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Sökning: WFRF:(Hye Abdul)

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1.
  • Ashton, Nicholas J., et al. (författare)
  • A multicentre validation study of the diagnostic value of plasma neurofilament light.
  • 2021
  • Ingår i: Nature communications. - 2041-1723. ; 12:1
  • 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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2.
  • Ashton, Nicholas J., et al. (författare)
  • A plasma protein classifier for predicting amyloid burden for preclinical Alzheimer's disease.
  • 2019
  • Ingår i: Science advances. - 2375-2548. ; 5:2
  • 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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3.
  • Ashton, Nicholas J., et al. (författare)
  • An update on blood-based biomarkers for non-Alzheimer neurodegenerative disorders.
  • 2020
  • Ingår i: Nature Reviews Neurology. - : Nature Publishing Group. - 1759-4766. ; 16:5, s. 265-284
  • 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.
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4.
  • Ashton, Nicholas J., et al. (författare)
  • Increased plasma neurofilament light chain concentration correlates with severity of post-mortem neurofibrillary tangle pathology and neurodegeneration
  • 2019
  • Ingår i: Acta Neuropathologica Communications. - : BioMed Central (BMC). - 2051-5960. ; 7:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Alzheimer's disease (AD) is pathologically characterized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tangles and widespread neuronal loss in the brain. In recent years, blood biomarkers have emerged as a realistic prospect to highlight accumulating pathology for secondary prevention trials. Neurofilament light chain (NfL), a marker of axonal degeneration, is robustly elevated in the blood of many neurological and neurodegenerative conditions, including AD. A strong relationship with cerebrospinal fluid (CSF) NfL suggests that these biomarker modalities reflect the same pathological process. Yet, the connection between blood NfL and brain tissue pathology has not been directly compared. In this study, longitudinal plasma NfL from cognitively healthy controls (n = 12) and AD participants (n = 57) were quantified by the Simoa platform. On reaching post-mortem, neuropathological assessment was performed on all participants, with additional frozen and paraffin-embedded tissue acquired from 26 participants for further biochemical (Aβ1-42, Aβ1-40, tau) and histological (NfL) evaluation. Plasma NfL concentrations were significantly increased in AD and correlated with cognitive decline, independent of age. Retrospective stratification based on Braak staging revealed that baseline plasma NfL concentrations were associated with higher neurofibrillary tangle pathology at post-mortem. Longitudinal increases in plasma NfL were observed in all Braak groupings; a significant negative association, however, was found between plasma NfL at time point 1 and both its rate of change and annual percentage increase. Immunohistochemical evaluation of NfL in the medial temporal gyrus (MTG) demonstrated an inverse relationship between Braak stages and NfL staining. Importantly, a significant negative correlation was found between the plasma NfL measurement closest to death and the level of NfL staining in the MTG at post-mortem. For the first time, we demonstrate that plasma NfL associates with the severity of neurofibrillary tangle pathology and neurodegeneration in the post-mortem brain.
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5.
  • Ashton, Nicholas J., et al. (författare)
  • Plasma levels of soluble TREM2 and neurofilament light chain in TREM2 rare variant carriers.
  • 2019
  • Ingår i: Alzheimer's research & therapy. - 1758-9193. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Results from recent clinical studies suggest that cerebrospinal fluid (CSF) biomarkers that are indicative of Alzheimer's disease (AD) can be replicated in blood, e.g. amyloid-beta peptides (Aβ42 and Aβ40) and neurofilament light chain (NFL). Such data proposes that blood is a rich source of potential biomarkers reflecting central nervous system pathophysiology and should be fully explored for biomarkers that show promise in CSF. Recently, soluble fragments of the triggering receptor expressed on myeloid cells 2 (sTREM2) protein in CSF have been reported to be increased in prodromal AD and also in individuals with TREM2 rare genetic variants that increase the likelihood of developing dementia.In this study, we measured the levels of plasma sTREM2 and plasma NFL using the MesoScale Discovery and single molecule array platforms, respectively, in 48 confirmed TREM2 rare variant carriers and 49 non-carriers.Our results indicate that there are no changes in plasma sTREM2 and NFL concentrations between TREM2 rare variant carriers and non-carriers. Furthermore, plasma sTREM2 is not different between healthy controls, mild cognitive impairment (MCI) or AD.Concentrations of plasma sTREM2 do not mimic the recent changes found in CSF sTREM2.
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6.
