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

Brain disconnectome mapping and serum neurofilament light levels in multiple sclerosis

The pathophysiological mechanisms for classical plaque characteristics and their predictive value for clinical course and outcome in multiple sclerosis is unclear. Connectivity-based approaches incorporating the distribution and magnitude of the extended brain network aberrations caused by lesions may offer higher sensitivity for axonal damage. Using individual brain disconnectome mapping, we tested the longitudinal associations between putative brain network aberrations and levels of serum neurofilament light chain (sNfL) as a neuroaxonal injury biomarker. Multiple sclerosis patients (n = 328, mean age 42.9 years, 71 % female) were prospectively enrolled at four European multiple sclerosis centres, and reassessed after two years (n = 280). Post-processing of 3 Tesla (3T) 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 and centre as a random factor, sNfL, age, sex, timepoint for visit, diagnosis, and treatment as fixed factors were run. Robust LMM revealed significant associations between higher levels of GD and increased sNfL (t = 2.30, β = 0.03, p = 0.02), age (t = 5.01, β = 0.32, p < 5.5 x 10-7), and diagnosis progressive multiple sclerosis (PMS); t = 1.97, β = 1.06, p = 0.05), but not for sex (t = 0.78, p = 0.43), treatments (effective; t = 0.85, p = 0.39, highly-effective; t = 0.86, p = 0.39) or sNfL change between base line and two-year follow up (t = -1.65, p = 0.10). Voxel-wise analyses revealed distributed associations in cerebellar and brainstem regions. In our prospective multi-site multiple sclerosis cohort, rLMMs demonstrated that the extent of global brain disconnectivity is sensitive to a systemic biomarker of axonal damage, sNfL, in patients with multiple sclerosis. These findings provide a neuropathological correlate of advanced disconnectome mapping and provide a platform for further investigations of the functional and clinical relevance in patients with brain disorders

[Carta a Ignacio Hernando de Larramendi y Montiano]

Información adicional de autor de la carta: Chairman, China Bills Finance CorporationFotografía número: 97

Proteomics profiling of epidermal mucus secretion of a cichlid (Symphysodon aequifasciata) demonstrating parental care behavior

Proteomics672251-2258PROT

Sorption and desorption of chlorinated hydrocarbon pesticides in aquatic sediment minerals

Students supported: 3 Master's Students, several undergradsThe fundamental sorption and desorption reactions between selected chlorinated hydrocarbon pesticides and clay minerals were established in this study. The effects of several important environmental factors, including pH, temperature, salt (NaCl) concentration, and organic content, on the sorption and desorption reactions were also ascertained. Results obtained in this study reveal that organochlorine pesticides are rapidly adsorbed by clays and also retained strongly after adsorption. Only small fractions of the adsorbed pesticides can be desorbed. The environmental factors of pH, temperature and salt content appear to exert no significant effect on the sorption and desorption reactions. The organic pollutants present in the water phase also bear no effect on the reactions. However, the organic humus present in the sediment phase is able to enhance the pesticide adsorption because chlorinated hydrocarbon pesticides are adsorbed in much greater quantities by organic humus than by clay minerals. Based on this study it seems promising that the sludge materials generated by waste treatment plant can be used as the pesticide carrier or diluent in future agricultural applications.Project # B-037-MO Agreement # 14-31-0001-310