Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease

Nature Medicine, Journal Year: 2022, Volume and Issue: unknown

Published: Aug. 11, 2022

Abstract Blood biomarkers indicating elevated amyloid-β (Aβ) pathology in preclinical Alzheimer’s disease are needed to facilitate the initial screening process of participants disease-modifying trials. Previous biofluid data suggest that phosphorylated tau231 (p-tau231) could indicate incipient Aβ pathology, but a comprehensive comparison with other putative blood is lacking. In ALFA+ cohort, all tested plasma (p-tau181, p-tau217, p-tau231, GFAP, NfL and Aβ42/40) were significantly changed disease. However, p-tau231 reached abnormal levels lowest burden. Plasma p-tau217 had strongest association positron emission tomography (PET) retention early accumulating regions associated longitudinal increases PET uptake individuals without overt at baseline. summary, better capture earliest cerebral changes, before plaque present, promising enrich population for clinical

Language: Английский

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Longitudinal Associations of Blood Phosphorylated Tau181 and Neurofilament Light Chain With Neurodegeneration in Alzheimer Disease

JAMA Neurology, Journal Year: 2021, Volume and Issue: 78(4), P. 396 - 396

Published: Jan. 14, 2021

Plasma phosphorylated tau at threonine 181 (p-tau181) has been proposed as an easily accessible biomarker for the detection of Alzheimer disease (AD) pathology, but its ability to monitor progression in AD remains unclear.To study potential longitudinal plasma p-tau181 measures assessing neurodegeneration and cognitive decline comparison neurofilament light chain (NfL), a disease-nonspecific marker neuronal injury.This cohort included data from Alzheimer's Disease Neuroimaging Initiative February 1, 2007, June 6, 2016. Follow-up blood sampling was performed up 8 years. measurements were 2020. This multicentric observational 1113 participants, including cognitively unimpaired participants well patients with impairment (mild dementia). Participants eligible inclusion if they had available NfL least 1 fluorine-18-labeled fluorodeoxyglucose (FDG) positron emission tomography (PET) or structural magnetic resonance imaging scan same visit. Exclusion criteria any significant neurologic disorder other than suspected AD; presence infection, infarction, multiple lacunes detected by imaging; systemic condition that could lead difficulty complying protocol.Plasma measured single-molecule array technology.Longitudinal markers (FDG PET imaging) test scores (Preclinical Cognitive Composite Assessment Scale-Cognitive Subscale 13 tasks). Data analyzed 20 August 15, 2020.Of (mean [SD] age, 74.0 [7.6] years; 600 men [53.9%]; 992 non-Hispanic White [89.1%]), total 378 individuals (34.0%) (CU) 735 (66.0%) impaired (CImp). Of CImp group, 537 (73.1%) mild impairment, 198 (26.9%) dementia. Longitudinal changes associated (CU: r = -0.24, P < .001; CImp: 0.34, .001) prospective decrease glucose metabolism -0.05, .48; -0.27, gray matter volume -0.19, -0.31, highly AD-characteristic brain regions. These associations restricted amyloid-β-positive individuals. Both independently cognition regions typically affected AD. However, also exceeding this AD-typical spatial pattern amyloid-β-negative participants. Mediation analyses found approximately 25% 45% outcomes on mediated neuroimaging-derived neurodegeneration, suggesting links between independent these measures.Study findings suggest scalable predicting monitoring was, unlike NfL, specific. The implications use biomarkers clinical practice treatment trials.

Language: Английский

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Blood‐based biomarkers for Alzheimer's disease

EMBO Molecular Medicine, Journal Year: 2021, Volume and Issue: 14(1)

Published: Dec. 3, 2021

Language: Английский

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Blood phospho-tau in Alzheimer disease: analysis, interpretation, and clinical utility

Nature Reviews Neurology, Journal Year: 2022, Volume and Issue: 18(7), P. 400 - 418

Published: May 18, 2022

Language: Английский

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Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies

Frontiers in Neuroscience, Journal Year: 2021, Volume and Issue: 15

Published: Sept. 27, 2021

Biomarkers of neurodegeneration and neuronal injury have the potential to improve diagnostic accuracy, disease monitoring, prognosis, measure treatment efficacy. Neurofilament proteins (NfPs) are well suited as biomarkers in these contexts because they major neuron-specific components that maintain structural integrity sensitive across a wide range neurologic diseases. Low levels NfPs constantly released from neurons into extracellular space ultimately reach cerebrospinal fluid (CSF) blood under physiological conditions throughout normal brain development, maturation, aging. NfP CSF rise above response independently cause. measured by lumbar puncture about 40-fold more concentrated than healthy individuals. New ultra-sensitive methods now allow minimally invasive measurement low serum or plasma track onset progression neurological disorders nervous system assess responses therapeutic interventions. Any five Nf subunits – neurofilament light chain (NfL), medium (NfM), heavy (NfH), alpha-internexin (INA) peripherin (PRPH) may be altered given neuropathological condition. In familial sporadic Alzheimer’s (AD), NfL early 22 years before clinical AD 10 AD. The determinants elevated degradation fragments magnitude damaged degenerating axons fiber tracks, affected axon caliber sizes rate release at different stages condition directly indirectly affecting central (CNS) and/or peripheral (PNS). rapidly emerging transformative neurology providing novel insights diseases advancing trials. Here we summarize current understanding intracellular physiology, pathophysiology kinetics biofluids review value limitations injury.

Language: Английский

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Time course of phosphorylated-tau181 in blood across the Alzheimer’s disease spectrum

Brain, Journal Year: 2020, Volume and Issue: 144(1), P. 325 - 339

Published: Oct. 26, 2020

Abstract Tau phosphorylated at threonine 181 (p-tau181) measured in blood plasma has recently been proposed as an accessible, scalable, and highly specific biomarker for Alzheimer’s disease. Longitudinal studies, however, investigating the temporal dynamics of this novel are lacking. It is therefore unclear when disease process p-tau181 increases above physiological levels how it relates to spatiotemporal progression characteristic pathologies. We aimed establish natural time course across sporadic spectrum comparison those established imaging fluid-derived biomarkers examined longitudinal data from a large prospective cohort elderly individuals enrolled Disease Neuroimaging Initiative (ADNI) (n = 1067) covering wide clinical normal cognition dementia, with measures 18F-florbetapir amyloid-β PET scan baseline. A subset participants 864) also had amyloid-β1–42 CSF, another 298) undergone 18F-flortaucipir tau 6 years later. performed brain-wide analyses investigate associations baseline change regional pathology burden later, estimated changes other using previously developed method construction long-term trajectories shorter-term data. Smoothing splines demonstrated that earliest occurred even before markers reached abnormal levels, greater rates correlating increased pathology. Voxel-wise yielded relatively weak, yet significant, early accumulating brain regions cognitively healthy individuals, while strongest were observed late patients mild cognitive impairment. Cross-sectional particularly associated widespread cortical aggregation temporoparietal typical neurofibrillary tangle distribution Finally, we reaches ∼6.5 5.7 after CSF amyloid-β, respectively, following similar p-tau181. Our findings suggest presence aggregation, providing clear implications use diagnostic screening tool

Language: Английский

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Comorbid neuropathological diagnoses in early versus late-onset Alzheimer’s disease

Brain, Journal Year: 2021, Volume and Issue: 144(7), P. 2186 - 2198

Published: March 6, 2021

Abstract Co-pathologies play an important role in the expression of Alzheimer’s disease clinical phenotype and may influence treatment efficacy. Early-onset disease, defined as manifesting before age 65, is viewed a relatively pure form with more homogeneous neuropathological substrate. We sought to compare frequency common diagnoses consecutive autopsy series 96 patients early-onset (median onset = 55 years, 44 females) 48 late-onset 73 14 females). The UCSF Neurodegenerative Disease Brain Bank database was reviewed identify primary pathological diagnosis disease. Prevalence stage Lewy body limbic age-related TDP-43 encephalopathy (LATE), argyrophilic grain hippocampal sclerosis, cerebral amyloid angiopathy, vascular brain injury were compared between two cohorts. found at least one non-Alzheimer’s 98% (versus 100% late onset), number comorbid per patient lower than 2 versus 3, Mann-Whitney Z 3.00, P 0.002). angiopathy both early (cerebral angiopathy: 86% 79%, Fisher exact 0.33; disease: 49% 42%, 0.48, respectively), although amygdala-predominant (22% 6%, 0.02). In contrast, LATE (35% 8%, &lt; 0.001), sclerosis (15% 3%, 0.02), (58% 41%, 0.052), (65% 39%, 0.004) respectively. co-pathologies predicted worse cognitive performance time death on Mini-Mental State Examination [1.4 points/pathology (95% confidence interval, CI −2.5 −0.2) Clinical Dementia Rating-Sum Boxes (1.15 point/pathology, 95% 0.45 1.84)], across effect sex not significant (P 0.17). APOE ε4 allele similar cohorts (52% 54%) associated greater (+0.40, 0.01 0.79, 0.047), independent symptom onset, sex, duration. Females showed higher density neurofibrillary tangles males, controlling for ε4, Our findings suggest that potentially implications practice trials design.

