[<sup>18</sup>F]flutemetamol amyloid positron emission tomography in preclinical and symptomatic Alzheimer's disease: Specific detection of advanced phases of amyloid‐β pathology

Thal, Dietmar Rudolf; Beach, Thomas G.; Zanette, Michelle; Heurling, Kerstin; Chakrabarty, Aruna; Ismail, Azzam; Smith, Adrian; Buckley, Christopher

doi:10.1016/j.jalz.2015.05.018

Cited by 122 publications

(131 citation statements)

References 38 publications

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“…Above the Aβ threshold, we found tau-associated hypometabolism in regions commonly used as FDG biomarker readouts for AD. Our finding of tau-related increasing metabolism in subjects with sub-threshold Aβ is consistent with postmortem-PET correlations showing that Aβ is evident in a subset of individuals below typical PET thresholds 37, 38 .…”

Section: Discussionsupporting

confidence: 90%

Fluorodeoxyglucose metabolism associated with tau‐amyloid interaction predicts memory decline

Hanseeuw

Betensky

Schultz

et al. 2017

Annals of Neurology

117

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Objective To evaluate in normal older adults and preclinical Alzheimer’s disease (AD) the impact of amyloid and regional tauopathy on cerebral glucose metabolism and subsequent memory decline. Methods We acquired positron emission tomography using F18 Flortaucipir (tau), C11 Pittsburgh Compound B (amyloid) and F18 Fluorodeoxyglucose in 90 clinically normal elderly of the Harvard Aging Brain Study. Results Posterior cingulate metabolism decreased when both amyloid and neocortical tau were high and predicted subsequent memory decline in a larger sample of normal elderly. In contrast, frontal hypometabolism related to the common age-related entorhinal tauopathy, but this dysfunction was independent of amyloid, and did not predict significant memory decline. Neocortical tauopathy was positively associated with metabolism in individuals with sub-threshold amyloid, suggesting that glucose metabolism increases before decreasing in the course of preclinical AD. Interpretation Our study identified a synergistic effect of amyloid and tau deposits and demonstrated for the first time in normal elderly its link to AD-like hypometabolism and to AD-like memory decline. The amyloid effect was seen with tau in neocortex, but not with tau in entorhinal cortex, which is the common site of age-related tauopathy. Entorhinal tau was associated with frontal hypometabolism, but this dysfunction was not associated with memory loss.

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Section: Discussionsupporting

confidence: 90%

Fluorodeoxyglucose metabolism associated with tau‐amyloid interaction predicts memory decline

Hanseeuw

Betensky

Schultz

et al. 2017

Annals of Neurology

117

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“…The probability of a positive PET image interpretation in this study was 50% in the sparse category, suggesting that this may be possible, but it seems likely that analysis of other regions, such as the striatum or, better yet, a measurable, reliable quantification method, would likely improve the lower detection limit, enabling assessment of β-amyloid in preclinical AD, a stage of disease almost certainly more amenable to preventative treatment strategies or disease-modifying therapeutics. In this context, it is necessary to note that recent studies reported that amyloid PET only detects cases with already advanced amyloid phases (3 and higher) whereas initial phases (1 and 2) could not be identified with [ 18 F]flutemetamol or [ 11 C]PIB [45, 55]. Conversely, increasing the sensitivity of PET β-amyloid scans may decrease the specificity to predict clinically significant AD neuropathology.…”

Section: Discussionmentioning

confidence: 99%

Post-mortem histopathology underlying β-amyloid PET imaging following flutemetamol F 18 injection

