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Anti-GQ1b antibodies can be detected in the serum of patients with Miller Fisher syndrome (MFS) and its incomplete forms such as acute ophthalmoparesis (AO), acute ptosis, acute mydriasis, acute oropharyngeal palsy and acute ataxic neuropathy (AAN), as well as in pharyngeal–cervical–brachial weakness, Bickerstaff brainstem encephalitis (BBE) and in overlap syndromes with Guillain–Barre syndrome (MFS–GBS, BBE–GBS). We searched the laboratory medicine database at University Hospitals Leuven between 2002 and 2017 for serum samples with anti-GQ1b IgG antibodies. We identified eight patients with anti-GQ1b antibodies: 4 MFS, 2 AO, 1 MFS–GBS and 1 AAN. Mean age was 57 years and five patients were males. Preceding illness was present in all patients. At nadir, we observed most frequently gait disturbance, external ophthalmoplegia and absent/decreased reflexes. Albumino-cytological dissociation was present in four patients. Mean time between onset and nadir was 4 days, between onset and recovery 2.5 months. Five patients recovered completely and three had minor residual symptoms. Interestingly, one patient with AO experienced a second identical episode, approximately 1 year after the first one. Our data confirm the broad clinical spectrum associated with the presence of anti-GQ1b IgG antibodies. Incomplete MFS subtypes such as AO are a challenge for diagnosis, because of the limited (though invalidating) clinical presentation and the lack of confirming ancillary tests. Subacute onset of ophthalmoplegia and/or ataxia should urge the clinician to include the anti-GQ1b antibody syndrome in the differential diagnosis.

Solid phase assays (SPAs) and automated microscope systems are increasingly used to screen for antinuclear antibodies (ANAs). The goal of this study was to evaluate the performance of three automated ANA screening assays; NOVA Lite HEp-2 using NOVA View® (NV, Inova Diagnostics), an automated indirect immunofluorescence method, EliA™ CTD Screen (Fluorescence Enzyme Immunoassay, FEIA; Thermo Fisher) and QUANTA Flash® CTD Screen Plus (Chemiluminescence immunoassay, CIA; Inova Diagnostics). The assays were performed on 480 diagnostic samples from patients with an ANA-associated rheumatic disease (AARD; systemic lupus erythematosus, primary Sjögren's syndrome, systemic sclerosis, inflammatory myopathy, mixed connective tissue disease) and on 767 samples from diseased and healthy controls. Using cut-offs proposed by the manufacturers, the sensitivity was 95%, 80.5% and 86% for NV, FEIA and CIA, respectively. The corresponding specificity was 61% (NV), 97.5% (FEIA) and 88% (CIA). The sensitivity associated with a specificity of ~95% was 79%, 82% and 78% for NV, FEIA, and CIA, respectively. Receiver operating characteristics (ROC) curve analysis revealed no differences in area under the curve (AUC) between the 3 assays when all diseases were grouped. For Sjögren's syndrome, the AUC was higher for SPAs than for NV, whereas for systemic sclerosis, the AUC was higher for NV than for CIA. For all assays, the likelihood ratio for AARD increased with increasing antibody levels and for double positivity of NV with SPA. In conclusion, the performance of automated SPA and IIF was assay- and disease-dependent. Taking into account antibody levels and combining IIF with SPA adds value. ispartof: Autoimmunity Reviews vol:17 issue:6 pages:533-540 ispartof: location:Netherlands status: published

The lack of (inter-)laboratory standardization has hampered the application of universal cutoff values for Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers and their transfer to general clinical practice. The automation of the AD biomarker immunoassays is suggested to generate more robust results than using manual testing. Open-access platforms will facilitate the integration of automation for novel biomarkers, allowing the introduction of the protein profiling concept. A feasibility study was performed on an automated open-access platform of the commercial immunoassays for the 42-amino-acid isoform of amyloid-β (Aβ1-42), Aβ1-40, and total tau in CSF. Automated Aβ1-42, Aβ1-40, and tau immunoassays were performed within predefined acceptance criteria for bias and imprecision. Similar accuracy was obtained for ready-to-use calibrators as for reconstituted lyophilized kit calibrators. When compared with the addition of a standard curve in each test run, the use of a master calibrator curve, determined before and applied to each batch analysis as the standard curve, yielded an acceptable overall bias of -2.6% and -0.9% for Aβ1-42 and Aβ1-40, respectively, with an imprecision profile of 6.2% and 8.4%, respectively. Our findings show that transfer of commercial manual immunoassays to fully automated open-access platforms is feasible, as it performs according to universal acceptance criteria. ispartof: SLAS technology vol:23 issue:2 pages:188-197 ispartof: location:United States status: published

AIMS: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron degeneration disease with a diagnostic delay of about 1 year after symptoms onset. In ALS, blood neurofilament light chain (NfL) levels are elevated, but it is not entirely clear what drives this increase and what the diagnostic performance of serum NfL is in terms of predictive values and likelihood ratios. The aims of this study were to further explore the prognostic and diagnostic performances of serum NfL to discriminate between patients with ALS and ALS mimics, and to investigate the relationship between serum NfL with motor neuron degeneration. METHODS: The diagnostic performances of serum NfL were based on a cohort of 149 serum samples of patients with ALS, 19 serum samples of patients with a disease mimicking ALS and 82 serum samples of disease control patients. The serum NfL levels were correlated with the number of regions (thoracic, bulbar, upper limb and lower limb) displaying upper and/or lower motor neuron degeneration. The prognostic performances of serum NfL were investigated based on a Cox regression analysis. RESULTS: The associated predictive values and likelihood ratio to discriminate patients with ALS and ALS mimics were established. Serum NfL was associated with motor neuron degeneration driven by upper motor neuron (UMN) degeneration and was independently associated with survival in patients with ALS. CONCLUSIONS: Altogether, these findings suggest that elevated serum NfL levels in ALS are driven by UMN degeneration and the disease progression rate and are independently associated with survival at time of diagnosis. ispartof: Neuropathology And Applied Neurobiology vol:45 issue:3 pages:291-304 ispartof: location:England status: published

Consider the diagnosis of autoimmune encephalitis in patients with progressive disorders of voluntary eye movements in the context of encephalopathy.

