| 1. |
- Karikari, Thomas, et al.
(författare)
-
The C291R Tau Variant Forms Different Types of Protofibrils
- 2020
-
Ingår i: Frontiers in Molecular Neuroscience. - : Frontiers Media SA. - 1662-5099. ; 13
-
Tidskriftsartikel (refereegranskat)abstract
- Mutations in the MAPT gene can lead to disease-associated variants of tau. However, the pathological mechanisms behind these genetic tauopathies are poorly understood. Here, we characterized the aggregation stages and conformational changes of tau C291R, a recently described MAPT mutation with potential pathogenic functions. The C291R variant of the tau four-repeat domain (tau-K18; a functional fragment with increased aggregation propensity compared with the full-length protein), aggregated into a mix of granular oligomers, amorphous and annular pore-like aggregates, in native-state and heparin-treated reactions as observed using atomic force microscopy (AFM) and negative-stained electron microscopy. On extended incubation in the native-state, tau-K18 C291R oligomers, unlike wild type (WT) tau-K18, aggregated to form protofibrils of four different phenotypes: (1) spherical annular; (2) spherical annular encapsulating granular oligomers; (3) ring-like annular but non-spherical; and (4) linear protofibrils. The ring-like tau-K18 C291R aggregates shared key properties of annular protofibrils previously described for other amyloidogenic proteins, in addition to two unique features: irregular/non-spherical-shaped annular protofibrils, and spherical protofibrils encapsulating granular oligomers. Tau-K18 C291R monomers had a circular dichroism (CD) peak at similar to 210 nm compared with similar to 199 nm for tau-K18 WT. These data suggest mutation-enhanced beta-sheet propensity. Together, we describe the characterization of tau-K18 C291R, the first genetic mutation substituting a cysteine residue. The aggregation mechanism of tau-K18 C291R appears to involve beta-sheet-rich granular oligomers which rearrange to form unique protofibrillar structures.
|
|
| 2. |
- Keshavan, Ashvini, et al.
(författare)
-
Population-based blood screening for preclinical Alzheimer's disease in a British birth cohort at age 70.
- 2021
-
Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 144:2, s. 434-449
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease has a preclinical stage when cerebral amyloid-β deposition occurs before symptoms emerge, and when amyloid-β-targeted therapies may have maximum benefits. Existing amyloid-β status measurement techniques, including amyloid PET and CSF testing, are difficult to deploy at scale, so blood biomarkers are increasingly considered for screening. We compared three different blood-based techniques-liquid chromatography-mass spectrometry measures of plasma amyloid-β, and single molecule array (Simoa) measures of plasma amyloid-β and phospho-tau181-to detect cortical 18F-florbetapir amyloid PET positivity (defined as a standardized uptake value ratio of >0.61 between a predefined cortical region of interest and eroded subcortical white matter) in dementia-free members of Insight 46, a substudy of the population-based British 1946 birth cohort. We used logistic regression models with blood biomarkers as predictors of amyloid PET status, with or without age, sex and APOE ε4 carrier status as covariates. We generated receiver operating characteristics curves and quantified areas under the curves to compare the concordance of the different blood tests with amyloid PET. We determined blood test cut-off points using Youden's index, then estimated numbers needed to screen to obtain 100 amyloid PET-positive individuals. Of the 502 individuals assessed, 441 dementia-free individuals with complete data were included; 82 (18.6%) were amyloid PET-positive. The area under the curve for amyloid PET status using a base model comprising age, sex and APOE ε4 carrier status was 0.695 (95% confidence interval: 0.628-0.762). The two best-performing Simoa plasma biomarkers were amyloid-β42/40 (0.620; 0.548-0.691) and phospho-tau181 (0.707; 0.646-0.768), but neither outperformed the base model. Mass spectrometry plasma measures performed significantly better than any other measure (amyloid-β1-42/1-40: 0.817; 0.770-0.864 and amyloid-β composite: 0.820; 0.775-0.866). At a cut-off point of 0.095, mass spectrometry measures of amyloid-β1-42/1-40 detected amyloid PET positivity with 86.6% sensitivity and 71.9% specificity. Without screening, to obtain 100 PET-positive individuals from a population with similar amyloid PET positivity prevalence to Insight 46, 543 PET scans would need to be performed. Screening using age, sex and APOE ε4 status would require 940 individuals, of whom 266 would proceed to scan. Using mass spectrometry amyloid-β1-42/1-40 alone would reduce these numbers to 623 individuals and 243 individuals, respectively. Across a theoretical range of amyloid PET positivity prevalence of 10-50%, mass spectrometry measures of amyloid-β1-42/1-40 would consistently reduce the numbers proceeding to scans, with greater cost savings demonstrated at lower prevalence.
|
|
| 3. |
- Vlegels, Naomi, et al.
(författare)
-
Brain-derived Tau for Monitoring Brain Injury in Acute Ischemic Stroke.
- 2023
-
Ingår i: medRxiv : the preprint server for health sciences.
