The PrecivityAD™ test: Accurate and reliable LC-MS/MS assays for quantifying plasma amyloid beta 40 and 42 and apolipoprotein E proteotype for the assessment of brain amyloidosis

Kirmess, Kristopher M.; Meyer, Matthew R.; Holubasch, Mary S.; Knapik, S; Hu, Yan; Jackson, Erin; Harpstrite, Scott E.; Verghese, Philip B.; West, Tim; Fogelman, Ilana; Braunstein, Joel B.; Yarasheski, Kevin E.; Contois, John H.

doi:10.1016/j.cca.2021.05.011

Cited by 67 publications

(61 citation statements)

References 28 publications

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“…The samples were tested utilizing liquid chromatography-mass spectrometry as previously described [8]. Additionally, an Amyloid Probability Score (APS) was determined for each participant by C2N Diagnostics based upon plasma Aβ42/Aβ40 ratio, age and ApoE status [10]. All participants had prime and boost vaccination with BCG Tice strain.…”

Section: Recruitmentmentioning

confidence: 99%

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Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer’s Disease

et al. 2022

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BCG vaccine has been used for 100 years to prevent tuberculosis. Not all countries, including the United States, adopted the initial World Health Organization recommendation to use BCG. Moreover, many Western countries that had routinely used BCG have discontinued its use. Recent population studies demonstrate lower prevalence of Alzheimer’s disease (AD) in countries with high BCG coverage. Intravesicular instillation of BCG is also used to treat bladder cancer that has not invaded the bladder muscle wall and has been shown to reduce recurrence. Several retrospective studies of bladder cancer patients demonstrated that BCG treatment was associated with a significantly reduced risk of developing AD. Plasma amyloid β assessment has become a fertile area of study for an AD biomarker that is predictive of a positive amyloid PET scan. Mass spectrometry-based plasma amyloid 42/40 ratio has proven to be accurate and robust, and when combined with age and ApoE, is shown to accurately predict current and future brain amyloid status. These parameters, amyloid 42/40 ratio, age and ApoE genotype are incorporated into an Amyloid Probability Score (APS)–a score that identifies low, intermediate or high risk of having a PET scan positive for cerebral amyloid. Community recruitment was used for this open-label pilot study. Forty-nine BCG-naïve, immunocompetent individuals completed our study: prior to BCG prime and boost, as determined by the APS, 34 had low risk (APS 0–35), 5 had intermediate risk (APS 36–57) and 10 had high risk (APS 58–100). The APS range for the participant group was 0 to 94. Follow-up plasma amyloid testing 9 months after vaccination revealed a reduction in the APS in all the risk groups: low risk group (p = 0. 37), intermediate risk group (p = 0.13) and the high-risk group (statistically significant, p = 0.016). Greater benefit was seen in younger participants and those with the highest risk. The small number of participants and the nascent status of plasma amyloid testing will rightfully temper embracement of these results. However, both the favorable direction of change after BCG as well as the utility of the APS—a valuable surrogate AD biomarker—may prompt a definitive large-scale multicenter investigation of BCG and AD risk as determined by plasma amyloid peptide ratios and APS.

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Section: Recruitmentmentioning

confidence: 99%

“…Moreover, in a small subset of individuals who were negative for amyloid on PET imaging at baseline, the plasma assay predicted future amyloid positivity on PET imaging [8]. Plasma Aβ42/Aβ40 ratio with age and APOE status have been combined into an Amyloid Probability Score (APS) [10].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer’s Disease

et al. 2022

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“…In 2019, recognizing the major unmet need for blood-based diagnostic tests to identify AD earlier than current practice allows, the U.S. Food and Drug Administration granted a “Breakthrough Device” designation for a blood test through a federal program designed to accelerate the path to approval. As a result, in 49 US States a test is now available, which quantifies Aβ 42/40 ratio and detects Apolipoprotein E proteotype in blood samples, using a mass spectrometry platform [ 21, 22 ]. On the other hand, there is still ongoing debate about which specific proteins and enzymes to consider in the blood analysis of patients with cognitive decline, alongside the limitation of not having standardized values and methodology.…”

