Grothe MJ, Barthel H, Sepulcre J, Dyrba M, Sabri O, Teipel SJ, Alzheimer's Disease Neuroimaging Initiative. In vivo staging of regional amyloid deposition. Neurology. 2017 Nov 14;89(20):2031-2038. Epub 2017 Oct 18 PubMed.

Recommends

Please login to recommend the paper.

Comments

  1. This is an interesting study by Grothe and colleagues that suggests a typical pattern of regional deposition for neocortical Aβ in AD. Interestingly, the staging criteria they apply to the regional deposition allows for more than 45 percent of older clinically normal people to be identified as having unusual amyloid deposition, opposed to the ~30 percent identified using traditional dichotomous categorizations. This could have implications for clinical trials, allowing individuals to be identified at even earlier stages of the disease pathogenesis. However, caution must be taken as these findings are based on cross-sectional data. It will be important to validate these findings, particularly by understanding the rates of progression through the stages identified as well as rates of progression towards disease.

    View all comments by Samantha Burnham

  2. In this staging scheme proposed by the authors, the consistency of the pattern is certainly striking and will be very useful in terms of recruitment into clinical trials and diagnostic prognosis. What strikes me is the discordance between very early pre-symptomatic appearance of striatal Aβ in autosomal-dominant AD (ADAD), as shown by myself, Bill Klunk, and Victor Villemagne years ago, and the very late appearance in sporadic disease, something Grothe and colleagues also point out in their discussion. This is certainly something to think about when using ADAD as a model for Alzheimer’s disease in general.

    View all comments by Michael Schöll

  3. In this experiment, Grothe and colleagues find evidence for in vivo staging of amyloid based on regional uptake values extracted from florbetapir PET data from the ADNI. To do this, the authors examine regional positivity within the clinically normal sample, and determine the frequency by which this positivity occurs. For instance, the anterior cingulate and fusiform gyrus are in the earliest stage since they are positive in the most individuals; the striatum is in the final stage since the prevalence of positivity is lowest in that region. The overall result is a four-stage model of amyloid accumulation that for the most part recapitulates postmortem Thal staging. However, the results suggest finer resolution than Thal Stage 1 by implying specific regions within the neocortex (inferior/basal temporal and anterior cingulate). In my view, the “Grothe Stage 1” result is the most important finding in this paper. It has long been observed that amyloid deposition observed with PET imaging, even among normals, shows a widely distributed regional pattern that impacts multiple cortical regions. This work contradicts that dogma by suggesting a subset of regions show early amyloid accumulation. Importantly, Grothe Stage 1 already shows reduced CSF amyloid, suggesting that this staging procedure may be able to capture very early amyloid pathology that is regionally restricted. The consequences of early deposition in the inferior/basal temporal lobe and anterior cingulate among clinically normal individuals remains unknown, and may provide important insights for the early consequences on cognition and neuronal integrity in older normal individuals. Interestingly, an initial site of tau deposition within amyloid-positive normals seems to be in the inferior temporal cortex (Schöll et al., 2016), suggesting there may be some unique vulnerability in this region. Furthermore, over the past few years we have witnessed a shift in clinical trial design, such that many strategies are currently underway to target asymptomatic individuals with evidence of abnormal amyloid as early as possible. As shown in this article, traditional global cut offs are missing 81 percent of Grothe Stage 1. Thus, implementation of a more regionally specific mask may enable the detection of individuals who are at the earliest stages of amyloid accumulation for enrollment into prevention trials.

    A few new directions can be suggested based on the results of this work. As mentioned by the authors, it may be important to consider region-specific cut-offs, given that differences in gray-matter density and surface area may influence the PET signal extracted across regions; thus a general cut-off may not be appropriate. The fact that Grothe Stage 1 already showed reduced CSF amyloid suggests that the involvement of these regions is not purely driven by cut-off selection. It would be interesting to apply this approach to young APOE4-positive subjects as a “control” to ensure that these gold-standard amyloid cases would fall into Grothe Stage 0. Finally, it would be informative to see these patterns longitudinally, given that the thrust of this work is to provide a sequence of involvement across amyloid stages. If Stage 1 becomes Stage 2 over time, then that would provide convincing evidence for Grothe Staging.

    References:

    Schöll M, Lockhart SN, Schonhaut DR, O'Neil JP, Janabi M, Ossenkoppele R, Baker SL, Vogel JW, Faria J, Schwimmer HD, Rabinovici GD, Jagust WJ. PET Imaging of Tau Deposition in the Aging Human Brain. Neuron. 2016 Mar 2;89(5):971-82. PubMed.

    View all comments by Elizabeth Mormino

Make a Comment

To make a comment you must login or register.

This paper appears in the following:

News

  1. PET Staging Charts Gradual Course of Amyloid Deposition in Alzheimer’s