Quantitative amyloid PET in Alzheimer's disease: the AMYPAD prognostic and natural history study

Alves, Isadora Lopes; Collij, Lyduine E.; Altomare, Daniele; Frisoni, Giovanni B.; Saint‐Aubert, Laure; Payoux, Pierre; Kivipelto, Miia; Jessen, Frank; Drzezga, Alexander; Leeuwis, Anna E.; Wink, Alle Meije; Visser, Pieter Jelle; Berckel, Bart N.M. van; Scheltens, Philip; Gray, Katherine R.; Wolz, Robin; Stephens, Andrew; Gismondi, Rossella; Buckely, C; Gispert, Juan Domingo; Schmidt, Mark E.; Ford, Lisa; Ritchie, Craig W.; Farrar, Gill; Barkhof, Frederik; Molinuevo, José Luís

doi:10.1002/alz.12069

Cited by 40 publications

(42 citation statements)

References 45 publications

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“…Thus although baseline amyloid burden illustrates the extent of amyloid pathology, rate of change reflects a subject's position in the amyloid accumulation process, enabling the stratification of individu-als according to their placement in the AD disease course and improving risk-profiling efforts. 32 In individuals classified as Aβ− at baseline, only Aβ slope and its interaction with baseline Aβ burden could predict working and semantic memory performance. This illustrates that longitudinal PET measures are able to identify subjects at the beginning of the amyloid accumulation process, even when they are classified as Aβ− at their baseline visit.…”

Section: Discussionmentioning

confidence: 95%

“…Therefore, replication of these results in an independent prospective data set is important and already planned within the Amyloid Imaging to Prevent Alzheimer's Disease (AMYPAD) consortium. 32 Fourth, due to the focus on a CU population, the study sample had a relatively limited representation of high Aβ burden levels, and partial volume error (PVE) correction was not performed because considerable atrophy was not expected. In fact, previous work in this data set demonstrated a strong correlation between PVE-corrected and PVE-uncorrected quantitative values, 23 suggesting that this methodological aspect would likely have minimal effect on our results.…”

Section: Discussionmentioning

confidence: 99%

“…Replication of these results in an independent prospective data set is warranted and already planned within the AMYPAD Prognostic and Natural History Study (PNHS). 32…”

Section: Discussionmentioning

confidence: 99%

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Regional amyloid accumulation predicts memory decline in initially cognitively unimpaired individuals

Collij

Mastenbroek

Salvadó

et al. 2021

Alzheimer's & Dementia

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Introduction:The value of quantitative longitudinal and regional amyloid beta (Aβ) measurements in predicting cognitive decline in initially cognitively unimpaired (CU) individuals remains to be determined. Methods: We selected 133 CU individuals with two or more [ 11 C]Pittsburgh compound B ([ 11 C]PiB) scans and neuropsychological data from Open Access Series of Imaging Studies (OASIS-3). Baseline and annualized distribution volume ratios were computed for a global composite and four regional clusters. The predictive value of Aβ measurements (baseline, slope, and interaction) on longitudinal cognitive performance was examined.Results: Global performance could only be predicted by Aβ burden in an early cluster (precuneus, lateral orbitofrontal, and insula) and the precuneus region of interest (ROI) by itself significantly improved the model. Precuneal Aβ burden was also predictive of immediate and delayed episodic memory performance. In Aβ subjects at baseline (N = 93), lateral orbitofrontal Aβ burden predicted working and semantic memory performance.Discussion: Quantifying longitudinal and regional changes in Aβ can improve the prediction of cognitive functioning in initially CU individuals.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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Regional amyloid accumulation predicts memory decline in initially cognitively unimpaired individuals

Collij

Mastenbroek

Salvadó

et al. 2021

Alzheimer's & Dementia

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“…For this reason, topographically defined distribution and early Aβ accumulation measured by PET may not necessarily agree with histopathology findings. Despite these discrepancies with neuropathology results, several studies have shown the utility of amyloid PET topographical quantification in staging AD [21][22][23], determining the risk of subsequent cognitive decline [23,25], optimal subject selection for anti-amyloid interventional trials [22,42], and reducing sample size in anti-amyloid interventional trials [43,44]. Pascoal et al also showed that the topographical pattern of individuals with MCI that progress to dementia is "traditionally AD-like," while that of non-converters includes more temporal and occipital regions instead [24].…”

