| 1. |
- 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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| 2. |
- Ashton, Nicholas J., et al.
(författare)
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An update on blood-based biomarkers for non-Alzheimer neurodegenerative disorders.
- 2020
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Ingår i: Nature Reviews Neurology. - : Springer Science and Business Media LLC. - 1759-4766 .- 1759-4758. ; 16
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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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| 3. |
- Ashton, Nicholas J., et al.
(författare)
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Increased plasma neurofilament light chain concentration correlates with severity of post-mortem neurofibrillary tangle pathology and neurodegeneration
- 2019
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Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 7:1
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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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| 4. |
- Boccardi, M., et al.
(författare)
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The strategic biomarker roadmap for the validation of Alzheimer's diagnostic biomarkers: methodological update
- 2021
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 48
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Tidskriftsartikel (refereegranskat)abstract
- Background The 2017 Alzheimer's disease (AD) Strategic Biomarker Roadmap (SBR) structured the validation of AD diagnostic biomarkers into 5 phases, systematically assessing analytical validity (Phases 1-2), clinical validity (Phases 3-4), and clinical utility (Phase 5) through primary and secondary Aims. This framework allows to map knowledge gaps and research priorities, accelerating the route towards clinical implementation. Within an initiative aimed to assess the development of biomarkers of tau pathology, we revised this methodology consistently with progress in AD research. Methods We critically appraised the adequacy of the 2017 Biomarker Roadmap within current diagnostic frameworks, discussed updates at a workshop convening the Alzheimer's Association and 8 leading AD biomarker research groups, and detailed the methods to allow consistent assessment of aims achievement for tau and other AD diagnostic biomarkers. Results The 2020 update applies to all AD diagnostic biomarkers. In Phases 2-3, we admitted a greater variety of study designs (e.g., cross-sectional in addition to longitudinal) and reference standards (e.g., biomarker confirmation in addition to clinical progression) based on construct (in addition to criterion) validity. We structured a systematic data extraction to enable transparent and formal evidence assessment procedures. Finally, we have clarified issues that need to be addressed to generate data eligible to evidence-to-decision procedures. Discussion This revision allows for more versatile and precise assessment of existing evidence, keeps up with theoretical developments, and helps clinical researchers in producing evidence suitable for evidence-to-decision procedures. Compliance with this methodology is essential to implement AD biomarkers efficiently in clinical research and diagnostics.
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| 5. |
- Ferreira, Pamela C. L., et al.
(författare)
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Endocannabinoid System Biomarkers in Alzheimer's Disease
- 2023
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Ingår i: CANNABIS AND CANNABINOID RESEARCH. - : Mary Ann Liebert Inc. - 2578-5125 .- 2378-8763. ; 8:1, s. 77-91
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alterations in the endocannabinoid system (ES) have been described in Alzheimer's disease (AD) pathophysiology. In the past years, multiple ES biomarkers have been developed, promising to advance our understanding of ES changes in AD.Discussion: ES biomarkers, including positron emission tomography with cannabinoid receptors tracers and biofluid-based endocannabinoids, are associated with AD disease progression and pathological features.Conclusion: Although not specific enough for AD diagnosis, ES biomarkers hold promise for prognosis, drug-target engagement, and a better understanding of the disease. Here, we summarize currently available ES biomarker findings and discuss their potential applications in the AD research field.
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| 6. |
- Heurling, Kerstin, et al.
(författare)
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Imaging β-amyloid using [(18)F]flutemetamol positron emission tomography : from dosimetry to clinical diagnosis
- 2016
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 43:2, s. 362-373
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Forskningsöversikt (refereegranskat)abstract
- In Alzheimer's disease (AD), the deposition of β-amyloid (Aβ) is hypothesized to result in a series of secondary neurodegenerative processes, leading ultimately to synaptic dysfunction and neuronal loss. Since the advent of the first Aβ-specific positron emission tomography (PET) ligand, (11)C-Pittsburgh compound B ([(11)C]PIB), several (18)F ligands have been developed that circumvent the limitations of [(11)C]PIB tied to its short half-life. To date, three such compounds have been approved for clinical use by the US and European regulatory bodies, including [(18)F]AV-45 ([(18)F]florbetapir; Amyvid™), [(18)F]-BAY94-9172 ([(18)F]florbetaben; Neuraceq™) and [(18)F]3'-F-PIB ([(18)F]flutemetamol; Vizamyl™). The present review aims to summarize and discuss the currently available knowledge on [(18)F]flutemetamol PET. As the (18)F analogue of [(11)C]PIB, [(18)F]flutemetamol may be of use in the differentiation of AD from related neurodegenerative disorders and may help with subject selection and measurement of target engagement in the context of clinical trials testing anti-amyloid therapeutics. We will also discuss its potential use in non-AD amyloidopathies.
