| 1. |
- Brum, Wagner S., et al.
(författare)
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A two-step workflow based on plasma p-tau217 to screen for amyloid β positivity with further confirmatory testing only in uncertain cases
- 2023
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Ingår i: Nature Aging. - 2662-8465. ; 3:9, s. 1079-1090
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Tidskriftsartikel (refereegranskat)abstract
- Cost-effective strategies for identifying amyloid-beta (A beta) positivity in patients with cognitive impairment are urgently needed with recent approvals of anti-A beta immunotherapies for Alzheimer's disease (AD). Blood biomarkers can accurately detect AD pathology, but it is unclear whether their incorporation into a full diagnostic workflow can reduce the number of confirmatory cerebrospinal fluid (CSF) or positron emission tomography (PET) tests needed while accurately classifying patients. We evaluated a two-step workflow for determining A beta-PET status in patients with mild cognitive impairment (MCI) from two independent memory clinic-based cohorts (n = 348). A blood-based model including plasma tau protein 217 (p-tau217), age and APOE epsilon 4 status was developed in BioFINDER-1 (area under the curve (AUC) = 89.3%) and validated in BioFINDER-2 (AUC = 94.3%). In step 1, the blood-based model was used to stratify the patients into low, intermediate or high risk of A beta-PET positivity. In step 2, we assumed referral only of intermediate-risk patients to CSF A beta 42/A beta 40 testing, whereas step 1 alone determined A beta-status for low-and high-risk groups. Depending on whether lenient, moderate or stringent thresholds were used in step 1, the two-step workflow overall accuracy for detecting A beta-PET status was 88.2%, 90.5% and 92.0%, respectively, while reducing the number of necessary CSF tests by 85.9%, 72.7% and 61.2%, respectively. In secondary analyses, an adapted version of the BioFINDER-1 model led to successful validation of the two-step workflow with a different plasma p-tau217 immunoassay in patients with cognitive impairment from the TRIAD cohort (n = 84). In conclusion, using a plasma p-tau217-based model for risk stratification of patients with MCI can substantially reduce the need for confirmatory testing while accurately classifying patients, offering a cost-effective strategy to detect AD in memory clinic settings.
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| 2. |
- Cullen, Nicholas C., et al.
(författare)
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Individualized prognosis of cognitive decline and dementia in mild cognitive impairment based on plasma biomarker combinations
- 2021
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Ingår i: Nature Aging. - : Springer Science and Business Media LLC. - 2662-8465. ; 1, s. 114-123
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Tidskriftsartikel (refereegranskat)abstract
- We developed models for individualized risk prediction of cognitive decline in mild cognitive impairment (MCI) using plasma biomarkers of β-amyloid (Aβ), tau and neurodegeneration. A total of 573 patients with MCI from the Swedish BioFINDER study and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included in the study. The primary outcomes were longitudinal cognition and conversion to Alzheimer’s disease (AD) dementia. A model combining tau phosphorylated at threonine 181 (P-tau181) and neurofilament light (NfL), but not Aβ42/Aβ40, had the best prognosis performance of all models (area under the curve = 0.88 for 4-year conversion to AD in BioFINDER, validated in ADNI), was stronger than a basic model of age, sex, education and baseline cognition, and performed similarly to cerebrospinal fluid biomarkers. A publicly available online tool for individualized prognosis in MCI based on our combined plasma biomarker models is introduced. Combination of plasma biomarkers may be of high value to identify individuals with MCI who will progress to AD dementia in clinical trials and in clinical practice.
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| 3. |
- Scheeren Brum, Wagner, 1997, et al.
(författare)
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A blood-based biomarker workflow for optimal tau-PET referral in memory clinic settings.
- 2024
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Ingår i: Nature communications. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Blood-based biomarkers for screening may guide tau positrion emissition tomography (PET) scan referrals to optimize prognostic evaluation in Alzheimer's disease. Plasma Aβ42/Aβ40, pTau181, pTau217, pTau231, NfL, and GFAP were measured along with tau-PET in memory clinic patients with subjective cognitive decline, mild cognitive impairment or dementia, in the Swedish BioFINDER-2 study (n=548) and in the TRIAD study (n=179). For each plasma biomarker, cutoffs were determined for 90%, 95%, or 97.5% sensitivity to detect tau-PET-positivity. We calculated the percentage of patients below the cutoffs (who would not undergo tau-PET; "saved scans") and the tau-PET-positivity rate among participants above the cutoffs (who would undergo tau-PET; "positive predictive value"). Generally, plasma pTau217 performed best. At the 95% sensitivity cutoff in both cohorts, pTau217 resulted in avoiding nearly half tau-PET scans, with a tau-PET-positivity rate among those who would be referred for a scan around 70%. And although tau-PET was strongly associated with subsequent cognitive decline, in BioFINDER-2 it predicted cognitive decline only among individuals above the referral cutoff on plasma pTau217, supporting that this workflow could reduce prognostically uninformative tau-PET scans. In conclusion, plasma pTau217 may guide selection of patients for tau-PET, when accurate prognostic information is of clinical value.
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| 4. |
- Sumaila, U. Rashid, et al.
(författare)
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WTO must ban harmful fisheries subsidies
- 2021
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 374:6567, s. 544-544
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 5. |
- Tustison, Nicholas J., et al.
(författare)
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The ANTsX ecosystem for quantitative biological and medical imaging
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 9068-9068
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Tidskriftsartikel (refereegranskat)abstract
- The Advanced Normalizations Tools ecosystem, known as ANTsX, consists of multiple open-source software libraries which house top-performing algorithms used worldwide by scientific and research communities for processing and analyzing biological and medical imaging data. The base software library, ANTs, is built upon, and contributes to, the NIH-sponsored Insight Toolkit. Founded in 2008 with the highly regarded Symmetric Normalization image registration framework, the ANTs library has since grown to include additional functionality. Recent enhancements include statistical, visualization, and deep learning capabilities through interfacing with both the R statistical project (ANTsR) and Python (ANTsPy). Additionally, the corresponding deep learning extensions ANTsRNet and ANTsPyNet (built on the popular TensorFlow/Keras libraries) contain several popular network architectures and trained models for specific applications. One such comprehensive application is a deep learning analog for generating cortical thickness data from structural T1-weighted brain MRI, both cross-sectionally and longitudinally. These pipelines significantly improve computational efficiency and provide comparable-to-superior accuracy over multiple criteria relative to the existing ANTs workflows and simultaneously illustrate the importance of the comprehensive ANTsX approach as a framework for medical image analysis.
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| 6. |
- Alifier, Marek, et al.
(författare)
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Cardiac Surgery is Associated with Biomarker Evidence of Neuronal Damage.
