| 21. |
- Leckey, Claire A, et al.
(author)
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CSF neurofilament light chain profiling and quantitation in neurological diseases.
- 2024
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In: Brain communications. - 2632-1297. ; 6:3
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Journal article (peer-reviewed)abstract
- Neurofilament light chain is an established marker of neuroaxonal injury that is elevated in CSF and blood across various neurological diseases. It is increasingly used in clinical practice to aid diagnosis and monitor progression and as an outcome measure to assess safety and efficacy of disease-modifying therapies across the clinical translational neuroscience field. Quantitative methods for neurofilament light chain in human biofluids have relied on immunoassays, which have limited capacity to describe the structure of the protein in CSF and how this might vary in different neurodegenerative diseases. In this study, we characterized and quantified neurofilament light chain species in CSF across neurodegenerative and neuroinflammatory diseases and healthy controls using targeted mass spectrometry. We show that the quantitative immunoprecipitation-tandem mass spectrometry method developed in this study strongly correlates to single-molecule array measurements in CSF across the broad spectrum of neurodegenerative diseases and was replicable across mass spectrometry methods and centres. In summary, we have created an accurate and cost-effective assay for measuring a key biomarker in translational neuroscience research and clinical practice, which can be easily multiplexed and translated into clinical laboratories for the screening and monitoring of neurodegenerative disease or acute brain injury.
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| 22. |
- Obrocki, Pawel, et al.
(author)
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Perspectives in fluid biomarkers in neurodegeneration from the 2019 biomarkers in neurodegenerative diseases course - A joint PhD student course at University College London and University of Gothenburg
- 2020
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In: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12:1
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Research review (peer-reviewed)abstract
- Until relatively recently, a diagnosis of probable Alzheimer's disease (AD) and other neurodegenerative disorders was principally based on clinical presentation, with post-mortem examination remaining a gold standard for disease confirmation. This is in sharp contrast to other areas of medicine, where fluid biomarkers, such as troponin levels in myocardial infarction, form an integral part of the diagnostic and treatment criteria. There is a pressing need for such quantifiable and easily accessible tools in neurodegenerative diseases. In this paper, based on lectures given at the 2019 Biomarkers in Neurodegenerative Diseases Course, we provide an overview of a range of cerebrospinal fluid (CSF) and blood biomarkers in neurodegenerative disorders, including the 'core' AD biomarkers amyloid β (Aβ) and tau, as well as other disease-specific and general markers of neuroaxonal injury. We then highlight the main challenges in the field, and how those could be overcome with the aid of new methodological advances, such as assay automation, mass spectrometry and ultrasensitive immunoassays. As we hopefully move towards an era of disease-modifying treatments, reliable biomarkers will be essential to increase diagnostic accuracy, allow for earlier diagnosis, better participant selection and disease activity and treatment effect monitoring.
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| 23. |
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| 24. |
- Paterson, Ross W, et al.
(author)
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Biomarker Modelling of Early Molecular Changes in Alzheimer's Disease.
- 2014
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In: Molecular diagnosis & therapy. - : Springer Science and Business Media LLC. - 1179-2000 .- 1177-1062. ; 18:2, s. 213-227
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Research review (peer-reviewed)abstract
- The preclinical phase of Alzheimer's disease (AD) occurs years, possibly decades, before the onset of clinical symptoms. Being able to detect the very earliest stages of AD is critical to improving understanding of AD biology, and identifying individuals at greatest risk of developing clinical symptoms with a view to treating AD pathophysiology before irreversible neurodegeneration occurs. Studies of dominantly inherited AD families and longitudinal studies of sporadic AD have contributed to knowledge of the earliest AD biomarkers. Here we appraise this evidence before reviewing novel, particularly fluid, biomarkers that may provide insights into AD pathogenesis and relate these to existing hypothetical disease models.
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| 25. |
- Paterson, Ross W, et al.
