| 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. |
- 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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| 3. |
- 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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| 4. |
- Ashton, Nicholas J., et al.
(författare)
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Effects of pre-analytical procedures on blood biomarkers for Alzheimer's pathophysiology, glial activation, and neurodegeneration.
- 2021
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Ingår i: Alzheimer's & dementia (Amsterdam, Netherlands). - : Wiley. - 2352-8729. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- We tested how tube types (ethylenediaminetetraacetic acid [EDTA], serum, lithium heparin [LiHep], and citrate) and freeze-thaw cycles affect levels of blood biomarkers for Alzheimer's disease (AD) pathophysiology, glial activation, and neuronal injury.Amyloid beta (Aβ)42, Aβ40, phosphorylated tau181 (p-tau181), glial fibrillary acidic protein, total tau (t-tau), neurofilament light, and phosphorylated neurofilament heavy protein were measured using single molecule arrays.LiHep demonstrated the highest mean value for all biomarkers. Tube types were highly correlated for most biomarkers (r>0.95) but gave significantly different absolute concentrations. Weaker correlations between tube types were found for Aβ42/40 (r=0.63-0.86) and serum t-tau (r=0.46-0.64). Freeze-thaw cycles highly influenced levels of serum Aβ and t-tau (P<.0001), and minor decreases in EDTA Aβ40 and EDTA p-tau181 were found after freeze-thaw cycle 4 (P<.05).The same tube type should be used in research studies on blood biomarkers. Individual concentration cut-offs are needed for each tube type in all tested biomarkers despite being highly correlated. Serum should be avoided for Aβ42, Aβ40, and t-tau. Freeze-thaw cycles>3 should be avoided for p-tau181.
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| 5. |
- Ashton, Nicholas J., et al.
(författare)
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Plasma and CSF biomarkers in a memory clinic: Head-to-head comparison of phosphorylated tau immunoassays
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:5, s. 1913-1924
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Direct comparisons of the main blood phosphorylated tau immunoassays in memory clinic populations are needed to understand possible differences. Methods In the BIODEGMAR study, 197 participants presenting with cognitive complaints were classified into an Alzheimer's disease (AD) or a non-AD cerebrospinal fluid (CSF) profile group, according to their amyloid beta 42/ phosphorylated tau (A beta 42/p-tau) ratio. We performed a head-to-head comparison of nine plasma and nine CSF tau immunoassays and determined their accuracy to discriminate abnormal CSF A beta 42/p-tau ratio. Results All studied plasma tau biomarkers were significantly higher in the AD CSF profile group compared to the non-AD CSF profile group and significantly discriminated abnormal CSF A beta 42/p-tau ratio. For plasma p-tau biomarkers, the higher discrimination accuracy was shown by Janssen p-tau217 (r = 0.76; area under the curve [AUC] = 0.96), ADx p-tau181 (r = 0.73; AUC = 0.94), and Lilly p-tau217 (r = 0.73; AUC = 0.94). Discussion Several plasma p-tau biomarkers can be used in a specialized memory clinic as a stand-alone biomarker to detect biologically-defined AD. Highlights Patients with an Alzheimer's disease cerebrospinal fluid (AD CSF) profile have higher plasma phosphorylated tau (p-tau) levels than the non-AD CSF profile group. All plasma p-tau biomarkers significantly discriminate patients with an AD CSF profile from the non-AD CSF profile group. Janssen p-tau217, ADx p-tau181, and Lilly p-tau217 in plasma show the highest accuracy to detect biologically defined AD. Janssen p-tau217, ADx p-tau181, Lilly p-tau217, Lilly p-tau181, and UGot p-tau231 in plasma show performances that are comparable to their CSF counterparts.
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| 6. |
- Ashton, Nicholas J., et al.
(författare)
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Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology.