- 2020
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 74:4, s. 1211-1220
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Tidskriftsartikel (refereegranskat)abstract
- Anesthesia and surgery is commonly associated with central nervous system sequelae and cognitive symptoms, which may be caused by neuronal injury. Neuronal injury can be monitored by plasma concentrations of the neuronal biomarkers tau and neurofilament light protein (NFL). Currently, there are no studies examining whether neuronal injury varies between surgical procedures.Our aim was to investigate if neuronal damage is more frequent after cardiac than after otolaryngeal surgery, as estimated by tau and NFL concentrations in plasma.Blood samples were drawn before, during, and after surgery and concentrations of tau, NFL, Aβ40, and Aβ42 were measured in 25 patients undergoing cardiac surgery (9 off-pump and 16 on-pump) and 26 patients undergoing otolaryngeal surgery.Tau increased during surgery (1752%, p=0.0001) and NFL rose seven days post-surgery (1090%, p<0.0001) in patients undergoing cardiac surgery; even more in patients on-pump than off-pump. No changes were observed in patients undergoing otolaryngeal surgery and only minor fluctuations were observed for Aβ40 and Aβ42.Cardiac surgery is associated with neuronal injury, which is aggravated by extracorporeal circulation. Analyses of NFL and tau in blood may guide development of surgical procedures to minimize neuronal damage, and may also be used in longitudinal clinical studies to assess the relationship of surgery with future neurocognitive impairment or dementia.
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| 7. |
- Arvidsson, Ida, et al.
(författare)
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Comparing a pre-defined versus deep learning approach for extracting brain atrophy patterns to predict cognitive decline due to Alzheimer’s disease in patients with mild cognitive symptoms
- 2024
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Ingår i: Alzheimer's Research and Therapy. - 1758-9193. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Predicting future Alzheimer’s disease (AD)-related cognitive decline among individuals with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) is an important task for healthcare. Structural brain imaging as measured by magnetic resonance imaging (MRI) could potentially contribute when making such predictions. It is unclear if the predictive performance of MRI can be improved using entire brain images in deep learning (DL) models compared to using pre-defined brain regions. Methods: A cohort of 332 individuals with SCD/MCI were included from the Swedish BioFINDER-1 study. The goal was to predict longitudinal SCD/MCI-to-AD dementia progression and change in Mini-Mental State Examination (MMSE) over four years. Four models were evaluated using different predictors: (1) clinical data only, including demographics, cognitive tests and APOE ε4 status, (2) clinical data plus hippocampal volume, (3) clinical data plus all regional MRI gray matter volumes (N = 68) extracted using FreeSurfer software, (4) a DL model trained using multi-task learning with MRI images, Jacobian determinant images and baseline cognition as input. A double cross-validation scheme, with five test folds and for each of those ten validation folds, was used. External evaluation was performed on part of the ADNI dataset, including 108 patients. Mann-Whitney U-test was used to determine statistically significant differences in performance, with p-values less than 0.05 considered significant. Results: In the BioFINDER cohort, 109 patients (33%) progressed to AD dementia. The performance of the clinical data model for prediction of progression to AD dementia was area under the curve (AUC) = 0.85 and four-year cognitive decline was R2 = 0.14. The performance was improved for both outcomes when adding hippocampal volume (AUC = 0.86, R2 = 0.16). Adding FreeSurfer brain regions improved prediction of four-year cognitive decline but not progression to AD (AUC = 0.83, R2 = 0.17), while the DL model worsened the performance for both outcomes (AUC = 0.84, R2 = 0.08). A sensitivity analysis showed that the Jacobian determinant image was more informative than the MRI image, but that performance was maximized when both were included. In the external evaluation cohort from ADNI, 23 patients (21%) progressed to AD dementia. The results for predicted progression to AD dementia were similar to the results for the BioFINDER test data, while the performance for the cognitive decline was deteriorated. Conclusions: The DL model did not significantly improve the prediction of clinical disease progression in AD, compared to regression models with a single pre-defined brain region.
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| 8. |
- Borland, Emma, et al.
(författare)
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Clinically Relevant Changes for Cognitive Outcomes in Preclinical and Prodromal Cognitive Stages : Implications for Clinical Alzheimer Trials
- 2022
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Ingår i: Neurology. - 0028-3878. ; 99:11, s. 1142-1153
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Tidskriftsartikel (refereegranskat)abstract
- Background and ObjectivesIdentifying a clinically meaningful change in cognitive test score is essential when using cognition as an outcome in clinical trials. This is especially relevant because clinical trials increasingly feature novel composites of cognitive tests. Our primary objective was to establish minimal clinically important differences (MCIDs) for commonly used cognitive tests, using anchor-based and distribution-based methods, and our secondary objective was to investigate a composite cognitive measure that best predicts a minimal change in the Clinical Dementia Rating - Sum of Boxes (CDR-SB).MethodsFrom the Swedish BioFINDER cohort study, we consecutively included cognitively unimpaired (CU) individuals with and without subjective or mild cognitive impairment (MCI). We calculated MCIDs associated with a change of ≥0.5 or ≥1.0 on CDR-SB for Mini-Mental State Examination (MMSE), ADAS-Cog delayed recall 10-word list, Stroop, Letter S Fluency, Animal Fluency, Symbol Digit Modalities Test (SDMT) and Trailmaking Test (TMT) A and B, and triangulated MCIDs for clinical use for CU, MCI, and amyloid-positive CU participants. For investigating cognitive measures that best predict a change in CDR-SB of ≥0.5 or ≥1.0 point, we conducted receiver operating characteristic analyses.ResultsOur study included 451 cognitively unimpaired individuals, 90 with subjective cognitive decline and 361 without symptoms of cognitive decline (pooled mean follow-up time 32.4 months, SD 26.8, range 12-96 months), and 292 people with MCI (pooled mean follow-up time 19.2 months, SD 19.0, range 12-72 months). We identified potential triangulated MCIDs (cognitively unimpaired; MCI) on a range of cognitive test outcomes: MMSE -1.5, -1.7; ADAS delayed recall 1.4, 1.1; Stroop 5.5, 9.3; Animal Fluency: -2.8, -2.9; Letter S Fluency -2.9, -1.8; SDMT: -3.5, -3.8; TMT A 11.7, 13.0; and TMT B 24.4, 20.1. For amyloid-positive CU, we found the best predicting composite cognitive measure included gender and changes in ADAS delayed recall, MMSE, SDMT, and TMT B. This produced an AUC of 0.87 (95% CI 0.79-0.94, sensitivity 75%, specificity 88%).DiscussionOur MCIDs may be applied in clinical practice or clinical trials for identifying whether a clinically relevant change has occurred. The composite measure can be useful as a clinically relevant cognitive test outcome in preclinical AD trials.
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| 9. |
- Conti, David, V, et al.
(författare)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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| 10. |
- Cullen, Nicholas, et al.
