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| 2. |
- Leuzy, A., et al.
(författare)
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Robustness of CSF A beta 42/40 and A beta 42/P-tau181 measured using fully automated immunoassays to detect AD-related outcomes
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:7, s. 2994-3004
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionThis study investigated the comparability of cerebrospinal fluid (CSF) cutoffs for Elecsys immunoassays for amyloid beta (A beta)42/A beta 40 or A beta 42/phosphorylated tau (p-tau)181 and the effects of measurement variability when predicting Alzheimer's disease (AD)-related outcomes (i.e., A beta-positron emission tomography [PET] visual read and AD neuropathology). MethodsWe studied 750 participants (BioFINDER study, Alzheimer's Disease Neuroimaging Initiative [ADNI], and University of California San Francisco [UCSF]). Youden's index was used to identify cutoffs and to calculate accuracy (A beta-PET visual read as outcome). Using longitudinal variability in A beta-negative controls, we identified a gray zone around cut-points where the risk of an inconsistent predicted outcome was >5%. ResultsFor A beta 42/A beta 40, cutoffs across cohorts were <0.059 (BioFINDER), <0.057 (ADNI), and <0.058 (UCSF). For A beta 42/p-tau181, cutoffs were <41.90 (BioFINDER), <39.20 (ADNI), and <46.02 (UCSF). Accuracy was approximate to 90% for both A beta 42/A beta 40 and A beta 42/p-tau181 using these cutoffs. Using A beta-PET as an outcome, 8.7% of participants fell within a gray zone interval for A beta 42/A beta 40, compared to 4.5% for A beta 42/p-tau181. Similar findings were observed using a measure of overall AD neuropathologic change (7.7% vs. 3.3%). In a subset with CSF and plasma A beta 42/40, the number of individuals within the gray zone was approximate to 1.5 to 3 times greater when using plasma A beta 42/40. DiscussionCSF A beta 42/p-tau181 was more robust to the effects of measurement variability, suggesting that it may be the preferred Elecsys-based measure in clinical practice and trials.
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| 3. |
- Ashton, Nicholas J., et al.
(författare)
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The validation status of blood biomarkers of amyloid and phospho-tau assessed with the 5-phase development framework for AD biomarkers
- 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, s. 2140-2156
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The development of blood biomarkers that reflect Alzheimer's disease (AD) pathophysiology (phosphorylated tau and amyloid-beta) has offered potential as scalable tests for dementia differential diagnosis and early detection. In 2019, the Geneva AD Biomarker Roadmap Initiative included blood biomarkers in the systematic validation of AD biomarkers. Methods A panel of experts convened in November 2019 at a two-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of blood biomarkers was assessed based on the Biomarker Roadmap methodology and discussed fully during the workshop which also evaluated cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers. Results Plasma p-tau has shown analytical validity (phase 2 primary aim 1) and first evidence of clinical validity (phase 3 primary aim 1), whereas the maturity level for A beta remains to be partially achieved. Full and partial achievement has been assigned to p-tau and A beta, respectively, in their associations to ante-mortem measures (phase 2 secondary aim 2). However, only preliminary evidence exists for the influence of covariates, assay comparison and cut-off criteria. Conclusions Despite the relative infancy of blood biomarkers, in comparison to CSF biomarkers, much has already been achieved for phases 1 through 3 - with p-tau having greater success in detecting AD and predicting disease progression. However, sufficient data about the effect of covariates on the biomarker measurement is lacking. No phase 4 (real-world performance) or phase 5 (assessment of impact/cost) aim has been tested, thus not achieved.
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| 4. |
- Cicognola, C., et al.
