Projection of Interspecific Competition (PIC) Matrices: A Conceptual Framework for Inclusion in Population Risk Assessments.

Accounting for intraspecific and interspecific competition when assessing the effects of chemical and nonchemical stressors is an important uncertainty in ecological risk assessments. We developed novel projection of interspecific competition (PIC) matrices that allow for analysis of population dynamics of two or more species exposed to a given stressor(s) that compete for shared resources within a landscape. We demonstrate the application of PIC matrices to investigate the population dynamics of two hypothetical fish species that compete with one another and have differences in net reproductive rate and intrinsic rate of population increase. Population status predictions were made under scenarios that included exposure to a chemical stressor that reduced fecundity for one or both species. The results of our simulations demonstrated that measures obtained from the life table and Leslie matrix of an organism, including net reproductive rate and intrinsic rate of increase, can result in erroneous conclusions of population status and viability in the absence of a consideration of resource limitation and interspecific competition. This modeling approach can be used in conjunction with field monitoring efforts and/or laboratory testing to link effects due to stressors to possible outcomes within an ecosystem. In addition, PIC matrices could be combined with adverse outcome pathways to allow for ecosystem projection based on taxonomic conservation of molecular targets of chemicals to predict the likelihood of relative cross-species susceptibility. Overall, the present study shows how PIC matrices can integrate effects across the life cycles of multiple species, provide a linkage between endpoints observed in individual and population-level responses, and project outcomes at the community level for multiple generations for multiple species that compete for limited resources. Environ Toxicol Chem 2024;43:1406-1422. Published 2024. This article is a U.S. Government work and is in the public domain in the USA.

AOP Report: Adverse Outcome Pathways for Aromatase Inhibition or Androgen Receptor Agonism Leading to Male-Biased Sex Ratio and Population Decline in Fish.

Screening and testing of potential endocrine-disrupting chemicals for ecological effects are examples of risk assessment/regulatory activities that can employ adverse outcome pathways (AOPs) to establish linkages between readily measured alterations in endocrine function and whole organism- and population-level responses. Of particular concern are processes controlled by the hypothalamic-pituitary-gonadal/thyroidal (HPG/T) axes. However, the availability of AOPs suitable to meet this need is currently limited in terms of species and life-stage representation relative to the diversity of endpoints influenced by HPG/T function. In our report we describe two novel AOPs that comprise a simple AOP network focused on the effects of chemicals on sex differentiation during early development in fish. The first AOP (346) documents events starting with inhibition of cytochrome P450 aromatase (CYP19), resulting in decreased availability of 17ß-estradiol during gonad differentiation, which increases the occurrence of testis formation, resulting in a male-biased sex ratio and consequent population-level declines. The second AOP (376) is initiated by activation of the androgen receptor (AR), also during sexual differentiation, again resulting in a male-biased sex ratio and population-level effects. Both AOPs are strongly supported by existing physiological and toxicological evidence, including numerous fish studies with model CYP19 inhibitors and AR agonists. Accordingly, AOPs 346 and 376 provide a basis for more focused screening and testing of chemicals with the potential to affect HPG function in fish during early development. Environ Toxicol Chem 2023;42:747-756. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.

Investigating Vernal Pool Fairy Shrimp Exposure to Organophosphate Pesticides: Implications for Population-Level Risk Assessment.

Vernal pool fairy shrimp, Branchinecta lynchi, is a freshwater crustacean endemic to California and Oregon, including California's Central Valley. B. lynchi is listed as a Federally Threatened species under the US Endangered Species Act, and as a vulnerable species on the IUCN Red List. Threats that may negatively impact vernal pool fairy shrimp populations include pesticide applications to agricultural land use (e.g., agrochemicals such as organophosphate pesticides) and climate changes that impact vernal pool hydrology. Pop-GUIDE (Population model Guidance, Use, Interpretation, and Development for Ecological risk assessment) is a comprehensive tool that facilitates development and implementation of population models for ecological risk assessment and can be used to document the model derivation process. We employed Pop-GUIDE to document and facilitate the development of a population model for investigating impacts of organophosphate pesticides on vernal pool fairy shrimp populations in California's Central Valley. The resulting model could be applied in combination with field assessment and laboratory-based chemical analysis to link effects from pesticide exposure to adverse outcomes in populations across their range. B. lynchi has a unique intra-annual life cycle that is largely dependent upon environmental conditions. Future deployment of this population model should include complex scenarios consisting of multiple stressors, whereby the model is used to examine scenarios that combine chemical stress resulting from exposure to pesticides and climate changes.

