Background:
The importance of predicting disease progression in multiple sclerosis (MS) has increasingly been recognized, and hence reliable biomarkers are needed.
Objectives:
To investigate the ...prognostic role of cerebrospinal fluid (CSF) amyloid beta1–42 (Aβ) levels by the determination of a cut-off value to classify patients in slow and fast progressors. To evaluate possible association with white matter (WM) and grey matter (GM) damage at early disease stages.
Methods:
Sixty patients were recruited and followed up for 3–5 years. Patients underwent clinical assessment, brain magnetic resonance imaging (MRI; at baseline and after 1 year), and CSF analysis to determine Aβ levels. T1-weighted volumes were calculated. T2-weighted scans were used to quantify WM lesion loads.
Results:
Lower CSF Aβ levels were observed in patients with a worse follow-up Expanded Disability Status Scale (EDSS; r = −0.65, p < 0.001). The multiple regression analysis confirmed CSF Aβ concentration as a predictor of patients’ EDSS increase (r = −0.59, p < 0.0001). Generating a receiver operating characteristic curve, a cut-off value of 813 pg/mL was determined as the threshold able to identify patients with worse prognosis (95% confidence interval (CI): 0.690–0.933, p = 0.0001). No differences in CSF tau and neurofilament light chain (NfL) levels were observed (p > 0.05).
Conclusion:
Low CSF Aβ levels may represent a predictive biomarker of disease progression in MS.
Personalised medicine is a medical model that aims to provide tailor-made prevention and treatment strategies for defined groups of individuals. The concept brings new challenges to the translational ...step, both in clinical relevance and validity of models. We have developed a set of recommendations aimed at improving the robustness of preclinical methods in translational research for personalised medicine.
These recommendations have been developed following four main steps: (1) a scoping review of the literature with a gap analysis, (2) working sessions with a wide range of experts in the field, (3) a consensus workshop, and (4) preparation of the final set of recommendations.
Despite the progress in developing innovative and complex preclinical model systems, to date there are fundamental deficits in translational methods that prevent the further development of personalised medicine. The literature review highlighted five main gaps, relating to the relevance of experimental models, quality assessment practices, reporting, regulation, and a gap between preclinical and clinical research. We identified five points of focus for the recommendations, based on the consensus reached during the consultation meetings: (1) clinically relevant translational research, (2) robust model development, (3) transparency and education, (4) revised regulation, and (5) interaction with clinical research and patient engagement. Here, we present a set of 15 recommendations aimed at improving the robustness of preclinical methods in translational research for personalised medicine.
Appropriate preclinical models should be an integral contributor to interventional clinical trial success rates, and predictive translational models are a fundamental requirement to realise the dream of personalised medicine. The implementation of these guidelines is ambitious, and it is only through the active involvement of all relevant stakeholders in this field that we will be able to make an impact and effectuate a change which will facilitate improved translation of personalised medicine in the future.
ObjectivePersonalised medicine (PM) allows treating patients based on their individual demographic, genomic or biological characteristics for tailoring the ‘right treatment for the right person at ...the right time’. Robust methodology is required for PM clinical trials, to correctly identify groups of participants and treatments. As an initial step for the development of new recommendations on trial designs for PM, we aimed to present an overview of the study designs that have been used in this field.DesignScoping review.MethodsWe searched (April 2020) PubMed, Embase and the Cochrane Library for all reports in English, French, German, Italian and Spanish, describing study designs for clinical trials applied to PM. Study selection and data extraction were performed in duplicate resolving disagreements by consensus or by involving a third expert reviewer. We extracted information on the characteristics of trial designs and examples of current applications of these approaches. The extracted information was used to generate a new classification of trial designs for PM.ResultsWe identified 21 trial designs, 10 subtypes and 30 variations of trial designs applied to PM, which we classified into four core categories (namely, Master protocol, Randomise-all, Biomarker strategy and Enrichment). We found 131 clinical trials using these designs, of which the great majority were master protocols (86/131, 65.6%). Most of the trials were phase II studies (75/131, 57.2%) in the field of oncology (113/131, 86.3%). We identified 34 main features of trial designs regarding different aspects (eg, framework, control group, randomisation). The four core categories and 34 features were merged into a double-entry table to create a new classification of trial designs for PM.ConclusionsA variety of trial designs exists and is applied to PM. A new classification of trial designs is proposed to help readers to navigate the complex field of PM clinical trials.
The introduction of personalized medicine, through the increasing multi-omics characterization of disease, brings new challenges to disease modeling. The scope of this review was a broad evaluation ...of the relevance, validity, and predictive value of the current preclinical methodologies applied in stratified medicine approaches. Two case models were chosen: oncology and brain disorders. We conducted a scoping review, following the Joanna Briggs Institute guidelines, and searched PubMed, EMBASE, and relevant databases for reports describing preclinical models applied in personalized medicine approaches. A total of 1292 and 1516 records were identified from the oncology and brain disorders search, respectively. Quantitative and qualitative synthesis was performed on a final total of 63 oncology and 94 brain disorder studies. The complexity of personalized approaches highlights the need for more sophisticated biological systems to assess the integrated mechanisms of response. Despite the progress in developing innovative and complex preclinical model systems, the currently available methods need to be further developed and validated before their potential in personalized medicine endeavors can be realized. More importantly, we identified underlying gaps in preclinical research relating to the relevance of experimental models, quality assessment practices, reporting, regulation, and a gap between preclinical and clinical research. To achieve a broad implementation of predictive translational models in personalized medicine, these fundamental deficits must be addressed.
