| 1. |
- Tabiri, S, et al.
(author)
-
- 2021
-
swepub:Mat__t
|
|
| 2. |
- Bravo, L, et al.
(author)
-
- 2021
-
swepub:Mat__t
|
|
| 3. |
- Khatri, C, et al.
(author)
-
Outcomes after perioperative SARS-CoV-2 infection in patients with proximal femoral fractures: an international cohort study
- 2021
-
In: BMJ open. - : BMJ. - 2044-6055. ; 11:11, s. e050830-
-
Journal article (peer-reviewed)abstract
- Studies have demonstrated high rates of mortality in people with proximal femoral fracture and SARS-CoV-2, but there is limited published data on the factors that influence mortality for clinicians to make informed treatment decisions. This study aims to report the 30-day mortality associated with perioperative infection of patients undergoing surgery for proximal femoral fractures and to examine the factors that influence mortality in a multivariate analysis.SettingProspective, international, multicentre, observational cohort study.ParticipantsPatients undergoing any operation for a proximal femoral fracture from 1 February to 30 April 2020 and with perioperative SARS-CoV-2 infection (either 7 days prior or 30-day postoperative).Primary outcome30-day mortality. Multivariate modelling was performed to identify factors associated with 30-day mortality.ResultsThis study reports included 1063 patients from 174 hospitals in 19 countries. Overall 30-day mortality was 29.4% (313/1063). In an adjusted model, 30-day mortality was associated with male gender (OR 2.29, 95% CI 1.68 to 3.13, p<0.001), age >80 years (OR 1.60, 95% CI 1.1 to 2.31, p=0.013), preoperative diagnosis of dementia (OR 1.57, 95% CI 1.15 to 2.16, p=0.005), kidney disease (OR 1.73, 95% CI 1.18 to 2.55, p=0.005) and congestive heart failure (OR 1.62, 95% CI 1.06 to 2.48, p=0.025). Mortality at 30 days was lower in patients with a preoperative diagnosis of SARS-CoV-2 (OR 0.6, 95% CI 0.6 (0.42 to 0.85), p=0.004). There was no difference in mortality in patients with an increase to delay in surgery (p=0.220) or type of anaesthetic given (p=0.787).ConclusionsPatients undergoing surgery for a proximal femoral fracture with a perioperative infection of SARS-CoV-2 have a high rate of mortality. This study would support the need for providing these patients with individualised medical and anaesthetic care, including medical optimisation before theatre. Careful preoperative counselling is needed for those with a proximal femoral fracture and SARS-CoV-2, especially those in the highest risk groups.Trial registration numberNCT04323644
|
|
| 4. |
|
|
| 5. |
- Bousquet, J, et al.
(author)
-
Nrf2-interacting nutrients and COVID-19: time for research to develop adaptation strategies
- 2020
-
In: Clinical and translational allergy. - : Wiley. - 2045-7022. ; 10:1, s. 58-
-
Journal article (peer-reviewed)abstract
- There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPARγ:Peroxisome proliferator-activated receptor, NFκB: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2α:Elongation initiation factor 2α). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT1R axis (AT1R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity.
|
|
| 6. |
|
|
| 7. |
- Jansen, Willemijn J, et al.
(author)
-
Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.
- 2022
-
In: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:3, s. 228-243
-
Journal article (peer-reviewed)abstract
- One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Alzheimer disease biomarkers detected on PET or in CSF.Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%]) included, 10139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P=.04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P=.004), subjective cognitive decline (9%; 95% CI, 3%-15%; P=.005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P=.004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P=.18).This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Bousquet, Jean, et al.
(author)
-
ARIA digital anamorphosis : Digital transformation of health and care in airway diseases from research to practice
- 2021
-
In: Allergy. European Journal of Allergy and Clinical Immunology. - : John Wiley & Sons. - 0105-4538 .- 1398-9995. ; 76:1, s. 168-190
-
Research review (peer-reviewed)abstract
- Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.
|
|
| 11. |
- Li, Yan, et al.
