ECTRIMS 2019: Biomarkers

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ECTRIMS, Stockholm Biomarkers session

Finally in the ECTRIMS mood! Hundred

Unbelievable that an year has passed already since the last one, but before I get maudlin, lets get some focus back in.

I’ll be co-chairing a session this Friday with Dr Salzer, from Umea University, Sweden (Rituximab man). You can see all the topics of discussion in the program above, but for those of you who haven’t looked at the scientific program as yet, here is the link: https://www.professionalabstracts.com/ectrims2019/programme-ectrims2019.pdf

282 – Moving from CSF to blood: monitoring disease activity in MS using serum neurofilament light protein

J. Lycke, Clinical Neuroscience, Gothenburg University/Institution of Neuroscience and Physiology, Gothenburg, Sweden

Neurofilament light (NFL) has the potential to become the first soluble biomarker to monitor disease activity and treatment response in clinical practice of multiple sclerosis (MS). This step was achieved by the evolution of ultrasensitive immunoassays for determination of neuro-specific proteins in blood, making NFL a more accessible biomarker. This may completely change the perspectives of monitoring disease activity and therapeutic interventions in MS. NFL specifically reflect neuro-axonal damage and degeneration and may serve as a biomarker during all stages of MS. Previous studies show that NFL may predict the risk of conversion from radiologically isolated syndrome to clinically isolated syndrome and relapsing remitting (RR) MS. The NFL level at disease onset is associated with disease severity, disability development and risk of conversion from RRMS to secondary progressive (SP) MS. NFL levels at clinical onset also correlate with brain and spinal cord atrophy development. Although NFL may predict the rate of degeneration, NFL is predominantly a disease activity marker in MS. Highest NFL levels are associated with relapses and correlate with number of contrast enhancing lesions and number of new T2 lesions. Disease modifying therapies (DMTs) reduce NFL to similar levels as found in healthy controls. In clinical trials and in observational studies NFL levels reflect the efficacy of the treatment. Compared to inflammatory soluble biomarkers, NFL is not directly influenced by immunomodulatory or immunosuppressive therapies, but reflects instead the extent of the autoimmune attack. Furthermore, NFL is not dependent on the pathological process of MS but may also be useful in the evaluation of therapies that directly reduce neurodegeneration. In the current evaluation of patients and for monitoring therapeutic efficacy clinical and cerebral MRI measures may not detect activity that cause diffuse neuro-axonal degeneration, spinal cord involvement or cortical lesions. Determination of NFL in blood may improve the assessment of patients and should be considered as part of No Evidence of Disease Activity (NEDA).

Without a doubt neurofilament is now the best way of picking up subclinical disease activity in MS (the disease that brews in the background in your body unseen). The light chain (NfL, named after its size) is felt to be more reflective of inflammatory mediated damage. So, I’m curious as to why Prof Lycke states that ‘Compared inflammatory soluble biomarkers, NFL is not directly influenced by immunomodulatory or immunosuppressive therapies, but reflects instead the extent of the autoimmune attack’. Methinks he’s splitting hairs…

283 – OCT as a prognostic marker

P. Calabresi, Neurology, Johns Hopkins School of Medicine, Baltimore, MD, United States

Biomarkers that help to predict MS disease course and facilitate therapeutic decision making are needed in MS. The visual pathway is recognized as an important site for MS-related inflammation and neuroaxonal degeneration. Approximately 50% of MS patients will experience an episode of clinical optic neuritis (ON) and post-mortem studies demonstrate optic nerve pathology and retinal ganglion cell loss in almost all MS eyes (regardless of a history of ON). Given the virtually ubiquitous involvement of the anterior visual pathway (AVP) in MS, the retina may therefore represent an opportune and accessible site for quantifying and tracking neurodegeneration in patients with MS.
Optical coherence tomography (OCT) is a rapid, well-tolerated, inexpensive, non-invasive imaging tool that uses near infrared light to quantify retinal layers. There has been significant interest in OCT measurements as an in-vivo biomarker of disease processes in MS. Reductions in peri-papillary retinal nerve fiber layer (pRNFL) thickness, macular volume and ganglion cell + inner plexiform layer (GCIP) thickness have been robustly demonstrated in MS eyes, both with and without a history of ON, as compared to healthy controls (HCs). Longitudinal studies have confirmed that retinal atrophy in MS eyes is progressive. Furthermore, OCT measurements in MS have demonstrated associations with clinical disability, brain atrophy and quantitative spinal cord measures, suggesting that retinal layer atrophy may be a marker of global CNS neurodegeneration. Recent work has shown that baseline retinal layer measurements may predict disability worsening over subsequent 5 and 10 year periods of follow up. Finally, OCT measures of retinal thinning are associated with serum levels of neurofilament light, a biomarker of neurodegeneration. In summary, OCT data support longitudinal structure-function relationships in the visual pathway in MS, and add to the evidence for retinal layer atrophy as a biomarker of MS-related global neurodegeneration.

