09 Feb 2015

At the 9th Human Amyloid Imaging Conference, held January 14 to 16 in Miami Beach, Florida, 19 presentations by scientists at six different centers showcased data gathered thus far with T807. Now called AV1451, it is the most widely studied tau PET tracer to date, though others are pressing in fast (see Part 1 of this series). Overall, researchers showed largely converging results indicating that tau correlates more strongly than amyloid with neurodegeneration and cognitive decline in Alzheimer’s disease. Together, the data strengthen a growing sense that while amyloid and tau pathology first start up independently in separate regions in an aging person’s brain, the presence of amyloid somehow intensifies and accelerates an otherwise limited tauopathy. Exactly how that happens is one of the great mysteries in AD research these days, said Reisa Sperling of Harvard Medical School.

Researchers are starting to relate tau PET to CSF tau, and are beginning to track people over time with serial tau scans (see Part 3 of this series). Importantly, they are characterizing exactly what the tracer is binding. This is being done in postmortem brain slices from people who have not had a tau PET scan during life, because the tracers are so new that few cases have come to autopsy, the gold standard for this kind of validation. Scientists were pleased to find that T807/AV1451 does not appear to bind TDP-43 or a-synuclein, and hence will be helpful with the difficult task of differential diagnosis in the spectrum of frontotemporal and Lewy body dementias.

T807/AV1451 showed promise in detecting both atypical variants of AD and non-AD tauopathies; however, this story is only beginning to emerge. Scientists at HAI were puzzled by why T807/AV1451 appears to bind some regions considered devoid of tau pathology in AD (see Part 4 of this series). More worrisome to some, the tracer’s uptake in the cortex does not stabilize into a steady state but keeps climbing during the scanning period. This is not a problem for an up-down verdict of whether there is significant tau pathology in a given brain area, but it does raise questions about whether the measurement techniques for T807/AV1451 are quite ready for use in longitudinal and therapeutic studies that aim to quantify small changes over time (see Part 5).

“The pendulum has swung to one side, and we are rushing to use this tracer now in trials. I do not want it to swing back, but we should clean up those questions fast so the data we gather in trials are robust,” said Bill Klunk of the University of Pittsburgh Medical School.

Eli Lilly and Company owns the imaging company Avid Radiopharmaceuticals and bought the tau tracer T807 from Siemens (see Apr 2013 news). By now Avid has 11 clinical studies in various stages of planning or completion (see clinicaltrials.gov). At HAI, Avid’s Michael Pontecorvo presented the first cut of cross-sectional data, taken in September 2014, of an ongoing multicenter Phase 2 trial. This study has enrolled 230 cognitively normal and clinically affected volunteers and will follow some of them with repeat tau scans at nine and 18 months.

This first cut captured data on 156 people: 14 controls under 50 years old, 39 controls over 50, 70 people with mild cognitive impairment, and 33 with Alzheimer’s dementia. As a group, people with AD had more tau pathology than people with MCI, who had more than controls. At HAI, Pontecorvo’s colleague Mark Mintun told the audience that this largest study to date with AV1451 supports a simple graph by Pete Nelson and other leading neuropathologists in the field that was frequently cited at the HAI conference. It plots MMSE values at the time a person died against the amount of neurofibrillary tangles in their cortex to show that tau pathology correlates with cognitive impairment (Nelson et al., 2012). Tau PET now appears to bear this out.

Most importantly, perhaps, this ongoing AV1451 study points toward an interaction between amyloid and tau pathology. Like ADNI and several treatment trials, both the AD and MCI groups in this PET study contained some people who, despite their clinical diagnosis, had a negative florbetapir scan. These peoples’ cortical AV1451 uptakes were low, indicating that their symptoms were due to something other than Alzheimer’s. Among the cognitively normal volunteers, the picture was similar. In low-amyloid volunteers, T807/AV1451 uptake in the hippocampus did appear with age but stayed within a few small spots in medial temporal regions; in contrast, high-amyloid cognitively normal controls showed more tau pathology in a broader set of areas, particularly the inferior temporal cortex.

