Faculty Bibliography

BACKGROUND:Age is the strongest factor determining disease expression in multiple sclerosis (MS). We previously demonstrated biological age acceleration in pediatric-onset MS (POMS) compared to controls with both epigenetic clocks (DNAm) and telomere length (TL). It is unknown whether these markers report overlapping or distinct aging-related processes. OBJECTIVES/OBJECTIVE:To determine the correlation between DNAm and TL aging markers. METHODS:We conducted a cross-sectional case-control study within the US Network of Pediatric MS Centers. We calculated age acceleration residuals for the Horvath, Hannum, PhenoAge, and GrimAge epigenetic clocks and measured TL from whole blood samples to estimate telomere to somatic DNA ratios (T/S ratio). We employed multivariable analysis of covariance to assess the correlation between DNAm estimates and TL. RESULTS: = 0.06). CONCLUSIONS:DNAm did not correlate with TL in this sample of POMS and controls, suggesting that these biomarkers may capture complementary and non-overlapping elements of aging-related biology.

Smouldering disease in multiple sclerosis (MS) refers to chronic central nervous system processes that occur beyond acute inflammation, driving long-term disability. Although current therapies effectively reduce relapse rates and MRI lesions, many individuals experience progression independent of relapse activity. While clinical progression is uncommon during childhood or adolescence, growing evidence suggests that subclinical progressive disease biology is already active even in this young age group, warranting early intervention to preserve function. Conventional MRI, while critical for diagnosis, lacks sensitivity for subtle damage. Advanced MRI techniques, including detection of chronic active lesions, global and focal brain damage, hold promise for early identification. Fluid biomarkers, such as neurofilament light chain and glial fibrillary acidic protein, provide non-invasive measures of neuroaxonal injury and ongoing chronic inflammation. This review summarises the role of MRI and fluid biomarkers in detecting smouldering disease in paediatric-onset MS and their application in supporting therapeutic decision-making.

BACKGROUND AND OBJECTIVES/OBJECTIVE:While reductions in optical coherence tomography (OCT) pRNFL and ganglion cell-inner plexiform layer thicknesses have been shown to be associated with brain atrophy in adult-onset MS (AOMS) cohorts, the relationship between OCT and brain MRI measures is less established in pediatric-onset MS (POMS). Our aim was to examine the associations of OCT measures with volumetric MRI in a cohort of patients with POMS to determine whether OCT measures reflect CNS neurodegeneration in this patient population, as is seen in AOMS cohorts. METHODS:This was a cross-sectional study with retrospective ascertainment of patients with POMS evaluated at a single center with expertise in POMS and neuro-ophthalmology. As part of routine clinical care, patients with POMS are evaluated by a POMS expert and undergo volumetric brain MRI, including whole-brain (WB), subregional, and gray matter (GM) volume analyses. Patients with POMS are routinely referred to neuro-ophthalmology for evaluation that includes high-contrast visual acuity, color vision testing, and OCT. Generalized estimating equation (GEE) models, accounting for within-patient, intereye correlations (both eyes of each patient were included), MS disease duration, and disease-modifying therapy efficacy, were used to determine the relationship between visual pathway structure and function and volumetric MRI measures. RESULTS:= 0.015, respectively). DISCUSSION/CONCLUSIONS:Our results demonstrate that changes in visual pathway structures are associated with reductions in overall brain volume and GM volumes, as well as greater lesion and black hole burden. Collectively, our results emphasize the importance of visual assessment in POMS and suggest that OCT reflects overall CNS neurodegeneration in this cohort.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Pediatric multiple sclerosis (MS) affects children and adolescents at an important time for neurologic and cognitive development. Although cognitive impairment has been described, few longitudinal studies of cognitive functioning in pediatric MS with matched controls are available. Here, we report the 2-year follow-up cognitive results of a cohort of participants with MS and healthy controls (HCs) recruited from multiple regions of the United States. METHODS:Three cohorts-participants with pediatric MS, age-matched pediatric HC, and adults with early-onset MS-were recruited across 7 sites through the United States Network of Pediatric MS Centers. Two cognitive batteries, Cogstate Brief Battery (CBB) and Brief International Cognition Assessment for MS (BICAMS), were administered at baseline and follow-up. The primary outcome was the change in CBB composite z-score compared between groups. Change in BICAMS composite z-score was also compared, as were change in z-scores of individual measures. Reliable change indices (RCIs) were calculated to determine meaningful change over time. RESULTS:= 0.022. DISCUSSION/CONCLUSIONS:Most individuals with pediatric MS early in their disease showed stable cognitive function over a 2-year period and had longitudinal changes that were largely similar to pediatric controls. A subset of participants with pediatric MS declined in cognitive processing speed relative to pediatric controls.

