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.

OBJECTIVE Vascular permeability and iron leakage are central features of cerebral cavernous malformation (CCM) pathogenesis. The authors aimed to correlate prospective clinical behavior of CCM lesions with longitudinal changes in biomarkers of dynamic contrast-enhanced quantitative permeability (DCEQP) and quantitative susceptibility mapping (QSM) assessed by MRI. METHODS Forty-six patients with CCMs underwent 2 or more permeability and/or susceptibility studies in conjunction with baseline and follow-up imaging and clinical surveillance during a mean 12.05 months of follow-up (range 2.4-31.27 months). Based on clinical and imaging features, cases/lesions were classified as stable, unstable, or recovering. Associated and predictive changes in quantitative permeability and susceptibility were investigated. RESULTS Lesional mean permeability and QSM values were not significantly different in stable versus unstable lesions at baseline. Mean lesional permeability in unstable CCMs with lesional bleeding or growth increased significantly (+85.9% change; p = 0.005), while mean permeability in stable and recovering lesions did not significantly change. Mean lesional QSM values significantly increased in unstable lesions (+44.1% change; p = 0.01), decreased slightly with statistical significance in stable lesions (-3.2% change; p = 0.003), and did not significantly change in recovering lesions. Familial cases developing new lesions during the follow-up period showed a higher background brain permeability at baseline (p = 0.001), as well as higher regional permeability (p = 0.003) in the area that would later develop a new lesion as compared with the homologous contralateral brain region. CONCLUSIONS In vivo assessment of vascular permeability and iron deposition on MRI can serve as objective and quantifiable biomarkers of disease activity in CCMs. This may be applied in natural history studies and may help calibrate clinical trials. The 2 techniques are likely applicable in other disorders of vascular integrity and iron leakage such as aging, hemorrhagic microangiopathy, and traumatic brain injury.

Patients with the familial form of cerebral cavernous malformations (CCMs) are haploinsufficient for the CCM1, CCM2, or CCM3 gene. Loss of corresponding CCM proteins increases RhoA kinase-mediated endothelial permeability in vitro, and in mouse brains in vivo. A prospective case-controlled observational study investigated whether the brains of human subjects with familial CCM show vascular hyperpermeability by dynamic contrast-enhanced quantitative perfusion magnetic resonance imaging, in comparison with CCM cases without familial disease, and whether lesional or brain vascular permeability correlates with CCM disease activity. Permeability in white matter far (WMF) from lesions was significantly greater in familial than in sporadic cases, but was similar in CCM lesions. Permeability in WMF increased with age in sporadic patients, but not in familial cases. Patients with more aggressive familial CCM disease had greater WMF permeability compared to those with milder disease phenotype, but similar lesion permeability. Subjects receiving statin medications for routine cardiovascular indications had a trend of lower WMF, but not lesion, permeability. This is the first demonstration of brain vascular hyperpermeability in humans with an autosomal dominant disease, as predicted mechanistically. Brain permeability, more than lesion permeability, may serve as a biomarker of CCM disease activity, and help calibrate potential drug therapy.

Objectives To investigate and validate quantitative susceptibility mapping (QSM) for lesional iron quantification in cerebral cavernous malformations (CCM). Materials and Methods Magnetic resonance imaging (MRI) studies were performed in phantoms and 16 patients on a 3T scanner. QSM, susceptibility weighted imaging (SWI), and R2* maps were reconstructed from in vivo data acquired with a three-dimensional, multi-echo, and T2*-weighted gradient echo sequence. Magnetic susceptibility measurements were correlated to SWI and R2* results. In addition, iron concentrations from surgically excised CCM lesion specimens were determined using inductively coupled plasma mass spectrometry and correlated with QSM measurements. Results The QSM images demonstrated excellent image quality for depicting CCM lesions in both sporadic and familial cases. Susceptibility measurements revealed a positive linear correlation with R2* values (R2 = 0.99 for total, R2 = 0.69 for mean; p < 0.01). QSM values of known iron-rich brain regions matched closely with previous studies and in interobserver consistency. A strong correlation was found between QSM and the concentration of iron phantoms (0.925, p < 0.01), as well as between QSM and mass spectroscopy estimation of iron deposition (0.999 for total iron, 0.86 for iron concentration; p < 0.01) in 18 fragments of 4 excised human CCM lesion specimens. Conclusions The ability of QSM to evaluate iron deposition in CCM lesions was illustrated via phantom, in vivo and ex vivo validation studies. QSM may be a potential biomarker for monitoring CCM disease activity and response to treatments.

Background and Purpose To correlate lesional iron deposition assessed by quantitative susceptibility mapping (QSM) with clinical and disease features in patients with cerebral cavernous malformations (CCM). Materials and Methods This study was approved by the local Institutional Review Boards, and informed consent was obtained from each participant. Patients underwent routine clinical scan in addition to QSM on 3 Tesla systems. Data from 105 patients met inclusion criteria. CCM lesions identified on susceptibility maps were cross-verified by T2 weighted images and differentiated based on prior overt hemorrhage. Mean susceptibility per CCM lesion (χ̄lesion) was measured to correlate with lesion volume, age at scan, and hemorrhagic history. Temporal rates of change in χ̄lesion was evaluated in 33 patients. Results Average χ̄lesion per patient was positively correlated with patient age at scan (p < 0.05, 4.1% change with each decade of life). CCM lesions with prior overt hemorrhages exhibited higher χ̄lesion than those without (p < 0.05). Changes in χ̄lesion during 3 – 15 months follow-up period were small in patients without new hemorrhage between the two scans [bias = −0.0003, 95% CI = [−0.06, 0.06]). Conclusion The study revealed a positive correlation between mean QSM signal and patient age in CCM lesions, higher mean QSM signal in hemorrhagic lesions, and minimum longitudinal QSM signal change in clinically stable lesions. QSM has the potential to be a novel imaging biomarker supplementing conventional imaging in CCM. The clinical significance of such measures merits further study.