(författare)
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Association of CSF Aβ38Levels with Risk of Alzheimer Disease-Related Decline
- 2022
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Ingår i: Neurology. - 0028-3878. ; 98:9, s. 958-967
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Tidskriftsartikel (refereegranskat)abstract
- Background and ObjectiveExperimental studies suggest that the balance between short and long β-amyloid (Aβ) species might modulate the toxic effects of Aβ in Alzheimer disease (AD), but clinical evidence is lacking. We studied whether Aβ38 levels in CSF relate to risk of AD dementia and cognitive decline.MethodsCSF Aβ38 levels were measured in 656 individuals across 2 clinical cohorts: the Swedish BioFINDER study and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cox regression models were used to evaluate the association between baseline Aβ38 levels and risk of AD dementia in AD biomarker-positive individuals (AD+; determined by CSF phosphorylated tau [P-tau]/Aβ42 ratio) with subjective cognitive decline (SCD) or mild cognitive impairment (MCI). Linear mixed-effects models were used to evaluate the association between baseline Aβ38 levels and cognitive decline as measured by the Mini-Mental State Examination (MMSE) in AD+ participants with SCD, MCI, or AD dementia.ResultsIn the BioFINDER cohort, high Aβ38 levels were associated with slower decline in MMSE score (β = 0.30 points per SD, p = 0.001) and with lower risk of conversion to AD dementia (hazard ratio 0.83 per SD, p = 0.03). In the ADNI cohort, higher Aβ38 levels were associated with less decline in MMSE score (β = 0.27, p = 0.01) but not risk of conversion to AD dementia (p = 0.66). Aβ38 levels in both cohorts were significantly associated with both cognitive and clinical outcomes when further adjusted for CSF P-tau or CSF Aβ42 levels.DiscussionHigher CSF Aβ38 levels are associated with lower risk of AD-related changes in 2 independent clinical cohorts. These findings suggest that γ-secretase modulators could be effective as disease-altering therapy.Trial Registration InformationClinicalTrials.gov Identifier: NCT03174938.
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| 11. |
- Cullen, Nicholas C., et al.
(författare)
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Accelerated inflammatory aging in Alzheimer’s disease and its relation to amyloid, tau, and cognition
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- It is unclear how pathological aging of the inflammatory system relates to Alzheimer’s disease (AD). We tested whether age-related inflammatory changes in cerebrospinal fluid (CSF) and plasma exist across different stages of AD, and whether such changes related to AD pathology. Linear regression was first used model chronological age in amyloid-β negative, cognitively unimpaired individuals (Aβ− CU; n = 312) based on a collection of 73 inflammatory proteins measured in both CSF and plasma. Fitted models were then applied on protein levels from Aβ+ individuals with mild cognitive impairment (Aβ+ MCI; n = 150) or Alzheimer’s disease dementia (Aβ+ AD; n = 139) to test whether the age predicted from proteins alone (“inflammatory age”) differed significantly from true chronological age. Aβ− individuals with subjective cognitive decline (Aβ− SCD; n = 125) or MCI (Aβ− MCI; n = 104) were used as an independent contrast group. The difference between inflammatory age and chronological age (InflammAGE score) was then assessed in relation to core AD biomarkers of amyloid, tau, and cognition. Both CSF and plasma inflammatory proteins were significantly associated with age in Aβ− CU individuals, with CSF-based proteins predicting chronological age better than plasma-based counterparts. Meanwhile, the Aβ− SCD and validation Aβ− CU groups were not characterized by significant inflammatory aging, while there was increased inflammatory aging in Aβ− MCI patients for CSF but not plasma inflammatory markers. Both CSF and plasma inflammatory changes were seen in the Aβ+ MCI and Aβ+ AD groups, with varying degrees of change compared to Aβ− CU and Aβ− SCD groups. Finally, CSF inflammatory changes were highly correlated with amyloid, tau, general neurodegeneration, and cognition, while plasma changes were mostly associated with amyloid and cognition. Inflammatory pathways change during aging and are specifically altered in AD, tracking closely with pathological hallmarks. These results have implications for tracking AD progression and for suggesting possible pathways for drug targeting.
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| 12. |
- Cullen, Nicholas C., et al.
(författare)
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Comparing progression biomarkers in clinical trials of early Alzheimer's disease
- 2020
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Ingår i: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 7:9, s. 1661-1673
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the statistical power of plasma, imaging, and cognition biomarkers as Alzheimer's disease (AD) clinical trial outcome measures. Methods: Plasma neurofilament light, structural magnetic resonance imaging, and cognition were measured longitudinally in the Alzheimer's Disease Neuroimaging Initiative (ADNI) in control (amyloid PET or CSF A beta 42 negative [A beta-] with Clinical Dementia Rating scale [CDR] = 0; n = 330), preclinical AD (A beta + with CDR = 0; n = 218) and mild AD (A beta + with CDR = 0.5-1; n = 697) individuals. A statistical power analysis was performed across biomarkers and groups based on longitudinal mixed effects modeling and using several different clinical trial designs. Results: For a 30-month trial of preclinical AD, both the temporal composite and hippocampal volumes were superior to plasma neurofilament light and cognition. For an 18-month trial of mild AD, hippocampal volume was superior to all other biomarkers. Plasma neurofilament light became more effective with increased trial duration or sampling frequency. Imaging biomarkers were characterized by high slope and low within-subject variability, while plasma neurofilament light and cognition were characterized by higher within-subject variability. Interpretation: MRI measures had properties that made them preferable to cognition and pNFL as outcome measures in clinical trials of early AD, regardless of cognitive status. However, pNfL and cognition can still be effective depending on inclusion criteria, sampling frequency, and response to therapy. Future trials will help to understand how sensitive pNfL and MRI are to detect downstream effects on neurodegeneration of drugs targeting amyloid and tau pathology in AD.
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| 13. |
- Cullen, Nicholas C., et al.
(författare)
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Efficacy assessment of an active tau immunotherapy in Alzheimer's disease patients with amyloid and tau pathology : a post hoc analysis of the “ADAMANT” randomised, placebo-controlled, double-blind, multi-centre, phase 2 clinical trial
- 2024
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Ingår i: EBioMedicine. - 2352-3964. ; 99
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Tidskriftsartikel (refereegranskat)abstract
- Background: Tau pathology correlates with and predicts clinical decline in Alzheimer's disease. Approved tau-targeted therapies are not available. Methods: ADAMANT, a 24-month randomised, placebo-controlled, parallel-group, double-blinded, multicenter, Phase 2 clinical trial (EudraCT2015-000630-30, NCT02579252) enrolled 196 participants with Alzheimer's disease; 119 are included in this post-hoc subgroup analysis. AADvac1, active immunotherapy against pathological tau protein. A machine learning model predicted likely Amyloid+Tau+ participants from baseline MRI. Statistical methods: MMRM for change from baseline in cognition, function, and neurodegeneration; linear regression for associations between antibody response and endpoints. Results: The prediction model achieved PPV of 97.7% for amyloid, 96.2% for tau. 119 participants in the full analysis set (70 treatment and 49 placebo) were classified as A+T+. A trend for CDR-SB 104-week change (estimated marginal means [emm] = −0.99 points, 95% CI [−2.13, 0.13], p = 0.0825]) and ADCS-MCI-ADL (emm = 3.82 points, CI [−0.29, 7.92], p = 0.0679) in favour of the treatment group was seen. Reduction was seen in plasma NF-L (emm = −0.15 log pg/mL, CI [−0.27, −0.03], p = 0.0139). Higher antibody response to AADvac1 was related to slowing of decline on CDR-SB (rho = −0.10, CI [−0.21, 0.01], p = 0.0376) and ADL (rho = 0.15, CI [0.03, 0.27], p = 0.0201), and related to slower brain atrophy (rho = 0.18–0.35, p < 0.05 for temporal volume, whole cortex, and right and left hippocampus). Conclusions: In the subgroup of ML imputed or CSF identified A+T+, AADvac1 slowed AD-related decline in an antibody-dependent manner. Larger anti-tau trials are warranted. Funding: AXON Neuroscience SE.
