Perfusion and permeability as diagnostic biomarkers of cavernous angioma with symptomatic hemorrhage

Abstract

Cavernous angiomas with symptomatic hemorrhage (CASH) have a high risk of rebleeding, and hence an accurate diagnosis is needed. With blood flow and vascular leak as established mechanisms, we analyzed perfusion and permeability derivations of dynamic contrast-enhanced quantitative perfusion (DCEQP) MRI in 745 lesions of 205 consecutive patients. Thirteen respective derivations of lesional perfusion and permeability were compared between lesions that bled within a year prior to imaging (N = 86), versus non-CASH (N = 659) using machine learning and univariate analyses. Based on logistic regression and minimizing the Bayesian information criterion (BIC), the best diagnostic biomarker of CASH within the prior year included brainstem lesion location, sporadic genotype, perfusion skewness, and high-perfusion cluster area (BIC = 414.9, sensitivity = 74%, specificity = 87%). Adding a diagnostic plasma protein biomarker enhanced sensitivity to 100% and specificity to 85%. A slightly modified derivation achieved similar accuracy (BIC = 321.6, sensitivity = 80%, specificity = 82%) in the cohort where CASH occurred 3–12 months prior to imaging after signs of hemorrhage would have disappeared on conventional MRI sequences. Adding the same plasma biomarker enhanced sensitivity to 100% and specificity to 87%. Lesional blood flow on DCEQP may distinguish CASH after hemorrhagic signs on conventional MRI have disappeared and are enhanced in combination with a plasma biomarker.

Perfusion and Permeability MRI Predicts Future Cavernous Angioma Hemorrhage and Growth

“…Permeability and perfusion descriptors of the prognostic model may reflect the dysregulated angiogenesis and angioarchitecture of CA disease modulated by vascular endothelial growth factor 31,32 and its functionally related proteins. 33 The previous diagnostic study by Sone et al 17 and our prognostic results herein both suggest that dysregulated perfusion and permeability may reflect pathophysiological changes of CA disease before and after bleed/growth. Ultimately, the diagnostic 17 and prognostic biomarkers have complementary b One patient declined to provide information on their ethnicity/race.…”

“…A previous report identified that features reflecting inhomogeneous and dysregulated perfusion could best diagnose CASH. 17 Our current study now suggests that increased permeability and decreased perfusion cluster may predict future lesional bleed/growth. This prognostic model is consistent with the existing knowledge on CA disease, including hyperpermeability's longitudinal association with CA bleed/ growth.…”

“…Maximum lesion diameter was measured manually using the clinical MRI instrument software, and the lesion diameter threshold corresponded to "large lesion" diameter threshold in ongoing clinical research studies meant to exclude smaller lesions or hemorrhagic microangiopathies with unknown clinical significance. 2,6,7,13,14,16,17 Each CA lesion was classified as its own observation point, and was categorized as familial/multifocal if there were multiple CAs in the brain on magnetic resonance susceptibility-weighted imaging (SWI, GRE with repetition time/ echo time 49 msec/40 msec, axial plane, flip angle 15 , field of view 230 mm  200 mm, matrix 256  177, section thickness 2 mm), 19 a documented CCM1, CCM2, or CCM3 germline mutation on genetic testing, and/or first-degree relative with CA history. Lesions were categorized as sporadic/solitary if they presented a single CA lesion on SWI or a cluster of CAs associated with a developmental venous anomaly.…”

“…Lesions were also categorized by brainstem location (yes or no) and prior symptomatic hemorrhage (yes or no) in the year preceding the DCEQP imaging. 17 CAs showing acute or subacute bleeding on follow-up CT or clinical MRI (including evidence of new fluid-attenuated inversion recovery (FLAIR) signal on MRI, and/or lesion expansion in any diameter by ≥3 mm on comparable T 1 -or T 2 -weighted clinical MRI sequences 2,6,14,16,20 were categorized as bleed/growth for further prognostic analyses. The ≥3 mm threshold on comparable T 1 -or T 2 -weighted MRI was previously used in the analysis of subclinical changes in CAs 6 and is meant to exclude insignificant changes and those within errors of manual measurement on non-research MRI scans.…”

“…17 Lesional permeability entropy, skewness, and highpermeability cluster area also significantly distinguished a prior symptomatic hemorrhage but did not complement nor enhance the perfusion imaging models. 17 These results supported laboratory studies linking hypoperfusion measured by low fluid shear stress with upregulated Rho kinase activity, inflammation, and signaling pathways associated with CA pathogenesis. 12 A recent study in zebrafish also suggested that blood flow may be a crucial factor in CA pathogenesis.…”