Jeffrey P. Greenfield

Estrogen lowers Alzheimer β-amyloid generation by stimulating trans-Golgi network vesicle biogenesis

Estrogen reduces the risk of Alzheimers disease in post-menopausal women, β-amyloid (Aβ) burden in animal models of Alzheimers disease, and secretion of Aβ from neuronal cultures. The biological basis for these effects remains unknown. Here, utilizing cell-free systems derived from both neuroblastoma cells and primary neurons, we demonstrate that 17β-estradiol (17β-E2) stimulates formation of vesicles containing the β-amyloid precursor protein (βAPP) from the trans-Golgi network (TGN). Accelerated βAPP trafficking precludes maximal Aβ generation within the TGN. 17β-E2 appears to modulate TGN phospholipid levels, particularly those of phosphatidylinositol, and to recruit soluble trafficking factors, such as Rab11, to the TGN. Together, these results suggest that estrogen may exert its anti-Aβ effects by regulating βAPP trafficking within the late secretory pathway. These results suggest a novel mechanism through which 17β-E2 may act in estrogen-responsive tissues and illustrate how altering the kinetics of the transport of a protein can influence its metabolic fate.

Endoscopic, endonasal resection of craniopharyngiomas: analysis of outcome including extent of resection, cerebrospinal fluid leak, return to preoperative productivity, and body mass index.

BACKGROUND The endoscopic, endonasal, extended transsphenoidal approach is a minimal-access technique for managing craniopharyngiomas. Outcome measures such as return to employment and body mass index (BMI) have not been reported and are necessary for comparison with open transcranial approaches. Most prior reports of the endoscopic, endonasal approach have reported unacceptably high cerebrospinal fluid (CSF) leak rates. OBJECTIVE To assess the outcome of endoscopic, endonasal surgery in a consecutive series of craniopharyngiomas with special attention to extent of resection, CSF leak, return to employment, and BMI. METHODS Twenty-six surgeries were performed on 24 patients at Weill Cornell Medical College-New York Presbyterian Hospital. Five patients had recurrent lesions. Gross-total resection (GTR) was attempted in 21 surgeries. Indications for intended subtotal resection were advanced age, medical comorbidities, preservation of pituitary function, and hypothalamic invasion. RESULTS Mean tumor diameter was 2.9 cm. GTR (18 surgeries) or near-total (>95%) resection (2 surgeries) was achieved in 95% when GTR was the goal. Seven patients received postoperative radiation therapy. Mean follow-up was 35 months with no recurrences in GTR cases and stable disease in all patients at last follow-up. Vision improved in 77%. Diabetes insipidus and panhypopituitarism developed in 42% and 38%, respectively. A more than 9% increase in BMI occurred in 39%; 69% returned to their preoperative profession/schooling. The postoperative CSF leak rate was 3.8%. CONCLUSION Minimal-access, endoscopic, endonasal surgery for craniopharyngioma can achieve high rates of GTR with low rates of CSF leak. Return to employment and obesity rates are comparable to microscope-assisted transcranial and transsphenoidal reports.

Endoscopic endonasal transethmoidal transcribriform transfovea ethmoidalis approach to the anterior cranial fossa and skull base.

OBJECTIVEThe anterior skull base, in front of the sphenoid sinus, can be approached using a variety of techniques including extended subfrontal, transfacial, and craniofacial approaches. These methods include risks of brain retraction, contusion, cerebrospinal fluid leak, meningitis, and cosmetic deformity. An alternate and more direct approach is the endonasal, transethmoidal, transcribriform, transfovea ethmoidalis approach. METHODSAn endoscopic, endonasal approach was used to treat a variety of conditions of the anterior skull base arising in front of the sphenoid sinus and between the orbits in a series of 44 patients. A prospective database was used to detail the corridor of approach, closure technique, use of intraoperative lumbar drainage, operative time, and postoperative complications. Extent of resection was determined by a radiologist using volumetric analysis. RESULTSPathology included meningo/encephaloceles (19), benign tumors (14), malignant tumors (9), and infectious lesions (2). Lumbar drains were placed intraoperatively in 20 patients. The CSF leak rate was 6.8% for the whole series and 9% for intradural cases. Leaks were effectively managed with lumbar drainage. Early reoperation for cerebrospinal fluid (CSF) leak occurred in 1 patient (2.2%). There were no intracranial infections. Greater than 98% resection was achieved in 12 of 14 benign and 5 of 9 malignant tumors. CONCLUSIONThe endoscopic, endonasal, transethmoidal, transcribriform, transfovea ethmoidalis approach is versatile and suitable for managing a variety of pathological entities. This minimal access surgery is a feasible alternative to transcranial, transfacial, or combined craniofacial approaches to the anterior skull base and anterior cranial fossa in front of the sphenoid sinus. The risk of CSF leak and infection are reasonably low and decrease with experience. Longer follow-up and larger series of patients will be required to validate the long-term efficacy of this minimally invasive approach.

