Brain disconnectome mapping derived from white matter lesions and serum neurofilament light levels in multiple sclerosis: A longitudinal multicenter study.

BACKGROUND AND OBJECTIVES: Connectivity-based approaches incorporating the distribution and magnitude of the extended brain network aberrations caused by lesions may offer higher sensitivity for axonal damage in patients with multiple sclerosis (MS) than conventional lesion characteristics. Using individual brain disconnectome mapping, we tested the longitudinal associations between putative imaging-based brain network aberrations and levels of serum neurofilament light chain (NfL) as a neuroaxonal injury biomarker. METHODS: MS patients (n = 312, mean age 42.9 years, 71 % female) and healthy controls (HC) (n = 59, mean age 39.9 years, 78 % female) were prospectively enrolled at four European MS centres, and reassessed after two years (MS, n = 242; HC, n = 30). Post-processing of 3 Tesla (3 T) MRI data was performed at one centre using a harmonized pipeline, and disconnectome maps were calculated using BCBtoolkit based on individual lesion maps. Global disconnectivity (GD) was defined as the average disconnectome probability in each patient's white matter. Serum NfL concentrations were measured by single molecule array (Simoa). Robust linear mixed models (rLMM) with GD or T2-lesion volume (T2LV) as dependent variables, patient as a random factor, serum NfL, age, sex, timepoint for visit, diagnosis, treatment, and center as fixed factors were run. RESULTS: rLMM revealed significant associations between GD and serum NfL (t = 2.94, p = 0.003), age (t = 4.21, p = 2.5 × 10-5), and longitudinal changes in NfL (t = -2.29, p = 0.02), but not for sex (t = 0.63, p = 0.53) or treatments (t = 0.80-0.83, p = 0.41-0.42). Voxel-wise analyses revealed significant associations between dysconnectivity in cerebellar and brainstem regions and serum NfL (t = 7.03, p < 0.001). DISCUSSION: In our prospective multi-site MS cohort, rLMMs demonstrated that the extent of global and regional brain disconnectivity is sensitive to a systemic biomarker of axonal damage, serum NfL, in patients with MS. These findings provide a neuroaxonal correlate of advanced disconnectome mapping and provide a platform for further investigations of the functional and potential clinical relevance of brain disconnectome mapping in patients with brain disorders.

5 Years of Exercise Intervention Did Not Benefit Cognition Compared to the Physical Activity Guidelines in Older Adults, but Higher Cardiorespiratory Fitness Did. A Generation 100 Substudy.

Background: Aerobic exercise is proposed to attenuate cognitive decline in aging. We investigated the effect of different aerobic exercise interventions and cardiorespiratory fitness (CRF) upon cognition throughout a 5-year exercise intervention in older adults. Methods: 106 older adults (52 women, age 70-77 years) were randomized into high-intensity interval training (HIIT; ∼90% peak heart rate), moderate-intensity continuous training (MICT; ∼70% peak heart rate), or control for 5 years. The HIIT and MICT groups performed supervised training twice weekly, while the control group was asked to follow the national physical activity guidelines (30 min of physical activity/day). At baseline, 1-, 3-, and 5-year follow-up, participants partook in cognitive testing (spatial memory, verbal memory, pattern separation, processing speed, working memory, and planning ability), underwent clinical testing, and filled out health-related questionnaires. Linear mixed models were used to assess the effects of the exercise group and CRF (measured as peak and max oxygen uptake) on each cognitive test. The effects of changes in CRF on changes in each cognitive test score throughout the intervention were also assessed. The associations between baseline CRF and cognitive abilities at the follow-ups were investigated using linear regressions. Results: There was no group-by-time interaction on the cognitive measures, and neither HIIT nor MICT participation was associated with better cognitive performance than control at any time point during the 5-year intervention. All groups increased their CRF similarly during the 1st year and subsequently declined back to baseline levels after 5 years. A higher CRF was associated with higher processing speed throughout the intervention while increasing CRF during the intervention was associated with better working memory and worse pattern separation. Higher CRF at baseline predicted consistently better processing speed and verbal memory performance. Conclusion: In this first 5-year randomized controlled trial investigating the effects of HIIT, MICT, and physical activity according to national guidelines on cognition, we observed no effect of exercise intervention group on cognition when compared to following the national physical activity guidelines. Still, the results showed that higher CRF and increasing CRF benefited multiple, but not all, cognitive abilities in older adults. Clinical Trial Registration: www.ClinicalTrials.gov, identifier [NCT01666340].