Exploring the spatial variation of mercury in the Gulf of St. Lawrence using northern gannets as fish samplers.

Mercury (Hg) is a ubiquitous and pervasive environmental contaminant with detrimental effects on wildlife, which originates from both natural and anthropogenic sources. Its distribution within ecosystems is influenced by various biogeochemical processes, making it crucial to elucidate the factors driving this variability. To explore these factors, we employed an innovative method to use northern gannets (Morus bassanus) as biological samplers of regurgitated fish in the Gulf of St. Lawrence. We assessed fish total Hg (THg) concentrations in relation to their geographical catch location as well as to pertinent biotic and anthropogenic factors. In small fish species, trophic position, calculated from compound-specific stable nitrogen isotopes in amino acids, emerged as the most influential predictor of THg concentrations. For large fish species, THg concentrations were best explained by δ13C, indicating higher concentrations in inshore habitats. No anthropogenic factors, such as pollution, shipping traffic, or coastal development, were significantly related to THg concentrations in fish. Moreover, previously published THg data in mussels sampled nearby were positively linked with THg concentrations in gannet prey, suggesting consistent mercury distribution across trophic levels in the Gulf of St. Lawrence. Our findings point to habitat-dependent variability in THg concentrations across multiple trophic levels. Our study could have many potential uses in the future, including the identification of vulnerability hotspots for fish populations and their predators, or assessing risk factors for seabirds themselves by using biologically relevant prey.

Intensity warping for multisite MRI harmonization.

In multisite neuroimaging studies there is often unwanted technical variation across scanners and sites. These "scanner effects" can hinder detection of biological features of interest, produce inconsistent results, and lead to spurious associations. We propose mica (multisite image harmonization by cumulative distribution function alignment), a tool to harmonize images taken on different scanners by identifying and removing within-subject scanner effects. Our goals in the present study were to (1) establish a method that removes scanner effects by leveraging multiple scans collected on the same subject, and, building on this, (2) develop a technique to quantify scanner effects in large multisite studies so these can be reduced as a preprocessing step. We illustrate scanner effects in a brain MRI study in which the same subject was measured twice on seven scanners, and assess our method's performance in a second study in which ten subjects were scanned on two machines. We found that unharmonized images were highly variable across site and scanner type, and our method effectively removed this variability by aligning intensity distributions. We further studied the ability to predict image harmonization results for a scan taken on an existing subject at a new site using cross-validation.

Concordance between physiotherapists and physicians for care of patients with musculoskeletal disorders presenting to the emergency department.

BACKGROUND: Overcrowding in emergency departments (ED) is a major concern worldwide. To answer increasing health care demands, new models of care including advanced practice physiotherapists (APP) have been implemented in EDs. The purpose of this study was to assess diagnostic, treatment and discharge plan concordance between APPs and ED physicians for patients consulting to the ED for minor musculoskeletal disorders (MSKD). METHODS: Patients presenting to two EDs in Montréal (Canada) with a minor MSKD were recruited and independently assessed by an APP and ED physician. Both providers had to formulate diagnosis, treatment and discharge plans. Cohen's kappa (κ) and Prevalence and Bias Adjusted Kappas (PABAK) with associated 95%CI were calculated. Chi Square and t-tests were used to compare treatment, discharge plan modalities and patient satisfaction between providers. RESULTS: One hundred and thirteen participants were recruited, mean age was 50.3 ± 17.4 years old and 51.3% had an atraumatic MSKD. Diagnostic inter-rater agreement between providers was very good (κ = 0.81; 95% CI: 0.72-0.90). In terms of treatment plan, APPs referred significantly more participants to physiotherapy care than ED physicians (κ = 0.27; PABAK = 0.27; 95% CI: 0.07-0.45; p = 0.003). There was a moderate inter-rater agreement (κ = 0.46; PABAK = 0.64; 95% CI: 0.46-0.77) for discharge plans. High patient satisfaction was reported with no significant differences between providers (p = 0.57). CONCLUSION: There was significant agreement between APPs and ED physicians in terms of diagnosis and discharge plans, but more discrepancies regarding treatment plans. These results tend to support the integration of APPs in ED settings, but further prospective evaluation of the efficiency of these types of models is warranted.

An Automated Statistical Technique for Counting Distinct Multiple Sclerosis Lesions.