Personalised medicine (PM) presents a great opportunity to improve the future of individualised healthcare. Recent advances in -omics technologies have led to unprecedented efforts characterising the ...biology and molecular mechanisms that underlie the development and progression of a wide array of complex human diseases, supporting further development of PM. This article reflects the outcome of the 2021 EATRIS-Plus Multi-omics Stakeholder Group workshop organised to 1) outline a global overview of common promises and challenges that key European stakeholders are facing in the field of multi-omics research, 2) assess the potential of new technologies, such as artificial intelligence (AI), and 3) establish an initial dialogue between key initiatives in this space. Our focus is on the alignment of agendas of European initiatives in multi-omics research and the centrality of patients in designing solutions that have the potential to advance PM in long-term healthcare strategies.
Objective
Evidence for a role of microglia in the pathogenesis of multiple sclerosis (MS) is growing. We investigated association of microglial markers at time of diagnostic lumbar puncture (LP) with ...different aspects of disease activity (relapses, disability, magnetic resonance imaging parameters) up to 6 years later in a cohort of 143 patients.
Methods
In cerebrospinal fluid (CSF), we measured 3 macrophage and microglia‐related proteins, chitotriosidase (CHIT1), chitinase‐3–like protein 1 (CHI3L1 or YKL‐40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2), as well as a marker of neuronal damage, neurofilament light chain (NfL), using enzyme‐linked immunosorbent assay and electrochemiluminescence. We investigated the same microglia‐related markers in publicly available RNA expression data from postmortem brain tissue.
Results
CHIT1 levels at diagnostic LP correlated with 2 aspects of long‐term disease activity after correction for multiple testing. First, CHIT1 increased with reduced tissue integrity in lesions at a median 3 years later (p = 9.6E‐04). Second, CHIT1 reflected disease severity at a median 5 years later (p = 1.2E‐04). Together with known clinical covariates, CHIT1 levels explained 12% and 27% of variance in these 2 measures, respectively, and were able to distinguish slow and fast disability progression (area under the curve = 85%). CHIT1 was the best discriminator of chronic active versus chronic inactive lesions and the only marker correlated with NfL (r = 0.3, p = 0.0019). Associations with disease activity were, however, independent of NfL.
Interpretation
CHIT1 CSF levels measured during the diagnostic LP reflect microglial activation early on in MS and can be considered a valuable prognostic biomarker for future disease activity. ANN NEUROL 2020;87:633–645
Background: Several studies performed in the last years on the brain, showed that beta2-microglobulin (β2m) and MHC can act independently of their canonical immune function to regulate normal brain ...development, synaptic plasticity and behaviour. Increased systemic levels of soluble β2m have been implicated in cognitive impairments like that associated with chronic haemodialysis, or aortic valve replacement. Increased soluble β2m has also been detected in the cerebral spinal fluid (CSF) of patients with HIV-associated dementia and Alzheimer's disease (AD).
Objective: To compare plasma β2m levels in healthy subjects and subjects with dementia or cognitive impairment.
Methods: We measured the concentration of β2m in a cohort of 245 individuals and compared sex matched, cognitive healthy individuals.
Results: We found higher levels of β2m in AD patients compared to non-AD MCI and healthy controls (2063 ng/mL ±852 versus 1613 ± 503 and 1832 ± 382 ng/mL, p< 0.001 and <0.033, respectively), while there was no difference between mild cognitive impairment (MCI) and healthy controls (p > 0.05).
Conclusions: Our data confirm that β2m could play a role in AD. However, a replication study in an independent cohort would be necessary to confirm our preliminary results.
An effective response to the coronavirus disease 2019 (COVID-19) pandemic requires a better understanding of the biology of the infection and the identification of validated biomarker profiles that ...would increase the availability, accuracy, and speed of COVID-19 testing. Here, we describe the strategic objectives and action lines of the European Alliance of Medical Research Infrastructures (AMRI), established to improve the research process and tackle challenges related to diagnostic tests and biomarker development. Recommendations include: the creation of a European taskforce for validation of novel diagnostic products, the definition and promotion of criteria for COVID-19 samples biobanking, the identification and validation of biomarkers as clinical endpoints for clinical trials, and the definition of immune biomarker signatures at different stages of the disease. An effective management of the COVID-19 pandemic is possible only if there is a high level of knowledge and coordination between the public and private sectors within a robust quality framework.
LncRNA PCR arrays containing 90 common LncRNAs were used to screen lncRNA expression levels in PBMC from a discovery population of patients with MS. Data from discovery and replications cohorts ...showed a generalized dysregulation of lncRNA levels in MS patients compared with controls. MALAT1, MEG9, NRON, ANRIL, TUG1, XIST, SOX2OT, GOMAFU, HULC, BACE-1AS were significantly downregulated in MS patients in comparison with controls. Therefore, we performed a validation analysis in an independent cohort of Belgian origin. In this study, NRON and TUG1 downregulations in MS patients compared with controls were confirmed (p ≤ .05 and p ≤ .0001 respectively), whereas considering the other lncRNAs, the statistical threshold was not reached. LncRNAs profiling could thus represent a new challenge in the research of easy detectable biomarkers of disease susceptibility and progression.
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•Long non coding RNAs (lncRNAs) have recently found to be dysregulated in MS patients.•LncRNA PCR arrays were used to screen lncRNA expression levels in PBMC from MS patients.•Several lncRNAs were significantly downregulated in MS patients.•NRON and TUG1 downregulations were then confirmed in the Belgian population.•LncRNAs profiling could represent a new challenge in the research of easy detectable biomarkers of disease.
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