Novel blood‐based proteomic signatures across multiple neurodegenerative diseases

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(3)

Published: March 1, 2025

Abstract INTRODUCTION Blood‐based biomarkers have the potential to support early and accurate diagnoses of neurodegenerative diseases, which are sensitive molecular pathology predictive outcome. We evaluated a novel multiplex proteomic method in people with diverse diseases. METHODS Serum from Alzheimer's disease ( N = 36), Lewy body dementia 34), frontotemporal progressive supranuclear palsy 36) age‐matched controls 30) was analyzed nucleic acid linked immuno‐sandwich assay (NULISA) central nervous system panel (≈ 120 analytes) inflammation (250 analytes). Biomarkers were compared across groups included as predictors survival. RESULTS The NULISA panels demonstrated high sensitivity reliability for detecting multiple disorders. There condition‐specific biomarkers, while neurofilament light chain, corticotropin‐releasing hormone, CD276, data‐driven pattern significant transdiagnostic outcome predictors. DISCUSSION approach supports differential diagnosis target identification, prognostically informative dementia‐related biomarkers. Highlights tested technology serum samples. results single molecule array (Simoa) plasma assays phosphorylated tau (p‐tau)217, p‐tau231, chain (NfL), glial fibrillary acidic protein, finding strong correlations. Increased levels NfL identified all patient most elevated (FTD) (PSP) cohorts, p‐tau epitopes markers patients (AD) dementia. Patients FTD PSP showed upregulation many markers, AD. found NfL, immune signatures clinical outcomes (survival rates).

Language: Английский

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A Comprehensive Head-to-Head Comparison of Key Plasma Phosphorylated Tau 217 Biomarker Tests

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 5, 2024

Abstract Plasma phosphorylated-tau 217 (p-tau217) is currently the most promising biomarkers for reliable detection of Alzheimer’s disease (AD) pathology. Various p-tau217 assays have been developed, but their relative performance unclear. We compared key plasma tests using cross-sectional and longitudinal measures amyloid-β (Aβ)-PET, tau-PET, cognition as outcomes, benchmarked them against cerebrospinal fluid (CSF) biomarker tests. Samples from 998 individuals (mean[range] age 68.5[20.0-92.5], 53% female) Swedish BioFINDER-2 cohort were analyzed. was measured with mass spectrometry (MS) (the ratio between phosphorylated non-phosphorylated [%p-tau217 WashU ]and ) well immunoassays (p-tau217 Lilly , Janssen ALZpath ). CSF included FDA-approved p-tau181/Aβ42 Elecsys p-tau181 . All exhibited high ability to detect abnormal Aβ-PET (AUC range: 0.91-0.96) tau-PET 0.94-0.97). %p-tau217 had highest performance, significantly higher AUCs than all ( P diff <0.007). For detecting status, an accuracy 0.93 (immunoassays: 0.83-0.88), sensitivity 91% 84-87%), a specificity 94% 85-89%). Among immunoassays, status <0.006), outperformed =0.025). associations PET load outcomes immunoassays; baseline (R 2 : 0.72; immunoassays: 0.47-0.58; <0.001), 0.51; 0.38-0.45; 0.53; 0.31-0.38; <0.001) 0.50; 0.35-0.43; <0.014). more strongly associated <0.020) both (all <0.010). also correlated (Mini-Mental State Examination[MMSE]) 0.33; 0.27-0.30; <0.024). The main results replicated in external Washington University St Louis n =219). Finally, Nulisa showed similar other subsets cohorts. In summary, MS-and immunoassay-based generally perform identifying Aβ-PET, cognitive abnormalities, performed better examined immunoassays. may be considered stand-alone confirmatory test AD pathology, while some might suited triage where positive are confirmed second test.

Language: Английский

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Novel plasma biomarkers of amyloid plaque pathology and cortical thickness: Evaluation of the NULISA targeted proteomic platform in an ethnically diverse cohort

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(2)

Published: Feb. 1, 2025

Abstract INTRODUCTION Proteomic evaluation of plasma samples could accelerate the identification novel Alzheimer's disease (AD) biomarkers. We evaluated NUcleic acid Linked Immuno‐Sandwich Assay (NULISA) proteomic method in an ethnically diverse cohort. METHODS Plasma biomarkers were measured with NULISA Human Connectome Project, a predominantly preclinical biracial community cohort southwestern Pennsylvania. Selected additionally using Simoa and Quest immunoassays compared. RESULTS On NULISA, phosphorylated tau (p‐tau217, p‐tau231, p‐tau181), glial fibrillary acidic protein (GFAP), microtubule‐associated (MAPT‐tau) showed top significant association amyloid beta (Aβ) positron emission tomography (PET) status, followed by neuroinflammation markers C‐C motif ligand 2 (CCL2), chitotriosidase 1 (CHIT1) interleukin‐8 (CXCL8), synaptic marker neurogranin (NRGN). Biomarkers associated cortical thickness included astrocytic chitinase‐3‐like (CHI3L1), cytokine CD40 (CD40LG), brain‐derived neurotrophic factor (BDNF), Aβ‐associated metalloprotein TIMP3 (tissue inhibitor 3), ficolin (FCN2). Furthermore, moderate to strong between‐platform correlations observed for various assays. DISCUSSION multiplexing advantage allowed concurrent assessment established Aβ pathology neurodegeneration. Highlights Classical next‐generation sequencing readout (NULISAseq) CNS panel concordance those immunoassay methods from Quanterix Quest, (GFAP) neurofilament light (NfL) exhibiting strongest correlation. NULISAseq analysis identified several strongly AD older adults. Notably, tau‐217 (p‐tau217), GFAP, p‐tau231 displayed pathology, whereas (BDNF) was demonstrate that biomarker levels be influenced age, sex, apolipoprotein E ( APOE ) genotype, self‐identified race. Specifically, NfL, surfactant D (SFTPD) age; CD63 S100 calcium‐binding B (S100B) race; synaptosomal‐associated 25 (SNAP25) genotype; serum A1 (SAA1) superoxide dismutase (SOD1) sex differences.

