Author Of 4 Presentations
P0530 - Understanding the metabolic profile of relapses in multiple sclerosis (ID 326)
Abstract
Background
Accurate determination of relapses in multiple sclerosis (MS) is important for subtype classification and therapeutic decisions. However, there are currently no validated bio-fluid markers of relapses.
Objectives
To determine if metabolic perturbations are present during relapses, and if so, to identify candidate metabolite biomarkers and evaluate their discriminatory value both at group and individual levels, in comparison with serum neurofilament-light (NfL).
Methods
Global and targeted serum high resolution 1H nuclear magnetic resonance metabolomics and serum NfL (Simoa® assay) were performed on 4 groups of relapsing-remitting MS (RRMS) patients; (1) in relapses (in-R), (2) last relapse (LR) ≥1 month (M) to <6 M ago, (3) LR ≥6 M to <24 M ago, and (4) LR ≥24 M ago. Supervised multivariate analyses were used to determine metabolic differences between patient groups.
Results
Two hundred and one RRMS patients were recruited; in-R (n=38), LR 1–6 M (n=28), LR 6–24 M (n=34), LR ≥24 M (n=101). The global metabolic profile of in-R was significantly perturbed compared to LR ≥24 M (mean predictive accuracy ± SD, 62.6 ± 4.8% vs. 50.9 ± 8.2%; p <0.0001). Identified discriminatory metabolites were quantified, when possible, using targeted metabolomics. Lysine (high in-R), asparagine (high), isoleucine (low) and leucine (low) were shortlisted as potential metabolite biomarkers. One-way ANOVA of these metabolites showed significant differences across the 4 patient groups, with a clear trend (increasing or decreasing) with time away from relapse. Multivariable receiver operating characteristics (ROC) analysis of these 4 metabolites in discriminating in-R vs. LR ≥24 months showed an area under the curve (AUC) of 0.758, while serum NfL had an AUC of 0.575. Within individual patients (n=9) with paired relapse-remission samples (remission sample taken within 6 months of relapse), all 4 metabolites were significantly different in relapse and in remission, with directions consistent with that observed at group level, while serum NfL was not significant. Multivariable ROC of the 4 metabolites showed an AUC of 0.911. At group level, lysine and asparagine were higher in patients with gadolinium enhancing lesions in the last 1 year prior to sampling. No potential confounders were identified on further analyses, notably; none of in-R was on steroids at blood sampling.
Conclusions
Metabolomics identify perturbations in metabolites relating to energy deficiency and immune activation in relapses, and the use of these metabolites, singly or in combination, are useful in identifying relapses, both at group and individual level.
P0942 - Astrocyte Topography Throughout the Multiple Sclerosis Motor Cortex and its Relationships with Genotype and Pathological Outcome (ID 87)
Abstract
Background
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, leading to substantial and irreversible disability. HLA-DRB1*15 gene confers the greatest MS risk, with MS 15+ individuals displaying more severe inflammation and demyelination. Yet, the mechanisms underlying this specific genotype remain elusive. Astrocytes are likely early and active contributors of MS pathogenesis due to their integral role in blood-brain barrier maintenance, neurotrophic support, and immune regulation. Dysfunctional astrocytes can lead to cytotoxicity, engaging with activated microglia to create a toxic cycle of inflammation and neurodegeneration. However, astrocyte topography in the MS motor cortex and its relationships with genotype and pathological outcome have been overlooked and is therefore, the focus of this study.
Objectives
To characterize astrocyte pathology in the post-mortem MS motor cortex by assessing the morphological phenotypes of astrocyte populations in MS, evaluating the influence of HLA-DRB1*15 status, and relating pathological outcomes to astroglial phenotypes.
Methods
A cohort of pathological confirmed MS (n=47; HLA-DRB1*15-, n=26; HLA-DRB1*15+, n=21), and non-neurological control cases (n=7) was used. Adjacent formalin-fixed, paraffin-embedded motor cortical sections were immunolabelled for astrocytes (ALDH1L1, GFAP). Pixel density (pixel/mm2) was used to asses astrocyte expression in pre-defined trajectories spaced at systematic intervals of the motor cortex and correlated to genotype status, neuronal (NeuN), and microglia/macrophage densities (IBA1; CD68).
Results
ALDH1L1 expression was greatest in the grey matter (p<0.0001), whereas GFAP expression was greatest in the white matter (p<0.0001). GFAP was influenced by HLA-DRB1*15, especially in cases equal to or younger than the median age of 62-years old, with 15+ individuals expressing greater GFAP expression than their 15- counterparts (p=0.014). Although CD68 correlation with GFAP was lost in MS (r=-0.107, p=0.473), ALDH1L1 positively correlated with CD68 in HLA-DRB1*15-cases (r=-.549, p=0.004), especially in cases older than 62-years old (r=0.936, p=0.006).
Conclusions
The striking differences between ALDH1L1 and GFAP, suggest that there are distinct astrocyte populations present in the MS motor cortex, which may play a crucial role in understanding MS heterogeneity. HLA-DRB1*15 genotype appears to influences astrocyte reactivity and likely mitigates components of the astrocyte-microglia/macrophage relationship. These findings suggest a significant impact of genetic background on MS astrocyte populations, which when disrupted from appropriate expression, may contribute to cytotoxic inflammation and subsequent disability.