BACKGROUND AND PURPOSE: Lesion load is a common biomarker in multiple sclerosis, yet it has historically shown modest association with clinical outcome. Lesion count, which encapsulates the natural history of lesion formation and is thought to provide complementary information, is difficult to assess in patients with confluent (ie, spatially overlapping) lesions. We introduce a statistical technique for cross-sectionally counting pathologically distinct lesions. MATERIALS AND METHODS: MR imaging was used to assess the probability of a lesion at each location. The texture of this map was quantified using a novel technique, and clusters resembling the center of a lesion were counted. Validity compared with a criterion standard count was demonstrated in 60 subjects observed longitudinally, and reliability was determined using 14 scans of a clinically stable subject acquired at 7 sites. RESULTS: The proposed count and the criterion standard count were highly correlated (r = 0.97, P < .001) and not significantly different (t59 = -.83, P = .41), and the variability of the proposed count across repeat scans was equivalent to that of lesion load. After accounting for lesion load and age, lesion count was negatively associated (t58 = -2.73, P < .01) with the Expanded Disability Status Scale. Average lesion size had a higher association with the Expanded Disability Status Scale (r = 0.35, P < .01) than lesion load (r = 0.10, P = .44) or lesion count (r = -.12, P = .36) alone. CONCLUSIONS: This study introduces a novel technique for counting pathologically distinct lesions using cross-sectional data and demonstrates its ability to recover obscured longitudinal information. The proposed count allows more accurate estimation of lesion size, which correlated more closely with disability scores than either lesion load or lesion count alone.

Volumetric Analysis from a Harmonized Multisite Brain MRI Study of a Single Subject with Multiple Sclerosis.

BACKGROUND AND PURPOSE: MR imaging can be used to measure structural changes in the brains of individuals with multiple sclerosis and is essential for diagnosis, longitudinal monitoring, and therapy evaluation. The North American Imaging in Multiple Sclerosis Cooperative steering committee developed a uniform high-resolution 3T MR imaging protocol relevant to the quantification of cerebral lesions and atrophy and implemented it at 7 sites across the United States. To assess intersite variability in scan data, we imaged a volunteer with relapsing-remitting MS with a scan-rescan at each site. MATERIALS AND METHODS: All imaging was acquired on Siemens scanners (4 Skyra, 2 Tim Trio, and 1 Verio). Expert segmentations were manually obtained for T1-hypointense and T2 (FLAIR) hyperintense lesions. Several automated lesion-detection and whole-brain, cortical, and deep gray matter volumetric pipelines were applied. Statistical analyses were conducted to assess variability across sites, as well as systematic biases in the volumetric measurements that were site-related. RESULTS: Systematic biases due to site differences in expert-traced lesion measurements were significant (P < .01 for both T1 and T2 lesion volumes), with site explaining >90% of the variation (range, 13.0-16.4 mL in T1 and 15.9-20.1 mL in T2) in lesion volumes. Site also explained >80% of the variation in most automated volumetric measurements. Output measures clustered according to scanner models, with similar results from the Skyra versus the other 2 units. CONCLUSIONS: Even in multicenter studies with consistent scanner field strength and manufacturer after protocol harmonization, systematic differences can lead to severe biases in volumetric analyses.

ToxEvaluator: an integrated computational platform to aid the interpretation of toxicology study-related findings.

Attempts are frequently made to investigate adverse findings from preclinical toxicology studies in order to better understand underlying toxicity mechanisms. These efforts often begin with limited information, including a description of the adverse finding, knowledge of the structure of the chemical associated with its cause and the intended pharmacological target. ToxEvaluator was developed jointly by Pfizer and the Comparative Toxicogenomics Database (http://ctdbase.org) team at North Carolina State University as an in silico platform to facilitate interpretation of toxicity findings in light of prior knowledge. Through the integration of a diverse set of in silico tools that leverage a number of public and proprietary databases, ToxEvaluator streamlines the process of aggregating and interrogating diverse sources of information. The user enters compound and target identifiers, and selects adverse event descriptors from a safety lexicon and mapped MeSH disease terms. ToxEvaluator provides a summary report with multiple distinct areas organized according to what target or structural aspects have been linked to the adverse finding, including primary pharmacology, structurally similar proprietary compounds, structurally similar public domain compounds, predicted secondary (i.e. off-target) pharmacology and known secondary pharmacology. Similar proprietary compounds and their associated in vivo toxicity findings are reported, along with a link to relevant supporting documents. For similar public domain compounds and interacting targets, ToxEvaluator integrates relationships curated in Comparative Toxicogenomics Database, returning all direct and inferred linkages between them. As an example of its utility, we demonstrate how ToxEvaluator rapidly identified direct (primary pharmacology) and indirect (secondary pharmacology) linkages between cerivastatin and myopathy.