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| 14. |
- Cullen, Nicholas C., et al.
(författare)
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Plasma amyloid-β42/40 and apolipoprotein E for amyloid PET pre-screening in secondary prevention trials of Alzheimer's disease
- 2023
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Ingår i: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 5:2
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Tidskriftsartikel (refereegranskat)abstract
- The extent to which newly developed blood-based biomarkers could reduce screening costs in secondary prevention trials of Alzheimer's disease is mostly unexplored. We collected plasma amyloid-β42/40, apolipoprotein E ϵ4 status and amyloid PET at baseline in 181 cognitively unimpaired participants [the age of 72.9 (5.3) years; 61.9% female; education of 11.9 (3.4) years] from the Swedish BioFINDER-1 study. We tested whether a model predicting amyloid PET status from plasma amyloid-β42/40, apolipoprotein E status and age (combined) reduced cost of recruiting amyloid PET + cognitively unimpaired participants into a theoretical trial. We found that the percentage of cognitively unimpaired participants with an amyloid PET + scan rose from 29% in an unscreened population to 64% [(49, 79); P < 0.0001] when using the biomarker model to screen for high risk for amyloid PET + status. In simulations, plasma screening also resulted in a 54% reduction of the total number of amyloid PET scans required and reduced total recruitment costs by 43% [(31, 56), P < 0.001] compared to no pre-screening when assuming a 16× PET-to-plasma cost ratio. Total savings remained significant when the PET-to-plasma cost ratio was assumed to be 8× or 4×. This suggests that a simple plasma biomarker model could lower recruitment costs in Alzheimer's trials requiring amyloid PET positivity for inclusion.
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| 15. |
- Cullen, Nicholas C., et al.
(författare)
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Plasma biomarkers of Alzheimer’s disease improve prediction of cognitive decline in cognitively unimpaired elderly populations
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Plasma biomarkers of amyloid, tau, and neurodegeneration (ATN) need to be characterized in cognitively unimpaired (CU) elderly individuals. We therefore tested if plasma measurements of amyloid-β (Aβ)42/40, phospho-tau217 (P-tau217), and neurofilament light (NfL) together predict clinical deterioration in 435 CU individuals followed for an average of 4.8 ± 1.7 years in the BioFINDER study. A combination of all three plasma biomarkers and basic demographics best predicted change in cognition (Pre-Alzheimer’s Clinical Composite; R2 = 0.14, 95% CI [0.12–0.17]; P < 0.0001) and subsequent AD dementia (AUC = 0.82, 95% CI [0.77–0.91], P < 0.0001). In a simulated clinical trial, a screening algorithm combining all three plasma biomarkers would reduce the required sample size by 70% (95% CI [54–81]; P < 0.001) with cognition as trial endpoint, and by 63% (95% CI [53–70], P < 0.001) with subsequent AD dementia as trial endpoint. Plasma ATN biomarkers show usefulness in cognitively unimpaired populations and could make large clinical trials more feasible and cost-effective.
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| 16. |
- Cullen, Nicholas C., et al.
(författare)
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Test-retest variability of plasma biomarkers in Alzheimer's disease and its effects on clinical prediction models
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:3, s. 797-806
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION The effect of random error on the performance of blood-based biomarkers for Alzheimer's disease (AD) must be determined before clinical implementation. METHODS We measured test-retest variability of plasma amyloid beta (A beta)42/A beta 40, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau (p-tau)217 and simulated effects of this variability on biomarker performance when predicting either cerebrospinal fluid (CSF) A beta status or conversion to AD dementia in 399 non-demented participants with cognitive symptoms. RESULTS Clinical performance was highest when combining all biomarkers. Among single-biomarkers, p-tau217 performed best. Test-retest variability ranged from 4.1% (A beta 42/A beta 40) to 25% (GFAP). This variability reduced the performance of the biomarkers (approximate to Delta AUC [area under the curve] -1% to -4%) with the least effects on models with p-tau217. The percent of individuals with unstable predicted outcomes was lowest for the multi-biomarker combination (14%). DISCUSSION Clinical prediction models combining plasma biomarkers-particularly p-tau217-exhibit high performance and are less effected by random error. Individuals with unstable predicted outcomes ("gray zone") should be recommended for further tests.
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| 17. |
- Cullen, Nicholas
(författare)
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The future of clinical trials for Alzheimer's disease. A blood-based biomarker perspective
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Objectives: The primary objective was to investigate the utility of blood-basedbiomarkers of amyloid, tau, and neurodegeneration for (i) screening, (ii)enrichment, and (iii) tracking response to treatment in clinical trials of Alzheimer’sdisease.Methods: Longitudinal, participant-level data used in these studies was drawn fromthe Swedish BioFINDER study and the ADNI study. Participants were classified ascognitively unimpaired, mild cognitive impairment, or Alzheimer’s diseasedementia. For screening, logistic regression was used to predict amyloid PET statusin CU individuals from plasma Aβ42/Aβ40, APOE status, and age. For enrichment,Linear mixed effects models were used to predict longitudinal cognitive decline andfuture risk of AD dementia in CU individuals or in MCI individuals from a basicmodel (age, sex, education, APOE status) and varying combinations of blood-basedbiomarkers (plasma Aβ42/Aβ40, plasma pTau181, plasma pTau217, plasma NfL).For treatment response, plasma NfL was measured longitudinally in MCI or ADpatients and properties such as slope, inter-subject variability, and intra-subjectvariability were calculated. Plasma NfL was then compared with MRI andcognition.Results: The amyloid PET screening model had an AUC of 0.87, with a significantindependent effect for plasma Aβ42/Aβ40 and APOE status, but not age. This modelwas estimated to reduce total cost of recruiting 500 amyloid-positive CUparticipants by 31 – 42%, depending on the relative cost of amyloid scanning toplasma measurement. For enrichment, plasma pTau181 and pTau217 had the largesteffect on predicting cognitive decline in CU and MCI participants, with Aβ42/Aβ40and NfL having significant effects in some scenarios. Using these biomarkers in aclinical trial could reduce the required sample size of a clinical trial in CUparticipants by up to 70%. Finally, plasma NfL was shown to have worse theoreticalperformance as a trial progression marker compared to MRI-based measures,primarily due to its high within-subject variability. NfL compared better to cognitivemeasures as endpoints.Discussion: The future of AD clinical trials will likely leverage plasma biomarkersfor initial screening. Their utility for enrichment and tracking treatment responsestill needs to be evaluated in the context of other biomarkers measured in CSF, MRI,or PET. The plasma ATN biomarkers evaluated here all appear to be independentlyuseful, but there is strong potential for more plasma biomarkers to be added to sucha panel.
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| 18. |
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| 19. |
- Gertje, Eske Christiane, et al.
