Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid β peptide (Aβ) within walls of cerebral arteries and is an important cause of intracerebral hemorrhage, ischemic stroke, and cognitive dysfunction in elderly patients with and without Alzheimer's Disease (AD). NADPH oxidase-derived oxidative stress plays a key role in soluble Aβ-induced vessel dysfunction, but the mechanisms by which insoluble Aβ in the form of CAA causes cerebrovascular (CV) dysfunction are not clear. Here, we demonstrate evidence that reactive oxygen species (ROS) and, in particular, NADPH oxidase-derived ROS are a key mediator of CAA-induced CV deficits. First, the NADPH oxidase inhibitor, apocynin, and the nonspecific ROS scavenger, tempol, are shown to reduce oxidative stress and improve CV reactivity in aged Tg2576 mice. Second, the observed improvement in CV function is attributed both to a reduction in CAA formation and a decrease in CAA-induced vasomotor impairment. Third, anti-ROS therapy attenuates CAA-related microhemorrhage. A potential mechanism by which ROS contribute to CAA pathogenesis is also identified because apocynin substantially reduces expression levels of ApoE-a factor known to promote CAA formation. In total, these data indicate that ROS are a key contributor to CAA formation, CAA-induced vessel dysfunction, and CAA-related microhemorrhage. Thus, ROS and, in particular, NADPH oxidase-derived ROS are a promising therapeutic target for patients with CAA and AD.Alzheimer's disease | cerebral amyloid angiopathy | reactive oxygen species | NADPH oxidase | vasomotor dysfunction

Background Vasospasm-induced delayed cerebral ischemia (DCI) remains a major source of morbidity in patients with aneurysmal subarachnoid hemorrhage (SAH). We hypothesized that activating innate neurovascular protective mechanisms by preconditioning (PC) may represent a novel therapeutic approach against SAH-induced vasospasm and neurological deficits; and secondarily, that the neurovascular protection it provides is mediated by endothelial nitric oxide synthase (eNOS). Methods Wild type (WT) mice were subjected to hypoxic PC or normoxia followed 24 h later by SAH. Neurological function was analyzed daily; vasospasm was assessed on post-surgery day 2. NO availability, eNOS expression, and eNOS activity were also assessed. In a separate experiment, WT and eNOS-null mice were subjected to hypoxic PC or normoxia followed by SAH and assessed for vasospasm and neurological deficits. Results PC nearly completely prevented SAH-induced vasospasm and neurological deficits. It also prevented SAH-induced reduction in NO availability and increased eNOS activity in mice with and without SAH. PC-induced protection against vasospasm and neurological deficits was lost in WT mice treated with the NOS inhibitor L-NAME and in eNOS-null mice. Conclusion Endogenous protective mechanisms against vasospasm exist, are powerful, and can be induced via PC. eNOS-derived NO is a critical mediator of PC-induced neurovascular protection. These data provide strong “proof-of-principle” evidence that PC represents a promising new strategy to reduce vasospasm and DCI after SAH.

Background Optimal treatment for patients with symptomatic intraluminal carotid thrombus (ICT) remains poorly defined. Methods We performed a retrospective chart review of patients presenting to our institution between 2001 and 2011 with symptomatic ICT. Results Twenty-four patients (16 males, 8 females) with ICT presented with ischemic stroke (n=18) or TIA (n=6). All were treated initially with anticoagulation ± antiplatelet drugs. Eight of these patients had no or mild carotid stenosis on initial angiography and were treated with medical management alone. The remaining 16 patients had moderate or severe carotid stenosis on initial angiography. Of these, 10 underwent delayed revascularization (endarterectomy, n=8; angioplasty and stenting, n=2), 2 refused revascularization, and 4 were treated with medical therapy alone. One patient had multiple TIAs despite medical therapy and eventually underwent CEA; the remaining 23 patients had no TIAs. No patient suffered ischemic or hemorrhagic stroke while on anticoagulation, during the perioperative period or in long-term follow up; one patient died of an unrelated condition (mean follow-up = 16.4 months). Conclusion Our results suggest that initial anticoagulation of symptomatic ICT results in a low rate of recurrent ischemic events and that carotid revascularization, if indicated, can be safely performed in a delayed manner.

