Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations.

PurposeThe phenotypic manifestations of cerebral cavernous malformation disease caused by rare PDCD10 mutations have not been systematically examined, and a mechanistic link to Rho kinase-mediated hyperpermeability, a potential therapeutic target, has not been established.MethodsWe analyzed PDCD10 small interfering RNA-treated endothelial cells for stress fibers, Rho kinase activity, and permeability. Rho kinase activity was assessed in cerebral cavernous malformation lesions. Brain permeability and cerebral cavernous malformation lesion burden were quantified, and clinical manifestations were assessed in prospectively enrolled subjects with PDCD10 mutations.ResultsWe determined that PDCD10 protein suppresses endothelial stress fibers, Rho kinase activity, and permeability in vitro. Pdcd10 heterozygous mice have greater lesion burden than other Ccm genotypes. We demonstrated robust Rho kinase activity in murine and human cerebral cavernous malformation vasculature and increased brain vascular permeability in humans with PDCD10 mutation. Clinical phenotype is exceptionally aggressive compared with the more common KRIT1 and CCM2 familial and sporadic cerebral cavernous malformation, with greater lesion burden and more frequent hemorrhages earlier in life. We first report other phenotypic features, including scoliosis, cognitive disability, and skin lesions, unrelated to lesion burden or bleeding.ConclusionThese findings define a unique cerebral cavernous malformation disease with exceptional aggressiveness, and they inform preclinical therapeutic testing, clinical counseling, and the design of trials.Genet Med 17 3, 188-196

Impact of Leukoaraiosis Severity on the Association of Time to Successful Reperfusion with 90-Day Functional Outcome After Large Vessel Occlusion Stroke

The chance for a favorable outcome after mechanical thrombectomy (MT) for large vessel occlusion stroke decreases with the symptom onset-to-reperfusion time (OTR). Patients with severe leukoaraiosis are at increased risk for a poor outcome after MT. However, whether leukoaraiosis modulates to the association between OTR and 90-day functional outcome is uncertain. We retrospectively analyzed 144 consecutive patients with successful (TICI \u3e /= 2b/3) MT for anterior circulation large vessel occlusion within 24 h form OTR between January 2012 to November 2016. Leukoaraiosis was dichotomized to absent-to-mild (van Swieten scale score 0-2) versus moderate-to-severe (3-4) as assessed on admission head CT. Multiple linear, logistic, and ordinal regression analyses were used to determine the association between leukoaraiosis, OTR, and 90-day modified Rankin Scale (mRS) score, after adjustment for pertinent covariates. Leukoaraiosis was independently associated with the OTR on multivariable linear regression (p = 0.003). The association between OTR and 90-day outcome depended on the degree of pre-existing leukoaraiosis burden as shown by a significant leukoaraiosis-by-OTR interaction on multivariable logistic regression (OR 0.76, 95% CI 0.58-0.98, p = 0.037) and multivariable ordinal regression (OR 0.87, 95% CI 0.78-0.97, p = 0.011). Pre-existing leukoaraiosis is associated with the 90-day functional outcome after successful reperfusion and impacts the association between the OTR and 90-day mRS among patients undergoing MT. Patients with high leukoaraiosis burden need to present earlier than patients with low leukoaraiosis burden for a similar favorable outcome. Pending confirmation, these results may have important implications for optimizing patient selection for acute stroke therapies

Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations.

PurposeThe phenotypic manifestations of cerebral cavernous malformation disease caused by rare PDCD10 mutations have not been systematically examined, and a mechanistic link to Rho kinase-mediated hyperpermeability, a potential therapeutic target, has not been established.MethodsWe analyzed PDCD10 small interfering RNA-treated endothelial cells for stress fibers, Rho kinase activity, and permeability. Rho kinase activity was assessed in cerebral cavernous malformation lesions. Brain permeability and cerebral cavernous malformation lesion burden were quantified, and clinical manifestations were assessed in prospectively enrolled subjects with PDCD10 mutations.ResultsWe determined that PDCD10 protein suppresses endothelial stress fibers, Rho kinase activity, and permeability in vitro. Pdcd10 heterozygous mice have greater lesion burden than other Ccm genotypes. We demonstrated robust Rho kinase activity in murine and human cerebral cavernous malformation vasculature and increased brain vascular permeability in humans with PDCD10 mutation. Clinical phenotype is exceptionally aggressive compared with the more common KRIT1 and CCM2 familial and sporadic cerebral cavernous malformation, with greater lesion burden and more frequent hemorrhages earlier in life. We first report other phenotypic features, including scoliosis, cognitive disability, and skin lesions, unrelated to lesion burden or bleeding.ConclusionThese findings define a unique cerebral cavernous malformation disease with exceptional aggressiveness, and they inform preclinical therapeutic testing, clinical counseling, and the design of trials.Genet Med 17 3, 188-196

Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations

PURPOSE: The phenotypic manifestations of cerebral cavernous malformation (CCM) disease caused by rare PDCD10 mutations have not been systematically examined, and a mechanistic link to Rho kinase (ROCK) mediated hyperpermeability, a potential therapeutic target, has not been established. METHODS: We analyze PDCD10-siRNA treated endothelial cells for stress fibers, ROCK activity and permeability. ROCK activity is assessed in CCM lesions. Brain permeability and CCM lesion burden is quantified, and clinical manifestations are assessed in prospectively enrolled subjects with PDCD10 mutations. RESULTS: We determine that PDCD10 protein suppresses endothelial stress fibers, ROCK activity and permeability in vitro. Pdcd10 heterozygous mice have greater lesion burden than other Ccm genotypes. We demonstrate robust ROCK activity in murine and human CCM vasculature, and increased brain vascular permeability in humans with PDCD10 mutation. Clinical phenotype is exceptionally aggressive compared to the more common KRIT1 and CCM2 familial and sporadic CCM, with greater lesion burden and more frequent hemorrhages earlier in life. We first report other phenotypic features including scoliosis, cognitive disability and skin lesions, unrelated to lesion burden or bleeding. CONCLUSION: These findings define a unique CCM disease with exceptional aggressiveness, and they inform preclinical therapeutic testing, clinical counseling and the design of trials