This hints that when there is amyloid, tau starts to aggregate beyond its initial confines in the medial temporal lobe. Other groups see this, as well. At HAI, Samuel Lockhart and others working with Bill Jagust at the University of California, Berkeley, showed in a series of 17 cognitively normal people that those without amyloid tended to accumulate tau pathology in the medial temporal lobe as they got older, but people with amyloid had tau pathology also spreading to the neocortex. Aaron Schultz and others in Keith Johnson’s group at Massachusetts General Hospital showed that among 75 older participants in the Harvard Aging Brain Study, the more amyloid a person had, the more tau pathology they also had in the inferior temporal cortex, an early “breakout” region of medial temporal lobe tau pathology.

The early confines of tau pathology in the medial temporal lobe are the hippocampus and parahippocampus, as well as entorhinal cortex. For cognitively normal people, tau spreading far beyond these small regions is bad news—and bad on a different scale than having a head full of amyloid, said Sperling. In previous work, she and colleagues had reported a cross-sectional link between the presence of brain amyloid and worse memory; however, her lab calls this the “weeny amyloid effect” because it is so small. Pathologists have claimed for years that neocortical tau pathology is more closely linked to cognitive impairment than amyloid, but the situation is complicated because some tau pathology also occurs with aging. This phenomenon recently got a new name, PART (Crary 2014). Now with both amyloid and tau tracers in hand, researchers can finally tease out in living people what matters most to cognition.

Sperling’s group reported on 97 older participants of the Harvard Aging Brain Study who had an AV1451/T807 scan within six months of cognitive testing. The scientists expressed cognition with a memory and an executive function score, each of which subsumed performance on three difficult tests. More tau accumulation in an early area of tau spread, the inferior temporal lobe, was associated with worse memory. The tau correlation was much stronger than that between amyloid burden and memory, and it held when adjusted for age, sex, and education. The same was not true of executive function in this study, Sperling said. “People with more amyloid also tend to have more tau, but the link between memory and tau is tighter in people with amyloid,” she said.  Playing with these factors in a multiple regression model suggested, in essence, that tau mediates the association between amyloid and memory.

This would jibe with a new network analysis study that assigns different consequences to amyloid and tau pathology in several different lines of transgenic mice. At least in those models, amyloid touches off neuroinflammation, while tangles destroy synapses, according to this work by Frances Edwards and colleagues at University College London (see Jan 2015 news).

A definitive grasp of how amyloid, tau, and other factors drive AD requires longitudinal observation of where the pathologies accumulate locally, when they spread, and how that relates to neurodegeneration and evolving symptoms, Sperling said.—Gabrielle Strobel

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References

News Citations

1. Human Amyloid Imaging Meeting Was Abuzz With Talk of Tau 6 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
5. Lilly Buys Tau Tracers From Siemens 17 Apr 2013
6. Network Analysis Points to Distinct Effects of Amyloid, Tau 25 Jan 2015

Paper Citations

1. Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del Tredici K, Duyckaerts C, Frosch MP, Haroutunian V, Hof PR, Hulette CM, Hyman BT, Iwatsubo T, Jellinger KA, Jicha GA, Kövari E, Kukull WA, Leverenz JB, Love S, Mackenzie IR, Mann DM, Masliah E, McKee AC, Montine TJ, Morris JC, Schneider JA, Sonnen JA, Thal DR, Trojanowski JQ, Troncoso JC, Wisniewski T, Woltjer RL, Beach TG. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012 May;71(5):362-81. PubMed.
2. Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alafuzoff I, Arnold SE, Attems J, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Gearing M, Grinberg LT, Hof PR, Hyman BT, Jellinger K, Jicha GA, Kovacs GG, Knopman DS, Kofler J, Kukull WA, Mackenzie IR, Masliah E, McKee A, Montine TJ, Murray ME, Neltner JH, Santa-Maria I, Seeley WW, Serrano-Pozo A, Shelanski ML, Stein T, Takao M, Thal DR, Toledo JB, Troncoso JC, Vonsattel JP, White CL 3rd, Wisniewski T, Woltjer RL, Yamada M, Nelson PT. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 2014 Dec;128(6):755-66. Epub 2014 Oct 28 PubMed.

External Citations

1. clinicaltrials.gov
2. Phase 2 trial

Further Reading

No Available Further Reading