(författare)
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Associations of CSF PDGFR & beta; With Aging, Blood-Brain Barrier Damage, Neuroinflammation, and Alzheimer Disease Pathologic Changes
- 2023
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Ingår i: NEUROLOGY. - 0028-3878. ; 101:1
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Tidskriftsartikel (refereegranskat)abstract
- Background and ObjectivesInjured pericytes in the neurovascular unit release platelet-derived growth factor & beta; (PDGFR & beta;) into the CSF. However, it is not clear how pericyte injury contributes to Alzheimer disease (AD)-related changes and blood-brain barrier (BBB) damage. We aimed to test whether CSF PDGFR & beta; was associated with different AD-associated and age-associated pathologic changes leading to dementia.MethodsPDGFR & beta; was measured in the CSF of 771 participants with cognitively unimpaired (CU, n = 408), mild cognitive impairment (MCI, n = 175), and dementia (n = 188) from the Swedish BioFINDER-2 cohort. We then checked association with & beta;-amyloid (A & beta;)-PET and tau-PET standardized uptake value ratio, APOE & epsilon;4 genotype and MRI measurements of cortical thickness, white matter lesions (WMLs), and cerebral blood flow. We also analyzed the role of CSF PDGFR & beta; in the relationship between aging, BBB dysfunction (measured by CSF/plasma albumin ratio, QAlb), and neuroinflammation (i.e., CSF levels of YKL-40 and glial fibrillary acidic protein [GFAP], preferentially expressed in reactive astrocytes).ResultsThe cohort had a mean age of 67 years (CU = 62.8, MCI = 69.9, dementia = 70.4), and 50.1% were male (CU = 46.6%, MCI = 53.7%, dementia = 54.3%). Higher CSF PDGFR & beta; concentrations were related to higher age (b = 19.1, & beta; = 0.5, 95% CI 16-22.2, p < 0.001), increased CSF neuroinflammatory markers of glial activation YKL-40 (b = 3.4, & beta; = 0.5, 95% CI 2.8-3.9, p < 0.001), GFAP (b = 27.4, & beta; = 0.4, 95% CI 20.9-33.9, p < 0.001), and worse BBB integrity measured by QAlb (b = 37.4, & beta; = 0.2, 95% CI 24.9-49.9, p < 0.001). Age was also associated with worse BBB integrity, and this was partly mediated by PDGFR & beta; and neuroinflammatory markers (16%-33% of total effect). However, PDGFR & beta; showed no associations with APOE & epsilon;4 genotype, PET imaging of A & beta; and tau pathology, or MRI measures of brain atrophy and WMLs (p > 0.05).DiscussionIn summary, pericyte damage, reflected by CSF PDGFR & beta;, may be involved in age-related BBB disruption together with neuroinflammation, but is not related to Alzheimer-related pathologic changes.
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| 6. |
- Ehrenberg, Alexander J., et al.
(författare)
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Relevance of biomarkers across different neurodegenerative
- 2020
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12
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Forskningsöversikt (refereegranskat)abstract
- Background: The panel of fluid- and imaging-based biomarkers available for neurodegenerative disease research is growing and has the potential to close important gaps in research and the clinic. With this growth and increasing use, appropriate implementation and interpretation are paramount. Various biomarkers feature nuanced differences in strengths, limitations, and biases that must be considered when investigating disease etiology and clinical utility. For example, neuropathological investigations of Alzheimer's disease pathogenesis can fall in disagreement with conclusions reached by biomarker-based investigations. Considering the varied strengths, limitations, and biases of different research methodologies and approaches may help harmonize disciplines within the neurodegenerative disease field. Purpose of review: Along with separate review articles covering fluid and imaging biomarkers in this issue of Alzheimer's Research and Therapy, we present the result of a discussion from the 2019 Biomarkers in Neurodegenerative Diseases course at the University College London. Here, we discuss themes of biomarker use in neurodegenerative disease research, commenting on appropriate use, interpretation, and considerations for implementation across different neurodegenerative diseases. We also draw attention to areas where biomarker use can be combined with other disciplines to understand issues of pathophysiology and etiology underlying dementia. Lastly, we highlight novel modalities that have been proposed in the landscape of neurodegenerative disease research and care.
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| 7. |
- Leuzy, A., et al.
(författare)
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2020 update on the clinical validity of cerebrospinal fluid amyloid, tau, and phospho-tau as biomarkers for Alzheimer's disease in the context of a structured 5-phase development framework
- 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, s. 2121-2139
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Tidskriftsartikel (refereegranskat)abstract
- Purpose In the last decade, the research community has focused on defining reliable biomarkers for the early detection of Alzheimer's disease (AD) pathology. In 2017, the Geneva AD Biomarker Roadmap Initiative adapted a framework for the systematic validation of oncological biomarkers to cerebrospinal fluid (CSF) AD biomarkers-encompassing the 42 amino-acid isoform of amyloid-beta (A beta 42), phosphorylated-tau (P-tau), and Total-tau (T-tau)-with the aim to accelerate their development and clinical implementation. The aim of this work is to update the current validation status of CSF AD biomarkers based on the Biomarker Roadmap methodology. Methods A panel of experts in AD biomarkers convened in November 2019 at a 2-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of CSF AD biomarkers was assessed based on the Biomarker Roadmap methodology before the meeting and presented and discussed during the workshop. Results By comparison to the previous 2017 Geneva Roadmap meeting, the primary advances in CSF AD biomarkers have been in the area of a unified protocol for CSF sampling, handling and storage, the introduction of certified reference methods and materials for A beta 42, and the introduction of fully automated assays. Additional advances have occurred in the form of defining thresholds for biomarker positivity and assessing the impact of covariates on their discriminatory ability. Conclusions Though much has been achieved for phases one through three, much work remains in phases four (real world performance) and five (assessment of impact/cost). To a large degree, this will depend on the availability of disease-modifying treatments for AD, given these will make accurate and generally available diagnostic tools key to initiate therapy.
