Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer’s disease

Brain, Год журнала: 2022, Номер 146(4), С. 1592 - 1601

Опубликована: Сен. 10, 2022

Plasma phospho-tau (p-tau) species have emerged as the most promising blood-based biomarkers of Alzheimer's disease. Here, we performed a head-to-head comparison p-tau181, p-tau217 and p-tau231 measured using 10 assays to detect abnormal brain amyloid-β (Aβ) status predict future progression dementia. The study included 135 patients with baseline diagnosis mild cognitive impairment (mean age 72.4 years; 60.7% women) who were followed for an average 4.9 years. Seventy-one participants had Aβ-status (i.e. CSF Aβ42/40) at baseline; 45 these Aβ-positive progressed dementia during follow-up. P-tau concentrations determined in plasma CSF. P-tau217 p-tau181 both immunoassays developed by Lilly Research Laboratories (Lilly) mass spectrometry Washington University (WashU). was also analysed Simoa immunoassay Janssen Development (Janss). P-tau181 from ADxNeurosciences (ADx), Lumipulse Fujirebio (Fuji) Splex Mesoscale Discovery (Splex). Both quantified Gothenburg (UGOT). We found that spectrometry-based (p-tau217WashU) exhibited significantly better performance than all other p-tau when detecting Aβ [area under curve (AUC) = 0.947; Pdiff < 0.015] or (AUC 0.932; 0.027). Among immunoassays, p-tau217Lilly highest AUCs (0.886-0.889), which not different p-tau217Janss, p-tau181ADx p-tau181WashU (AUCrange 0.835-0.872; > 0.09), but higher compared AUC p-tau231UGOT, p-tau181Lilly, p-tau181UGOT, p-tau181Fuji p-tau181Splex 0.642-0.813; ≤ 0.029). Correlations between values strongest p-tau217WashU (R 0.891) 0.755; 0.003 versus p-tau217WashU) weak moderate rest (Rrange 0.320-0.669). In conclusion, our findings suggest among tested assays, measures perform best identifying those will subsequently progress Several (p-tau217Lilly, p-tau181WashU) showed relatively high consistent accuracy across outcomes. results further indicate performing metrics rival gold standards Aβ-PET If validated, significant impacts diagnosis, screening treatment future.

Язык: Английский

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Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline

Nature Medicine, Год журнала: 2022, Номер 28(11), С. 2381 - 2387

Опубликована: Ноя. 1, 2022

A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer's disease neuropathological hallmarks (that is, amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid positron emission tomography (PET) study (n = 1,325), we examined risk for future progression mild cognitive impairment rate of decline among were PET-positive (A+) (T+) medial temporal lobe (A+TMTL+) and/or neocortex (A+TNEO-T+) compared them with A+T- A-T- groups. Cox proportional-hazards models showed a substantially increased A+TNEO-T+ (hazard ratio (HR) 19.2, 95% confidence interval (CI) 10.9-33.7), A+TMTL+ (HR 14.6, CI 8.1-26.4) 2.4, 1.4-4.3) groups versus (reference) group. Both 6.0, 3.4-10.6) 7.9, 4.7-13.5) also faster clinical than Linear mixed-effect indicated that (β -0.056 ± 0.005, T -11.55, P < 0.001), -0.024 -4.72, 0.001) -0.008 0.002, -3.46, significantly longitudinal global group (all 0.001). (P 0.002) progressed summary, evidence advanced pathological changes provided by combination abnormal PET examinations strongly associated short-term 3-5 years) therefore high relevance.

Язык: Английский

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A biological classification of Parkinson's disease: the SynNeurGe research diagnostic criteria

The Lancet Neurology, Год журнала: 2024, Номер 23(2), С. 191 - 204

Опубликована: Янв. 22, 2024

Язык: Английский

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Emerging diagnostics and therapeutics for Alzheimer disease

Nature Medicine, Год журнала: 2023, Номер 29(9), С. 2187 - 2199

Опубликована: Сен. 1, 2023

Язык: Английский

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Association of Donanemab Treatment With Exploratory Plasma Biomarkers in Early Symptomatic Alzheimer Disease

JAMA Neurology, Год журнала: 2022, Номер 79(12), С. 1250 - 1250

Опубликована: Окт. 17, 2022

Importance Plasma biomarkers of Alzheimer disease may be useful as minimally invasive pharmacodynamic measures treatment outcomes. Objective To analyze the association donanemab with plasma associated disease. Design, Setting, and Participants TRAILBLAZER-ALZ was a randomized, double-blind, placebo-controlled clinical trial conducted from December 18, 2017, to 4, 2020, across 56 sites in US Canada. Exploratory were prespecified post hoc addition glial fibrillary acidic protein amyloid-β. Men women aged 60 85 years gradual progressive change memory function for at least 6 months included. A total 1955 participants assessed eligibility. Key eligibility criteria include Mini-Mental State Examination scores 20 28 elevated amyloid intermediate tau levels. Interventions Randomized received or placebo every 4 weeks up 72 weeks. The first 3 doses given 700 mg then increased 1400 blinded dose reductions specified based on reduction. Main Outcomes Measures Change biomarker levels after treatment. Results In TRAILBLAZER-ALZ, 272 (mean [SD] age, 75.2 [5.5] years; 145 [53.3%] female) randomized. phosphorylated 217 (pTau ) significantly lower compared early 12 start (least square mean difference vs placebo, –0.04 [95% CI, –0.07 –0.02]; P = .002 –0.01]; .01, respectively). No significant differences amyloid-β 42/40 neurofilament light chain observed between arms end Changes pTau correlated Centiloid percent (Spearman rank correlation coefficient [ R ] 0.484 0.359-0.592]; &amp;lt; .001 0.453 0.306-0.579]; .001, respectively) following Additionally, baseline ( 0.399 0.278-0.508], 0.393 0.254-0.517]; Conclusions Relevance Significant patients symptomatic These easily accessible might provide additional evidence pathology through anti-amyloid therapy. Usefulness assessing response will require further evaluation. Trial Registration ClinicalTrials.gov Identifier: NCT03367403

