No Plasmatic Proteomic Signature at Clinical Disease Onset Associated With 11 Year Clinical, Cognitive and MRI Outcomes in Relapsing-Remitting Multiple Sclerosis Patients

Background: The clinical course of relapsing-remitting multiple sclerosis (RRMS) is highly heterogeneous and prognostic biomarkers at time of diagnosis are lacking.Objective: We investigated the predictive value of the plasma proteome at time of diagnosis in RRMS patients.Methods: The plasma proteome was interrogated using a novel aptamer-based proteomics platform, which allows to measure the levels of a predefined set of 1310 proteins.Results: In 67 clinically and radiologically well characterized RRMS patients, we found no association between the plasma proteome at diagnosis and clinical, cognitive or MRI outcomes after 11 years.Conclusions: Proteomics studies on cerebrospinal fluid may be better suited to identify prognostic biomarkers in early RRMS

Diagnostic value of kappa free light chain index in patients with primary progressive multiple sclerosis – a multicentre study

BackgroundKappa free light chains (κ-FLC) in the cerebrospinal fluid (CSF) are an emerging biomarker in multiple sclerosis (MS).ObjectiveTo investigate whether κ-FLC index has similar diagnostic value in patients with primary progressive multiple sclerosis (PPMS) compared to oligoclonal bands (OCB).MethodsPatients with PPMS were recruited through 11 MS centres across 7 countries. κ-FLC were measured by immunonephelometry/-turbidimetry. OCB were determined by isoelectric focusing and immunofixation.ResultsA total of 174 patients (mean age of 52±11 years, 51% males) were included. κ-FLC index using a cut-off of 6.1 was positive in 161 (93%) and OCB in 153 (88%) patients.Conclusionκ-FLC index shows similar diagnostic sensitivity than OCB in PPMS

Deep gray matter volume loss drives disability worsening in multiple sclerosis.

OBJECTIVE: Gray matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS. METHODS: We analyzed 3,604 brain high-resolution T1-weighted magnetic resonance imaging scans from 1,417 participants: 1,214 MS patients (253 clinically isolated syndrome [CIS], 708 relapsing-remitting [RRMS], 128 secondary-progressive [SPMS], and 125 primary-progressive [PPMS]), over an average follow-up of 2.41 years (standard deviation [SD] = 1.97), and 203 healthy controls (HCs; average follow-up = 1.83 year; SD = 1.77), attending seven European centers. Disability was assessed with the Expanded Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem, and cerebral white matter. Hierarchical mixed models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time-to-EDSS progression. RESULTS: SPMS showed the lowest baseline volumes of cortical GM and DGM. Of all baseline regional volumes, only that of the DGM predicted time-to-EDSS progression (hazard ratio = 0.73; 95% confidence interval, 0.65, 0.82; p < 0.001): for every standard deviation decrease in baseline DGM volume, the risk of presenting a shorter time to EDSS worsening during follow-up increased by 27%. Of all longitudinal measures, DGM showed the fastest annual rate of atrophy, which was faster in SPMS (-1.45%), PPMS (-1.66%), and RRMS (-1.34%) than CIS (-0.88%) and HCs (-0.94%; p < 0.01). The rate of temporal GM atrophy in SPMS (-1.21%) was significantly faster than RRMS (-0.76%), CIS (-0.75%), and HCs (-0.51%). Similarly, the rate of parietal GM atrophy in SPMS (-1.24-%) was faster than CIS (-0.63%) and HCs (-0.23%; all p values <0.05). Only the atrophy rate in DGM in patients was significantly associated with disability accumulation (beta = 0.04; p < 0.001). INTERPRETATION: This large, multicenter and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS. The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions. Ann Neurol 2018;83:210-222

Detection and localization of early- and late-stage cancers using platelet RNA

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I–IV cancer patients and in half of 352 stage I–III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening

Body fluid biomarkers for multiple sclerosis — the long road to clinical application

There is a strong unmet clinical need for objective body fluid biomarkers to assist early diagnosis and estimate long-term prognosis, monitor treatment response and predict potential adverse effects in multiple sclerosis (MS). Here, we review recent studies (focusing on 2012 to early 2015) on body fluid markers in MS from the perspective of their clinical utility. Because the first step towards clinical implementation of a newly discovered biomarker is independent replication, we focus on biomarkers that have been validated in at least two independent cohorts. We also discuss recent data challenging earlier findings, and biomarkers for which new clinical uses are suggested. For early MS diagnosis and prediction of conversion from clinically isolated syndrome to MS, several new B-cell-associated candidate blood biomarkers have emerged. For prognosis, several novel axonal damage markers should be adopted to biomarker panels. The number of disease-modifying treatments for MS has increased sharply, but biomarkers for treatment response monitoring and adverse effect prediction are scarce, and markers for subtyping and staging of MS are still lacking. In view of the availability and implementation of several standardized protocols to optimize biomarker studies, we expect biomarker development for MS to be improved and accelerated, with clinical implementation in the near future