(author)
-
Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques
- 2022
-
In: Neurology. - 0028-3878. ; 98:7, s. 688-699
-
Journal article (peer-reviewed)abstract
- Background and Objectives To determine the diagnostic accuracy of a plasma Aβ42/Aβ40 assay in classifying amyloid PET status across global research studies using samples collected by multiple centers that utilize different blood collection and processing protocols.MethodsPlasma samples (n = 465) were obtained from 3 large Alzheimer disease (AD) research cohorts in the United States (n = 182), Australia (n = 183), and Sweden (n = 100). Plasma Aβ42/Aβ40 was measured by a high precision immunoprecipitation mass spectrometry (IPMS) assay and compared to the reference standards of amyloid PET and CSF Aβ42/Aβ40.ResultsIn the combined cohort of 465 participants, plasma Aβ42/Aβ40 had good concordance with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.84, 95% confidence interval [CI] 0.80-0.87); concordance improved with the inclusion of APOE ϵ4 carrier status (AUC 0.88, 95% CI 0.85-0.91). The AUC of plasma Aβ42/Aβ40 with CSF amyloid status was 0.85 (95% CI 0.78-0.91) and improved to 0.93 (95% CI 0.89-0.97) with APOE ϵ4 status. These findings were consistent across the 3 cohorts, despite differences in protocols. The assay performed similarly in both cognitively unimpaired and impaired individuals.DiscussionPlasma Aβ42/Aβ40 is a robust measure for detecting amyloid plaques and can be utilized to aid in the diagnosis of AD, identify those at risk for future dementia due to AD, and improve the diversity of populations enrolled in AD research and clinical trials.Classification of EvidenceThis study provides Class II evidence that plasma Aβ42/Aβ40, as measured by a high precision IPMS assay, accurately diagnoses brain amyloidosis in both cognitively unimpaired and impaired research participants.
|
|
| 12. |
- van Hilst, Jony, et al.
(author)
-
Minimally invasive versus open distal pancreatectomy for pancreatic ductal adenocarcinoma (DIPLOMA) : study protocol for a randomized controlled trial
- 2021
-
In: Trials. - : BMC. - 1745-6215. ; 22:1
-
Journal article (peer-reviewed)abstract
- Background: Recently, the first randomized trials comparing minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) for non-malignant and malignant disease showed a 2-day reduction in time to functional recovery after MIDP. However, for pancreatic ductal adenocarcinoma (PDAC), concerns have been raised regarding the oncologic safety (i.e., radical resection, lymph node retrieval, and survival) of MIDP, as compared to ODP. Therefore, a randomized controlled trial comparing MIDP and ODP in PDAC regarding oncological safety is warranted. We hypothesize that the microscopically radical resection (R0) rate is non-inferior for MIDP, as compared to ODP. Methods/design: DIPLOMA is an international randomized controlled, patient- and pathologist-blinded, non-inferiority trial performed in 38 pancreatic centers in Europe and the USA. A total of 258 patients with an indication for elective distal pancreatectomy with splenectomy because of proven or highly suspected PDAC of the pancreatic body or tail will be randomly allocated to MIDP (laparoscopic or robot-assisted) or ODP in a 1:1 ratio. The primary outcome is the microscopically radical resection margin (R0, distance tumor to pancreatic transection and posterior margin >= 1 mm), which is assessed using a standardized histopathology assessment protocol. The sample size is calculated with the following assumptions: 5% one-sided significance level (alpha), 80% power (1-beta), expected R0 rate in the open group of 58%, expected R0 resection rate in the minimally invasive group of 67%, and a non-inferiority margin of 7%. Secondary outcomes include time to functional recovery, operative outcomes (e.g., blood loss, operative time, and conversion to open surgery), other histopathology findings (e.g., lymph node retrieval, perineural- and lymphovascular invasion), postoperative outcomes (e.g., clinically relevant complications, hospital stay, and administration of adjuvant treatment), time and site of disease recurrence, survival, quality of life, and costs. Follow-up will be performed at the outpatient clinic after 6, 12, 18, 24, and 36 months postoperatively. Discussion: The DIPLOMA trial is designed to investigate the non-inferiority of MIDP versus ODP regarding the microscopically radical resection rate of PDAC in an international setting.
|
|
| 13. |
- Zicha, S., et al.