It was with much interest that we read the recent European League Against Rheumatism/American College of Rheumatology classification criteria for idiopathic inflammatory myopathies.1 These criteria include Jo-1 autoantibodies, and the authors discussed that future updates of the criteria should also include the more recently identified myositis-specific autoantibodies.1 2 The interest in autoantibodies for classification is also illustrated by a recent proposal for a new clinicoserological classification of adult autoimmune myositis, which is based on the association of autoantibodies with distinct clinical phenotypes.3 4 For example, antibodies to synthetases (eg, Jo-1, PL-7 and PL-12) define the antisynthetase syndrome, anti-MDA-5 antibodies are associated with myositis with overlap features such as interstitial lung disease, anti-TIF-1γ and anti-NXP-2 define a subgroup of dermatomyositis and anti-SRP and anti-HMGCR are associated with necrotising autoimmune myositis.2 As autoantibodies play a role in the newly proposed classifications,1 …

ispartof: ALZHEIMER DISEASE & ASSOCIATED DISORDERS vol:32 issue:2 pages:156-157 ispartof: location:United States status: published

ispartof: LEUKEMIA vol:32 issue:8 pages:1815-1818 ispartof: location:England status: published

ispartof: CLINICAL CHEMISTRY AND LABORATORY MEDICINE vol:56 issue:9 pages:E235-E238 ispartof: location:Germany status: published

ObjectiveTo examine neurofilament (Nf) concentrations according to symptom onset and clinical diagnostic certainty categories of amyotrophic lateral sclerosis (ALS).MethodsWe measured Nf light chain (NfL) and phosphorylated Nf heavy chain (pNfH) CSF and NfL serum levels in patients with ALS with first symptom onset ≤6 months (n = 54) or >6 months (n = 135) from sampling, and patients with other neurologic diseases, differential diagnoses of a motor neuron disease (MND mimics), and other MND variants to determine the diagnostic accuracy in patients with ALS with early symptom onset. Samples were received multicentric and analyzed by ELISA and Simoa platform and related to other clinical measures.ResultsNfL and pNfH in CSF and NfL in serum were increased in early and later symptomatic phase ALS (p < 0.0001). CSF and serum NfL and CSF pNfH discriminated patients with ALS with early symptom onset from those with other neurologic diseases and MND mimics with high sensitivity (94%, 88%, 98%, and 89%, 100%, 78%) and specificity (86%, 92%, 91%, and 94%, 90%, 98%) and did not vary between clinical diagnostic categories of ALS in the early symptomatic phase group. Baseline NfL and pNfH levels were not significantly different in patients with ALS with clinical progression to definite or probable ALS at follow-up.ConclusionThe measurement of Nf has potential to enhance diagnostic accuracy of ALS in those presenting soon after symptom onset, and is measurable across multiple centers.Classification of evidenceThis study provides Class II evidence that CSF and serum Nf concentrations discriminate ALS with early symptom onset from other neurologic diseases.

SummaryBackground Xenon has repeatedly been demonstrated to have only minimal hemodynamic side effects when compared to other anesthetics. Moreover, in experimental models, xenon was found to be neuroprotective and devoid of developmental neurotoxicity. These properties could render xenon attractive for the anesthesia in neonates and infants with congenital heart disease. However, experience with xenon anesthesia in children is scarce. Aims We hypothesized that in children undergoing cardiac catheterization, general anesthesia with a combination of sevoflurane with xenon results in superior hemodynamic stability, compared to sevoflurane alone. Methods In this prospective, randomized, single-blinded, controlled clinical trial, children with a median age of 12 [IQR 3-36] months undergoing diagnostic/interventional cardiac catheterization were randomized to either general anesthesia with 50-65vol% xenon plus sevoflurane or sevoflurane alone. The primary outcome was the incidence of intraprocedural hemodynamic instability, defined as the occurrence of: (i) a heart rate change >20% from baseline; or (ii) a change in mean arterial blood pressure >20% from baseline; or (iii) the requirement of vasopressors, inotropes, chronotropes, or fluid boluses. Secondary endpoints included recovery characteristics, feasibility criteria, and safety (incidence of emergence agitation and postoperative vomiting. Results After inclusion of 40 children, the trial was stopped as an a priori planned blinded interim analysis revealed that the overall rate of hemodynamic instability did not differ between groups [100% in both the xenon-sevoflurane and the sevoflurane group. However, the adjuvant administration of xenon decreased vasopressor requirements, preserved better cerebral oxygen saturation, and resulted in a faster recovery. Xenon anesthesia was feasible (with no differences in the need for rescue anesthetics in both groups). Conclusion Our observations suggest that combining xenon with sevoflurane in preschool children is safe, feasible, and facilitates hemodynamic management. Larger and adequately powered clinical trials are warranted to investigate the impact of xenon on short- and long-term outcomes in pediatric anesthesia.

Connective tissue growth factor (CTGF) is an important mediator of renal allograft fibrosis, and urinary CTGF (CTGFu) levels correlate with the development of human allograft interstitial fibrosis. We evaluated the predictive value of CTGF protein expression in 160 kidney transplant recipients with paired protocol biopsies at 3 months and 5 years after transplantation. At month 3 and year 1, CTGFu was measured using ELISA, and biopsies were immunohistochemically stained for CTGF, with semiquantitative scoring of tubulointerstitial CTGF-positive area (CTGFti). Predictors of interstitial fibrosis and tubular atrophy (IF/TA) severity at 5 years were donor age [OR 1.05 (1.02–1.08), P = 0.001], female donor [OR 0.40 (0.18–0.90), P = 0.026], induction therapy [OR 2.76 (1.10–6.89), P = 0.030], and CTGFti >10% at month 3 [OR 2.72 (1.20–6.15), P = 0.016]. In subgroups of patients with little histologic damage at 3 months [either ci score 0 (n = 119), IF/TA score ≤1 (n = 123), or absence of IF/TA, interstitial inflammation, and tubulitis (n = 45)], consistent predictors of progression of chronic histologic damage by 5 years were donor age, induction therapy, CTGFti >10%, and CTGFu. These results suggest that, even in patients with favorable histology at 3 months, significant CTGF expression is often present which may predict accelerated accumulation of histologic damage.

