| 1. |
- Leuzy, Antoine, et al.
(författare)
-
Longitudinal uncoupling of cerebral perfusion, glucose metabolism, and tau deposition in Alzheimer's disease
- 2018
-
Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14:5, s. 652-663
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Cross-sectional findings using the tau tracer [F-18] THK5317 (THK5317) have shown that [F-18]fluorodeoxyglucose (FDG) positron emission tomography (PET) data can be approximated using perfusion measures (early-frame standardized uptake value ratio; ratio of tracer delivery in target to reference regions). In this way, a single PET study can provide both functional and molecular information. Methods: We included 16 patients with Alzheimer's disease who completed follow-up THK5317 and FDG studies 17 months after baseline investigations. Linear mixed-effects models and annual percentage change maps were used to examine longitudinal change. Results: Limited spatial overlap was observed between areas showing declines in THK5317 perfusion measures and FDG. Minimal overlap was seen between areas showing functional change and those showing increased retention of THK5317. Discussion: Our findings suggest a spatiotemporal offset between functional changes and tau pathology and a partial uncoupling between perfusion and metabolism, possibly as a function of Alzheimer's disease severity.
|
|
| 2. |
- Simrén, Joel, 1996, et al.
(författare)
-
The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer's disease
- 2021
-
Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 17:7, s. 1145-1156
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: This study investigated the diagnostic and disease-monitoring potential of plasma biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and cognitively unimpaired (CU) individuals. Methods: Plasma was analyzed using Simoa assays from 99 CU, 107 MCI, and 103 AD dementia participants. Results: Phosphorylated-tau181 (P-tau181), neurofilament light, amyloid-β (Aβ42/40), Total-tau and Glial fibrillary acidic protein were altered in AD dementia but P-tau181 significantly outperformed all biomarkers in differentiating AD dementia from CU (area under the curve [AUC] = 0.91). P-tau181 was increased in MCI converters compared to non-converters. Higher P-tau181 was associated with steeper cognitive decline and gray matter loss in temporal regions. Longitudinal change of P-tau181 was strongly associated with gray matter loss in the full sample and with Aβ measures in CU individuals. Discussion: P-tau181 detected AD at MCI and dementia stages and was strongly associated with cognitive decline and gray matter loss. These findings highlight the potential value of plasma P-tau181 as a non-invasive and cost-effective diagnostic and prognostic biomarker in AD.
|
|
| 3. |
- 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.
|
|
| 4. |
- Heurling, Kerstin, et al.
(författare)
-
Synaptic vesicle protein 2A as a potential biomarker in synaptopathies
- 2019
-
Ingår i: Molecular and Cellular Neuroscience. - : Elsevier. - 1044-7431 .- 1095-9327. ; 97, s. 34-42
-
Tidskriftsartikel (refereegranskat)abstract
- Measuring synaptic density in vivo using positron emission tomography (PET) imaging-based biomarkers targeting the synaptic vesicle protein 2A (SV2A) has received much attention recently due to its potential research and clinical applications in synaptopathies, including neurodegenerative and psychiatric diseases. Fluid-based biomarkers in proteinopathies have previously been suggested to provide information on pathology and disease status that is complementary to PET-based measures, and the same can be hypothesized with respect to SV2A. This review provides an overview of the current state of SV2A PET imaging as a biomarker of synaptic density, the potential role of fluid-based biomarkers for SV2A, and related future perspectives.
|
|
| 5. |
- Lessa Benedet, Andréa, et al.
(författare)
-
Stage-specific links between plasma neurofilament light and imaging biomarkers of Alzheimer's disease
- 2020
-
Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:12, s. 3793-3804
-
Tidskriftsartikel (refereegranskat)abstract
- Neurofilament light (NfL) is a marker of neuroaxonal injury, a prominent feature of Alzheimer's disease. It remains uncertain, however, how it relates to amyloid and tau pathology or neurodegeneration across the Alzheimer's disease continuum. The aim of this study was to investigate how plasma NfL relates to amyloid and tau PET and MRI measures of brain atrophy in participants with and without cognitive impairment. We retrospectively examined the association between plasma NfL and MRI measures of grey/white matter volumes in the Alzheimer's Disease Neuroimaging Initiative [ADNI: n = 1149; 382 cognitively unimpaired control subjects and 767 cognitively impaired participants (mild cognitive impairment n = 420, Alzheimer's disease dementia n = 347)]. Longitudinal plasma NfL was measured using single molecule array (Simoa) technology. Cross-sectional associations between plasma NfL and PET amyloid and tau measures were independently assessed in two cohorts: ADNI [n = 198; 110 cognitively unimpaired, 88 cognitively impaired (MCI n = 67, Alzheimer's disease dementia n = 21), data accessed October 2018]; and Translational Biomarkers in Aging and Dementia [TRIAD, n = 116; 74 cognitively unimpaired, 42 cognitively impaired (MCI n = 16, Alzheimer's disease dementia n = 26), data obtained November 2017 to January 2019]. Associations between plasma NfL and imaging-derived measures were examined voxel-wise using linear regression (cross-sectional) and linear mixed effect models (longitudinal). Cross-sectional analyses in both cohorts showed that plasma NfL was associated with PET findings in brain regions typically affected by Alzheimer's disease; associations were specific to amyloid PET in cognitively unimpaired and tau PET in cognitively impaired (P < 0.05). Longitudinal analyses showed that NfL levels were associated with grey/white matter volume loss; grey matter atrophy in cognitively unimpaired was specific to APOE ϵ4 carriers (P < 0.05). These findings suggest that plasma NfL increases in response to amyloid-related neuronal injury in preclinical stages of Alzheimer's disease, but is related to tau-mediated neurodegeneration in symptomatic patients. As such, plasma NfL may a useful measure to monitor effects in disease-modifying drug trials.
|
|
| 6. |
- Leuzy, Antoine, et al.