(author)
-
Comparative analytical performance of multiple plasma A beta 42 and A beta 40 assays and their ability to predict positron emission tomography amyloid positivity
- 2022
-
In: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279.
-
Journal article (peer-reviewed)abstract
- Introduction This report details the approach taken to providing a dataset allowing for analyses on the performance of recently developed assays of amyloid beta (A beta) peptides in plasma and the extent to which they improve the prediction of amyloid positivity. Methods Alzheimer's Disease Neuroimaging Initiative plasma samples with corresponding amyloid positron emission tomography (PET) data were run on six plasma A beta assays. Statistical tests were performed to determine whether the plasma A beta measures significantly improved the area under the receiver operating characteristic curve for predicting amyloid PET status compared to age and apolipoprotein E (APOE) genotype. Results The age and APOE genotype model predicted amyloid status with an area under the curve (AUC) of 0.75. Three assays improved AUCs to 0.81, 0.81, and 0.84 (P < .05, uncorrected for multiple comparisons). Discussion Measurement of A beta in plasma contributes to addressing the amyloid component of the ATN (amyloid/tau/neurodegeneration) framework and could be a first step before or in place of a PET or cerebrospinal fluid screening study. Highlights The Foundation of the National Institutes of Health Biomarkers Consortium evaluated six plasma amyloid beta (A beta) assays using Alzheimer's Disease Neuroimaging Initiative samples. Three assays improved prediction of amyloid status over age and apolipoprotein E (APOE) genotype. Plasma A beta 42/40 predicted amyloid positron emission tomography status better than A beta 42 or A beta 40 alone.
|
|
| 14. |
- Amaral, Andre F. S., et al.
(author)
-
Chronic airflow obstruction and ambient particulate air pollution
- 2021
-
In: Thorax. - : BMJ Publishing Group Ltd. - 0040-6376 .- 1468-3296. ; 76:12, s. 1236-1241
-
Journal article (peer-reviewed)abstract
- Smoking is the most well-established cause of chronic airflow obstruction (CAO) but particulate air pollution and poverty have also been implicated. We regressed sex-specific prevalence of CAO from 41 Burden of Obstructive Lung Disease study sites against smoking prevalence from the same study, the gross national income per capita and the local annual mean level of ambient particulate matter (PM2.5) using negative binomial regression. The prevalence of CAO was not independently associated with PM2.5 but was strongly associated with smoking and was also associated with poverty. Strengthening tobacco control and improved understanding of the link between CAO and poverty should be prioritised.
|
|
| 15. |
- Brand, Abby L., et al.
(author)
-
The performance of plasma amyloid beta measurements in identifying amyloid plaques in Alzheimer's disease : a literature review
- 2022
-
In: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 14:1, s. 195-195
-
Research review (peer-reviewed)abstract
- The extracellular buildup of amyloid beta (Aβ) plaques in the brain is a hallmark of Alzheimer's disease (AD). Detection of Aβ pathology is essential for AD diagnosis and for identifying and recruiting research participants for clinical trials evaluating disease-modifying therapies. Currently, AD diagnoses are usually made by clinical assessments, although detection of AD pathology with positron emission tomography (PET) scans or cerebrospinal fluid (CSF) analysis can be used by specialty clinics. These measures of Aβ aggregation, e.g. plaques, protofibrils, and oligomers, are medically invasive and often only available at specialized medical centers or not covered by medical insurance, and PET scans are costly. Therefore, a major goal in recent years has been to identify blood-based biomarkers that can accurately detect AD pathology with cost-effective, minimally invasive procedures.To assess the performance of plasma Aβ assays in predicting amyloid burden in the central nervous system (CNS), this review compares twenty-one different manuscripts that used measurements of 42 and 40 amino acid-long Aβ (Aβ42 and Aβ40) in plasma to predict CNS amyloid status. Methodologies that quantitate Aβ42 and 40 peptides in blood via immunoassay or immunoprecipitation-mass spectrometry (IP-MS) were considered, and their ability to distinguish participants with amyloidosis compared to amyloid PET and CSF Aβ measures as reference standards was evaluated. Recent studies indicate that some IP-MS assays perform well in accurately and precisely measuring Aβ and detecting brain amyloid aggregates.
|
|
| 16. |
|
|
| 17. |
|
|
| 18. |
- Buddenkotte, Thomas, et al.
