Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques

Objective:To determine the diagnostic accuracy of a plasma Aβ42/Aβ40 assay in classifying amyloid PET status across global research studies using samples collected by multiple centers that utilize different blood collection and processing protocols.Methods:Plasma samples (n=465) were obtained from three large Alzheimer’s Disease (AD) research cohorts in the US (n=182), Australia (n=183), and Sweden (n=100). Plasma Aβ42/Aβ40 was measured by a high precision immunoprecipitation mass spectrometry (IPMS) assay and compared to the reference standards of amyloid PET and CSF Aβ42/Aβ40.Results:In the combined cohort of 465 participants, plasma Aβ42/Aβ40 had good concordance with amyloid PET status (Receiver Operating Characteristic Area Under the Curve [AUC] of 0.84, 95% confidence interval [CI] 0.80-0.87); concordance improved with the inclusion of APOE ε4 status (AUC 0.88, 95% CI 0.85-0.91). The AUC of plasma Aβ42/Aβ40 with CSF amyloid status was 0.85 (95% CI 0.78-0.91) and improved to 0.93 (95% CI 0.89-0.97) with APOE ε4 status. These findings were consistent across the three cohorts, despite differences in protocols. Further, the assay performed similarly in both cognitively unimpaired and impaired individuals.Conclusions:Plasma Aβ42/Aβ40 is a robust measure for detecting amyloid plaques and can be utilized to aid in the diagnosis of AD, identify those at risk for future dementia due to AD, and improve the diversity of populations enrolled in AD research and clinical trials.Classification of Evidence:This study provides Class II evidence that plasma Aβ42/Aβ40, as measured by a high precision IPMS assay, accurately diagnoses brain amyloidosis in both cognitively unimpaired and impaired research participants.

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Aducanumab: Appropriate Use Recommendations

Journal of Prevention of Alzheimer's Disease ◽

10.14283/jpad.2021.45 ◽

2021 ◽

pp. 1-2

Author(s):

P. Scheltens ◽

E.G.B. Vijverberg

Keyword(s):

Eligible Patient ◽

Surrogate Marker ◽

Amyloid Plaques ◽

Phase Iii ◽

Amyloid Pet ◽

Small Step ◽

Appropriate Use ◽

The Us ◽

General Feeling ◽

Giant Leap

June 7, 2021 will not likely be forgotten soon by many Alzheimer Disease (AD) researchers. To paraphrase a famous quote: ”a small step for man, but a giant leap forwards for the field”. That day, AduhelmTM (aducanumab) was approved by the US Food and Drug administration (FDA), because of its profound effect on amyloid plaques as shown by amyloid PET as a surrogate marker. Although this decision was not met with great enthusiasm uniformly, the general feeling during a 4 hour webinar hosted by the Alzheimer Association (1) was that the benefits seem to outweigh the risks, but proper guidance was needed on who would be eligible for treatment, because all attendees felt the label was far too broad and unspecific. The latter was amended on july 8, jointly by FDA and Biogen to more accurately reflect the eligible patient population that was studied in the Phase III program.

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Plasma Amyloid-β Oligomerization Tendency Predicts Amyloid PET Positivity

10.21203/rs.3.rs-67588/v1 ◽

2020 ◽

Author(s):

Jung-Min Pyun ◽

Ji Sun Ryu ◽

Ryan Lee ◽

KyuHawn Shim ◽

Young Chul Youn ◽

...

Keyword(s):