Vitamin D in clinically isolated syndrome: evidence for possible neuroprotection.

BACKGROUND AND PURPOSE: Vitamin D status has been associated with inflammatory activity in multiple sclerosis (MS), but it is not known if it is associated with gray matter volume, the loss of which predicts long-term disability in MS. The association of vitamin D levels with brain volume measures and inflammatory activity in patients with clinically isolated syndrome (CIS) was investigated. METHODS: In the phase 2 CIS trial of atorvastatin, 25-hydroxyvitamin D levels were evaluated for their age-adjusted associations with normalized gray matter and brain parenchymal volumes on brain magnetic resonance imaging (MRI). The relationships between 25-hydroxyvitamin D levels and clinical and MRI measures of inflammatory activity were also assessed. RESULTS: In 65 patients in this substudy, each 25 nmol/l higher 25-hydroxyvitamin D level was associated with 7.8 ml higher gray matter volume (95% confidence interval 1.0, 14.6, P = 0.025). There was a tendency for an inverse association of average 25-hydroxyvitamin D levels and the composite end-point of ≥3 new brain T2 lesions or ≥1 relapse within a year (odds ratio per 25 nmol/l higher 25-hydroxyvitamin D level 0.66, 95% confidence interval 0.41, 1.08, P = 0.096). CONCLUSIONS: Vitamin D status may impact neurodegeneration after CIS, although these results should be replicated in a second study. If confirmed in clinical trials, vitamin D supplementation may reduce long-term disability.

Retinal axonal loss in very early stages of multiple sclerosis.

BACKGROUND AND PURPOSE: The lack of surrogates of clinical progression has limited the design of neuroprotection trials in multiple sclerosis (MS). Our aim was to study the association between time-domain optical coherence tomography measures and clinical and magnetic resonance imaging outcomes in early MS. METHODS: Forty-three relapsing-remitting MS patients within 1 year of onset were followed for up to 3 years. RESULTS: The peripapillary retinal nerve fiber layer (RNFL) decreased annually by 2 µm (95% confidence interval -3.89, -0.11; P = 0.038). The RNFL tended to be associated with normalized normal appearing white matter volume in cross-sectional (P = 0.08) and longitudinal analyses (P = 0.06). CONCLUSIONS: There is substantial RNFL loss even in very early MS. Our data suggest that retinal axonal atrophy is associated with atrophy in global white matter volume in early MS.

Genetic associations with brain cortical thickness in multiple sclerosis.

Multiple sclerosis (MS) is characterized by temporal and spatial dissemination of demyelinating lesions in the central nervous system. Associated neurodegenerative changes contributing to disability have been recognized even at early disease stages. Recent studies show the importance of gray matter damage for the accrual of clinical disability rather than white matter where demyelination is easily visualized by magnetic resonance imaging (MRI). The susceptibility to MS is influenced by genetic risk, but genetic factors associated with the disability are not known. We used MRI data to determine cortical thickness in 557 MS cases and 75 controls and in another cohort of 219 cases. We identified nine areas showing different thickness between cases and controls (regions of interest, ROI) (eight of them were negatively correlated with Kurtzke's expanded disability status scale, EDSS) and conducted genome-wide association studies (GWAS) in 464 and 211 cases available from the two data sets. No marker exceeded genome-wide significance in the discovery cohort. We next combined nominal statistical evidence of association with physical evidence of interaction from a curated human protein interaction network, and searched for subnetworks enriched with nominally associated genes and for commonalities between the two data sets. This network-based pathway analysis of GWAS detected gene sets involved in glutamate signaling, neural development and an adjustment of intracellular calcium concentration. We report here for the first time gene sets associated with cortical thinning of MS. These genes are potentially correlated with disability of MS.

Do positive or negative stressful events predict the development of new brain lesions in people with multiple sclerosis?

