Vessel Wall Enhancement on Black-Blood MRI Predicts Acute and Future Stroke in Cerebral Amyloid Angiopathy.

BACKGROUND AND PURPOSE: Cerebral amyloid angiopathy (CAA) is a known risk factor for ischemic stroke though angiographic imaging is often negative. Our goal was to determine the relationship between vessel wall enhancement (VWE) in acute and future ischemic stroke in CAA patients. MATERIALS AND METHODS: This was a retrospective study of patients with new-onset neurologic symptoms undergoing 3T vessel wall MR imaging from 2015 to 2019. Vessel wall enhancement was detected on pre- and postcontrast flow-suppressed 3D T1WI. Interrater agreement was evaluated in cerebral amyloid angiopathy-positive and age-matched negative participants using a prevalence- and bias-adjusted kappa analysis. In patients with cerebral amyloid angiopathy, multivariable Poisson and Cox regression were used to determine the association of vessel wall enhancement with acute and future ischemic stroke, respectively, using backward elimination of confounders to P < .20. RESULTS: Fifty patients with cerebral amyloid angiopathy underwent vessel wall MR imaging, including 35/50 (70.0%) with ischemic stroke and 29/50 (58.0%) with vessel wall enhancement. Prevalence- and bias-corrected kappa was 0.82 (95% CI, 0.71-0.93). The final regression model for acute ischemic stroke included vessel wall enhancement (prevalence ratio = 1.5; 95% CI, 1.1-2.2; P = .022), age (prevalence ratio = 1.02; 95% CI, 1.0-1.05; P = .036), time between symptoms and MR imaging (prevalence ratio = 0.9; 95% CI, 0.8-0.9; P < .001), and smoking (prevalence ratio = 0.7; 95% CI, 0.5-1.0; P = .042) with c-statistic = 0.92 (95% CI, 0.84-0.99). Future ischemic stroke incidence with cerebral amyloid angiopathy was 49.7% (95% CI, 34.5%-67.2%) per year over a total time at risk of 37.5 person-years. Vessel wall enhancement-positive patients with cerebral amyloid angiopathy demonstrated significantly shorter stroke-free survival with 63.9% (95% CI, 43.2%-84.0%) versus 32.2% (95% CI, 14.4%-62.3%) ischemic strokes per year, chi-square = 4.9, P = .027. The final model for future ischemic stroke had a c-statistic of 0.70 and included initial ischemic stroke (hazard ratio = 3.4; 95% CI, 1.0-12.0; P = .053) and vessel wall enhancement (hazard ratio = 2.5; 95% CI, 0.9-7.0; P = .080). CONCLUSIONS: Vessel wall enhancement is associated with both acute and future stroke in patients with cerebral amyloid angiopathy.

HBEGF promotes gliomagenesis in the context of Ink4a/Arf and Pten loss.

Heparin-binding epidermal growth factor (EGF)-like growth factor (HBEGF) is a ligand for the EGF receptor (EGFR), one of the most commonly amplified receptor tyrosine kinases (RTKs) in glioblastoma (GBM). While HBEGF has been found to be expressed in a subset of malignant gliomas, its sufficiency for glioma initiation has not been evaluated. In this study, we demonstrate that HBEGF can initiate GBM in mice in the context of Ink4a/Arf and Pten loss, and that these tumors are similar to the classical GBM subtype observed in patients. Isogenic astrocytes from these mice showed activation not only of Egfr but also the RTK Axl in response to HBEGF stimulation. Deletion of either Egfr or Axl decreased the tumorigenic properties of HBEGF-transformed cells; however, only EGFR was able to rescue the phenotype in cells lacking both RTKs indicating that Egfr is required for activation of Axl in this context. Silencing of HBEGF in vivo resulted in tumor regression and significantly increased survival, suggesting that HBEGF may be a clinically relevant target.

Neural transplantation in Huntington disease: long-term grafts in two patients.

OBJECTIVE: Clinical trials of fetal neural tissue transplantation for Huntington disease (HD) have been conducted with variable clinical results. However, no long-term analysis of graft survival and integration has been published. Here, we report the pathologic findings in two patients with HD who died 74 and 79 months after transplantation. METHODS: Methods used were pathologic examination, histochemistry, and immunohistochemistry. RESULTS: Neostriatum from both patients showed typical neuropathologic changes of advanced HD. Surviving grafts were identified in both patients (6/6 sites and 7/8 sites, respectively) as well-demarcated nests within host neostriatum with associated needle tracts. Grafted neurons adopted either dominant calbindin/parvalbumin or calretinin immunoreactivity (IR). Few neurofilament, MAP-2, DARPP-32, tyrosine hydroxylase, or calbindin IR processes traversed the host parenchyma-graft interface despite minimal junctional gliosis. Immunohistochemistry for CD68 showed microgliosis that was more pronounced in host striatum than graft. Scattered CD45 and CD3 IR cells were present within grafts and host parenchyma. No ubiquitin IR neuronal intranuclear inclusions were identified in graft neurons, although these were prevalent in host cells. CONCLUSIONS: These two autopsies confirm previous findings of neuronal differentiation and survival of transplanted fetal tissue from the ganglionic eminence and also demonstrate viability of neurons from fetal transplants in human neostriatum for more than 6 years. Despite prolonged survival, these grafts had poor integration with host striatum that is likely responsible for lack of clear clinical improvement in these patients.