Endonasal endoscopic resection of the odontoid process in a nonachondroplastic dwarf with juvenile rheumatoid arthritis: feasibility of the approach and utility of the intraoperative Iso-C three-dimensional navigation : Case report

The authors report a case of a nonachondroplastic dwarf with severe basilar invagination and compression of the cervicomedullary junction (CMJ) due to juvenile rheumatoid arthritis. Initially excellent reduction of the invagination and decompression of the CMJ was achieved using posterior fixation. However, 1 month postoperatively symptoms recurred and the authors found imaging evidence of recurrence as well. The patient subsequently underwent an endoscopic transnasal resection of the dens with assistance of Iso-C navigation. He recovered well and tolerated regular diet on postoperative Day 2.

Stereotactic Minimally Invasive Tubular Retractor System for Deep Brain Lesions

OBJECTIVE Deep-seated supratentorial intraparenchymal and intraventricular brain lesions can be difficult to access without causing significant trauma to the overlying cortex and intervening white matter tracts. Traditional brain retractors use multiple blades, which do not exert pressure in an equally distributed fashion. Tubular retractors offer an advantage. Although a commercially available frame-based tubular retractor system is on the market (COMPASS; Compass, Inc., Rochester, MN), we modified existing off-the-shelf equipment at our institution into a frameless tubular brain retractor. METHODS We used 14- to 22-mm METRx (Medtronic, Minneapolis, MN) tubular retractors in combination with a frameless stereotactic navigation system to remove 10 deep lesions. Histological findings included 6 periventricular metastases, 1 insular glioblastoma multiforme, 1 periventricular glioblastoma multiforme, 1 intraventricular meningioma, and 1 hippocampal cavernous malformation. RESULTS Radiographic gross total resection was achieved in all patients. One patient experienced a transient worsening of an existing preoperative Wernickes aphasia; otherwise, there were no intra- or postoperative complications. One patient with radiographic gross total resection of a metastatic lesion experienced a local recurrence of disease, requiring stereotactic radiosurgery. CONCLUSION A frameless stereotactic tubular retractor system for deep brain lesions can be assembled with equipment already available at many institutions. Use of this system can decrease incision and craniotomy size, decrease retractor-induced trauma to overlying cortex, and help prevent damage to underlying white matter tracts.

Vagus nerve stimulation vs. corpus callosotomy in the treatment of Lennox–Gastaut syndrome: A meta-analysis

PURPOSE Lennox-Gastaut syndrome (LGS) is an epileptogenic disorder that arises in childhood and is typically characterized by multiple seizure types, slow spike-and-wave complexes on EEG and cognitive impairment. If medical treatment fails, patients can proceed to one of two palliative surgeries, vagus nerve stimulation (VNS) or corpus callosotomy (CC). Their relative seizure control rates in LGS have not been well studied. The purpose of this paper is to compare seizure reduction rates between VNS and CC in LGS using meta-analyses of published data. METHODS A systematic search of Pubmed, Ovidsp, and Cochrane was performed to find articles that met the following criteria: (1) prospective or retrospective study, (2) at least one patient diagnosed with Lennox-Gastaut syndrome, and (3) well-defined measure of seizure frequency reduction. Seizure reduction rates were divided into seizure subtypes, as well as total seizures, and categorized as 100%, >75%, and >50%. Patient groups were compared using chi-square tests for categorical variables and t-test for continuous measures. Pooled proportions with 95% confidence interval (95% CI) of seizure outcomes were estimated for total seizures and seizure subtypes using random effects methods. RESULTS 17 VNS and 9 CC studies met the criteria for inclusion. CC had a significantly better outcome than VNS for >50% atonic seizure reduction (80.0% [67.0-90.0%] vs. 54.1% [32.1-75.4%], p<0.05) and for >75% atonic seizure reduction (70.0% [48.05-87.0%] vs. 26.3% [5.8-54.7%], p<0.05). All other seizure types, as well as total number of seizures, showed no statistically significant difference between VNS and CC. CONCLUSIONS CC may be more beneficial for LGS patients whose predominant disabling seizure type is atonic. For all other seizure types, VNS offers comparable rates to CC.

