| 1. |
- Alifier, Marek, et al.
(författare)
-
Cardiac Surgery is Associated with Biomarker Evidence of Neuronal Damage.
- 2020
-
Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 74:4, s. 1211-1220
-
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.
|
|
| 2. |
- Andreasson, Ulf, 1968, et al.
(författare)
-
Assessing the commutability of candidate reference materials for the harmonization of neurofilament light measurements in blood
- 2023
-
Ingår i: Clinical Chemistry and Laboratory Medicine. - : Walter de Gruyter GmbH. - 1434-6621 .- 1437-4331. ; 61:7, s. 1245-1254
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives Neurofilament light chain (NfL) concentration in blood is a biomarker of neuro-axonal injury in the nervous system and there now exist several assays with high enough sensitivity to measure NfL in serum and plasma. There is a need for harmonization with the goal of creating a certified reference material (CRM) for NfL and an early step in such an effort is to determine the best matrix for the CRM. This is done in a commutability study and here the results of the first one for NfL in blood is presented.Methods Forty paired individual serum and plasma samples were analyzed for NfL on four different analytical platforms. Neat and differently spiked serum and plasma were evaluated for their suitability as a CRM using the difference in bias approach.Results The correlation between the different platforms with regards to measured NfL concentrations were very high (Spearman's rho >= 0.96). Samples spiked with cerebrospinal fluid (CSF) showed higher commutability compared to samples spiked with recombinant human NfL protein and serum seems to be a better choice than plasma as the matrix for a CRM.Conclusions The results from this first commutability study on NfL in serum/plasma showed that it is feasible to create a CRM for NfL in blood and that spiking should be done using CSF rather than with recombinant human NfL protein.
|
|
| 3. |
- Andreasson, Ulf, 1968, et al.
(författare)
-
Method and Clinical Validation of Biomarkers for Neurodegenerative Diseases
- 2021
-
Ingår i: Cerebrospinal Fluid Biomarkers. Neuromethods, vol 168. Teunissen C.E., Zetterberg H. (eds). - New York, NY : Springer. - 0893-2336. - 9781071613184 ; , s. 163-173
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- In the Merriam-Webster dictionary, one definition of the word valid is “well-grounded or justifiable: being at once relevant and meaningful.” Validation is then the process of determining the degree of validity. From this broad definition, it follows that validations can be made in many different fields with quite different implications. When talking about validation, it is therefore important to specify the subject under scrutiny and in this chapter the focus will be on validation of biomarkers. © 2021, Springer Science+Business Media, LLC, part of Springer Nature.
|
|
| 4. |
- Arvidsson Rådestig, Maya, et al.
(författare)
-
Cerebrospinal fluid biomarkers of axonal and synaptic degeneration in a population-based sample
- 2023
-
Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 15:1
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundNeurofilament light (NfL) and neurogranin (Ng) are promising candidate AD biomarkers, reflecting axonal and synaptic damage, respectively. Since there is a need to understand the synaptic and axonal damage in preclinical Alzheimer's disease (AD), we aimed to determine the cerebrospinal fluid (CSF) levels of NfL and Ng in cognitively unimpaired elderly from the Gothenburg H70 Birth Cohort Studies classified according to the amyloid/tau/neurodegeneration (A/T/N) system.MethodsThe sample consisted of 258 cognitively unimpaired older adults (age 70, 129 women and 129 men) from the Gothenburg Birth Cohort Studies. We compared CSF NfL and Ng concentrations in A/T/N groups using Student's T-test and ANCOVA.ResultsCSF NfL concentration was higher in the A-T-N+ group (p=0.001) and the A-T+N+ group (p=0.006) compared with A-T-N-. CSF Ng concentration was higher in the A-T-N+, A-T+N+, A+T-N+, and A+T+N+ groups (p<0.0001) compared with A-T-N-. We found no difference in NfL or Ng concentration in A+ compared with A- (disregarding T- and N- status), whereas those with N+ had higher concentrations of NfL and Ng compared with N- (p<0.0001) (disregarding A- and T- status).ConclusionsCSF NfL and Ng concentrations are increased in cognitively normal older adults with biomarker evidence of tau pathology and neurodegeneration.
|
|
| 5. |
- Boulo, S., et al.