(author)
-
Deep learning-based segmentation of multisite disease in ovarian cancer
- 2023
-
In: EUROPEAN RADIOLOGY EXPERIMENTAL. - : Springer Nature. - 2509-9280. ; 7:1
-
Journal article (peer-reviewed)abstract
- Purpose: To determine if pelvic/ovarian and omental lesions of ovarian cancer can be reliably segmented on computed tomography (CT) using fully automated deep learning-based methods.Methods: A deep learning model for the two most common disease sites of high-grade serous ovarian cancer lesions (pelvis/ovaries and omentum) was developed and compared against the well-established “no-new-Net” framework and unrevised trainee radiologist segmentations. A total of 451 CT scans collected from four different institutions were used for training (n = 276), evaluation (n = 104) and testing (n = 71) of the methods. The performance was evaluated using the Dice similarity coefficient (DSC) and compared using a Wilcoxon test.Results: Our model outperformed no-new-Net for the pelvic/ovarian lesions in cross-validation, on the evaluation and test set by a significant margin (p values being 4 × 10–7, 3 × 10–4, 4 × 10–2, respectively), and for the omental lesions on the evaluation set (p = 1 × 10–3). Our model did not perform significantly differently in segmenting pelvic/ovarian lesions (p = 0.371) compared to a trainee radiologist. On an independent test set, the model achieved a DSC performance of 71 ± 20 (mean ± standard deviation) for pelvic/ovarian and 61 ± 24 for omental lesions.Conclusion: Automated ovarian cancer segmentation on CT scans using deep neural networks is feasible and achieves performance close to a trainee-level radiologist for pelvic/ovarian lesions.Relevance statement: Automated segmentation of ovarian cancer may be used by clinicians for CT-based volumetric assessments and researchers for building complex analysis pipelines.Key points:The first automated approach for pelvic/ovarian and omental ovarian cancer lesion segmentation on CT images has been presented.Automated segmentation of ovarian cancer lesions can be comparable with manual segmentation of trainee radiologists.Careful hyperparameter tuning can provide models significantly outperforming strong state-of-the-art baselines. Graphical Abstract: [Figure not available: see fulltext.]
|
|
| 19. |
- Burney, Peter, et al.
(author)
-
Prevalence and Population-Attributable Risk for Chronic Airflow Obstruction in a Large Multinational Study
- 2021
-
In: American Journal of Respiratory and Critical Care Medicine. - 1073-449X .- 1535-4970. ; 203:11, s. 1353-1365
-
Journal article (peer-reviewed)abstract
- Rationale: The Global Burden of Disease program identified smoking and ambient and household air pollution as the main drivers of death and disability from chronic obstructive pulmonary disease (COPD).Objectives: To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors.Methods: The Burden of Obstructive Lung Disease study is a cross-sectional study of adults, aged ≥40, in a globally distributed sample of 41 urban and rural sites. Based on data from 28,459 participants, we estimated the prevalence of CAO, defined as a postbronchodilator FEV1-to-FVC ratio less than the lower limit of normal, and the relative risks associated with different risk factors. Local relative risks were estimated using a Bayesian hierarchical model borrowing information from across sites. From these relative risks and the prevalence of risk factors, we estimated local population attributable risks.Measurements and Main Results: The mean prevalence of CAO was 11.2% in men and 8.6% in women. The mean population attributable risk for smoking was 5.1% in men and 2.2% in women. The next most influential risk factors were poor education levels, working in a dusty job for ≥10 years, low body mass index, and a history of tuberculosis. The risk of CAO attributable to the different risk factors varied across sites.Conclusions: Although smoking remains the most important risk factor for CAO, in some areas, poor education, low body mass index, and passive smoking are of greater importance. Dusty occupations and tuberculosis are important risk factors at some sites.