-
Tidskriftsartikel (refereegranskat)abstract
- The evolution of infarcts varies widely among patients with acute ischemic stroke (IS) and influences treatment decisions. Neuroimaging is not applicable for frequent monitoring and there is no blood-based biomarker to track ongoing brain injury in acute IS. Here, we examined the utility of plasma brain-derived tau (BD-tau) as a biomarker for brain injury in acute IS. We conducted the prospective, observational Precision Medicine in Stroke [PROMISE] study with serial blood sampling upon hospital admission and at days 2, 3, and 7 in patients with acute ischemic stroke (IS) and for comparison, in patients with stroke mimics (SM). We determined the temporal course of plasma BD-tau, its relation to infarct size and admission imaging-based metrics of brain injury, and its value to predict functional outcome. Upon admission (median time-from-onset, 4.4h), BD-tau levels in IS patients correlated with ASPECTS ( ρ =-0.21, P <.0001) and were predictive of final infarct volume ( ρ =0.26, P <.0001). In contrast to SM patients, BD-tau levels in IS patients increased from admission (median, 2.9 pg/ml [IQR, 1.8-4.8]) to day 2 (median time-from-onset, 22.7h; median BD-tau, 5.0 pg/ml [IQR, 2.6-10.3]; P <.0001). The rate of change of BD-tau from admission to day 2 was significantly associated with collateral supply ( R 2 =0.10, P <.0001) and infarct progression ( ρ =0.58, P <.0001). At day 2, BD-tau was predictive of final infarct volume ( ρ =0.59, P <.0001) and showed superior value for predicting the 90-day mRS score compared with final infarct volume. In conclusion, in 502 patients with acute IS, plasma BD-tau was associated with imaging-based metrics of brain injury upon admission, increased within the first 24 hours in correlation with infarct progression, and at 24 hours was superior to final infarct volume in predicting 90-day functional outcome. Further research is needed to determine whether BD-tau assessments can inform decision-making in stroke care.
|
|
| 4. |
- Alawode, Deborah O T, et al.
(författare)
-
Transitioning from cerebrospinal fluid to blood tests to facilitate diagnosis and disease monitoring in Alzheimer's disease.
- 2021
-
Ingår i: Journal of internal medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 290:3, s. 583-601
-
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.
|
|
| 5. |
- Alcolea, D., et al.
(författare)
-
Use of plasma biomarkers for AT(N) classification of neurodegenerative dementias
- 2021
-
Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 92:11, s. 1206-1214
-
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.
|
|
| 6. |
- Ally, M., et al.
(författare)
-
Cross-sectional and longitudinal evaluation of plasma glial fibrillary acidic protein to detect and predict clinical syndromes of Alzheimer's disease
- 2023
-
Ingår i: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. - 2352-8729. ; 15:4
-
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.
|
|
| 7. |
- Amoateng, P., et al.
(författare)
-
Synedrella nodiflora Extract Depresses Excitatory Synaptic Transmission and Chemically-Induced In Vitro Seizures in the Rat Hippocampus
- 2021
-
Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Extracts of the tropical Cinderella plant Synedrella nodiflora are used traditionally to manage convulsive conditions in the West African sub-region. This study sought to determine the neuronal basis of the effectiveness of these plant extracts to suppress seizure activity. Using the hippocampal slice preparation from rats, the ability of the extract to depress excitatory synaptic transmission and in vitro seizure activity were investigated. Bath perfusion of the hydro-ethanolic extract of Synedrella nodiflora (SNE) caused a concentration-dependent depression of evoked field excitatory postsynaptic potentials (fEPSPs) recorded extracellularly in the CA1 region of the hippocampus with maximal depression of about 80% and an estimated IC50 of 0.06 mg/ml. The SNE-induced fEPSP depression was accompanied by an increase in paired pulse facilitation. The fEPSP depression only recovered partially after 20 min washing out. The effect of SNE was not stimulus dependent as it was present even in the absence of synaptic stimulation. Furthermore, it did not show desensitization as repeat application after 10 min washout produced the same level of fEPSP depression as the first application. The SNE effect on fEPSPs was not via adenosine release as it was neither blocked nor reversed by 8-CPT, an adenosine A(1) receptor antagonist. In addition, SNE depressed in vitro seizures induced by zero Mg2+ and high K+ -containing artificial cerebrospinal fluid (aCSF) in a concentration-dependent manner. The results show that SNE depresses fEPSPs and spontaneous bursting activity in hippocampal neurons that may underlie its ability to abort convulsive activity in persons with epilepsy.
|
|
| 8. |
- Ashton, Nicholas J., et al.
(författare)
-
A multicentre validation study of the diagnostic value of plasma neurofilament light
- 2021
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12, s. 1-12
-
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.
|
|
| 9. |
- Ashton, Nicholas J., et al.
(författare)
-
Alzheimer Disease Blood Biomarkers in Patients With Out-of-Hospital Cardiac Arrest
- 2023
-
Ingår i: Jama Neurology. - : American Medical Association (AMA). - 2168-6149. ; 80:4, s. 388-396
-
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.
|
|
| 10. |
- Ashton, Nicholas J., et al.
(författare)
-
An update on blood-based biomarkers for non-Alzheimer neurodegenerative disorders.
- 2020
-
Ingår i: Nature Reviews Neurology. - : Springer Science and Business Media LLC. - 1759-4766 .- 1759-4758. ; 16
-
Forskningsöversikt (refereegranskat)abstract
- Cerebrospinal fluid analyses and neuroimaging can identify the underlying pathophysiology at the earliest stage of some neurodegenerative disorders, but do not have the scalability needed for population screening. Therefore, a blood-based marker for such pathophysiology would have greater utility in a primary care setting and in eligibility screening for clinical trials. Rapid advances in ultra-sensitive assays have enabled the levels of pathological proteins to be measured in blood samples, but research has been predominantly focused on Alzheimer disease (AD). Nonetheless, proteins that were identified as potential blood-based biomarkers for AD, for example, amyloid-β, tau, phosphorylated tau and neurofilament light chain, are likely to be relevant to other neurodegenerative disorders that involve similar pathological processes and could also be useful for the differential diagnosis of clinical symptoms. This Review outlines the neuropathological, clinical, molecular imaging and cerebrospinal fluid features of the most common neurodegenerative disorders outside the AD continuum and gives an overview of the current status of blood-based biomarkers for these disorders.
|
|
