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

Clusters of co-abundant proteins in the brain cortex associated with fronto-temporal lobar degeneration

Background: \nFrontotemporal lobar degeneration (FTLD) is characterized pathologically by neuronal and glial inclusions of hyperphosphorylated tau or by neuronal cytoplasmic inclusions of TDP43. This study aimed at deciphering the molecular mechanisms leading to these distinct pathological subtypes. \n \nMethods: \nTo this end, we performed an unbiased mass spectrometry-based proteomic and systems-level analysis of the middle frontal gyrus cortices of FTLD-tau (n = 6), FTLD-TDP (n = 15), and control patients (n = 5). We validated these results in an independent patient cohort (total n = 24). \n \nResults: \nThe middle frontal gyrus cortex proteome was most significantly altered in FTLD-tau compared to controls (294 differentially expressed proteins at FDR = 0.05). The proteomic modifications in FTLD-TDP were more heterogeneous (49 differentially expressed proteins at FDR = 0.1). Weighted co-expression network analysis revealed 17 modules of co-regulated proteins, 13 of which were dysregulated in FTLD-tau. These modules included proteins associated with oxidative phosphorylation, scavenger mechanisms, chromatin regulation, and clathrin-mediated transport in both the frontal and temporal cortex of FTLD-tau. The most strongly dysregulated subnetworks identified cyclin-dependent kinase 5 (CDK5) and polypyrimidine tract-binding protein 1 (PTBP1) as key players in the disease process. Dysregulation of 9 of these modules was confirmed in independent validation data sets of FLTD-tau and control temporal and frontal cortex (total n = 24). Dysregulated modules were primarily associated with changes in astrocyte and endothelial cell protein abundance levels, indicating pathological changes in FTD are not limited to neurons. \n \nConclusions: \nUsing this innovative workflow and zooming in on the most strongly dysregulated proteins of the identified modules, we were able to identify disease-associated mechanisms in FTLD-tau with high potential as biomarkers and/or therapeutic targets

Aerosols Transmit Prions to Immunocompetent and Immunodeficient Mice

Prions, the agents causing transmissible spongiform encephalopathies, colonize the brain of hosts after oral, parenteral, intralingual, or even transdermal uptake. However, prions are not generally considered to be airborne. Here we report that inbred and crossbred wild-type mice, as well as tga20 transgenic mice overexpressing PrPC, efficiently develop scrapie upon exposure to aerosolized prions. NSE-PrP transgenic mice, which express PrPC selectively in neurons, were also susceptible to airborne prions. Aerogenic infection occurred also in mice lacking B- and T-lymphocytes, NK-cells, follicular dendritic cells or complement components. Brains of diseased mice contained PrPSc and transmitted scrapie when inoculated into further mice. We conclude that aerogenic exposure to prions is very efficacious and can lead to direct invasion of neural pathways without an obligatory replicative phase in lymphoid organs. This previously unappreciated risk for airborne prion transmission may warrant re-thinking on prion biosafety guidelines in research and diagnostic laboratories

Variations in consecutive serum neurofilament light levels in healthy controls and multiple sclerosis patients

Background Neurofilament light is a neuronal protein detectable in serum (sNfL), with high potential as disease activity biomarker in multiple sclerosis (MS). To date, little is known about sNfL fluctuations between 2 consecutive measurements in healthy controls (HC) and MS patients. Yet this information is critical, as it will help define a clinically significant variation. Methods sNfL was measured at 2 consecutive time points in a cohort of 90 MS patients (untreated relapsing remitting MS (uRRMS), n=35; treated relapsing remitting MS (tRRMS), n= 21; secondary progressive MS, SPMS, n=21; primary progressive MS, PPMS, n=13), and 90 age-matched HC, using the Simoa NfL light® assay. Results Mean sNfL was elevated in all MS subtypes compared to HC (p<0.0001), and positively associated with age in HC (r=0.70, p<0.001), confirming previous reports. Mean sNfL was higher at follow-up compared to baseline in HC (p<0.001), and lower in uRRMS(p=0.036) and tRRMS (p=0.008). At follow-up, a similar proportion of HC (50.0%), untreated RRMS (51.4%), treated RRMS (33.3%), SPMS (45.0%) and PPMS (46.2%) had variations in sNfL levels exceeding 20% of baseline levels. Conclusions Our data suggest variations in sNfL occur both in HC and MS populations to a similar extent and magnitude. Variations between two consecutive sNfL measurements may reflect natural variations and not necessarily variations in inflammatory disease activity

Regulator of oligodendrocyte maturation, miR-219, a potential biomarker for MS

textabstractBackground: Multiple sclerosis (MS) is a demyelinating and degenerative disease of the central nervous system. Normally, demyelination is followed by remyelination, which requires repopulation of a demyelinated area by oligodendrocyte precursor cells. Although large numbers of precursor cells are present in MS lesions, remyelination often fails, in part by the inability of precursor cells to differentiate into mature myelin-forming cells. In mouse and rat, miR-219 is required for this differentiation. Previously, we identified decreased miR-219 expression in tissue of MS patients compared to controls. Cell-free miRNAs have been detected in many different body fluids including cerebrospinal fluid (CSF) and may reflect disease processes going on in the central nervous system. This prompted us to investigate the biomarker performance of CSF miR-219 for MS diagnosis. Methods: Quantitative PCR was performed measuring miR-219 levels in CSF of MS patients and controls in three inde

Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach

BACKGROUND: Diagnosis of dementia with Lewy bodies (DLB) is challenging, largely due to a lack of diagnostic tools. Cerebrospinal fluid (CSF) biomarkers have been proven useful in Alzheimer's disease (AD) diagnosis. Here, we aimed to identify novel CSF biomarkers for DLB using a high-throughput proteomic approach. METHODS: We applied liquid chromatography/tandem mass spectrometry with label-free quantification to identify biomarker candidates to individual CSF samples from a well-characterized cohort comprising patients with DLB (n = 20) and controls (n = 20). Validation was performed using (1) the identical proteomic workflow in an independent cohort (n = 30), (2) proteomic data from patients with related neurodegenerative diseases (n = 149) and (3) orthogonal techniques in an extended cohort consisting of DLB patients and controls (n = 76). Additionally, we utilized random forest analysis to identify the subset of candidate markers that best distinguished DLB from all other groups. RESULTS: In total, we identified 1995 proteins. In the discovery cohort, 69 proteins were differentially expressed in DLB compared to controls (p < 0.05). Independent cohort replication confirmed VGF, SCG2, NPTX2, NPTXR, PDYN and PCSK1N as candidate biomarkers for DLB. The downregulation of the candidate biomarkers was somewhat more pronounced in DLB in comparison with related neurodegenerative diseases. Using random forest analysis, we identified a panel of VGF, SCG2 and PDYN to best differentiate between DLB and other clinical groups (accuracy: 0.82 (95%CI: 0.75-0.89)). Moreover, we confirmed the decrease of VGF and NPTX2 in DLB by ELISA and SRM methods. Low CSF levels of all biomarker candidates, except PCSK1N, were associated with more pronounced cognitive decline (0.37 < r < 0.56, all p < 0.01). CONCLUSION: We identified and validated six novel CSF biomarkers for DLB. These biomarkers, particularly when used as a panel, show promise to improve diagnostic accuracy and strengthen the importance of synaptic dysfunction in the pathophysiology of DLB