Update on ultrasensitive technologies to facilitate research on blood biomarkers for central nervous system disorders

Most research on fluid biomarkers for central nervous system (CNS) disorders has so far been performed using cerebrospinal fluid (CSF) as the biomarker source. CSF has the advantage of being closer to the brain than serum or plasma with a relative enrichment of CNS-specific proteins that are present at very low concentrations in the blood and thus difficult to reliably quantify using standard immunochemical technologies. Recent technical breakthroughs in the field of ultrasensitive assays have started to change this. Here, we review the most established ultrasensitive quantitative technologies that are currently available to general biomarker laboratories and discuss their use in research on biomarkers for CNS disorders

Equivalence in scientific and technical translation : a text-in-context-based study

Scientific and technical translation has always played a pivotal role in disseminating knowledge. Today, the domain of science and technology is the main area of translation work. Nevertheless, there is still a discrepancy between the growing need for high-quality technical translations and the short supply of competent technical translators to produce them, a situation which may be due in part to the recent neglect of the equivalence concept in the theoretical/descriptive and applied branches of translation studies (TS). This thesis sets out to redefine, reassess, and reinstate equivalence as a useflul concept in TS by adopting an approach based on the English-German language pair and on one specific text genre and type. The investigation of equivalence as a qualitative complete-text-in-context-based concept is embedded in an equivalence-relevant methodology based on two methodological pillars, the first being a theoretically sound translation comparison and the second a highly refined translation corpus. Within this methodological framework, equivalence-relevant features are investigated and described at the syntactic, lexical-semantic, terminological-phraseological and overall textual levels. These levels are hierarchically interrelated in descending and ascending order and may be conditioned by pragmatic aspects, viz., domain knowledge and register considerations. The comparison is made using a high-quality corpus selected on the basis of a threefold set of selection criteria, with a special emphasis on the qualitative criteria. This helps us generate well-underpinned intersubjectifiable regularities in the form of potential equivalents established in the TT for ST equivalence-relevant features and enables us to obtain meaningful generalizations. Both regularities and generalizations should be capable of implementation in the applied branches of TS and, at the same time, help dynamize and intersubjectify the complex concept of equivalence. So, hopefully, this thesis will also contribute toward creating a link between the methodological, theoretical/descriptive and applied branches of TS to their mutual benefit.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Equivalence in scientific and technical translation : a text-in-context-based study

Scientific and technical translation has always played a pivotal role in disseminatingknowledge. Today, the domain of science and technology is the main area oftranslation work. Nevertheless, there is still a discrepancy between the growing needfor high-quality technical translations and the short supply of competent technicaltranslators to produce them, a situation which may be due in part to the recentneglect of the equivalence concept in the theoretical/descriptive and applied branchesof translation studies (TS).This thesis sets out to redefine, reassess, and reinstate equivalence as a useflul conceptin TS by adopting an approach based on the English-German language pair and onone specific text genre and type. The investigation of equivalence as a qualitativecomplete-text-in-context-based concept is embedded in an equivalence-relevantmethodology based on two methodological pillars, the first being a theoreticallysound translation comparison and the second a highly refined translation corpus.Within this methodological framework, equivalence-relevant features are investigatedand described at the syntactic, lexical-semantic, terminological-phraseological andoverall textual levels. These levels are hierarchically interrelated in descending andascending order and may be conditioned by pragmatic aspects, viz., domainknowledge and register considerations. The comparison is made using a high-qualitycorpus selected on the basis of a threefold set of selection criteria, with a specialemphasis on the qualitative criteria. This helps us generate well-underpinnedintersubjectifiable regularities in the form of potential equivalents established in theTT for ST equivalence-relevant features and enables us to obtain meaningfulgeneralizations.Both regularities and generalizations should be capable of implementation in theapplied branches of TS and, at the same time, help dynamize and intersubjectify thecomplex concept of equivalence. So, hopefully, this thesis will also contribute towardcreating a link between the methodological, theoretical/descriptive and appliedbranches of TS to their mutual benefit

Prognostic biomarkers in primary progressive multiple sclerosis: validating and scrutinizing multimodal evoked potentials

OBJECTIVE: To validate the prognostic value of multimodal evoked potentials (mmEP) in primary progressive multiple sclerosis (PPMS) and to determine the most predictive EP-modalities. METHODS: Thirty-nine patients with PPMS (expanded disability status scale (EDSS): 2.0-6.5; mean clinical follow-up: 2.8 years) had visual (VEP), upper and lower limb somatosensory (SEP) and motor EP (MEP) at baseline. Quantitative EP-scores for single (qVEP, qSEP, qMEP) and combined modalities were correlated to EDSS and compared to previously published data of 21 PPMS patients. Predictors of EDSS-change were analyzed in pooled data by linear regression. RESULTS: Samples were comparable. Except qVEP, all EP-scores were correlated to EDSS at baseline (Rho: 0.45-0.69; p < 0.01) and follow-up (Rho: 0.59-0.80; p < 0.001). Combined EP-modalities significantly predicted EDSS-change (R(2)adj: 0.24), while EDSS and age did not. Tibial qSEP (R(2)adj: 0.22) and qMEP (R(2)adj: 0.26) were the best single modality predictors, outperformed by their combination (R(2)adj: 0.32). CONCLUSIONS: Quantitative EP-scores predict up to 32% of EDSS-change over three years. Modalities representing motor and long tract function carry the main prognostic information. SIGNIFICANCE: Replication of previous results corroborates the use of mmEP as a prognostic biomarker candidate in PPMS

Evolution of Cortical and White Matter Lesion Load in Early-Stage Multiple Sclerosis: Correlation With Neuroaxonal Damage and Clinical Changes.