Section: Resultsmentioning

confidence: 99%

Lights and Shadows of Cerebrospinal Fluid Biomarkers in the Current Alzheimer’s Disease Framework

Gallucci

Cenesi

White

et al. 2022

JAD

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Background: The most significant biomarkers that are included in the Alzheimer’s disease (AD) research framework are amyloid-β plaques deposition, p-tau, t-tau, and neurodegeneration. Although cerebrospinal fluid (CSF) biomarkers are included in the most recent AD research criteria, their use is increasing in the routine clinical practice and is applied also to the preclinical phases of AD, including mild cognitive impairment. The role of these biomarkers is still unclear concerning the preclinical stage of AD diagnosis, the CSF methodology, and the costs-benefits of the biomarkers’ tests. The controversies regarding the use of biomarkers in the clinical practice are related to the concepts of analytical validity, clinical validity, and clinical utility and to the question of whether they are able to diagnose AD without the support of AD clinical phenotypes. Objective: The objective of the present work is to expose the strengths and weaknesses of the use of CSF biomarkers in the diagnosis of AD in a clinical context. Methods: We used PubMed as main source for articles published and the final reference list was generated on the basis of relevance to the topics covered in this work. Results: The use of CSF biomarkers for AD diagnosis is certainly important but its indication in routine clinical practice, especially for prodromal conditions, needs to be regulated and also contextualized considering the variety of possible clinical AD phenotypes. Conclusion: We suggest that the diagnosis of AD should be understood both as clinical and pathological.

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“…Plasma Aβ42 alone is not an accurate biomarker of AD brain pathology, but the ratio of Aβ42 to Aβ40 predicts which individuals have significant AD brain pathology 28,29 . The first clinical blood test developed for AD uses plasma Aβ42/Aβ40, age, and apolipoprotein E proteotype to stratify the probability of significant AD brain pathology ( case 8-2 ) 3,4 . As with CSF tests for AD biomarkers, this test is not yet fully approved by the FDA.…”

Section: Blood-based Biomarkersmentioning

confidence: 99%

Fluid Biomarkers in Dementia Diagnosis

Schindler¹

2022

CONTINUUM: Lifelong Learning in Neurology

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PURPOSE OF REVIEWThis article discusses how fluid biomarkers can augment the routine dementia evaluation and improve diagnostic accuracy. The tests that are currently available and the indications for their use are described. Further, tests that are under development and likely to be used in the future are identified.RECENT FINDINGSTechnical improvements in assay sensitivity and precision have led to the rapid development of blood-based biomarkers for Alzheimer disease (AD) over the past several years. Studies have found that the ratio of amyloid-β (Aβ) peptides (Aβ42/Aβ40) and concentrations of phosphorylated tau isoforms in plasma can identify individuals with AD brain pathology. Blood-based tests may enable much broader use of AD biomarkers in the evaluation of patients with cognitive impairment.SUMMARYEven after a detailed history, examination, routine laboratory testing, and brain imaging, the cause of dementia sometimes remains unclear. CSF and blood-based biomarkers can evaluate for a range of neurologic disorders that are associated with dementia, including AD. Integrating data from fluid biomarker tests and the routine dementia evaluation may improve the accuracy of dementia diagnosis.

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The PrecivityAD™ test: Accurate and reliable LC-MS/MS assays for quantifying plasma amyloid beta 40 and 42 and apolipoprotein E proteotype for the assessment of brain amyloidosis

Cited by 67 publications

References 28 publications

Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer’s Disease

Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer’s Disease

Lights and Shadows of Cerebrospinal Fluid Biomarkers in the Current Alzheimer’s Disease Framework

Fluid Biomarkers in Dementia Diagnosis

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