(författare)
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Associations Between CSF Markers of Inflammation, White Matter Lesions, and Cognitive Decline in Individuals Without Dementia
- 2023
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Ingår i: Neurology. - 0028-3878. ; 100:17, s. 1812-1824
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives Small vessel disease (SVD) and neuroinflammation both occur in Alzheimer disease (AD) and other neurodegenerative diseases. It is unclear whether these processes are related or independent mechanisms in AD, especially in the early stages of disease. We therefore investigated the association between white matter lesions (WML; the most common manifestation of SVD) and CSF biomarkers of neuroinflammation and their effects on cognition in a population without dementia. Methods Individuals without dementia from the Swedish BioFINDER study were included. The CSF was analyzed for proinflammatory markers (interleukin [IL]-6 and IL-8), cytokines (IL-7, IL-15, and IL-16), chemokines (interferon γ-induced protein 10, monocyte chemoattractant protein 1), markers of vascular injury (soluble intercellular adhesion molecule 1, soluble vascular adhesion molecule 1), and markers of angiogenesis (placental growth factor [PlGF], soluble fms-related tyrosine kinase 1 [sFlt-1], vascular endothelial growth factors [VEGF-A and VEFG-D]), and amyloid β (Aβ)42 Aβ40, and p-tau217. WML volumes were determined at baseline and longitudinally over 6 years. Cognition was measured at baseline and follow-up over 8 years. Linear regression models were used to test associations. Results A total of 495 cognitively unimpaired (CU) elderly individuals and 247 patients with mild cognitive impairment (MCI) were included. There was significant worsening in cognition over time, measured by Mini-Mental State Examination, Clinical Dementia Rating, and modified preclinical Alzheimer composite score in CU individuals and patients with MCI, with more rapid worsening in MCI for all cognitive tests. At baseline, higher levels of PlGF (β = 0.156, p < 0.001), lower levels of sFlt-1 (β = −0.086, p = 0.003), and higher levels of IL-8 (β = 0.07, p = 0.030) were associated with more WML in CU individuals. In those with MCI, higher levels of PlGF (β = 0.172, p = 0.001), IL-16 (β = 0.125, p = 0.001), IL-8 (β = 0.096, p = 0.013), IL-6 (β = 0.088, p = 0.023), VEGF-A (β = 0.068, p = 0.028), and VEGF-D (β = 0.082, p = 0.028) were associated with more WML. PlGF was the only biomarker that was associated with WML independent of Aβ status and cognitive impairment. Longitudinal analyses of cognition showed independent effects ofCSF inflammatory markers andWMLon longitudinal cognition, especially in peoplewithout cognitive impairment at baseline. Discussion Most neuroinflammatory CSF biomarkers were associated with WML in individuals without dementia. Our findings especially highlight a role for PlGF, which was associated with WML independent of Aβ status and cognitive impairment.
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| 20. |
- Hansson, Oskar, et al.
(författare)
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Plasma phosphorylated tau181 and neurodegeneration in Alzheimer’s disease
- 2021
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Ingår i: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 8:1, s. 259-265
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Tidskriftsartikel (refereegranskat)abstract
- We examined if plasma phosphorylated tau is associated with neurodegeneration in Alzheimer’s disease. We investigated 372 cognitively unimpaired participants, 554 mild cognitive impairment patients, and 141 Alzheimer’s disease dementia patients. Tau phosphorylated at threonine 181, regional cortical thickness (using magnetic resonance imaging) and hypometabolism (using fluorodeoxyglucose positron emission tomography) were measured longitudinally. High plasma tau was associated with hypometabolism and cortical atrophy at baseline and over time, and longitudinally increased tau was associated with accelerated atrophy, but these associations were only observed in Aβ-positive participants. Plasma phosphorylated tau may identify and track processes linked to neurodegeneration in Alzheimer’s disease.
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| 21. |
- Harper, Luke, et al.
(författare)
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Anterior cingulate sulcation is associated with onset and survival in frontotemporal dementia
- 2023
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Ingår i: Brain Communications. - 2632-1297. ; 5:5
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Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal dementia is the second most common form of early onset dementia (<65 years). Despite this, there are few known disease-modifying factors. The anterior cingulate is a focal point of pathology in behavioural variant frontotemporal dementia. Sulcation of the anterior cingulate is denoted by the presence of a paracingulate sulcus, a tertiary sulcus developing, where present during the third gestational trimester and remaining stable throughout life. This study aims to examine the impact of right paracingulate sulcal presence on the expression and prognosis of behavioural variant frontotemporal dementia. This retrospective analysis drew its population from two clinical samples recruited from memory clinics at university hospitals in the USA and The Netherlands. Individuals with sporadic behavioural variant frontotemporal dementia were enrolled between 2000 and 2022 and followed up for an average of 7.71 years. T1-MRI data were evaluated for hemispheric paracingulate sulcal presence in accordance with an established protocol by two blinded raters. Outcome measures included age at onset, survival, cortical thickness and Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating determined clinical disease progression. The study population consisted of 186 individuals with sporadic behavioural variant frontotemporal dementia (113 males and 73 females), mean age 63.28 years (SD 8.32). The mean age at onset was 2.44 years later in individuals possessing a right paracingulate sulcus [60.2 years (8.54)] versus individuals who did not [57.76 (8.05)], 95% confidence interval > 0.41, P = 0.02. Education was not associated with age at onset (β = -0.05, P = 0.75). The presence of a right paracingulate sulcus was associated with an 83% increased risk of death per year after age at onset (hazard ratio 1.83, confidence interval [1.09-3.07], P < 0.02), whilst the mean age at death was similar for individuals with a present and absent right paracingulate sulcus (P = 0.7). Right paracingulate sulcal presence was not associated with baseline cortical thickness. Right paracingulate sulcal presence is associated with disease expression and survival in sporadic behavioural variant frontotemporal dementia. Findings provide evidence of neurodevelopmental brain reserve in behavioural variant frontotemporal dementia that may be important in the design of trials for future therapeutic approaches.
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| 22. |
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| 23. |
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| 24. |
- Jaffe, Allan S., et al.
(författare)
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The retirement of CKMB
- 2022
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Ingår i: European Heart Journal: Acute Cardiovascular Care. - : Oxford University Press (OUP). - 2048-8726 .- 2048-8734. ; 11:10, s. 784-785
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Tidskriftsartikel (refereegranskat)
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| 25. |
- Leuzy, Antoine, et al.