Introduction: Changes in cortical and white matter lesion (CL, WML) load are pivotal metrics to diagnose and monitor multiple sclerosis patients. Yet, the relationship between (i) changes in CL/WML load and disease progression and between (ii) changes in CL/WML load and neurodegeneration at early MS stages is not yet established. In this work, we have assessed the hypothesis that the combined CL and WML load as well as their 2-years evolution are surrogate markers of neurodegeneration and clinical progression at early MS stages. To achieve this goal, we have studied a group of RRMS patients and have investigated the impact of both CL and WML load on neuroaxonal damage as measured by serum neurofilament light chain (sNfL). Next, we have explored whether changes in CL/WML load over 2 years in the same cohort of early-MS are related to motor and cognitive changes. Methods: Thirty-two RRMS patients (&lt;5 years disease duration) underwent: (i) 3T MRI for CL/WML detection and clinical assessment at baseline and 2-years follow-up; and (ii) baseline blood test for sNfL. The correlation between the number and volume of CL/WML and sNfL was assessed by using the Spearman's rank correlation coefficient and a generalized linear model (GLM). A GLM was also used to assess the relationship between (i) the number/volume of new, enlarged, resolved, shrunken, stable lesions and (ii) the difference in clinical scores between two time-points. Results: At baseline, sNfL levels correlated with both total CL count/volume (ρ = 0.6/0.7, Corr-P &lt;0.017/Corr-P &lt; 0.001) and with total WML count/volume (ρ = 0.6/0.6, Corr-P &lt; 0.01 for both). Baseline sNfL levels also correlated with new WML count/volume (ρ = 0.6/0.5, Corr-P &lt; 0.01/Corr-P &lt; 0.05) but not with new CL. Longitudinal changes in CL and WML count and volume were significantly associated with (i) sustained attention, auditory information, processing speed and flexibility (p &lt; 0.01), (ii) verbal memory (p &lt; 0.01); (iii) verbal fluency (p &lt; 0.05); and (iv) hand-motor function (p &lt; 0.05). Discussion: Changes in cortical and white matter focal damage in early MS patients correlate with global neuroaxonal damage and is associated to cognitive performances

Serum neurofilament light chain in patients with acute cerebrovascular events

BACKGROUND AND PURPOSE Serum neurofilaments are markers of axonal injury. We addressed their diagnostic and prognostic role in acute ischemic stroke (AIS) and transient ischemic attack (TIA). METHODS Nested within a prospective cohort study, we compared levels of serum neurofilament light chain (sNfL) drawn within 24 h from symptom onset in patients with AIS or TIA. Patients without magnetic resonance imaging on admission were excluded. We assessed whether sNfL was associated with: (i) clinical severity on admission, (ii) diagnosis of AIS vs. TIA, (iii) infarct size on admission magnetic resonance diffusion-weighted imaging (MR-DWI) and (iv) functional outcome at 3 months. RESULTS We analyzed 504 patients with AIS and 111 patients with TIA. On admission, higher National Institutes of Health Stroke Scale (NIHSS) scores were associated with higher sNfL: NIHSS score 15, 21.0 pg/mL (IQR, 9.3-40.4) (P = 0.01). Compared with AIS, patients with TIA had lower sNfL levels [9.0 pg/mL (95% confidence interval, 4.0-19.0) vs. 16.0 pg/mL (95% confidence interval, 7.3-34.4), P < 0.001], also after adjusting for age and NIHSS score (P = 0.006). Among patients with AIS, infarct size on admission MR-DWI was not associated with sNfL, either in univariate analysis (P = 0.15) or after adjusting for age and NIHSS score on admission (P = 0.56). Functional outcome 3 months after stroke was not associated with sNfL after adjusting for established predictors. CONCLUSIONS In conclusion, among patients admitted within 24 h of AIS or TIA onset, admission sNfL levels were associated with clinical severity on admission and TIA diagnosis, but not with infarct size on MR-DWI acquired on admission or functional outcome at 3 months

Kappa free light chains is a valid tool in the diagnostics of MS: A large multicenter study

To validate kappa free light chain (KFLC) and lambda free light chain (LFLC) indices as a diagnostic biomarker in multiple sclerosis (MS).We performed a multicenter study including 745 patients from 18 centers (219 controls and 526 clinically isolated syndrome (CIS)/MS patients) with a known oligoclonal IgG band (OCB) status. KFLC and LFLC were measured in paired cerebrospinal fluid (CSF) and serum samples. Gaussian mixture modeling was used to define a cut-off for KFLC and LFLC indexes.The cut-off for the KFLC index was 6.6 (95% confidence interval (CI) = 5.2-138.1). The cut-off for the LFLC index was 6.9 (95% CI = 4.5-22.2). For CIS/MS patients, sensitivity of the KFLC index (0.88; 95% CI = 0.85-0.90) was higher than OCB (0.82; 95%CI = 0.79-0.85; p < 0.001), but specificity (0.83; 95% CI = 0.78-0.88) was lower (OCB = 0.92; 95% CI = 0.89-0.96; p < 0.001). Both sensitivity and specificity for the LFLC index were lower than OCB.Compared with OCB, the KFLC index is more sensitive but less specific for diagnosing CIS/MS. Lacking an elevated KFLC index is more powerful for excluding MS compared with OCB but the latter is more important for ruling in a diagnosis of CIS/MS