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
- Janelidze, Shorena, et al.
(author)
-
Plasma Phosphorylated Tau 217 and Aβ42/40 to Predict Early Brain Aβ Accumulation in People Without Cognitive Impairment
- 2024
-
In: JAMA NEUROLOGY. - 2168-6149 .- 2168-6157.
-
Journal article (peer-reviewed)abstract
- IMPORTANCE Phase 3 trials of successful antiamyloid therapies in Alzheimer disease (AD) have demonstrated improved clinical efficacy in people with less severe disease. Plasma biomarkers will be essential for efficient screening of participants in future primary prevention clinical trials testing antiamyloid therapies in cognitively unimpaired (CU) individuals with initially low brain beta-amyloid (A beta) levels who are at high risk of accumulating A beta. OBJECTIVE To investigate if combining plasma biomarkers could be useful in predicting subsequent development of A beta pathology in CU individuals with subthreshold brain A beta levels (defined as A beta levels <40 Centiloids) at baseline. DESIGN, SETTING, AND PARTICIPANTS This was a longitudinal study including Swedish BioFINDER-2 (enrollment 2017-2022) and replication in 2 independent cohorts, the Knight Alzheimer Disease Research Center (Knight ADRC; enrollment 1988 and 2019) and Swedish BioFINDER-1 (enrollment 2009-2015). Included for analysis was a convenience sample of CU individuals with baseline plasma phosphorylated tau 217 (p-tau217) and A beta 42/40 assessments and A beta assessments with positron emission tomography (A beta-PET) or cerebrospinal fluid (CSF) A beta 42/40. Data were analyzed between April 2023 and May 2024. EXPOSURES Baseline plasma levels of A beta 42/40, p-tau217, the ratio of p-tau217 to nonphosphorylated tau (%p-tau217), p-tau231, and glial fibrillary acidic protein (GFAP). MAIN OUTCOMES AND MEASURES Cross-sectional and longitudinal PET and CSF measures of brain A beta pathology. RESULTS This study included 495 (BioFINDER-2), 283 (Knight ADRC), and 205 (BioFINDER-1) CU participants. In BioFINDER-2, the mean (SD) age was 65.7 (14.4) with 261 females (52.7%). When detecting abnormal CSF A beta-status, a combination of plasma %p-tau217 and A beta 42/40 showed better performance (area under the curve = 0.949; 95% CI, 0.929-0.970; P <.02) than individual biomarkers. In CU participants with subthreshold baseline A beta-PET, baseline plasma %p-tau217 and A beta 42/40 levels were significantly associated with baseline A beta-PET (n = 384) and increases in A beta-PET over time (n = 224). Associations of plasma %p-tau217 and A beta 42/40 and their interaction with baseline A beta-PET (%p-tau217: beta = 2.77; 95% CI, 1.84-3.70; A beta 42/40: beta = -1.64; 95% CI, -2.53 to -0.75; %p-tau217 x A beta 42/40: beta = -2.14; 95% CI, -2.79 to -1.49; P < .001) and longitudinal A beta-PET (%p-tau217: beta = 0.67; 95% CI, 0.48-0.87; A beta 42/40: beta = -0.33; 95% CI, -0.51 to -0.15; %p-tau217 x A beta 42/40: beta = -0.31; 95% CI, -0.44 to -0.18; P < .001) were also significant in the models combining the 2 baseline biomarkers as predictors. Similarly, baseline plasma p-tau217 and A beta 42/40 were independently associated with longitudinal A beta-PET in Knight ADRC (%p-tau217: beta = 0.71; 95% CI, 0.26-1.16; P = .002; A beta 42/40: beta = -0.74; 95% CI, -1.26 to -0.22; P = .006) and longitudinal CSF A beta 42/40 in BioFINDER-1 (p-tau217: beta = -0.0003; 95% CI, -0.0004 to -0.0001; P = .01; A beta 42/40: beta = 0.0004; 95% CI, 0.0002-0.0006; P < .001) in CU participants with subthreshold A beta levels at baseline. Plasma p-tau231 and GFAP did not provide any clear independent value. CONCLUSIONS AND RELEVANCE Results of this cohort study suggest that combining plasma p-tau217and A beta 42/40 levels could be useful for predicting development of A beta pathology in people with early stages of subthreshold A beta accumulation. These biomarkers might thus facilitate screening of participants for future primary prevention trials.
|
|
| 23. |
- Mattsson-Carlgren, Niklas, et al.