A Multidimensional Matrix Model for Predicting the Effects of Male-Biased Sex Ratios on Fish Populations.

Laboratory experiments have established that exposure to certain endocrine-active substances prior to and/or during the period of sexual differentiation can lead to skewed sex ratios in fish. However, the potential long-term population impact of biased sex ratio depends on multiple factors including the life history of the species and whether the ratio is male or female-biased. In the present study, we describe a novel multidimensional, density-dependent matrix model that analyzes age class-structure of both males and females over time, allowing for the quantitative evaluation of the effects of biased sex ratio on population status. This approach can be used in conjunction with field monitoring efforts and/or laboratory testing to link effects on sex ratio due to chemical and/or nonchemical stressors to adverse outcomes in whole organisms and populations. For demonstration purposes, we applied the model to evaluate population trajectories for fathead minnow (Pimephales promelas) exposed to prochloraz, an aromatase inhibitor, during sexual differentiation. The model also was used to explore the population impact in a more realistic exposure scenario in which both adult and early life stages of fish are exposed concurrently to prochloraz, which, in addition to altering sex ratio during development, can decrease vitellogenin and egg production in adult females. For each exposure scenario, the model was used to analyze total population size, numbers of females and of males, and sex specific recruitment of the F1 generation. The present study illustrates the utility of multidimensional matrix population models for ecological risk assessment in terms of integrating effects across a population of an organism even when chemical effects on individuals are manifested via different pathways depending on life stage. Environ Toxicol Chem 2022;41:1066-1077. Published 2022. This article is a U.S. Government work and is in the public domain in the USA.

A 30-Year Study of Impacts, Recovery, and Development of Critical Effect Sizes for Endocrine Disruption in White Sucker (Catostomus commersonii) Exposed to Bleached-Kraft Pulp Mill Effluent at Jackfish Bay, Ontario, Canada.

Jackfish Bay is an isolated bay on the north shore of Lake Superior, Canada that has received effluent from a large bleached-kraft pulp mill since the 1940s. Studies conducted in the late 1980s found evidence of reductions in sex steroid hormone levels in multiple fish species living in the Bay, and increased growth, condition and relative liver weights, with a reduction in internal fat storage, reduced gonadal sizes, delayed sexual maturation, and altered levels of circulating sex steroid hormones in white sucker (Catostomus commersonii). These early studies provided some of the first pieces of evidence of endocrine disruption in wild animals. Studies on white sucker have continued at Jackfish Bay, monitoring fish health after the installation of secondary waste treatment (1989), changes in the pulp bleaching process (1990s), during facility maintenance shutdowns and during a series of facility closures associated with changing ownership (2000s), and were carried through to 2019 resulting in a 30-year study of fish health impacts, endocrine disruption, chemical exposure, and ecosystem recovery. The objective of the present study was to summarize and understand more than 75 physiological, endocrine, chemical and whole organism endpoints that have been studied providing important context for the complexity of endocrine responses, species differences, and challenges with extrapolation. Differences in body size, liver size, gonad size and condition persist, although changes in liver and gonad indices are much smaller than in the early years. Population modeling of the initial reproductive alterations predicted a 30% reduction in the population size, however with improvements over the last couple of decades those population impacts improved considerably. Reflection on these 30 years of detailed studies, on environmental conditions, physiological, and whole organism endpoints, gives insight into the complexity of endocrine responses to environmental change and mitigation.

A multidimensional density dependent matrix population model for assessing risk of stressors to fish populations.

