ADNI Biomarker Core: A review of progress since 2004 and future challenges.

Background: We describe the Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core major activities from October 2004 to March 2024, including biobanking ADNI cerebrospinal fluid (CSF), plasma, and serum biofluid samples, biofluid analyses for Alzheimer's disease (AD) biomarkers in the Biomarker Core and various non-ADNI laboratories, and continuous assessments of pre-analytics.

Results: Validated immunoassay and mass spectrometry-based assays were performed in CSF with a shift to plasma, a more accessible biofluid, as qualified assays became available. Performance comparisons across different CSF and plasma AD biomarker measurement platforms have enriched substantially the ADNI participant database enabling method performance determinations for AD pathology detection and longitudinal assessments of disease progression.

The ADNI4 Digital Study: A novel approach to recruitment, screening, and assessment of participants for AD clinical research.

Introduction: We evaluated preliminary feasibility of a digital, culturally-informed approach to recruit and screen participants for the Alzheimer's Disease Neuroimaging Initiative (ADNI4).

Methods: Participants were recruited using digital advertising and completed digital surveys (e.g.

Alzheimer Disease Biomarkers: Moving from CSF to Plasma for Reliable Detection of Amyloid and tau Pathology.

Background: Development of validated biomarkers to detect early Alzheimer disease (AD) neuropathology is needed for therapeutic AD trials. Abnormal concentrations of "core" AD biomarkers, cerebrospinal fluid (CSF) amyloid beta1-42, total tau, and phosphorylated tau correlate well with neuroimaging biomarkers and autopsy findings. Nevertheless, given the limitations of established CSF and neuroimaging biomarkers, accelerated development of blood-based AD biomarkers is underway.

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

Background And Objectives: 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 3 large Alzheimer disease (AD) research cohorts in the United States (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.

The global Alzheimer's Association round robin study on plasma amyloid β methods.

Introduction: Blood-based assays to measure brain amyloid beta (Aβ) deposition are an attractive alternative to the cerebrospinal fluid (CSF)-based assays currently used in clinical settings. In this study, we examined different blood-based assays to measure Aβ and how they compare among centers and assays.

Methods: Aliquots from 81 plasma samples were distributed to 10 participating centers.

Mass spectrometry-based methods for robust measurement of Alzheimer's disease biomarkers in biological fluids.

Alzheimer's disease (AD) is the most common form of dementia affecting 60%-70% of people afflicted with this disease. Accurate antemortem diagnosis is urgently needed for early detection of AD to enable reliable estimation of prognosis, intervention, and monitoring of the disease. The National Institute on Aging/Alzheimer's Association sponsored the 'Research Framework: towards a biological definition of AD', which recommends using different biomarkers in living persons for a biomarker-based definition of AD regardless of clinical status.

Effect of escitalopram dose and treatment duration on CSF Aβ levels in healthy older adults: A controlled clinical trial.

Objective: To determine whether treatment with escitalopram compared with placebo would lower CSF β-amyloid 42 (Aβ) levels.

Rationale: Serotonin signaling suppresses Aβ in animal models of Alzheimer disease (AD) and young healthy humans. In a prospective study in older adults, we examined dose and treatment duration effects of escitalopram.

Analytical and Clinical Performance of Amyloid-Beta Peptides Measurements in CSF of ADNIGO/2 Participants by an LC-MS/MS Reference Method.

Background: Cerebrospinal fluid (CSF) amyloid-β1-42 (Aβ42) reliably detects brain amyloidosis based on its high concordance with plaque burden at autopsy and with amyloid positron emission tomography (PET) ligand retention observed in several studies. Low CSF Aβ42 concentrations in normal aging and dementia are associated with the presence of fibrillary Aβ across brain regions detected by amyloid PET imaging.

Methods: An LC-MS/MS reference method for Aβ42, modified by adding Aβ40 and Aβ38 peptides to calibrators, was used to analyze 1445 CSF samples from ADNIGO/2 participants.

Detection of Alzheimer Disease Pathology in Patients Using Biochemical Biomarkers: Prospects and Challenges for Use in Clinical Practice.

Background: Thirty-four years ago, amyloid-β 1-42 peptide was identified in amyloid plaques from brain tissue obtained from patients with Alzheimer disease (AD) and Down syndrome. This finding led to development of immunoassays for this marker of amyloid plaque burden in cerebrospinal fluid (CSF) approximately 10 years later. Subsequently, research immunoassays were developed for total τ protein and τ phosphorylated at the threonine 181 position.

Derivation of cutoffs for the Elecsys amyloid β (1-42) assay in Alzheimer's disease.

Introduction: An Elecsys® Amyloid β (Aβ [1-42]) immunoassay cutoff for classification of patients with Alzheimer's disease was investigated.