BACKGROUND: Stressful life events have long been suspected to contribute to multiple sclerosis (MS) disease activity. The few studies examining the relationship between stressful events and neuroimaging markers have been small and inconsistent. This study examined whether different types of stressful events and perceived stress could predict the development of brain lesions. METHOD: This was a secondary analysis of 121 patients with MS followed for 48 weeks during a randomized controlled trial comparing stress management therapy for MS (SMT-MS) to a waitlist control (WLC). Patients underwent magnetic resonance imaging (MRI) scans every 8 weeks. Every month, patients completed an interview measure assessing stressful life events and self-report measures of perceived stress, anxiety and depressive symptoms, which were used to predict the presence of gadolinium-enhancing (Gd+) and T2 lesions on MRI scans 29-62 days later. Participants classified stressful events as positive or negative. Negative events were considered 'major' if they involved physical threat or threat to the patient's family structure, and 'moderate' otherwise. RESULTS: Positive stressful events predicted decreased risk for subsequent Gd+ lesions in the control group [odds ratio (OR) 0.53 for each additional positive stressful event, 95% confidence interval (CI) 0.30-0.91] and less risk for new or enlarging T2 lesions regardless of group assignment (OR 0.74, 95% CI 0.55-0.99). Across groups, major negative stressful events predicted Gd+ lesions (OR 1.77, 95% CI 1.18-2.64) and new or enlarging T2 lesions (OR 1.57, 95% CI 1.11-2.23) whereas moderate negative stressful events, perceived stress, anxiety and depressive symptoms did not. CONCLUSIONS: Major negative stressful events predict increased risk for Gd+ and T2 lesions whereas positive stressful events predict decreased risk.

Randomized controlled trial of atorvastatin in clinically isolated syndrome: the STAyCIS study.

OBJECTIVE: To test efficacy and safety of atorvastatin in subjects with clinically isolated syndrome (CIS). METHODS: Subjects with CIS were enrolled in a phase II, double-blind, placebo-controlled, 14-center randomized trial testing 80 mg atorvastatin on clinical and brain MRI activity. Brain MRIs were performed quarterly. The primary endpoint (PEP) was development of ≥ 3 new T2 lesions, or one clinical relapse within 12 months. Subjects meeting the PEP were offered additional weekly interferon ß-1a (IFNß-1a). RESULTS: Due to slow recruitment, enrollment was discontinued after 81 of 152 planned subjects with CIS were randomized and initiated study drug. Median (interquartile range) numbers of T2 and gadolinium-enhancing (Gd) lesions were 15.0 (22.0) and 0.0 (0.0) at baseline. A total of 53.1% of atorvastatin recipients (n = 26/49) met PEP compared to 56.3% of placebo recipients (n = 18/32) (p = 0.82). Eleven atorvastatin subjects (22.4%) and 7 placebo subjects (21.9%) met the PEP by clinical criteria. Proportion of subjects who did not develop new T2 lesions up to month 12 or to starting IFNß-1a was 55.3% in the atorvastatin and 27.6% in the placebo group (p = 0.03). Likelihood of remaining free of new T2 lesions was significantly greater in the atorvastatin group compared with placebo (odds ratio [OR] = 4.34, p = 0.01). Likelihood of remaining free of Gd lesions tended to be higher in the atorvastatin group (OR = 2.72, p = 0.11). Overall, atorvastatin was well tolerated. No clear antagonistic effect of atorvastatin plus IFNß-1a was observed on MRI measures. CONCLUSION: Atorvastatin treatment significantly decreased development of new brain MRI T2 lesion activity, although it did not achieve the composite clinical and imaging PEP. CLASSIFICATION OF EVIDENCE: This study provided Class II evidence that atorvastatin did not reduce the proportion of patients with CIS meeting imaging and clinical criteria for starting immunomodulating therapy after 12 months, compared to placebo. In an analysis of a secondary endpoint (Class III), atorvastatin was associated with a reduced risk for developing new T2 lesions.

Impact of pregnancy on conversion to clinically isolated syndrome in a radiologically isolated syndrome cohort.

BACKGROUND: In multiple sclerosis (MS), the relapse rate declines during pregnancy and increases during the first three months post-partum before returning to the pre-pregnancy rate. It is unknown whether pregnancy impacts the risk of clinical conversion in those within the presymptomatic period. OBJECTIVES: We investigate the impact of pregnancy on developing a clinical event in women diagnosed with radiologically isolated syndrome (RIS). METHODS: All women with RIS underwent clinical and radiological assessments as part of an observational, prospective, longitudinal study. Clinical and MRI outcomes were analyzed during and after pregnancy. Subjects who became pregnant were compared with an age-matched female RIS group who did not become pregnant during the same follow-up period. RESULTS: A total of 60 women with RIS were followed for up to seven years. Among them, seven became pregnant and were compared with 53 age-matched control women with RIS who did not become pregnant during the observation period. A significantly shorter time of conversion to the first neurological event was observed in the pregnant group [15.3 months (10-18)] compared with the non-pregnant controls [35.7 months (8-76)], yielding an absolute difference of 20.4 months (p<0.05). The mean (SD) number of active lesions on a subsequent brain MRI scan was significantly higher in the pregnant group [3.2 (±1.7)] compared with the control group [1.8 (±0.6)]. CONCLUSIONS: The risk for clinical conversion from RIS to a clinical event and new MRI disease activity seems to be influenced by pregnancy. Pregnancy related physiological changes could operate as early as the presymptomatic period in patients with MS.

