first data from people who have undergone both amyloid and tau scans strengthens the old concept that almost everyone develops circumscribed tau pathology with age. It impairs cognition slightly but falls well short of Alzheimer’s dementia. In the subset of people who also develop amyloid pathology, somehow this previously limited tau pathology intensifies, breaks out of the confines of the hitherto small brain regions it inhabited, and spreads catastrophically across the cortex. In other words, the idea is that amyloid pathology unleashes tau pathology, which then marches in lockstep with neurodegeneration and cognitive decline.

Clifford Jack of the Mayo Clinic in Rochester, Minnesota, summed it up this way: “Neuropathologists, for example Delacourte, Duyckaerts, and Price and Morris, proposed that medial temporal lobe age-related tauopathy happens in everybody, amyloid pathology happens in some, and amyloid accelerates tauopathy. PET imaging now validates what pathologists have said since the 1990s.”

Having stated the big idea, HAI attendees hastened to add that it’s extremely early days for tau PET. Altogether, fewer than 500 people have been scanned. For any given non-AD tauopathy, each research group has scanned barely more than a handful. And not all data fits. Off-target binding and some technical problems are cropping up that require more groundwork before tau PET will perform robustly and reproducibly in multicenter trials. “We are far from having a PiB for tau,” said Victor Villemagne of the University of Melbourne, Australia, referring to the amyloid tracer that is considered the gold standard on the Aβ side of things.

The tau PET field is expanding rapidly. The early lead belongs to ¹⁸F T807, a tracer Avid/Lilly bought from Siemens and renamed ¹⁸F AV1451. It is being studied by scientists at Avid and in academia, and scientists from six centers presented at HAI this year (see Part 2, Part 3, Part 4 , and Part 5 of this series). Having generated most of the early tau PET data known thus far, ¹⁸F AV1451 is already being prepared for use in several clinical trials, including the A4 Study. A second tracer called PBB3 is being studied by its developers at the National Institute of Radiological Sciences in Chiba, Japan, and by academic collaborators.

At HAI, a new tracer burst on the scene to general acclaim, and additional tracers are already nipping at its heels. Called ¹⁸F THK-5351, the new tracer is the latest in a series of PET compounds that researchers led by Nobuyuki Okamura at Tohoku University in Sendai, Japan, have been presenting over the past four years. Unlike its predecessors THK-523, THK-5105, and THK-5117, the new compound appears to have all the technical features nuclear medicine specialists are looking for, and some scientists at HAI declared ¹⁸F THK-5351 as being possibly the best of the bunch to date.

At HAI, Tohoku University’s Ryuichi Harada presented results from the first human trial of THK-5351. Harada acknowledged research support by GE Healthcare, which has previously collaborated with a Tohoku University biotech company on the university’s series of tau PET tracers. Scientists at HAI have therefore widely assumed that GE Healthcare will develop THK-5351 into a commercial tracer.  GE Healthcare developed the FDA-approved amyloid tracer ¹⁸F flutemetamol, which grew out of ¹¹C PiB.

Harada said that while previous Tohoku tracers visualized tau deposits in the brains of AD patients, their non-specific white-matter binding crowded out detection of small amounts of tau and made it impossible for the scans to be read visually. In contrast, when tested with autoradiography of AD brain sections, THK-5351 bound the same regions as tau antibodies, such as the hippocampus and inferior temporal cortex, with a high signal-to-noise ratio in gray versus white matter.

The scientists evaluated THK-5351 in 16 healthy controls, five people with mild cognitive impairment, and 13 AD patients. Two of them were scanned with both 5351 and the older 5117 tracer. THK 5351 entered the brain quickly, shooting up to peak retention five minutes after injection and leaving the brain by 90 minutes, Harada reported. Fifty minutes into this time window, the values for the SUVR—the most commonly used semi-quantitative measure of PET tracer uptake—stabilized at around 1.5 in the control group and 2.5 in the AD group. This is the best time window for imaging, Harada said.

The signal for THK-5351 has a larger dynamic range than that of its predecessors, Harada said. Together with the tracer’s quick clearance from white matter, this means the scans can be interpreted with the naked eye, an important criterion for future clinical use. THK-5351 distinguished AD from controls, and in MCI cases the amount of tau in signature regions such as the inferior temporal or parietal cortex was in-between. A voxel-by-voxel comparison of where PiB and THK-5351 bind across the Alzheimer’s brain aligned THK-5351 with the place where tau pathology would be expected according to Braak staging. THK-5351 does not bind Aβ, Harada said.

Adding his group’s data to the emerging sense that circumscribed tau pathology is quite common with age, Harada showed cross-sectional data suggesting that among the 16 cognitively healthy controls, THK-5351 uptake nudged upward with age in the hippocampus and, to a lesser degree, in the inferior temporal cortex.

On non-AD tauopathies, Harada showed first images of a patient with progressive supranuclear palsy, a rare disease that is currently a bit of a head-scratcher for PET imagers(see Part 4 of this series). The scan showed uptake in the patient’s midbrain, where it would be expected in this movement disorder. It also bound to those midbrain areas in micro-autoradiography of brain slices from a separate, postmortem PSP case.