(author)
-
Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau
- 2021
-
In: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 13:6
-
Journal article (peer-reviewed)abstract
- Alzheimer’s disease is characterized by β-amyloid plaques and tau tangles. Plasma levels of phospho-tau217 (P-tau217) accurately differentiate Alzheimer’s disease dementia from other dementias, but it is unclear to what degree this reflects β-amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post-mortem neuropathological data (N = 88), both plaque and tangle density contributed independently to higher P-tau217, but P-tau217 was not elevated in patients with non-Alzheimer’s disease tauopathies (N = 9). Several findings were replicated in a cohort with PET imaging (“BioFINDER-2”, N = 426), where β-amyloid and tau PET were independently associated with P-tau217. P-tau217 concentrations correlated with β-amyloid PET (but not tau PET) in early disease stages and with both β-amyloid and (more strongly) tau PET in late disease stages. Finally, P-tau217 mediated the association between β-amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe. These findings support the hypothesis that plasma P-tau217 concentration is increased by both β-amyloid plaques and tau tangles and is congruent with the hypothesis that P-tau is involved in β-amyloid-dependent formation of neocortical tau tangles.
|
|
| 24. |
- Morenas-Rodriguez, E., et al.
(author)
-
Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer acute accent s disease: a longitudinal observational study
- 2022
-
In: LANCET NEUROLOGY. - 1474-4422. ; 21:4, s. 329-341
-
Journal article (peer-reviewed)abstract
- Background Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer's disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer's pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer's disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid beta (A beta) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer's disease. Methods We did a longitudinal analysis of data from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes families with a history of autosomal dominant Alzheimer's disease. Participants aged over 18 years who were enrolled in DIAN between Jan 1, 2009, and July 31, 2019, were categorised as either carriers of pathogenic variants in PSEN1 , PSEN2 , and APP genes (n=155) or non-carriers (n=93). We measured amounts of cleaved soluble TREM2 using a novel immunoassay in CSF samples obtained every 2 years from participants who were asymptomatic (Clinical Dementia Rating [CDR]=0) and annually for those who were symptomatic (CDR > 0). CSF concentrations of A beta 40, A beta 42, total tau (t-tau), and tau phosphorylated on threonine 181 (p-tau) were measured by validated immunoassays. Predefined neuroimaging measurements were total cortical uptake of Pittsburgh compound B PET (PiB-PET), cortical thickness in the precuneus ascertained by MRI, and hippocampal volume determined by MRI. Cognition was measured using a validated cognitive composite (including DIAN word list test, logical memory delayed recall, digit symbol coding test [total score], and minimental status examination). We based our statistical analysis on univariate and bivariate linear mixed effects models. Findings In carriers of pathogenic variants, a high amyloid burden at baseline, represented by low CSF A beta 42 (beta=-4.28 x 10(-2) [SE 0.013], p=0.0012), but not high cortical uptake in PiB-PET (beta=-5.51 x 10(-3) [0.011], p=0.63), was the only predictor of an augmented annual rate of subsequent increase in soluble TREM2. Augmented annual rates of increase in soluble TREM2 were associated with a diminished rate of decrease in amyloid deposition, as measured by A beta 42 in CSF (r=0.56 [0.22], p=0.011), in presymptomatic carriers of pathogenic variants, and with diminished annual rate of increase in PiB-PET (r=-0.67 [0.25], p=0.0060) in symptomatic carriers of pathogenic variants. Presymptomatic carriers of pathogenic variants with annual rates of increase in soluble TREM2 lower than the median showed a correlation between enhanced annual rates of increase in p-tau in CSF and augmented annual rates of increase in PiB-PET signal (r=0.45 [0.21], p=0.035), that was not observed in those with rates of increase in soluble TREM2 higher than the median. Furthermore, presymptomatic carriers of pathogenic variants with rates of increase in soluble TREM2 above or below the median had opposite associations between A beta 42 in CSF and PiB-PET uptake when assessed longitudinally. Augmented annual rates of increase in soluble TREM2 in presymptomatic carriers of pathogenic variants correlated with decreased cortical shrinkage in the precuneus (r=0.46 [0.22]), p=0.040) and diminished cognitive decline (r=0.67 [0.22], p=0.0020). Interpretation Our findings in autosomal dominant Alzheimer's disease position the TREM2 response within the amyloid cascade immediately after the first pathological changes in A beta aggregation and further support the role of TREM2 on A beta plaque deposition and compaction. Furthermore, these findings underpin a beneficial effect of TREM2 on A beta deposition, A beta-dependent tau pathology, cortical shrinkage, and cognitive decline. Soluble TREM2 could, therefore, be a key marker for clinical trial design and interpretation. Efforts to develop TREM2-boosting therapies are ongoing. Funding German Research Foundation, US National Institutes of Health.Copyright (C) 2022 Elsevier Ltd. All rights reserved.