P1045 - Predicting fall risk in persons with Multiple Sclerosis utilizing the 12-Item Multiple Sclerosis Walking Scale (ID 262)
Abstract
Background
Evidence suggests that 50-80% of persons with Multiple Sclerosis (PwMS) have difficulty walking and impaired balance, with half of them falling at least once a year. Falls can lead to increased risk of injury and fear of falling, which may further impair a person’s function. Studies have previously shown that patient-reported outcomes (PRO’s) predict PwMS’ risk of falling but small sample sizes and variable cut-off scores have limited generalization of the findings.
Objectives
To determine the predictive value of a cut-off score for the 12-Item Multiple Sclerosis Walking Scale (MSWS-12) to identify PwMS with greater fall risk.
Methods
A total of 135 PwMS were included as part of a preliminary analysis of an ongoing, larger cross-sectional study in which the MSWS-12 and frequency of falls (self-reported over past 6 months) were collected. PwMS were designed as “faller” if they had >1 fall in the past 6 months. Descriptive statistics were used to describe the clinical characteristics of the fallers (n=82) and non-fallers (n=53) (age, gender, disease duration, use of assistance, and Patient Determined Disease Steps; PDDS). Clinical characteristics and MSWS-12 scores of the faller and non-faller groups were compared. A Receiver Operating Characteristic (ROC) curve was used to estimate the classification accuracy of the MSWS-12. Optimal cut-off scores were calculated using the Youden index and sensitivity and specificity were calculated.
Results
There were no differences in age, gender, or disease duration between fallers and non-fallers. Fallers had higher median PDDS scores (3; 0-6 versus 1, 0-6; (p< 0.01)) and higher median MSWS-12 scores (67.5 versus 38.3; p<0.001) than non-fallers. Fallers were more dependent on assistive devices compared to non-fallers (p<0.01). The MSWS-12 cutoff score for fallers was ≥45.83 (Youden index: 0.46), with a sensitivity of 78.1%, specificity of 67.9% and a classification accuracy of 76.7% to detect fallers.
Conclusions
MSWS-12 was found to be predictive of fall risk in PwMS with a cut-off score much lower than previously reported. These findings indicate a lower threshold of the MSWS-12 score may help clinicians identify PwMS at greatest fall risk so that appropriate fall risk prevention interventions may be implemented.
P1110 - The impact of lower limb strength on walking in persons with Multiple Sclerosis: a preliminary analysis (ID 263)
Abstract
Background
Persons with MS (PwMS) report weakness and walking difficulty as some of their most disabling symptoms. Lower limb (LL) weakness is prevalent in PwMS and is associated with more significant disability, impaired balance, and increased difficulty walking. However, limited research exists describing the relationship between strength of specific LL muscle groups and walking in the same cohort.
Objectives
To determine the impact of dominant (D) and non-dominant (ND) LL strength on Patient Reported Outcomes (PROs) and objective walking outcome measures in PwMS.
Methods
A cross-sectional sample of PwMS (n = 137) derived from a larger, ongoing study was used. The following walking measures were collected at a single visit: 12-item MS Walking Scale (MSWS-12), Timed 25 foot walk (T25FW), and D and ND Stride Length (StrL), Step Length (SL), and Double Support Time (DStime). Isometric peak torque of Hip extension and flexion (HExt; Flex) Knee extension and flexion (KExt; Flex), Ankle plantar and dorsiflexion (APF; DF), and Hip abduction (HAbd) were also collected. Descriptive statistics were performed (age, gender, disease duration and disability level: Patient Determined Disease Steps; PDDS) and a correlational analysis was used to determine the strength of the association of walking to strength in muscle groups.
Results
The MS cohort had a mean age of 51.4 yrs (range: 21-75), disease duration of 14.5 yrs (range: 0.3-40.0), and median PDDS of 2.5 (range: 0-7), with 74.1% being female. All muscle groups were correlated with SL and StrL, and inversely correlated with T25FW, MSWS-12, and DStime. Strong associations were observed between D HFlex and StrL (D: r=.621,p <0.001; and ND: r=.636,p <0.001), D HFlex and ND SL (r=.608,p <0.001), ND KFlex and StrL (D: r=.610,p <0.001; and ND: r=.622,p <0.001), ND HAbd and ND SL (r=.640,p <0.001) and ND HAbd and StrL (r=.605,p <0.001). Weak to moderate correlations (r = ± .190 to .599, p<0.05) were found for all remaining strength and walking measures assessed.
Conclusions
All LL muscle groups (HExt, HFlex, KExt, KFlex, APF, ADF, and HAbd) were associated with the PRO (MSWS-12) and objective walking variables (T25FW, gait parameters: StrL, SL, and DStime) collected. These findings suggest that strength training interventions of these muscles may improve walking in PwMS. Importantly, this study improves understanding of the relationship between different major LL muscle groups with both walking performance and perceived difficulty walking in PwMS.