Biomarkers for neurodegenerative diseases

Nature Medicine, Journal Year: 2021, Volume and Issue: 27(6), P. 954 - 963

Published: June 1, 2021

Language: Английский

---

Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology

Acta Neuropathologica, Journal Year: 2021, Volume and Issue: 141(5), P. 709 - 724

Published: Feb. 14, 2021

Abstract The quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise detecting Alzheimer’s disease (AD) pathophysiology. Tau at threonine 231 (p-tau231) is one such biomarker CSF but its usefulness as a blood currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the plasma p-tau231 which was validated four independent cohorts ( n = 588) different settings, including full AD continuum and non-AD neurodegenerative disorders. Plasma able to identify patients with differentiate them from amyloid-β negative cognitively unimpaired (CU) older adults high accuracy (AUC 0.92–0.94). also distinguished disorders 0.93), well MCI 0.89). In neuropathology cohort, samples taken on avergae 4.2 years prior post-mortem very accurately identified comparison 0.99), this despite all being given dementia diagnosis during life. highly correlated p-tau231, pathology assessed by [ 18 F]MK-6240 positron emission tomography (PET), brain amyloidosis F]AZD469 PET. Remarkably, inflection point increasing function continuous PET standardized uptake value ratio, be earlier than standard thresholds positivity increase p-tau181. Furthermore, significantly increased quartiles 2–4, whereas p-tau217 p-tau181 only 3–4 4, respectively. Finally, differentiated individuals across entire Braak stage spectrum, staging 0 through I–II, not observed To conclude, novel assay identifies clinical stages equally p-tau181, increases earlier, already subtle deposition, threshold been attained, response early deposition. Thus, promising emerging potential facilitate trials vulnerable populations below apparent entorhinal

Language: Английский

---

A multicentre validation study of the diagnostic value of plasma neurofilament light

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: June 7, 2021

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as marker of 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) the Swedish BioFINDER study 1,464). Plasma was significantly increased all cortical amyotrophic lateral sclerosis atypical parkinsonian disorders. We demonstrate clinically useful identifying disorders patients with parkinsonism, dementia individuals among psychiatric frontotemporal cognitive impairment. Data-driven cut-offs highlighted fundamental importance age-related clinical younger age onset. Finally, performs best when applied to indicate no underlying neurodegeneration, low false positives, cut-offs.

Language: Английский

---

Differences Between Plasma and Cerebrospinal Fluid Glial Fibrillary Acidic Protein Levels Across the Alzheimer Disease Continuum

JAMA Neurology, Journal Year: 2021, Volume and Issue: 78(12), P. 1471 - 1471

Published: Oct. 20, 2021

Glial fibrillary acidic protein (GFAP) is a marker of reactive astrogliosis that increases in the cerebrospinal fluid (CSF) and blood individuals with Alzheimer disease (AD). However, it not known whether there are differences GFAP levels across entire AD continuum its performance similar to CSF GFAP.To evaluate plasma throughout continuum, from preclinical dementia, compared GFAP.This observational, cross-sectional study collected data July 29, 2014, January 31, 2020, 3 centers. The Translational Biomarkers Aging Dementia (TRIAD) cohort (Montreal, Canada) included continuum. Results were confirmed Alzheimer's Families (ALFA+) (Barcelona, Spain), which AD, BioCogBank Paris Lariboisière (Paris, France), symptomatic AD.Plasma measured Simoa assay main outcome. Other measurements amyloid-β 42/40 (Aβ42/40), phosphorylated tau181 (p-tau181), neurofilament light (NfL), Chitinase-3-like 1 (YKL40), soluble triggering receptor expressed on myeloid cells 2 (sTREM2) p-tau181 NfL. amyloid positron emission tomography (PET) available TRIAD ALFA+, results tau PET TRIAD.A total 300 participants (177 women [59.0%]; mean [SD] age, 64.6 [17.6] years), 384 ALFA+ (234 [60.9%]; 61.1 [4.7] 187 (116 [62.0%]; 69.9 [9.2] years) included. Plasma significantly higher comparison cognitively unimpaired (CU) Aβ-negative (TRIAD: [SD], 185.1 [93.5] pg/mL, Aβ-positive 285.0 [142.6] pg/mL; ALFA+: 121.9 [42.4] 169.9 [78.5] pg/mL). also among stages CU mild cognitive impairment [MCI] 332.5 [153.6] 388.1 [152.8] pg/mL vs Paris: MCI Aβ-positive, 368.6 [158.5] 376.4 [179.6] 161.2 [67.1] magnitude changes consistently than those GFAP. more accurately discriminated (area under curve for GFAP, 0.69-0.86; area 0.59-0.76). Moreover, positively associated pathology only concomitant Aβ pathology.This suggests sensitive biomarker detecting tracking even early AD.