(författare)
-
Tau PET imaging in neurodegenerative tauopathies-still a challenge
- 2019
-
Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 24:8, s. 1112-1134
-
Forskningsöversikt (refereegranskat)abstract
- The accumulation of pathological misfolded tau is a feature common to a collective of neurodegenerative disorders known as tauopathies, of which Alzheimer's disease (AD) is the most common. Related tauopathies include progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), Down's syndrome (DS), Parkinson's disease (PD), and dementia with Lewy bodies (DLB). Investigation of the role of tau pathology in the onset and progression of these disorders is now possible due the recent advent of tau-specific ligands for use with positron emission tomography (PET), including first-(e.g., [F-18] THK5317, [F-18] THK5351, [F-18] AV1451, and [C-11] PBB3) and second-generation compounds [namely [F-18] MK-6240, [F-18] RO-948 (previously referred to as [F-18] RO69558948), [F-18] PI-2620, [F-18] GTP1, [F-18] PM-PBB3, and [F-18] JNJ64349311 ([F-18] JNJ311) and its derivative [F-18] JNJ-067)]. In this review we describe and discuss findings from in vitro and in vivo studies using both initial and new tau ligands, including their relation to biomarkers for amyloid-beta and neurodegeneration, and cognitive findings. Lastly, methodological considerations for the quantification of in vivo ligand binding are addressed, along with potential future applications of tau PET, including therapeutic trials.
|
|
| 7. |
- Rodriguez-Vieitez, Elena, et al.
(författare)
-
Comparability of [F-18]THK5317 and [C-11]PIB blood flow proxy images with [F-18]FDG positron emission tomography in Alzheimer's disease
- 2017
-
Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE PUBLICATIONS INC. - 0271-678X .- 1559-7016. ; 37:2, s. 740-749
-
Tidskriftsartikel (refereegranskat)abstract
- For amyloid positron emission tomography tracers, the simplified reference tissue model derived ratio of influx rate in target relative to reference region (R-1) has been shown to serve as a marker of brain perfusion, and, due to the strong coupling between perfusion and metabolism, as a proxy for glucose metabolism. In the present study, 11 prodromal Alzheimer's disease and nine Alzheimer's disease dementia patients underwent [F-18]THK5317, carbon-11 Pittsburgh Compound-B ([C-11]PIB), and 2-deoxy-2-[F-18]fluoro-D-glucose ([F-18]FDG) positron emission tomography to assess the possible use of early-phase [F-18]THK5317 and R-1 as proxies for brain perfusion, and thus, for glucose metabolism. Discriminative performance (prodromal vs Alzheimer's disease dementia) of [F-18]THK5317 (early-phase SUVr and R-1) was compared with that of [C-11]PIB (early-phase SUVr and R-1) and [F-18]FDG. Strong positive correlations were found between [F-18]THK5317 (early-phase, R-1) and [F-18]FDG, particularly in frontal and temporoparietal regions. Differences in correlations between early-phase and R-1 ([F-18]THK5317 and [C-11]PIB) and [F-18]FDG, were not statistically significant, nor were differences in area under the curve values in the discriminative analysis. Our findings suggest that early-phase [F-18]THK5317 and R-1 provide information on brain perfusion, closely related to glucose metabolism. As such, a single positron emission tomography study with [F-18]THK5317 may provide information about both tau pathology and brain perfusion in Alzheimer's disease, with potential clinical applications.
|
|
| 8. |
- 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, 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.
|
|
| 9. |
- Boccardi, M., et al.
(författare)
-
The strategic biomarker roadmap for the validation of Alzheimer's diagnostic biomarkers: methodological update
- 2021
-
Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 48, s. 2070-2085
-
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.
|
|
| 10. |
- Leuzy, Antoine, et al.
(författare)
-
In vivo Detection of Alzheimer's Disease.
- 2018
-
Ingår i: The Yale journal of biology and medicine. - 1551-4056 .- 0044-0086. ; 91:3, s. 291-300
-
Forskningsöversikt (refereegranskat)abstract
- Recent revisions to the diagnostic criteria for Alzheimer's disease (AD) incorporated conceptual advances in the field. Specifically, AD is now recognized to encompass a continuum, spanning from preclinical (accruing brain pathology in the absence of symptoms) through symptomatic predementia (prodromal AD, mild cognitive impairment) and dementia phases. The role of biological markers (biomarkers) of both the underlying molecular pathologies and related neurodegenerative changes has also been acknowledged. In this abridged review, we provide an overview of fluid (cerebrospinal fluid and blood) and molecular imaging-based biomarkers used within the field and discuss the potential role of computer driven artificial intelligence approaches for both the early and accurate identification of AD and as a tool for population enrichment in clinical trials testing candidate disease modifying therapies.
|
|