High Performance ◽

Prediction Models ◽

Mmse Score ◽

Detection System ◽

Amyloid Β ◽

Visual Assessment ◽

Research Field ◽

Amyloid Pet ◽

Apoe Ε4 ◽

Auc Value

Abstract Background: Among other emerging amyloid-targeting blood-based biomarkers, Multimer Detection System-Oligomeric Amyloid-β (MDS-OAβ) measures dynamic changes in concentration of oligomeric amyloid-β (OAβ), which is considered the main pathogenic culprit of Alzheimer’s disease (AD), in plasma after spiking with synthetic amyloid-β (Aβ). We aimed to investigate predictability of MDS-OAβ on amyloid Positron Emission Tomography (PET) positivity.Methods: A total of 96 subjects who visited Seoul National University Bundang Hospital for medical check-up complaining of cognitive decline and had undergone extensive medical assessment were recruited. Amyloid statuses were dichotomized into positive or negative based on visual assessment of amyloid PET. Plasma OAβ concentration was measured by MDS-OAβ. In the previous validation study, 0.78ng/ml was established as the cut-off value and the plasma OAβ concentration higher than or equal to the cut-off value was defined MDS-OAβ positive.Results: MDS-OAβ positivity could discriminate amyloid PET positivity with the AUC value of 0.855 (95% CI 0.776–0.933). Adding MDS-OAβ positivity to prediction models including age, MMSE score, and APOE ε4 status improved the performance up to the AUC value of 0.926 (95% CI 0.871–0.980).Conclusions: The Aβ oligomerization tendency in plasma could predict amyloid PET positivity with high performance, and when it is combined with age, MMSE score, and APOE ε4 status, the predictability was improved substantially. This suggests the potential of MDS-OAβ as a useful initial stage test in clinical and research field of AD.

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Disruption of Arterial Perivascular Drainage of Amyloid-β from the Brains of Mice Expressing the Human APOE ε4 Allele

PLoS ONE ◽

10.1371/journal.pone.0041636 ◽

2012 ◽

Vol 7 (7) ◽

pp. e41636 ◽

Cited By ~ 105

Author(s):

Cheryl A. Hawkes ◽

Patrick M. Sullivan ◽

Sarah Hands ◽

Roy O. Weller ◽

James A. R. Nicoll ◽

...

Keyword(s):

Amyloid Β ◽

Human Apoe ◽

Apoe Ε4 ◽

Ε4 Allele ◽

Perivascular Drainage

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An evaluation of the self-assembly enhancing properties of cell-derived hexameric amyloid-β

Scientific Reports ◽

10.1038/s41598-021-90680-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Devkee M. Vadukul ◽

Céline Vrancx ◽

Pierre Burguet ◽

Sabrina Contino ◽

Nuria Suelves ◽

...

Keyword(s):

Amyloid Precursor Protein ◽

Self Assembly ◽

Critical Nucleus ◽

Amyloid Fibril ◽

Amyloid Β ◽

Amyloid Plaques ◽

The Self ◽

Aβ Peptide ◽

Amyloid Fibril Formation ◽

Secretase Activity

AbstractA key hallmark of Alzheimer’s disease is the extracellular deposition of amyloid plaques composed primarily of the amyloidogenic amyloid-β (Aβ) peptide. The Aβ peptide is a product of sequential cleavage of the Amyloid Precursor Protein, the first step of which gives rise to a C-terminal Fragment (C99). Cleavage of C99 by γ-secretase activity releases Aβ of several lengths and the Aβ42 isoform in particular has been identified as being neurotoxic. The misfolding of Aβ leads to subsequent amyloid fibril formation by nucleated polymerisation. This requires an initial and critical nucleus for self-assembly. Here, we identify and characterise the composition and self-assembly properties of cell-derived hexameric Aβ42 and show its assembly enhancing properties which are dependent on the Aβ monomer availability. Identification of nucleating assemblies that contribute to self-assembly in this way may serve as therapeutic targets to prevent the formation of toxic oligomers.

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A MYC-Driven Plasma Polyamine Signature for Early Detection of Ovarian Cancer

Cancers ◽

10.3390/cancers13040913 ◽

2021 ◽

Vol 13 (4) ◽

pp. 913

Author(s):

Johannes Fahrmann ◽

Ehsan Irajizad ◽

Makoto Kobayashi ◽

Jody Vykoukal ◽

Jennifer Dennison ◽

...

Keyword(s):