Asymptomatic spinal cord lesions predict disease progression in radiologically isolated syndrome.

BACKGROUND: Technological advancements in neuroimaging and the increased use of these diagnostic modalities are responsible for the discovery of incidentally identified anomalies within the CNS. In addition to the identification of unanticipated brain MRI abnormalities suggestive of demyelinating disease in patients undergoing neuroimaging for a medical reason other than evaluation for multiple sclerosis (MS), asymptomatic spinal cord lesions are periodically identified. OBJECTIVE: To determine if asymptomatic spinal cord lesions are associated with clinical progression in subjects with radiologically isolated syndrome (RIS). METHODS: A retrospective review of RIS cases at the University of California, San Francisco Multiple Sclerosis Center was performed. The presence of asymptomatic cervical spinal cord MRI lesions was analyzed as a potential predictor for clinical progression. RESULTS: Twenty-five of 71 subjects with RIS possessed findings within the cervical spine that were highly suggestive of demyelinating disease. Of these subjects, 21 (84%) progressed clinically to clinically isolated syndrome (n = 19) or primary progressive multiple sclerosis (n = 2) over a median time of 1.6 years from the date of RIS identification (interquartile range 0.8-3.8). The sensitivity, specificity, and positive predictive value of an asymptomatic spinal cord lesion for subsequent development of either a first demyelinating attack or primary progressive MS were 87.5%, 91.5%, and 84%, respectively. The odds ratio of clinical progression was 75.3 (95% confidence interval 16.1-350.0, p < 0.0001). This association remained significant after adjusting for potential confounders. CONCLUSION: These findings suggest that the presence of asymptomatic spinal cord lesions place subjects with RIS at substantial risk for clinical conversion to either an acute or progressive event, a risk that is independent of brain lesions on MRI.

Quality of life in multiple sclerosis is associated with lesion burden and brain volume measures.

BACKGROUND: Health-related quality of life (HRQOL) is reduced in multiple sclerosis (MS). It is unclear whether HRQOL is associated with white matter lesion burden or measures of brain atrophy. METHODS: A cross-sectional baseline analysis of 507 patients with MS in a prospective cohort study at the University of California, San Francisco was performed. Multivariate linear regression models were used to determine whether MRI measures were associated with the Emotional Well-Being and Thinking/Fatigue subscale scores of the Functional Assessment in Multiple Sclerosis, a validated HRQOL measure in MS. The difference in each MRI metric associated with a minimal clinically important difference in each HRQOL subscale was calculated. RESULTS: Higher T1 lesion load (15 mL; p = 0.024), normalized T1 lesion volume (20 mL; p = 0.016), or T2 lesion load (25 mL; p = 0.028) was associated with worse scores for Emotional Well-Being. Meaningfully lower scores on this subscale were correlated with lower normalized gray matter volume (118 mL; p = 0.037). Reduced Thinking/Fatigue scores were associated with higher normalized T1 lesion volume (21 mL; p = 0.024), or T2 lesion load (22 mL; p = 0.010) and with lower normalized gray matter (87 mL; p = 0.004), white matter (85 mL; p = 0.025), or brain parenchymal (98 mL; p = 0.001) volume. CONCLUSIONS: Aspects of health-related quality of life (HRQOL) in multiple sclerosis are associated with MRI evidence of white matter lesions and brain atrophy. These findings strengthen the argument for the use of HRQOL outcome measures in trials and suggest that lesion burden on conventional MRI is important for HRQOL.

Genotype-Phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures.