Modeling exposure and recovery of fish and wildlife populations after stressor mitigation serves as a basis for evaluating remediation success. Herein, we develop a novel multidimensional density dependent matrix population model that analyzes both size-structure and age class-structure simultaneously. This modeling approach emphasizes application in conjunction with field monitoring efforts (e.g., through effects-based monitoring programs) and/or laboratory analysis to link effects due to stressors to outcomes in populations. We applied the model to investigate Atlantic killifish (Fundulus heteroclitus) exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin with effects on fertility and survival rates. The Atlantic killifish is an important and well-studied model organism for understanding the effects of pollutants and other stressors in estuarine and marine ecosystems. For each exposure concentration, the corresponding plots of total population size, population size structure, and age structure over time were generated. The present study serves as an example of how a multidimensional matrix population model can integrate effects across the life cycle, provide a linkage between endpoints observed in the individual and ecological risk to the population as a whole, and project outcomes for multiple generations.

Beta Amyloid Deposition Is Not Associated With Cognitive Impairment in Parkinson's Disease.

The extent to which Alzheimer neuropathology, particularly the accumulation of misfolded beta-amyloid, contributes to cognitive decline and dementia in Parkinson's disease (PD) is unresolved. Here, we used Florbetaben PET imaging to test for any association between cerebral amyloid deposition and cognitive impairment in PD, in a sample enriched for cases with mild cognitive impairment. This cross-sectional study used Movement Disorders Society level II criteria to classify 115 participants with PD as having normal cognition (PDN, n = 23), mild cognitive impairment (PD-MCI, n = 76), or dementia (PDD, n = 16). We acquired 18F-Florbetaben (FBB) amyloid PET and structural MRI. Amyloid deposition was assessed between the three cognitive groups, and also across the whole sample using continuous measures of both global cognitive status and average performance in memory domain tests. Outcomes were cortical FBB uptake, expressed in centiloids and as standardized uptake value ratios (SUVR) using the Centiloid Project whole cerebellum region as a reference, and regional SUVR measurements. FBB binding was higher in PDD, but this difference did not survive adjustment for the older age of the PDD group. We established a suitable centiloid cut-off for amyloid positivity in Parkinson's disease (31.3), but there was no association of FBB binding with global cognitive or memory scores. The failure to find an association between PET amyloid deposition and cognitive impairment in a moderately large sample, particularly given that it was enriched with PD-MCI patients at risk of dementia, suggests that amyloid pathology is not the primary driver of cognitive impairment and dementia in most patients with PD.

Functional Connectivity Alterations Reveal Complex Mechanisms Based on Clinical and Radiological Status in Mild Relapsing Remitting Multiple Sclerosis.

Resting state functional MRI (rs-fMRI) has provided important insights into functional reorganization in subjects with Multiple Sclerosis (MS) at different stage of disease. In this cross-sectional study we first assessed, by means of rs-fMRI, the impact of overall T2 lesion load (T2LL) and MS severity score (MSSS) on resting state networks (RSNs) in 62 relapsing remitting MS (RRMS) patients with mild disability (MSSS < 3). Independent Component Analysis (ICA) followed by dual regression analysis confirmed functional connectivity (FC) alterations of many RSNs in RRMS subjects compared to healthy controls. The anterior default mode network (DMNa) and the superior precuneus network (PNsup) showed the largest areas of decreased FC, while the sensory motor networks area M1 (SMNm1) and the medial visual network (MVN) showed the largest areas of increased FC. In order to better understand the nature of these alterations as well as the mechanisms of functional alterations in MS we proposed a method, based on linear regression, that takes into account FC changes and their correlation with T2LL and MSSS. Depending on the sign of the correlation between FC and T2LL, and furthermore the sign of the correlation with MSSS, we suggested the following possible underlying mechanisms to interpret altered FC: (1) FC reduction driven by MS lesions, (2) "true" functional compensatory mechanism, (3a) functional compensation attempt, (3b) "false" functional compensation, (4a) neurodegeneration, (4b) pre-symptomatic condition (damage precedes MS clinical manifestation). Our data shows areas satisfying 4 of these 6 conditions (i.e., 1,2,3b,4b), supporting the suggestion that increased FC has a complex nature that may exceed the simplistic assumption of an underlying compensatory mechanism attempting to limit the brain damage caused by MS progression. Exploring differences between RRMS subjects with short disease duration (MSshort) and RRMS with similar disability but longer disease duration (MSlong), we found that MSshort and MSlong were characterized by clearly distinct pattern of FC, involving predominantly sensory and cognitive networks respectively. Overall, these results suggest that the analysis of FC alterations in multiple large-scale networks in relation to radiological (T2LL) and clinical (MSSS, disease duration) status may provide new insights into the pathophysiology of relapse onset MS evolution.