(författare)
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Biomarker-Based Prediction of Longitudinal Tau Positron Emission Tomography in Alzheimer Disease
- 2022
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 79:2, s. 149-158
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Tidskriftsartikel (refereegranskat)abstract
- Importance: There is currently no consensus as to which biomarkers best predict longitudinal tau accumulation at different clinical stages of Alzheimer disease (AD). Objective: To describe longitudinal [18F]RO948 tau positron emission tomography (PET) findings across the clinical continuum of AD and determine which biomarker combinations showed the strongest associations with longitudinal tau PET and best optimized clinical trial enrichment. Design, Setting, and Participants: This longitudinal cohort study consecutively enrolled amyloid-β (Aβ)-negative cognitively unimpaired (CU) participants, Aβ-positive CU individuals, Aβ-positive individuals with mild cognitive impairment (MCI), and individuals with AD dementia between September 2017 and November 2020 from the Swedish BioFINDER-2 (discovery cohort) and BioFINDER-1 (validation cohort) studies. Exposures: Baseline plasma and cerebrospinal fluid Aβ42/Aβ40, tau phosphorylated at threonine-217 (p-tau217), p-tau181 and neurofilament light, magnetic resonance imaging, amyloid PET ([18F]flutemetamol), and tau PET ([18F]RO948 in the BioFINDER-2 study; [18F]flortaucipir in the BioFINDER-1 study). Main Outcomes and Measures: Baseline tau PET standardized uptake value ratio (SUVR) and annual percent change in tau PET SUVR across regions of interest derived using a data-driven approach combining clustering and event-based modeling. Regression models were used to examine associations between individual biomarkers and longitudinal tau PET and to identify which combinations best predicted longitudinal tau PET. These combinations were then entered in a power analysis to examine how their use as an enrichment strategy would affect sample size in a simulated clinical trial. Results: Of 343 participants, the mean (SD) age was 72.56 (7.24) years, and 157 (51.1%) were female. The clustering/event-based modeling-based approach identified 5 regions of interest (stages). In Aβ-positive CU individuals, the largest annual increase in tau PET SUVR was seen in stage I (entorhinal cortex, hippocampus, and amygdala; 4.04% [95% CI, 2.67%-5.32%]). In Aβ-positive individuals with MCI and with AD dementia, the greatest increases were seen in stages II (temporal cortical regions; 4.45% [95% CI, 3.41%-5.49%]) and IV (certain frontal regions; 5.22% [95% CI, 3.95%-6.49%]), respectively. In Aβ-negative CU individuals and those with MCI, modest change was seen in stage I (1.38% [95% CI, 0.78%-1.99%] and 1.80% [95% CI, 0.76%-2.84%], respectively). When looking at individual predictors and longitudinal tau PET in the stages that showed most change, plasma p-tau217 (R2= 0.27, P <.005), tau PET (stage I baseline SUVR; R2= 0.13, P <.05) and amyloid PET (R2= 0.10, P <.05) were significantly associated with longitudinal tau PET in stage I in Aβ-positive CU individuals. In Aβ-positive individuals with MCI, plasma p-tau217 (R2= 0.24, P <.005) and tau PET (stage II baseline SUVR; R2= 0.44, P <.001) were significantly associated with longitudinal tau PET in stage II. Findings were replicated in BioFINDER-1 using longitudinal [18F]flortaucipir. For the power analysis component, plasma p-tau217 with tau PET resulted in sample size reductions of 43% (95% CI, 34%-46%; P <.005) in Aβ-positive CU individuals and of 68% (95% CI, 61%-73%; P <.001) in Aβ-positive individuals with MCI. Conclusions and Relevance: In trials using tau PET as the outcome, plasma p-tau217 with tau PET may prove optimal for enrichment in preclinical and prodromal AD. However, plasma p-tau217 was most important in preclinical AD, while tau PET was more important in prodromal AD..
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| 26. |
- Leuzy, Antoine, et al.
(författare)
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Current advances in plasma and cerebrospinal fluid biomarkers in Alzheimer's disease
- 2021
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Ingår i: Current Opinion in Neurology. - 1473-6551. ; 34:2, s. 266-274
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE OF REVIEW: This review provides a concise overview of recent advances in cerebrospinal fluid (CSF) and blood-based biomarkers of Alzheimer's disease lesions. RECENT FINDINGS: Important recent advances for CSF Alzheimer's disease biomarkers include the introduction of fully automated assays, the development and implementation of certified reference materials for CSF Aβ42 and a unified protocol for handling of samples, which all support reliability and availability of CSF Alzheimer's disease biomarkers. Aβ deposition can be detected using Aβ42/Aβ40 ratio in both CSF and plasma, though a much more modest change is seen in plasma. Tau aggregation can be detected using phosphorylated tau (P-tau) at threonine 181 and 217 in CSF, with similar accuracy in plasma. Neurofilament light (NfL) be measured in CSF and shows similar diagnostic accuracy in plasma. Though total tau (T-tau) can also be measured in plasma, this measure is of limited clinical relevance for Alzheimer's disease in its current immunoassay format. SUMMARY: Alzheimer's disease biomarkers, including Aβ, P-tau and NfL can now be reliably measured in both CSF and blood. Plasma-based measures of P-tau show particular promise, with potential applications in both clinical practice and in clinical trials.
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| 27. |
- Leuzy, Antoine, et al.
(författare)
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Robustness of CSF Aβ42/40 and Aβ42/P-tau181 measured using fully automated immunoassays to detect AD-related outcomes
- 2023
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:7, s. 2994-3004
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: This study investigated the comparability of cerebrospinal fluid (CSF) cutoffs for Elecsys immunoassays for amyloid beta (Aβ)42/Aβ40 or Aβ42/phosphorylated tau (p-tau)181 and the effects of measurement variability when predicting Alzheimer's disease (AD)-related outcomes (i.e., Aβ-positron emission tomography [PET] visual read and AD neuropathology). Methods: We 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 (Aβ-PET visual read as outcome). Using longitudinal variability in Aβ-negative controls, we identified a gray zone around cut-points where the risk of an inconsistent predicted outcome was >5%. Results: For Aβ42/Aβ40, cutoffs across cohorts were <0.059 (BioFINDER), <0.057 (ADNI), and <0.058 (UCSF). For Aβ42/p-tau181, cutoffs were <41.90 (BioFINDER), <39.20 (ADNI), and <46.02 (UCSF). Accuracy was ≈90% for both Aβ42/Aβ40 and Aβ42/p-tau181 using these cutoffs. Using Aβ-PET as an outcome, 8.7% of participants fell within a gray zone interval for Aβ42/Aβ40, compared to 4.5% for Aβ42/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 Aβ42/40, the number of individuals within the gray zone was ≈1.5 to 3 times greater when using plasma Aβ42/40. Discussion: CSF Aβ42/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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| 28. |
- Mair, Johannes, et al.
(författare)
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Application of the fourth universal definition of myocardial infarction in clinical practice
- 2020
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Ingår i: Biomarkers. - 1354-750X .- 1366-5804. ; 25:4, s. 322-330
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Forskningsöversikt (refereegranskat)abstract
- Purpose: The Fourth Universal Definition of Myocardial Infarction (MI) has highlighted the different pathophysiological mechanisms that may lead to ischaemic and non-ischaemic myocardial injury and has emphasised that the diagnosis of myocardial infarction requires the presence of acute myocardial ischaemia in the setting of acute myocardial injury. This case based review intends to illustrate basic principles on how to apply this new, revised definition in clinical practice.Methods and Results: The distinction between different types of MIs (type 1 or type 2) and the delineation of MI from acute non-ischaemic myocardial injury may be challenging in individual patients, which is illustrated by presenting and discussing real-life routine cases.Conclusions: Type 1 MI is a consequence of coronary plaque rupture or erosion with intracoronary thrombus formation that is usually apparent on coronary angiography. Plausible triggering mechanisms causing myocardial oxygen supply/demand mismatch must be identified for the diagnosis of type 2 MI and its treatment should focus initially on management of the underlying disease attributable to acute myocardial ischaemia.
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| 29. |
- Mair, Johannes, et al.
