Detection of β-amyloid positivity in Alzheimer’s Disease Neuroimaging Initiative participants with demographics, cognition, MRI and plasma biomarkers

Tosun, Duygu; Veitch, Dallas P.; Aisen, Paul S.; Jack, Clifford R.; Jagust, William J.; Petersen, Ronald C.; Saykin, Andrew J.; Bollinger, James G.; Ovod, Vitaliy; Mawuenyega, Kwasi G.; Bateman, Randall J.; Shaw, Leslie M.; Trojanowski, John Q.; Blennow, Kaj; Zetterberg, Henrik; Weiner, Michael W.

doi:10.1093/braincomms/fcab008

Cited by 61 publications

(62 citation statements)

References 98 publications

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“…An imbalance between production and clearance of Aβ occurs early in AD and is typically followed by the accumulation of tau (T in A/T/N) protein tangles (another key pathological hallmark of AD) and neurodegeneration (N in A/T/N) detectable on brain MRI scans ( Hardy and Selkoe, 2002 ; Sperling et al, 2011 ; Jack et al, 2016 ). Therefore, there has been great interest in developing techniques to associate Aβ and tau deposition with MRI measures ( Tosun et al, 2013 , 2014 , 2016 , 2021 ; Ten Kate et al, 2018 ; Petrone et al, 2019 ; Ansart et al, 2020 ; Ezzati et al, 2020 ; Sun et al, 2020 ; Dahl et al, 2021 ). In the structural MRI, the hippocampus is a primary target region across the spectrum of dementia research from clinically normal to late stages of AD ( Shi et al, 2011 ; Li B. et al, 2016 ; Dong et al, 2019 ; Cullen et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Federated Morphometry Feature Selection for Hippocampal Morphometry Associated Beta-Amyloid and Tau Pathology

Dong

Zhang

et al. 2021

Front. Neurosci.

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Amyloid-β (Aβ) plaques and tau protein tangles in the brain are now widely recognized as the defining hallmarks of Alzheimer’s disease (AD), followed by structural atrophy detectable on brain magnetic resonance imaging (MRI) scans. One of the particular neurodegenerative regions is the hippocampus to which the influence of Aβ/tau on has been one of the research focuses in the AD pathophysiological progress. This work proposes a novel framework, Federated Morphometry Feature Selection (FMFS) model, to examine subtle aspects of hippocampal morphometry that are associated with Aβ/tau burden in the brain, measured using positron emission tomography (PET). FMFS is comprised of hippocampal surface-based feature calculation, patch-based feature selection, federated group LASSO regression, federated screening rule-based stability selection, and region of interest (ROI) identification. FMFS was tested on two Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts to understand hippocampal alterations that relate to Aβ/tau depositions. Each cohort included pairs of MRI and PET for AD, mild cognitive impairment (MCI), and cognitively unimpaired (CU) subjects. Experimental results demonstrated that FMFS achieves an 89× speedup compared to other published state-of-the-art methods under five independent hypothetical institutions. In addition, the subiculum and cornu ammonis 1 (CA1 subfield) were identified as hippocampal subregions where atrophy is strongly associated with abnormal Aβ/tau. As potential biomarkers for Aβ/tau pathology, the features from the identified ROIs had greater power for predicting cognitive assessment and for survival analysis than five other imaging biomarkers. All the results indicate that FMFS is an efficient and effective tool to reveal associations between Aβ/tau burden and hippocampal morphometry.

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Section: Introductionmentioning

confidence: 99%

Federated Morphometry Feature Selection for Hippocampal Morphometry Associated Beta-Amyloid and Tau Pathology

Dong

Zhang

et al. 2021

Front. Neurosci.

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“…However, the samples in these studies were clinical trial populations, the performance of these biomarkers in community-based populations was much worse. For example, one study in ADNI reported that among people who are cognitively impaired, plasma p-tau181 distinguished amyloid-positives with a moderate area under curve (AUC) of 0.67 (Tosun et al, 2021), much lower than the AUCs of 0.77-0.91 reported in some memory clinic cohorts (Karikari et al, 2020;Thijssen et al, 2020). Likewise, another study using a small cohort found that plasma p-tau181 discriminated 20 cognitively normal amyloid-positive people from 31 amyloidnegative people with an AUC of only 0.67 (Barthélemy et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Plasma Proteomic Biomarkers Relating to Alzheimer’s Disease: A Meta-Analysis Based on Our Own Studies

Shi

Buckley

Bos

et al. 2021

Front. Aging Neurosci.