Ovarian Cancer ◽

Early Stage ◽

Area Under The Curve ◽

Polyamine Metabolism ◽

Healthy Controls ◽

Test Set ◽

Exact Test ◽

Oncogenic Driver ◽

Characteristic Area ◽

Validation Set

MYC is an oncogenic driver in the pathogenesis of ovarian cancer. We previously demonstrated that MYC regulates polyamine metabolism in triple-negative breast cancer (TNBC) and that a plasma polyamine signature is associated with TNBC development and progression. We hypothesized that a similar plasma polyamine signature may associate with ovarian cancer (OvCa) development. Using mass spectrometry, four polyamines were quantified in plasma from 116 OvCa cases and 143 controls (71 healthy controls + 72 subjects with benign pelvic masses) (Test Set). Findings were validated in an independent plasma set from 61 early-stage OvCa cases and 71 healthy controls (Validation Set). Complementarity of polyamines with CA125 was also evaluated. Receiver operating characteristic area under the curve (AUC) of individual polyamines for distinguishing cases from healthy controls ranged from 0.74–0.88. A polyamine signature consisting of diacetylspermine + N-(3-acetamidopropyl)pyrrolidin-2-one in combination with CA125 developed in the Test Set yielded improvement in sensitivity at >99% specificity relative to CA125 alone (73.7% vs 62.2%; McNemar exact test 2-sided P: 0.019) in the validation set and captured 30.4% of cases that were missed with CA125 alone. Our findings reveal a MYC-driven plasma polyamine signature associated with OvCa that complemented CA125 in detecting early-stage ovarian cancer.

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Selective Secretase Targeting for Alzheimer’s Disease Therapy

Journal of Alzheimer s Disease ◽

10.3233/jad-201027 ◽

2021 ◽

pp. 1-17

Author(s):

Alvaro Miranda ◽

Enrique Montiel ◽

Henning Ulrich ◽

Cristian Paz

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Amyloid Plaques ◽

Neuroprotective Activity ◽

Amyloid Β Protein ◽

Secretase Activity ◽

Membrane Bound ◽

Aβ Production ◽

Bace 1

Alzheimer’s disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-β (Aβ) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-β protein precursor (AβPP) producing the membrane-bound fragment CTFα and the soluble fragment sAβPPα with neuroprotective activity; β-secretase produces membrane-bound fragment CTFβ and a soluble fragment sAβPPβ. After α-secretase cleavage of AβPP, γ-secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFβ is cleaved by γ-secretase producing AICD as well as Aβ in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, β-secretase inhibitors (BACE-1), and γ-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aβ42. In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979, Verubecestat, LY2886721, Lanabecestat, LY2811376, and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aβ production did not recover cognitive functions or reverse the disease. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ-secretase modulators or α-secretase enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and the activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.

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Texture-Based Analysis of 18F-Labeled Amyloid PET Brain Images

Applied Sciences ◽

10.3390/app11051991 ◽

2021 ◽

Vol 11 (5) ◽

pp. 1991

Author(s):

Alexander P. Seiffert ◽

Adolfo Gómez-Grande ◽

Eva Milara ◽

Sara Llamas-Velasco ◽

Alberto Villarejo-Galende ◽

...

Keyword(s):

Area Under The Curve ◽

Standardized Uptake Value ◽

Texture Features ◽

Roc Curves ◽

Significant Feature ◽

Study Cohort ◽

Amyloid Pet ◽

Reference Region ◽

Brain Images ◽

Positron Emission

Amyloid positron emission tomography (PET) brain imaging with radiotracers like [18F]florbetapir (FBP) or [18F]flutemetamol (FMM) is frequently used for the diagnosis of Alzheimer’s disease. Quantitative analysis is usually performed with standardized uptake value ratios (SUVR), which are calculated by normalizing to a reference region. However, the reference region could present high variability in longitudinal studies. Texture features based on the grey-level co-occurrence matrix, also called Haralick features (HF), are evaluated in this study to discriminate between amyloid-positive and negative cases. A retrospective study cohort of 66 patients with amyloid PET images (30 [18F]FBP and 36 [18F]FMM) was selected and SUVRs and 6 HFs were extracted from 13 cortical volumes of interest. Mann–Whitney U-tests were performed to analyze differences of the features between amyloid positive and negative cases. Receiver operating characteristic (ROC) curves were computed and their area under the curve (AUC) was calculated to study the discriminatory capability of the features. SUVR proved to be the most significant feature among all tests with AUCs between 0.692 and 0.989. All HFs except correlation also showed good performance. AUCs of up to 0.949 were obtained with the HFs. These results suggest the potential use of texture features for the classification of amyloid PET images.

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Gallium nanoparticles as novel inhibitors of Aβ40 aggregation

Materials Advances ◽

10.1039/d1ma00461a ◽

2021 ◽

Author(s):

Rolando Oyola ◽

Deguo Du ◽

Idalia Ramos ◽

Kyabeth Torres ◽

Ambar S Delgado ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Amyloid Plaques ◽

Aβ Peptides ◽

Gallium Nanoparticles

Alzheimer’s disease (AD) has been consistently related to the formation of senile amyloid plaques mainly composed of amyloid β (Aβ) peptides. The toxicity of Aβ aggregates has been indicated to...