Inclusion of optic nerve involvement in dissemination in space criteria for multiple sclerosis.

OBJECTIVE: To investigate the effect of including optic nerve involvement in dissemination in space (DIS) criteria for diagnosis of multiple sclerosis (MS) in patients with clinically isolated syndrome (CIS). METHODS: We studied 160 patients with CIS: 129 with optic neuritis (ON) and 31 with non-ON CIS. MRI brain/spinal cord was done at the time of presentation and a follow-up MRI brain after 3-12 months. We evaluated optic nerve involvement clinically or with visual evoked potentials (VEPs, n = 42). We investigated the performance of the McDonald 2017 DIS criteria and modified DIS criteria including optic nerve involvement for development of clinically definite MS after ∼15 years. RESULTS: In the ON group, including symptomatic optic nerve involvement identified an additional 15 patients with DIS. The modified DIS criteria that included optic nerve involvement were more sensitive (95% vs 83%) and more accurate (81% vs 78%) than the McDonald 2017 DIS criteria, but less specific (57% vs 68%). In combination with dissemination in time criteria, the modified DIS criteria remained more sensitive (83% vs 74%) and accurate (81% vs 75%), and the specificity was the same (77%). Including asymptomatic optic nerve involvement in DIS the non-ON group did not identify any additional patients and the performance of the McDonald 2017 criteria and the modified criteria was the same. CONCLUSION: The inclusion of symptomatic optic nerve involvement in DIS in patients with ON improved the overall performance of MS diagnostic criteria. Including asymptomatic optic nerve involvement in DIS in patients with a non-ON CIS may be of limited value. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with suspected MS, inclusion of symptomatic optic nerve involvement in DIS criteria improves the overall performance of diagnostic criteria for MS.

Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the INFORMS study.

Objective: To investigate the relationship between brain volume and disability worsening over ≥3 years in the natural history of primary progressive multiple sclerosis using data from the placebo group of the INFORMS trial (n = 487; clinicaltrials.gov NCT00731692). Methods: Magnetic resonance imaging scans were collected annually. Brain volume loss was determined using SIENA. Patients were stratified by baseline normalized brain volume after adjusting for demographic and disease-burden covariates. Results: Baseline normalized brain volume was predictive of disability worsening: Risk of 3-month confirmed disability progression was reduced by 36% for high versus low baseline normalized brain volume (Cox's model hazard ratio 0.64, P = 0.0339; log-rank test: P = 0.0297). Moreover, on-study brain volume loss was significantly associated with disability worsening (P = 0.012) and was evident in patients with or without new lesions or relapses. Brain volume loss depended significantly on baseline T2 lesion volume (P < 0.0001). Despite low inflammatory activity at baseline (13% of patients had gadolinium-enhancing lesions) and throughout the study (mean 0.5 new/enlarging T2 lesions and 172 mm3 T2 lesion volume increase per year), baseline T2 lesion volume was substantial (mean 10 cm3). Lower normalized brain volume at baseline correlated with higher baseline T2 volume and older age (both P < 0.0001). Interpretation: Baseline brain volume and the rate of ongoing brain atrophy are significantly associated with disability worsening in primary progressive multiple sclerosis. Brain volume loss is significantly related to baseline T2 lesion volume, but partially independent of new lesion activity, which might explain the limited efficacy of anti-inflammatory treatment.

ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a complex disease with new drugs becoming available in the past years. There is a need for a reference tool compiling current data to aid professionals in treatment decisions. OBJECTIVES: To develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS. METHODS: This guideline has been developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology and following the updated EAN recommendations. Clinical questions were formulated in Patients-Intervention-Comparator-Outcome (PICO) format and outcomes were prioritized. The quality of evidence was rated into four categories according to the risk of bias. The recommendations with assigned strength (strong and weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panelists was reached by use of the modified nominal group technique. RESULTS: A total of 10 questions were agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency (EMA) at the time of publication. A total of 21 recommendations were agreed by the guideline working group after three rounds of consensus. CONCLUSION: The present guideline will enable homogeneity of treatment decisions across Europe.

Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria.

The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers.

Environmental modifiable risk factors for multiple sclerosis: Report from the 2016 ECTRIMS focused workshop.

Multiple sclerosis (MS) is an inflammatory and neurodegenerative demyelinating disease of the central nervous system (CNS), most likely autoimmune in origin, usually beginning in early adulthood. The aetiology of the disease is not well understood; it is viewed currently as a multifactorial disease which results from complex interactions between genetic predisposition and environmental factors, of which a few are potentially modifiable. Improving our understanding of these factors can lead to new and more effective approaches to patient counselling and, possibly, prevention and management of the disease. The 2016 focused workshop of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) addressed the topic of environmental, modifiable risk factors for MS, gathering experts from around the world, to collate experimental and clinical research into environmental factors that have been associated with the disease onset and, in a few cases, disease activity and progression. A number of factors, including infections, vitamin D deficiency, diet and lifestyle factors, stress and comorbidities, were discussed. The meeting provided a forum to analyse available evidence, to identify inconsistencies and gaps in current knowledge and to suggest avenues for future research.

Spinal cord atrophy as a primary outcome measure in phase II trials of progressive multiple sclerosis.

OBJECTIVES: To measure the development of spinal cord (SC) atrophy over 1 year in patients with progressive multiple sclerosis (PMS) and determine the sample sizes required to demonstrate a reduction in spinal cord cross-sectional area (SC-CSA) as an outcome measure in clinical trials. METHODS: In total, 44 PMS patients (26 primary progressive multiple sclerosis (PPMS), 18 secondary progressive multiple sclerosis (SPMS)) and 29 healthy controls (HCs) were studied at baseline and 12 months. SC-CSA was measured using the three-dimensional (3D) fast field echo sequences acquired at 3T and the active surface model. Multiple linear regressions were used to investigate changes in imaging measurements. RESULTS: PPMS patients had shorter disease duration, lower Expanded Disability Status Scale (EDSS) and larger SC-CSA than SPMS patients. All patients together showed a significantly greater decrease in percentage SC-CSA change than HCs, which was driven by the PPMS. All patients deteriorated over 1 year, but no association was found between percentage SC-CSA change and clinical changes. The sample size per arm required to detect a 50% treatment effect over 1 year, at 80% power, was 57 for PPMS and 546 for SPMS. CONCLUSION: SC-CSA may become an outcome measure in trials of PPMS patients, when they are at an early stage of the disease, have moderate disability and modest SC atrophy.

Sensitivity of multi-shell NODDI to multiple sclerosis white matter changes: a pilot study.

Diffusion tensor imaging (DTI) is sensitive to white matter (WM) damage in multiple sclerosis (MS), not only in focal lesions but also in the normal-appearing WM (NAWM). However, DTI indices can also be affected by natural spatial variation in WM, as seen in crossing and dispersing white matter fibers. Neurite orientation dispersion and density imaging (NODDI) is an advanced diffusion-weighted imaging technique that provides distinct indices of fiber density and dispersion. We performed NODDI of lesion tissue and NAWM in five MS patients and five controls, comparing the technique with traditional DTI. Both DTI and NODDI identified tissue damage in NAWM and in lesions. NODDI was able to detect additional changes and it provided better contrast in MS-NAWM microstructure, because it distinguished orientation dispersion and fiber density better than DTI. We showed that NODDI is viable in MS patients and that it offers, compared with DTI parameters, improved sensitivity and possibly greater specificity to microstructure features such as neurite orientation.

Quantitative Adverse Outcome Pathways and Their Application to Predictive Toxicology.