|
|
| 25. |
- Pannee, Josef, 1979, et al.
(author)
-
The global Alzheimer's Association round robin study on plasma amyloid beta methods
- 2021
-
In: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 13:1
-
Journal article (peer-reviewed)abstract
- Introduction Blood-based assays to measure brain amyloid beta (A beta) deposition are an attractive alternative to the cerebrospinal fluid (CSF)-based assays currently used in clinical settings. In this study, we examined different blood-based assays to measure A beta and how they compare among centers and assays. Methods Aliquots from 81 plasma samples were distributed to 10 participating centers. Seven immunological assays and four mass-spectrometric methods were used to measure plasma A beta concentrations. Results Correlations were weak for A beta 42 while A beta 40 correlations were stronger. The ratio A beta 42/A beta 40 did not improve the correlations and showed weak correlations. Discussion The poor correlations for A beta 42 in plasma might have several potential explanations, such as the high levels of plasma proteins (compared to CSF), sensitivity to pre-analytical sample handling and specificity, and cross-reactivity of different antibodies. Different methods might also measure different pools of plasma A beta 42. We, however, hypothesize that greater correlations might be seen in future studies because many of the methods have been refined during completion of this study.
|
|
| 26. |
- Pérez-Escobar, Oscar, et al.
(author)
-
Resolving relationships in an exceedingly young Neotropical orchid lineage using Genotyping-by-sequencing data
- 2020
-
In: Molecular Phylogenetics and Evolution. - : Elsevier BV. - 1055-7903. ; 144
-
Journal article (peer-reviewed)abstract
- Poor morphological and molecular differentiation in recently diversified lineages is a widespread phenomenon in plants. Phylogenetic relationships within such species complexes are often difficult to resolve because of the low variability in traditional molecular loci. Furthermore, biological phenomena responsible for topological incongruence such as Incomplete Lineage Sorting (ILS) and hybridisation complicate the resolution of phylogenetic relationships among closely related taxa. In this study, we employ a Genotyping-by-sequencing (GBS) approach to disentangle evolutionary relationships within a species complex belonging to the Neotropical orchid genus Cycnoches. This complex includes seven taxa distributed through Central America and the Colombian Choco, and is nested within a Glade estimated to have first diversified in the early Quaternary. Previous phylogenies inferred from few loci failed to provide support for internal relationships within the complex. Our Neighbour-net and coalescent-based analyses inferred from ca. 13,000 GBS loci obtained from 31 individuals belonging to six of the seven traditionally accepted Cycnoches taxa provided a robust phylogeny for this group. The genus Cycnoches includes three main clades that are further supported by morphological traits and geographic distributions. Similarly, a topology reconstructed through maximum likelihood (ML) inference of con-catenated GBS loci produced results that are comparable with those reconstructed through coalescence and network-based methods. Our comparative phylogenetic informativeness analyses suggest that the low support evident in the ML phylogeny might be attributed to the abundance of uninformative GBS loci, which can account for up to 50% of the total number of loci recovered. The phylogenomic framework provided here, as well as morphological evidence and geographical patterns, suggest that the six entities previously thought to be different species or subspecies might actually represent only three distinct segregates. We further discuss the limited phylogenetic informativeness found in our GBS approach and its utility to disentangle relationships within recent and rapidly evolving species complexes. Our study is the first to demonstrate the utility of GBS data to reconstruct relationships within young (similar to 2 Ma) Neotropical plant clades, opening new avenues for studies of species complexes that populate the species-rich orchid family.
