Prospects and challenges in using neuronal extracellular vesicles in biomarker research

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(9), P. 6632 - 6638

Published: July 15, 2024

Abstract Extracellular vesicles (EVs) hold promise as a source of disease biomarkers. The diverse molecular cargo EVs can potentially indicate the status their tissue origin, even against complex background whole plasma. main tools currently available for assessing biomarkers brain health include imaging and analysis cerebrospinal fluid patients. Given costs difficulties associated with these methods, isolation neuronal origin (NEVs) from blood is an attractive approach to identify brain‐specific This perspective describes current key challenges in EV‐ NEV‐based biomarker research. These relative low abundance EVs, lack validated difficult search adequate target immunocapturing NEVs. We discuss that must be addressed before NEVs fulfill potential Highlights are promising sources disorders. Immunocapturing biofluids presents several challenges. choice surface capture will determine NEV yield. Contamination by non‐EV relevant at concentrations.

Language: Английский

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Differences of longitudinal plasma biomarkers between single memory domain and multidomain subject cognitive decline: Evidence from SILCODE

Journal of Alzheimer s Disease, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

Background Plasma biomarkers demonstrated potential in identifying amyloid pathology early Alzheimer's disease. Different subtypes of subjective cognitive decline (SCD) may lead to different impairment conversion risks. Objective To investigate the differences plasma SCD individuals, which were unclear. Methods The 347 individuals involved, including 93 normal controls (NC), 76 single memory domain (sd-SCD), 79 multidomain (md-SCD), 55 mild and 44 dementia. We investigated (Aβ 42/40 , p-tau181, p-tau217, NfL, GFAP) neuropsychological scales baseline follow-up. Kaplan-Meier survival analysis Cox proportional hazards model performed risk conversion. t-test, Mann-Whitney U multiple linear regression employed evaluate rate change correlation between PET-SUVR biomarker change. Results In cognitively subjects, md-SCD exhibited lower Aβ higher p-tau181 p-tau217 levels. revealed that group a compared NC sd-SCD. Within subgroups, those with positive GFAP status showed than negative. model, was 2.77 times faster Conclusions study utilized highlight significance staging SCD. presents sd-SCD, providing valuable reference convenient tool for identification at AD.

Language: Английский

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Blood phosphorylated Tau217 distinguishes amyloid-positive from amyloid-negative subjects in the Alzheimer's disease continuum. A systematic review and meta-analysis

Journal of Neurology, Journal Year: 2025, Volume and Issue: 272(3)

Published: March 1, 2025

Alzheimer's disease (AD) is the leading cause of dementia worldwide, and cost-effective tools to detect amyloid pathology are urgently needed. Blood-based Tau phosphorylated at threonine 217 (pTau217) seems promising, but its reliability as a proxy for cerebrospinal fluid (CSF) status ability identify patients within AD spectrum remain unclear. We performed systematic review meta-analysis on potential blood pTau217 differentiate amyloid-positive (A+) amyloid-negative (A-) subjects. included original studies reporting quantitative data concentrations in both CSF continuum. The single-group computed pooled levels CSF, separately A+ A- groups, while head-to-head compared mean versus subjects, stratifying by assessment method cases. Ten (819 A+; 1055 A-) were included. resulted higher than and, crucially, individuals ones, regardless laboratory employed. Most importantly, all techniques reliably distinguished from whether applied or samples. These results confirm that blood-based reliable marker with significant implications clinical practice Indeed, might be non-invasive, scalable biomarker early detection, reducing reliance more invasive, expansive, less accessible methods. Prospero CRD42024565187.

Language: Английский

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Biofluid-based staging of Alzheimer’s disease

Acta Neuropathologica, Journal Year: 2025, Volume and Issue: 149(1)

Published: March 17, 2025

Abstract Recently, conceptual systems for the in vivo staging of Alzheimer’s disease (AD) using fluid biomarkers have been suggested. Thus, it is important to assess whether available can successfully stage AD into clinically and biologically relevant categories. In TRIAD cohort, we explored p-tau217, p-tau205 NTA-tau (biomarkers early, intermediate late pathology, respectively) potential biofluid-based cerebrospinal (CSF; n = 219) plasma ( 150), compared them a paired CSF subset 76). Our findings suggest good concordance between biofluid underlying pathology when classifying amyloid-positivity three categories based on neurofibrillary pathology: minimal/non-existent (p-tau217 positive), early-to-intermediate positivity), advanced tau tangle deposition (p-tau217, as indexed by tau-PET. Discordant cases accounted 4.6% 13.3% all measurements respectively (9.2% 11.8% samples). Notably, CSF- plasma-based matched one another 61.7% cases, while approximately 32% remaining participants were stages higher plasma. Overall, these exploratory results that holds offering valuable insights hallmarks severity. However, its applicability beyond molecular characterization at research settings has yet be demonstrated.

Language: Английский

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Study on the Modulation of NLRP1 by Natural Products in Neurodegenerative Diseases

Natural Product Communications, Journal Year: 2025, Volume and Issue: 20(3)

Published: March 1, 2025

Neuronal pyroptosis is one of the crucial pathogenesis neurodegenerative diseases, and signaling pathway mediated by inflammasome main pyroptosis. Neuroinflammation not only a common feature, but also an essential basis for diagnosis diseases. important pathological feature nervous system diseases such as Alzheimer's disease (AD), Parkinson's (PD). NLRP1 plays role in activating inducing inflammatory response, so development drugs targeting regulation has become reasonable research direction treatment By analyzing current progress which affects process neuronal related Chinese medicine, natural products were docked with targets to find higher activity. The target CB-Dock molecular docking platform. Molecular results showed that silibinin, crocin, hyperoside had excellent binding affinity, most promising potential active compounds AD regulating NLRP1. This paper discusses feasibility rationality medicine on future.