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| 7. |
- Jonasson, My, et al.
(författare)
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Optimal timing of tau pathology imaging and automatic extraction of a reference region using dynamic [18F]THK5317 PET
- 2019
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Ingår i: NeuroImage. - : Elsevier BV. - 2213-1582. ; 22
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Tidskriftsartikel (refereegranskat)abstract
- [F-18]THK5317 is a PET tracer for in-vivo imaging of tau associated with Alzheimer's disease (AD). This work aimed to evaluate optimal timing for standardized uptake value ratio (SUVR) measures with [F-18]THK5317 and automated generation of SUVR-1 and relative cerebral blood flow (R-1) parametric images. Nine AD patients and nine controls underwent 90 min [F-18]THK5317 scans. SUVR-1 was calculated at transient equilibrium (TE) and for seven different 20 min intervals and compared with distribution volume ratio (DVR; reference Logan). Cerebellar grey matter (MRI) was used as reference region. A supervised cluster analysis (SVCA) method was implemented to automatically generate a reference region, directly from the dynamic PET volume without the need of a structural MRI scan, for computation of SUVR-1 and R-1 images for a scan duration matching the optimal timing. TE was reached first in putamen, frontal- and parietal cortex at 22 +/- 4 min for AD patients and in putamen at 20 +/- 0 min in controls. Over all regions and subjects, SUVR20-40-1 correlated best with DVR-1, R-2 = 0.97. High correlation was found between values generated using MRI- and SVCA-based reference (R-2 = 0.93 for SUVR20-40-1; R-2 = 0.94 for R-1). SUVR20-40 allows for accurate semi-quantitative assessment of tau pathology and SVCA may be used to obtain a reference region for calculation of both SUVR-1 and R-1 with 40 min scan duration.
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| 8. |
- Leuzy, Antoine, et al.
(författare)
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Clinical impact of [18F]flutemetamol PET among memory clinic patients with an unclear diagnosis.
- 2019
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 46:6, s. 1276-1286
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To investigate the impact of amyloid PET with [18F]flutemetamol on diagnosis and treatment management in a cohort of patients attending a tertiary memory clinic in whom, despite extensive cognitive assessment including neuropsychological testing, structural imaging, CSF biomarker analysis and in some cases [18F]FDG PET, the diagnosis remained unclear.METHODS: The study population consisted of 207 patients with a clinical diagnosis prior to [18F]flutemetamol PET including mild cognitive impairment (MCI; n = 131), Alzheimer's disease (AD; n = 41), non-AD (n = 10), dementia not otherwise specified (dementia NOS; n = 20) and subjective cognitive decline (SCD; n = 5).RESULTS: Amyloid positivity was found in 53% of MCI, 68% of AD, 20% of non-AD, 20% of dementia NOS, and 60% of SCD patients. [18F]Flutemetamol PET led, overall, to a change in diagnosis in 92 of the 207 patients (44%). A high percentage of patients with a change in diagnosis was observed in the MCI group (n = 67, 51%) and in the dementia NOS group (n = 11; 55%), followed by the non-AD and AD (30% and 20%, respectively). A significant increase in cholinesterase inhibitor treatment was observed after [18F]flutemetamol PET (+218%, 34 patients before and 108 patients after).CONCLUSION: The present study lends support to the clinical value of amyloid PET in patients with an uncertain diagnosis in the tertiary memory clinic setting.
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| 9. |
- Leuzy, Antoine, et al.
