| 1. |
- Alawode, Deborah O T, et al.
(författare)
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Transitioning from cerebrospinal fluid to blood tests to facilitate diagnosis and disease monitoring in Alzheimer's disease.
- 2021
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Ingår i: Journal of internal medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 290:3, s. 583-601
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is increasingly prevalent worldwide, and disease-modifying treatments may soon be at hand; hence now, more than ever, there is a need to develop techniques that allow earlier and more secure diagnosis. Current biomarker-based guidelines for AD diagnosis, which have replaced the historical symptom-based guidelines, rely heavily on neuroimaging and cerebrospinal fluid (CSF) sampling. Whilst these have greatly improved the diagnostic accuracy of AD pathophysiology, they are less practical for application in primary care, population-based and epidemiological settings, or where resources are limited. In contrast, blood is a more accessible and cost-effective source of biomarkers in AD. In this review paper, using the recently proposed amyloid, tau and neurodegeneration [AT(N)] criteria as a framework towards a biological definition of AD, we discuss recent advances in biofluid-based biomarkers, with a particular emphasis on those with potential to be translated into blood-based biomarkers. We provide an overview of the research conducted both in CSF and in blood to draw conclusions on biomarkers that show promise. Given the evidence collated in this review, plasma neurofilament light chain (N), and phosphorylated tau (p-tau; T) show particular potential for translation into clinical practice. However, p-tau requires more comparisons to be conducted between its various epitopes before conclusions can be made as to which one most robustly differentiates AD from non-AD dementias. Plasma amyloid beta (A) would prove invaluable as an early screening modality, but it requires very precise tests and robust pre-analytical protocols.
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| 2. |
- Alcolea, D., et al.
(författare)
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Use of plasma biomarkers for AT(N) classification of neurodegenerative dementias
- 2021
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 92:11, s. 1206-1214
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: All categories included in the AT(N) classification can now be measured in plasma. However, their agreement with cerebrospinal fluid (CSF) markers is not fully established. A blood signature to generate the AT(N) classification would facilitate early diagnosis of patients with Alzheimer's disease (AD) through an easy and minimally invasive approach. Methods: We measured Aβ, pTau181 and neurofilament light (NfL) in 150 plasma samples of the Sant Pau Initiative on Neurodegeneration cohort including patients with mild cognitive impairment, AD dementia, frontotemporal dementia, dementia with Lewy bodies and cognitively normal participants. We classified participants in the AT(N) categories according to CSF biomarkers and studied the diagnostic value of plasma biomarkers within each category individually and in combination. Results: The plasma Aβ composite, pTau181 and NfL yielded areas under the curve (AUC) of 0.75, 0.78 and 0.88 to discriminate positive and negative participants in their respective A, T and N categories. The combination of all three markers did not outperform pTau181 alone (AUC=0.81) to discriminate A+T+ from A-T- participants. There was a moderate correlation between plasma Aβ composite and CSF Aβ1-42/Aβ1-40 (Rho=-0.5, p<0.001) and between plasma pTau181 and CSF pTau181 in the entire cohort (Rho=0.51, p<0.001). NfL levels in plasma showed high correlation with those in CSF (Rho=0.78, p<0.001). Conclusions: Plasma biomarkers are useful to detect the AT(N) categories, and their use can differentiate patients with pathophysiological evidence of AD. A blood AT(N) signature may facilitate early diagnosis and follow-up of patients with AD through an easy and minimally invasive approach. © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.
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| 3. |
- Ally, M., et al.
(författare)
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Cross-sectional and longitudinal evaluation of plasma glial fibrillary acidic protein to detect and predict clinical syndromes of Alzheimer's disease
- 2023
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Ingår i: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. - 2352-8729. ; 15:4
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: This study examined plasma glial fibrillary acidic protein (GFAP) as a biomarker of cognitive impairment due to Alzheimer's disease (AD) with and against plasma neurofilament light chain (NfL), and phosphorylated tau (p-tau)181+231.Methods: Plasma samples were analyzed using Simoa platform for 567 participants spanning the AD continuum. Cognitive diagnosis, neuropsychological testing, and dementia severity were examined for cross-sectional and longitudinal outcomes.Results: Plasma GFAP discriminated AD dementia from normal cognition (adjusted mean difference = 0.90 standard deviation [SD]) and mild cognitive impairment (adjusted mean difference = 0.72 SD), and demonstrated superior discrimination compared to alternative plasma biomarkers. Higher GFAP was associated with worse dementia severity and worse performance on 11 of 12 neuropsychological tests. Longitudinally, GFAP predicted decline in memory, but did not predict conversion to mild cognitive impairment or dementia.Discussion: Plasma GFAP was associated with clinical outcomes related to suspected AD and could be of assistance in a plasma biomarker panel to detect in vivo AD.