(författare)
-
First amyloid β1-42 certified reference material for re-calibrating commercial immunoassays
- 2020
-
Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 16:11, s. 1493-1503
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Reference materials based on human cerebrospinal fluid were certified for the mass concentration of amyloid beta (Aβ)1-42 (Aβ42). They are intended to be used to calibrate diagnostic assays for Aβ42. Methods: The three certified reference materials (CRMs), ERM-DA480/IFCC, ERM-DA481/IFCC and ERM-DA482/IFCC, were prepared at three concentration levels and characterized using isotope dilution mass spectrometry methods. Roche, EUROIMMUN, and Fujirebio used the three CRMs to re-calibrate their immunoassays. Results: The certified Aβ42 mass concentrations in ERM-DA480/IFCC, ERM-DA481/IFCC, and ERM-DA482/IFCC are 0.45, 0.72, and 1.22μg/L, respectively, with expanded uncertainties (k=2) of 0.07, 0.11, and 0.18μg/L, respectively. Before re-calibration, a good correlation (Pearson's r>0.97), yet large biases, were observed between results from different commercial assays. After re-calibration the between-assay bias was reduced to<5%. Discussion: The Aβ42 CRMs can ensure the equivalence of results between methods and across platforms for the measurement of Aβ42. © 2020 the Alzheimer's Association
|
|
| 6. |
- Boza-Serrano, A., et al.
(författare)
-
Galectin-3 is elevated in CSF and is associated with A beta deposits and tau aggregates in brain tissue in Alzheimer's disease
- 2022
-
Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533.
-
Tidskriftsartikel (refereegranskat)abstract
- Galectin-3 (Gal-3) is a beta-galactosidase binding protein involved in microglial activation in the central nervous system (CNS). We previously demonstrated the crucial deleterious role of Gal-3 in microglial activation in Alzheimer's disease (AD). Under AD conditions, Gal-3 is primarily expressed by microglial cells clustered around A beta plaques in both human and mouse brain, and knocking out Gal-3 reduces AD pathology in AD-model mice. To further unravel the importance of Gal-3-associated inflammation in AD, we aimed to investigate the Gal-3 inflammatory response in the AD continuum. First, we measured Gal-3 levels in neocortical and hippocampal tissue from early-onset AD patients, including genetic and sporadic cases. We found that Gal-3 levels were significantly higher in both cortex and hippocampus in AD subjects. Immunohistochemistry revealed that Gal-3+ microglial cells were associated with amyloid plaques of a larger size and more irregular shape and with neurons containing tau-inclusions. We then analyzed the levels of Gal-3 in cerebrospinal fluid (CSF) from AD patients (n=119) compared to control individuals (n= 36). CSF Gal-3 levels were elevated in AD patients compared to controls and more strongly correlated with tau (p-Tau181 and t-tau) and synaptic markers (GAP-43 and neurogranin) than with amyloid-beta. Lastly, principal component analysis (PCA) of AD biomarkers revealed that CSF Gal-3 clustered and associated with other CSF neuroinflammatory markers, including sTREM-2, GFAP, and YKL-40. This neuroinflammatory component was more highly expressed in the CSF from amyloid-beta positive (A+), CSF p-Tau181 positive (T+), and biomarker neurodegeneration positive/negative (N+/-) (A + T +N+/-) groups compared to the A + T-N- group. Overall, Gal-3 stands out as a key pathological biomarker of AD pathology that is measurable in CSF and, therefore, a potential target for disease-modifying therapies involving the neuroinflammatory response.
|
|
| 7. |
- Camu, W., et al.