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| 9. |
- Palmqvist, Sebastian, et al.
(författare)
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Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders
- 2020
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Ingår i: Jama-Journal of the American Medical Association. - : American Medical Association (AMA). - 0098-7484. ; 324:8, s. 772-781
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Tidskriftsartikel (refereegranskat)abstract
- Key PointsQuestionWhat is the discriminative accuracy of plasma phospho-tau217 (P-tau217) for differentiating Alzheimer disease from other neurodegenerative disorders? FindingsIn this cross-sectional study that included 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated Alzheimer disease from other neurodegenerative diseases (area under the receiver operating characteristic curve of 0.89 in a neuropathologically defined cohort and 0.96 in a clinically defined cohort), with performance that was significantly better than established Alzheimer disease plasma- and MRI-based biomarkers but not significantly different from key CSF- or PET-based biomarkers. MeaningAlthough plasma P-tau217 was able to discriminate Alzheimer disease from other neurodegenerative diseases, further research is needed to validate the findings in unselected and diverse populations, optimize the assay, and determine its potential role in clinical care. ImportanceThere are limitations in current diagnostic testing approaches for Alzheimer disease (AD). ObjectiveTo examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD. Design, Setting, and ParticipantsThree cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n=301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n=178), AD dementia (n=121), and other neurodegenerative diseases (n=99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017). ExposuresPlasma P-tau217. Main Outcomes and MeasuresPrimary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography [PET]). ResultsMean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve [AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P<.05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 [95% CI, 0.93-0.98]) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P<.001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P>.15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman rho =0.64; P<.001), but not without (Spearman =0.15; P=.33), beta -amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 [95% CI, 0.91-0.96]) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF A beta 42:A beta 40 ratio, and MRI measures (AUC range, 0.67-0.90; P<.05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P=.22). Conclusions and RelevanceAmong 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care. This cross-sectional study compares the accuracy of plasma tau phosphorylated at threonine 217 (P-tau217) levels vs other plasma-, MRI-, CSF-, and PET-based markers for distinguishing Alzheimer from other neurodegenerative diseases in 3 cohorts in Arizona, Sweden, and Columbia with or at risk for dementia.
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| 10. |
- Provost, Karine, et al.
(författare)
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Comparing ATN-T designation by tau PET visual reads, tau PET quantification, and CSF PTau181 across three cohorts
- 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. ; 48:7, s. 2259-2271
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To compare rates of tau biomarker positivity (T-status) per the 2018 Alzheimer’s Disease (AD) Research Framework derived from [18F]flortaucipir (FTP) PET visual assessment, FTP quantification, and cerebrospinal fluid (CSF) phosphorylated Tau-181 (PTau181). Methods: We included 351 subjects with varying clinical diagnoses from three cohorts with available FTP PET and CSF PTau181 within 18 months. T-status was derived from (1) FTP visual assessment by two blinded raters; (2) FTP standardized uptake value ratio (SUVR) quantification from a temporal meta-ROI (threshold: SUVR ≥1.27); and (3) Elecsys® Phospho-Tau (181P) CSF (Roche Diagnostics) concentrations (threshold: PTau181 ≥ 24.5 pg/mL). Results: FTP visual reads yielded the highest rates of T+, while T+ by SUVR increased progressively from cognitively normal (CN) through mild cognitive impairment (MCI) and AD dementia. T+ designation by CSF PTau181 was intermediate between FTP visual reads and SUVR values in CN, similar to SUVR in MCI, and lower in AD dementia. Concordance in T-status between modality pairs ranged from 68 to 76% and varied by clinical diagnosis, being highest in patients with AD dementia. In discriminating Aβ + MCI and AD subjects from healthy controls and non-AD participants, FTP visual assessment was most sensitive (0.96) but least specific (0.60). Specificity was highest with FTP SUVR (0.91) with sensitivity of 0.89. Sensitivity (0.73) and specificity (0.72) were balanced for PTau181. Conclusion: The choice of tau biomarker may differ by disease stage and research goals that seek to maximize sensitivity or specificity. Visual interpretations of tau PET enhance sensitivity compared to quantification alone, particularly in early disease stages.
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