IgM anti-MAG± peripheral neuropathy (IMAGiNe) study protocol: An international, observational, prospective registry of patients with IgM M-protein peripheral neuropathies

Background: International consensus on IgM ± anti-MAG ± PNP (IgM PNP) is lacking. Despite increasing interest in clinical trials, validated disease-specific measures are needed to adequately capture limitations and changes over time. The IMAGiNe (IgM ± anti-myelin associated glycoprotein [MAG] peripheral neuropathy) study surges as an international collaboration to create a standardized registry of patients with IgM ± anti-MAG PNP. The consortium, which currently consists of 11 institutions from 7 countries, presents here the IMAGiNe study design and protocol. Aims: Functional outcome measures will be constructed at the level of impairment, as well as activity and participation. We aim to describe the natural history of the cohort, the role of anti-MAG antibodies, the presence of clinical subtypes, and potential biomarkers. Methods: The IMAGiNe study is a prospective, observational cohort study with a 3-year follow-up. At each assessment, researchers collect clinical data and subjects complete a list of preselected outcome measures. Among these, the “Pre-Rasch-built Overall Disability Scale (Pre-RODS)” questionnaire will be submitted to Rasch analysis to assess classic and modern clinimetric requirements. Results: The final measures will include the IgM-PNP-specific RODS and Ataxia Rating Scale (IgM-PNP-ARS). Descriptions of the disease course, clinical heterogeneity, treatment regimes, variations in laboratory values, and antibody titers will help reach consensus on diagnosis and follow-up strategies. Conclusion: The constructed interval scales will be cross-culturally valid and suitable for use in future clinical trials and daily practice. The ultimate goals are to improve functional individualized assessment, reach international consensus, and lay the foundations for successful designs in future studies

Plasma proteomic analysis on neuropathic pain in idiopathic peripheral neuropathy patients

Background and Aims: Why only half of the idiopathic peripheral neuropathy (IPN) patients develop neuropathic pain remains unknown. By conducting a proteomics analysis on IPN patients, we aimed to discover proteins and new pathways that are associated with neuropathic pain. Methods: We conducted unbiased mass-spectrometry proteomics analysis on blood plasma from 31 IPN patients with severe neuropathic pain and 29 IPN patients with no pain, to investigate protein biomarkers and protein–protein interactions associated with neuropathic pain. Univariate modeling was done with linear mixed modeling (LMM) and corrected for multiple testing. Multivariate modeling was performed using elastic net analysis and validated with internal cross-validation and bootstrapping. Results: In the univariate analysis, 73 proteins showed a p-value <.05 and 12 proteins showed a p-value <.01. None were significant after Benjamini–Hochberg adjustment for multiple testing. Elastic net analysis created a model containing 12 proteins with reasonable discriminatory power to differentiate between painful and painless IPN (false-negative rate 0.10, false-positive rate 0.18, and an area under the curve 0.75). Eight of these 12 proteins were clustered into one interaction network, significantly enriched for the complement and coagulation pathway (Benjamini–Hochberg adjusted p-value =.0057), with complement component 3 (C3) as the central node. Bootstrap validation identified insulin-like growth factor-binding protein 2 (IGFBP2), complement factor H-related protein 4 (CFHR4), and ferritin light chain (FTL), as the most discriminatory proteins of the original 12 identified. Interpretation: This proteomics analysis suggests a role for the complement system in neuropathic pain in IPN

Vegetarians, Pescatarians and Flexitarians with Adequate Vitamin B12 Levels Have No Increased Risk of Polyneuropathy

Background: In recent years, an increasing number of people adapt to a vegetarian, pescatarian or flexitarian dietary pattern that reduces the consumption of meat and fish. Although these dietary patterns have a risk for developing vitamin B12 deficiency associated polyneuropathy, it is unknown whether this risk is still increased when vitamin B12 levels are adequate. Objective: To examine whether a vegetarian, pescatarian or flexitarian dietary pattern is associated with an increased risk for idiopathic axonal polyneuropathy. Methods: We conducted a case-control study that included 256 idiopathic axonal polyneuropathy patients with adequate vitamin B12 blood levels and 630 controls. We used questionnaire data to determine the frequency of meat and fish consumption and defined dietary patterns. Results: The vegetarian (no meat or fish consumption) and the pescatarian (fish consumption, no meat consumption) dietary patterns showed no increased risk of axonal polyneuropathy. Frequency-effect analysis and quantity-effect analysis also did not show that a reduction of meat or fish consumption (flexitarian dietary pattern), either small or large, changed the risk of axonal polyneuropathy. Conclusions: We did not find an increased risk for axonal polyneuropathy among people with a vegetarian, pescatarian or flexitarian diet and an adequate vitamin B12 level

Project MinE : study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis

The most recent genome-wide association study in amyotrophic lateral sclerosis (ALS) demonstrates a disproportionate contribution from low-frequency variants to genetic susceptibility to disease. We have therefore begun Project MinE, an international collaboration that seeks to analyze whole-genome sequence data of at least 15 000 ALS patients and 7500 controls. Here, we report on the design of Project MinE and pilot analyses of successfully sequenced 1169 ALS patients and 608 controls drawn from the Netherlands. As has become characteristic of sequencing studies, we find an abundance of rare genetic variation (minor allele frequency < 0.1%), the vast majority of which is absent in public datasets. Principal component analysis reveals local geographical clustering of these variants within The Netherlands. We use the whole-genome sequence data to explore the implications of poor geographical matching of cases and controls in a sequence-based disease study and to investigate how ancestry-matched, externally sequenced controls can induce false positive associations. Also, we have publicly released genome-wide minor allele counts in cases and controls, as well as results from genic burden tests