Brier MR, Gordon B, Friedrichsen K, McCarthy J, Stern A, Christensen J, Owen C, Aldea P, Su Y, Hassenstab J, Cairns NJ, Holtzman DM, Fagan AM, Morris JC, Benzinger TL, Ances BM. Tau and Aβ imaging, CSF measures, and cognition in Alzheimer's disease. Sci Transl Med. 2016 May 11;8(338):338ra66. PubMed.

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  1. In this paper, Brier and colleagues investigated the topography of in vivo tau and Aβ deposition in a multimodal setting.

    This new study offers interesting and innovative approaches to investigate the regional pattern of the pathological markers of Alzheimer’s disease in vivo, and their relationship with other key biomarkers. Interestingly, the authors showed that tau and Aβ deposition (as measured by 18F-T807 and 18F-florbetapir, respectively), while exhibiting different patterns, correlate together in distinct combinations of regions (“topographies”). Of course their findings will need to be replicated in larger cohorts.

    The strength of this study is the multivariate approach, not only using PET imaging but also CSF as well as cognitive measurements. In a research field where the underlying mechanisms triggering the symptoms are not yet understood, it appears fundamental to look at combinations of actors instead of single variables, in order to comprehend the whole pathogenic process.

    The participants in this study underwent exhaustive neuropsychological testing, allowing the authors to determine whether the regional tau deposition could predict the performance in several cognitive domains. They found that tau deposition pattern predicted cognition performance better than Aβ deposition did. It cannot, however, be excluded that these associations with cognition might be driven by the few AD patients included in the study (no association remained when looking at the cognitively normal population only). This illustrates nonetheless the importance of looking at cognition in greater details, and not considering MMSE or other simplistic measures as a good (sensitive enough) assessment tools for cognition.

    This should be considered as more a study on normal aging than disease, since most participants are cognitively normal volunteers (36 out of the 46 participants). There has been an increasing interest in assessing tau deposition in normal elderly subjects. Brier and colleagues’ findings are in agreement overall with a recent report on cognitively normal subjects using the same tau tracer (Johnson et al., 2016). 

    The authors were also able to compare 18F-T807 and 18F-florbetapir PET imaging findings with CSF biomarkers. Such investigations are, of course, highly valuable, and the rather intriguing results reported in the paper will hopefully raise more attention and discussion from the scientific community. 

    Several crucial questions regarding tau imaging that could not be addressed by this study remain open, the most important one being whether the signal we observe in PET is specific of tau pathology, or whether we might be targeting additional unknown features. There has been active discussion on this topic, and while in vitro analyses show good affinity from the tau tracers to their target (Feb 2016 news), their specificity and the correspondence between in vitro and in vivo signal remain unclear. The development of tau tracers offers exciting opportunities, and, hopefully, with the help of in vitro work and future multimodal studies like the present one, we will crack the code of AD’s pathological cascade.

    References:

    Johnson KA, Schultz A, Betensky RA, Becker JA, Sepulcre J, Rentz D, Mormino E, Chhatwal J, Amariglio R, Papp K, Marshall G, Albers M, Mauro S, Pepin L, Alverio J, Judge K, Philiossaint M, Shoup T, Yokell D, Dickerson B, Gomez-Isla T, Hyman B, Vasdev N, Sperling R. Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol. 2016 Jan;79(1):110-9. Epub 2015 Dec 15 PubMed.

    View all comments by Laure Saint-Aubert

  2. The ability to study the interplay between Aβ and tau in vivo across the aging-to-AD spectrum is incredibly exciting and in my opinion highly likely to yield new insights into disease mechanisms. This study adds to a growing literature on this topic (e.g. Johnson et al., 2016; Scholl et al., 2016; Ossenkoppele et al., 2016). 

    This study took a unique approach to identifying spatial patterns of Aβ (florbetapir) and tau (T807) deposition and found that while amyloid and tau are clearly related to each other, they are separated in space, with different brain regions showing an early proclivity for each pathology. Though we have known about this paradox for some time from neuropathology studies, the imaging findings highlight the need to integrate these findings into unifying models of AD that will better explain how amyloid and tau interact with each other and synergize to drive disease.