OCT image of the back of the eye

People call eyes the windows to the soul. Maybe they’re not far out – it is definitely a window into the brain. The retina and the Cranial Nerve II (or the optic nerve) allow you to view the MS disease activity real-time. The OCT therefore becomes an important biomarker, especially in optic neuritis for evaluating neuroprotective strategies and remyelination therapies.

284 – Serum neurofilament light chain as a presymptomatic biomarker in multiple sclerosis

K. Bjornevik1, K.L. Munger1, M. Cortese1, C. Barro2, B.C. Healy3, D.W. Niebuhr4, A.I. Scher4, J. Kuhle2, A. Ascherio1,5 1Harvard T.H. Chan School of Public Health, Boston, MA, United States, 2University Hospital Basel, University of Basel, Basel, Switzerland, 3Brigham and Women’s Hospital, Boston, MA, 4Uniformed Services University of the Health Sciences, Bethesda, MD, 5Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States

Introduction: The clinical onset of multiple sclerosis (MS) is often preceded by unrecognized demyelinating events. Identification of these events at the time of occurrence would have implications for early diagnosis and treatment, as well as the search of causal factors for the disease.

Objectives:
To assess whether concentrations of serum neurofilament light chain (sNfL), a biomarker of neuroaxonal damage, are elevated before the clinical onset of MS, and whether changes in sNfL contribute to identifying individuals with prodromal MS.

Methods: We conducted a nested case-control study among active-duty US military personnel who have serum samples stored in the Department of Defense Serum Repository. We selected 60 MS cases, either with two serum samples both collected before MS onset or with one sample collected before and one after MS onset. For each case, we selected one control matched by age, sex, race/ethnicity, and dates of sample collection. sNfL concentrations were measured using an ultrasensitive single-molecule array (Simoa) assay, and we compared the levels in cases and controls using conditional logistic regression and linear mixed effects models.

Results: The levels of sNfL were higher in MS cases compared to their matched controls in serum samples drawn six years (median) before the clinical onset (p = 0.043). This difference increased with decreasing time to the case clinical onset (p = 0.002). A within-person increase in presymptomatic sNfL levels was associated with a higher risk of MS (rate ratio [RR] for ≥ 5 pg/mL increase: 7.50, 95% CI: 1.72 – 32.80). The clinical onset of MS was associated with a marked increase in sNfL levels (p = 0.009).

Conclusions: The levels of sNfL were increased six years before the clinical onset of MS. This indicates that MS has a prodromal phase lasting several years and that neuroaxonal damage occurs already during this phase.

Well, if you’ve ever wandered at what the lag period before you develop MS, then this abstract goes some ways to giving you an idea. The neurofilament samples used here were on average 6 years prior to MS diagnosis! Definitely, MS is an iceberg, so much more to know – maybe biomarkers are the answer?

285 – Serum neurofilament light chain levels correlate with peripapillary retinal nerve fibre layer thinning as measured by optical coherence tomography in multiple sclerosis

G. Bsteh1,2, K. Berek2, H. Hegen2, B. Teuchner3, M. Auer2, S. Wurth2, A. Zinganell2, F. Di Pauli2, F. Deisenhammer2, M. Khalil4, T. Berger11Neurology, Medical University of Vienna, Vienna, 2Neurology, 3Ophtalmology, Medical University of Innsbruck, Innsbruck, 4Neurology, Medical University of Graz, Graz, Austria

Background: Serum neurofilament light chain levels (sNfL) and peripapillary retinal nerve fiber layer (pRNFL) thinning are both emerging biomarkers of neuro-axonal damage in MS. However, data on the relation between sNfL and pRNFL are lacking.

