17 Aug 2016

Part 3 of a five-part report.

Overall in the Dominantly Inherited Alzheimer’s Network (DIAN), the brain imaging news was twofold. On the larger goal of putting cross-sectional data on a longitudinal footing, Nick Fox of University College, London, showed that for brain atrophy, longitudinal data on the DIAN cohort are confirming the hypotheses suggested by cross-sectional and previous, much smaller serial studies. The new data is mostly adding precision for rates of change of this “final common pathway” of neurodegeneration, Fox said during the Alzheimer’s Association International Conference held July 22-28 in Toronto. In contrast, tau PET data is emerging and less consistent across mutations thus far.

Broadly, the annual gray-matter atrophy among mutation non-carriers in DIAN matches the 0.3 percent per year that has been found in huge population studies of aging. In contrast, in symptomatic mutation carriers, the brain shrinks a whopping six times faster than that, Fox said. In asymptomatic mutation carriers, atrophy rates differ by region and by disease stage. For example, the precuneus, which crops up frequently in imaging studies of preclinical AD, thins noticeably starting a decade before a person’s estimated year of onset (EYO). Atrophy there, and in other areas, accelerates as people approach their EYO.

For modeling rates of shrinkage in the whole brain and hippocampus, as well as modeling the corresponding expansion of the brain’s ventricles, change-point analysis is proving useful, Fox said. This kind of statistical approach also works well for the modeling of cognitive and CSF trajectories in DIAN (see Part 2 of this story). In particular, for MRI, change-point analysis indicates an inflection point around 7.5 years prior to EYO, when many markers appear to begin changing more rapidly.

The other imaging news of DIAN concerns tau PET. For the past three years, DIAN leaders tried to get tau PET up and running across DIAN sites and in the DIAN-TU trial in order to get baselines for longitudinal data collection tout de suite. Alas, DIAN got bogged down by similar difficulties that many groups throughout the AD field have experienced in getting access to the first widely studied tracer—T807, aka AV1451, now named flortaucipir in analogy to Avid/Lilly’s florbetapir. A new arrangement negotiated since then does offer this tracer, though only to U.S. and Australian sites, and in the form of an ancillary study that has to be taken under contract directly between Avid and each site. The sites can then donate their tau PET data back to the DIAN database. At AAIC, DIAN investigators decided to pursue this deal to get the science started, but they will also explore other tracers and possibly switch once a better or more easily available one comes to the fore. The German sites and some others have already decided to use the Tohoku/GE tracer THK5351, according to Johannes Levin of Ludwig-Maximilian-University in Munich.

Thus far, only Tammie Benzinger at Washington University, St. Louis, has had access to flortaucipir for DIAN participants for long enough to be able to present cross-sectional data on the first 19 participants. And the small data set available thus far is not straightforward. At AAIC, Benzinger explained that she is testing whether the regional spread of tau pathology in ADAD follows the Braak and Braak stages—after all, stages I and II of this classification scheme are often attributed to age, and the asymptomatic DIAN mutation carriers are in their 20s and 30s. She also asks whether the spread of tau pathology follows the proposed stages of the NIA-AA criteria of preclinical AD, or is better described by the more recent A/T/N scheme proposed by Cliff Jack at the Mayo Clinic in Rochester, Minnesota, and colleagues (Sperling et al., 2011; Jack et al., 2016). Benzinger’s ability to interpret the data is somewhat limited because, to stay blinded to who carries the AD mutation, she looks at all asymptomatic participants in one group. But that is not the main reason the initial findings don’t quite fit expectations, she told Alzforum.

Some of the asymptomatic people are in early stages of amyloid deposition; they retain no tau tracer. Some are positive on both amyloid and tau scans, but have much less tau than the symptomatic participants. “This confirms that amyloid is first and tau comes later,” Benzinger said. Beyond that, it gets complicated.

One person has most of his or her tau uptake in the brain’s occipital area, not in the four areas where tau is typically thought to spread first once it leaves the entorhinal cortex. (They are the entorhinal, lateral occipital, inferior temporal lobe cortex, and precuneus). Confusing matters further, this person has a normal FDG scan but is mildly symptomatic. Another symptomatic person with high amyloid load retained a low level of tau tracer on one side of his or her occipital lobe, but was hypometabolic in both temporal lobes. A third amyloid-positive person fit conceived wisdom better in that he or she had high tau and hypometabolism in the same area, but the location of that coupling was again in more posterior regions than Benzinger expected to see. “We see little tau tracer uptake in the medial temporal lobe, and more in the precuneus and posterior cortex,” she said. More data in more people, serial scans, and also analyses by gene or mutation may solve the questions raised by these early data.

Curiously, tau PET imaging of the PS-1 E280A “Paisa” mutation afflicting families in Colombia shows less variability. Like Benzinger, Yakeel Quiroz of Massachusetts General Hospital had presented a first, small data set at the last Human Amyloid Imaging conference in Miami Beach, Florida (Feb 2016 conference news), and at AAIC Quiroz followed up with results from a larger group. In her ongoing project, a handful of relatives fly from Medellin to Boston every few months for PiB and AV1451 scans. They are not enrolled in the Alzheimer Prevention Initiative trial of Genentech’s antibody crenezumab because they failed screening, or for other reasons; others are already symptomatic and hence are excluded from the trial. Yet they still participate in Quiroz’s research.

Of the 21 Colombians Quiroz has scanned so far, eight are asymptomatic carriers aged 28 to 44, two carriers have amnestic MCI. In contrast to the variability emerging in DIAN, Quiroz continues to see a consistent pattern. Tau in non-carriers matches that in age-matched controls, but in mutation carriers it starts in the medial temporal lobe, especially the entorhinal cortex. PiB uptake starts around age 28. Until age 35 people have very little tau tracer uptake in the entorhinal cortex, but starting at age 36, tau pathology increases and spreads rapidly to the inferior temporal and lateral temporal lobe, and from there to other cortical regions—all while people remain asymptomatic. The two people with MCI have much higher levels and a broader cortical distribution of tau uptake.

While her scans thus far broadly resemble what is seen in LOAD, Quiroz said she needs many more to fill in current gaps in the age range before she can obtain at least a cross-sectional picture of exactly how tau pathology appears to develop before clinical onset. “My goal is to have 50 subjects in this study,” she said. With that number, she can analyze the relationship between tau, other biomarkers, and cognitive decline, and compare the E280A data set to the LOAD data currently being gathered within the ongoing Harvard Aging Brain Study.—Gabrielle Strobel 

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References

News Citations

1. DIAN Longitudinal Data Say Cognition Goes Earlier Than Previously Thought 16 Aug 2016
2. Tau Tracers Track First Emergence of Tangles in Familial Alzheimer’s 2 Feb 2016

Therapeutics Citations

1. Crenezumab

Paper Citations

1. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):280-92. Epub 2011 Apr 21 PubMed.
2. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Feldman HH, Frisoni GB, Hampel H, Jagust WJ, Johnson KA, Knopman DS, Petersen RC, Scheltens P, Sperling RA, Dubois B. A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology. 2016 Aug 2;87(5):539-47. Epub 2016 Jul 1 PubMed.

Other Citations

1. PS-1 E280A “Paisa” mutation

Further Reading

No Available Further Reading