Comparison of diffusion MRI and CLARITY fiber orientation estimates in both gray and white matter regions of human and primate brain.

Diffusion MRI (dMRI) represents one of the few methods for mapping brain fiber orientations non-invasively. Unfortunately, dMRI fiber mapping is an indirect method that relies on inference from measured diffusion patterns. Comparing dMRI results with other modalities is a way to improve the interpretation of dMRI data and help advance dMRI technologies. Here, we present methods for comparing dMRI fiber orientation estimates with optical imaging of fluorescently labeled neurofilaments and vasculature in 3D human and primate brain tissue cuboids cleared using CLARITY. The recent advancements in tissue clearing provide a new opportunity to histologically map fibers projecting in 3D, which represents a captivating complement to dMRI measurements. In this work, we demonstrate the capability to directly compare dMRI and CLARITY in the same human brain tissue and assess multiple approaches for extracting fiber orientation estimates from CLARITY data. We estimate the three-dimensional neuronal fiber and vasculature orientations from neurofilament and vasculature stained CLARITY images by calculating the tertiary eigenvector of structure tensors. We then extend CLARITY orientation estimates to an orientation distribution function (ODF) formalism by summing multiple sub-voxel structure tensor orientation estimates. In a sample containing part of the human thalamus, there is a mean angular difference of 19o±15o between the primary eigenvectors of the dMRI tensors and the tertiary eigenvectors from the CLARITY neurofilament stain. We also demonstrate evidence that vascular compartments do not affect the dMRI orientation estimates by showing an apparent lack of correspondence (mean angular difference = 49o±23o) between the orientation of the dMRI tensors and the structure tensors in the vasculature stained CLARITY images. In a macaque brain dataset, we examine how the CLARITY feature extraction depends on the chosen feature extraction parameters. By varying the volume of tissue over which the structure tensor estimates are derived, we show that orientation estimates are noisier with more spurious ODF peaks for sub-voxels below 30 µm3 and that, for our data, the optimal gray matter sub-voxel size is between 62.5 µm3 and 125 µm3. The example experiments presented here represent an important advancement towards robust multi-modal MRI-CLARITY comparisons.

Patient Outcomes and Cerebral Infarction after Ruptured Anterior Communicating Artery Aneurysm Treatment.

BACKGROUND AND PURPOSE: Anterior communicating artery aneurysm rupture and treatment is associated with high rates of dependency, which are more severe after clipping compared with coiling. To determine whether ischemic injury might account for these differences, we characterized cerebral infarction burden, infarction patterns, and patient outcomes after surgical or endovascular treatment of ruptured anterior communicating artery aneurysms. MATERIALS AND METHODS: We performed a retrospective cohort study of consecutive patients with ruptured anterior communicating artery aneurysms. Patient data and neuroimaging studies were reviewed. A propensity score for outcome measures was calculated to account for the nonrandom assignment to treatment. Primary outcome was the frequency of frontal lobe and striatum ischemic injury. Secondary outcomes were patient mortality and clinical outcome at discharge and at 3 months. RESULTS: Coiled patients were older (median, 55 versus 50 years; P = .03), presented with a worse clinical status (60% with Hunt and Hess Score >2 versus 34% in clipped patients; P = .02), had a higher modified Fisher grade (P = .01), and were more likely to present with intraventricular hemorrhage (78% versus 56%; P = .03). Ischemic frontal lobe infarction (OR, 2.9; 95% CI, 1.1-8.4; P = .03) and recurrent artery of Heubner infarction (OR, 20.9; 95% CI, 3.5-403.7; P < .001) were more common in clipped patients. Clipped patients were more likely to be functionally dependent at discharge (OR, 3.2; P = .05) compared with coiled patients. Mortality and clinical outcome at 3 months were similar between coiled and clipped patients. CONCLUSIONS: Frontal lobe and recurrent artery of Heubner infarctions are more common after surgical clipping of ruptured anterior communicating artery aneurysms, and are associated with poorer clinical outcomes at discharge.

Electroencephalographic features of moyamoya in adults.