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Background and Objective: Plasma biomarkers for the diagnosis and stratification of Alzheimer’s disease (AD) are intensively sought. However, no plasma markers are well established so far for AD diagnosis. Our group has identified and validated various blood-based proteomic biomarkers relating to AD pathology in multiple cohorts. The study aims to conduct a meta-analysis based on our own studies to systematically assess the diagnostic performance of our previously identified blood biomarkers.Methods: To do this, we included seven studies that our group has conducted during the last decade. These studies used either Luminex xMAP or ELISA to measure proteomic biomarkers. As proteins measured in these studies differed, we selected protein based on the criteria that it must be measured in at least four studies. We then examined biomarker performance using random-effect meta-analyses based on the mean difference between biomarker concentrations in AD and controls (CTL), AD and mild cognitive impairment (MCI), MCI, and CTL as well as MCI converted to dementia (MCIc) and non-converted (MCInc) individuals.Results: An overall of 2,879 subjects were retrieved for meta-analysis including 1,053 CTL, 895 MCI, 882 AD, and 49 frontotemporal dementia (FTD) patients. Six proteins were measured in at least four studies and were chosen for meta-analyses for AD diagnosis. Of them, three proteins had significant difference between AD and controls, among which alpha-2-macroglobulin (A2M) and ficolin-2 (FCN2) increased in AD while fibrinogen gamma chain (FGG) decreased in AD compared to CTL. Furthermore, FGG significantly increased in FTD compared to AD. None of the proteins passed the significance between AD and MCI, or MCI and CTL, or MCIc and MCInc, although complement component 4 (CC4) tended to increase in MCIc individuals compared to MCInc.Conclusions: The results suggest that A2M, FCN2, and FGG are promising biomarkers to discriminate AD patients from controls, which are worthy of further validation.

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“…However, the results of different studies are still controversial. Studies adopting the SIMOA platform showed lower levels of plasma Aβ42 and Aβ42/Aβ40 in patients with AD than in controls (Janelidze et al, 2016 ; Li et al, 2019 ; Tosun et al, 2021 ). By contrast, some studies found that the levels of Aβ42 and Aβ42/Aβ40 were significantly increased in patients with mild cognitive impairment (MCI) or AD (Teunissen et al, 2018 ; Palmqvist et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Performance of Plasma Amyloid β, Total Tau, and Neurofilament Light Chain in the Identification of Probable Alzheimer's Disease in South China

Jiao

Liu

Guo

et al. 2021

Front. Aging Neurosci.

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Background: Alzheimer's disease (AD) is the most common type of dementia and has no effective treatment to date. It is essential to develop a minimally invasive blood-based biomarker as a tool for screening the general population, but the efficacy remains controversial. This cross-sectional study aimed to evaluate the ability of plasma biomarkers, including amyloid β (Aβ), total tau (t-tau), and neurofilament light chain (NfL), to detect probable AD in the South Chinese population.Methods: A total of 277 patients with a clinical diagnosis of probable AD and 153 healthy controls with normal cognitive function (CN) were enrolled in this study. The levels of plasma Aβ42, Aβ40, t-tau, and NfL were detected using ultra-sensitive immune-based assays (SIMOA). Lumbar puncture was conducted in 89 patients with AD to detect Aβ42, Aβ40, t-tau, and phosphorylated (p)-tau levels in the cerebrospinal fluid (CSF) and to evaluate the consistency between plasma and CSF biomarkers through correlation analysis. Finally, the diagnostic value of plasma biomarkers was further assessed by constructing a receiver operating characteristic (ROC) curve.Results: After adjusting for age, sex, and the apolipoprotein E (APOE) alleles, compared to the CN group, the plasma t-tau, and NfL were significantly increased in the AD group (p < 0.01, Bonferroni correction). Correlation analysis showed that only the plasma t-tau level was positively correlated with the CSF t-tau levels (r = 0.319, p = 0.003). The diagnostic model combining plasma t-tau and NfL levels, and age, sex, and APOE alleles, showed the best performance for the identification of probable AD [area under the curve (AUC) = 0.89, sensitivity = 82.31%, specificity = 83.66%].Conclusion: Blood biomarkers can effectively distinguish patients with probable AD from controls and may be a non-invasive and efficient method for AD pre-screening.

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Detection of β-amyloid positivity in Alzheimer’s Disease Neuroimaging Initiative participants with demographics, cognition, MRI and plasma biomarkers

Cited by 61 publications

References 98 publications

Federated Morphometry Feature Selection for Hippocampal Morphometry Associated Beta-Amyloid and Tau Pathology

Federated Morphometry Feature Selection for Hippocampal Morphometry Associated Beta-Amyloid and Tau Pathology

Plasma Proteomic Biomarkers Relating to Alzheimer’s Disease: A Meta-Analysis Based on Our Own Studies

Performance of Plasma Amyloid β, Total Tau, and Neurofilament Light Chain in the Identification of Probable Alzheimer's Disease in South China

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