PET Tracer PI-2620 Detects 4R Tau Deposits

Tau tracers have invigorated Alzheimer’s research, but they initially proved disappointing for other tauopathies. That is now changing, with at least two tracers, PI-2620 and APN-1607, that appear to bind specifically to the 4R tau deposits present in diseases such as progressive supranuclear palsy (Mar 2020 conference news). In the July 7 JAMA Neurology, researchers led by Matthias Brendel at the University of Munich, Germany, formally publish PI-2620 findings previously presented at the Human Amyloid Imaging conference in January (Feb 2020 conference news). The data indicate that PI-2620, made by Life Molecular Imaging, can detect 4R tau deposits in living and postmortem brains.

  • Tau tracer PI-2620 distinguishes PSP from controls and other disorders.
  • It binds aggregated 4R tau in postmortem PSP brains.
  • It is being tested in other 4R tauopathies, such as corticobasal degeneration.

The researchers scanned 40 patients with typical PSP, known as Richardson’s syndrome, and 20 patients with atypical PSP at five centers in Germany, the U.S., and Australia. They compared their scans with those from 10 healthy controls, 10 Alzheimer’s patients, and 10 people with Parkinson’s disease or multiple system atrophy. The tau tracer signal was stronger in Richardson’s syndrome than in atypical PSP. For Richardson’s syndrome, PI-2620 distinguished PSP from controls with a sensitivity of 85 percent and specificity of 77 percent, while for those with atypical PSP, sensitivity and specificity were 65 and 77 percent, respectively.

In regard to differential diagnosis, AD patients were most likely to be misdiagnosed by tau PET, with six out of 10 rating positively on PI-2620 scans. The authors noted that this misdiagnosis could be minimized by combining visual and quantitative reads to improve specificity, because AD and PSP patterns of tau accumulation look distinct. Tau tracer uptake did not correlate with age or the severity of PSP.

Andrew Stephens at LMI said PI-2620 appears to have higher sensitivity and specificity for PSP than does measuring midbrain atrophy on MRI scans, which is currently used as an imaging biomarker for PSP. He believes PI-2620 might aid differential diagnosis of atypical movement disorders when the diagnosis remains unclear after a clinical workup. The researchers continue to recruit new participants, and follow current ones to characterize longitudinal changes in tracer uptake.

Most participants in this cohort are still living. Four who died consented to autopsy. All had Richardson syndrome. More radiolabeled PI-2620 bound to basal ganglia and frontal cortex in sections from these brains than it did to sections from healthy control brains. Binding corresponded to staining with the AT-8 antibody, which detects aggregated tau.

Chet Mathis at the University of Pittsburgh Medical Center noted that autoradiography studies of PI-2620 have been puzzling, with some groups reporting no binding when using fresh frozen brain tissue. The Munich group used fixed tissue embedded in paraffin, which gives consistent positive results, Stephens said. Mathis agreed, “The autoradiography in fixed PSP tissues looks genuine.”

Mathis noted, however, that PI-2620 uptake in living PSP brain is weaker than in AD, having less than 20 percent of the peak intensity of the latter. This might be expected because the density of tau aggregates is lower in PSP than AD, he added. Mathis co-leads a project along with Gil Rabinovici at the University of California, San Francisco, to develop higher-affinity ligands for 4R tau, which could produce a stronger signal.

Because scientists don’t yet have a cryoEM structure for PSP 4R tau, it is unclear if tracers that bind this form will also bind 4R tau deposits found in other diseases. Brendel’s group is investigating PI-2620 uptake in people with the 4R tauopathy corticobasal degeneration and will present that data at the virtual Alzheimer’s Association International Conference later this month, Stephens said. The three-dimensional structure of CBD tau deposits was solved by cryoEM early this year (Feb 2020 news).—Madolyn Bowman Rogers

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References

News Citations

  1. Primary Tauopathies Get New PET Ligands
  2. Tau PET: The Field Expands Rapidly
  3. CryoEM of CBD Tau Suggests Another Unique Protofibril

Further Reading

Primary Papers

  1. Brendel M, Barthel H, van Eimeren T, Marek K, Beyer L, Song M, Palleis C, Gehmeyr M, Fietzek U, Respondek G, Sauerbeck J, Nitschmann A, Zach C, Hammes J, Barbe MT, Onur O, Jessen F, Saur D, Schroeter ML, Rumpf JJ, Rullmann M, Schildan A, Patt M, Neumaier B, Barret O, Madonia J, Russell DS, Stephens A, Roeber S, Herms J, Bötzel K, Classen J, Bartenstein P, Villemagne V, Levin J, Höglinger GU, Drzezga A, Seibyl J, Sabri O. Assessment of 18F-PI-2620 as a Biomarker in Progressive Supranuclear Palsy. JAMA Neurol. 2020 Nov 1;77(11):1408-1419. PubMed.

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