Ikonomović

Buckley²,

Heurling

et al. 2016

acta neuropathol commun

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In vivo imaging of fibrillar β-amyloid deposits may assist clinical diagnosis of Alzheimer’s disease (AD), aid treatment selection for patients, assist clinical trials of therapeutic drugs through subject selection, and be used as an outcome measure. A recent phase III trial of [18F]flutemetamol positron emission tomography (PET) imaging in 106 end-of-life subjects demonstrated the ability to identify fibrillar β-amyloid by comparing in vivo PET to post-mortem histopathology. Post-mortem analyses demonstrated a broad and continuous spectrum of β-amyloid pathology in AD and other dementing and non-dementing disease groups. The GE067-026 trial demonstrated 91% sensitivity and 90% specificity of [18F]flutemetamol PET by majority read for the presence of moderate or frequent plaques. The probability of an abnormal [18F]flutemetamol scan increased with neocortical plaque density and AD diagnosis. All dementia cases with non-AD neurodegenerative diseases and those without histopathological features of β-amyloid deposits were [18F]flutemetamol negative. Majority PET assessments accurately reflected the amyloid plaque burden in 90% of cases. However, ten cases demonstrated a mismatch between PET image interpretations and post-mortem findings. Although tracer retention was best associated with amyloid in neuritic plaques, amyloid in diffuse plaques and cerebral amyloid angiopathy best explain three [18F]flutemetamol positive cases with mismatched (sparse) neuritic plaque burden. Advanced cortical atrophy was associated with the seven false negative [18F]flutemetamol images. The interpretation of images from pathologically equivocal cases was associated with low reader confidence and inter-reader agreement. Our results support that amyloid in neuritic plaque burden is the primary form of β-amyloid pathology detectable with [18F]flutemetamol PET imaging. ClinicalTrials.gov NCT01165554. Registered June 21, 2010; NCT02090855. Registered March 11, 2014.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0399-z) contains supplementary material, which is available to authorized users.

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“…Thus, these data do not support the hypothesis that the biomarker construct of SNAP is analogous to the post-mortem construct of primary age-related tauopathy (PART) 10 . Approximately 42% of the sample described by Crary et al (182/434) would, if they had undergone Amyloid PET, likely be classified as Aβ − because they were Thal Aβ Phase 0–2 35 . Of these 182 Aβ − cases, 77 (42%) were Braak Stage III or IV, were age~90, and MMSE~23 10 .…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity in Suspected Non–Alzheimer Disease Pathophysiology Among Clinically Normal Older Individuals

et al. 2016

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[¹⁸F]flutemetamol amyloid positron emission tomography in preclinical and symptomatic Alzheimer's disease: Specific detection of advanced phases of amyloid‐β pathology

Abstract: [(18)F]flutemetamol amyloid PET detects primarily advanced stages of Aβ pathology in preclinical and symptomatic AD cases.

Cited by 122 publications

References 38 publications

Fluorodeoxyglucose metabolism associated with tau‐amyloid interaction predicts memory decline

Fluorodeoxyglucose metabolism associated with tau‐amyloid interaction predicts memory decline

Post-mortem histopathology underlying β-amyloid PET imaging following flutemetamol F 18 injection

Heterogeneity in Suspected Non–Alzheimer Disease Pathophysiology Among Clinically Normal Older Individuals

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[18F]flutemetamol amyloid positron emission tomography in preclinical and symptomatic Alzheimer's disease: Specific detection of advanced phases of amyloid‐β pathology

Abstract: [(18)F]flutemetamol amyloid PET detects primarily advanced stages of Aβ pathology in preclinical and symptomatic AD cases.

Cited by 122 publications

References 38 publications

Fluorodeoxyglucose metabolism associated with tau‐amyloid interaction predicts memory decline

Fluorodeoxyglucose metabolism associated with tau‐amyloid interaction predicts memory decline

Post-mortem histopathology underlying β-amyloid PET imaging following flutemetamol F 18 injection

Heterogeneity in Suspected Non–Alzheimer Disease Pathophysiology Among Clinically Normal Older Individuals

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[¹⁸F]flutemetamol amyloid positron emission tomography in preclinical and symptomatic Alzheimer's disease: Specific detection of advanced phases of amyloid‐β pathology