Do Tau Tracers Track Cognitive Decline in Disease?

Series - Clinical Trials on Alzheimer’s Disease 2013:

Pathology studies show that tau tangles, unlike amyloid, track closely with the cognitive decline of Alzheimer’s disease. This has raised hope that the tau PET tracers being developed will allow researchers to stage disease, and early results do seem to bear this out, as tracer uptake correlates with the degree of cognitive impairment. But does this relationship hold true even at preclinical stages? At the Sixth Clinical Trials Conference on Alzheimer’s Disease (CTAD) held November 14–16 in San Diego, Keith Johnson at Massachusetts General Hospital, Boston, presented data showing that uptake of Eli Lilly and Company’s tau tracer T807 in the hippocampus correlated with subtle memory problems in a small number of cognitively normal elderly people. If this finding holds up in larger studies, it would imply that tau imaging could serve as an early disease biomarker.

In the same session, Mark Mintun at the Lilly subsidiary Avid Radiopharmaceuticals confirmed previous reports that AD patients with more severe dementia retain more T807 in their brains. Mintun also added to data indicating that which brain regions take up the tracer matches the typical pattern of tau deposition in AD. However, some findings did not fit the mold. Some people showed much higher binding than their level of impairment would predict, he reported. It is unclear what causes this variability, or if it will complicate the use of tau imaging. Much work remains to be done before these tracers are ready for more widespread clinical use, including confirming tau binding through autopsy studies, Mintun noted.

“It’s an exciting area,” said Ron Petersen at the Mayo Clinic in Rochester, Minnesota, who heard the talks. He plans to start using T807 in research studies in his clinic. At the same time, Petersen cautioned that researchers need more information about these agents. “We need to know about the specificity of the binding for certain isoforms or conformations of tau,” he told Alzforum. For example, in early studies the three existing classes of tau tracer appear specific for different tauopathies, suggesting they bind distinct forms of the protein (see Jan 2013 news story; Sep 2013 news story).

Johnson and colleagues wanted to investigate the relationship between AD pathology and the earliest signs of cognitive impairment. The researchers used T807 and Pittsburgh Compound B (PiB), which binds amyloid deposits, to scan the brains of 12 cognitively normal people whose average age was 73. Participants also took a battery of standard cognitive tests. In this cohort, the hippocampus took up the highest levels of T807, consistent with neuropathological findings that neurofibrillary tangles accumulate in this region even during normal aging. Those with the most hippocampal tau scored lowest on a test of delayed recall, the Logical Memory IIa test. These people also had the most amyloid deposits throughout the cortex, but amyloid by itself correlated only weakly with memory scores, as had been found previously (see, e.g., Dec 2008 news story; Rowe et al., 2010).

While these findings hint that tau uptake might serve as a biomarker in preclinical populations, Johnson emphasized that he is still analyzing data and that it is too early to draw firm conclusions. In ongoing work, he is testing the hypothesis that more advanced levels of impairment are associated with the spread of tau from the hippocampus into the neocortex, as described in Heiko Braak’s foundational pathology work. Johnson showed data indicating that the strength of tau binding in these areas differentiates normal elderly controls from people with mild cognitive impairment (MCI) and dementia, while uptake in the hippocampus alone does not.

Mintun also studies T807 retention in people with MCI and AD. At last July’s Alzheimer’s Association International Conference in Boston, he presented data from the first 10 people scanned with this tracer (see Jul 2013 news story). At CTAD, Mintun added results from 12 more people. The total group includes young and old controls as well as five people with MCI and nine with AD. People at more severe disease stages had dramatically higher uptake of tau tracer, which correlated with lower scores on the Mini Mental State Exam, Mintun said. The pattern matched Braak staging, with areas such as the somatosensory and occipital cortices, which are known to be spared until late in the disease, showing little retention. The new data “increases our confidence that our tracer is imaging tau deposits,” Mintun told Alzforum.

One surprise emerged from the 12 additional volunteers: Some people showed a much stronger signal than average, although their regional uptake pattern was the same. In discussions at the conference, attendees speculated that these individuals might harbor a genetic susceptibility to misfold tau. “That will be a very interesting topic for further research,” Mintun noted. One important question is whether people with abnormally high tracer retention have more accumulated tau, or simply bind the tracer more strongly, which could make it difficult to interpret tau scans. In microglial imaging studies, for example, a genetic polymorphism that increases affinity of the TPSO receptor for ligands helped scuttle development of TPSO-based glial tracers (see Apr 2012 news story).

Mintun plans to conduct longitudinal studies of people at different disease stages to see if changes in tau uptake track disease progression. In addition, he will investigate how tracer uptake correlates with other biomarkers such as tau in cerebrospinal fluid. Such data would help to validate tau tracers for use as biomarkers in clinical trials.—Madolyn Bowman Rogers.

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References

News Citations

  1. HAI—Spotlight on Tau Tracers at Human Amyloid Imaging Meeting
  2. Tau Tracer May Light Up All Tauopathies
  3. DC: Amyloid-Laden Brains—What Do They Mean for Healthy Seniors?
  4. Imaging Inflammation: Can Glial PET Tracers Make a Mark?

Paper Citations

  1. Rowe CC, Ellis KA, Rimajova M, Bourgeat P, Pike KE, Jones G, Fripp J, Tochon-Danguy H, Morandeau L, O'Keefe G, Price R, Raniga P, Robins P, Acosta O, Lenzo N, Szoeke C, Salvado O, Head R, Martins R, Masters CL, Ames D, Villemagne VL. Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol Aging. 2010 Aug;31(8):1275-83. PubMed.

Other Citations

  1. Jul 2013 news story

Further Reading

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