(författare)
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The clinical approach to diagnosing peri-procedural myocardial infarction after percutaneous coronary interventions according to the fourth universal definition of myocardial infarction - from the study group on biomarkers of the European Society of Cardiology (ESC) Association for Acute CardioVascular Care (ACVC)
- 2022
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Ingår i: Biomarkers. - : Taylor & Francis. - 1354-750X .- 1366-5804. ; 27:5, s. 407-417
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Forskningsöversikt (refereegranskat)abstract
- Purpose This review intends to illustrate basic principles on how to apply the Fourth Universal Definition of Myocardial Infarction (UDMI) for the diagnosis of peri-procedural myocardial infarction (MI) after percutaneous coronary interventions (PCI) in clinical practice.Methods and Results Review of routine case-based events. Increases in cardiac troponin (cTn) concentrations are common after elective PCI in patients with chronic coronary syndrome (CCS). Peri-procedural PCI-related MI (type 4a MI) in CCS patients should be diagnosed in cases of major peri-procedural acute myocardial injury indicated by an increase in cTn concentrations of >5-times the 99th percentile upper reference limit (URL) together with evidence of new peri-procedural myocardial ischaemia as demonstrated by electrocardiography (ECG), imaging, or flow-limiting peri-procedural complications in coronary angiography. Measurement of cTn baseline concentrations before elective PCI is useful. In patients presenting with acute MI undergoing PCI, peri-procedural increases in cTn concentrations are usually due to their index presentation and not PCI-related, apart from obvious major peri-procedural complications, such as persistent occlusion of a large side branch or no-reflow after stent implantation.Conclusion The distinction between type 4a MI, PCI-related acute myocardial injury, and chronic myocardial injury can be challenging in individuals undergoing PCI. Careful integration of all available clinical data is essential for correct classification.
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| 30. |
- Mattsson-Carlgren, Niklas, et al.
(författare)
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Longitudinal plasma p-tau217 is increased in early stages of Alzheimer's disease
- 2020
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 143:11, s. 3234-3241
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Tidskriftsartikel (refereegranskat)abstract
- Plasma levels of tau phosphorylated at threonine-217 (p-tau217) is a candidate tool to monitor Alzheimer's disease. We studied 150 cognitively unimpaired participants and 100 patients with mild cognitive impairment in the Swedish BioFINDER study. P-tau217 was measured repeatedly for up to 6 years (median three samples per person, median time from first to last sample, 4.3 years). Preclinical (amyloid-β-positive cognitively unimpaired, n = 62) and prodromal (amyloid-β-positive mild cognitive impairment, n = 49) Alzheimer's disease had accelerated p-tau217 compared to amyloid-β-negative cognitively unimpaired (β = 0.56, P < 0.001, using linear mixed effects models) and amyloid-β-negative mild cognitive impairment patients (β = 0.67, P < 0.001), respectively. Mild cognitive impairment patients who later converted to Alzheimer's disease dementia (n = 40) had accelerated p-tau217 compared to other mild cognitive impairment patients (β = 0.79, P < 0.001). P-tau217 did not change in amyloid-β-negative participants, or in patients with mild cognitive impairment who did not convert to Alzheimer's disease dementia. For 80% power, 109 participants per arm were required to observe a slope reduction in amyloid-β-positive cognitively unimpaired (71 participants per arm in amyloid-β-positive mild cognitive impairment). Longitudinal increases in p-tau217 correlated with longitudinal worsening of cognition and brain atrophy. In summary, plasma p-tau217 increases during early Alzheimer's disease and can be used to monitor disease progression.
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| 31. |
- Mingels, Alma M., et al.
(författare)
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Cardiac troponin T and I: back to basics
- 2023
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Ingår i: European Heart Journal: Acute Cardiovascular Care. - 2048-8726 .- 2048-8734. ; 12:9, s. 631-632
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Tidskriftsartikel (refereegranskat)
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| 32. |
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| 33. |
- Neumann, Johannes Tobias, et al.
(författare)
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Personalized diagnosis in suspected myocardial infarction
- 2023
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Ingår i: Clinical Research in Cardiology. - : Springer. - 1861-0684 .- 1861-0692. ; 112, s. 1288-1301
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Tidskriftsartikel (refereegranskat)abstract
- Background: In suspected myocardial infarction (MI), guidelines recommend using high-sensitivity cardiac troponin (hscTn)- based approaches. These require fixed assay-specific thresholds and timepoints, without directly integrating clinical information. Using machine-learning techniques including hs-cTn and clinical routine variables, we aimed to build a digital tool to directly estimate the individual probability of MI, allowing for numerous hs-cTn assays.Methods: In 2,575 patients presenting to the emergency department with suspected MI, two ensembles of machine-learning models using single or serial concentrations of six different hs-cTn assays were derived to estimate the individual MI probability ( ARTEMIS model). Discriminative performance of the models was assessed using area under the receiver operating characteristic curve (AUC) and logLoss. Model performance was validated in an external cohort with 1688 patients and tested for global generalizability in 13 international cohorts with 23,411 patients.Results: Eleven routinely available variables including age, sex, cardiovascular risk factors, electrocardiography, and hs-cTn were included in the ARTEMIS models. In the validation and generalization cohorts, excellent discriminative performance was confirmed, superior to hs-cTn only. For the serial hs-cTn measurement model, AUC ranged from 0.92 to 0.98. Good calibration was observed. Using a single hs-cTn measurement, the ARTEMIS model allowed direct rule-out of MI with very high and similar safety but up to tripled efficiency compared to the guideline- recommended strategy.Conclusion We developed and validated diagnostic models to accurately estimate the individual probability of MI, which allow for variable hs-cTn use and flexible timing of resampling. Their digital application may provide rapid, safe and efficient personalized patient care.
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| 34. |
- Palmqvist, Sebastian, et al.
(författare)
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An accurate fully automated panel of plasma biomarkers for Alzheimer's disease
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:4, s. 1204-1215
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Tidskriftsartikel (refereegranskat)abstract
- Introduction There is a great need for fully automated plasma assays that can measure amyloid beta (A beta) pathology and predict future Alzheimer's disease (AD) dementia. Methods Two cohorts (n = 920) were examined: Panel A+ (n = 32 cognitively unimpaired [CU], n = 106 mild cognitive impairment [MCI], and n = 89 AD) and BioFINDER-1 (n = 461 CU, n = 232 MCI). Plasma A beta 42/A beta 40, phosphorylated tau (p-tau)181, two p-tau217 variants, ApoE4 protein, neurofilament light, and GFAP were measured using Elecsys prototype immunoassays. Results The best biomarker for discriminating A beta-positive versus A beta-negative participants was A beta 42/A beta 40 (are under the curve [AUC] 0.83-0.87). Combining A beta 42/A beta 40, p-tau181, and ApoE4 improved the AUCs significantly (0.90 to 0.93; P< 0.01). Adding additional biomarkers had marginal effects (Delta AUC <= 0.01). In BioFINDER, p-tau181, p-tau217, and ApoE4 predicted AD dementia within 6 years in CU (AUC 0.88) and p-tau181, p-tau217, and A beta 42/A beta 40 in MCI (AUC 0.87). Discussion The high accuracies for A beta pathology and future AD dementia using fully automated instruments are promising for implementing plasma biomarkers in clinical trials and clinical routine.
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| 35. |
- Palmqvist, Sebastian, et al.