OBJECTIVE: Electroencephalography is useful for evaluating transient neurological events in the setting of moyamoya disease. METHODS: EEG findings of adults with moyamoya seen at a large moyamoya referral center are summarized. Patients were identified by retrospective chart review. RESULTS: EEGs were ordered after cerebral revascularization for altered mental status, aphasia, limb shaking, or facial twitching. Among the study population of 103 patients having EEGs, 24% of adults with moyamoya had a history of clinical seizures. Ischemic or hemorrhagic strokes were associated with a twofold relative risk of seizures. Overall, 90% of EEGs were abnormal, most commonly focally (78%), or diffusely slow (68%). Epileptiform EEG discharges were seen in 24%. Whereas hemispheres with an ischemic stroke had a 19% risk of epileptiform discharges and an 8% risk of seizures on EEG, hemispheres with hemorrhagic stroke had a 35% risk of epileptiform discharges and 19% risk of seizures on EEG. Focal amplitude attenuation was seen in 19%, breach rhythm in 15%, rhythmic delta in 14%, and electrographic seizures in 12%. CONCLUSIONS: Seizures and epileptiform EEG changes are common in patients with moyamoya disease. SIGNIFICANCE: Transient events in patients with moyamoya can result from seizures as well as ischemia.

Phosphorylated mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 may not always represent its kinase activity in a rat model of focal cerebral ischemia with or without ischemic preconditioning.

The extracellular signal-regulated kinase (ERK) 1/2 protein requires a dual phosphorylation at conserved threonine and tyrosine residues to be fully activated under normal physiological conditions. Thus, ERK1/2 kinase activity is often defined by the quantity of phosphorylated kinase. However, this may not accurately represent its true activity under certain pathological conditions. We investigated whether ERK1/2 kinase activity is proportional to its phosphorylation state in a rat focal ischemia model with and without rapid ischemic preconditioning. We showed that phosphorylated-ERK1/2 protein levels were increased 2.6±0.07-fold, and ERK1/2 kinase activity was increased 10.6±1.9-fold in animals receiving ischemic preconditioning alone without test ischemia compared with sham group (P<0.05, n=6/group), suggesting that phosphorylated-ERK1/2 protein levels represent its kinase activity under these conditions. However, preconditioning plus test ischemia robustly blocked ERK1/2 kinase activity, whereas it increased phosphorylated-ERK1/2 protein levels beyond those receiving test ischemia alone, suggesting that phosphorylated-ERK1/2 protein levels were not representative of actual kinase activity in this pathological condition. In conclusion, protein phosphorylation levels of ERK1/2 do not always correspond to kinase activity, thus, measuring the true kinase activity is essential.

Neuroradiologic correlates of cognitive impairment in adult Moyamoya disease.

BACKGROUND AND PURPOSE: MMD has been shown to result in impairment of executive functioning in adults. The purpose of this study was to correlate presurgical neuropsychological assessments with the severity of primary MMD as measured by CBF and CVR and with secondary damage from MMD as estimated by cortical stroke and WMD. MATERIALS AND METHODS: A retrospective analysis of 31 adult patients with MMD was performed. Xe-CT was used to obtain CBF and CVR, and MRI was reviewed to grade cortical stroke and WMD. Two tests of executive functioning (FAS and TMT-B) were correlated with imaging findings. A multiple regression analysis was performed. RESULTS: There was a significant overall positive relationship between mean CBF and FAS (P = .038) and TMT-B scores (P = .014). A significant negative relationship was present between the WMD score and the FAS (P = .009) and TMT-B scores (P = .015). Per-region analysis demonstrated that FAS and TMT-B scores were significantly decreased by the presence of a posterior stroke (P < .0001 and P = .001) or WMD (P = .006 and P = .004). All patients with posterior parieto-occipital WMD or stroke also had secondary disease in the anterior regions. CONCLUSIONS: Impaired executive functioning in adults with MMD is most strongly associated secondary damage in the form of WMD or cortical stroke. The effect is most profound with parieto-occipital lobe involvement, likely a reflection of overall disease severity. Increasing global WMD burden may be a better indicator of cognitive decline than cortical infarction. Patients with higher baseline CBF seem to have better cognitive functioning.

Intraoperative angiography for cranial dural arteriovenous fistula.