(author)
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Cerebrospinal fluid in the differential diagnosis of Alzheimer's disease: clinical utility of an extended panel of biomarkers in a specialist cognitive clinic
- 2018
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In: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 10, s. 1-11
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Journal article (peer-reviewed)abstract
- Cerebrospinal fluid (CSF) biomarkers are increasingly being used to support a diagnosis of Alzheimer's disease (AD). Their clinical utility for differentiating AD from non-AD neurodegenerative dementias, such as dementia with Lewy bodies (DLB) or frontotemporal dementia (FTD), is less well established. We aimed to determine the diagnostic utility of an extended panel of CSF biomarkers to differentiate AD from a range of other neurodegenerative dementias.We used immunoassays to measure conventional CSF markers of amyloid and tau pathology (amyloid beta (Aβ)1-42, total tau (T-tau), and phosphorylated tau (P-tau)) as well as amyloid processing (AβX-38, AβX-40, AβX-42, soluble amyloid precursor protein (sAPP)α, and sAPPβ), large fibre axonal degeneration (neurofilament light chain (NFL)), and neuroinflammation (YKL-40) in 245 patients with a variety of dementias and 30 controls. Patients fulfilled consensus criteria for AD (n=156), DLB (n=20), behavioural variant frontotemporal dementia (bvFTD; n=45), progressive non-fluent aphasia (PNFA; n=17), and semantic dementia (SD; n=7); approximately 10% were pathology/genetically confirmed (n=26). Global tests based on generalised least squares regression were used to determine differences between groups. Non-parametric receiver operating characteristic (ROC) curves and area under the curve (AUC) analyses were used to quantify how well each biomarker discriminated AD from each of the other diagnostic groups (or combinations of groups). CSF cut-points for the major biomarkers found to have diagnostic utility were validated using an independent cohort which included causes of AD (n=104), DLB (n=5), bvFTD (n=12), PNFA (n=3), SD (n=9), and controls (n=10).There were significant global differences in Aβ1-42, T-tau, T-tau/Aβ1-42 ratio, P-tau-181, NFL, AβX-42, AβX-42/X-40 ratio, APPα, and APPβ between groups. At a fixed sensitivity of 85%, AβX-42/X-40 could differentiate AD from controls, bvFTD, and SD with specificities of 93%, 85%, and 100%, respectively; for T-tau/Aβ1-42 these specificities were 83%, 70%, and 86%. AβX-42/X-40 had similar or higher specificity than Aβ1-42. No biomarker or ratio could differentiate AD from DLB or PNFA with specificity >50%. Similar sensitivities and specificities were found in the independent validation cohort for differentiating AD and other dementias and in a pathology/genetically confirmed sub-cohort.CSF AβX-42/X-40 and T-tau/Aβ1-42 ratios have utility in distinguishing AD from controls, bvFTD, and SD. None of the biomarkers tested had good specificity at distinguishing AD from DLB or PNFA.
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| 26. |
- Paterson, Ross W, et al.
(author)
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Dissecting IWG-2 typical and atypical Alzheimer's disease: insights from cerebrospinal fluid analysis.
- 2015
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In: Journal of neurology. - : Springer Science and Business Media LLC. - 1432-1459 .- 0340-5354. ; 262, s. 2722-2730
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Journal article (peer-reviewed)abstract
- Pathobiological factors underlying phenotypic diversity in Alzheimer's disease (AD) are incompletely understood. We used an extended cerebrospinal fluid (CSF) panel to explore differences between "typical" with "atypical" AD and between amnestic, posterior cortical atrophy, logopenic aphasia and frontal variants. We included 97 subjects fulfilling International Working Group-2 research criteria for AD of whom 61 had "typical" AD and 36 "atypical" syndromes, and 30 controls. CSF biomarkers included total tau (T-tau), phosphorylated tau (P-tau), amyloid β1-42, amyloid βX-38/40/42, YKL-40, neurofilament light (NFL), and amyloid precursor proteins α and β. The typical and atypical groups were matched for age, sex, severity and rate of cognitive decline and had similar biomarker profiles, with the exception of NFL which was higher in the atypical group (p=0.03). Sub-classifying the atypical group into its constituent clinical syndromes, posterior cortical atrophy was associated with the lowest T-tau [604.4 (436.8-675.8) pg/mL], P-tau (79.8±21.8pg/L), T-tau/Aβ1-42 ratio [2.3 (1.4-2.6)], AβX-40/X-42 ratio (22.1±5.8) and rate of cognitive decline [1.9 (0.75-4.25) MMSE points/year]. Conversely, the frontal variant group had the highest levels of T-tau [1185.4 (591.7-1329.3) pg/mL], P-tau (116.4±45.4pg/L), T-tau/Aβ1-42 ratio [5.2 (3.3-6.9)] and AβX-40/X-42 ratio (27.9±7.5), and rate of cognitive decline. Whilst on a group level IWG-2 "typical" and "atypical" AD share similar CSF profiles, which are very different from controls, atypical AD is a heterogeneous entity with evidence for subtle differences in amyloid processing and neurodegeneration between different clinical syndromes. These findings also have practical implications for the interpretation of clinical CSF biomarker results.