The majority of natalizumab-treated MS patients have high natalizumab concentrations at time of re-dosing

Natalizumab is efficacious in the treatment of relapsing-remitting multiple sclerosis. All patients receive the same treatment regimen of 300 mg every 4 weeks, despite differences in pharmacokinetics between individual patients. To give neurologists insight into natalizumab concentrations at time of re-dosing, we investigated longitudinal natalizumab concentrations in 80 patients in relation to disease activity, with possible influencing factors. In a prospective observational cohort study, natalizumab trough serum concentrations were measured in 80 patients. Data on demographics, duration of treatment, Expanded Disability Status Scale, clinical exacerbations, brain magnetic resonance imaging (MRI), and body weight were collected. We measured high (≥10 µg/mL) natalizumab trough concentrations in 94% of patients. Intra-individual concentrations were stable. The spread in concentrations was substantial and did not correlate with disease activity. We found a negative association between natalizumab concentration and body weight (β = -0.30, p = 0.010). The majority of patients showed high natalizumab serum concentrations at time of re-dosing. Alternative treatment regimens could lead to more efficient use of natalizumab, but caution is warranted regarding the possibility of recurrence of disease activity. Prospective clinical trials are needed to establish the safety of extended dose intervals in natalizumab treatmen

Switching natalizumab to fingolimod within 6 weeks reduces recurrence of disease activity in MS patients

BACKGROUND: Natalizumab is an effective treatment in relapsing-remitting multiple sclerosis (MS). Mainly because of the risk of progressive multifocal leukoencephalopathy (PML), a substantial proportion of John Cunningham (JC) virus-positive patients switch to fingolimod. Previous reports show a clear benefit when the duration of a washout (WO) period of natalizumab is 0-3 months in comparison to longer WO periods. However, there is no consensus regarding the optimal duration of a WO period under 3 months. OBJECTIVE: We compared MS disease activity after different WO periods. In addition, we investigated several factors that possibly influence recurrence of disease activity, including serum natalizumab concentration and lymphocyte counts. METHODS: From a prospective observational cohort study of natalizumab-treated patients, we selected 52 patients who switched to fingolimod. We divided the patients in three groups (8 weeks WO). Serum natalizumab concentration and lymphocyte count were assessed during and after natalizumab treatment. RESULTS: Patients with a WO period of >8 weeks had a significant higher recurrence of disease activity (odds ratio, 6.8; 95% confidence interval, 1.4-32.8) compared to patients with a WO period of <6 weeks. Serum natalizumab concentration and lymphocyte count did not predict recurrence of disease activity. INTERPRETATION: A short WO period decreases the risk of recurrence of disease activity. The possible impact of a short WO period on the risk of carry-over PML in JC virus-positive patients remains uncertain

Natalizumab-associated progressive multifocal leukoencephalopathy is not preceded by elevated drug concentrations

Background: In recent years, a small but increasing number of neurologists choose to extend dose intervals of natalizumab with the aim of reducing the risk of progressive multifocal leukoencephalopathy (PML). This idea is based on the hypothesis that high drug concentrations increase the risk of PML. Objective: We investigated the relation between longitudinal natalizumab concentrations in patients who developed PML and patients who did not develop PML. Methods: In a prospective observational cohort study of 219 patients with relapsing-remitting multiple sclerosis treated with natalizumab, serum samples were taken every 12weeks prior to natalizumab infusion. In this cohort, 5 patients developed PML and were matched with 10 patients from the cohort who did not develop PML. Natalizumab concentrations were measured in available samples, and the longitudinal results were compared between the two patient groups. Results: Mean natalizumab concentrations in the five patients developing PML was 18.9 mu g/mL (standard deviation (SD): 13.4) versus 23.8 mu g/mL (SD: +/- 11.5) of the control patients. Furthermore, we did not observe a clear rise in concentration levels in patients subsequently developing PML. Conclusion: Our results provide preliminary evidence that contradicts the hypothesis that exposure to elevated concentrations of natalizumab is a relevant risk factor of developing PM