BACKGROUND AND PURPOSE: IA is a valuable adjunct during surgery for a variety of neurovascular diseases; however, there are no reported series describing IA for DAVFs. This study was undertaken to evaluate the safety and efficacy of IA for DAVFs. MATERIALS AND METHODS: A retrospective review of DAVF surgical cases during a 20-year period was conducted, and cases with IA were evaluated. Clinical details, surgical and angiographic findings, and postoperative outcomes were reviewed. The incidence of residual fistula on IAs, the utility of the surgical procedure, and the incidence of false-negative findings on IA were also determined. RESULTS: IA was performed in 29 patients (31 DAVFs) for DAVFs. The distribution of the fistulas was the following: transverse-sigmoid (n = 9), tentorial (n = 6), torcular (n = 3), cavernous sinus (n = 4), SSS (n = 4), foramen magnum (n = 3), and temporal-middle fossa (n = 2). Twelve patients had undergone prior embolization, while 6 patients had unsuccessful embolization procedures. Thirty-eight surgeries were performed for DAVF in 29 patients, and IA was performed in 34 surgeries. Forty-four angiographic procedures were performed in the 34 surgeries. Nine patients underwent multiple angiographies. In 11 patients (37.9%), IA revealed residual fistula after the surgeon determined that no lesion remained. This led to further exploration at the same sitting in 10 patients, while in 1 patient, further surgery was performed at a later date. False-negative findings on IA occurred in 3 patients (10.7%). CONCLUSIONS: IA is an important adjunct in surgery for DAVF. In this series, it resulted in further surgical treatment in 37.9% of patients. However, there was a 10% false-negative rate, which justified subsequent postoperative angiography.

Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning.

Remote ischemic preconditioning is an emerging concept for stroke treatment, but its protection against focal stroke has not been established. We tested whether remote preconditioning, performed in the ipsilateral hind limb, protects against focal stroke and explored its protective parameters. Stroke was generated by a permanent occlusion of the left distal middle cerebral artery (MCA) combined with a 30 min occlusion of the bilateral common carotid arteries (CCA) in male rats. Limb preconditioning was generated by 5 or 15 min occlusion followed with the same period of reperfusion of the left hind femoral artery, and repeated for two or three cycles. Infarct was measured 2 days later. The results showed that rapid preconditioning with three cycles of 15 min performed immediately before stroke reduced infarct size from 47.7+/-7.6% of control ischemia to 9.8+/-8.6%; at two cycles of 15 min, infarct was reduced to 24.7+/-7.3%; at two cycles of 5 min, infarct was not reduced. Delayed preconditioning with three cycles of 15 min conducted 2 days before stroke also reduced infarct to 23.0+/-10.9%, but with two cycles of 15 min it offered no protection. The protective effects at these two therapeutic time windows of remote preconditioning are consistent with those of conventional preconditioning, in which the preconditioning ischemia is induced in the brain itself. Unexpectedly, intermediate preconditioning with three cycles of 15 min performed 12 h before stroke also reduced infarct to 24.7+/-4.7%, which contradicts the current dogma for therapeutic time windows for the conventional preconditioning that has no protection at this time point. In conclusion, remote preconditioning performed in one limb protected against ischemic damage after focal cerebral ischemia.

Neurologic complications of arteriovenous malformation embolization using liquid embolic agents.

BACKGROUND AND PURPOSE: Embolization of arteriovenous malformations (AVMs) is commonly used to achieve nidal volume reduction before microsurgical resection or stereotactic radiosurgery. The purpose of this study was to examine the overall neurologic complication rate in patients undergoing AVM embolization and analyze the factors that may determine increased risk. MATERIALS AND METHODS: We performed a retrospective review of all patients with brain AVMs embolized at 1 center from 1995 through 2005. Demographics, including age, sex, presenting symptoms, and clinical condition, were recorded. Angiographic factors including maximal nidal size, presence of deep venous drainage, and involvement of eloquent cortex were also recorded. For each embolization session, the agent used, number of pedicles embolized, the percentage of nidal obliteration, and any complications were recorded. Complications were classified as the following: none, non-neurologic (mild), transient neurologic deficit, and permanent nondisabling and permanent disabling deficits. The permanent complications were also classified as ischemic or hemorrhagic. Modified Rankin Scale (mRS) scores were collected pre- and postembolization on all patients. Univariate regression analysis of factors associated with the development of any neurologic complication was performed. RESULTS: Four hundred eighty-nine embolization procedures were performed in 192 patients. There were 6 Spetzler-Martin grade I (3.1%), 26 grade II (13.5%), 71 grade III (37.0%), 57 grade IV (29.7%), and 32 grade V (16.7%) AVMs. Permanent nondisabling complications occurred in 5 patients (2.6%) and permanent disabling complications or deaths occurred in 3 (1.6%). In addition, there were non-neurologic complications in 4 patients (2.1%) and transient neurologic deficits in 22 (11.5%). Five of the 8 permanent complications (2.6% overall) were ischemic, and 3 of 8 (1.6% overall) were hemorrhagic. Of the 178 patients who were mRS 0-2 pre-embolization, 4 (2.3%) were dependent or dead (mRS >2) at follow-up. Univariate analysis of risk factors for permanent neurologic deficits following embolization showed that basal ganglia location was weakly associated with a new postembolization neurologic deficit. CONCLUSION: Embolization of brain AVMs can be performed with a high degree of technical success and a low rate of permanent neurologic complications.