- 2021
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 141:5, s. 709-724
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Tidskriftsartikel (refereegranskat)abstract
- The quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise in detecting Alzheimer's disease (AD) pathophysiology. Tau phosphorylated at threonine 231 (p-tau231) is one such biomarker in CSF but its usefulness as a blood biomarker is currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the quantification of plasma p-tau231 which was validated in four independent cohorts (n=588) in different settings, including the full AD continuum and non-AD neurodegenerative disorders. Plasma p-tau231 was able to identify patients with AD and differentiate them from amyloid-β negative cognitively unimpaired (CU) older adults with high accuracy (AUC=0.92-0.94). Plasma p-tau231 also distinguished AD patients from patients with non-AD neurodegenerative disorders (AUC=0.93), as well as from amyloid-β negative MCI patients (AUC=0.89). In a neuropathology cohort, plasma p-tau231 in samples taken on avergae 4.2years prior to post-mortem very accurately identified AD neuropathology in comparison to non-AD neurodegenerative disorders (AUC=0.99), this is despite all patients being given an AD dementia diagnosis during life. Plasma p-tau231 was highly correlated with CSF p-tau231, tau pathology as assessed by [18F]MK-6240 positron emission tomography (PET), and brain amyloidosis by [18F]AZD469 PET. Remarkably, the inflection point of plasma p-tau231, increasing as a function of continuous [18F]AZD469 amyloid-β PET standardized uptake value ratio, was shown to be earlier than standard thresholds of amyloid-β PET positivity and the increase of plasma p-tau181. Furthermore, plasma p-tau231 was significantly increased in amyloid-β PET quartiles 2-4, whereas CSF p-tau217 and plasma p-tau181 increased only at quartiles 3-4 and 4, respectively. Finally, plasma p-tau231 differentiated individuals across the entire Braak stage spectrum, including Braak staging from Braak 0 through Braak I-II, which was not observed for plasma p-tau181. To conclude, this novel plasma p-tau231 assay identifies the clinicalstages of ADand neuropathology equally well as plasma p-tau181, but increases earlier, already with subtle amyloid-β deposition, prior to the threshold for amyloid-β PET positivity has been attained, and also in response to early brain tau deposition. Thus, plasma p-tau231 is a promising novel biomarker of emerging AD pathology with the potential to facilitate clinical trials to identify vulnerable populations below PET threshold of amyloid-β positivity or apparent entorhinal tau deposition.
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| 7. |
- Benussi, Alberto, et al.
(författare)
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Diagnostic and prognostic value of serum NfL and p-Tau181 in frontotemporal lobar degeneration.
- 2020
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Ingår i: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 91:9, s. 960-967
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Tidskriftsartikel (refereegranskat)abstract
- To assess the diagnostic and prognostic value of serum neurofilament light (NfL) and serum phospho-Tau181 (p-Tau181) in a large cohort of patients with frontotemporal lobar degeneration (FTLD).In this retrospective study, performed on 417 participants, we analysed serum NfL and p-Tau181 concentrations with an ultrasensitive single molecule array (Simoa) approach. We assessed the diagnostic values of serum biomarkers in the differential diagnosis between FTLD, Alzheimer's disease (AD) and healthy ageing; their role as markers of disease severity assessing the correlation with clinical variables, cross-sectional brain imaging and neurophysiological data; their role as prognostic markers, considering their ability to predict survival probability in FTLD.We observed significantly higher levels of serum NfL in patients with FTLD syndromes, compared with healthy controls, and lower levels of p-Tau181 compared with patients with AD. Serum NfL concentrations showed a high accuracy in discriminating between FTLD and healthy controls (area under the curve (AUC): 0.86, p<0.001), while serum p-Tau181 showed high accuracy in differentiating FTLD from patients with AD (AUC: 0.93, p<0.001). In FTLD, serum NfL levels correlated with measures of cognitive function, disease severity and behavioural disturbances and were associated with frontotemporal atrophy and indirect measures of GABAergic deficit. Moreover, serum NfL concentrations were identified as the best predictors of survival probability.The assessment of serum NfL and p-Tau181 may provide a comprehensive view of FTLD, aiding in the differential diagnosis, in staging disease severity and in defining survival probability.
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| 8. |
- Benussi, Alberto, et al.
(författare)
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Serum Glial Fibrillary Acidic Protein (GFAP) Is a Marker of Disease Severity in Frontotemporal Lobar Degeneration.
- 2020
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 77:3, s. 1129-1141
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Tidskriftsartikel (refereegranskat)abstract
- It is still unknown if serum glial fibrillary acidic protein (GFAP) is a useful marker in frontotemporal lobar degeneration (FTLD).To assess the diagnostic and prognostic value of serum GFAP in a large cohort of patients with FTLD.In this retrospective study, performed on 406 participants, we measured serum GFAP concentration with an ultrasensitive Single molecule array (Simoa) method in patients with FTLD, Alzheimer's disease (AD), and in cognitively unimpaired elderly controls. We assessed the role of GFAP as marker of disease severity by analyzing the correlation with clinical variables, neurophysiological data, and cross-sectional brain imaging. Moreover, we evaluated the role of serum GFAP as a prognostic marker of disease survival.We observed significantly higher levels of serum GFAP in patients with FTLD syndromes, except progressive supranuclear palsy, compared with healthy controls, but not compared with AD patients. In FTLD, serum GFAP levels correlated with measures of cognitive dysfunction and disease severity, and were associated with indirect measures of GABAergic deficit. Serum GFAP concentration was not a significant predictor of survival.Serum GFAP is increased in FTLD, correlates with cognition and GABAergic deficits, and thus shows promise as a biomarker of disease severity in FTLD.