Background Myositis-specific autoantibodies (MSA) are increasingly recognized as important diagnostic and prognostic markers in idiopathic inflammatory myopathies (IIM) (polymyositis, dermatomyositis, sporadic inclusion body myositis and necrotizing autoimmune myositis). The prevalence of these MSAs in other systemic autoimmune rheumatic diseases and neuromuscular diseases is unclear. Objectives To compare positivity of MSA in a cohort of IIM patients to positivity in healthy controls and different systemic autoimmune rheumatic diseases (SARD) or chronic inflammatory demyelinating polyneuropathy (CIDP). Methods A line immunoassay (Myositis 12 IgG DOT for BlueDiver) for IgG autoantibodies against Jo-1, PL-7, PL-12, EJ, SRP, Mi-2, MDA-5, TIF1-γ, HMGCR, SSA/Ro52kD, SAE1/2 and NXP-2 antigens was performed in patients with IIM (n=146), healthy controls (blood donors, n=40) and disease controls (n=200). The disease control group consisted of patients with other SARD (rheumatoid arthritis, RA; systemic sclerosis, Ssc; Sjogren9s syndrome, SjS; and systemic lupus erythematosus, SLE) (n=40 for each disease group) and CIDP (n=40). A result >10 arbitrary units was considered significantly positive. Results 50% of 146 patients with IIM tested positive for an MSA (table 1), compared to 3,5% of 200 disease controls (table 1). 1 SSc patient was positive for Jo-1, 1 CIDP patient was positive for PL12, 2 SSc patients were positive for TIF1-gamma, 2 patients (1 SSc and 1 SjS patient) were positive for SAE1/2, and 1 SjS patient was positive for NXP2. The prevalence of SAE1/2 and TIF1-gamma positivity was similar in the IIM and disease control group. No healthy control had a significantly positive MSA. Conclusions MSA positivity in patients with a clinical non-IIM diagnosis (other SARD or CIDP) is infrequent compared to positivity in the IIM group. For TIF1-gamma and SAE1/2 assay performance may need to be optimized. The distribution of subtypes of MSA in this IIM cohort is consistent with data of previous studies.1 References Allenbach Y, Benveniste O. Diagnostic Utility of Autoantibodies in Inflammatory Muscle Diseases. J Neuromuscul Dis. 2015; 2:13–25. Disclosure of Interest None declared

ABSTACT Introduction: Disturbances of eye movements are infrequently encountered in motor neuron diseases (MNDs) or motor neuropathies, and there is no known syndrome that combines progressive muscle weakness with downbeat nystagmus. Methods: To describe the core clinical features of a syndrome of MND associated with downbeat nystagmus, clinical features were collected from 6 patients. Results: All patients had slowly progressive muscle weakness and wasting in combination with downbeat nystagmus, which was clinically most obvious in downward and lateral gaze. Onset was in the second to fourth decade with finger extension weakness, progressing to other distal and sometimes more proximal muscles. Visual complaints were not always present. Electrodiagnostic testing showed signs of regional motor axonal loss in all patients. Discussion: The etiology of this syndrome remains elusive. Because finger extension weakness and downbeat nystagmus are the discriminating clinical features of this MND, we propose the name FEWDON‐MND syndrome. Muscle Nerve 56: 1164–1168, 2017

ispartof: EBIOMEDICINE vol:33 pages:6-7 ispartof: location:Netherlands status: published

Besides its prominent role in angiogenesis, the vascular endothelial growth factor (VEGF) also exerts important protective effects on neurons. In particular, mice expressing reduced levels of VEGF suffer from late-onset motor neuron degeneration, whereas VEGF delivery significantly delays motor neuron death in ALS mouse models, at least partly through neuroprotective effects. Additionally, VEGF protects dorsal root ganglion (DRG) neurons against paclitaxel-induced neurotoxicity. Here, we demonstrate that VEGF also protects DRG neurons against hyperglycemia-induced neuronal stress as a model of diabetes-induced peripheral neuropathy. Specifically, VEGF decreased expression of the stress-related gene activating transcription factor 3 (ATF3) in DRG neurons isolated from streptozotocin-induced diabetic mice (ex vivo) and in isolated DRG neurons exposed to high glucose concentrations (in vitro). In vivo, local VEGF application also protected against paclitaxel- and diabetes-induced neuropathies without causing side effects. A small synthetic VEGF mimicking pentadecapeptide (QK) exerted similar effects on DRG cultures: the peptide reduced ATF3 expression in vitro and ex vivo in paclitaxel- and hyperglycemia-induced models of neuropathy to a similar extent as the full-length recombinant VEGF protein. By using transgenic mice selectively overexpressing the VEGF receptor 2 in postnatal neurons, these neuroprotective effects were shown to be mediated through VEGF receptor 2. Overall, these results underscore the potential of VEGF and VEGF-derived peptides for the treatment of peripheral neuropathies. (c) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

In light of the widespread use of ecstasy, it is surprising that only few cases of intoxicated young children have been reported. Patients almost invariably present with convulsions accompanied by sympathetic signs and symptoms such as hyperthermia. Two new cases of toddlers intoxicated with ecstasy are described. The first patient, a 19-month-old boy, presented with convulsions but no sympathetic signs. The pediatrician's suspicion was raised because of the absence of a postictal state. The second patient, a 20-month-old girl, had a more typical presentation with convulsions and hyperthermia. Her story illustrates the fact that immunoassays for toxicological screening can easily miss traces of additional illicit drugs present in the urine such as cocaine. The presence of other illicit drugs provides clues to the child's risky environment and should lead to further investigation. Finally, we review the available literature on ecstasy intoxication to summarize the key presenting manifestations.

