Use of plasma biomarkers for AT(N) classification of neurodegenerative dementias

Abstract

ObjectivesAll categories included in the AT(N) classification can now be measured in plasma. However, their agreement with cerebrospinal fluid (CSF) markers is not fully established. A blood signature to generate the AT(N) classification would facilitate early diagnosis of patients with Alzheimer’s disease (AD) through an easy and minimally invasive approach.MethodsWe measured Aβ, pTau181 and neurofilament light (NfL) in 150 plasma samples of the Sant Pau Initiative on Neurodegeneration cohort including patients with mild cognitive impairment, AD dementia, frontotemporal dementia, dementia with Lewy bodies and cognitively normal participants. We classified participants in the AT(N) categories according to CSF biomarkers and studied the diagnostic value of plasma biomarkers within each category individually and in combination.ResultsThe plasma Aβ composite, pTau181 and NfL yielded areas under the curve (AUC) of 0.75, 0.78 and 0.88 to discriminate positive and negative participants in their respective A, T and N categories. The combination of all three markers did not outperform pTau181 alone (AUC=0.81) to discriminate A+T+ from A–T– participants. There was a moderate correlation between plasma Aβ composite and CSF Aβ1–42/Aβ1–40 (Rho=−0.5, p<0.001) and between plasma pTau181 and CSF pTau181 in the entire cohort (Rho=0.51, p<0.001). NfL levels in plasma showed high correlation with those in CSF (Rho=0.78, p<0.001).ConclusionsPlasma biomarkers are useful to detect the AT(N) categories, and their use can differentiate patients with pathophysiological evidence of AD. A blood AT(N) signature may facilitate early diagnosis and follow-up of patients with AD through an easy and minimally invasive approach.

Differential levels of plasma biomarkers of neurodegeneration in Lewy body dementia, Alzheimer’s disease, frontotemporal dementia and progressive supranuclear palsy

“…Clinical diagnostics and clinical trials will benefit from scalable non-invasive biomarkers moving beyond positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) analysis to blood based assays 1. Recent years have seen the emergence of many new plasma biomarkers, but head-to-head comparisons, across multiple dementias and over time, are required to assess their potential for differential diagnosis and trials monitoring 2. Here we jointly evaluate a set of biomarkers in Alzheimer’s disease (AD; the most common type of neurodegenerative dementia), Lewy body dementia (LBD; dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD)), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) 3.…”

From Cerebrospinal Fluid Neurochemistry to Clinical Diagnosis of Alzheimer’s Disease in the Era of Anti-Amyloid Treatments. Report of Four Patients

“…Both αand β-synuclein may be early markers of AD, even in non-demented elder subjects [83,84], while the ratio of total tau/α-synuclein may serve as a marker of tau phosphorylation, even allowing patients with the A − T + (N + ) profile to re-enter the AD diagnostic group [85]. Blood-based classical [86,87] and exosomal [88] biomarkers may prove helpful, especially for frequent monitoring of the biochemical effects of anti-amyloid antibodies. The AT(N) system is flexible and may expand to an ATX(N) form, incorporating such new or evolving biomarkers of AD-related or additional non-AD pathologies [89].…”

Blood amyloid and tau biomarkers as predictors of cerebrospinal fluid profiles

“…Three different approaches were used to measure plasma levels of Aβ 1–42 and Aβ 1–40 : “Neurology 3-Plex A” (Q3, both cohorts) and “Neurology 4-plex E Advantage kit” (Q4, Montpellier cohort) in the Simoa platform (Quanterix) and an IP-MS approach from Shimadzu (Nakamura et al 2018 ) (both cohorts) implemented in Montpellier’s laboratory and slightly modified from the original protocol (Alcolea et al 2021 ). Levels of p-tau(181) were measured in the Simoa platform (Quanterix).…”

“…The possibility of detecting amyloid peptides and tau proteins in plasma has recently shaken the field of neurodegenerative diseases detection. Many research groups, including ours, are evaluating the diagnostic value of these biomarkers for the accurate detection of AD, through cross sectional or longitudinal studies using retrospective samples (Alcolea et al 2021 ; Lewczuk et al 2018 ; Brickman et al 2021 ).…”