Dataset Information

Spatial extent as a sensitive amyloid-PET metric in preclinical Alzheimer's disease.

ABSTRACT:

Introduction

Spatial extent-based measures of how far amyloid beta (Aβ) has spread throughout the neocortex may be more sensitive than traditional Aβ-positron emission tomography (PET) measures of Aβ level for detecting early Aβ deposits in preclinical Alzheimer's disease (AD) and improve understanding of Aβ's association with tau proliferation and cognitive decline.

Methods

Pittsburgh Compound-B (PIB)-PET scans from 261 cognitively unimpaired older adults from the Harvard Aging Brain Study were used to measure Aβ level (LVL; neocortical PIB DVR) and spatial extent (EXT), calculated as the proportion of the neocortex that is PIB+.

Results

EXT enabled earlier detection of Aβ deposits longitudinally confirmed to reach a traditional LVL-based threshold for Aβ+ within 5 years. EXT improved prediction of cognitive decline (Preclinical Alzheimer Cognitive Composite) and tau proliferation (flortaucipir-PET) over LVL.

Discussion

These findings indicate EXT may be more sensitive to Aβ's role in preclinical AD than level and improve targeting of individuals for AD prevention trials.

Highlights

Aβ spatial extent (EXT) was measured as the percentage of the neocortex with elevated Pittsburgh Compound-B. Aβ EXT improved detection of Aβ below traditional PET thresholds. Early regional Aβ deposits were spatially heterogeneous. Cognition and tau were more closely tied to Aβ EXT than Aβ level. Neocortical tau onset aligned with reaching widespread neocortical Aβ.

SUBMITTER: Farrell ME

PROVIDER: S-EPMC11350060 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Publications

Spatial extent as a sensitive amyloid-PET metric in preclinical Alzheimer's disease.

Farrell Michelle E ME Thibault Emma G EG Becker J Alex JA Price Julie C JC Healy Brian C BC Hanseeuw Bernard J BJ Buckley Rachel F RF Jacobs Heidi I L HIL Schultz Aaron P AP Chen Charles D CD Sperling Reisa A RA Johnson Keith A KA

Alzheimer's & dementia : the journal of the Alzheimer's Association 20240710 8

<h4>Introduction</h4>Spatial extent-based measures of how far amyloid beta (Aβ) has spread throughout the neocortex may be more sensitive than traditional Aβ-positron emission tomography (PET) measures of Aβ level for detecting early Aβ deposits in preclinical Alzheimer's disease (AD) and improve understanding of Aβ's association with tau proliferation and cognitive decline.<h4>Methods</h4>Pittsburgh Compound-B (PIB)-PET scans from 261 cognitively unimpaired older adults from the Harvard Aging B ...[more]

PMID: 38988055

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Project description:ImportancePreventive trials of anti-amyloid agents might preferably recruit persons showing earliest biologically relevant β-amyloid (Aβ) binding on positron emission tomography (PET).ObjectiveTo investigate the timing at which Aβ-PET binding starts showing associations with other markers of Alzheimer disease.Design, setting, and participantsThis longitudinal multicentric cohort study included 3 independent cohorts: Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) (data collected from 2012-2020), Alzheimer Disease Neuroimaging Initiative (ADNI) (data collected from 2005-2019), and Harvard Aging Brain Study (HABS) (data collected from 2011-2019). In a 3-tiered categorization of Aβ-PET binding spatial extent, individuals were assigned as having widespread Aβ deposition if they showed positive signal throughout a designated set of brain regions prone to early Aβ accumulation. Those with binding in some but not all were categorized as having regional deposition, while those who failed to show any criterion Aβ signal were considered Aβ-negative. All participants who were cognitively unimpaired at their first Aβ PET scan.Main outcomes and measuresDifferences in cerebrospinal fluid (CSF), genetics, tau-PET burden, and cognitive decline.ResultsA total of 817 participants were included, including 129 from the PREVENT-AD cohort (mean [SD] age, 63.5 [4.7] years; 33 [26%] male; 126 [98%] White), 400 from ADNI (mean [SD] age, 73.6 [5.8] years; 190 [47%] male; 10 [5%] Hispanic, 338 [91%] White), and 288 from HABS (mean [SD] age, 73.7 [6.2] years; 117 [40%] male; 234 [81%] White). Compared with Aβ-negative persons, those with regional Aβ binding showed proportionately more APOE ε4 carriers (18 [64%] vs 22 [27%] in PREVENT-AD and 34 [31%] vs 38 [19%] in ADNI), reduced CSF Aβ1-42 levels (F = 24 and 71), and greater longitudinal Aβ-PET accumulation (significant β = 0.019 to 0.056). Participants with widespread amyloid binding further exhibited notable cognitive decline (significant β = -0.014 to -0.08), greater CSF phosphorylated tau181 (F = 5 and 27), and tau-PET binding (all F > 7.55). Using each cohort's specified dichotomous threshold for Aβ positivity or a visual read classification, most participants (56% to 100%, depending on classification method and cohort) with regional Aβ would have been classified Aβ-negative.Conclusions and relevanceRegional Aβ binding appears to be biologically relevant and participants at this stage remain relatively free from CSF phosphorylated tau181, tau-PET binding, and related cognitive decline, making them ideal targets for anti-amyloid agents. Most of these individuals would be classified as negative based on classical thresholds of Aβ positivity.