Objective:To determine the diagnostic performance and prognostic value of phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL) in CSF as possible biomarkers for amyotrophic lateral sclerosis (ALS) at the diagnostic phase.Methods:We measured CSF pNfH and NfL concentrations in 220 patients with ALS, 316 neurologic disease controls (DC), and 50 genuine disease mimics (DM) to determine and assess the accuracy of the diagnostic cutoff value for pNfH and NfL and to correlate with other clinical parameters.Results:pNfH was most specific for motor neuron disease (specificity 88.2% [confidence interval (CI) 83.0%–92.3%]). pNfH had the best performance to differentially diagnose patients with ALS from DM with a sensitivity of 90.7% (CI 84.9%–94.8%), a specificity of 88.0% (CI 75.7%–95.5%) and a likelihood ratio of 7.6 (CI 3.6–16.0) at a cutoff of 768 pg/mL. CSF pNfH and NfL levels were significantly lower in slow disease progressors, however, with a poor prognostic performance with respect to the disease progression rate. CSF pNfH and NfL levels increased significantly as function of the number of regions with both upper and lower motor involvement.Conclusions:In particular, CSF pNfH concentrations show an added value as diagnostic biomarkers for ALS, whereas the prognostic value of pNfH and NfL warrants further investigation. Both pNfH and NfL correlated with the extent of motor neuron degeneration.Classification of evidence:This study provides Class II evidence that elevated concentrations of CSF pNfH and NfL can accurately identify patients with ALS.

OBJECTIVE: Neurofilaments are leading neurochemical biomarkers for amyotrophic lateral sclerosis (ALS). Here, we investigated the effect of preanalytical factors on neurofilament concentrations in cerebrospinal fluid (CSF) in a “reverse” round-robin with 15 centers across Europe/U.S. METHODS: Samples from ALS and control patients (5/5 each center, n = 150) were analyzed for phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL) at two laboratories. RESULTS: CSF pNfH was increased (p 568.5 pg/mL for pNfH (sensitivity 78.7%, specificity 93.3%) and >1,431pg/mL for NfL (sensitivity 79.0%, specificity 86.4%). CONCLUSION: Values in ALS patients are already comparable between most centers, supporting eventual implementation into clinical routine. However, continuous quality control programs will be necessary for inclusion in the diagnostic work-up. © 2016 World Federation of Neurology on behalf of the Research Group on Motor Neuron Diseases

Even though VEGF-B is a homologue of the potent angiogenic factor VEGF, its angiogenic activities have been controversial. Intrigued by findings that VEGF-B may also affect neuronal cells, we assessed the neuroprotective and vasculoprotective effects of VEGF-B in the skin, in which vessels and nerves are functionally intertwined. Although VEGF-B and its FLT1 receptor were prominently expressed in dorsal root ganglion (DRG) neurons innervating the hindlimb skin, they were not essential for nerve function or vascularization of the skin. However, primary DRG cultures lacking VEGF-B or FLT1 exhibited increased neuronal stress and were more susceptible to paclitaxel-induced cell death. Concomitantly, mice lacking VEGF-B or a functional FLT1 developed more retrograde degeneration of sensory neurons in a model of distal neuropathy. On the other hand, the addition of the VEGF-B isoform, VEGF-B186, to DRG cultures antagonized neuronal stress, maintained the mitochondrial membrane potential and stimulated neuronal survival. Mice overexpressing VEGF-B186 or FLT1 selectively in neurons were protected against the distal neuropathy, whereas exogenous VEGF-B186, either delivered by gene transfer or as a recombinant factor, was protective by directly affecting sensory neurons and not the surrounding vasculature. Overall, this indicates that VEGF-B, instead of acting as an angiogenic factor, exerts direct neuroprotective effects through FLT1. These findings also suggest a clinically relevant role for VEGF-B in preventing distal neuropathies.—Dhondt, J., Peeraer, E., Verheyen, A., Nuydens, R., Buysschaert, I., Poesen, K., Van Geyte, K., Beerens, M., Shibuya, M., Haigh, J. J., Meert, T., Carmeliet, P., Lambrechts, D. Neuronal FLT1 receptor and its selective ligand VEGF-B protect against retrograde degeneration of sensory neurons.

Influx of Ca(2+) ions through the α-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) receptors is toxic to neurons and contributes to motor neuron degeneration observed in amyotrophic lateral sclerosis (ALS). The Ca(2+) permeability of the AMPA receptor depends on its subunit composition. If the GluR2 subunit is present in the receptor complex, the AMPA receptor is impermeable to Ca(2+). In this study, we identified vascular endothelial growth factor-A (VEGF) as a GluR2 inducing molecule. Cultured motor neurons pretreated with VEGF displayed higher GluR2 levels. This resulted in AMPA receptor currents with a low relative Ca(2+) permeability and in motor neurons that were less vulnerable to AMPA receptor-mediated excitotoxicity. This effect of VEGF was mediated through the VEGFR2 present on the motor neurons and was due to stimulation of GluR2 transcription. Intracerebroventricular treatment with VEGF similarly induced GluR2 expression in the ventral spinal cord of rats and this mechanism contributes to the protective effect of VEGF on motor neurons.

Targeted delivery of the angiogenic factor, vascular endothelial growth factor (VEGF), to motor neurons prolongs survival in rodent models of amyotrophic lateral sclerosis (ALS), while mice expressing reduced VEGF concentrations develop motor neuron degeneration reminiscent of ALS, raising the question whether VEGF contributes to the pathogenesis of ALS. An initial association study reported that VEGF haplotypes conferred increased susceptibility to ALS in humans, but later studies challenged this initial finding.A meta-analysis was undertaken to critically reappraise whether any of the three common VEGF gene variations (-2578C/A, -1154G/A and -634G/C) increase the risk of ALS. Over 7000 subjects from eight European and three American populations were included in the analysis. Pooled odds ratios were calculated using fixed-effects and random-effects models, and four potential sources of heterogeneity (location of disease onset, gender, age at disease onset and disease duration) were assessed. After correction, none of the genotypes or haplotypes was significantly associated with ALS. Subgroup analysis by gender revealed, however, that the -2578AA genotype, which lowers VEGF expression, increased the risk of ALS in males (OR = 1.46 males vs females; 95% CI = 1.19 to 1.80; p = 7.8 10E-5), even after correction for publication bias and multiple testing.This meta-analysis does not support the original conclusion that VEGF haplotypes increase the risk of ALS in humans, but the significant association of the low-VEGF -2578AA genotype with increased susceptibility to ALS in males reappraises the link between reduced VEGF concentrations and ALS, as originally revealed by the fortuitous mouse genetic studies.