This study evaluated the efficacy of the multiple sclerosis disease-modifying therapies, intramuscular interferon beta-1a (Avonex) and subcutaneous peginterferon beta-1a (Plegridy), using data from the United States Network of Pediatric Multiple Sclerosis Centers. In this retrospective analysis, 154 patients with multiple sclerosis were included who were treated with Avonex (n = 130), Plegridy (n = 23), or both treatments (n = 1) before the age of 18 years. After 3 months' sustained use acclimation ("wash-in"), the probability of being relapse-free during the first year was 68.3% for Avonex-treated patients and 69.9% for Plegridy-treated patients; annualized relapse rates were 0.50 and 0.59, respectively. Both disease-modifying therapies demonstrated efficacy similar to that reported in adult populations. Despite the lack of formal approval for pediatric multiple sclerosis, these outcomes indicate that patients may benefit from treatment with Avonex or Plegridy. Understanding efficacy of specific disease-modifying therapies in pediatric multiple sclerosis is essential to making informed treatment decisions.

BACKGROUND/UNASSIGNED:Cognitive impairment is common in multiple sclerosis (MS). Transcranial direct current stimulation (tDCS) combined with adaptive cognitive training (aCT) may improve clinical outcomes. OBJECTIVE/UNASSIGNED:To evaluate the effect of active vs. sham home-based tDCS + aCT on cognitive function. METHODS/UNASSIGNED:-scores. RESULTS/UNASSIGNED: = .411). CONCLUSIONS/UNASSIGNED:Active vs. sham tDCS + aCT resulted in significantly better cognitive outcomes, with the greatest benefit in those with high neurologic disability.CLINICALTRIALS.GOV; https://clinicaltrials.gov/study/NCT03838770; IDENTIFIER: NCT03838770.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Older chronological age is associated with decreased multiple sclerosis (MS) relapse rates and increased risk of progressive disease. Measurement of biological age may be more precise than birthdate in understanding these aging effects. In addition to normal aging, MS-related accelerated aging may contribute. Measurement of biological age in adults may be confounded by the effects of natural aging and age-related comorbidities. Examining age extremes can be informative, and demonstrating accelerated biological aging in children would support a hypothesis of MS driving premature aging. We sought to compare epigenetic age in participants with pediatric-onset MS (POMS) and age-similar controls. METHODS:We performed a multicenter case-control analysis of epigenetic age in a prospectively collected set of whole blood DNA samples and clinical data. Quantitative methylation scores were derived for approximately 850,000 cytosine-phosphate-guanine (CpG) sites. Epigenetic age was calculated based on 4 established epigenetic clock algorithms. Epigenetic age and age acceleration residual (AAR) were compared between participants with POMS and age-similar controls using multivariate regression analysis, adjusted for demographic variables. RESULTS:= 0.004). DISCUSSION/CONCLUSIONS:We observed greater point estimates of epigenetic age in participants with POMS compared with healthy controls in all epigenetic clocks tested. This difference was statistically significant for the Hannum and PhenoAge clocks after multivariable modeling. These results are consistent with those of studies in adult MS and suggest that accelerated aging may be present even in the youngest people living with MS.

BACKGROUND:Childhood environmental factors back to the prenatal environment can contribute to MS risk. Childhood adversity, which causes biological, behavioral, and epigenetic changes that can be passed down through families, has been understudied in MS. Here, we emphasize the need to understand the role that intergenerational adversity may play among families affected by MS. OBJECTIVE:To evaluate the frequency and types of adverse childhood experiences among parents of children with MS. METHODS:Individuals with pediatric MS (n = 68) were enrolled in a longitudinal study of cognition. At enrollment, the patient and one caregiver or parent completed questionnaires. As the pediatric participants were under age 18 at time of enrollment, one parent completed the Adverse Childhood Experiences (ACEs, a 10-item self-report measure) about the parents' own childhood. Results from the ACE questionnaire among parents of pediatric healthy controls (n = 96) and adults in a national cohort are also reported for comparison. RESULTS:Over half of pediatric MS parents reported at least one ACE exposure. Of parents that did have ACE exposures, the exposures were broad in terms of abuse, neglect, and household dysfunction. Over 10 % of parents reported total ACE scores of 7 or above. CONCLUSION/CONCLUSIONS:Over half of pediatric MS parents experienced some degree of childhood adversity. The impact of intergenerational adversity on the development of pediatric onset MS warrants further study.

This scientific commentary refers to 'Fatigue in early multiple sclerosis: MRI metrics of neuroinflammation, relapse and neurodegeneration', by Meijboom et al. (https://doi.org/10.1093/braincomms/fcae278).