{"doi":"10.1093/brain/awab088","title":"Myelin and axon pathology in multiple sclerosis assessed by myelin water and multi-shell diffusion imaging","abstract":"Damage to the myelin sheath and the neuroaxonal unit is a cardinal feature of multiple sclerosis; however, a detailed characterization of the interaction between myelin and axon damage in vivo remains challenging. We applied myelin water and multi-shell diffusion imaging to quantify the relative damage to myelin and axons (i) among different lesion types; (ii) in normal-appearing tissue; and (iii) across multiple sclerosis clinical subtypes and healthy controls. We also assessed the relation of focal myelin/axon damage with disability and serum neurofilament light chain as a global biological measure of neuroaxonal damage. Ninety-one multiple sclerosis patients (62 relapsing-remitting, 29 progressive) and 72 healthy controls were enrolled in the study. Differences in myelin water fraction and neurite density index were substantial when lesions were compared to healthy control subjects and normal-appearing multiple sclerosis tissue: both white matter and cortical lesions exhibited a decreased myelin water fraction and neurite density index compared with healthy (P < 0.0001) and peri-plaque white matter (P < 0.0001). Periventricular lesions showed decreased myelin water fraction and neurite density index compared with lesions in the juxtacortical region (P < 0.0001 and P < 0.05). Similarly, lesions with paramagnetic rims showed decreased myelin water fraction and neurite density index relative to lesions without a rim (P < 0.0001). Also, in 75% of white matter lesions, the reduction in neurite density index was higher than the reduction in the myelin water fraction. Besides, normal-appearing white and grey matter revealed diffuse reduction of myelin water fraction and neurite density index in multiple sclerosis compared to healthy controls (P < 0.01). Further, a more extensive reduction in myelin water fraction and neurite density index in normal-appearing cortex was observed in progressive versus relapsing-remitting participants. Neurite density index in white matter lesions correlated with disability in patients with clinical deficits (P < 0.01, beta = -10.00); and neurite density index and myelin water fraction in white matter lesions were associated to serum neurofilament light chain in the entire patient cohort (P < 0.01, beta = -3.60 and P < 0.01, beta = 0.13, respectively). These findings suggest that (i) myelin and axon pathology in multiple sclerosis is extensive in both lesions and normal-appearing tissue; (ii) particular types of lesions exhibit more damage to myelin and axons than others; (iii) progressive patients differ from relapsing-remitting patients because of more extensive axon/myelin damage in the cortex; and (iv) myelin and axon pathology in lesions is related to disability in patients with clinical deficits and global measures of neuroaxonal damage.","journal":"Brain","year":2021,"id":149121,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":112,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9525,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":320262,"name":"Po‐Jui Lu","orcid":"0000-0001-6031-6865","position":1,"is_corresponding":false},{"id":467184,"name":"Muhamed Baraković","orcid":"0000-0001-8557-9223","position":2,"is_corresponding":false},{"id":320264,"name":"Matthias Weigel","orcid":"0000-0002-4910-1414","position":3,"is_corresponding":false},{"id":247662,"name":"Pietro Maggi","orcid":"0000-0003-1697-5585","position":4,"is_corresponding":false},{"id":314691,"name":"Thanh D. Nguyen","orcid":"0000-0002-1411-7694","position":5,"is_corresponding":false},{"id":553909,"name":"Simona Schiavi","orcid":"0000-0003-1641-186X","position":6,"is_corresponding":false},{"id":467188,"name":"Alessandro Daducci","orcid":"0000-0002-4677-6678","position":7,"is_corresponding":false},{"id":308518,"name":"Francesco La Rosa","orcid":"0000-0002-9224-4664","position":8,"is_corresponding":false},{"id":635545,"name":"Sabine Schaedelin","orcid":null,"position":9,"is_corresponding":false},{"id":247676,"name":"Martina Absinta","orcid":"0000-0003-0276-383X","position":10,"is_corresponding":false},{"id":230800,"name":"Daniel S. Reich","orcid":"0000-0002-2628-4334","position":11,"is_corresponding":false},{"id":247663,"name":"Pascal Sati","orcid":"0000-0002-6763-0125","position":12,"is_corresponding":false},{"id":634454,"name":"Yi Wang","orcid":"0000-0002-0818-724X","position":13,"is_corresponding":false},{"id":308520,"name":"Meritxell Bach Cuadra","orcid":"0000-0003-2730-4285","position":14,"is_corresponding":false},{"id":635546,"name":"Ernst-Wilhelm Radüe","orcid":null,"position":15,"is_corresponding":false},{"id":634455,"name":"Jens Kuhle","orcid":"0000-0002-3713-9570","position":16,"is_corresponding":false},{"id":27468,"name":"Ludwig Kappos","orcid":"0000-0003-4175-5509","position":17,"is_corresponding":false},{"id":308521,"name":"Cristina Granziera","orcid":"0000-0002-4917-8761","position":18,"is_corresponding":false},{"id":320263,"name":"Reza Rahmanzadeh","orcid":"0000-0002-5091-0585","position":0,"is_corresponding":true}],"reference_count":85,"raw_metadata":null,"created_at":"2026-07-18T23:42:51.282401Z","pmid":"33693571","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}