The Use of Tau PET to Stage Alzheimer Disease According to the Braak Staging Framework

Abstract

Amyloid-β plaques and neurofibrillary tangles (NFTs) are the 2 histopathologic hallmarks of Alzheimer disease (AD). On the basis of the pattern of NFT distribution in the brain, Braak and Braak proposed a histopathologic staging system for AD. Braak staging provides a compelling framework for staging and monitoring of NFT progression in vivo using PET imaging. Because AD staging remains based on clinical features, there is an unmet need to translate neuropathologic staging to a biologic clinical staging system. Such a biomarker staging system might play a role in staging preclinical AD or in improving recruitment strategies for clinical trials. Here, we review the literature regarding AD staging with the Braak framework using tau PET imaging, here called PET-based Braak staging. Our aim is to summarize the efforts of implementing Braak staging using PET and assess correspondence with the Braak histopathologic descriptions and with AD biomarkers. Methods: We conducted a systematic literature search in May 2022 on PubMed and Scopus combining the terms “Alzheimer” AND “Braak” AND (“positron emission tomography” OR “PET”). Results: The database search returned 262 results, and after assessment for eligibility, 21 studies were selected. Overall, most studies indicate that PET-based Braak staging may be an efficient method to stage AD since it presents an adequate ability to discriminate between phases of the AD continuum and correlates with clinical, fluid, and imaging biomarkers of AD. However, the translation of the original Braak descriptions to tau PET was done taking into account the limitations of this imaging technique. This led to important interstudy variability in the anatomic definitions of Braak stage regions of interest. Conclusion: Refinements in this staging system are necessary to incorporate atypical variants and Braak-nonconformant cases. Further studies are needed to understand the possible applications of PET-based Braak staging to clinical practice and research. Furthermore, there is a need for standardization in the topographic definitions of Braak stage regions of interest to guarantee reproducibility and methodologic homogeneity across studies.

Cryo-EM structure of Alzheimer’s disease tau filaments with PET ligand MK-6240

“…Alzheimer's Disease (AD) is characterized by the progressive accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), with tau protein aggregates forming paired helical filaments (PHFs) and straight filaments (SFs) central to AD pathogenesis (1)(2)(3)(4)(5)(6). Positron emission tomography (PET) imaging with Aβ and tau ligands has enhanced diagnostic accuracy and understanding of AD progression (7). First-generation tau-PET ligands have enabled in vivo detection of tau tangles and have predictive capabilities for brain atrophy and cognitive decline in pre-symptomatic individuals (8)(9)(10)(11)(12)(13)(14).…”

Drosophilaappear resistant to trans-synaptic tau propagation

“…In AD, pathological tau appears early in the disease process in the entorhinal cortex and brainstem then progresses to synaptically connected brain regions in such a stereotypical fashion that the pattern of tau pathology is used to determine the stage of disease in post-mortem tissue 2 . This progressive tau spread has also been confirmed longitudinally in living people with AD through positron emission tomography with tracers that bind tau pathology [3][4][5] . Similarly, in primary tauopathies, tau pathology generally starts in restricted brain regions and spreads through the brain.…”

“…In this work, we sought to generate a Drosophila model of trans-synaptic tau spread. Despite testing multiple different experimental paradigms, we found that Drosophila are remarkably resistant to the trans-synaptic tau spread evidenced in human tauopathies and observed in mammalian model systems [3][4][5][6][7][8][9][10][11][12]16,17,21,22,55,56 . This important negative data demonstrates that, whilst exceptionally useful for a number of other studies in neurodegeneration, including modifiers of tau toxicity [57][58][59][60] , Drosophila are unlikely to be a suitable model for screening modifiers of trans-synaptic tau spread.…”

Cerebral tau pathology in cerebral amyloid angiopathy

“…The T807 PET scans were assessed to determine the SUVRs for the inferior temporal lobe and Braak stage ROIs [Braak Stages I/II (transentorhinal), III/IV (limbic) and V/VI (neocortical)]. 17 , 28 We defined tau PET positivity based on a cut-off value of a SUVR ≥ 1.3 in any of the ROIs, according to a previous report. 29 …”