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It is expected that Braak staging using brain imaging can stratify living individuals according to their individual patterns of tau deposition, which may prove crucial for clinical trials and practice. However, previous studies using the first-generation tau PET agents have shown a low sensitivity to detect tau pathology in areas corresponding to early Braak histopathological stages (\u223c20% of cognitively unimpaired elderly with tau deposition in regions corresponding to Braak I\u2013II), in contrast to \u223c80\u201390% reported in post-mortem cohorts. Here, we tested whether the novel high affinity tau tangles tracer 18F-MK-6240 can better identify individuals in the early stages of tau accumulation. To this end, we studied 301 individuals (30 cognitively unimpaired young, 138 cognitively unimpaired elderly, 67 with mild cognitive impairment, 54 with Alzheimer\u2019s disease dementia, and 12 with frontotemporal dementia) with amyloid-\u03b2 18F-NAV4694, tau 18F-MK-6240, MRI, and clinical assessments. 18F-MK-6240 standardized uptake value ratio images were acquired at 90\u2013110 min after the tracer injection. 18F-MK-6240 discriminated Alzheimer\u2019s disease dementia from mild cognitive impairment and frontotemporal dementia with high accuracy (\u223c85\u2013100%). 18F-MK-6240 recapitulated topographical patterns consistent with the six hierarchical stages proposed by Braak in 98% of our population. Cognition and amyloid-\u03b2 status explained most of the Braak stages variance (P\u2009&amp;lt;\u20090.0001, R2 = 0.75). No single region of interest standardized uptake value ratio accurately segregated individuals into the six topographic Braak stages. Sixty-eight per cent of the cognitively unimpaired elderly amyloid-\u03b2-positive and 37% of the cognitively unimpaired elderly amyloid-\u03b2-negative subjects displayed tau deposition, at least in the transentorhinal cortex (Braak I). Tau deposition solely in the transentorhinal cortex was associated with an elevated prevalence of amyloid-\u03b2, neurodegeneration, and cognitive impairment (P\u2009&amp;lt;\u20090.0001). 18F-MK-6240 deposition in regions corresponding to Braak IV\u2013VI was associated with the highest prevalence of neurodegeneration, whereas in Braak V\u2013VI regions with the highest prevalence of cognitive impairment. Our results suggest that the hierarchical six-stage Braak model using 18F-MK-6240 imaging provides an index of early and late tau accumulation as well as disease stage in preclinical and symptomatic individuals. Tau PET Braak staging using high affinity tracers has the potential to be incorporated in the diagnosis of living patients with Alzheimer\u2019s disease in the near future.<\/jats:p>","DOI":"10.1093\/brain\/awaa180","type":"journal-article","created":{"date-parts":[[2020,5,16]],"date-time":"2020-05-16T12:32:52Z","timestamp":1589632372000},"page":"2818-2830","source":"Crossref","is-referenced-by-count":258,"title":["18F-MK-6240 PET for early and late detection of neurofibrillary tangles"],"prefix":"10.1093","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9057-8014","authenticated-orcid":false,"given":"Tharick A","family":"Pascoal","sequence":"first","affiliation":[{"name":"Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Alzheimer\u2019s Disease ResearchUnit, McGill University, Montreal, Canada"},{"name":"Douglas Research Institute, Le Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et de services sociaux (CIUSSS) de l'Ouest-de-l'\u00cele-de-Montr\u00e9al, McGill University, Montreal, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, Canada"},{"name":"Department of Psychiatry, McGill University, Montreal, Canada"},{"name":"Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7826-4781","authenticated-orcid":false,"given":"Joseph","family":"Therriault","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Alzheimer\u2019s Disease ResearchUnit, McGill University, Montreal, Canada"},{"name":"Douglas Research Institute, Le Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et de services sociaux (CIUSSS) de l'Ouest-de-l'\u00cele-de-Montr\u00e9al, McGill University, Montreal, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, Canada"},{"name":"Department of Psychiatry, McGill University, Montreal, Canada"},{"name":"Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea L","family":"Benedet","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Alzheimer\u2019s Disease ResearchUnit, McGill University, Montreal, Canada"},{"name":"Douglas Research Institute, Le Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et