Darin T. Okuda

Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis

Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotype.

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.

Quantitative In Vivo Magnetic Resonance Imaging of Multiple Sclerosis at 7 Tesla with Sensitivity to Iron

Magnetic resonance imaging at 7 Tesla produces high‐resolution gradient‐echo phase images of patients with multiple sclerosis (MS) that quantify the local field shifts from iron in the basal ganglia and lesions. Phase imaging is easily integrated into clinical examinations because it is a postprocessing technique and does not require additional scanning. The purpose of this study was to quantify local field shifts in MS and to investigate their relation to disease duration and disability status.

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.

Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis.

We sought to determine whether vitamin D status is associated with developing new T2 lesions or contrast‐enhancing lesions on brain magnetic resonance imaging (MRI) in relapsing multiple sclerosis (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.

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.

Radiologically Isolated Syndrome: 5-Year Risk for an Initial Clinical Event

Objective To report the 5-year risk and to identify risk factors for the development of a seminal acute or progressive clinical event in a multi-national cohort of asymptomatic subjects meeting 2009 RIS Criteria. Methods Retrospectively identified RIS subjects from 22 databases within 5 countries were evaluated. Time to the first clinical event related to demyelination (acute or 12-month progression of neurological deficits) was compared across different groups by univariate and multivariate analyses utilizing a Cox regression model. Results Data were available in 451 RIS subjects (F: 354 (78.5%)). The mean age at from the time of the first brain MRI revealing anomalies suggestive of MS was 37.2 years (y) (median: 37.1 y, range: 11–74 y) with mean clinical follow-up time of 4.4 y (median: 2.8 y, range: 0.01–21.1 y). Clinical events were identified in 34% (standard error = 3%) of individuals within a 5-year period from the first brain MRI study. Of those who developed symptoms, 9.6% fulfilled criteria for primary progressive MS. In the multivariate model, age [hazard ratio (HR): 0.98 (95% CI: 0.96–0.99); p = 0.03], sex (male) [HR: 1.93 (1.24–2.99); p = 0.004], and lesions within the cervical or thoracic spinal cord [HR: 3.08 (2.06–4.62); p = <0.001] were identified as significant predictors for the development of a first clinical event. Interpretation These data provide supportive evidence that a meaningful number of RIS subjects evolve to a first clinical symptom. An age <37 y, male sex, and spinal cord involvement appear to be the most important independent predictors of symptom onset.

Connecting white matter injury and thalamic atrophy in clinically isolated syndromes

Previous studies suggest that thalamic degeneration is prominent in multiple sclerosis (MS) and even in pre-MS patients presenting with a clinically isolated syndrome (CIS). However, the relationships between white matter lesions and deep grey matter loss are not well understood. We analyzed the association between white matter lesions and the thalami in CIS patients to determine if connectivity is an important determinant. We studied 24 CIS patients and 18 normal controls with anatomical and diffusion tensor (DTI) MRI images. DTI fiber tracking was used to create probabilistic templates of the thalamocortical white matter and to define white matter connecting lesions and thalami. DTI metrics in the lesions and normal-appearing white matter (NAWM) regions were compared between CIS and controls, and correlated with thalamic volume changes estimated by voxel-based morphometry. There was 10 times higher density of lesions in thalamocortical compared to other brain white matter. Increased diffusivities and decreased fractional anisotropies were measured in the thalamocortical NAWM of CIS patients compared to controls. A step-wise regression analysis demonstrated that thalamocortical lesion volume and the mean diffusivity in track regions connecting lesion and thalami were significantly correlated with thalamic volumes in patients (Rsq=0.66, p<0.001), a finding not observed in regions outside the thalamocortical white matter. These results provide compelling evidence for a direct relationship between white matter lesions and thalamic atrophy in CIS patients.

Difference in Disease Burden and Activity in Pediatric Patients on Brain Magnetic Resonance Imaging at Time of Multiple Sclerosis Onset vs Adults

OBJECTIVE To compare initial brain magnetic resonance imaging (MRI) characteristics of children and adults at multiple sclerosis (MS) onset. DESIGN Retrospective analysis of features of first brain MRI available at MS onset in patients with pediatric-onset and adult-onset MS. SETTING A pediatric and an adult MS center. PATIENTS Patients with pediatric-onset <18 years) and adult-onset (> or =18 years) MS. MAIN OUTCOME MEASURES We evaluated initial and second (when available) brain MRI scans obtained at the time of first MS symptoms for lesions that were T2-bright, ovoid and well defined, large (> or =1cm), or enhancing. RESULTS We identified 41 patients with pediatric-onset MS and 35 patients with adult-onset MS. Children had a higher number of total T2- (median, 21 vs 6; P < .001) and large T2-bright areas (median, 4 vs 0; P < .001) than adults. Children more frequently had T2-bright foci in the posterior fossa (68.3% vs 31.4%; P = .001) and enhancing lesions (68.4% vs 21.2%; P < .001) than adults. On the second brain MRI, children had more new T2-bright (median, 2.5 vs 0; P < .001) and gadolinium-enhancing foci (P < .001) than adults. Except for corpus callosum involvement, race/ethnicity was not strongly associated with disease burden or lesion location on the first scan, although other associations cannot be excluded because of the width of the confidence intervals. CONCLUSION While it is unknown whether the higher disease burden, posterior fossa involvement, and rate of new lesions in pediatric-onset MS are explained by age alone, these characteristics have been associated with worse disability progression in adults.