. 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.


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  1. Very good to learn that protein tau is making more headlines in the AD field and that ardent baptists see the "tau-light." We just added our contribution to tau diagnostics, see below. The data is in mouse models for the time being. There can never be enough tools nor data in the battle against Alzheimer's disease and the many other tauopathies.


    . Small-Animal PET Imaging of Tau Pathology with 18F-THK5117 in 2 Transgenic Mouse Models. J Nucl Med. 2016 May;57(5):792-8. Epub 2016 Feb 11 PubMed.

    View all comments by Fred Van Leuven
  2. In science, it often pays to see what is in front of you, without being encumbered by preconceptions. The pivotal 1991 study by Heiko Braak and Eva Braak did just that (Braak and Braak, 1991). It showed that tau inclusions form in a stereotypical fashion, allowing classification depending on where the inclusions are found and in what number. Cross-sectional autopsy studies of argyrophilic tau pathology showed first deposits in transentorhinal cortex (stages I/II), followed by hippocampus (stages III/IV) and neocortex (stages V/VI). These findings suggested that the biological process of Alzheimer’s disease begins decades before clinical symptoms appear. They are also compatible with the view that argyrophilic tau inclusions first appear in the transentorhinal cortex, from where they spread to distant brain regions, given enough time. In recent years, much experimental evidence has been adduced in favor of the spreading of tau inclusions from an initial site of formation (Goedert, 2015). What causes the formation of tau inclusions at this site is not known.

    The development of tau inclusions in transentorhinal cortex and hippocampus may be necessary (but not sufficient) for Alzheimer’s disease (Braak and Del Tredici, 2015; Duyckaerts et al., 2015). The latter is always present when abundant Aβ and tau deposits have formed in neocortex (Price and Morris, 1999). The lack of topological correlation between both types of deposits has suggested that they may form independently, but that neocortical Aβ deposits may come to drive the development of tau inclusions and may cause the spread of tau pathology. This interpretation is compatible with the amyloid cascade hypothesis, which was put forward around the time Braaks’ paper was published (Hardy and Allsop, 1991). However, it remains to be seen if stereotypical tau staging also applies to dominantly inherited cases of Alzheimer’s disease with mutations in APP; it was the study of those cases that led to the amyloid cascade hypothesis.

    Until recently, the anatomical distribution of tau inclusions could not be mapped directly in living individuals. This has changed with the arrival of PET tracers specific for aggregated tau. 18F-AV-1451 binds preferentially to tau filaments from Alzheimer’s disease brain, but not to Aβ, α-synuclein, or TDP-43 deposits. It came out of compound library screens that used brain sections from Alzheimer’s disease patients (Xia et al., 2013). Tau filaments from Alzheimer’s disease brains are made of all six human brain isoforms. The same is the case of tau filaments that form as function of age; it is also true of a number of other tauopathies, including chronic traumatic encephalopathy, tangle-only dementia, Niemann-Pick disease type C, the parkinsonism-dementia complex of Guam, cases of Gerstmann-Sträussler-Scheinker disease, and some cases with MAPT mutations (such as V337M and R406W). 18F-AV-1451 may be of use in all these conditions. However, it may not be of sufficient sensitivity in progressive supranuclear palsy and corticobasal degeneration, where tau filaments only comprise isoforms with four repeats, or in Pick’s disease, where tau isoforms with three repeats predominate in the filaments (Marquié et al., 2015). This imaging tool makes it possible to stage tau pathology longitudinally and across the disease spectrum. Prior to the current studies, PET scans had already shown a significantly greater retention of 18F-AV-1451 in the brains of patients with Alzheimer’s disease compared to individuals with mild cognitive impairment and controls (Chien et al., 2013Johnson et al., 2016). 

    The new studies by Schöll et al. and Schwarz et al. show that 18F-AV-1451 PET images from subjects aged 50-95 years with or without Alzheimer’s disease can be classified into patterns similar to those described by the Braaks in their neuropathological staging of tau pathology. By applying an algorithm based on the histological staging procedure, it has been possible to estimate Braak stages directly from PET scans. However, the relationship between Braak stages assigned by in vivo imaging and postmortem neuropathology remains to be defined. Both methods are likely to look at the same structures, paired helical and straight tau filaments, but they may differ in sensitivity. Our recent findings (Jackson et al., 2016) have shown that short fibrils constitute the major species of seed-competent tau in the brains of mice transgenic for human P301S tau. If the same holds true of aging and Alzheimer’s disease, increasing Braak tau stages may reflect the spreading of inclusions.

    Young adults showed only minimal brain uptake of ligand, consistent with Braak stage 0. Most older adults were at Braak stages I/II (76 percent) and a smaller proportion was at Braak stages III/IV (18 percent) or Braak stage 0 (6 percent). Patients with clinical Alzheimer’s disease were predominantly at stages V/VI (87 percent). However, a minority (13 percent) was at stages III/IV, showing an overlap with the changes seen in some older individuals without Alzheimer’s disease. No cases of Alzheimer’s disease were at stages I/II. The studies of Braak and colleagues had shown previously that individuals at stages I/II of tau pathology did not have cognitive impairment, whereas those at stages V/VI had Alzheimer’s disease clinically. Assuming that there is a continuum between stages, it follows that preventing the spreading of tau inclusions from stages I/II to stages V/VI might well prevent disease symptoms. It will be important to see if, using PET imaging with 18F-AV-1451, tau pathology progresses over time from stages I/II to stages III/IV in a given individual. It will be equally interesting to find out if stages III/IV are a necessary prerequisite for the development of stages V/VI.


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    View all comments by Michel Goedert

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