Objectives: We aimed to determine the relation of sNfL levels and pRNFL thinning in a large cohort of relapsing-remitting (RR)-MS patients.

Methods: We identified 80 patients from a prospective, 3-year observational study on retinal changes in RRMS with annual blood samples available. sNfL was measured using a single molecule array (SIMOA) assay. Annualized pRNFLthinning rates (aLpRNFL) were determined by individual linear regression models.Correlations between single and averaged sNfL levels and aLpRNFL were analyzed using univariate and multivariate linear regression models.

Results: We found a significant association after correction for sex, age and disease duration between aLpRNFL and sNfL levels at years 1 and 2 with an increase of 10pg/ml transferring to an additional aLpRNFLof 0.9mm (95%CI: 0.4 – 1.5; p=0.002) and 0.7mm (95%CI: -1.4 – -0.1; p=0.042), respectively. About 15-20% of the aLpRNFL variance could be predicted from sNfL levels.

Conclusions: sNfL contributes to the prediction of retinal thinning in patients with RRMS strengthening its value as biomarker of neuro-axonal damage.

Now, how is it that something that’s taking place in the back of the eye correlating with a blood biomarker of neuro-axonal loss? If you remember, earlier I said the OCT is the window into your brain? You’re then simply looking at an association between two different measures of bulk neuro-axonal loss.

286 – Markers of glial processes and axonal damage in CSF and serum help to differentiate between relapsing-remitting and progressive forms of MS

A. Huss1, A. Abdelhak1,2, F. Bachhuber1, M. Senel1, M. Otto1, H. Tumani1,3 1Neurology, University Hospital Ulm, Ulm, 2Neurology, University Hospital Tuebingen, Tuebingen, 3Specialty Hospital of Neurology Dietenbronn, Schwendi, Germany

Background: The investigation of central nervous system (CNS) markers in body fluids of multiple sclerosis (MS) patients is a promising approach to monitor different pathophysiological aspects of the disease. We previously reported higher CSF and serum levels of glial fibrillary acidic protein (GFAP) but not Neurofilament light chain (NfL) in progressive (PMS) compared to relapsing-remitting (RMS) MS patients.

Objectives: To evaluate the proportion of glial processes and extent of axonal damage in different subtypes of MS we analyzed the glial markers GFAP and CHI3L1 in comparison to NfL as a marker for axonal damage in the CSF and serum from patients with RMS and PMS.

Methods: For this study we included 86 MS patients (47 RMS and 39 PMS) and 20 patients with other neurological diseases (OND) as controls.
NfL and GFAP levels were determined by the Single molecule array (Simoa) and CHI3L1 levels were measured with conventional ELISA. A score was calculated based on glial markers to axonal markers (CHI3L1*GFAP/NfL, referred to as “Glia-score”) to capture the extent of glial processes in relation to axonal damage in each individual patient.

Results: GFAP levels were higher in the CSF and serum of PMS patients in comparison to RMS and controls (p< 0.01 and p< 0.05, respectively). Likewise, CSF and serum NfL levels were higher in RMS and PMS patients than in controls (CSF p< 0.0001 for both comparisons, serum p< 0.001 and 0.0001, respectively), but no significant difference between the PMS and RMS was observed. CHI3L1 showed higher CSF levels in PMS vs. RMS and controls (p< 0.001 and p< 0.0001), RMS vs. controls (p< 0.01) and higher serum levels for PMS vs. controls (p< 0.05).
The Glia-score was higher in the CSF of PMS patients compared to RMS and controls (p< 0.01 and p< 0.001, respectively) and in the serum of PMS patients compared to RMS and controls (p< 0.0001 for both comparisons).
Furthermore, the Glia-score in serum but not CSF correlated with the disability as detected by EDSS in the PMS group but not in the RMS group (Spearman ρ= 0.56 and 0.09, p= 0.003 and 0.56, respectively).

Conclusions: Our data indicate the involvement of glial mechanisms during the pathogenesis of PMS. Moreover, a calculated score helps to differentiate between PMS and RMS especially in the serum making it an easily accessible and promising marker.