Language: Английский

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Highly accurate blood test for Alzheimer’s disease is similar or superior to clinical cerebrospinal fluid tests

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(4), P. 1085 - 1095

Published: Feb. 21, 2024

With the emergence of Alzheimer's disease (AD) disease-modifying therapies, identifying patients who could benefit from these treatments becomes critical. In this study, we evaluated whether a precise blood test perform as well established cerebrospinal fluid (CSF) tests in detecting amyloid-β (Aβ) plaques and tau tangles. Plasma %p-tau217 (ratio phosporylated-tau217 to non-phosphorylated tau) was analyzed by mass spectrometry Swedish BioFINDER-2 cohort (n = 1,422) US Charles F. Joanne Knight Alzheimer Disease Research Center (Knight ADRC) 337). Matched CSF samples were with clinically used FDA-approved automated immunoassays for Aβ42/40 p-tau181/Aβ42. The primary secondary outcomes detection brain Aβ or pathology, respectively, using positron emission tomography (PET) imaging reference standard. Main analyses focused on individuals cognitive impairment (mild mild dementia), which is target population available treatments. equivalent classifying PET status, an area under curve (AUC) both between 0.95 0.97. generally superior classification tau-PET AUCs 0.95-0.98. cognitively impaired subcohorts (BioFINDER-2: n 720; ADRC: 50), plasma had accuracy, positive predictive value negative 89-90% 87-88% tests, further improving 95% two-cutoffs approach. Blood demonstrated performance that AD pathology. Use high-performance clinical practice can improve access accurate diagnosis AD-specific

Language: Английский

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Plasma biomarkers for Alzheimer’s Disease in relation to neuropathology and cognitive change

Acta Neuropathologica, Journal Year: 2022, Volume and Issue: 143(4), P. 487 - 503

Published: Feb. 23, 2022

Plasma biomarkers related to amyloid, tau, and neurodegeneration (ATN) show great promise for identifying these pathological features of Alzheimer's Disease (AD) as shown by recent clinical studies selected autopsy studies. We have evaluated ATN plasma in a series 312 well-characterized longitudinally followed research subjects with available within 5 years or less before examined relation spectrum AD pathologies. Aβ42, Aβ40, total Tau, P-tau181, P-tau231 neurofilament light (NfL) were measured using Single molecule array (Simoa) assays. Neuropathological findings assessed standard protocols. Comparing pathology diagnoses ratings, we found that P-tau181 (AUC = 0.856) 0.773) showed the strongest overall sensitivity specificity neuropathological change (ADNC). increases at earlier ADNC stages than other biomarkers. Aβ42/40 was decreased amyloid pathology, modest diagnostic accuracy 0.601). NfL increased non-AD cases subset those ADNC. did not changes Lewy body disease (LBD), hippocampal sclerosis aging (HS) limbic-predominant age-related TDP-43 encephalopathy (LATE) unless present. Higher levels 231 predicted faster cognitive decline, early 10 prior autopsy, even among people normal cognition mild impairment. These results support also can help predict future predementia stages. Although consistently shows several neurological disorders, it had utility decline. this study relatively weak predictor different assay methods may be needed improve on this. Additional are detect presence impact LBD LATE pathology.

Language: Английский

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Moving fluid biomarkers for Alzheimer’s disease from research tools to routine clinical diagnostics

Molecular Neurodegeneration, Journal Year: 2021, Volume and Issue: 16(1)

Published: Feb. 19, 2021

Abstract Four fluid-based biomarkers have been developed into diagnostic tests for Alzheimer’s disease (AD) pathology: the ratio of 42 to 40 amino acid-long amyloid β, a marker plaque pathology; total-tau and phosphorylated tau, markers AD-related changes in tau metabolism secretion; neurofilament light, neurodegeneration. When measured cerebrospinal fluid, these can be used clinical practice support diagnosis mild cognitive impairment or dementia due AD. Recently, technological breakthroughs made it possible measure them standard blood samples as well. Here, we give an updated account current state AD biomarker research field. We discuss how new may practice, what role they play relation more established tests, such CSF positron emission tomography, facilitate effective implementation future disease-modifying therapies.

Language: Английский

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