Object Stabilization of the cervical spine can be challenging when instrumentation involves the axis. Fixation with C1–2 transarticular screws combined with posterior wiring and bone graft placement has yielded excellent fusion rates, but the technique is technically demanding and places the vertebral arteries (VAs) at risk. Placement of screws in the pars interarticularis of C-2 as described by Harms and Melcher has allowed rigid fixation with greater ease and theoretically decreases the risk to the VA. However, fluoroscopy is suggested to avoid penetration laterally, medially, and superiorly to avoid damage to the VA, spinal cord, and C1–2 joint, respectively. The authors describe how, after meticulous dissection of the C-2 pars interarticularis, such screws can be placed accurately and safely without the use of fluoroscopy. Methods Prospective follow-up was performed in 55 consecutive patients who underwent instrumented fusion of C-2 by a single surgeon. The causes of spinal instability and type and extent of instrumentation were documented. All patients underwent preoperative CT or MR imaging scans to determine the suitability of C-2 screw placement. Intraoperatively, screws were placed following dissection of the posterior pars interarticularis. Postoperative CT scans were performed to determine the extent of cortical breach. Patients underwent clinical follow-up, and complications were recorded as vascular or neurological. A CT-based grading system was created to characterize such breaches objectively by location and magnitude via percentage of screw diameter beyond the cortical edge (0 = none; I = < 25% of screw diameter; II = 26–50%; III = 51–75%; IV = 76–100%). Results One-hundred consecutive screws were placed in the pedicle of the axis by a single surgeon using external landmarks only. In 10 cases, only 1 screw was placed because of a preexisting VA anatomy or bone abnormality noted preoperatively. In no case was screw placement aborted because of complications noted during drilling. Early complications occurred in 2 patients and were limited to 1 wound infection and 1 transient C-2 radiculopathy. There were 15 total breaches (15%), 2 of which occurred in the same patient. Twelve breaches were lateral (80%), and 3 were superior (20%). There were no medial breaches. The magnitude of the breach was classified as I in 10 cases (66.7% of breaches), II in 3 cases (20% of breaches), III in 1 case (6.7%), and IV in 1 case (6.7%). Conclusions Free-hand placement of screws in the C-2 pedicle can be done safely and effectively without the use of intraoperative fluoroscopy or navigation when the pars interarticularis/pedicle is assessed preoperatively with CT or MR imaging and found to be suitable for screw placement. When breaches do occur, they are overwhelmingly lateral in location, breach < 50% of the screw diameter, and in the authors' experience, are not clinically significant.

BackgroundCerebral amyloid angiopathy (CAA) is characterized by deposition of fibrillar amyloid β (Aβ) within cerebral vessels. It is commonly seen in the elderly and almost universally present in patients with Alzheimer's Disease (AD). In both patient populations, CAA is an independent risk factor for lobar hemorrhage, ischemic stroke, and dementia. To date, definitive diagnosis of CAA requires obtaining pathological tissues via brain biopsy (which is rarely clinically indicated) or at autopsy. Though amyloid tracers labeled with positron-emitting radioligands such as [11C]PIB have shown promise for non-invasive amyloid imaging in AD patients, to date they have been unable to clarify whether the observed amyloid load represents neuritic plaques versus CAA due in large part to the low resolution of PET imaging and the almost equal affinity of these tracers for both vascular and parenchymal amyloid. Therefore, the development of a precise and specific non-invasive technique for diagnosing CAA in live patients is desired.ResultsWe found that the phenoxazine derivative resorufin preferentially bound cerebrovascular amyloid deposits over neuritic plaques in the aged Tg2576 transgenic mouse model of AD/CAA, whereas the congophilic amyloid dye methoxy-X34 bound both cerebrovascular amyloid deposits and neuritic plaques. Similarly, resorufin-positive staining was predominantly noted in fibrillar Aβ-laden vessels in postmortem AD brain tissues. Fluorescent labeling and multi-photon microscopy further revealed that both resorufin- and methoxy-X34-positive staining is colocalized to the vascular smooth muscle (VSMC) layer of vessel segments that have severe disruption of VSMC arrangement, a characteristic feature of CAA. Resorufin also selectively visualized vascular amyloid deposits in live Tg2576 mice when administered topically, though not systemically. Resorufin derivatives with chemical modification at the 7-OH position of resorufin also displayed a marked preferential binding affinity for CAA, but with enhanced lipid solubility that indicates their use as a non-invasive imaging tracer for CAA is feasible.ConclusionsTo our knowledge, resorufin analogs are the fist class of amyloid dye that can discriminate between cerebrovascular and neuritic forms of amyloid. This unique binding selectivity suggests that this class of dye has great potential as a CAA-specific amyloid tracer that will permit non-invasive detection and quantification of CAA in live patients.