(författare)
-
Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial
- 2020
-
Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 59
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Low-dose interleukin-2 (ld-IL-2) enhances regulatory T-cell (Treg) function in auto-inflammatory conditions. Neuroinflammation being a pathogenic feature of amyotrophic lateral sclerosis (ALS), we evaluated the pharmacodynamics and safety of ld-IL-2 in ALS subjects. Methods: We performed a single centre, parallel three-arm, randomised, double-blind, placebo-controlled study. Eligibility criteria included age < 75 years, disease duration < 5 years, riluzole treatment > 3 months, and a slow vital capacity ≥ 70% of normal. Patients were randomised (1:1:1) to aldesleukin 2 MIU, 1 MIU, or placebo once daily for 5 days every 4 weeks for 3 cycles. Primary outcome was change from baseline in Treg percentage of CD4+ T cells (%Tregs) following a first cycle. Secondary laboratory outcomes included: %Treg and Treg number following repeated cycles, and plasma CCL2 and neurofilament light chain protein (NFL) concentrations as surrogate markers of efficacy. Safety outcomes included motor-function (ALSFRS-R), slow vital capacity (SVC), and adverse event reports. This trial is registered with ClinicalTrials.gov, NCT02059759. Findings: All randomised patients (12 per group), recruited from October 2015 to December 2015, were alive at the end of follow-up and included in the intent-to-treat (ITT) analysis. No drug-related serious adverse event was observed. Non-serious adverse events occurred more frequently with the 1 and 2 MIU IL-2 doses compared to placebo, including injection site reactions and flu-like symptoms. Primary outcome analysis showed a significant increase (p < 0·0001) in %Tregs in the 2 MIU and 1 MIU arms (mean [SD]: 2 MIU: +6·2% [2·2]; 1 MIU: +3·9% [1·2]) as compared to placebo (mean [SD]: -0·49% [1·3]). Effect sizes (ES) were large in treated groups: 2 MIU ES=3·7 (IC95%: 2·3–4·9) and 1 MIU ES=3·5 (IC95%: 2·1–4·6). Secondary outcomes showed a significant increase in %Tregs following repeated cycles (p < 0·0001) as compared to placebo, and a dose-dependent decrease in plasma CCL2 (p = 0·0049). There were no significant differences amongst the three groups on plasma NFL levels. Interpretation: Ld-IL-2 is well tolerated and immunologically effective in subjects with ALS. These results warrant further investigation into their eventual therapeutic impact on slowing ALS disease progression. Funding: : The French Health Ministry (PHRC-I-14-056), EU H2020 (grant #633413), and the Association pour la Recherche sur la SLA (ARSLA). © 2020 The Authors
|
|
| 8. |
- Cullen, Nicholas C., et al.
(författare)
-
Comparing progression biomarkers in clinical trials of early Alzheimer's disease
- 2020
-
Ingår i: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 7:9, s. 1661-1673
-
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.
|
|
| 9. |
- Dutkiewicz, Robert, et al.
(författare)
-
Dementia and CSF-biomarkers for Alzheimer's disease predict mortality after acute hip fracture
- 2020
-
Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 64:1, s. 93-103
-
Tidskriftsartikel (refereegranskat)abstract
- Background Mortality is high after an acute hip fracture (AHF) surgery. Are cognitive impairment and/or altered levels of Alzheimer's Disease (AD)-biomarkers in cerebrospinal fluid (CSF) predictors of mortality in AHF-patients, as retrospective studies indicate? Methods Prospective single-center study including 373 AHF-patients, operated in spinal anesthesia. Cognitive status was evaluated by clinical dementia rating (CDR); CSF was analyzed for AD-biomarker concentrations (total tau (T-tau), phosphorylated tau (P-tau), amyloid beta ratio (A beta 42/A beta 40). CDR and biomarker levels were related to mortality up to one-year post-surgery, using univariate logistic regression analysis. Results Survival analyses showed that mortality was associated to the degree of dementia. In the entire patient cohort 30-, 90-, and 365-day mortality rates were 7.2%, 15.5%, and 25.5%, respectively, but only 2.7%, 5.5%, and 12.6%, for cognitively intact vs 16.3%, 31.7%, and 42.3% for demented patients (OR = 2.2-2.8 [CI = 1.6-4.9]; P = .0001). High CSF T-tau (OR = 1.19 [CI = 1.05-1.33]; P = .004) and low A beta 42/A beta 40-ratio (OR = 0.85 [CI = 0.74-0.97]; P = .017) were associated with increased 90-day mortality. Analysis of 4 subgroups (Cognitive impairment +/- and Biomarkers +/-) showed significant associations of dementia and CSF biomarker concentrations to mortality after an AHF. Even cognitively intact patients presenting with abnormal AD-biomarkers showed an increased 90-day mortality which, however, was statistically insignificant. Conclusions Cognitive impairment and altered CSF biomarker concentrations indicative of AD pathology can predict increased mortality in patients with an AHF, and so probably even before clinical dementia diagnosis by early biomarker analysis; a notion that may have substantial clinical implications by improving perioperative treatment and postoperative rehabilitation.