Project description:BackgroundThe deposition of β-amyloid (Aβ) in the brain is a biomarker of Alzheimer's disease (AD). Highly sensitive Aβ positron emission tomography (PET) imaging plays an essential role in diagnosing and evaluating the therapeutic effects of AD.AimTo synthesize a new Aβ tracer [18F]DRKXH1 (5-(4-(6-(2-[18]fluoroethoxy)ethoxy)imidazo[1,2-alpha]pyridin-2-yl)phenyl) and evaluate the tracer performance by biodistribution analysis, in vivo small-animal PET-CT dynamic scan, ex vivo and in vitro autoradiography, and PET in human subjects.Methods[18F]DRKXH1 was synthesized automatically by the GE FN module. Log D (pH 7.4) and biodistribution of [18F]DRKXH1 were investigated. Small-animal-PET was used for [18F]DRKXH1 and [18F]AV45 imaging study in AD transgenic mice (APPswe/PSEN1dE9) and age-matched normal mice. The distribution volume ratios (DVR) and standardized uptake value ratios (SUVRs) were calculated with the cerebellum as the reference region. The deposition of Aβ plaques in the brain of AD transgenic mice was determined by ex vivo autoradiography and immunohistochemistry. In vitro autoradiography was performed in the postmortem brain sections of AD patients and healthy controls. Two healthy control subjects and one AD patient was subjected to in vivo PET study using [18F]DRKXH1.ResultsThe yield of [18F]DRKXH1 was 40%, and the specific activity was 156.64 ± 11.55 GBq/μmol. [18F]DRKXH1 was mainly excreted through the liver and kidney. The small-animal PET study showed high initial brain uptake and rapid washout of [18F]DRKXH1. The concentration of [18F]DRKXH1 was detected in the cortex and hippocampus of AD transgenic mice brain. The cortex DVR of AD transgenic mice was higher than that of WT mice (P < 0.0001). Moreover, the SUVRs of AD transgenic mice were higher than those of WT mice based on the 0-60-min dynamic scanning. In vitro autoradiography showed a significant concentration of tracer in the Aβ plaque-rich areas in the brain of AD transgenic mice. The DVR value of [18F]-DRKXH1 is higher than that of [18F]-AV45 (1.29 ± 0.05 vs. 1.05 ± 0.08; t = 5.33, P = 0.0003). Autoradiography of postmortem human brain sections showed [18F]DRKXH1-labeled Aβ plaques in the AD brain. The AD patients had high retention in cortical regions, while healthy control subjects had uniformly low radioactivity uptake.Conclusions[18F]DRKXH1 is an Aβ tracer with high sensitivity in preclinical study and has the potential for in vivo detection of the human brain.

Project description:BackgroundIn contrast to sporadic Alzheimer's disease, autosomal dominant Alzheimer's disease (ADAD) is associated with greater neuropathological evidence of cerebellar amyloid plaque (Aβ) deposition. In this study, we used positron emission tomography (PET) measurements of fibrillar Aβ burden to characterize the presence and age at onset of cerebellar Aβ deposition in cognitively unimpaired (CU) Presenilin-1 (PSEN1) E280A mutation carriers from the world's largest extended family with ADAD.Methods18F florbetapir and 11C Pittsburgh compound B (PiB) PET data from two independent studies - API ADAD Colombia Trial (NCT01998841) and Colombia-Boston (COLBOS) longitudinal biomarker study were included. The tracers were selected independently by the respective sponsors prior to the start of each study and used exclusively throughout. Template-based cerebellar Aβ-SUVR (standard-uptake value ratios) using a known-to-be-spared pons reference region (cerebellar SUVR_pons), to a) compare 28-56-year-old CU carriers and non-carriers; b) estimate the age at which cerebellar SUVR_pons began to differ significantly in carrier and non-carrier groups; and c) characterize in carriers associations with age, cortical SUVR_pons, delayed recall memory, and API ADAD composite score.ResultsFlorbetapir and PiB cerebellar SUVR_pons were significantly higher in carriers than non-carriers (p < 0.0001). Cerebellar SUVR_pons began to distinguish carriers from non-carriers at age 34, 10 years before the carriers' estimated age at mild cognitive impairment onset. Florbetapir and PiB cerebellar SUVR_pons in carriers were positively correlated with age (r = 0.44 & 0.69, p < 0.001), cortical SUVR_pons (r = 0.55 & 0.69, p < 0.001), and negatively correlated with delayed recall memory (r = -0.21 & -0.50, p < 0.05, unadjusted for cortical SUVR_pons) and API ADAD composite (r = -0.25, p < 0.01, unadjusted for cortical SUVR_pons in florbetapir API ADAD cohort).ConclusionThis PET study provides evidence of cerebellar Aβ plaque deposition in CU carriers starting about a decade before the clinical onset of ADAD. Additional studies are needed to clarify the impact of using a cerebellar versus pons reference region on the power to detect and track ADAD changes, even in preclinical stages of this disorder.

Dataset Information

Spatial extent as a sensitive amyloid-PET metric in preclinical Alzheimer's disease.

Introduction

Methods

Results

Discussion

Highlights

Publications

Spatial extent as a sensitive amyloid-PET metric in preclinical Alzheimer's disease.

Similar Datasets

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