Trials 16(1), 449 (2015). doi:10.1186/s13063-015-0987-4, Published by BioMed Central, London

Off-pump coronary artery bypass (OPCAB) surgery carries a high risk for haemodynamic instability and perioperative organ injury. Favourable haemodynamic effects and organ-protective properties could render xenon an attractive anaesthetic for OPCAB surgery. The primary aim of this study was to assess whether xenon anaesthesia for OPCAB surgery is non-inferior to sevoflurane anaesthesia with regard to intraoperative vasopressor requirements.Forty-two patients undergoing elective OPCAB surgery were enrolled in this prospective, single-blind, randomized controlled pilot trial. Patients were randomized to either xenon (50-60 vol%) or sevoflurane (1.1-1.4 vol%) anaesthesia. Primary outcome was intraoperative noradrenaline requirements necessary to achieve predefined haemodynamic goals. Secondary outcomes included safety variables such as the occurrence of adverse events (intraoperatively and during a 6-month follow-up after surgery) and the perioperative cardiorespiratory and inflammatory profile.Baseline and intraoperative data did not differ between groups. Xenon was non-inferior to sevoflurane, as xenon patients required significantly less noradrenaline intraoperatively to achieve the predefined haemodynamic goals {geometric mean 428 [95% confidence interval (CI) 312, 588] vs 1702 [1267, 2285] µg, P0.0001}. No differences were found for safety. Significantly more sevoflurane patients developed postoperative delirium (POD) (hazard ratio 4.2, P=0.044). The average arterial pressure was lower in the sevoflurane group {median75 [interquartile range (IQR) 6] vs 72 [4] mmHg, P=0.002}. No differences were found for other haemodynamic parameters, the respiratory profile and the perioperative release of inflammatory cytokines, troponin T, serum protein S-100β and erythropoietin.Compared with sevoflurane, xenon anaesthesia allows a significant reduction in vasopressor administration in OPCAB surgery. Moreover, xenon anaesthesia was associated with a lower risk for POD, a finding that has to be confirmed in larger studies.ClinicalTrials.gov (NCT01757106) and EudraCT (2012-002316-12).

Introduction In this study of preclinical Alzheimer’s disease (AD) we assessed the added diagnostic value of using cerebrospinal fluid (CSF) Aβ ratios rather than Aβ42 in isolation for detecting individuals who are positive on amyloid positron emission tomography (PET). Methods Thirty-eight community-recruited cognitively intact older adults (mean age 73, range 65–80 years) underwent 18F-flutemetamol PET and CSF measurement of Aβ1-42, Aβ1-40, Aβ1-38, and total tau (ttau). 18F-flutemetamol retention was quantified using standardized uptake value ratios in a composite cortical region (SUVRcomp) with reference to cerebellar grey matter. Based on a prior autopsy validation study, the SUVRcomp cut-off was 1.57. Sensitivities, specificities and cut-offs were defined based on receiver operating characteristic analysis with CSF analytes as variables of interest and 18F-flutemetamol positivity as the classifier. We also determined sensitivities and CSF cut-off values at fixed specificities of 90 % and 95 %. Results Seven out of 38 subjects (18 %) were positive on amyloid PET. Aβ42/ttau, Aβ42/Aβ40, Aβ42/Aβ38, and Aβ42 had the highest accuracy to identify amyloid-positive subjects (area under the curve (AUC) ≥ 0.908). Aβ40 and Aβ38 had significantly lower discriminative power (AUC = 0.571). When specificity was fixed at 90 % and 95 %, Aβ42/ttau had the highest sensitivity among the different CSF markers (85.71 % and 71.43 %, respectively). Sensitivity of Aβ42 alone was significantly lower under these conditions (57.14 % and 42.86 %, respectively). Conclusion For the CSF-based definition of preclinical AD, if a high specificity is required, our data support the use of Aβ42/ttau rather than using Aβ42 in isolation.

Three unrelated urine immunofixations, ordered for diagnostic purposes of monoclonal gammopathy of renal significance (MGRS) (1, 2), exhibited several abnormal fractions in the protein electrophoresis lane (Fig. 1, A–C). Corresponding monoclonal fractions were undetectable in the immunofixation lane against γ/α/μ heavy chains and κ or λ (free) light chains. All patients had a medical history of type 1 diabetes mellitus and a combined …

Importance Hepatitis E virus (HEV) recently has been shown to be an antecedent infection in Guillain-Barre syndrome (GBS), but the clinical spectrum of HEV-associated GBS is not yet documented, and diagnosing acute HEV infection can be a challenge. Objectives To determine the prevalence of HEV-associated GBS in a Belgian cohort, study the clinical spectrum of HEV-associated GBS, and discuss difficulties in diagnosing acute HEV infection. Design, Setting, and Participants This single-center, retrospective cohort study was conducted between January 1, 2007, and November 1, 2015. All patients with GBS or a GBS variant who presented to the adult neurology department of the University Hospital Leuven were identified via a search of the electronic medical records. Hepatitis E virus IgM and IgG reactivity was determined. In a subgroup, polymerase chain reaction for HEV was performed. Main Outcomes and Measures Hepatitis E virus IgM and IgG reactivity. Results Of 73 eligible patients (mean [SD] age, 52 [18] years; 29 females and 44 males), 6 (8%) showed positive reactivity on IgM assays for HEV, indicating a possible acute HEV infection. Four of the 6 patients (67%) had increased alanine aminotransferase levels of more than 1.5 times the upper limit of normal, while 4 of 22 patients (18%) with increased alanine aminotransferase levels showed positive reactivity on HEV IgM assays. Serum samples of 2 of 6 patients with positive reactivity on HEV IgM assays also revealed positive test results for cytomegalovirus or Epstein-Barr virus, indicating possible cross-reactivity. Thus, 4 patients (6%) in our cohort had probable acute HEV infection. Two of these patients presented with an infrequent GBS variant. Conclusions and Relevance Acute HEV infection was frequently associated with GBS in our cohort. Abnormal alanine aminotransferase levels at admission can indicate the presence of an associated HEV infection. When HEV testing is considered, it is important to test for other infectious agents in parallel, as cross-reactivity can occur. Further studies are required to guide neurologists in their workup of underlying triggers of GBS.

between Wave1 and Wave2. Results: Individuals with greater Ab burden had lower CVR at both Wave1 and Wave2, with the effect being most pronounced in the occipital lobe (Fig.1). The reduced CVRmay be attributed to Ab-induced angiopathy. CBF at Wave1 did not show a significant relationship with Ab deposition (Fig.2a). However, Wave2 CBF showed a positive correlation (p1⁄40.01) with Wave1 Ab burden (Fig.2b). Analysis of CBF change revealed that individuals with greater Ab burden tended to show an increase in CBF over the four-year interval (p1⁄40.009, Fig.2c). The increased CBF might be due to compensatory processes, as more neuronal processing might be needed to achieve the same computational power when neural efficiency is dampened by Ab-induced neurotoxicity. Conclusions: Ab burden appears to have a negative impact on cerebral vascular parameters. Greater Ab burden reduces the vessel’s ability to dilate. The impact of Ab on CBF may be a slower process. But over time, individuals with high Ab show elevated CBF, suggesting that more neural resources are needed to maintain the same brain function.