Well, I think this abstract supports my earlier assertions that NfL is more reflective of inflammation induced neuro-axonal injury than pure neurodegeneration per se. RRMS where inflammation is at the forefront leads to higher NfL levels than progressive MS.

The second point is, how sure are we that the microglia are the culprits in progressive MS.

Why walk when you can jump, huh?

287 – Soluble CD27 a biomarker of T cell activity in intrathecal inflammation in patients with relapsing-remitting multiple sclerosis

M.T. Cencioni1, S. Yusuf2, I. Palmisano1, S. Boyeon Lee1, R. Ali1, N.D. Mazarakis1, R. Nicholas1, L. Costa_Frossard3, L.M. Villar Guimerans3, P.A. Muraro1 1Brain Sciences, Imperial College London, London, 2NDORMS, Kennedy Institute of Rheumatology, Oxford University, Oxford, United Kingdom, 3Immunology, Hospital Ramon y Cajal, Madrid, Spain

Background: An increasing number of disease modifying treatments are available for Multiple Sclerosis (MS) and patient stratification towards personalised therapy would be an important improvement over current treatment algorithms. MRI is routinely used as a biomarker of inflammatory disease but it is insensitive to the ongoing inflammation in the CNS, particularly of low grade inflammation occurring without blood-brain barrier disruption. Sensitive biomarkers of ongoing inflammatory activity in the CNS are lacking. Soluble CD27 (sCD27) has been demonstrated as being abnormally high in the cerebrospinal fluid (CSF) of patients with clinically isolated syndrome as well as in adult and paediatric MS and it is also associated with higher relapse frequency after diagnosis. The levels of sCD27 were found to correlate with the presence of oligoclonal bands (OCBs) and the IgG index.

Goal: We aimed to further investigate sCD27 levels in CSF and serum in respect of their association with MS diagnosis and clinical features. We attempted to elucidate the cellular origin and modelled, in vitro, the mechanism of CD27 release.

Methods: CSF samples were collected from 80 relapsing-remitting MS (RRMS) patients and 12 controls. Serum samples were obtained from 58 RR-MS patients and 9 controls.
Lymphocytes were isolated from peripheral blood of healthy donors and CD27 knockdown CD4 T cells were produced by lentiviral shRNA vectors. These cells were used for proliferation assays and activated for 24, 48 and 96 hrs and the supernatants were collected for further analysis.
ELISA and Meso Scale Discovery Scale were performed to quantify analytes in the CSF, serum and culture medium.

Results: We detected a significant increase of sCD27 in both CSF and serum of RR-MS patients compared to controls and an association with MS disease activity. We demonstrate that purified CD4+ and CD8+ T cells are the main source of sCD27; this is released upon cell activation. We also demonstrate that CD27 knockdown in CD4 T cells release less IFNg and show a reduced proliferation as compared to wild-type CD4+T cells.

Conclusions: Our results show that sCD27 is an indicator of T cell activation in the intrathecal compartment in RR-MS patients but that it is also detectable at increased levels in the serum suggestive of concomitant systemic activation. Our results also suggest a direct implication of CD27 in inflammatory T cell effector function which warrants further investigation.

I’m sure this one is going to send off MD and MD2 on another epic of is MS a T cell or a B cell disease. How about both for a change, one happy dysfunctional family.

Incidentally, sCD21 is a B cell marker – would be interested to learn the ratios between the two. Done in 2016, I believe.

I’m now off to find out what MD’s strategy to get into Sweden?! He may have won the sweepstakes for a cruise to Sweden…

About the author

Neuro Doc Gnanapavan

5 comments

Leave a Reply to luis fernando Cancel reply

  • The neurofilament samples used here were on average 6 years prior to MS diagnosis!

    Will this apply to a young kid 10 years old with ms?

    Thanks

  • Thanks NDG after having a no show taxi moment….public transport does the business but with the panic , I think I need a new change of clothes. Neurofilament unrelated to inflammation.?…suggests no understanding of what is going on.

  • Thanks NDG after having a no show taxi moment….public transport does the business but with the panic , I think I need a new change of clothes. Neurofilament unrelated to inflammation.?…suggests no understanding of what is going on.

    As for soluble CD27 I have commented on this before so a depleting CD27 mab is what we need

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