LONG-TERM EXPANSION OF ADULT HUMAN BRAIN SUBVENTRICULAR ZONE PRECURSORS

OBJECTIVEMany common neurosurgical procedures, including anterior temporal lobectomy and endoscopic ventricular puncture, allow neurosurgeons to retrieve portions of the germinal subventricular zone (SVZ). Isolation and maintenance of precursor cells from this zone can be used for hypothesis-driven experiments with a goal of improving our understanding of the basic mechanisms of central nervous system injury or disease and the potential of cell-based therapies to treat them. This article details our ability to reliably harvest, isolate, characterize, and maintain normal adult human brain SVZ precursor cells. METHODSNormal SVZ specimens were retrieved as part of anterior temporal lobe resections during planned epilepsy surgery. Dissociated SVZ specimens were plated and incubated in epidermal growth factor and basic fibroblast growth factor for more than 1 year to select for and expand normal neural precursor cells. RESULTSSelf-renewal and immunocytochemical experiments proved the feasibility of long-term expansion of a slowly dividing nestin+, vimentin+, and glial fibrillary acidic protein-positive astrocyte capable of generating new neurons and glia. These mitotically active bipotent human precursors generated a large number of progeny and possessed significant self-renewal capacity, demonstrated by their ability to generate neurospheres. Cryopreservation was reliable with no loss of the precursor phenotype. CONCLUSIONWe have adapted techniques to allow for the isolation and long-term propagation of human adult neural precursors that are capable of generating both neurons and astrocytes in vitro. We have exploited the cells self-renewal capacity to significantly and consistently expand human neural precursor cells for as long as 20 months. These findings suggest that cells derived from the SVZ during routine surgery may provide a renewable source of human neural precursor cells to study the biological mechanism of central nervous system disease or for application in cell-based human transplantation paradigms.

Age-Specific Cerebral Perfusion Pressure Thresholds and Survival in Children and Adolescents With Severe Traumatic Brain Injury

Objectives: Evidence-based traumatic brain injury guidelines support cerebral perfusion pressure thresholds for adults at a class 2 level, but evidence is lacking in younger patients. The purpose of this study is to identify the impact of age-specific cerebral perfusion pressure thresholds on short-term survival among patients with severe traumatic brain injury. Design: Institutional review board-approved, prospective, observational cohort study. Setting: Level I or II trauma centers in New York State. Patients: Data on all patients with a postresuscitation Glasgow Coma Score less than 9 were added in the Brain Trauma Foundation prospective New York State TBI-trac database. Measurements and Main Results: We calculated the survival rates and relative risks of mortality for patients with severe traumatic brain injury based on predefined age-specific cerebral perfusion pressure thresholds. A higher threshold and a lower threshold were defined for each age group: 60 and 50 mm Hg for 12 years old or older, 50 and 35 mm Hg for 6–11 years, and 40 and 30 mm Hg for 0–5 years. Patients were stratified into age groups of 0–11, 12–17, and 18 years old or older. Three exclusive groups of CPP-L (events below low cerebral perfusion pressure threshold), CPP-B (events between high and low cerebral perfusion pressure thresholds), and CPP-H (events above high cerebral perfusion pressure threshold) were defined. As an internal control, we evaluated the associations between cerebral perfusion pressure events and events of hypotension and elevated intracranial pressure. Survival was significantly higher in 0–11 and 18 years old or older age groups for patients with CPP-H events compared with those with CPP-L events. There was a significant decrease in survival with prolonged exposure to CPP-B events for the 0–11 and 18 years old and older age groups when compared with the patients with CPP-H events (p = 0.0001 and p = 0.042, respectively). There was also a significant decrease in survival with prolonged exposure to CPP-L events in all age groups compared with the patients with CPP-H events (p< 0.0001 for 0- to 11-yr olds, p = 0.0240 for 12- to 17-yr olds, and p < 0.0001 for 18-yr old and older age groups). The 12- to 17-year olds had a significantly higher likelihood of survival compared with adults with prolonged exposure to CPP-L events (< 50 mm Hg). CPP-L events were significantly related to systemic hypotension for the 12- to 17-year-old group (p = 0.004) and the 18-year-old and older group (p < 0.0001). CPP-B events were significantly related to systemic hypotension in the 0- to 11-year-old group (p = 0.014). CPP-B and CPP-L events were significantly related to elevated intracranial pressure in all age groups. Conclusions: Our data provide new evidence that cerebral perfusion pressure targets should be age specific. Furthermore, cerebral perfusion pressure goals above 50 or 60 mm Hg in adults, above 50 mm Hg in 6- to 17-year olds, and above 40 mm Hg in 0- to 5-year olds seem to be appropriate targets for treatment-based studies. Systemic hypotension had an inconsistent relationship to events of low cerebral perfusion pressure, whereas elevated intracranial pressure was significantly related to all low cerebral perfusion pressure events across all age groups. This may impart a clinically important difference in care, highlighting the necessity of controlling intracranial pressure at all times, while targeting systolic blood pressure in specific instances.