Language: Английский

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Biomarker-guided decision making in clinical drug development for neurodegenerative disorders

Nature Reviews Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: April 4, 2025

Language: Английский

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Targeted proteomic biomarker profiling using NULISA in a cohort enriched with risk for Alzheimer's disease and related dementias

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(5)

Published: May 1, 2025

Abstract INTRODUCTION Targeted proteomic assays may be useful for diagnosing and staging Alzheimer's disease related dementias (ADRD). We evaluated the performance of a 120‐marker central nervous system (CNS) NUcleic acid Linked Immuno‐Sandwich Assay (NULISA) panel in samples spanning (AD) spectrum. METHODS Cross‐sectional plasma ( n = 252) were analyzed using NULISAseq CNS from Alamar Biosciences. Receiver‐operating characteristic (ROC) analyses demonstrated accuracy NULISAseq‐tau phosphorylated at threonine 217 (pTau217) detecting amyloid (A) tau (T) positron emission tomography (PET) positivity. Differentially expressed proteins identified volcano plots. RESULTS NULISAseq‐pTau217 accurately classified A/T PET status with ROC areas under curve 0.92/0.86; pTau217 was upregulated A+, T+, impaired groups log 2 ‐fold changes 1.21, 0.57, 4.63, respectively, compared to A−. Of interest, TAR DNA‐binding protein 43 (TDP‐43) serine 409 (pTDP43‐409) also group correlated declining hippocampal volume cognitive trajectories. DISCUSSION This study shows potential targeted proteomics characterizing brain pertinent ADRD. The promising pTDP43‐409 findings require further replication. Highlights assay comparable Simoa assay, both utilizing ALZpath antibody, positivity, each greater than 90%. Nineteen differentially participants mild impairment (MCI) those who unimpaired. Markers non‐AD proteinopathies such as pTDP43‐409, oligomeric alpha‐synuclein, huntingtin (HTT), among MCI. High levels associated worsening atrophy decline, clinical indicators limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), low pTDP43‐409.

Language: Английский

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Plasma p‐tau immunoassays in clinical research for Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 3, 2024

Abstract The revised biomarker framework for diagnosis and staging of Alzheimer's disease (AD) relies on amyloid beta (Aβ) tau pathologies as core markers, markers adjacent pathophysiology, such neurodegeneration inflammation. Many the fluid biomarkers are phosphorylated (p‐tau) fragments, with p‐tau217 showing a prominent association Aβ tau. While positron emission tomography (PET) imaging is well established, plasma p‐tau assays newer likely to reduce use expensive, less accessible cerebrospinal PET tests, thereby promoting wider access AD screening. There need greater understanding how various species reflect different pathological processes immunoassays perform. This review surveys available highlights their strengths limitations in contexts use. Assays be standardized maximize impact clinical research, patient management. Highlights Different (AD), p‐tau231 greatest earliest increases brain accumulation, while shows both early pathology, other fragment show later stages pathology. Plasma has proven an excellent pathology due its close large dynamic range. varying performance exist same species, mass spectrometry performing uniformly well, several achieving comparable performance. “Round robin” head‐to‐head studies have been performed compare key biomarkers, including p‐tau181 p‐tau217, but additional needed, especially new analytes measuring diverse populations. potential increase accessibility diagnostic testing broad population, historically under‐represented under‐served populations, implemented globally, primary care settings; however, further research needed validate optimal cutoffs each assay real‐world usage. Eventually, implementation two‐step workflow may allow standalone certain contexts, minimizing confirmation costly fluid/positron testing.

Language: Английский

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The Bayesian approach for real‐world implementation of plasma p‐tau217 in tertiary care memory clinics in Thailand

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(9), P. 6456 - 6467

Published: July 17, 2024

Abstract INTRODUCTION Plasma phosphorylated tau (p‐tau)217 is a promising biomarker for Alzheimer's disease (AD) diagnosis, but its clinical implementation remains challenging. We propose strategy based on Bayes’ theorem and test it in real‐life memory clinics. METHODS Memory clinic patients were evaluated by neurocognitive specialists prespecified diagnosis subsequently underwent blood collection p‐tau217, cerebrospinal fluid, or amyloid positron emission tomography. Using cross‐validation, the Bayesian approach (pretest probability × individualized likelihood ratio) was compared to other models AD diagnosis. RESULTS The demonstrated an area under receiver operating characteristic curve (AUC) of 0.98 (95% confidence interval [CI]: 0.96–1.0), significantly outperforming multivariable logistic regression (p‐tau217, age, apolipoprotein E; AUC 0.95, p = 0.024) p‐tau217 alone (AUC 0.94, 0.007). When applying two‐threshold approach, yielded accuracy 0.94 CI: 0.88–1.0) without requiring confirmatory tests 62.9% iterations. DISCUSSION offers effective flexible address limitations plasma practice. Highlights Incorporating pretest into interpretation improves diagnostic performance significantly. could obviate need testing most patients. proves useful as low‐ middle‐income country such Thailand.

Language: Английский

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Fluid biomarkers unveil signatures of pathological aging

Seizure, Journal Year: 2024, Volume and Issue: unknown

Published: May 1, 2024

Aging is a multifaceted and highly varied process in the brain. Identifying aging biomarkers one means of distinguishing pathological from physiological aging. The aim this narrative review to focus on two new developments field fluid draw attention excellent tool for early detection potential brain pathologies that delay, alter, or enable become pathological. Pathological can lower threshold development specific diseases such as late-onset epilepsy. Fluid reveal levels at an stage thus indicate disease processes begin before symptoms develop; they differ

Language: Английский

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