Background: With the use of a traditional blood gas analyzer (BGA) (ABL800 Radiometer) for blood glucose monitoring, tight glucose control (TGC) reduced in-hospital mortality and morbidity of surgical intensive care unit (ICU) adult and pediatric patients. Such BGAs are now superseded by cassette-based BGAs. We assessed the analytical reliability of cassette-based BGAs to monitor patient's metabolic status in an ICU setting. Methods: We evaluated recovery/linearity, imprecision/repeatability and relative accuracy vs. comparison methods for glucose [coupled hexokinase glucose-6-phosphate dehydrogenase (HK/G6PD) assay] and lactate (lactate dehydrogenase assay) in ICU patient samples with two cassette-based BGAs [RP500 (Siemens) and ABL90 (Radiometer)] and with the ABL800 BGA. Results: Recovery of spiked glucose up to 348 mg/dL (19.3 mmol/L) was complete for all BGAs. Repeatability of ABL800 and ABL90 was comparable with the comparison method (about 1%), but higher for RP500 (about 2.4%). All BGAs were in agreement with the comparison method, with all glucose measurements falling within preset 10% criteria suggested by Karon. Recovery of spiked lactate (up to 25 mmol/L) was incomplete at all levels. Repeatability of ABL800 and ABL90 was comparable with the comparison method (about 4%), and 5.5% for RP500. All BGAs were in agreement with the comparison method, with >98% of the lactate measurements falling within 30% biological-variation-based criteria. Conclusions: The cassette-based BGAs quantified blood glucose and lactate levels in ICU patients within the acceptable error ranges. Cassette-based BGAs can be used for monitoring patient's metabolic status in an ICU setting. ispartof: Clinical Chemistry and Laboratory Medicine vol:51 issue:7 pages:1417-1427 ispartof: location:Germany status: published

SummaryReceptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects. Inhibition by SSR is highly conserved throughout the animal kingdom. Oral delivery of SSR inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies. Thus, orally active, extracellularly acting small-molecule modulators of RTKs with allosteric properties can be developed and may offer opportunities to improve anticancer treatment.

Background: The cerebrospinal fluid (CSF) biomarkers amyloid beta 1-42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories. Methods: Data from the first nine rounds of the Alzheimer's Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Molndal, Sweden) were analyzed by single-analyte enzyme-linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection. Results: A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within-run CVs, less than 5% to 10%; and longitudinal within-laboratory CVs, 5% to 19%. Interestingly, longitudinal within-laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1-42 measurements, but for total tau and phosphorylated tau, between-kit lot effects were much less than between-laboratory effects. Despite the measurement variability, the between-laboratory consistency in classification of samples (using prehoc-derived cutoffs for AD) was high (>90% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP). Conclusions: The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians. (C) 2013 The Alzheimer's Association. All rights reserved.

Systemic vascular endothelial growth factor inhibition, in combination with chemotherapy, improves the outcome of patients with metastatic cancer. Peripheral sensory neuropathies occurring in patients receiving both drugs are attributed to the chemotherapy. Here, we provide unprecedented evidence that vascular endothelial growth factor receptor inhibitors trigger a painful neuropathy and aggravate paclitaxel-induced neuropathies in mice. By using transgenic mice with altered neuronal vascular endothelial growth factor receptor expression, systemic inhibition of vascular endothelial growth factor receptors was shown to interfere with the endogenous neuroprotective activities of vascular endothelial growth factor on sensory neurons. In vitro , vascular endothelial growth factor prevented primary dorsal root ganglion cultures from paclitaxel-induced neuronal stress and cell death by counteracting mitochondrial membrane potential decreases and normalizing hyperacetylation of α-tubulin. In contrast, vascular endothelial growth factor receptor inhibitors exerted opposite effects. Intriguingly, vascular endothelial growth factor or vascular endothelial growth factor receptor inhibitors exerted their effects through a mechanism whereby Hdac6, through Hsp90, controls vascular endothelial growth factor receptor-2-mediated expression of the anti-apoptotic Bcl2. Our observations that systemic anti-vascular endothelial growth factor therapies interfere with the neuroprotective activities of vascular endothelial growth factor may have important implications for the application of anti-vascular endothelial growth factor therapies in cancer patients. * Abbreviations : VEGF : vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) regulates angiogenesis, but also has important, yet poorly characterized roles in neuronal wiring. Using several genetic and in vitro approaches, we discovered a novel role for VEGF in the control of cerebellar granule cell (GC) migration from the external granule cell layer (EGL) toward the Purkinje cell layer (PCL). GCs express the VEGF receptor Flk1, and are chemoattracted by VEGF, whose levels are higher in the PCL than EGL. Lowering VEGF levels in mice in vivo or ectopic VEGF expression in the EGL ex vivo perturbs GC migration. Using GC-specific Flk1 knock-out mice, we provide for the first time in vivo evidence for a direct chemoattractive effect of VEGF on neurons via Flk1 signaling. Finally, using knock-in mice expressing single VEGF isoforms, we show that pericellular deposition of matrix-bound VEGF isoforms around PC dendrites is necessary for proper GC migration in vivo. These findings identify a previously unknown role for VEGF in neuronal migration., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Background— Control of peripheral resistance arteries by autonomic nerves is essential for the regulation of blood flow. The signals responsible for the maintenance of vascular neuroeffector mechanisms in the adult, however, remain largely unknown. Methods and Results— Here, we report that VEGF ∂/∂ mice with low vascular endothelial growth factor (VEGF) levels suffer defects in the regulation of resistance arteries. These defects are due to dysfunction and structural remodeling of the neuroeffector junction, the equivalent of a synapse between autonomic nerve endings and vascular smooth muscle cells, and to an impaired contractile smooth muscle cell phenotype. Notably, short-term delivery of a VEGF inhibitor to healthy mice also resulted in functional and structural defects of neuroeffector junctions. Conclusions— These findings uncover a novel role for VEGF in the maintenance of arterial neuroeffector function and may help us better understand how VEGF inhibitors cause vascular regulation defects in cancer patients.