Methods: Cerebrospinal fluid samples collected from patients with mild-to-moderate Alzheimer's disease were analyzed by Elecsys® immunoassays: (1) Aβ (1-42), (2) total tau, and (3) phosphorylated tau. Cutoffs (Aβ [1-42] and ratios with tau) were estimated by method comparison between AlzBio3 ( = 206), mixture modeling ( = 216), and concordance with florbetapir F 18 imaging-based classification ( = 75).

Active Cigarette Smoking in Cognitively-Normal Elders and Probable Alzheimer's Disease is Associated with Elevated Cerebrospinal Fluid Oxidative Stress Biomarkers.

Neurodegenerative diseases and chronic cigarette smoking are associated with increased cerebral oxidative stress (OxS). Elevated F2-isoprostane levels in biological fluid is a recognized marker of OxS. This study assessed the association of active cigarette smoking with F2-isoprostane in concentrations in cognitively-normal elders (CN), and those with mild cognitive impairment (MCI) and probable Alzheimer's disease (AD).

CSF Aβ - an excellent but complicated Alzheimer's biomarker - a route to standardisation.

The 42 amino acid form of amyloid β (Aβ-) in cerebrospinal fluid (CSF) has been widely accepted as a central biomarker for Alzheimer's disease. Several immunoassays for CSF Aβ are commercially available, but can suffer from between laboratory and batch-to-batch variability as well as lack of standardisation across assays. As a consequence, no general cut-off values have been established for a specific context of use (e.

Round robin test on quantification of amyloid-β 1-42 in cerebrospinal fluid by mass spectrometry.

Introduction: Cerebrospinal fluid (CSF) amyloid-β 1-42 (Aβ42) is an important biomarker for Alzheimer's disease, both in diagnostics and to monitor disease-modifying therapies. However, there is a great need for standardization of methods used for quantification. To overcome problems associated with immunoassays, liquid chromatography-tandem mass spectrometry (LC-MS/MS) has emerged as a critical orthogonal alternative.

The Alzheimer's Disease Neuroimaging Initiative 2 Biomarker Core: A review of progress and plans.

Introduction: We describe Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core progress including: the Biobank; cerebrospinal fluid (CSF) amyloid beta (Aβ1-42), t-tau, and p-tau181 analytical performance, definition of Alzheimer's disease (AD) profile for plaque, and tangle burden detection and increased risk for progression to AD; AD disease heterogeneity; progress in standardization; and new studies using ADNI biofluids.

Methods: Review publications authored or coauthored by ADNI Biomarker core faculty and selected non-ADNI studies to deepen the understanding and interpretation of CSF Aβ1-42, t-tau, and p-tau181 data.

Results: CSF AD biomarker measurements with the qualified AlzBio3 immunoassay detects neuropathologic AD hallmarks in preclinical and prodromal disease stages, based on CSF studies in non-ADNI living subjects followed by the autopsy confirmation of AD.

History of cigarette smoking in cognitively-normal elders is associated with elevated cerebrospinal fluid biomarkers of oxidative stress.

Background: Cigarette smoking in adults is associated with abnormalities in brain neurobiology. Smoking-induced central nervous system oxidative stress (OxS) is a potential mechanism associated with these abnormalities. The goal of this study was to compare cognitively-normal elders on cerebrospinal fluid (CSF) levels of F2-isoprostane biomarkers of OxS.

Qualification of a surrogate matrix-based absolute quantification method for amyloid-β₄₂ in human cerebrospinal fluid using 2D UPLC-tandem mass spectrometry.

The primary aims of this work were to: 1) establish a calibrator surrogate matrix for quantification of amyloid-β (Aβ)42 in human cerebrospinal fluid (CSF) and preparation of quality control samples for LC-MS-MS methodology, 2) validate analytical performance of the assay, and 3) evaluate its diagnostic utility and compare it with the AlzBio3 immunoassay. The analytical methodology was based on a 2D-UPLC-MS-MS platform. Sample pretreatment used 5 M guanidine hydrochloride and extraction on μElution SPE columns as previously described.

Clinical utility and analytical challenges in measurement of cerebrospinal fluid amyloid-β(1-42) and τ proteins as Alzheimer disease biomarkers.

Background: Over the past 2 decades, clinical studies have provided evidence that cerebrospinal fluid (CSF) amyloid β(1-42) (Aβ(1-42)), total τ (t-τ), and τ phosphorylated at Thr181 (p-τ(181)) are reliable biochemical markers of Alzheimer disease (AD) neuropathology.