Section: Discussionmentioning

confidence: 99%

Early detection of amyloid load using 18F-florbetaben PET

Bullich¹,

Roé-Vellvé²,

Marquié

et al. 2021

Alz Res Therapy

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Background A low amount and extent of Aβ deposition at early stages of Alzheimer’s disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using 18F-florbetaben PET. Quantitative thresholds for the early (SUVRearly) and established (SUVRestab) Aβ deposition were developed, and the topography of early Aβ deposition was assessed. Subsequently, Aβ accumulation over time, progression from mild cognitive impairment (MCI) to AD dementia, and tau deposition were assessed in subjects with early and established Aβ deposition. Methods The study population consisted of 686 subjects (n = 287 (cognitively normal healthy controls), n = 166 (subjects with subjective cognitive decline (SCD)), n = 129 (subjects with MCI), and n = 101 (subjects with AD dementia)). Three categories in the Aβ-deposition continuum were defined based on the developed SUVR cutoffs: Aβ-negative subjects, subjects with early Aβ deposition (“gray zone”), and subjects with established Aβ pathology. Results SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the “gray zone” or with established Aβ pathology accumulated more amyloid over time than Aβ-negative subjects. After a 4-year clinical follow-up, none of the Aβ-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aβ pathology progressed. Tau deposition was infrequent in those subjects without established Aβ pathology. Conclusions This study supports the utility of using two cutoffs for amyloid PET abnormality defining a “gray zone”: a lower cutoff of 13.5 CL indicating emerging Aβ pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention. Trial registration Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov (NCT00928304, NCT00750282, NCT01138111, NCT02854033) and EudraCT (2014-000798-38).

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“…It has been reported that early-phase data of many specific PET radioligands mimic brain perfusion in healthy subjects and in patients with neurodegenerative disorders. This had been validated in PET imaging studies of Alzheimer's disease [e.g., (34,35)]. Early-phase data from dopaminergic PET tracers such as 18 F-FDOPA (15), 11 C-raclopride (20), or DAT tracers such as 11 C-PE2I (21) can similarly be used to compute PDRP and PDCP expression in individual subjects.…”

Section: Discussionmentioning

confidence: 99%

Dynamic ¹⁸F-FPCIT PET: Quantification of Parkinson Disease Metabolic Networks and Nigrostriatal Dopaminergic Dysfunction in a Single Imaging Session

et al. 2021

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Previous multi-center imaging studies with 18 F-FDG PET have established the presence of Parkinson's disease motor-and cognition-related metabolic patterns termed PDRP and PDCP in patients with this disorder. Given that in PD cerebral perfusion and glucose metabolism are typically coupled in the absence of medication, we determined whether subject expression of these disease networks can be quantified in early-phase images from dynamic 18 F-FPCIT PET scans acquired to assess striatal dopamine transporter (DAT) binding. Methods: We studied a cohort of early-stage PD patients and age-matched healthy control subjects who underwent 18 F-FPCIT at baseline; scans were repeated 4 years later in a smaller subset of patients. The early 18 F-FPCIT frames, which reflect cerebral perfusion, were used to compute PDRP and PDCP expression (subject scores) in each subject, and compared to analogous measures computed based on 18 F-FDG PET scan when additionally available. The late 18 F-FPCIT frames were used to measure caudate and putamen DAT binding in the same individuals. Results: PDRP subject scores from early-phase 18 F-FPCIT and 18 F-FDG scans were elevated and striatal DAT binding reduced in PD versus healthy subjects. The PDRP scores from 18 F-FPCIT correlated with clinical motor ratings, disease duration, and with corresponding measures from 18 F-FDG PET. In addition to correlating with disease duration and analogous 18 F-FDG PET values, PDCP scores correlated with DAT binding in the caudate/anterior putamen. PDRP and PDCP subject scores using either method rose over 4 years whereas striatal DAT binding declined over the same time period. Conclusion: Early-phase images obtained with 18 F-FPCIT PET can provide an alternative to 18 F-FDG PET for PD network quantification. This technique therefore allows 3 PDRP/PDCP expression and caudate/putamen DAT binding to be evaluated with a single tracer in one scanning session.

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Quantitative amyloid PET in Alzheimer's disease: the AMYPAD prognostic and natural history study

Cited by 40 publications

References 45 publications

Regional amyloid accumulation predicts memory decline in initially cognitively unimpaired individuals

Regional amyloid accumulation predicts memory decline in initially cognitively unimpaired individuals

Early detection of amyloid load using 18F-florbetaben PET

Dynamic ¹⁸F-FPCIT PET: Quantification of Parkinson Disease Metabolic Networks and Nigrostriatal Dopaminergic Dysfunction in a Single Imaging Session

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Quantitative amyloid PET in Alzheimer's disease: the AMYPAD prognostic and natural history study

Cited by 40 publications

References 45 publications

Regional amyloid accumulation predicts memory decline in initially cognitively unimpaired individuals

Regional amyloid accumulation predicts memory decline in initially cognitively unimpaired individuals

Early detection of amyloid load using 18F-florbetaben PET

Dynamic 18F-FPCIT PET: Quantification of Parkinson Disease Metabolic Networks and Nigrostriatal Dopaminergic Dysfunction in a Single Imaging Session

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Product

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Dynamic ¹⁸F-FPCIT PET: Quantification of Parkinson Disease Metabolic Networks and Nigrostriatal Dopaminergic Dysfunction in a Single Imaging Session