    As with previous studies, the authors found that cognitive performance is more strongly related to tau than amyloid. A missing piece in this particular study is a measure of neurodegeneration (e.g. MRI), which may mediate the relationship between tau deposition and cognitive decline.

    This is also one of the first studies to assess the relationships between tau PET and CSF measures of total tau and p-tau. The initial findings suggest that these relationships are not as straightforward as the inverse relationship between CSF and PET measures of Aβ, and require further study.

    One limitation of the present study is that it is quite heavily weighted toward normal older individuals (75 percent of subjects with CDR=0). The relationships between tau PET and other imaging, cognitive, and CSF variables will likely vary across disease stages, and sampling a larger number of patients with MCI and AD dementia will be informative in this respect.

    References:

    Johnson KA, Schultz A, Betensky RA, Becker JA, Sepulcre J, Rentz D, Mormino E, Chhatwal J, Amariglio R, Papp K, Marshall G, Albers M, Mauro S, Pepin L, Alverio J, Judge K, Philiossaint M, Shoup T, Yokell D, Dickerson B, Gomez-Isla T, Hyman B, Vasdev N, Sperling R. Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol. 2016 Jan;79(1):110-9. Epub 2015 Dec 15 PubMed.

    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.

    Ossenkoppele R, Schonhaut DR, Schöll M, Lockhart SN, Ayakta N, Baker SL, O'Neil JP, Janabi M, Lazaris A, Cantwell A, Vogel J, Santos M, Miller ZA, Bettcher BM, Vossel KA, Kramer JH, Gorno-Tempini ML, Miller BL, Jagust WJ, Rabinovici GD. Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease. Brain. 2016 May;139(Pt 5):1551-67. Epub 2016 Mar 8 PubMed.

    View all comments by Gil Rabinovici

  3. This study by Brier et al. represents a thoughtful advance in our understanding of the relations between early stage Alzheimer’s disease pathology, measured using PET and CSF measures for amyloid as well as tau, and both clinical and cognitive measures. This study confirms and extends other recent AV-1451/T807 tau PET findings—to start to break down the specific topographies of pathology that are critical to brain and cognitive differences in late life (Johnson et al., 2016; Ossenkoppele et al., 2016; Schwarz et al. 2016; Schöll et al., 2016). The authors provide a useful next step toward taking greater advantage of the specificity of tau imaging, to start to convey topographical information of these relations. I appreciated the methodological approaches the authors used: singular value decomposition to summarize complex PET spatial patterns, canonical correlation to simplify amyloid-tau relations, and penalized regressions for relating PET/CSF with cognition. This paper helps lead me to ask the next questions, such as: What are the more specific patterns of spatial relations between amyloid and tau PET? Are there different temporal trajectories of topographies across people or across the brain? And lastly, how does the pattern of these relations, particularly in normal elderly, speak to the biological relationships between amyloid and tau pathologies?

    References:

    Johnson KA, Schultz A, Betensky RA, Becker JA, Sepulcre J, Rentz D, Mormino E, Chhatwal J, Amariglio R, Papp K, Marshall G, Albers M, Mauro S, Pepin L, Alverio J, Judge K, Philiossaint M, Shoup T, Yokell D, Dickerson B, Gomez-Isla T, Hyman B, Vasdev N, Sperling R. Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol. 2016 Jan;79(1):110-9. Epub 2015 Dec 15 PubMed.

    Ossenkoppele R, Schonhaut DR, Schöll M, Lockhart SN, Ayakta N, Baker SL, O'Neil JP, Janabi M, Lazaris A, Cantwell A, Vogel J, Santos M, Miller ZA, Bettcher BM, Vossel KA, Kramer JH, Gorno-Tempini ML, Miller BL, Jagust WJ, Rabinovici GD. Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease. Brain. 2016 May;139(Pt 5):1551-67. Epub 2016 Mar 8 PubMed.

    Schwarz AJ, Yu P, Miller BB, Shcherbinin S, Dickson J, Navitsky M, Joshi AD, Devous MD Sr, Mintun MS. Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages. Brain. 2016 May;139(Pt 5):1539-50. Epub 2016 Mar 2 PubMed.

    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 Samuel Lockhart

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