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- Frisoni, G. B., et al.
(författare)
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Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers
- 2017
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Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 16:8, s. 661-676
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Tidskriftsartikel (refereegranskat)abstract
- The diagnosis of Alzheimer's disease can be improved by the use of biological measures. Biomarkers of functional impairment, neuronal loss, and protein deposition that can be assessed by neuroimaging (ie, MRI and PET) or CSF analysis are increasingly being used to diagnose Alzheimer's disease in research studies and specialist clinical settings. However, the validation of the clinical usefulness of these biomarkers is incomplete, and that is hampering reimbursement for these tests by health insurance providers, their widespread clinical implementation, and improvements in quality of health care. We have developed a strategic five-phase roadmap to foster the clinical validation of biomarkers in Alzheimer's disease, adapted from the approach for cancer biomarkers. Sufficient evidence of analytical validity (phase 1 of a structured framework adapted from oncology) is available for all biomarkers, but their clinical validity (phases 2 and 3) and clinical utility (phases 4 and 5) are incomplete. To complete these phases, research priorities include the standardisation of the readout of these assays and thresholds for normality, the evaluation of their performance in detecting early disease, the development of diagnostic algorithms comprising combinations of biomarkers, and the development of clinical guidelines for the use of biomarkers in qualified memory clinics.
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| 5. |
- Leuzy, A., et al.
(författare)
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Longitudinal tau and metabolic PET imaging in relation to novel CSF tau measures in Alzheimer's disease
- 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. ; 46:5, s. 1152-1163
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Studies comparing CSF and PET tau biomarkers have included only commercial CSF assays examining specific phosphorylation sites (e.g. threonine 181, P-tau(181p)) and mid-domain tau (i.e. total tau, T-tau). Moreover, these studies did not examine CSF tau levels in relation to cerebral glucose metabolism. We thus aimed to examine CSF tau measures, using both commercial and novel assays, in relation to [F-18]THK5317 (tau) and [F-18]FDG PET (glucose metabolism). Methods Fourteen Alzheimer's disease (AD) patients (seven prodromal, seven dementia) underwent [F-18]THK5317 and [F-18]FDG PET studies, with follow-up performed in ten subjects (six prodromal, four dementia) after 17 months. In addition to commercial assays, novel measures capturing N-terminus+mid-domain (tau N-Mid) and C-terminally truncated (tau-368) fragments were included. Results While the levels of all forms of CSF tau were found to be inversely associated with baseline [F-18]FDG uptake, associations with baseline [F-18]THK5317 uptake varied in relation to the degree of isocortical hypometabolism ([F-18]FDG SUVR). Changes in the levels of the novel CSF markers tracked longitudinal changes in tracer uptake better than changes in P-tau(181p) and T-tau levels, and improved concordance with dichotomized regional [F-18]THK5317 measures. Conclusion Our findings suggest that neurodegeneration may modulate the relationship between CSF and PET tau biomarkers, and that, by comparison to P-tau(181p) and T-tau, tau-368 and tau N-Mid may better capturetau pathology and synaptic impairment.
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- 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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| 9. |
- Bucci, M, et al.
(författare)
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Alzheimer's disease profiled by fluid and imaging markers: tau PET best predicts cognitive decline
- 2021
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 26:10, s. 5888-5898
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Tidskriftsartikel (refereegranskat)abstract
- For early detection of Alzheimer’s disease, it is important to find biomarkers with predictive value for disease progression and clinical manifestations, such as cognitive decline. Individuals can now be profiled based on their biomarker status for Aβ42 (A) or tau (T) deposition and neurodegeneration (N). The aim of this study was to compare the cerebrospinal fluid (CSF) and imaging (PET/MR) biomarkers in each ATN category and to assess their ability to predict longitudinal cognitive decline. A subset of 282 patients, who had had at the same time PET investigations with amyloid-β and tau tracers, CSF sampling, and structural MRI (18% within 13 months), was selected from the ADNI dataset. The participants were grouped by clinical diagnosis at that time: cognitively normal, subjective memory concern, early or late mild cognitive impairment, or AD. Agreement between CSF (amyloid-β-1-42(A), phosphorylated-Tau181(T), total-Tau(N)), and imaging (amyloid-β PET (florbetaben and florbetapir)(A), tau PET (flortaucipir)(T), hippocampal volume (MRI)(N)) positivity in ATN was assessed with Cohen’s Kappa. Linear mixed-effects models were used to predict decline in the episodic memory. There was moderate agreement between PET and CSF for A biomarkers (Kappa = 0.39–0.71), while only fair agreement for T biomarkers (Kappa ≤ 0.40, except AD) and discordance for N biomarkers across all groups (Kappa ≤ 0.14) was found. Baseline PET tau predicted longitudinal decline in episodic memory irrespective of CSF p-Tau181 positivity (p ≤ 0.02). Baseline PET tau and amyloid-β predicted decline in episodic memory (p ≤ 0.0001), but isolated PET amyloid-β did not. Isolated PET Tau positivity was only observed in 2 participants (0.71% of the sample). While results for amyloid-β were similar using CSF or imaging, CSF and imaging results for tau and neurodegeneration were not interchangeable. PET tau positivity was superior to CSF p-Tau181 and PET amyloid-β in predicting cognitive decline in the AD continuum within 3 years of follow-up.
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| 10. |
- Bucci, M., et al.
(författare)
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Profiling of plasma biomarkers in the context of memory assessment in a tertiary memory clinic
- 2023
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Ingår i: Translational Psychiatry. - 2158-3188. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Plasma biomarkers have shown promising performance in research cohorts in discriminating between different stages of Alzheimer's disease (AD). Studies in clinical populations are necessary to provide insights on the clinical utility of plasma biomarkers before their implementation in real-world settings. Here we investigated plasma biomarkers (glial fibrillary acidic protein (GFAP), tau phosphorylated at 181 and 231 (pTau181, pTau231), amyloid & beta; (A & beta;) 42/40 ratio, neurofilament light) in 126 patients (age = 65 & PLUSMN; 8) who were admitted to the Clinic for Cognitive Disorders, at Karolinska University Hospital. After extensive clinical assessment (including CSF analysis), patients were classified as: mild cognitive impairment (MCI) (n = 75), AD (n = 25), non-AD dementia (n = 16), no dementia (n = 9). To refine the diagnosis, patients were examined with [F-18]flutemetamol PET (A & beta;-PET). A & beta;-PET images were visually rated for positivity/negativity and quantified in Centiloid. Accordingly, 68 A & beta;+ and 54 A & beta;- patients were identified. Plasma biomarkers were measured using single molecule arrays (SIMOA). Receiver-operated curve (ROC) analyses were performed to detect A & beta;-PET+ using the different biomarkers. In the whole cohort, the A & beta;-PET centiloid values correlated positively with plasma GFAP, pTau231, pTau181, and negatively with A & beta;42/40 ratio. While in the whole MCI group, only GFAP was associated with A & beta; PET centiloid. In ROC analyses, among the standalone biomarkers, GFAP showed the highest area under the curve discriminating A & beta;+ and A & beta;- compared to other plasma biomarkers. The combination of plasma biomarkers via regression was the most predictive of A & beta;-PET, especially in the MCI group (prior to PET, n = 75) (sensitivity = 100%, specificity = 82%, negative predictive value = 100%). In our cohort of memory clinic patients (mainly MCI), the combination of plasma biomarkers was sensitive in ruling out A & beta;-PET negative individuals, thus suggesting a potential role as rule-out tool in clinical practice.
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