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| 4. |
- Arslan, Burak, 1990, et al.
(författare)
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Blood-based biomarkers in Alzheimer's disease - moving towards a new era of diagnostics
- 2024
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Ingår i: CLINICAL CHEMISTRY AND LABORATORY MEDICINE. - 1434-6621 .- 1437-4331.
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD), a primary cause of dementia globally, is traditionally diagnosed via cerebrospinal fluid (CSF) measures and positron emission tomography (PET). The invasiveness, cost, and limited accessibility of these methods have led to exploring blood-based biomarkers as a promising alternative for AD diagnosis and monitoring. Recent advancements in sensitive immunoassays have identified potential blood-based biomarkers, such as A beta 42/A beta 40 ratios and phosphorylated tau (p-tau) species. This paper briefly evaluates the clinical utility and reliability of these biomarkers across various AD stages, highlighting challenges like refining plasma A beta 42/A beta 40 assays and enhancing the precision of p-tau, particularly p-tau181, p-tau217, and p-tau231. The discussion also covers other plasma biomarkers like neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and synaptic biomarkers, assessing their significance in AD diagnostics. The need for ongoing research and development of robust assays to match the performance of CSF and PET biomarkers is underscored. In summary, blood-based biomarkers are increasingly crucial in AD diagnosis, follow-up, prognostication, treatment response evaluation, and population screening, particularly in primary care settings. These developments are set to revolutionize AD diagnostics, offering earlier and more accessible detection and management options
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| 5. |
- Ashraf, A., et al.
(författare)
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Plasma transferrin and hemopexin are associated with altered A beta uptake and cognitive decline in Alzheimer's disease pathology
- 2020
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Heme and iron homeostasis is perturbed in Alzheimer's disease (AD); therefore, the aim of the study was to examine the levels and association of heme with iron-binding plasma proteins in cognitively normal (CN), mild cognitive impairment (MCI), and AD individuals from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) and Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) cohorts. Methods Non-targeted proteomic analysis by high-resolution mass spectrometry was performed to quantify relative protein abundances in plasma samples from 144 CN individuals from the AIBL and 94 CN from KARVIAH cohorts and 21 MCI and 25 AD from AIBL cohort. ANCOVA models were utilized to assess the differences in plasma proteins implicated in heme/iron metabolism, while multiple regression modeling (and partial correlation) was performed to examine the association between heme and iron proteins, structural neuroimaging, and cognitive measures. Results Of the plasma proteins implicated in iron and heme metabolism, hemoglobin subunit beta (p = 0.001) was significantly increased in AD compared to CN individuals. Multiple regression modeling adjusted for age, sex, APOE epsilon 4 genotype, and disease status in the AIBL cohort revealed lower levels of transferrin but higher levels of hemopexin associated with augmented brain amyloid deposition. Meanwhile, transferrin was positively associated with hippocampal volume and MMSE performance, and hemopexin was negatively associated with CDR scores. Partial correlation analysis revealed lack of significant associations between heme/iron proteins in the CN individuals progressing to cognitive impairment. Conclusions In conclusion, heme and iron dyshomeostasis appears to be a feature of AD. The causal relationship between heme/iron metabolism and AD warrants further investigation.
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| 6. |
- Ashton, Nicholas J., et al.
(författare)
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A multicentre validation study of the diagnostic value of plasma neurofilament light
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- 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 a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.
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| 7. |
- Ashton, Nicholas J., et al.
(författare)
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A plasma protein classifier for predicting amyloid burden for preclinical Alzheimer's disease.
