RESUMEN
Inclusion body myositis (IBM) is the most prevalent inflammatory muscle disease in older adults with no effective therapy available. In contrast to other inflammatory myopathies such as subacute, immune-mediated necrotizing myopathy (IMNM), IBM follows a chronic disease course with both inflammatory and degenerative features of pathology. Moreover, causal factors and molecular drivers of IBM progression are largely unknown. Therefore, we paired single-nucleus RNA sequencing with spatial transcriptomics from patient muscle biopsies to map cell-type-specific drivers underlying IBM pathogenesis compared with IMNM muscles and noninflammatory skeletal muscle samples. In IBM muscles, we observed a selective loss of type 2 myonuclei paralleled by increased levels of cytotoxic T and conventional type 1 dendritic cells. IBM myofibers were characterized by either upregulation of cell stress markers featuring GADD45A and NORAD or protein degradation markers including RNF7 associated with p62 aggregates. GADD45A upregulation was preferentially seen in type 2A myofibers associated with severe tissue inflammation. We also noted IBM-specific upregulation of ACHE encoding acetylcholinesterase, which can be regulated by NORAD activity and result in functional denervation of myofibers. Our results provide promising insights into possible mechanisms of myofiber degeneration in IBM and suggest a selective type 2 fiber vulnerability linked to genomic stress and denervation pathways.
RESUMEN
BACKGROUND: Mechanical thrombectomy (MT) is the standard of care for patients with a stroke and large vessel occlusion. Clot composition is not routinely assessed in clinical practice as no specific diagnostic value is attributed to it, and MT is performed in a standardized 'non-personalized' approach. Whether different clot compositions are associated with intrinsic likelihoods of recanalization success or treatment outcome is unknown. METHODS: We performed a prospective, non-randomized, single-center study and analyzed the clot composition in 60 consecutive patients with ischemic stroke undergoing MT. Clots were assessed by ex vivo multiparametric MRI at 9.4 T (MR microscopy), cone beam CT, and histopathology. Clot imaging was correlated with preinterventional CT and clinical data. RESULTS: MR microscopy showed red blood cell (RBC)-rich (21.7%), platelet-rich (white,38.3%) or mixed clots (40.0%) as distinct morphological entities, and MR microscopy had high accuracy of 95.4% to differentiate clots. Clot composition could be further stratified on preinterventional non-contrast head CT by quantification of the hyperdense artery sign. During MT, white clots required more passes to achieve final recanalization and were not amenable to contact aspiration compared with mixed and RBC-rich clots (maneuvers: 4.7 vs 3.1 and 1.2 passes, P<0.05 and P<0.001, respectively), whereas RBC-rich clots showed higher probability of first pass recanalization (76.9%) compared with white clots (17.4%). White clots were associated with poorer clinical outcome at discharge and 90 days after MT. CONCLUSION: Our study introduces MR microscopy to show that the hyperdense artery sign or MR relaxometry could guide interventional strategy. This could enable a personalized treatment approach to improve outcome of patients undergoing MT.