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- 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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| 2. |
- Leuzy, Antoine, et al.
(författare)
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In vivo Detection of Alzheimer's Disease.
- 2018
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Ingår i: The Yale journal of biology and medicine. - 1551-4056 .- 0044-0086. ; 91:3, s. 291-300
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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.
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| 3. |
- Leuzy, Antoine, et al.
(författare)
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Longitudinal uncoupling of cerebral perfusion, glucose metabolism, and tau deposition in Alzheimer's disease
- 2018
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14:5, s. 652-663
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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.
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