“There are not a lot of imaging data on the new THK compound, but it appears that THK-5351 may be the best tau compound in AD we have seen in vivo thus far. It has great kinetics, low white-matter binding, and a large specific signal,” said Mathis, who discovered PiB (with Klunk) and is working on tracers for both tau and α-synuclein. Other PET experts agreed.

Pushing closely behind THK-5351 are candidates from the pharmaceutical and diagnostics giant Hoffmann-La Roche. Roche decided to develop its own tau PET tracer rather than trying to obtain AV1451 or another tracer for use in clinical trials of its investigational drugs targeted to either Aβ or tau.  Besides tracking progression and drug response in therapeutic trials, companies are hoping the PET scans will become diagnostic tests in clinical practice.

Roche’s Michael Honer, Edilio Borroni, and colleagues collaborated with PET specialists led by Dean Wong at Johns Hopkins University School of Medicine in Baltimore. At HAI, they presented their in vitro and in vivo characterizations of three tracers called RO6931643, RO6924963, and RO6958948. If one of those early in vivo candidates shakes out as a keeper, it will get a more memorable name.

The Roche compounds displace the binding of the investigational Siemens tau tracer T808 to aggregated tau in human brain slices at Braak stages V/VI. Using both macro- and micro-autoradiography on human AD tissue, the Roche scientists showed that the binding of their candidate tracers co-localized with the immunohistochemistry of aggregated tau, but not Aβ. Then they shipped the precursor material to Baltimore, where Wong’s group radiolabeled and injected them into baboons. The baboons have no tau pathology, but are useful for measuring how quickly the tracers cross into the brain and wash out or become metabolized.

For their compounds, the Roche/Hopkins scientists reported high-affinity specific tau binding down to 5.5 nanomolars, strong selectivity over Aβ in human brain tissue, as well as low white-matter binding and rapid brain entry and washout in the baboons.

With that, Roche in August 2014 started a Phase 1 trial of all three tracer candidates in healthy controls and Alzheimer’s patients at Johns Hopkins. Importantly, Honer said, this trial will involve arterial blood sampling so that the tracer’s behavior over time can be understood in more depth than has been done with some previous tracers. Most years at HAI, debate flares up between scientists oriented toward the physics aspects of PET and researchers oriented more toward its medical applications. The former tend to argue the virtues of conducting dynamic imaging and detailed kinetic modeling studies of new tracers, while the latter emphasize getting the tracers out into the clinic and tend to favor simpler methods of static imaging. This technical debate surfaces when there is a new tracer, or later on when a tracer does not behave quite as scientists expected.

In essence, the choice boils down to using semi-quantitative measures such as standardized uptake values (SUV), which require only static scans, or quantitative measures such as distribution volumes, which require dynamic scans and blood samples, or binding potentials, which require dynamic scans but potentially not blood samples. The attraction of SUVs and static scans is that they make the data easier to acquire and analyze, but the researcher has to make more assumptions about how much non-specific binding or radiolabelled metabolites might contribute to the signal.  Quantitative measures require fewer assumptions and therefore can serve to validate the tracer’s in vivo signal before simpler measures are used in the clinic, but they require acquisition and analysis that may not be available outside of research centers.

The debate in the amyloid and now also tau PET fields is about whether using the SUV is sufficient, or whether a tracer’s properties ought first to be validated with quantitative imaging, before picking methods that are feasible in routine practice. For PiB this has been done (e.g. Price et al., 2005;  McNamee et al., 2009), and for the Roche tracers it is being done now; however, not all tracer developers believe this kind of work is necessary. For more on this issue, see Part 5 of this series.

For more information and freely downloadable program abstracts, see the conference website.—Gabrielle Strobel

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

1. Tau Tracer T807/AV1451 Tracks Neurodegenerative Progression 8 Feb 2015
2. Tau PET Fits With CSF, Grows Over Time, Picks up Frontotemporal Cases 9 Feb 2015
3. What If It’s Not Garden-Variety AD? Telling Variants Apart by Where Tau Is 10 Feb 2015
4. Mixed Bag on Tau Tracer Validation, Kinetics: Some Things Fit, Some Don’t 11 Feb 2015

Paper Citations

1. Price JC, Klunk WE, Lopresti BJ, Lu X, Hoge JA, Ziolko SK, Holt DP, Meltzer CC, Dekosky ST, Mathis CA. Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B. J Cereb Blood Flow Metab. 2005 Nov;25(11):1528-47. PubMed.
2. McNamee RL, Yee SH, Price JC, Klunk WE, Rosario B, Weissfeld L, Ziolko S, Berginc M, Lopresti B, Dekosky S, Mathis CA. Consideration of optimal time window for Pittsburgh compound B PET summed uptake measurements. J Nucl Med. 2009 Mar;50(3):348-55. PubMed.

External Citations

1. A4 Study
2. Phase 1 trial
3. conference website

Further Reading

No Available Further Reading