small cohorts. Aim of the study was to describe cerebral oxygen saturation during HCA and SACP in a large cohort of patients. Methods. With IRB approval, 215 patients (age 62 12) undergoing thoracic aortic surgery with HCA (24 18 min) and SACP (16 17 min) at 10 ml kg-1 min-1 were monitored with bifrontal NIRS (NIRO 200NX, Hamamatsu Photonics, Japan). Tissue oxygenation index (TOI) was measured continuously. Results. TOI dropped by 16% (95%CI, 17.6 to 15.1) during HCA and increased again up to 10.1% (95%CI, 8.9 to 11.3) during SACP. TOI at start of HCA correlated with TOI at SACP-start and HCAstop. Absolute TOI values and correlations are shown in Figures

Modified nucleosides play an important role in structure and function of tRNA. We have determined the solution structure of the anticodon stem-loop (ASL) of initiator tRNA of Schizosaccharomyces pombe. The incorporation of N6-threonylcarbamoyladenosine at the position 3' to the anticodon triplet (t6A37) results in the formation of a U-turn motif and enhances stacking interactions within the loop and stem regions (i.e. between A35 and t6A37) by bulging out U36. This conformation was not observed in a crystal structure of tRNAi including the same modification in its anticodon loop, nor in the solution structure of the unmodified ASL. A t6A modification also occurs in the well studied anti-stem-loop of lys-tRNA(UUU). A comparison of this stem-loop with our structure demonstrates different effects of the modification depending on the loop sequence. ispartof: Nucleic acids research vol:34 issue:10 pages:2878-86 ispartof: location:England status: published

