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Although the available first-generation tau PET tracers detect tau accumulation in symptomatic individuals, their nanomolar affinity offers limited sensitivity to detect early tau accumulation in asymptomatic subjects.<\/jats:p>\n                  <jats:p>Here, we hypothesized the novel subnanomolar affinity tau tangles tracer 18F-MK-6240 can detect longitudinal tau accumulation in asymptomatic and symptomatic subjects. We studied 125 living individuals (65 cognitively unimpaired elderly amyloid-\u03b2-negative, 22 cognitively unimpaired elderly amyloid-\u03b2-positive, 21 mild cognitive impairment amyloid-\u03b2-positive and 17 Alzheimer\u2019s disease dementia amyloid-\u03b2-positive individuals) with baseline amyloid-\u03b2 18F-AZD4694 PET and baseline and follow-up tau 18F-MK-6240 PET. The 18F-MK-6240 standardized uptake value ratio (SUVR) was calculated at 90\u2013110\u2009min after tracer injection and the cerebellar crus I was used as the reference region. In addition, we assessed the in vivo18F-MK-6240 SUVR and post-mortem phosphorylated tau pathology in two participants with Alzheimer\u2019s disease dementia who died after the PET scans.<\/jats:p>\n                  <jats:p>We found that the cognitively unimpaired amyloid-\u03b2-negative individuals had significant longitudinal tau accumulation confined to the PET Braak-like stage I (3.9%) and II (2.8%) areas. The cognitively unimpaired amyloid-\u03b2-positive individuals showed greater tau accumulation in Braak-like stage I (8.9%) compared with later Braak stages. The patients with mild cognitive impairment and those who were Alzheimer\u2019s dementia amyloid-\u03b2-positive exhibited tau accumulation in Braak regions III\u2013VI but not I\u2013II. Cognitively impaired amyloid-\u03b2-positive individuals that were Braak II\u2013IV at baseline displayed a 4.6\u20137.5% annual increase in tau accumulation in the Braak III\u2013IV regions, whereas those who were cognitively impaired amyloid-\u03b2-positive Braak V\u2013VI at baseline showed an 8.3\u201310.7% annual increase in the Braak regions V\u2013VI. Neuropathological assessments confirmed PET-based Braak stages V\u2013VI in the two brain donors.<\/jats:p>\n                  <jats:p>Our results suggest that the 18F-MK-6240 SUVR is able to detect longitudinal tau accumulation in asymptomatic and symptomatic Alzheimer\u2019s disease. The highest magnitude of 18F-MK-6240 SUVR accumulation moved from the medial temporal to sensorimotor cortex across the disease clinical spectrum. Trials using the 18F-MK-6240 SUVR in cognitively unimpaired individuals would be required to use regions of interest corresponding to early Braak stages, whereas trials in cognitively impaired subjects would benefit from using regions of interest associated with late Braak stages. Anti-tau trials should take into consideration an individual\u2019s baseline PET Braak-like stage to minimize the variability introduced by the hierarchical accumulation of tau tangles in the human brain. Finally, our post-mortem findings supported use of the 18F-MK-6240 SUVR as a biomarker to stage tau pathology in patients with Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.1093\/brain\/awab248","type":"journal-article","created":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T15:20:30Z","timestamp":1625066430000},"page":"3517-3528","source":"Crossref","is-referenced-by-count":121,"title":["Longitudinal 18F-MK-6240 tau tangles accumulation follows Braak stages"],"prefix":"10.1093","volume":"144","author":[{"given":"Tharick A","family":"Pascoal","sequence":"first","affiliation":[{"name":"Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 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, Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, Canada"},{"name":"Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada"},{"name":"Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea L","family":"Benedet","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 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, Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, Canada"},{"name":"Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, SE-43180 M\u00f6lndal, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana L","family":"Tudorascu","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"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, McGill University Research Centre for Studies in Aging, 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, Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sulantha","family":"Mathotaarachchi","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 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, Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Savard","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 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, Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6877-4825","authenticated-orcid":false,"given":"Firoza Z","family":"Lussier","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 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, Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9cile","family":"Tissot","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 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, Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mira","family":"Chamoun","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 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, Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0745-6222","authenticated-orcid":false,"given":"Min Su","family":"Kang","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 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, Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, Canada"},{"name":"Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna","family":"Stevenson","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 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, Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gassan","family":"Massarweh","sequence":"additional","affiliation":[{"name":"Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Christine","family":"Guiot","sequence":"additional","affiliation":[{"name":"Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, 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