de services sociaux (CIUSSS) de l'Ouest-de-l'\u00cele-de-Montr\u00e9al, McGill University, Montreal, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, Canada"},{"name":"Department of Psychiatry, McGill University, Montreal, Canada"},{"name":"Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Savard","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Alzheimer\u2019s Disease ResearchUnit, McGill University, Montreal, Canada"},{"name":"Douglas Research Institute, Le Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et de services sociaux (CIUSSS) de l'Ouest-de-l'\u00cele-de-Montr\u00e9al, McGill University, Montreal, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, Canada"},{"name":"Department of Psychiatry, McGill University, Montreal, Canada"},{"name":"Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Firoza Z","family":"Lussier","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Alzheimer\u2019s Disease ResearchUnit, McGill University, Montreal, Canada"},{"name":"Douglas Research Institute, Le Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et de services sociaux (CIUSSS) de l'Ouest-de-l'\u00cele-de-Montr\u00e9al, McGill University, Montreal, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, Canada"},{"name":"Department of Psychiatry, McGill University, Montreal, Canada"},{"name":"Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mira","family":"Chamoun","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Alzheimer\u2019s Disease ResearchUnit, McGill University, Montreal, Canada"},{"name":"Douglas Research Institute, Le Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et de services sociaux (CIUSSS) de l'Ouest-de-l'\u00cele-de-Montr\u00e9al, McGill University, Montreal, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, Canada"},{"name":"Department of Psychiatry, McGill University, Montreal, Canada"},{"name":"Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9cile","family":"Tissot","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Alzheimer\u2019s Disease ResearchUnit, McGill University, Montreal, Canada"},{"name":"Douglas Research Institute, Le Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et de services sociaux (CIUSSS) de l'Ouest-de-l'\u00cele-de-Montr\u00e9al, McGill University, Montreal, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, Canada"},{"name":"Department of Psychiatry, McGill University, Montreal, Canada"},{"name":"Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Naveed Iqbal","family":"Qureshi","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Alzheimer\u2019s Disease ResearchUnit, McGill University, Montreal, Canada"},{"name":"Douglas Research Institute, Le Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et de services sociaux (CIUSSS) de l'Ouest-de-l'\u00cele-de-Montr\u00e9al, McGill University, Montreal, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, Canada"},{"name":"Department of Psychiatry, McGill University, Montreal, Canada"},{"name":"Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Su","family":"Kang","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Alzheimer\u2019s Disease ResearchUnit, McGill University, Montreal, Canada"},{"name":"Douglas Research Institute, Le Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et de services sociaux (CIUSSS) de l'Ouest-de-l'\u00cele-de-Montr\u00e9al, McGill University, Montreal, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, Canada"},{"name":"Department of Psychiatry, McGill University, Montreal, Canada"},{"name":"Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sulantha","family":"Mathotaarachchi","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Alzheimer\u2019s Disease ResearchUnit, McGill 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Canada"},{"name":"Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,7,16]]},"reference":[{"key":"2020111212324957400_awaa180-B1","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1111\/j.1750-3639.2008.00147.x","article-title":"Staging of neurofibrillary pathology in Alzheimer\u2019s disease: a study of the BrainNet Europe Consortium","volume":"18","author":"Alafuzoff","year":"2008","journal-title":"Brain Pathol"},{"key":"2020111212324957400_awaa180-B2","doi-asserted-by":"crossref","first-page":"93","DOI":"10.2967\/jnumed.118.209650","article-title":"In vivo characterization and quantification of neurofibrillary tau PET radioligand (18)F-MK-6240 in humans from alzheimer disease dementia to young controls","volume":"60","author":"Betthauser","year":"2019","journal-title":"J Nucl 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