Viral caspase inhibitor p35, but not crmA, is neuroprotective in the ischemic penumbra following experimental stroke.

Apoptosis, a predominant cause of neuronal death after stroke, can be executed in a caspase-dependent or apoptosis inducing factor (AIF)-dependent manner. Herpes simplex virus (HSV) vectors expressing caspase inhibitors p35 and crmA have been shown to be neuroprotective against various excitotoxic insults. Here we further evaluated the possible neuroprotective role of p35 and crmA in a rat stroke model. Overexpression of p35, but not crmA, significantly increased neuronal survival. Results of double immunofluorescence staining indicate that compared with neurons infected with crmA or control vectors, p35-infected neurons had less active caspase-3 expression, cytosolic cytochrome c and nuclear AIF translocation.

Transplantation of hNT neurons into the ischemic cortex: cell survival and effect on sensorimotor behavior.

Cell transplantation offers a potential new treatment for stroke. Animal studies using models that produce ischemic damage in both the striatum and the frontal cortex have shown beneficial effects when hNT cells (postmitotic immature neurons) were transplanted into the ischemic striatum. In this study, we investigated the effect of hNT cells in a model of stroke in which the striatum remains intact and damage is restricted to the cortex. hNT cells were transplanted into the ischemic cortex 1 week after stroke induced by distal middle cerebral artery occlusion (dMCAo). The cells exhibited robust survival at 4 weeks posttransplant even at the lesion border. hNT cells did not migrate, but they did extend long neurites into the surrounding parenchyma mainly through the white matter. Neurite extension was predominantly toward the lesion in ischemic animals but was bidirectional in uninjured animals. Extension of neurites through the cortex toward the lesion was also seen when there was some surviving cortical tissue between the graft and the infarct. Prolonged deficits were obtained in four tests of sensory-motor function. hNT-transplanted animals showed a significant improvement in functional recovery on one motor test, but there was no effect on the other three tests relative to control animals. Thus, despite clear evidence of graft survival and neurite extension, the functional benefit of hNT cells after ischemia is not guaranteed. Functional benefit could depend on other variables, such as infarct location, whether the cells mature, the behavioral tests employed, rehabilitation training, or as yet unidentified factors.

Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex.

We characterize the survival, migration, and differentiation of human neurospheres derived from CNS stem cells transplanted into the ischemic cortex of rats 7 days after distal middle cerebral artery occlusion. Transplanted neurospheres survived robustly in naive and ischemic brains 4 wk posttransplant. Survival was influenced by proximity of the graft to the stroke lesion and was negatively correlated with the number of IB4-positive inflammatory cells. Targeted migration of the human cells was seen in ischemic animals, with many human cells migrating long distances ( approximately 1.2 mm) predominantly toward the lesion; in naive rats, cells migrated radially from the injection site in smaller number and over shorter distances (0.2 mm). The majority of migrating cells in ischemic rats had a neuronal phenotype. Migrating cells between the graft and the lesion expressed the neuroblast marker doublecortin, whereas human cells at the lesion border expressed the immature neuronal marker beta-tubulin, although a small percentage of cells at the lesion border also expressed glial fibrillary acid protein (GFAP). Thus, transplanted human CNS (hCNS)-derived neurospheres survived robustly in naive and ischemic brains, and the microenvironment influenced their migration and fate.

Glutathione peroxidase overexpression inhibits cytochrome C release and proapoptotic mediators to protect neurons from experimental stroke.