  • Ashton, Nicholas J., et al. (författare)
  • Update on biomarkers for amyloid pathology in Alzheimer's disease
  • 2018
  • Ingår i: Biomarkers in medicine. - : Future Medicine Ltd.. - 1752-0371 .- 1752-0363. ; 12:7, s. 799-812
  • Forskningsöversikt (refereegranskat)abstract
    • At the center of Alzheimer's disease pathogenesis is the aberrant aggregation of amyloid-β (Aβ) into oligomers, fibrils and plaques. Effective monitoring of Aβ deposition directly in patients is essential to assist anti-Aβ therapeutics in target engagement and participant selection. In the advent of approved anti-Aβ therapeutics, biomarkers will become of fundamental importance in initiating treatments having disease modifying effects at the earliest stage. Two well-established Aβ biomarkers are widely utilized: Aβ-binding ligands for positron emission tomography and immunoassays to measure Aβ42 in cerebrospinal fluid. In this review, we will discuss the current clinical, diagnostic and research state of biomarkers for Aβ pathology. Furthermore, we will explore the current application of blood-based markers to assess Aβ pathology.
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7.
  • Kim, Min, et al. (författare)
  • Primary fatty amides in plasma associated with brain amyloid burden, hippocampal volume, and memory in the European Medical Information Framework for Alzheimer's Disease biomarker discovery cohort
  • 2019
  • Ingår i: Alzheimer's & Dementia. - : Elsevier. - 1552-5260 .- 1552-5279. ; 15:6, s. 817-827
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION: A critical and as-yet unmet need in Alzheimer's disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers.METHODS: This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis.RESULTS: Eight metabolites were associated with amyloid β and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory.DISCUSSION: PFAMs have been found increased and associated with amyloid β burden in CSF and clinical measures.
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8.
  • Lantero Rodriguez, Juan, et al. (författare)
  • 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.
  • 2020
  • Ingår i: Acta neuropathologica. - 1432-0533. ; 140:3, s. 267-278
  • Tidskriftsartikel (refereegranskat)abstract
    • The neuropathological confirmation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFT) remains the gold standard for a definitive diagnosis of Alzheimer's disease (AD). Nowadays, the in vivo diagnosis of AD is greatly aided by both cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers. Although highly accurate, their broad implementation is restricted by high cost, limited accessibility and invasiveness. We recently developed a high-performance, ultrasensitive immunoassay for the quantification of tau phosphorylated at threonine-181 (p-tau181) in plasma, which identifies AD pathophysiology with high accuracy. However, it remains unclear whether plasma p-tau181, measured years before the death, can predict the eventual neuropathological confirmation of AD, and successfully discriminates AD from non-AD dementia pathologies. We studied a unique cohort of 115 individuals with longitudinal blood collections with clinical evaluation at 8, 4 and 2 years prior to neuropathological assessment at death. The results demonstrate that plasma p-tau181 associates better with AD neuropathology and Braak staging than a clinical diagnosis 8 years before post-mortem. Moreover, while all patients had a diagnosis of AD dementia during life, plasma p-tau181 proved to discriminate AD from non-AD pathologies with high accuracy (AUC = 97.4%, 95% CI = 94.1-100%) even 8 years before death. Additionally, the longitudinal trajectory of plasma p-tau181 was assessed in all patients. We found that the main increases in plasma p-tau181 occurred between 8 and 4 years prior to death in patients with AD neuropathology and later plateauing. In contrast, non-AD pathologies and controls exhibited minor, albeit significant, increases in p-tau181 up until death. Overall, our study demonstrates that plasma p-tau181 is highly predictive and specific of AD neuropathology years before post-mortem examination. These data add further support for the use of plasma p-tau181 to aid clinical management in primary care and recruitment for clinical trials.
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9.
  • Shi, Liu, et al. (författare)
  • Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology.
  • 2020
  • Ingår i: Journal of Alzheimer's disease : JAD. - : IOS Press. - 1875-8908 .- 1387-2877. ; 77:3, s. 1353-1368
  • Tidskriftsartikel (refereegranskat)abstract
    • Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown.We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes.We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677).We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts.Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.
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10.
  • Shi, Liu, et al. (författare)
  • Discovery and validation of plasma proteomic biomarkers relating to brain amyloid burden by SOMAscan assay.
  • 2019
  • Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Elsevier. - 1552-5279 .- 1552-5260. ; 15:11, s. 1478-1488
  • Tidskriftsartikel (refereegranskat)abstract
    • Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins.4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid.A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization.The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition.
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  • Resultat 1-10 av 19
  • [1]2Nästa

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