SURROGATE MARKERS PREDICT ANGIOGENIC POTENTIAL AND SURVIVAL IN PATIENTS WITH GLIOBLASTOMA MULTIFORME

OBJECTIVEThe neovascularization of malignant brain tumors is a poorly understood phenomenon. Radiographic and histological evidence of increased vascularity correlate with clinical grade of gliomas. However, a quantitative noninvasive assay to assess glioma vascularity and associated clinical aggressiveness has not been developed. Circulating endothelial progenitor cells are unique vascular precursors recruited from the bone marrow through the circulation to form new tumor blood vessels. These cells were measured in patients undergoing surgery for glioblastoma multiforme (GBM). We hypothesized that this might reflect the extent of tumor vascularity, predict prognosis, or be useful as an assay to assess response to antiangiogenesis therapies. In addition, we report on a novel in vitro assay to assess the proangiogenic activity within the plasma samples obtained from glioma patients. METHODSFifty-six patients with various-grade gliomas had peripheral venous blood collected at the time of surgery and at subsequent visits during the follow-up period. The blood was separated into plasma and cellular fractions. The plasma was utilized in a human umbilical vein endothelial cell-based angiogenic assay. The cellular fraction containing endothelial progenitor cells was isolated, and specific cellular phenotypes were immunologically separated and counted using flow cytometry. Pathological samples were reviewed at the time of initial resection, and each patients clinical course was monitored until the time of manuscript submission. RESULTSPlasma derived from peripheral blood of patients with GBM scored significantly higher on the functional angiogenic scale compared with plasma derived from patients with low-grade gliomas and from controls. In addition, all patients with GBM had measurable numbers of bone marrow-derived endothelial precursor cells coexpressing CD133 and vascular endothelial growth factor receptor 2 in their peripheral circulation at the time of tumor resection. These cells range from less than 0.1% to 1.6% of the entire circulating mononuclear white blood cell population, or approximately 200 000 cells in some patients. A statistically significant relationship was observed between the percentage of endothelial progenitor cells in the peripheral blood at the time of initial GBM resection and survival. CONCLUSIONThese studies suggest that plasma and circulating CD133+ vascular endothelial growth factor receptor 2+ proangiogenic cells are present in the peripheral blood of patients with glioma and can be used as a surrogate biomarker to measure tumor angiogenicity. These cells can be measured at the time of diagnosis and monitored in the postoperative period. These assays can be used to predict tumor aggressiveness. Also promising is their potential to identify patients with increased angiogenic activity who might respond maximally to antiangiogenesis therapies or to assess tumor response in patients using those therapies as the use of these adjuvant molecular modalities becomes more prevalent in neuro-oncology.

Cellular and molecular basis of beta-amyloid precursor protein metabolism.

In molecular neurobiology, perhaps no molecule has been as thoroughly examined as Alzheimers beta-amyloid precursor protein (betaAPP). In the ten years since the cDNA encoding betaAPP was cloned, the protein has been the subject of unparalleled scrutiny on all levels. From molecular genetics and cellular biology to neuroanatomy and epidemiology, no scientific discipline has been left unexplored - and with good reason. beta-amyloid (Abeta) is the main constituent of the amyloidogenic plaques which are a primary pathological hallmark of Alzheimers disease, and betaAPP is the protein from which Abeta is cleaved and released. Unraveling the molecular events underlying Abeta generation has been, and remains, of paramount importance to scientists in our field. In this review we will trace the progress that has been made in understanding the molecular and cellular basis of betaAPP trafficking and processing, or alternatively stated, the molecular basis for Abeta generation. Imperative to a complete understanding of Abeta generation is the delineation of its subcellular localization and the identification of proteins which play either direct or accessory roles in Abeta generation. We will focus on the regulation of betaAPP cleavage through diverse signal transduction mechanisms and discuss possible points of therapeutic intercession in what has been postulated to be a seminal molecular step in the cascade of events terminating in the onset of dementia, a loss of neurons, and tragically, eventual death from Alzheimers disease.