- 2019
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Ingår i: Science advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 5:2
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Tidskriftsartikel (refereegranskat)abstract
- A blood-based assessment of preclinical disease would have huge potential in the enrichment of participants for Alzheimer's disease (AD) therapeutic trials. In this study, cognitively unimpaired individuals from the AIBL and KARVIAH cohorts were defined as Aβ negative or Aβ positive by positron emission tomography. Nontargeted proteomic analysis that incorporated peptide fractionation and high-resolution mass spectrometry quantified relative protein abundances in plasma samples from all participants. A protein classifier model was trained to predict Aβ-positive participants using feature selection and machine learning in AIBL and independently assessed in KARVIAH. A 12-feature model for predicting Aβ-positive participants was established and demonstrated high accuracy (testing area under the receiver operator characteristic curve = 0.891, sensitivity = 0.78, and specificity = 0.77). This extensive plasma proteomic study has unbiasedly highlighted putative and novel candidates for AD pathology that should be further validated with automated methodologies.
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| 8. |
- Ashton, Nicholas J., et al.
(författare)
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Alzheimer Disease Blood Biomarkers in Patients With Out-of-Hospital Cardiac Arrest
- 2023
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Ingår i: Jama Neurology. - : American Medical Association (AMA). - 2168-6149. ; 80:4, s. 388-396
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Blood phosphorylated tau (p-tau) and amyloid-13 peptides (A13) are promising peripheral biomarkers of Alzheimer disease (AD) pathology. However, their potential alterations due to alternative mechanisms, such as hypoxia in patients resuscitated from cardiac arrest, are not known. OBJECTIVE To evaluate whether the levels and trajectories of blood p-tau, A1342, and A1340 following cardiac arrest, in comparison with neural injury markers neurofilament light (NfL) and total tau (t-tau), can be used for neurological prognostication following cardiac arrest.DESIGN, SETTING, AND PARTICIPANTS This prospective clinical biobank study used data from the randomized Target Temperature Management After Out-of-Hospital Cardiac Arrest (TTM) trial. Unconscious patients with cardiac arrest of presumed cardiac origin were included between November 11, 2010, and January 10, 2013, from 29 international sites. Serum analysis for serum NfL and t-tau were performed between August 1 and August 23, 2017. Serum p-tau, A1342, and A1340 were analyzed between July 1 and July 15, 2021, and between May 13 and May 25, 2022. A total of 717 participants from the TTM cohort were examined: an initial discovery subset (n = 80) and a validation subset. Both subsets were evenly distributed for good and poor neurological outcome after cardiac arrest.EXPOSURES Serum p-tau, A1342, and A1340 concentrations using single molecule array technology. Serum levels of NfL and t-tau were included as comparators.MAIN OUTCOMES AND MEASURES Blood biomarker levels at 24 hours, 48 hours, and 72 hours after cardiac arrest. Poor neurologic outcome at 6-month follow-up, defined according to the cerebral performance category scale as category 3 (severe cerebral disability), 4 (coma), or 5 (brain death).RESULTS This study included 717 participants (137 [19.1%] female and 580 male [80.9%]; mean [SD] age, 63.9 [13.5] years) who experienced out-of-hospital cardiac arrest. Significantly elevated serum p-tau levels were observed at 24 hours, 48 hours, and 72 hours in cardiac arrest patients with poor neurological outcome. The magnitude and prognostication of the change was greater at 24 hours (area under the receiver operating characteristic curve [AUC], 0.96; 95% CI, 0.95-0.97), which was similar to NfL (AUC, 0.94; 95% CI, 0.92-0.96). However, at later time points, p-tau levels decreased and were weakly associated with neurological outcome. In contrast, NfL and t-tau maintained high diagnostic accuracies, even 72 hours after cardiac arrest. Serum A1342 and A1340 concentrations increased over time in most patients but were only weakly associated with neurological outcome.CONCLUSIONS AND RELEVANCE In this case-control study, blood biomarkers indicative of AD pathology demonstrated different dynamics of change after cardiac arrest. The increase of p-tau at 24 hours after cardiac arrest suggests a rapid secretion from the interstitial fluid following hypoxic-ischemic brain injury rather than ongoing neuronal injury like NfL or t-tau. In contrast, delayed increases of A13 peptides after cardiac arrest indicate activation of amyloidogenic processing in response to ischemia.