BACKGROUND AND PURPOSE: Ischemic injury and reperfusion increases superoxide (O2-) production and reduces the ability of neurons to scavenge free radicals, leading to the release of cytochrome c and apoptosis. Here we test whether overexpression with the use of gene therapy of the antioxidant glutathione peroxidase (Gpx), delivered before or after experimental stroke, is protective against ischemic injury. METHODS: Sixty-two rats underwent middle cerebral artery occlusion for 1 hour. Defective herpes simplex viral vectors expressing Gpx/lacZ or lacZ alone (control) were delivered into each striatum 12 hours before or 2 or 5 hours after ischemia onset. RESULTS: Striatal neuron survival at 2 days was improved by 36% when Gpx was delivered 12 hours before ischemia onset, 26% with a 2-hour delay, and 25% when delayed 5 hours. After ischemia, Gpx overexpression significantly reduced cytosolic translocation of cytochrome c and increased the proportion of Bcl-2-positive cells compared with cells transfected with control vector. Bax and activated caspase-3, while present in control-transfected neurons after ischemia, were rarely noted in Gpx-transfected cells. CONCLUSIONS: Expression from these herpes simplex viral vectors begins 4 to 6 hours after injection, which suggests a 9- to 11-hour temporal therapeutic window for Gpx. This is the first study to show that overexpression of Gpx with the use of gene therapy protects against experimental stroke, even with postischemic transfection, and the neuroprotective mechanism involves attenuation of apoptosis-related events.

Parent vessel occlusion for vertebrobasilar fusiform and dissecting aneurysms.

BACKGROUND AND PURPOSE: Previous reports of outcome with permanent vessel occlusion (PVO) for large, giant, or fusiform aneurysms in the posterior circulation have been limited. We undertook this study to evaluate the perioperative (within 30 days) and follow-up outcomes for patients treated with permanent occlusion of the vertebral artery for vertebrobasilar fusiform and dissecting aneurysms. METHODS: Thirteen consecutive patients were studied. Two groups were defined for the study. Group I patients underwent PVO to achieve complete thrombosis of the aneurysm. Group II patients underwent PVO to reduce flow to the aneurysm where complete thrombosis was not desirable. Modified Rankin scores were obtained at presentation and at follow-up (follow-up range, 1-76 months; mean, 22.0 months). RESULTS: All group I aneurysms were shown to be thrombosed on the angiograms obtained at the immediate follow-up examinations. Improvement in outcome scores was achieved by all group I patients. Improvement in Rankin scores after endovascular treatment was statistically significant (P =.026). All group II patients had complete occlusion of the vertebral artery; however, continued filling of the fusiform aneurysm was still observed. Four patients in group II died during the follow-up period. Two of these deaths were attributable to the aneurysms. Of the remaining three patients, two experienced clinical worsening and one remained stable. CONCLUSION: In this series, PVO for chronic fusiform and acute dissecting aneurysms of the vertebrobasilar system proved to be a useful therapeutic endovascular technique. Long-term outcomes suggest that patients with aneurysms involving only one vertebral artery, where complete thrombosis can be achieved, have better clinical outcomes than those who have aneurysms involving the basilar artery or both vertebral arteries, where complete thrombosis cannot achieved by using PVO.

Mild hypothermia increases Bcl-2 protein expression following global cerebral ischemia.

Mild hypothermia protects the brain against experimental ischemia, but the reasons are not well known. We examined whether the protective effects of mild hypothermia could be correlated with alterations in expression of Bcl-2, an anti-apoptotic protein in a rat model of transient global ischemia. Following 10 min of forebrain ischemia, hippocampal neurons were examined 72 h later for survival, expression of Bcl-2 family proteins and apoptosis. Intraischemic mild hypothermia was applied for 3 h (33 degrees C, isch-33) or normal body temperature was maintained (37 degrees C, isch-37). Survival of CA1 neurons was significantly improved in the isch-33 group compared to the isch-37 group (90 vs. 53% survival; P<0.01). The proportion of Bcl-2-positive cells among surviving CA1 neurons in the isch-33 group was increased compared to that of sham and isch-37 groups (P<0.01). Bax expression in CA1 was no different between sham and isch-33 groups, but was significantly decreased in isch-37 (P<0.05). TUNEL staining was positive in many isch-37 CA1 neurons, but absent in isch-33. Utilizing electron microscopy, more cells meeting criteria for apoptosis were observed in the isch-37 than isch-33. These data suggest that mild hypothermia attenuates apoptotic death, and that this protection may be related to increases in Bcl-2.

Overexpression of HSP72 after induction of experimental stroke protects neurons from ischemic damage.