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| 9. |
- Brown, J., et al.
(författare)
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Tau in cerebrospinal fluid induces neuronal hyperexcitability and alters hippocampal theta oscillations
- 2023
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Ingår i: Acta Neuropathologica Communications. - 2051-5960. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) and other tauopathies are characterized by the aggregation of tau into soluble and insoluble forms (including tangles and neuropil threads). In humans, a fraction of both phosphorylated and non-phosphorylated N-terminal to mid-domain tau species, are secreted into cerebrospinal fluid (CSF). Some of these CSF tau species can be measured as diagnostic and prognostic biomarkers, starting from early stages of disease. While in animal models of AD pathology, soluble tau aggregates have been shown to disrupt neuronal function, it is unclear whether the tau species present in CSF will modulate neural activity. Here, we have developed and applied a novel approach to examine the electrophysiological effects of CSF from patients with a tau-positive biomarker profile. The method involves incubation of acutely-isolated wild-type mouse hippocampal brain slices with small volumes of diluted human CSF, followed by a suite of electrophysiological recording methods to evaluate their effects on neuronal function, from single cells through to the network level. Comparison of the toxicity profiles of the same CSF samples, with and without immuno-depletion for tau, has enabled a pioneering demonstration that CSF-tau potently modulates neuronal function. We demonstrate that CSF-tau mediates an increase in neuronal excitability in single cells. We then observed, at the network level, increased input-output responses and enhanced paired-pulse facilitation as well as an increase in long-term potentiation. Finally, we show that CSF-tau modifies the generation and maintenance of hippocampal theta oscillations, which have important roles in learning and memory and are known to be altered in AD patients. Together, we describe a novel method for screening human CSF-tau to understand functional effects on neuron and network activity, which could have far-reaching benefits in understanding tau pathology, thus allowing for the development of better targeted treatments for tauopathies in the future.
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| 10. |
- Brum, Wagner S., et al.
(författare)
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Biological variation estimates of Alzheimer's disease plasma biomarkers in healthy individuals
- 2024
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Ingår i: Alzheimer's and Dementia. - 1552-5260 .- 1552-5279. ; 20:2, s. 1284-1297
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Blood biomarkers have proven useful in Alzheimer's disease (AD) research. However, little is known about their biological variation (BV), which improves the interpretation of individual-level data. METHODS: We measured plasma amyloid beta (Aβ42, Aβ40), phosphorylated tau (p-tau181, p-tau217, p-tau231), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) in plasma samples collected weekly over 10weeks from 20 participants aged 40 to 60 years from the European Biological Variation Study. We estimated within- (CVI) and between-subject (CVG) BV, analytical variation, and reference change values (RCV). RESULTS: Biomarkers presented considerable variability in CVI and CVG. Aβ42/Aβ40 had the lowest CVI (≈ 3%) and p-tau181 the highest (≈ 16%), while others ranged from 6% to 10%. Most RCVs ranged from 20% to 30% (decrease) and 25% to 40% (increase). DISCUSSION: BV estimates for AD plasma biomarkers can potentially refine their clinical and research interpretation. RCVs might be useful for detecting significant changes between serial measurements when monitoring early disease progression or interventions. Highlights Plasma amyloid beta (Aβ42/Aβ40) presents the lowest between- and within-subject biological variation, but also changes the least in Alzheimer's disease (AD) patients versus controls. Plasma phosphorylated tau variants significantly vary in their within-subject biological variation, but their substantial fold-changes in AD likely limits the impact of their variability. Plasma neurofilament light chain and glial fibrillary acidic protein demonstrate high between-subject variation, the impact of which will depend on clinical context. Reference change values can potentially be useful in monitoring early disease progression and the safety/efficacy of interventions on an individual level. Serial sampling revealed that unexpectedly high values in heathy individuals can be observed, which urges caution when interpreting AD plasma biomarkers based on a single test result.
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