|
|
| 10. |
- Erickson, Pontus, et al.
(författare)
-
Prevalence and Clinical Implications of a β-Amyloid-Negative, Tau-Positive Cerebrospinal Fluid Biomarker Profile in Alzheimer Disease.
- 2023
-
Ingår i: JAMA neurology. - 2168-6157. ; 80:9, s. 969-979
-
Tidskriftsartikel (refereegranskat)abstract
- Knowledge is lacking on the prevalence and prognosis of individuals with a β-amyloid-negative, tau-positive (A-T+) cerebrospinal fluid (CSF) biomarker profile.To estimate the prevalence of a CSF A-T+ biomarker profile and investigate its clinical implications.This was a retrospective cohort study of the cross-sectional multicenter University of Gothenburg (UGOT) cohort (November 2019-January 2021), the longitudinal multicenter Alzheimer Disease Neuroimaging Initiative (ADNI) cohort (individuals with mild cognitive impairment [MCI] and no cognitive impairment; September 2005-May 2022), and 2 Wisconsin cohorts, Wisconsin Alzheimer Disease Research Center and Wisconsin Registry for Alzheimer Prevention (WISC; individuals without cognitive impairment; February 2007-November 2020). This was a multicenter study, with data collected from referral centers in clinical routine (UGOT) and research settings (ADNI and WISC). Eligible individuals had 1 lumbar puncture (all cohorts), 2 or more cognitive assessments (ADNI and WISC), and imaging (ADNI only) performed on 2 separate occasions. Data were analyzed on August 2022 to April 2023.Baseline CSF Aβ42/40 and phosphorylated tau (p-tau)181; cognitive tests (ADNI: modified preclinical Alzheimer cognitive composite [mPACC]; WISC: modified 3-test PACC [PACC-3]). Exposures in the ADNI cohort included [18F]-florbetapir amyloid positron emission tomography (PET), magnetic resonance imaging (MRI), [18F]-fluorodeoxyglucose PET (FDG-PET), and cross-sectional tau-PET (ADNI: [18F]-flortaucipir, WISC: [18F]-MK6240).Primary outcomes were the prevalence of CSF AT biomarker profiles and continuous longitudinal global cognitive outcome and imaging biomarker trajectories in A-T+ vs A-T- groups. Secondary outcomes included cross-sectional tau-PET.A total of 7679 individuals (mean [SD] age, 71.0 [8.4] years; 4101 male [53%]) were included in the UGOT cohort, 970 individuals (mean [SD] age, 73 [7.0] years; 526 male [54%]) were included in the ADNI cohort, and 519 individuals (mean [SD] age, 60 [7.3] years; 346 female [67%]) were included in the WISC cohort. The prevalence of an A-T+ profile in the UGOT cohort was 4.1% (95% CI, 3.7%-4.6%), being less common than the other patterns. Longitudinally, no significant differences in rates of worsening were observed between A-T+ and A-T- profiles for cognition or imaging biomarkers. Cross-sectionally, A-T+ had similar tau-PET uptake to individuals with an A-T- biomarker profile.Results suggest that the CSF A-T+ biomarker profile was found inapproximately5% of lumbar punctures and was not associated with a higher rate of cognitive decline or biomarker signs of disease progression compared with biomarker-negative individuals.
|
|