|
|
| 27. |
|
|
| 28. |
- Tosun, Duygu, et al.
(author)
-
Detection of β-amyloid positivity in Alzheimer's Disease Neuroimaging Initiative participants with demographics, cognition, MRI and plasma biomarkers.
- 2021
-
In: Brain communications. - : Oxford University Press (OUP). - 2632-1297. ; 3:2
-
Journal article (peer-reviewed)abstract
- In vivo gold standard for the ante-mortem assessment of brain β-amyloid pathology is currently β-amyloid positron emission tomography or cerebrospinal fluid measures of β-amyloid42 or the β-amyloid42/β-amyloid40 ratio. The widespread acceptance of a biomarker classification scheme for the Alzheimer's disease continuum has ignited interest in more affordable and accessible approaches to detect Alzheimer's disease β-amyloid pathology, a process that often slows down the recruitment into, and adds to the cost of, clinical trials. Recently, there has been considerable excitement concerning the value of blood biomarkers. Leveraging multidisciplinary data from cognitively unimpaired participants and participants with mild cognitive impairment recruited by the multisite biomarker study of Alzheimer's Disease Neuroimaging Initiative, here we assessed to what extent plasma β-amyloid42/β-amyloid40, neurofilament light and phosphorylated-tau at threonine-181 biomarkers detect the presence of β-amyloid pathology, and to what extent the addition of clinical information such as demographic data, APOE genotype, cognitive assessments and MRI can assist plasma biomarkers in detecting β-amyloid-positivity. Our results confirm plasma β-amyloid42/β-amyloid40 as a robust biomarker of brain β-amyloid-positivity (area under curve, 0.80-0.87). Plasma phosphorylated-tau at threonine-181 detected β-amyloid-positivity only in the cognitively impaired with a moderate area under curve of 0.67, whereas plasma neurofilament light did not detect β-amyloid-positivity in either group of participants. Clinical information as well as MRI-score independently detected positron emission tomography β-amyloid-positivity in both cognitively unimpaired and impaired (area under curve, 0.69-0.81). Clinical information, particularly APOE ε4 status, enhanced the performance of plasma biomarkers in the detection of positron emission tomography β-amyloid-positivity by 0.06-0.14 units of area under curve for cognitively unimpaired, and by 0.21-0.25 units for cognitively impaired; and further enhancement of these models with an MRI-score of β-amyloid-positivity yielded an additional improvement of 0.04-0.11 units of area under curve for cognitively unimpaired and 0.05-0.09 units for cognitively impaired. Taken together, these multi-disciplinary results suggest that when combined with clinical information, plasma phosphorylated-tau at threonine-181 and neurofilament light biomarkers, and an MRI-score could effectively identify β-amyloid+ cognitively unimpaired and impaired (area under curve, 0.80-0.90). Yet, when the MRI-score is considered in combination with clinical information, plasma phosphorylated-tau at threonine-181 and plasma neurofilament light have minimal added value for detecting β-amyloid-positivity. Our systematic comparison of β-amyloid-positivity detection models identified effective combinations of demographics, APOE, global cognition, MRI and plasma biomarkers. Promising minimally invasive and low-cost predictors such as plasma biomarkers of β-amyloid42/β-amyloid40 may be improved by age and APOE genotype.
|
|
