Genetic and Imaging Markers of Multiple Sclerosis Prognosis and Diagnosis

Polman, C.H. [Promotor]Barkhof, F. [Promotor]Geurts, J.J.G. [Copromotor]Vrenken, H. [Copromotor

Genetic and Imaging Markers of Multiple Sclerosis Prognosis and Diagnosis

promotiedatum: 13-3-201

Spinal cord lesions in patients with clinically isolated syndrome A powerful tool in diagnosis and prognosis

Objective: Spinal cord (SC) lesions are frequently found in multiple sclerosis (MS), but are rare in healthy aging and cerebrovascular patients.Our aimwas to analyze the contribution of SCinvolvement in clinically isolated syndrome (CIS) in diagnosing MS according the McDonald 2010 criteria and in predicting conversion to clinically definite MS (CDMS). Methods: We prospectively followed monofocal, relapsing onset CIS patients with either SC or brain symptom onset (including optic neuritis). MRI of the brain and SC were performed shortly after onset and patients were followed for 24 to 119 months (median 64months). SCMRI findings were assessed for their contribution to theMcDonald 2010 diagnostic criteria and their effect on conversion toCDMS. Results: One hundred twenty-one patients were included (63 spinal CIS). Based on the brain scan only, 36 patients fulfilled the McDonald criteria; by including SC findings, 6 additional patients fulfilled these criteria. To diagnose 1 additional nonspinal CIS patient, the number needed to scan is 7. In nonspinal CIS patients that did not fulfillMcDonald brainMRI criteria (n = 42), presence of an SClesionwas associated with a higher risk of conversion to CDMS (odds ratio: 14.4; 95% confidence interval: 2.6-80.0) and shorter time to conversion to CDMS (hazard ratio: 51.4; 95% confidence interval: 5.5-476.3). Conclusions: Presence of SC lesions facilitates diagnosing MS and is predictive for conversion to CDMS, especially in patients with nonspinal CIS who do not fulfill brainMRI criteria.We therefore recommend performing an SC scan in patients with nonspinal CIS who do not fulfill McDonald brain MRI criteria. © 2012 American Academy of Neurology

Cervical spinal cord volume loss is related to clinical disability progression in multiple sclerosis

Objective To examine the temporal evolution of spinal cord (SC) atrophy in multiple sclerosis (MS), and its association with clinical progression in a large MS cohort. Methods A total of 352 patients from two centres with MS (relapsing remitting MS (RRMS): 256, secondary progressive MS (SPMS): 73, primary progressive MS (PPMS): 23) were included. Clinical and MRI parameters were obtained at baseline, after 12 months and 24 months of follow-up. In addition to conventional brain and SC MRI parameters, the annualised percentage brain volume change and the annualised percentage upper cervical cord cross-sectional area change (aUCCA) were quantified. Main outcome measure was disease progression, defined by expanded disability status scale increase after 24 months. Results UCCA was lower in SPMS and PPMS compared with RRMS for all time points. aUCCA over 24 months was highest in patients with SPMS (-2.2% per year) and was significantly higher in patients with disease progress ion (-2.3% per year) than in stable patients (-1.2% per year; p=0.003), while annualised percentage brain volume change did not differ between subtypes (RRMS: -0.42% per year; SPMS -0.6% per year; PPMS: -0.46% per year) nor between progressive and stable patients (p=0.055). Baseline UCCA and aUCCA over 24 months were found to be relevant contributors of expanded disability status scale at month-24, while baseline UCCA as well as number of SC segments involved by lesions at baseline but not aUCCA were relevant contributors of disease progression. Conclusions SC MRI parameters including baseline UCCA and SC lesions were significant MRI predictors of disease progression. Progressive 24-month upper SC atrophy occurred in all MS subtypes, and was faster in patients exhibiting disease progression at month-24

Relevance of spinal cord abnormalities to clinical disability in multiple sclerosis: MR imaging findings in a large cohort of patients

Purpose To determine whether spinal cord atrophy differs among disease subtypes in multiple sclerosis (MS) and whether it offers diagnostic and clinical correlative information beyond that provided by other magnetic resonance (MR) imaging markers. Materials and Methods The institutional review board approved the study; all subjects gave written informed consent. Upper cervical cord cross-sectional area (UCCA), brain and spinal cord lesion loads, and brain atrophy were measured in 440 patients with MS (311 with relapsing-remitting [RR] MS, 92 with secondary-progressive [SP] MS, and 37 with primary-progressive [PP] MS) studied in two centers. Disability was scored with the Expanded Disability Status Scale (EDSS), the timed 25-foot walk test (TWT), and the nine-hole peg test. UCCA was compared between groups with the Mann-Whitney U test. Correlations were assessed with the Spearman ρ test. Multivariate associations between UCCA and clinical and other MR imaging parameters, including number of hypointense brain lesions on T1-weighted MR images, presence of diffuse abnormalities, and number of involved segments in the spinal cord, were assessed by using multiple linear regression, adjusted for study center site. Results The UCCA in patients with SP MS (median, 79 mm2; interquartile range, 72.4–84.9 mm2) and PP MS (median, 77.3 mm2; interquartile range, 69–82.5 mm2) was significantly smaller (P < .001) than that in patients with RR MS (median, 84 mm2; interquartile range, 78.7–89.3 mm2). UCCA was inversely correlated with EDSS score, TWT, and nine-hole peg test findings (ρ ≤ −0.29, P < .001 for all comparisons). UCCA, number of hypointense brain lesions on T1-weighted MR images, presence of diffuse abnormalities, and number of involved segments in the spinal cord were found to be significant explanatory factors for clinical disability (R2 = 0.564). The UCCA and the number of hypointense brain lesions on T1-weighted images were the strongest MR imaging parameters for explaining physical disability, as measured with the EDSS. Conclusion Spinal cord abnormalities have a strong effect on clinical disability in MS. MR imaging–derived UCCA was found to be the most significant spinal cord parameter for explaining EDSS score

Relationship between brain MRI lesion load and short-term disease evolution in non-disabling MS: a large-scale, multicentre study

Background and Objectives: We evaluated clinical and conventional MRI features of a large population of patients with non-disabling MS to identify potential markers of a benign disease course.Methods: In seven MAGNIMS centres we retrospectively identified 182 patients with benign (B) MS (EDSS score <= 3.0, disease duration >= 15 years) and 187 patients with non-disabling relapsing-remitting MS (NDRRMS) (Expanded Disability Status Scale score >= 3.0, disease duration between 5 and 14 years), in whom clinical data were collected within two weeks from a brain T2-weighted scan. Brain T2 lesion volume (LV) was measured in all patients. In 146 BMS and 146 NDRRMS patients, clinical data were also available after a median follow up of 29 months (range: 7-104 months).Results: Mean LV was higher in BMS than in NDRRMS patients (p < 0.001), but the mean ratio between LV and disease duration was higher in NDRRMS than in BMS patients (1.1 vs. 0.6 ml/year, p < 0.001). In BMS patients, brain LV was correlated with EDSS score increase at follow up (r=0.18, p=0.03).Conclusions: An overall low rate of brain LV increase during a long-lasting disease course might be a feature of BMS. In BMS patients, a high brain LV might be associated with worsening of locomotor disability at short-term follow up

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