Language: Английский

---

The Alzheimer's Association appropriate use recommendations for blood biomarkers in Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2022, Volume and Issue: 18(12), P. 2669 - 2686

Published: July 31, 2022

Abstract Blood‐based markers (BBMs) have recently shown promise to revolutionize the diagnostic and prognostic work‐up of Alzheimer's disease (AD), as well improve design interventional trials. Here we discuss in detail further research needed be performed before widespread use BBMs. We already now recommend BBMs (pre‐)screeners identify individuals likely AD pathological changes for inclusion trials evaluating disease‐modifying therapies, provided status is confirmed with positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. also encourage studying longitudinal BBM ongoing future However, should not yet used primary endpoints pivotal Further, cautiously start using specialized memory clinics part patients cognitive symptoms results whenever possible CSF PET. Additional data are stand‐alone markers, considering care.

Language: Английский

---

Blood-based biomarkers for Alzheimer's disease: towards clinical implementation

The Lancet Neurology, Journal Year: 2021, Volume and Issue: 21(1), P. 66 - 77

Published: Nov. 25, 2021

Language: Английский

---

Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer’s Disease Neuroimaging Initiative

Molecular Psychiatry, Journal Year: 2020, Volume and Issue: 26(2), P. 429 - 442

Published: Oct. 26, 2020

Language: Английский

---

The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2021, Volume and Issue: 17(7), P. 1145 - 1156

Published: Jan. 25, 2021

Abstract Introduction This study investigated the diagnostic and disease‐monitoring potential of plasma biomarkers in mild cognitive impairment (MCI) Alzheimer's disease (AD) dementia cognitively unimpaired (CU) individuals. Methods Plasma was analyzed using Simoa assays from 99 CU, 107 MCI, 103 AD participants. Results Phosphorylated‐tau181 (P‐tau181), neurofilament light, amyloid‐β (Aβ42/40), Total‐tau Glial fibrillary acidic protein were altered but P‐tau181 significantly outperformed all differentiating CU (area under curve [AUC] = 0.91). increased MCI converters compared to non‐converters. Higher associated with steeper decline gray matter loss temporal regions. Longitudinal change strongly full sample Aβ measures Discussion detected at stages loss. These findings highlight value as a non‐invasive cost‐effective prognostic biomarker AD.

Language: Английский

---

Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer’s trial selection and disease monitoring

Nature Medicine, Journal Year: 2022, Volume and Issue: 28(12), P. 2555 - 2562

Published: Dec. 1, 2022

Abstract Blood biomarkers indicative of Alzheimer’s disease (AD) pathology are altered in both preclinical and symptomatic stages the disease. Distinctive may be optimal for identification AD or monitoring progression. that correlate with changes cognition atrophy during course could used clinical trials to identify successful interventions thereby accelerate development efficient therapies. When disease-modifying treatments become approved use, blood-based might also inform on treatment implementation management practice. In BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 amyloid-β42/40 ratio were more changed at lower thresholds amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent over 4–6 years disease, no such observed p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein neurofilament light. Only longitudinal increases associated deterioration brain AD. The selective increase its associations cognitive decline was confirmed an independent cohort (Wisconsin Registry Prevention). These findings support differential association strongly highlight as a surrogate marker progression prodromal AD, impact new treatments.

Language: Английский

---

Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology

JAMA Neurology, Journal Year: 2024, Volume and Issue: 81(3), P. 255 - 255

Published: Jan. 22, 2024

Importance Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer disease (AD) pathology, with p-tau217 considered to have the most utility. However, availability of tests research and clinical use has been limited. Expanding access this highly accurate AD crucial wider evaluation implementation tests. Objective To determine utility novel commercially available immunoassay plasma detect pathology evaluate reference ranges abnormal amyloid β (Aβ) longitudinal change across 3 selected cohorts. Design, Setting, Participants This cohort study examined data from single-center observational cohorts: cross-sectional Translational Biomarkers in Aging Dementia (TRIAD) (visits October 2017–August 2021) Wisconsin Registry Alzheimer’s Prevention (WRAP) February 2007–November 2020) Sant Pau Initiative on Neurodegeneration (SPIN) (baseline visits March 2009–November 2021). included individuals without cognitive impairment grouped by (AT) status using PET or CSF biomarkers. Data were analyzed June 2023. Exposures Magnetic resonance imaging, Aβ positron emission tomography (PET), PET, cerebrospinal fluid (CSF) biomarkers (Aβ42/40 p-tau immunoassays), (ALZpath pTau217 assay). Main Outcomes Measures Accuracy detecting according baseline status. Results The 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] 282 males [35.9%]). High accuracy was observed identifying elevated (area under curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) (AUC, 0.93-0.97; 0.84-0.99) all These accuracies comparable determining signal. detection 3-range yielded reproducible results reduced confirmatory testing approximately 80%. Longitudinally, values showed an annual increase only Aβ-positive individuals, highest those positivity. Conclusions Relevance found that accurately identified biological AD, biomarkers, cut-offs It detected changes, including at preclinical stage.

Language: Английский

---