(författare)
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Concordance and Diagnostic Accuracy of [C-11]PIB PET and Cerebrospinal Fluid Biomarkers in a Sample of Patients with Mild Cognitive Impairment and Alzheimer's Disease
- 2015
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 45:4, s. 1077-1088
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease (AD) pathology can be quantified in vivo using cerebrospinal fluid (CSF) levels of amyloid-beta(1-42) (A beta(1-42)), total-tau (t-tau), and phosphorylated tau (p- tau(181p)), as well as with positron emission tomography (PET) using [C-11]Pittsburgh compound-B ([C-11]PIB). Studies assessing concordance between these measures, however, have provided conflicting results. Moreover, it has been proposed that [C-11]PIB PET may be of greater clinical utility in terms of identifying patients with mild cognitive impairment (MCI) who will progress to the dementia phase of AD. Objective: To determine concordance and classification accuracy of CSF biomarkers and [C-11]PIB PET in a cohort of patients with MCI and AD. Methods: 68 patients (MCI, n = 33; AD, n = 35) underwent [C-11]PIB PET and CSF sampling. Cutoffs of >1.41 ([C-11]PIB), <450 pg/mL-and a more lenient cutoff of 550 pg/mL-(A beta(1-42)), <6.5 (A beta(1-42)/p-tau181p), and 1.14 (A beta(1- 42)/t-tau), were used to determine concordance. Logistic regression was used to determine classification accuracy with respect to stable MCI (sMCI) versus MCI who progressed to AD (pMCI). Results: Concordance between [C-11]PIB and A beta(1-42) was highest for sMCI (67%), followed by AD (60%) and pMCI (33%). Agreement was increased across groups using A beta(1-42) < 550 pg/mL, or A beta(1-42) to tau ratios. Logistic regression showed that classification accuracy of [11C] PIB, between sMCI and pMCI, was superior to A beta(1-42) (73% versus 58%), A beta(1-42)/t-tau (63%), and A beta(1-42)/p-tau181p (65%). Conclusion: In the present study, [C-11]PIB proved a better predictor of progression to AD in patients with MCI, relative to CSF measures of A beta(1-42) or A beta(1-42)/tau. Discordance between PET and CSF markers for A beta(1-42) suggests they cannot be used interchangeably, as is currently the case.
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| 10. |
- Leuzy, Antoine
(författare)
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Dynamics of proteinopathies in Alzheimer’s disease as measured by PET and CSF biomarkers
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the extracellular aggregation of the amyloid-β (Aβ; amyloid) peptide and the intraneuronal accumulation of the protein tau. Independently, and in concert, these protein opathies lead to the loss of synapses and neurons (neurodegeneration). These processes can be measured in living individuals using positron emission tomography (PET) and cerebrospinal fluid (CSF) based measurements (biomarkers). Biomarkers for AD include the retention in the brain of varied PET ligands (e.g. [11C]PIB and [18F]flutemetamol, Aβ; [18F]THK5317, tau; and [18F]FDG, glucose metabolism, a proxy for synaptic integrity), as well as CSF levels of Aβ1-42, and tau phosphorylated at threonine 181 (p-tau181p), and total-tau (t-tau), reflecting Aβ, the formation tau tangle pathology, and axonal damage, respectively. The aim of this thesis, which comprises five studies, was to obtain new insight into how these biomarkers interrelate in AD, and to examine their potential utility from a clinical standpoint. In study I, agreement between dichotomised (i.e. normal/abnormal) [11C]PIB PET and CSF Aβ1-42 in AD and related disorders was found to persist after controlling for potential methodological confounds tied to CSF, suggesting biological underpinnings to biomarker mismatches. Concordance, however, was substantially improved across patient groups when using Aβ1-42 in ratio with Aβ1-40. In study II, the impact of amyloid imaging with [18F]flutemetamol PET was examined in a cohort of diagnostically unclear patients, drawn from a tertiary memory clinic. [18F]Flutemetamol investigations resulted in substantial changes to pre-amyloid PET diagnoses and an incease in the use of cholinesterase inhibitors, with the greatest impact seen among patients with a pre-[18F]flutemetamol diagnosis of MCI. In study III, the relationship between [18F]THK5317 tau PET and CSF tau, including measures derived from assays capturing novel fragments, was shown to vary by isocortical hypometabolism, suggesting that the relationship between tau biomarkers may vary by disease stage. Novel CSF markers better tracked longitudinal PET, as compared to p-tau181p and t-tau, and improved concordance with [18F]THK5317. Moreover, comparison of cross-sectional and rate of change findings suggest a temporal delay between tau pathology and synaptic impairment. In studies IV and V, perfusion information derived from [18F]THK5317 tau PET scans was shown to strongly correlate with [18F]FDG PET metabolic imaging; though our cross-sectional data support the use of perfusion parameters as a substitute for [18F]FDG, longitudinal findings suggest that the coupling between perfusion and metabolism may vary as a function of disease stage, warranting further studies.
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