Murphy, Alice

Abstract INTRODUCTION To examine the generalizability of Alzheimer's disease (AD) biomarker models in real‐world older adults, we examined AD biomarker relationships with cognition in two multicenter cohorts that differ with respect to recruitment approach and health risk factors but were matched on a variety of characteristics. METHODS We compared harmonized health and demographic data, AD and cerebrovascular biomarkers, and cognitive performance in the community‐recruited U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) Imaging substudy and a matched sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) which recruited primarily from academic specialty clinics. RESULTS Elevated β‐amyloid (Aβ) and tau were associated with cognitive performance in ADNI but not U.S. POINTER. Findings were consistent across different cohort matching schemes, and were not explained by discrepancies in vascular risk. DISCUSSION The role of Aβ and tau in cognitive performance may be reduced in real world samples compared to academic specialty clinics.

Abstract INTRODUCTION A key goal of the Alzheimer's Disease NeuroImaging Initiative (ADNI) positron emission tomography (PET) Core is to harmonize quantification of β‐amyloid (Aβ) and tau PET image data across multiple scanners and tracers. METHODS We developed an analysis pipeline (Berkeley PET Imaging Pipeline, B‐PIP) for ADNI Aβ and tau PET images and applied it to PET data from other multisite studies. Steps include image pre‐processing, refacing, magnetic resonance imaging (MRI)/PET co‐registration, visual quality control (QC), quantification of tracer uptake, and standardization of Aβ and tau standardized uptake value ratios (SUVrs) across tracers. RESULTS Measurements from 10,105 cross‐sectional and longitudinal Aβ and tau PET scans acquired in several studies between 2010 and 2024 can be processed, harmonized, and directly merged across tracers and cohorts. DISCUSSION The B‐PIP developed in ADNI is a scalable image harmonization approach used in several observational studies and clinical trials that facilitates rigorous Aβ and tau PET quantification and data sharing. Highlights Quantitative results from ADNI Aβ and tau PET data are generated using a rigorous, scalable image processing pipeline This pipeline has been applied to PET data from several other large, multisite studies and trials Quantitative outcomes are harmonizable across studies and are shared with the scientific community

AbstractBackgroundThe Standardized Centralized Alzheimer’s & related dementias Neuroimaging (SCAN) project harmonizes processing of prospectively acquired PET and MRI scans from Alzheimer’s disease research centers (ADRCs) across the USA. SCAN data will be integrated with other ADRC data streams within the National Alzheimer’s Coordinating Center (NACC), including the Uniform Data Set which includes rich longitudinal demographic, cognitive, and neuropathological data, resulting in a large, potentially representative cohort. The project has sought to accommodate site‐to‐site variation in image acquisition while permitting harmonization of imaging data, necessitating new analytic approaches for different PET tracers and PET scans without MRIs.MethodPET scans underwent preprocessing for quality control and smoothing to a uniform resolution. MRI‐free processing pipelines and positivity thresholds were developed for each beta‐amyloid (Aβ)‐PET tracer: [11C]PiB, [18F]florbetaben (FBB), [18F]florbetapir (FBP) and [18F]flutafuranol (NAV). A generic Aβ‐PET template was used for spatial normalization and cortical summary SUVRs were calculated in template space. Aβ‐positivity thresholds were determined by examining both MRI‐dependent thresholds transformed into MRI‐free units and a young control mean+2SD. Centiloid (CL) conversions were completed for each Aβ‐PET tracer. Tau‐PET tracers ([18F]flortaucipir (FTP) and [18F]MK‐6240) required tracer‐specific warping templates for best performance relative to gold‐standard MRI‐dependent processing. Demographic and clinical data were obtained from NACC.Result15 ADRCs have contributed data to SCAN as of January 2023. 477 participants had preprocessed, SCAN‐compliant (https://scan.naccdata.org/) Aβ‐PET scans and NACC data; 219 of these participants (46%) also had tau‐PET scans (Table 1). This cohort included 18% of individuals from underrepresented groups. Clinical diagnostic groups ranged from cognitively unimpaired to MCI and dementia (74% of whom had AD dementia). Using pooled Aβ‐PET data across 4 tracers in CLs, there were expected differences in Aβ burden by diagnosis group (Fig. 1) and positive associations with tau (Fig. 2).ConclusionSCAN has successfully harmonized PET data from more than a dozen US ADRCs yielding a large, clinically heterogeneous cohort of deeply phenotyped research participants. SCAN data will be compatible with ADNI data allowing for further pooling of data and greater statistical power to drive critical questions in AD and related dementias research.

