title: Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer's disease spectrum.
abstract: Thal amyloid phase, which describes the pattern of progressive amyloid-β plaque deposition in Alzheimer's disease, was incorporated into the latest National Institute of Ageing - Alzheimer's Association neuropathologic assessment guidelines. Amyloid biomarkers (positron emission tomography and cerebrospinal fluid) were included in clinical diagnostic guidelines for Alzheimer's disease dementia published by the National Institute of Ageing - Alzheimer's Association and the International Work group. Our first goal was to evaluate the correspondence of Thal amyloid phase to Braak tangle stage and ante-mortem clinical characteristics in a large autopsy cohort. Second, we examined the relevance of Thal amyloid phase in a prospectively-followed autopsied cohort who underwent ante-mortem (11)C-Pittsburgh compound B imaging; using the large autopsy cohort to broaden our perspective of (11)C-Pittsburgh compound B results. The Mayo Clinic Jacksonville Brain Bank case series (n = 3618) was selected regardless of ante-mortem clinical diagnosis and neuropathologic co-morbidities, and all assigned Thal amyloid phase and Braak tangle stage using thioflavin-S fluorescent microscopy. (11)C-Pittsburgh compound B studies from Mayo Clinic Rochester were available for 35 participants scanned within 2 years of death. Cortical (11)C-Pittsburgh compound B values were calculated as a standard uptake value ratio normalized to cerebellum grey/white matter. In the high likelihood Alzheimer's disease brain bank cohort (n = 1375), cases with lower Thal amyloid phases were older at death, had a lower Braak tangle stage, and were less frequently APOE-ε4 positive. Regression modelling in these Alzheimer's disease cases, showed that Braak tangle stage, but not Thal amyloid phase predicted age at onset, disease duration, and final Mini-Mental State Examination score. In contrast, Thal amyloid phase, but not Braak tangle stage or cerebral amyloid angiopathy predicted (11)C-Pittsburgh compound B standard uptake value ratio. In the 35 cases with ante-mortem amyloid imaging, a transition between Thal amyloid phases 1 to 2 seemed to correspond to (11)C-Pittsburgh compound B standard uptake value ratio of 1.4, which when using our pipeline is the cut-off point for detection of clear amyloid-positivity regardless of clinical diagnosis. Alzheimer's disease cases who were older and were APOE-ε4 negative tended to have lower amyloid phases. Although Thal amyloid phase predicted clinical characteristics of Alzheimer's disease patients, the pre-mortem clinical status was driven by Braak tangle stage. Thal amyloid phase correlated best with (11)C-Pittsburgh compound B values, but not Braak tangle stage or cerebral amyloid angiopathy. The (11)C-Pittsburgh compound B cut-off point value of 1.4 was approximately equivalent to a Thal amyloid phase of 1-2.
authors: 1 Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA murray.melissa@mayo.edu.
authors: Melissa E
authors: ME
authors: Murray
authors: 2 Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
authors: Val J
authors: VJ
authors: Lowe
authors: 3 Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
authors: Neill R
authors: NR
authors: Graff-Radford
authors: 1 Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors: Amanda M
authors: AM
authors: Liesinger
authors: 1 Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors: Ashley
authors: A
authors: Cannon
authors: 4 Department of Health Sciences Research (Biostatistics), Mayo Clinic, Rochester, Minnesota, USA.
authors: Scott A
authors: SA
authors: Przybelski
authors: 5 Department of Health Sciences Research (Biostatistics), Mayo Clinic, Jacksonville, Florida, USA.
authors: Bhupendra
authors: B
authors: Rawal
authors: 6 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
authors: Joseph E
authors: JE
authors: Parisi
authors: 7 Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
authors: Ronald C
authors: RC
authors: Petersen
authors: 2 Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
authors: Kejal
authors: K
authors: Kantarci
authors: 1 Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors: Owen A
authors: OA
authors: Ross
authors: 8 Department of Neurology, Wien Centre for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Centre, Miami Beach, and Miller School of Medicine, University of Miami, USA.
authors: Ranjan
authors: R
authors: Duara
authors: 7 Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
authors: David S
authors: DS
authors: Knopman
authors: 2 Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
authors: Clifford R
authors: CR
authors: Jack
authors: 1 Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors: Dennis W
authors: DW
authors: Dickson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000473:pathology*; D000682:Amyloid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000814:Aniline Compounds; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058225:Plaque, Amyloid / Q000473:pathology*; D049268:Positron-Emission Tomography / Q000379:methods; D013844:Thiazoles
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D000682:Amyloid; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D013844:Thiazoles
keywords: Alzheimer’s disease; Braak tangle stage; Pittsburgh compound B; Thal amyloid phase; neuropathology