The 72-kD inducible heat shock protein (HSP72) can attenuate cerebral ischemic injury when overexpressed before ischemia onset. Whether HSP72 overexpression is protective when applied after ischemia onset is not known, but would have important clinical implications. Fifty-seven rats underwent middle cerebral artery occlusion for 1 hour. Defective herpes simplex viral (HSV) vectors expressing hsp72 with lacZ as a reporter were delivered 0.5, 2, and 5 hours after ischemia onset into each striatum. Control animals received an identical vector containing only lacZ. Striatal neuron survival at 2 days was improved by 23% and 15% when HSP72 vectors were delayed 0.5 and 2 hours after ischemic onset, respectively ( P < 0.05). However, when delayed by 5 hours, HSP72 overexpression was no longer protective. This is the first demonstration that HSP72 gene transfer even after ischemia onset is neuroprotective. Because expression from these HSV vectors begins 4 to 6 hours after injection, this suggests that the temporal therapeutic window for HSP72 is at least 6 hours after ischemia onset. Future strategies aimed at enhancing HSP72 expression after clinical stroke may be worth pursuing. The authors suggest that in the future HSP72 may be an effective treatment for stroke.

Familial trigeminal neuralgia. Case report and review of the literature.

The authors report the case of a 45-year-old woman with medically intractable trigeminal neuralgia (TN) in whom a good clinical response to partial sectioning of the trigeminal nerve was attained. No evidence of vascular compression was found intraoperatively. Several other members of her family, involving three generations, also suffered from TN. The treatment of all affected patients is discussed in the context of a literature review in which the controversies surrounding the origins of the disease and treatment options for patients with the familial variant of TN are addressed.

Hyperperfusion syndrome with hemorrhage after angioplasty for middle cerebral artery stenosis.

Hyperperfusion syndrome is a well-documented complication of carotid endarterectomy, as well as internal carotid artery angioplasty and stent placement. We report a similar complication after distal intracranial (middle cerebral artery [MCA] M2 segment) angioplasty. To our knowledge, this is the first report of hyperperfusion syndrome after intracranial angioplasty of a distal MCA branch.

Imaging of cerebral and brain stem amyloidomas.

CNS amyloidomas are rare. We describe a 51-year-old man with isolated amyloidomas in the cerebral white matter and in the pons. CT and MR imaging showed a heterogeneous, enhancing mass in the deep cerebral white matter. A second, much smaller linear serpiginous lesion was present in the pons.

Gene therapy for treatment of cerebral ischemia using defective herpes simplex viral vectors.

Significant advances have been made over the past few years concerning the cellular and molecular events underlying neuron death. Recently, it is becoming increasingly clear that some of the genes induced during cerebral ischemia may actually serve to rescue the cell from death. However, the injured cell may not be capable of expressing protein at levels high enough to be protective. One of the most exciting arenas of such interventions is the use of viral vectors to deliver potentially neuroprotective genes at high levels. Neurotrophic herpes simplex viral strains are an obvious choice for gene therapy to the brain, and we have utilized bipromoter vectors that are capable of transferring various genes to neurons. Using this system in experimental models of stroke, cardiac arrest and excitotoxicity, we have found that it is possible to enhance neuron survival against such cerebral insults by over-expressing genes that target various facets of injury. These include energy restoration by the glucose transporter (GLUT-1), buffering calcium excess by calbindin, preventing protein malfolding or aggregation by stress proteins and inhibiting apoptotic death by BCL-2. We show that in some cases, gene therapy is also effective after the onset of injury, and also address whether successful gene therapy necessarily spares function. Although gene therapy is limited to the few hundred cells the vector is capable of transfecting, we consider the possibility of such gene therapy becoming relevant to clinical neurology in the future.

Gene therapy for treatment of cerebral ischemia using defective herpes simplex viral vectors.

Significant advances have been made over the past few years concerning the cellular and molecular events underlying neuron death. Recently, it is becoming increasingly clear that some of genes induced during cerebral ischemia may actually serve to rescue the cell from death. However, the injured cell may not be capable of expressing protein at high enough levels to be protective. One of the most exciting arenas of such interventions is the use of viral vectors to deliver potentially neuroprotective genes at high levels. Neurotropic herpes simplex viral (HSV) strains are an obvious choice for gene therapy to the brain, and we have used bipromoter vectors that are capable of transferring various genes to neurons. Using this system in experimental models of stroke, cardiac arrest, and excitotoxicity, we have found that it is possible to enhance neuron survival against such cerebral insults by overexpressing genes that target various facets of injury. These include energy restoration by the glucose transporter (GLUT-1), buffering calcium excess by calbindin, preventing protein malfolding or aggregation by stress proteins and inhibiting apoptotic death by BCL-2. We show that in some cases, gene therapy is also effective after the onset of injury, and also address whether successful gene therapy necessarily spares function. Although gene therapy is limited to the few hundred cells the vector is capable of transfecting, we consider the possibility of such gene therapy becoming relevant to clinical neurology in the future.