(författare)
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Prediction of future Alzheimer's disease dementia using plasma phospho-tau combined with other accessible measures
- 2021
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27, s. 1034-1042
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Tidskriftsartikel (refereegranskat)abstract
- Plasma P-tau, in combination with clinical measures, predicts future Alzheimer's disease dementia in two independent cohorts with high accuracy and is superior to the clinical diagnostic predictions of specialists. A combination of plasma phospho-tau (P-tau) and other accessible biomarkers might provide accurate prediction about the risk of developing Alzheimer's disease (AD) dementia. We examined this in participants with subjective cognitive decline and mild cognitive impairment from the BioFINDER (n = 340) and Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 543) studies. Plasma P-tau, plasma A beta 42/A beta 40, plasma neurofilament light, APOE genotype, brief cognitive tests and an AD-specific magnetic resonance imaging measure were examined using progression to AD as outcome. Within 4 years, plasma P-tau217 predicted AD accurately (area under the curve (AUC) = 0.83) in BioFINDER. Combining plasma P-tau217, memory, executive function and APOE produced higher accuracy (AUC = 0.91, P < 0.001). In ADNI, this model had similar AUC (0.90) using plasma P-tau181 instead of P-tau217. The model was implemented online for prediction of the individual probability of progressing to AD. Within 2 and 6 years, similar models had AUCs of 0.90-0.91 in both cohorts. Using cerebrospinal fluid P-tau, A beta 42/A beta 40 and neurofilament light instead of plasma biomarkers did not improve the accuracy significantly. The clinical predictions by memory clinic physicians had significantly lower accuracy (4-year AUC = 0.71). In summary, plasma P-tau, in combination with brief cognitive tests and APOE genotyping, might greatly improve the diagnostic prediction of AD and facilitate recruitment for AD trials.
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| 36. |
- Pichet Binette, Alexa, et al.
(författare)
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Confounding factors of Alzheimer's disease plasma biomarkers and their impact on clinical performance
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:4, s. 1403-1414
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Plasma biomarkers will likely revolutionize the diagnostic work-up of Alzheimer's disease (AD) globally. Before widespread use, we need to determine if confounding factors affect the levels of these biomarkers, and their clinical utility. Methods Participants with plasma and CSF biomarkers, creatinine, body mass index (BMI), and medical history data were included (BioFINDER-1: n = 748, BioFINDER-2: n = 421). We measured beta-amyloid (A beta 42, A beta 40), phosphorylated tau (p-tau217, p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Results In both cohorts, creatinine and BMI were the main factors associated with NfL, GFAP, and to a lesser extent with p-tau. However, adjustment for BMI and creatinine had only minor effects in models predicting either the corresponding levels in CSF or subsequent development of dementia. Discussion Creatinine and BMI are related to certain plasma biomarkers levels, but they do not have clinically relevant confounding effects for the vast majority of individuals. Highlights Creatinine and body mass index (BMI) are related to certain plasma biomarker levels. Adjusting for creatinine and BMI has minor influence on plasma-cerebrospinal fluid (CSF) associations. Adjusting for creatinine and BMI has minor influence on prediction of dementia using plasma biomarkers.
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| 37. |
- Salvadó, Gemma, et al.
(författare)
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Optimal combinations of CSF biomarkers for predicting cognitive decline and clinical conversion in cognitively unimpaired participants and mild cognitive impairment patients: A multi-cohort study
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:7, s. 2943-2955
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Our objective was determining the optimal combinations of cerebrospinal fluid (CSF) biomarkers for predicting disease progression in Alzheimer's disease (AD) and other neurodegenerative diseases.Methods: We included 1,983 participants from three different cohorts with longitudinal cognitive and clinical data, and baseline CSF levels of A beta 42, A beta 40, phosphorylated tau at threonine-181 (p-tau), neurofilament light (NfL), neurogranin, alpha-synuclein, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), glial fibrillary acidic protein (GFAP), YKL-40, S100b, and interleukin 6 (IL-6) (Elecsys NeuroToolKit).Results: Change of modified Preclinical Alzheimer's Cognitive Composite (mPACC) in cognitively unimpaired (CU) was best predicted by p-tau/A beta 42 alone (R-2 >= 0.31) or together with NfL (R-2 = 0.25), while p-tau/A beta 42 (R-2 >= 0.19) was sufficient to accurately predict change of the Mini-Mental State Examination (MMSE) in mild cognitive impairment (MCI) patients. P-tau/A beta 42 (AUC >= 0.87) and p-tau/A beta 42 together with NfL (AUC >= 0.75) were the best predictors of conversion to AD and all-cause dementia, respectively.Discussion: P-tau/A beta 42 is sufficient for predicting progression in AD, with very high accuracy. Adding NfL improves the prediction of all-cause dementia conversion and cognitive decline.
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| 38. |
- Smith, Ruben, et al.
(författare)
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Tau-PET is superior to phospho-tau when predicting cognitive decline in symptomatic AD patients
- 2023
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:6, s. 2497-2507
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Biomarkers for the prediction of cognitive decline in patients with amnestic mild cognitive impairment (MCI) and amnestic mild dementia are needed for both clinical practice and clinical trials. Methods: We evaluated the ability of tau-PET (positron emission tomography), cortical atrophy on magnetic resonance imaging (MRI), baseline cognition, apolipoprotein E gene (APOE) status, plasma and cerebrospinal fluid (CSF) levels of phosphorylated tau-217, neurofilament light (NfL), and amyloid beta (Aβ)42/40 ratio (individually and in combination) to predict cognitive decline over 2 years in BioFINDER-2 and Alzheimer's Disease Neuroimaging Initiative (ADNI). Results: Baseline tau-PET and a composite baseline cognitive score were the strongest independent predictors of cognitive decline. Cortical thickness and NfL provided some additional information. Using a predictive algorithm to enrich patient selection in a theoretical clinical trial led to a significantly lower required sample size. Discussion: Models including baseline tau-PET and cognition consistently provided the best prediction of change in cognitive function over 2 years in patients with amnestic MCI or mild dementia.
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| 39. |
- Strawbridge, Rona J., et al.
(författare)
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The overlap of genetic susceptibility to schizophrenia and cardiometabolic disease can be used to identify metabolically different groups of individuals
- 2021
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Understanding why individuals with severe mental illness (Schizophrenia, Bipolar Disorder and Major Depressive Disorder) have increased risk of cardiometabolic disease (including obesity, type 2 diabetes and cardiovascular disease), and identifying those at highest risk of cardiometabolic disease are important priority areas for researchers. For individuals with European ancestry we explored whether genetic variation could identify sub-groups with different metabolic profiles. Loci associated with schizophrenia, bipolar disorder and major depressive disorder from previous genome-wide association studies and loci that were also implicated in cardiometabolic processes and diseases were selected. In the IMPROVE study (a high cardiovascular risk sample) and UK Biobank (general population sample) multidimensional scaling was applied to genetic variants implicated in both psychiatric and cardiometabolic disorders. Visual inspection of the resulting plots used to identify distinct clusters. Differences between these clusters were assessed using chi-squared and Kruskall-Wallis tests. In IMPROVE, genetic loci associated with both schizophrenia and cardiometabolic disease (but not bipolar disorder or major depressive disorder) identified three groups of individuals with distinct metabolic profiles. This grouping was replicated within UK Biobank, with somewhat less distinction between metabolic profiles. This work focused on individuals of European ancestry and is unlikely
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