Alzheimer disease

Nature Reviews Disease Primers, Год журнала: 2021, Номер 7(1)

Опубликована: Май 13, 2021

Язык: Английский

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

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Июнь 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.

Язык: Английский

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Plasma p-tau181 accurately predicts Alzheimer’s disease pathology at least 8 years prior to post-mortem and improves the clinical characterisation of cognitive decline

Acta Neuropathologica, Год журнала: 2020, Номер 140(3), С. 267 - 278

Опубликована: Июль 27, 2020

The neuropathological confirmation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFT) remains the gold standard for a definitive diagnosis Alzheimer's disease (AD). Nowadays, in vivo AD is greatly aided by both cerebrospinal fluid (CSF) positron emission tomography (PET) biomarkers. Although highly accurate, their broad implementation restricted high cost, limited accessibility invasiveness. We recently developed high-performance, ultrasensitive immunoassay quantification phosphorylated at threonine-181 (p-tau181) plasma, which identifies pathophysiology with accuracy. However, it unclear whether plasma p-tau181, measured years before death, can predict eventual AD, successfully discriminates from non-AD dementia pathologies. studied unique cohort 115 individuals longitudinal blood collections clinical evaluation 8, 4 2 prior to assessment death. results demonstrate that p-tau181 associates better neuropathology Braak staging than 8 post-mortem. Moreover, while all patients had during life, proved discriminate pathologies accuracy (AUC = 97.4%, 95% CI 94.1-100%) even Additionally, trajectory was assessed patients. found main increases occurred between death later plateauing. In contrast, controls exhibited minor, albeit significant, up until Overall, our study demonstrates predictive specific post-mortem examination. These data add further support use aid management primary care recruitment trials.

Язык: Английский

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

Nature Reviews Neurology, Год журнала: 2022, Номер 18(7), С. 400 - 418

Опубликована: Май 18, 2022

Язык: Английский

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Tau: Enabler of diverse brain disorders and target of rapidly evolving therapeutic strategies

Science, Год журнала: 2021, Номер 371(6532)

Опубликована: Фев. 25, 2021

The many faces of tau protein is implicated in several brain disorders, including Alzheimer's disease, suggesting that it could be a target therapeutics. However, because unclear how the pleiotropic roles lead to neural pathology different diseases, drug development remains challenging. Chang et al. review possible mechanisms diseases and paths forward improving research development. Science , this issue p. eabb8255

Язык: Английский

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

Brain, Год журнала: 2020, Номер 144(1), С. 325 - 339

Опубликована: Окт. 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

Язык: Английский

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Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration

Brain, Год журнала: 2022, Номер 146(3), С. 1152 - 1165

Опубликована: Дек. 27, 2022

Blood-based biomarkers for amyloid beta and phosphorylated tau show good diagnostic accuracies agreements with their corresponding CSF neuroimaging in the amyloid/tau/neurodegeneration [A/T/(N)] framework Alzheimer's disease. However, blood-based neurodegeneration marker neurofilament light is not specific to disease while total-tau shows lack of correlation total-tau. Recent studies suggest that blood originates principally from peripheral, non-brain sources. We sought address this challenge by generating an anti-tau antibody selectively binds brain-derived avoids peripherally expressed 'big tau' isoform. applied develop ultrasensitive assay tau, validated it five independent cohorts (n = 609) including a blood-to-autopsy cohort, biomarker-classified memory clinic cohorts. In paired samples, serum were significantly correlated (rho 0.85, P < 0.0001), 0.23, 0.3364). showed equivalent performance as separate biomarker-positive participants biomarker-negative controls. Furthermore, plasma accurately distinguished autopsy-confirmed other neurodegenerative diseases (area under curve 86.4%) did 54.3%). These performances presence concomitant pathologies. Plasma 0.52-0.67, 0.003), but -0.14-0.17, 0.501), was associated global regional plaque neurofibrillary tangle counts. results further verified two where differentiated range disorders, frontotemporal lobar degeneration atypical parkinsonian disorders up 99.6%). Notably, plasma/serum only diseases. Across cohorts, AT(N) cognitive function. Brain-derived new biomarker outperforms and, unlike light, specificity disease-type neurodegeneration. Thus, demonstrates potential complete scheme blood, will be useful evaluate disease-dependent processes clinical research purposes.

Язык: Английский

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Differential levels of plasma biomarkers of neurodegeneration in Lewy body dementia, Alzheimer’s disease, frontotemporal dementia and progressive supranuclear palsy

Journal of Neurology Neurosurgery & Psychiatry, Год журнала: 2022, Номер 93(6), С. 651 - 658

Опубликована: Янв. 25, 2022

This longitudinal study compared emerging plasma biomarkers for neurodegenerative disease between controls, patients with Alzheimer's (AD), Lewy body dementia (LBD), frontotemporal (FTD) and progressive supranuclear palsy (PSP).

Язык: Английский

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Plasma phospho-tau in Alzheimer’s disease: towards diagnostic and therapeutic trial applications

Molecular Neurodegeneration, Год журнала: 2023, Номер 18(1)

Опубликована: Март 16, 2023

As the leading cause of dementia, Alzheimer's disease (AD) is a major burden on affected individuals, their families and caregivers, healthcare systems. Although AD can be identified diagnosed by cerebrospinal fluid or neuroimaging biomarkers that concord with neuropathological evidence clinical symptoms, challenges regarding practicality accessibility hinder widespread availability implementation. Consequently, many people suspected cognitive impairment due to do not receive biomarker-supported diagnosis. Blood have capacity help expand access diagnostics worldwide. One such promising biomarker plasma phosphorylated tau (p-tau), which has demonstrated specificity versus non-AD neurodegenerative diseases, will extremely important inform diagnosis eligibility for therapies recently been approved. This review provides an update diagnostic prognostic performances p-tau181, p-tau217 p-tau231, associations in vivo autopsy-verified pathological hallmarks. Additionally, we discuss potential applications unanswered questions p-tau therapeutic trials, given recent addition toolbox participant screening, recruitment during-trial monitoring. Outstanding include assay standardization, threshold generation verification diverse cohorts reflective wider community attending memory clinics included trials.

Язык: Английский

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The validation status of blood biomarkers of amyloid and phospho-tau assessed with the 5-phase development framework for AD biomarkers

European Journal of Nuclear Medicine and Molecular Imaging, Год журнала: 2021, Номер 48(7), С. 2140 - 2156

Опубликована: Март 6, 2021

Abstract Purpose The development of blood biomarkers that reflect Alzheimer’s disease (AD) pathophysiology (phosphorylated tau and amyloid-β) has offered potential as scalable tests for dementia differential diagnosis early detection. In 2019, the Geneva AD Biomarker Roadmap Initiative included in systematic validation biomarkers. Methods A panel experts convened November 2019 at a two-day workshop Geneva. level maturity (fully achieved, partly preliminary evidence, not unsuccessful) was assessed based on methodology discussed fully during which also evaluated cerebrospinal fluid (CSF) positron emission tomography (PET) Results Plasma p-tau shown analytical validity (phase 2 primary aim 1) first evidence clinical 3 1), whereas Aβ remains to be partially achieved. Full partial achievement been assigned Aβ, respectively, their associations ante-mortem measures secondary 2). However, only exists influence covariates, assay comparison cut-off criteria. Conclusions Despite relative infancy biomarkers, CSF much already achieved phases 1 through – with having greater success detecting predicting progression. sufficient data about effect covariates biomarker measurement is lacking. No phase 4 (real-world performance) or 5 (assessment impact/cost) tested, thus

Язык: Английский

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