Collins, D. Louis

Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

AbstractBackgroundThe European Alzheimer's Disease Consortium and Alzheimer's Disease Neuroimaging Initiative (ADNI) Harmonized Protocol (HarP) is a Delphi definition of manual hippocampal segmentation from magnetic resonance imaging (MRI) that can be used as the standard of truth to train new tracers, and to validate automated segmentation algorithms. Training requires large and representative data sets of segmented hippocampi. This work aims to produce a set of HarP labels for the proper training and certification of tracers and algorithms.MethodsSixty‐eight 1.5 T and 67 3 T volumetric structural ADNI scans from different subjects, balanced by age, medial temporal atrophy, and scanner manufacturer, were segmented by five qualified HarP tracers whose absolute interrater intraclass correlation coefficients were 0.953 and 0.975 (left and right). Labels were validated as HarP compliant through centralized quality check and correction.ResultsHippocampal volumes (mm3) were as follows: controls: left = 3060 (standard deviation [SD], 502), right = 3120 (SD, 897); mild cognitive impairment (MCI): left = 2596 (SD, 447), right = 2686 (SD, 473); and Alzheimer’s disease (AD): left = 2301 (SD, 492), right = 2445 (SD, 525). Volumes significantly correlated with atrophy severity at Scheltens' scale (Spearman's ρ = <−0.468, P = <.0005).Cerebrospinal fluid spaces (mm3) were as follows: controls: left = 23 (32), right = 25 (25); MCI: left = 15 (13), right = 22 (16); and AD: left = 11 (13), right = 20 (25). Five subjects (3.7%) presented with unusual anatomy.ConclusionsThis work provides reference hippocampal labels for the training and certification of automated segmentation algorithms. The publicly released labels will allow the widespread implementation of the standard segmentation protocol.

Abstract Background An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance. Methods Fourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web‐platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T. Results The agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P < .001), and physiological variability (49.2%, P < .001). Conclusions The HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms.

ABSTRACTBACKGROUND AND PURPOSEAn effort to define and validate a Harmonized Protocol for standard hippocampal segmentation is being carried out. We wished to estimate the effect of magnetic resonance image (MRI) spatial orientation on manual hippocampal segmentations to define optimal standard orientation of MRIs for hippocampal volumetry.METHODSThree expert tracers segmented twice the hippocampi of 10 ADNI subjects on MRI slices oriented perpendicular to the anterior‐posterior commissure (AC‐PC) line and the long hippocampal axes plane, following internationally harmonized landmarks. We computed intra and interrater reliability figures for total volumes and similarity coefficients.RESULTSTotal volume reliability was similar for both orientations. Similarity coefficients were significantly higher for the AC‐PC orientation (exact P = 0.002).DISCUSSIONThese data show that AC‐PC orientation is slightly more reliable for manual segmentations, possibly due to better visualization of the cerebrospinal fluid spaces separating hippocampal head and amygdala. A Delphi panel of experts has used these data to decide on the optimal orientation for a Harmonized Protocol for hippocampal segmentation.