A quantitative adverse outcome pathway (qAOP) consists of one or more biologically based, computational models describing key event relationships linking a molecular initiating event (MIE) to an adverse outcome. A qAOP provides quantitative, dose-response, and time-course predictions that can support regulatory decision-making. Herein we describe several facets of qAOPs, including (a) motivation for development, (b) technical considerations, (c) evaluation of confidence, and (d) potential applications. The qAOP used as an illustrative example for these points describes the linkage between inhibition of cytochrome P450 19A aromatase (the MIE) and population-level decreases in the fathead minnow (FHM; Pimephales promelas). The qAOP consists of three linked computational models for the following: (a) the hypothalamic-pitutitary-gonadal axis in female FHMs, where aromatase inhibition decreases the conversion of testosterone to 17ß-estradiol (E2), thereby reducing E2-dependent vitellogenin (VTG; egg yolk protein precursor) synthesis, (b) VTG-dependent egg development and spawning (fecundity), and (c) fecundity-dependent population trajectory. While development of the example qAOP was based on experiments with FHMs exposed to the aromatase inhibitor fadrozole, we also show how a toxic equivalence (TEQ) calculation allows use of the qAOP to predict effects of another, untested aromatase inhibitor, iprodione. While qAOP development can be resource-intensive, the quantitative predictions obtained, and TEQ-based application to multiple chemicals, may be sufficient to justify the cost for some applications in regulatory decision-making.

An abnormal periventricular magnetization transfer ratio gradient occurs early in multiple sclerosis.

In established multiple sclerosis, tissue abnormality-as assessed using magnetization transfer ratio-increases close to the lateral ventricles. We aimed to determine whether or not (i) these changes are present from the earliest clinical stages of multiple sclerosis; (ii) they occur independent of white matter lesions; and (iii) they are associated with subsequent conversion to clinically definite multiple sclerosis and disability. Seventy-one subjects had MRI scanning a median of 4.6 months after a clinically isolated optic neuritis (49 females, mean age 33.5 years) and were followed up clinically 2 and 5 years later. Thirty-seven healthy controls (25 females, mean age 34.4 years) were also scanned. In normal-appearing white matter, magnetization transfer ratio gradients were measured 1-5 mm and 6-10 mm from the lateral ventricles. In control subjects, magnetization transfer ratio was highest adjacent to the ventricles and decreased with distance from them; in optic neuritis, normal-appearing white matter magnetization transfer ratio was lowest adjacent to the ventricles, increased over the first 5 mm, and then paralleled control values. The magnetization transfer ratio gradient over 1-5 mm differed significantly between the optic neuritis and control groups [+0.059 percentage units/mm (pu/mm) versus -0.033 pu/mm, P = 0.010], and was significantly steeper in those developing clinically definite multiple sclerosis within 2 years compared to those who did not (0.132 pu/mm versus 0.016 pu/mm, P = 0.020). In multivariate binary logistic regression the magnetization transfer ratio gradient was independently associated with the development of clinically definite multiple sclerosis within 2 years (magnetization transfer ratio gradient odds ratio 61.708, P = 0.023; presence of T2 lesions odds ratio 8.500, P = 0.071). At 5 years, lesional measures overtook magnetization transfer ratio gradients as significant predictors of conversion to multiple sclerosis. The magnetization transfer ratio gradient was not significantly affected by the presence of brain lesions [T2 lesions (P = 0.918), periventricular T2 lesions (P = 0.580) or gadolinium-enhancing T1 lesions (P = 0.724)]. The magnetization transfer ratio gradient also correlated with Expanded Disability Status Scale score 5 years later (Spearman r = 0.313, P = 0.027). An abnormal periventricular magnetization transfer ratio gradient occurs early in multiple sclerosis, is clinically relevant, and may arise from one or more mechanisms that are at least partly independent of lesion formation.

Periventricular lesions and MS diagnostic criteria in young adults with typical clinically isolated syndromes.

In patients who present with a clinically isolated syndrome (CIS), whose features are suggestive of multiple sclerosis (MS), fulfilling McDonald 2010 magnetic resonance imaging (MRI) criteria for dissemination in space (DIS) and dissemination in time (DIT) enables a diagnosis of MS. While ⩾1 periventricular lesion is included in the 2010 DIS criteria, earlier McDonald criteria required ⩾3 periventricular lesions to confirm DIS and recent Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS)-recommended DIS criteria also require ⩾3 lesions. We investigated the effect of varying the required number of periventricular lesions and found that the best combination of specificity and sensitivity for clinically definite MS was seen for ⩾1 periventricular lesion using both the McDonald 2010 and MAGNIMS 2016 criteria.