Язык: Английский

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Anti-Amyloid Monoclonal Antibodies are Transformative Treatments that Redefine Alzheimer's Disease Therapeutics

Drugs, Год журнала: 2023, Номер 83(7), С. 569 - 576

Опубликована: Апрель 15, 2023

Two anti-amyloid monoclonal antibodies (MABs)—lecanemab (Leqembi®) and aducanumab (Aduhelm®)—have been approved in the USA for treatment of Alzheimer's disease (AD). Anti-amyloid are first disease-modifying therapies AD that achieve slowing clinical decline by intervening basic biological processes disease. These breakthrough agents can slow inevitable progression into more severe cognitive impairment. The results trials MABs support amyloid hypothesis as a target drug development. success reflects relentless application neuroscience knowledge to solving major challenges facing humankind. these transformative will foster development MABs, other types therapies, treatments targets biology, new approaches an array neurodegenerative disorders. Monoclonal have side effects and, during period initiation, patients must be closely monitored occurrence amyloid-related imaging abnormalities (ARIA) infusion reactions. A successful step therapy defines desirable features next phase therapeutic including less frequent ARIA, convenient administration, greater efficacy. Unprecedented make demands on care partners, clinicians, payers, health systems. Collaboration among stakeholders is essential take advantage benefits offered them widely available. usher era define landscape what possible

Язык: Английский

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Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Авг. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Язык: Английский

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CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer’s disease

Nature Medicine, Год журнала: 2023, Номер 29(8), С. 1954 - 1963

Опубликована: Июль 13, 2023

Abstract Aggregated insoluble tau is one of two defining features Alzheimer’s disease. Because clinical symptoms are strongly correlated with aggregates, drug development and diagnosis need cost-effective accessible specific fluid biomarkers aggregates; however, recent studies suggest that the currently available cannot specifically track aggregates. We show microtubule-binding region (MTBR) containing residue 243 (MTBR-tau243) a new cerebrospinal (CSF) biomarker for aggregates compared it to multiple other phosphorylated measures (p-tau181, p-tau205, p-tau217 p-tau231) in independent cohorts (BioFINDER-2, n = 448; Knight Alzheimer Disease Research Center, 219). MTBR-tau243 was most associated tau-positron emission tomography (PET) cognition, whereas showing lowest association amyloid-PET. In combination explained total variance tau-PET burden (0.58 ≤ R 2 0.75) performance predicting cognitive (0.34 0.48) approached (0.44 0.52). levels longitudinally increased unlike CSF p-tau species. aggregate pathology, which may be utilized interventional trials patients. Based on these findings, we propose revise A/T/(N) criteria include as representing (‘T’).

Язык: Английский

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Specific associations between plasma biomarkers and postmortem amyloid plaque and tau tangle loads

EMBO Molecular Medicine, Год журнала: 2023, Номер 15(5)

Опубликована: Март 13, 2023

Several promising plasma biomarkers for Alzheimer's disease have been recently developed, but their neuropathological correlates not yet fully determined. To investigate and compare independent associations between multiple (p-tau181, p-tau217, p-tau231, Aβ42/40, GFAP, NfL) neuropathologic measures of amyloid tau, we included 105 participants from the Arizona Study Aging Neurodegenerative Disorders (AZSAND) with antemortem samples a postmortem exam, 48 whom had longitudinal p-tau217 p-tau181. When simultaneously including plaque tangle loads, Aβ42/40 ratio p-tau231 were only associated plaques (ρAβ42/40 [95%CI] = -0.53[-0.65, -0.35], ρp-tau231 0.28[0.10, 0.43]), GFAP was tangles (ρGFAP 0.39[0.17, 0.57]), p-tau181 both (ρp-tau217 0.40[0.21, 0.56], ρp-tau181 0.36[0.15, 0.50]) 0.52[0.34, 0.66]; 0.36[0.17, 0.52]). A model combining showed highest accuracy predicting presence change (ADNC, AUC[95%CI] 0.89[0.82, 0.96]) load (R2 0.55), while alone optimal 0.45). Our results suggest that high-performing assays might be an combination to assess Alzheimer's-related pathology in vivo.

Язык: Английский

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Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease

Nature Medicine, Год журнала: 2023, Номер 29(8), С. 1979 - 1988

Опубликована: Авг. 1, 2023

Abstract Alzheimer’s disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes—aggregation amyloid-β (Aβ) peptide into plaques and microtubule protein tau neurofibrillary tangles (NFTs)—are hallmarks disease. However, other brain processes are thought to be key mediators Aβ plaque NFT pathology. How these additional pathologies evolve over course is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked coexpression can used characterize evolution a timescale spanning six decades. SMOC1 SPON1 proteins associated with were elevated CSF nearly 30 symptoms, followed by changes synaptic proteins, metabolic axonal inflammatory finally decreases neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers symptom as well or better than measures. Our results highlight multifaceted landscape pathophysiology its temporal evolution. Such knowledge will critical for developing precision therapeutic interventions biomarkers beyond those tau.

Язык: Английский

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