Multitracer model for staging cortical amyloid deposition using PET imaging

Collij, Lyduine E.; Heeman, Fiona; Salvadó, Gemma; Ingala, Silvia; Altomare, Daniele; Wilde, Arno de; Konijnenberg, Elles; Buchem, Marieke van; Yaqub, Maqsood; Markiewicz, Paweł; Golla, Sandeep S.V.; Wink, Alle Meije; Visser, Pieter Jelle; Teunissen, Charlotte E.; Lammertsma, Adriaan A.; Scheltens, Philip; Flier, Wiesje M. van der; Boellaard, Ronald; Berckel, Bart N.M. van; Molinuevo, José Luís; Gispert, Juan Domingo; Schmidt, Mark E.; Barkhof, Frederik; Alves, Isadora Lopes

doi:10.1212/wnl.0000000000010256

Cited by 67 publications

(112 citation statements)

References 33 publications

(23 reference statements)

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“…Some of these methodologic differences may be responsible for the discrepant regional sequences observed. For instance, entorhinal cortical accumulation occurred early in an autopsy study (14), but several PET studies contradicted this (27,35). Cingulate and medial frontal regions showed an early accumulation in most PET studies (26)(27)(28)(29)35,37); however, other early regions, such as precuneus, are less robustly reported.…”

Section: Discussion Of Applied Methodologiesmentioning

confidence: 99%

“…Additionally, a decreased PET sensitivity to amyloid at the extremes of deposition could occur; the first regional deposits with low amyloid concentrations may be missed by global PET imaging (9,12,23), and end-of-life regional deposits are often masked by cerebral atrophy (2,42). PET amyloid tracers also have varying dynamic ranges in terms of the maximum signal strength in positive compared with negative cases (35). These varying ranges could lead to discrepancies when comparing scans from different tracers, hence the value of normalization measures such as the centiloid scale (22).…”

Section: Discussion Of Applied Methodologiesmentioning

confidence: 99%

“…These varying ranges could lead to discrepancies when comparing scans from different tracers, hence the value of normalization measures such as the centiloid scale (22). Alternatively, when a tracer harmonization strategy is not implemented, staging models can be made more robust by integrating data from multiple tracers (35).…”

Section: Discussion Of Applied Methodologiesmentioning

confidence: 99%

“…Generally consistent results across all studies point to the possibility of identifying a high-level ordering of cerebral amyloid deposition, whereas details in regional ordering can be substantially affected by population and tracer differences (28,32) and generalizable staging models may need to allow a degree of heterogeneity to achieve high applicability. Therefore, the use of multiple cohorts and the use of distinct model generation and validation cohorts, biomarkers, and staging methods (35,40) is arguably the most appropriate strategy to derive both a sequence of regional deposition and a staging model with universal validity.…”

Section: Discussion Of Applied Methodologiesmentioning

confidence: 99%

“…Considering the above, recent work by Collij et al focused on overcoming the potential lack of cross-cohort and cross-tracer validity for previous staging models (35). Here, a 5-stage model was constructed from PET imaging data from 989 cognitively unimpaired subjects originating from 6 cohorts and scanned with 1 of 4 different PET tracers.…”

Section: Group 2: Studies Comparing Amyloid Pet Signal With Histologymentioning

confidence: 99%

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The Spatial-Temporal Ordering of Amyloid Pathology and Opportunities for PET Imaging

et al. 2019

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Although clinical routine focuses on dichotomous and visual interpretation of amyloid PET, regional image assessment in research settings may yield additional opportunities. Understanding the regional-temporal evolution of amyloid pathology may enable earlier identification of subjects in the Alzheimer Disease pathologic continuum, as well as a finer-grained assessment of pathology beyond traditional dichotomous measures. This review summarizes current research in the detection of regional amyloid deposition patterns and its potential for staging amyloid pathology. Pathology studies, cross-sectional and longitudinal PET-only studies, and comparative PET and autopsy studies are included. Despite certain differences, cortical deposition generally precedes striatal pathology, and in PETonly studies, medial cortical regions are seen to accumulate amyloid earlier than lateral regions. Based on regional amyloid PET, multiple studies have developed and implemented models for staging amyloid pathology that could improve subject selection into secondary prevention trials and visual assessment in clinical routine.

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Section: Discussion Of Applied Methodologiesmentioning

confidence: 99%

Section: Discussion Of Applied Methodologiesmentioning

confidence: 99%

Section: Discussion Of Applied Methodologiesmentioning

confidence: 99%

Section: Discussion Of Applied Methodologiesmentioning

confidence: 99%

Section: Group 2: Studies Comparing Amyloid Pet Signal With Histologymentioning

confidence: 99%

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The Spatial-Temporal Ordering of Amyloid Pathology and Opportunities for PET Imaging

et al. 2019

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Spatial Extent of Amyloid-β Levels and Associations With Tau-PET and Cognition

et al. 2022

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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 &gt; 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.

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Association of PET‐based stages of amyloid deposition with neuropathological markers of Aβ pathology

Teipel

Temp

Levin

et al. 2020

Ann Clin Transl Neurol

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Objective To determine if PET‐based stages of regional amyloid deposition are associated with neuropathological phases of Aβ pathology. Methods We applied data‐driven regional frequency‐based and a‐priori striatum‐based PET staging approaches to ante‐mortem 18F‐Florbetapir‐PET scans of 30 cases from the Alzheimer’s Disease Neuroimaging Initiative autopsy cohort, and used Bayesian regression analysis to study the associations of these in vivo amyloid stages with neuropathological Thal phases of regional Aβ plaque distribution and with semi‐quantitative ratings of neocortical and striatal plaque densities. Results Bayesian regression revealed extreme evidence for an association of both PET‐based staging approaches with Thal phases, and these associations were about 44 times more likely for frequency‐based stages and 89 times more likely for striatum‐based stages than for global cortical 18F‐Florbetapir‐PET signal. Early (i.e., neocortical‐only) PET‐based amyloid stages also predicted the absence of striatal/diencephalic cored plaques. Receiver operating characteristics curves revealed highly accurate discrimination between low/high Thal phases and the presence/absence of regional plaques. The median areas under the curve were 0.99 for frequency‐based staging (95% credibility interval 0.97–1.00), 0.93 for striatum‐based staging (0.83–1.00), and 0.87 for global 18F‐Florbetapir‐PET signal (0.72–0.98). Interpretation Our data indicate that both regional frequency‐ and striatum‐based amyloid‐PET staging approaches were superior to standard global amyloid‐PET signal for differentiating between low and high degrees of regional amyloid pathology spread. Despite this, we found no evidence for the ability of either staging scheme to differentiate between low and moderate degrees of amyloid pathology which may be particularly relevant for early, preclinical stages of Alzheimer’s disease.

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Multitracer model for staging cortical amyloid deposition using PET imaging

Cited by 67 publications

References 33 publications

The Spatial-Temporal Ordering of Amyloid Pathology and Opportunities for PET Imaging

The Spatial-Temporal Ordering of Amyloid Pathology and Opportunities for PET Imaging

Spatial Extent of Amyloid-β Levels and Associations With Tau-PET and Cognition

Association of PET‐based stages of amyloid deposition with neuropathological markers of Aβ pathology

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