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| 9. |
- Ashton, Nicholas J., et al.
(författare)
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Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease
- 2022
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Ingår i: Ebiomedicine. - : Elsevier BV. - 2352-3964. ; 76
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Tidskriftsartikel (refereegranskat)abstract
- Background: Phosphorylated tau (p-tau) epitopes in cerebrospinal fluid (CSF) are accurate biomarkers for a pathological and clinical diagnosis of Alzheimer's disease (AD) and are seen to be increased in preclinical stage of the disease. However, it is unknown if these increases transpire earlier, prior to amyloid-beta (Aβ) positivity as determined by position emission tomography (PET), and if an ordinal sequence of p-tau epitopes occurs at this incipient phase Methods: We measured CSF concentrations of p-tau181, p-tau217 and p-tau231 in 171 participants across the AD continuum who had undergone Aβ ([18F]AZD4694) and tau ([18F]MK6240) position emission tomography (PET) and clinical assessment Findings: All CSF p-tau biomarkers were accurate predictors of cognitive impairment but CSF p-tau217 demonstrated the largest fold-changes in AD patients in comparison to non-AD dementias and cognitively unimpaired individuals. CSF p-tau231 and p-tau217 predicted Aβ and tau to a similar degree but p-tau231 attained abnormal levels first. P-tau231 was sensitive to the earliest changes of Aβ in the medial orbitofrontal, precuneus and posterior cingulate before global Aβ PET positivity was reached Interpretation: We demonstrate that CSF p-tau231 increases early in development of AD pathology and is a principal candidate for detecting incipient Aβ pathology for therapeutic trial application Funding: Canadian Institutes of Health Research (CIHR), Canadian Consortium of Neurodegeneration and Aging, Weston Brain Institute, Brain Canada Foundation, the Fonds de Recherche du Québec. © 2022
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| 10. |
- Ashton, Nicholas J., et al.
(författare)
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Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology
- 2024
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Ingår i: JAMA NEUROLOGY. - 2168-6149 .- 2168-6157.
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Tidskriftsartikel (refereegranskat)abstract
- ImportancePhosphorylated 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 p-tau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests. ObjectiveTo determine the utility of a novel and commercially available immunoassay for plasma p-tau217 to detect AD pathology and evaluate reference ranges for abnormal amyloid beta (A beta) and longitudinal change across 3 selected cohorts. Design, Setting, and ParticipantsThis cohort study examined data from 3 single-center observational cohorts: cross-sectional and longitudinal data from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (visits October 2017-August 2021) and Wisconsin Registry for Alzheimer's Prevention (WRAP) cohort (visits February 2007-November 2020) and cross-sectional data from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort (baseline visits March 2009-November 2021). Participants included individuals with and without cognitive impairment grouped by amyloid and tau (AT) status using PET or CSF biomarkers. Data were analyzed from February to June 2023. ExposuresMagnetic resonance imaging, A beta positron emission tomography (PET), tau PET, cerebrospinal fluid (CSF) biomarkers (A beta 42/40 and p-tau immunoassays), and plasma p-tau217 (ALZpath pTau217 assay). Main Outcomes and MeasuresAccuracy of plasma p-tau217 in detecting abnormal amyloid and tau pathology, longitudinal p-tau217 change according to baseline pathology status. ResultsThe study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] and 282 males [35.9%]). High accuracy was observed in identifying elevated A beta (area under the curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95% CI, 0.84-0.99) across all cohorts. These accuracies were comparable with CSF biomarkers in determining abnormal PET signal. The detection of abnormal A beta pathology using a 3-range reference yielded reproducible results and reduced confirmatory testing by approximately 80%. Longitudinally, plasma p-tau217 values showed an annual increase only in A beta-positive individuals, with the highest increase observed in those with tau positivity. Conclusions and RelevanceThis study found that a commercially available plasma p-tau217 immunoassay accurately identified biological AD, comparable with results using CSF biomarkers, with reproducible cut-offs across cohorts. It detected longitudinal changes, including at the preclinical stage.
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