Introduction: the current practice of quantifying cerebrospinal fluid (CSF) biomarkers as an aid in the diagnosis of Alzheimer's disease (AD) varies from center to center. For a same biochemical profile, interpretation and reporting of results may differ, which can lead to misunderstandings and raises questions about the commutability of tests. Methods: We obtained a description of (pre-)analytical protocols and sample reports from 40 centers worldwide. A consensus approach allowed us to propose harmonized comments corresponding to the different CSF biomarker profiles observed in patients. Results: the (pre-)analytical procedures were similar between centers. There was considerable heterogeneity in cutoff definitions and report comments. We therefore identified and selected by consensus the most accurate and informative comments regarding the interpretation of CSF biomarkers in the context of AD diagnosis. Discussion: this is the first time that harmonized reports are proposed across worldwide specialized laboratories involved in the biochemical diagnosis of AD. This manuscript was facilitated by the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART), through the Biofluid Based Biomarkers Professional Interest Area (BBB-PIA). The views and opinions expressed in this publication represent those of the authors and do not necessarily reflect those of the BBB-PIA membership, ISTAART, or the Alzheimer's Association. The authors thank the French Society of Clinical Biology, the ISTAART BBB-PIA, and the Society for Neurochemistry and Clinical CSF analysis for their help in initiating this work. Constance Delaby received no support for the present manuscript. Charlotte Teunissen received the following grants during the last 36 months: Research of CET is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 [MIRIADE], and JPND), Health Holland, the Dutch Research Council (ZonMw), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, Alzheimer Association. CT and WF are recipients of ABOARD, which is a public-private partnership receiving funding from ZonMw (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD. ABOARD also receives funding from Edwin Bouw Fonds and Gieskes-Strijbisfonds. IV is appointed on a research grant by Alzheimer Nederland (NL-17004). She received no support for the present manuscript. Kaj Blennow is supported by the Swedish Alzheimer Foundation (#AF-742881) and Hjärnfonden, Sweden (#FO2017-0243). He received no support for the present manuscript. Daniel Alcolea received funding from Institute of Health Carlos III (ISCIII), Spain PI18/00435 and INT19/00016, and by the Department of Health Generalitat de Catalunya PERIS program SLT006/17/125. He received no support for the present manuscript. Ivan Arisi was partly supported by: Fondo Ordinario Enti (FOE D.M 865/2019) funds in the framework of a collaboration agreement between the Italian National Research Council and EBRI (2019-2021); POR (Operative Program Lazio Region, Italy) FESR (European Program Regional Development) 2014-2020, Public Notice “LIFE 2020” MODIAG Project. Elodie Bouaziz-Amar received no support for the present manuscript. Anne Beaume received no support for the present manuscript. Aurélie Bedel received no support for the present manuscript. Giovanni Bellomo is supported by University of Perugia, CIRMMP, IRST Istituto Romagnolo per lo Studio e la Cura dei Tumori, Innuvatech srl. He received no support for the present manuscript. Edith Bigot-Corbel received no support for the present manuscript. Maria Bjerke received no support for the present manuscript. Marie-Céline Blanc-Quintin received no support for the present manuscript. Mercè Boada received support from LA CAIXA, IMI, ISCIII H2020 the European Union/EFPIA Innovative Medicines Initiative Joint Undertaking MOPEAD project (Grants No. 115985) and is also supported by national grant, PI17/01474 from Acción Estratégica en Salud, integrated into the Spanish National Plan of R+D+I and founded by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- “Una manera de Hacer Europa”). She received no support for the present manuscript. Olivier Bousigues is supported by A2MCL Alsace Alzheimer. He received no support for the present manuscript. Miles D. Chapman received no support for the present manuscript. Mari L. DeMarco is supported by the Michael Smith Foundation for Health Research, Brain Canada (Canada Brain Research Fund), Health Canada, Women's Brain Health Initiative, Alzheimer Society of Canada, St. Paul's Foundation, Djavad Mowafaghian Centre for Brain Health at the University of British Columbia and the Canadian Consortium for Neurodegeneration and Aging; with all funds provided to the University of British Columbia. Mara D'Onofrio was partly supported by Fondo Ordinario Enti (FOE D.M 865/2019) funds in the framework of a collaboration agreement between the Italian National Research Council POR (Operative Program Lazio Region, Italy) FESR (European Program Regional Development) 2014-2020, Public Notice “LIFE 2020″, MODIAG Project. She received no support for the present manuscript. Julien Dumurgier received no support for the present manuscript. Diane Dufour received no support for the present manuscript. Sebastiaan Engelborghs is supported for various projects: Research Project GSKE/FMRE, Research Project FWO Vlaanderen, PhD fellowship FWO Vlaanderen (n = 3), VLAIO PhD fellowship. He received no support for the present manuscript. Hermann Esselmann received no support for the present manuscript. Anne Fogli received no support for the present manuscript. Audrey Gabelle received no support for the present manuscript. Elisabetta Galloni received no support for the present manuscript. Clémentine Gondolf received no support for the present manuscript. Frédérique Grandhomme received no support for the present manuscript. Oriol Grau-Rivera receives grants from the Spanish Ministry of Science, Innovation and Universities (FJCI-2017-33437), and from the Alzheimer's Association Research Fellowship Program (2019-AARF-644568). He received no support for the present manuscript. Melanie Hart receives UCLH Biomedical Research Centre support from NIHR (Neurosciences). She received no support for the present manuscript. Takeshi Ikeuchi received the following grants to his institution AMED: 21dk0207049, 21dk0207045, 21ek0109545, 20ek0109350, 20ek0109392. He received no support for the present manuscript. Andreas Jeromin received no support for the present manuscript. Kensaku Kasuga received no support for the present manuscript. Ashvini Keshavan is supported by the Weston Brain Institute/Selfridges Foundation grant UB170045. She received no support for the present manuscript. Michael Khalil received unrestricted research grants from Biogen and Novartis. He received no support for the present manuscript. Peter Körtvelyessy received no support for the present manuscript. Agnieszka Kulczynska-Przybik received no support for the present manuscript. Jean-Louis Laplanche received no support for the present manuscript. Qiao-Xin Li received no support for the present manuscript. Alberto Lleó is supported by grants from Generalitat de Catalunya (PERIS SLT002/16/00408), Instituto de Salud Carlos III (PI17/01896), Instituto de Salud Carlos III CIBERNED. He received no support for the present manuscript. Catherine Malaplate received no support for the present manuscript. Marta Marquié is supported by the Instituto de Salud Carlos III (ISCIII) Acción Estratégica en Salud, integrated in the Spanish National RCDCI Plan and financed by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-Una manera de hacer Europa) grant PI19/00335. She received no support for the present manuscript. Colin M. Masters received no support for the present manuscript. Barbara Mroczko received a grant from The Binding Site Group and Biokom Diagnostyka. She received no support for the present manuscript. Léonor Nogueira received no support for the present manuscript. Adelina Orellana received no support for the present manuscript. Markus Otto is supported by BMBF, Thierry Latran foundation, EU, DFG. He received no support for the present manuscript. Jean-Baptiste Oudart is supported by Astrazeneca grant for a research program on EGFR targeted therapy resistance in NSCLC. He received no support for the present manuscript. Claire Paquet received no support for the present manuscript. Federico Paolini received no support for the present manuscript. Lucilla Parnetti received no support for the present manuscript. Armand Perret-Liaudet received no support for the present manuscript. Katell Peoc'h is supported by contract with Siemens Healthineers. She received no support for the present manuscript. Koen Poesen received no support for the present manuscript. Albert Puig-Pijoan received no support for the present manuscript. Isabelle Quadrio received no support for the present manuscript. Murielle Quillard-Muraine received no support for the present manuscript. Benoît Rucheton received no support for the present manuscript. Susanne Schraen received no support for the present manuscript. Jonathan M. Schott is supported by the Medical Research Council, Alzheimer's Research UK, Weston Brain Institute, British Heart Foundation, Alzheimer's Association. He received no support for the present manuscript. Leslie M. Shaw is supported by NIA for ADNI Biomarker Core, UPENN ADRC Biomarker Corr, MJ Fox PPMI for CSF Biomarker measurements, Roche for IIS study of AD biomarkers. He received no support for the present manuscript. Marc Suárez-Calvet receives funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant agreement No. 948677). He also receives funding from the Instituto de Salud Carlos III (PI19/00155) and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I). He received no support for the present manuscript. Magda Tsolaki received no support for the present manuscript. Hayrettin Tumani is supported by Alexion, Bayer, Biogen, Celgene, Genzyme-Sanofi, Merck, Novartis, Roche, Teva. He received no support for the present manuscript. Chinedu T Udeh-Momoh is supported by Alzheimer research UK (Project Grant). He received no support for the present manuscript. Lucie Vaudran received no support for the present manuscript. Marcel M. Verbeek is supported by the BIONIC project (no. 733050822, which has been made possible by ZonMw within the framework of “Memorabel,” the research and innovation program for dementia, as part of the Dutch national “Deltaplan for Dementia”: zonmw.nl/dementiaresearch), and the CAFÉ project (the National Institutes of Health, USA, grant number 5R01NS104147-02). The BIONIC project is a consortium of Radboudumc, LUMC, ADX Neurosciences, and University of Rhode Island University. MM Verbeek is also supported by a grant from the Selfridges Group Foundation. He received no support for the present manuscript. Federico Verde received no support for the present manuscript. Lisa Vermunt is supported by Alzheimer Nederland. She received no support for the present manuscript. Jonathan Volgesgang is supported by Clinician Scientist Research Fellowship, German Research Foundation (Deutsche Forschungsgesellschaft, project number: 413501650; 09/01/2019-02/28/2021); Eric Dorris Memorial Fellowship (McLean Hospital; 07/01/2020-06/30/2021). He received no support for the present manuscript. Jens Wiltfang is supported by Federal Ministry of Education and Research (BMBF) State of Lower Saxony; He received no support for the present manuscript. Henrik Zetterberg is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. He received no support for the present manuscript. Sylvain Lehmann received no support for the present manuscript.