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| 27. |
- Paterson, Ross W, et al.
(author)
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Serum and cerebrospinal fluid biomarker profiles in acute SARS-CoV-2-associated neurological syndromes.
- 2021
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In: Brain communications. - : Oxford University Press (OUP). - 2632-1297. ; 3:3
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Journal article (peer-reviewed)abstract
- Preliminary pathological and biomarker data suggest that SARS-CoV-2 infection can damage the nervous system. To understand what, where and how damage occurs, we collected serum and CSF from patients with COVID-19 and characterized neurological syndromes involving the PNS and CNS (n=34). We measured biomarkers of neuronal damage and neuroinflammation, and compared these with non-neurological control groups, which included patients with (n=94) and without (n=24) COVID-19. We detected increased concentrations of neurofilament light, a dynamic biomarker of neuronal damage, in the CSF of those with CNS inflammation (encephalitis and acute disseminated encephalomyelitis) [14800pg/ml (400, 32400)], compared to those with encephalopathy [1410pg/ml (756, 1446)], peripheral syndromes (Guillain-Barré syndrome) [740pg/ml (507, 881)] and controls [872pg/ml (654, 1200)]. Serum neurofilament light levels were elevated across patients hospitalized with COVID-19, irrespective of neurological manifestations. There was not the usual close correlation between CSF and serum neurofilament light, suggesting serum neurofilament light elevation in the non-neurological patients may reflect peripheral nerve damage in response to severe illness. We did not find significantly elevated levels of serum neurofilament light in community cases of COVID-19 arguing against significant neurological damage. Glial fibrillary acidic protein, a marker of astrocytic activation, was not elevated in the CSF or serum of any group, suggesting astrocytic activation is not a major mediator of neuronal damage in COVID-19.
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| 28. |
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| 29. |
- Pemberton, Hugh G., et al.
(author)
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Automated quantitative MRI volumetry reports support diagnostic interpretation in dementia : a multi-rater, clinical accuracy study
- 2021
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In: European Radiology. - : Springer. - 0938-7994 .- 1432-1084. ; 31:7, s. 5312-5323
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Journal article (peer-reviewed)abstract
- Objectives We examined whether providing a quantitative report (QReport) of regional brain volumes improves radiologists' accuracy and confidence in detecting volume loss, and in differentiating Alzheimer's disease (AD) and frontotemporal dementia (FTD), compared with visual assessment alone. Methods Our forced-choice multi-rater clinical accuracy study used MRI from 16 AD patients, 14 FTD patients, and 15 healthy controls; age range 52-81. Our QReport was presented to raters with regional grey matter volumes plotted as percentiles against data from a normative population (n = 461). Nine raters with varying radiological experience (3 each: consultants, registrars, 'non-clinical image analysts') assessed each case twice (with and without the QReport). Raters were blinded to clinical and demographic information; they classified scans as 'normal' or 'abnormal' and if 'abnormal' as 'AD' or 'FTD'. Results The QReport improved sensitivity for detecting volume loss and AD across all raters combined (p = 0.015* and p = 0.002*, respectively). Only the consultant group's accuracy increased significantly when using the QReport (p = 0.02*). Overall, raters' agreement (Cohen's kappa) with the 'gold standard' was not significantly affected by the QReport; only the consultant group improved significantly (kappa(s) 0.41 -> 0.55, p = 0.04*). Cronbach's alpha for interrater agreement improved from 0.886 to 0.925, corresponding to an improvement from 'good' to 'excellent'. Conclusion Our QReport referencing single-subject results to normative data alongside visual assessment improved sensitivity, accuracy, and interrater agreement for detecting volume loss. The QReport was most effective in the consultants, suggesting that experience is needed to fully benefit from the additional information provided by quantitative analyses.
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| 30. |
- Su, Zhan, et al.
(author)
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Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus.
- 2012
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:10
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Journal article (peer-reviewed)abstract
- Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10(-9); odds ratio (OR)=1.21, 95% confidence interval (CI)=1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined=2.74×10(-10); OR=1.14, 95% CI=1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.
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