Content: In this review, we summarize the clinical performance and describe the major challenges for the analytical performance of the most widely used immunoassay platforms [based on ELISA or microbead-based multianalyte profiling (xMAP) technology] for the measurement of CSF AD biomarkers (Aβ(1-42), t-τ, and p-τ(181)). With foundational immunoassay data providing the diagnostic and prognostic values of CSF AD biomarkers, the newly revised criteria for the diagnosis of AD include CSF AD biomarkers for use in research settings.

Improved protocol for measurement of plasma β-amyloid in longitudinal evaluation of Alzheimer's Disease Neuroimaging Initiative study patients.

Background: The interassay variability and inconsistency of plasma β-amyloid (Aβ) measurements among centers are major factors precluding the interpretation of results and a substantial obstacle in the meta-analysis across studies of this biomarker. The goal of this investigation was to address these problems by improving the performance of the bioanalytical method.

Methods: We used the Luminex immunoassay platform with a multiplex microsphere-based reagent kit from Innogenetics.

Association of common genetic variants in GPCPD1 with scaling of visual cortical surface area in humans.

Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts.

Evaluation of performance of new, isotopically labeled internal standard ([13c2d4]RAD001) for everolimus using a novel high-performance liquid chromatography tandem mass spectrometry method.

Introduction: Everolimus was approved for the prevention of organ rejection of kidney transplants in adult patients in April 2010 by the US Food and Drug Administration. Therapeutic drug monitoring of everolimus is recommended for all patients receiving this immunosuppressant. The goal of this study was to improve and revalidate our previously published high-performance liquid chromatography tandem mass spectrometry method for the measurement of everolimus and to assess the performance of the recently introduced isotopically labeled internal standard (IS).

Simultaneous HPLC-MS-MS quantification of 8-iso-PGF(2alpha) and 8,12-iso-iPF(2alpha) in CSF and brain tissue samples with on-line cleanup.

Quantitation of isoprostanes such as 8-iso-PGF(2alpha) and 8,12-iso-iPF(2alpha)-VI in biological fluids has been proposed as a reliable test of oxidant stress and inflammation in a variety of disorders. This paper presents a liquid chromatography method with tandem mass spectrometry detection for the simultaneous analysis of these two isoprostanes in human CSF and brain tissue samples. An API 5000 triple quadrupole instrument (AB Sciex, Foster City, CA, USA) with an APCI ion source was used in this study.

Update on the biomarker core of the Alzheimer's Disease Neuroimaging Initiative subjects.

Here, we review progress by the Penn Biomarker Core in the Alzheimer's Disease Neuroimaging Initiative (ADNI) toward developing a pathological cerebrospinal fluid (CSF) and plasma biomarker signature for mild Alzheimer's disease (AD) as well as a biomarker profile that predicts conversion of mild cognitive impairment (MCI) and/or normal control subjects to AD. The Penn Biomarker Core also collaborated with other ADNI Cores to integrate data across ADNI to temporally order changes in clinical measures, imaging data, and chemical biomarkers that serve as mileposts and predictors of the conversion of normal control to MCI as well as MCI to AD, and the progression of AD. Initial CSF studies by the ADNI Biomarker Core revealed a pathological CSF biomarker signature of AD defined by the combination of Abeta1-42 and total tau (T-tau) that effectively delineates mild AD in the large multisite prospective clinical investigation conducted in ADNI.

Quantitation of sirolimus using liquid chromatography-tandem mass spectrometry (LC-MS-MS).

A multiple reaction monitoring positive ion HPLC method with tandem mass spectrometric detection (MS-MS) for determination of sirolimus in human blood samples is described. This method utilizes an online cleanup step that provides simple and rapid sample preparation with a switching valve technique. This procedure includes: instrumentation, API 3000 triple quadrupole with turbo-ion spray (Applied Biosystems, Foster City, CA); HPLC system (Agilent Technologies series 1100, Wilmington, DE); two position switching valve (Valco, Houston, TX); 10 mm guard cartridge (C(18)) used as an extraction column (Perkin Elmer, Norwalk, CT); analytical column (Nova-Pak C(18) column, 2.

High-performance liquid chromatography-mass spectroscopy/mass spectroscopy method for simultaneous quantification of total or free fraction of mycophenolic acid and its glucuronide metabolites.

Measurement of unbound fractions of mycophenolic acid and its metabolites may prove useful in explaining the complicated pharmacokinetic and pharmacodynamic behavior of this drug as well as in therapeutic drug monitoring. We developed a reliable, accurate, and sensitive liquid chromatography-tandem mass spectrometric method for the simultaneous quantification of mycophenolic acid (MPA), MPA glucuronide (MPAG), and MPA acyl-glucuronide (AcMPAG), total or unbound, in plasma, urine, and tissue extract. This method uses a single internal standard, carboxy-butoxy ether of mycophenolic acid (MPAC), and involves a simple sample preparation step.