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OncoGel™ incorporates paclitaxel, a mitotic inhibitor, into ReGel™, a thermosensitive gel depot system to provide local delivery, enhance efficacy and limit systemic toxicity. In previous studies the alkylating agent temozolomide (TMZ) incorporated into a polymer, pCPP:SA, also for local delivery, and OncoGel were individually shown to increase efficacy in a rat glioma model. We investigated the effects of OncoGel with oral TMZ or locally delivered TMZ polymer, with and without radiotherapy (XRT) in rats with intracranial gliosarcoma. Eighty-nine animals were intracranially implanted with a 9L gliosarcoma tumor and divided into 12 groups that received various combinations of 4 treatment options; OncoGel 6.3 mg/ml (Day 0), 20 Gy XRT (Day 5), 50 % TMZ–pCPP:SA (Day 5), or oral TMZ (50 mg/kg, qd, Days 5–9). Animals were followed for survival for 120 days. Median survival for untreated controls, XRT alone or oral TMZ alone was 15, 19 and 28 days, respectively. OncoGel 6.3 or TMZ polymer alone extended median survival to 33 and 35 days, respectively (p = 0.0005; p < 0.0001, vs. untreated controls) with 50 % living greater than 120 days (LTS) in both groups. Oral TMZ/XRT extended median survival to 36 days (p = 0.0002), with no LTS. The group that received OncoGel and Oral TMZ did not reach median survival with 57 % LTS (p = 0.0002). All other combination groups [OncoGel/XRT], [TMZ polymer/XRT], [OncoGel/TMZ polymer], [OncoGel/TMZ polymer/XRT], and [OncoGel/oral TMZ/XRT] yielded greater than 50 % LTS (p < 0.0001 for each combination as compared to controls), therefore median survival was not reached. OncoGel/TMZ polymer and OncoGel/oral TMZ/XRT had 100 % LTS (p < 0.0001 and p = 0.0001 vs. oral TMZ/XRT, respectively). These results indicate that OncoGel given locally with oral or locally delivered TMZ and/or XRT significantly increased the number of LTS and improved median survival compared to oral TMZ and XRT given alone or in combination in a rodent intracranial gliosarcoma model.

Functional magnetic resonance imaging (fMRI) is an important tool for pre-surgical evaluation of eloquent cortex. Classic task-based paradigms require patient participation and individual imaging sequence acquisitions for each functional domain that is being assessed. Resting state fMRI (rs-fMRI), however, enables functional localization without patient participation and can evaluate numerous functional domains with a single imaging session. To date, post-processing of this resting state data has been resource intensive, which limits its widespread application for routine clinical use. Through a novel automated algorithm and advanced imaging IT structure, we report the clinical application and the large-scale integration of rs-fMRI into routine neurosurgical practice. One hundred and ninety one consecutive patients underwent a 3T rs-fMRI, 83 of whom also underwent both motor and language task-based fMRI. Data were processed using a novel, automated, multi-layer perceptron algorithm and integrated into stereotactic navigation using a streamlined IT imaging pipeline. One hundred eighty-five studies were performed for intracranial neoplasm, 14 for refractory epilepsy and 33 for vascular malformations or other neurological disorders. Failure rate of rs-fMRI of 13% was significantly better than that for task-based fMRI (38.5%,) (p <0.001). In conclusion, at Washington University in St. Louis, rs-fMRI has become an integral part of standard imaging for neurosurgical planning. Resting state fMRI can be used in all patients, and due to its lower failure rate than task-based fMRI, it is useful for patients who are unable to cooperate with task-based studies.