Genetic susceptibility to multiple sclerosis (MS) is associated with the human leukocyte antigen (HLA) DRB1*1501 allele. Here we show a clear association between DRB1*1501 carrier status and four domains of disease severity in an investigation of genotype-phenotype associations in 505 robust, clinically well characterized MS patients evaluated cross-sectionally: (i) a reduction in the N-acetyl-aspartate (NAA) concentration within normal appearing white matter (NAWM) via (1)HMR spectroscopy (P = 0.025), (ii) an increase in the volume of white matter (WM) lesions utilizing conventional anatomical MRI techniques (1,127 mm(3); P = 0.031), (iii) a reduction in normalized brain parenchymal volume (nBPV) (P = 0.023), and (iv) impairments in cognitive function as measured by the Paced Auditory Serial Addition Test (PASAT-3) performance (Mean Z Score: DRB1*1501+: 0.110 versus DRB1*1501-: 0.048; P = 0.004). In addition, DRB1*1501+ patients had significantly more women (74% versus 63%; P = 0.009) and a younger mean age at disease onset (32.4 years versus 34.3 years; P = 0.025). Our findings suggest that DRB1*1501 increases disease severity in MS by facilitating the development of more T2-foci, thereby increasing the potential for irreversible axonal compromise and subsequent neuronal degeneration, as suggested by the reduction of NAA concentrations in NAWM, ultimately leading to a decline in brain volume. These structural aberrations may explain the significant differences in cognitive performance observed between DRB1*1501 groups. The overall goal of a deep phenotypic approach to MS is to develop an array of meaningful biomarkers to monitor the course of the disease, predict future disease behaviour, determine when treatment is necessary, and perhaps to more effectively recommend an available therapeutic intervention.

Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome.

BACKGROUND: The discovery and broad application of MRI in medicine has led to an increased awareness in the number of patients with incidental white matter pathology in the CNS. Routinely encountered in clinical practice, the natural history or evolution of such individuals with respect to their risk of developing multiple sclerosis (MS) is unclear. OBJECTIVE: To investigate the natural history of patients who exhibit incidental imaging findings highly suggestive of MS pathology. METHODS: Detailed clinical and radiologic data were obtained from asymptomatic patients with MRI anomalies suggestive of MS. RESULTS: The cohort consisted of 41 female and 3 male subjects (median age = 38.5, range: 16.2-67.1). Clinical evaluations were performed in 44 patients at the time of initial imaging; longitudinal clinical follow-up occurred for 30 patients, and longitudinal MRI data were acquired for 41 patients. Neurologic examination at the time of the initial MRI scans was normal in nearly all cases. While radiologic progression was identified in 59% of cases, only 10 patients converted to either clinically isolated syndrome or definite MS. The presence of contrast-enhancing lesions on the initial MRI was predictive of dissemination in time on repeat imaging of the brain (hazard ratio [HR] = 3.4, 95% confidence interval [1.3, 8.7], p = 0.01). CONCLUSION: Individuals with MRI anomalies highly suggestive of demyelinating pathology, not better accounted for by another disease process, are very likely to experience subsequent radiologic or clinical events related to multiple sclerosis. Additional studies will be necessary to fully define this risk.

Regional grey matter atrophy in clinically isolated syndromes at presentation.

BACKGROUND: The presence and degree of neuronal degeneration already existing in patients at their initial presentation with a clinically isolated syndrome suggestive of multiple sclerosis (CIS) is unclear, and whole brain or whole normalised grey matter analyses have not demonstrated significant atrophy in CIS cohorts at clinical presentation. Voxel-based analyses allow detection of regional atrophy throughout the brain and, therefore, may be sensitive to regional atrophy in CIS patients, and these changes may correspond with clinical disability. METHODS: This study used a modified voxel-based morphometry (VBM) method to correct for lesion effects to analyse regional atrophy and perform voxel-wise correlations between volume and clinical metrics in 41 untreated CIS patients at presentation compared with 49 healthy controls. RESULTS: The results confirmed that there was no significant difference in whole normalised grey matter volume between CIS and controls, whereas VBM showed significant areas of bilateral thalamic, hypothalamic, putamen and caudate atrophy. Voxel-wise correlations with clinical measures showed that cerebellar volumes correlated with clinical cerebellar function, nine-hole peg test scores and the Multiple Sclerosis Functional Composite (MSFC) score, and that the MSFC score was also correlated with putamen volume. Lastly, T1 lesion volumes were found to correlate with thalamic and hippocampal atrophy, suggesting a link between white matter lesions and grey matter degeneration at the earliest stages of multiple sclerosis. CONCLUSIONS: Atrophy is present in CIS patients at presentations, particularly in the thalamus, and other deep grey matter structures. Furthermore, the correlations with clinical metrics suggest the importance of this atrophy to clinical status and the correlation with T1 lesion load suggests a possible role of Wallerian degeneration.