AbstractBackgroundThe Standardized Centralized Alzheimer’s & related dementias Neuroimaging (SCAN) project harmonizes processing of prospectively acquired PET and MRI scans from Alzheimer’s disease research centers (ADRCs) across the USA. SCAN data will be integrated with other ADRC data streams within the National Alzheimer’s Coordinating Center (NACC), including the Uniform Data Set which includes rich longitudinal demographic, cognitive, and neuropathological data, resulting in a large, potentially representative cohort. The project has sought to accommodate site‐to‐site variation in image acquisition while permitting harmonization of imaging data, necessitating new analytic approaches for different PET tracers and PET scans without MRIs.MethodPET scans underwent preprocessing for quality control and smoothing to a uniform resolution. MRI‐free processing pipelines and positivity thresholds were developed for each beta‐amyloid (Aß)‐PET tracer: [11C]PiB, [18F]florbetaben (FBB), [18F]florbetapir (FBP) and [18F]flutafuranol (NAV). A generic Aß‐PET template was used for spatial normalization and cortical summary SUVRs were calculated in template space. Aß‐positivity thresholds were determined by examining both MRI‐dependent thresholds transformed into MRI‐free units and a young control mean+2SD. Centiloid (CL) conversions were completed for each Aß‐PET tracer. Tau‐PET tracers ([18F]flortaucipir (FTP) and [18F]MK‐6240) required tracer‐specific warping templates for best performance relative to gold‐standard MRI‐dependent processing. Demographic and clinical data were obtained from NACC.Result15 ADRCs have contributed data to SCAN as of January 2023. 477 participants had preprocessed, SCAN‐compliant (https://scan.naccdata.org/) Aß‐PET scans and NACC data; 219 of these participants (46%) also had tau‐PET scans (Table 1). This cohort included 18% of individuals from underrepresented groups. Clinical diagnostic groups ranged from cognitively unimpaired to MCI and dementia (74% of whom had AD dementia). Using pooled Aß‐PET data across 4 tracers in CLs, there were expected differences in Aß burden by diagnosis group (Fig. 1) and positive associations with tau (Fig. 2).ConclusionSCAN has successfully harmonized PET data from more than a dozen US ADRCs yielding a large, clinically heterogeneous cohort of deeply phenotyped research participants. SCAN data will be compatible with ADNI data allowing for further pooling of data and greater statistical power to drive critical questions in AD and related dementias research.

AbstractBackgroundThe U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2‐year randomized controlled trial to evaluate the effect of lifestyle interventions in older adults (60‐79 years) who are cognitively unimpaired but at increased risk for cognitive decline/dementia due to factors such as cardiovascular disease and family history. The POINTER Imaging ancillary study is collecting PET and MRI data to evaluate neuroimaging biomarkers of AD and cerebrovascular pathophysiology in this at‐risk sample.MethodPOINTER Imaging is actively enrolling 1250 participants, 23% from under‐represented racial/ethnic groups (URG), recruited from five U.S. POINTER clinical sites. Participants have undergone PET imaging with [18F]Florbetaben (FBB) to measure Aβ and [18F]MK‐6240 to measure tau burden, as well as MRI to measure brain morphometry, white matter hyperintensities and cerebral blood flow. FBB and MK‐6240 data were quality checked, pre‐processed, and quantified using previously validated methods. PET images were coregistered to a structural MRI, which was also used to create FreeSurfer‐defined reference regions and regions of interest. We examined PET imaging measures (global Aβ, regional tau) and basic demographic (age, sex, race/ethnicity) characteristics of the sample.Result96 participants (mean age 69.3±5.0) have been enrolled in POINTER Imaging. Of these, 59 (61%) are women and 22 (23%) are URG, which is similar to rates of women (75%) and URG (22%) in the main trial. This dataset is <10% of targeted enrollment, was predominantly recruited from 2/5 clinical sites and may not represent the final imaging cohort. FBB quantification (N=20) revealed a mean cortical summary SUVR of 1.09±0.12 (19.6±18.4 centiloids) (whole cerebellum normalization; previously validated positivity threshold=1.08), and 8/20 (40%) of these participants were Aβ+ (Fig. 1A). MK‐6240 quantification (N=23) showed predominantly no/minimal binding with a few exceptions in medial and lateral temporal lobes (Fig. 1B&C).ConclusionThe POINTER imaging study is meeting the target URG enrollment and representative of the main U.S. POINTER trial. Higher frequency of Aβ positivity than published in population cohorts coupled with greater cardiovascular risk factors among POINTER participants highlights our success in recruiting individuals at increased risk of cognitive decline.