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Model Development of CDK4/6 Predicted Efficacy in Patients With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced or Metastatic Breast Cancer

JCO Clinical Cancer Informatics ◽

10.1200/cci.21.00025 ◽

2021 ◽

pp. 758-767

Author(s):

Jeremy Mason ◽

Yutao Gong ◽

Laleh Amiri-Kordestani ◽

Suparna Wedam ◽

Jennifer J. Gao ◽

...

Keyword(s):

Breast Cancer ◽

Prediction Models ◽

Area Under The Curve ◽

Growth Factor Receptor ◽

Metastatic Breast ◽

Tumor Characteristics ◽

Average Area ◽

Hormone Receptor Positive ◽

The Us ◽

Epidermal Growth

PURPOSE Three cyclin-dependent kinase 4/6 inhibitors (CDKIs) are approved by the US Food and Drug Administration for the treatment of patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced or metastatic breast cancer in combination with hormonal therapy (HT). We hypothesized that on an individual basis, efficacy outcomes and adverse event (AE) development can be predicted using baseline patient and tumor characteristics. METHODS Individual-level data from seven randomized controlled trials submitted to the US Food and Drug Administration for new or supplemental marketing applications of CDKIs were pooled. Progression-free survival (PFS), overall survival (OS), and AE prediction models were developed for specific treatment regimens (HT v HT plus CDKI). An individual's characteristics were used in all models simultaneously to create a group of predicted outcomes that are comparable across treatment settings. RESULTS Accuracy of the PFS and OS prediction models for HT were 66% and 64%, respectively, with the strongest predictors being menopausal status and therapy line. The corresponding AE prediction models resulted in an average area under the curve of 0.613. Accuracy of the PFS and OS prediction models for HT plus CDKI were 62% and 63%, respectively, with the strongest predictors being histologic grade for both. The corresponding AE prediction models resulted in an average area under the curve of 0.639. CONCLUSION This exploratory analysis demonstrated that models of efficacy outcomes and AE development can be developed using baseline patient and tumor characteristics. Comparison of paired models can inform treatment selection for individuals on the basis of the patient's personalized goals and concerns. Although use of CDKIs is standard of care in the first- or second-line setting, this model provides prognostic information that may inform individual treatment decisions.

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Can Thyroid Ultrasonography Predict Substernal Extension or Tracheal Compression in Goiters?

Canadian Association of Radiologists Journal ◽

10.1016/j.carj.2018.07.007 ◽

2018 ◽

Vol 69 (4) ◽

pp. 422-429

Author(s):

Hedyeh Ziai ◽

Nicole L. Lebo ◽

Ania Z. Kielar ◽

Michael J. Odell

Keyword(s):

Thyroid Gland ◽

Characteristic Curve ◽

Area Under The Curve ◽

Thyroid Volume ◽

Classification Systems ◽

Tracheal Compression ◽

Gland Volume ◽

The Us ◽

Thyroid Gland Volume ◽

Preoperative Ct

Purpose To determine whether an ultrasonography (US)-defined thyroid volume can accurately predict substernal extension or tracheal narrowing. Methods After research ethics approval, we identified patients with thyroid nodules investigated with both US and computed tomography (CT). Reviewers assigned scores for both substernal extension and tracheal compression on CT using pre-established classification systems. Statistical analysis with receiver operating characteristic curve analysis was performed to find the US-determined thyroid volume thresholds that correlated with each substernal extension and tracheal compression. Results This study included 120 patients (mean age 63.4 years; SD ± 15.9; 67% female). Thirty-five patients (29%) had substernal extension. The mean US total thyroid gland volume in patients with and without substernal extension were 92.4 and 37.6 cm3, respectively ( P < .001). 86% of patients with substernal extension had tracheal narrowing vs. 27% of patients without substernal extension ( P < .0001). A cutoff dominant gland volume of ≥37.5 cm3 showed 83% sensitivity and 79% specificity for substernal extension (area under the curve [AUC] = 0.84). A total thyroid gland volume threshold of ≥37.8 cm3 showed 89% sensitivity and 87% specificity for any degree of tracheal narrowing (AUC = 0.90). Conclusions This study suggests that US volumes may be used as a predictor to identify those patients with thyroid enlargement who are most at risk of substernal extension and tracheal compression and who may benefit from preoperative CT imaging for optimal surgical and anesthetic planning.

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