Language: Английский

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Proteomic Subtyping of Alzheimer's Disease CSF links Blood-Brain Barrier Dysfunction to Reduced levels of Tau and Synaptic Biomarkers

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 15, 2025

Abstract Alzheimer’s disease (AD) is characterized by significant clinical and molecular heterogeneity, influenced genetic demographic factors. Using an unbiased, network-driven approach, we analyzed the cerebrospinal fluid (CSF) proteome from 431 individuals (483 samples), including 111 African American participants, to identify core protein modules associated with AD, race, sex, age. Our analysis revealed ten co-expression linked distinct biological pathways cell types, many of which correlated established AD biomarkers such as β-amyloid, tau, phosphorylated tau. To further resolve applied a proteomic subtyping identifying six CSF subtypes spanning pathological spectrum. These were validated across independent cohorts, aligning previously defined subtypes, those neuronal hyperplasticity, immune activation, blood-brain barrier (BBB) integrity. Notably, BBB subtype, enriched Americans men, was low high CSF/serum albumin ratios, reduced synaptic levels. This subtype also exhibited increased levels proteolytic enzymes, thrombin matrix metalloproteases, that cleave Plasma dilution into hyperplastic led tau module levels, indicating plasma protease activity contributes depletion underlying brain pathology. findings highlight impact integrity on particularly in men Americans, underscore need for diversity-informed biomarker strategies improve diagnostics therapeutic targeting populations.

Language: Английский

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Large-scale Plasma Proteomic Profiling Unveils Novel Diagnostic Biomarkers and Pathways for Alzheimer's Disease

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: March 18, 2025

Alzheimer disease (AD) is a complex neurodegenerative disorder. Proteomic studies have been instrumental in identifying AD-related proteins present the brain, cerebrospinal fluid, and plasma. This study comprehensively examined 6,905 plasma more than 3,300 well-characterized individuals to identify new proteins, pathways, predictive model for AD. With three-stage analysis (discovery, replication, meta-analysis) we identified 416 (294 novel) associated with clinical AD status findings were further validated two external datasets including 7,000 samples seven previous studies. Pathway revealed that these involved endothelial blood hemostatic (ACHE, SMOC1, SMOC2, VEGFA, VEGFB, SPARC), capturing brain barrier (BBB) disruption due disease. Other pathways known processes implicated AD, such as lipid dysregulation (APOE, BIN1, CLU, SMPD1, PLA2G12A, CTSF) or immune response (C5, CFB, DEFA5, FBXL4), which includes be part of causal pathway indicating some are pathogenesis. An enrichment neural (axonal guidance signaling myelination signaling) indicates that, fact, proteomics capture brain- disease-related changes, can lead identification novel biomarkers models. Machine learning was employed set highly both (AUC > 0.72) biomarker-defined 0.88), replicated multiple cohorts well orthogonal platforms. These extensive underscore potential using early detection monitoring potentially guiding treatment decisions.

Language: Английский

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Identify biological Alzheimer’s disease using a novel nucleic acid-linked protein immunoassay

Brain Communications, Journal Year: 2024, Volume and Issue: 7(1)

Published: Dec. 24, 2024

Blood-based biomarkers have been revolutionizing the detection, diagnosis and screening of Alzheimer's disease. Specifically, phosphorylated-tau variants (p-tau181, p-tau217 p-tau231) are promising for identifying disease pathology. Antibody-based assays such as single molecule arrays immunoassays powerful tools to investigate pathological changes indicated by blood-based studied extensively in research field. A novel proteomic technology-NUcleic acid Linked Immuno-Sandwich Assay (NULISA)-was developed improve sensitivity traditional proximity ligation offer a comprehensive outlook 120 protein neurodegenerative diseases. Due relative novelty NULISA technology quantifying biomarkers, validation through comparisons with more established methods is required. The main objective current study was determine capability p-tau quantified using abnormal amyloid-β tau We assessed 397 participants [mean (standard deviation) age, 64.8 (15.7) years; 244 females (61.5%) 153 males (38.5%)] from Translational Biomarkers Aging Dementia (TRIAD) cohort where had plasma measurements p-tau181, p-tau231 immunoassays. Participants also underwent neuroimaging assessments, including structural MRI, amyloid-PET tau-PET. Our findings suggest an excellent agreement between Plasma measured shows discriminative accuracy (area under receiver operating characteristic curve = 0.918, 95% confidence interval 0.883 0.953, P < 0.0001) tau-PET 0.939; 0.909 0.969, 0.0001). It presents differentiating staging. Validation NULISA-measured adds analytical diagnosis, staging could potentially expedite development biomarker panel.

Language: Английский

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