Survival and clinical outcomes of patients with melanoma brain metastasis in the era of checkpoint inhibitors and targeted therapies.

BACKGROUND: Melanoma brain metastasis is associated with an extremely poor prognosis, with a median overall survival of 4-5 months. Since 2011, the overall survival of patients with stage IV melanoma has been significantly improved with the advent of new targeted therapies and checkpoint inhibitors. We analyze the survival outcomes of patients diagnosed with brain metastasis after the introduction of these novel drugs. METHODS: We performed a retrospective analysis of our melanoma center database and identified 79 patients with brain metastasis between 2011 and 2015. RESULTS: The median time from primary melanoma diagnosis to brain metastasis was 3.2 years. The median overall survival duration from the time of initial brain metastasis was 12.8 months. Following a diagnosis of brain metastasis, 39 (49.4%), 28 (35.4%), and 24 (30.4%) patients were treated with anti-CTLA-4 antibody, anti-PD-1 antibody, or BRAF inhibitors (with or without a MEK inhibitor), with a median overall survival of 19.2 months, 37.9 months and 12.7 months, respectively. Factors associated with significantly reduced overall survival included male sex, cerebellar metastasis, higher number of brain lesions, and treatment with whole-brain radiation therapy. Factors associated with significantly longer overall survival included treatment with craniotomy, stereotactic radiosurgery, or with anti-PD-1 antibody after initial diagnosis of brain metastasis. CONCLUSIONS: These results show a significant improvement in the overall survival of patients with melanoma brain metastasis in the era of novel therapies. In addition, they suggest the activity of anti-PD-1 therapy specifically in the setting of brain metastasis.

The Unusual Presentation of a Myxoma Within the Sphenoid Sinus: Case Report and Review of the Literature.

BACKGROUND: We describe a rare case of a sphenoid sinus myxoma that was resected via an endoscopic endonasal skull base approach. We review the literature regarding these rare tumors of the paranasal sinuses. CASE DESCRIPTION: A 72-year-old woman was diagnosed with an incidental sphenoid sinus tumor and left sphenoid wing meningioma during a workup for left-sided proptosis and diplopia. Biopsies of the sphenoid wing and sphenoid sinus tumors were obtained. After undergoing surgical resection of the meningioma, the patient then underwent definitive resection of the sphenoid sinus myxoma via endoscopic endonasal skull base approach. Postoperative imaging demonstrated a gross total resection. The patient suffered postoperative thromboembolic complications due to underlying hypercoagulable state but made a complete recovery and returned to her neurologic baseline. There has been no evidence of recurrent myxoma in the sphenoid sinus 24 months after surgery. DISCUSSION: Myxomas are benign tumors derived from primitive mesenchyme. Myxomas very rarely present in the paranasal or skull base location. Complete surgical resection is the primary treatment for these tumors. The endoscopic endonasal approach is an effective technique for resecting various benign and more aggressive extradural skull base tumors. CONCLUSIONS: Myxomas of the sphenoid sinus are rare. The endoscopic endonasal skull base approach is an effective and minimal access technique for resection of this rare tumor of the sphenoid sinus.

Preoperative catheter spinal angiography and embolization of cervical spinal tumors: Outcomes from a single center.

OBJECTIVE: The existing literature regarding preoperative cervical spinal tumor embolization is sparse, with few discussions on the indications, risks, and best techniques. We present our experience with the preoperative endovascular management of hypervascular cervical spinal tumors. METHODS: We performed a retrospective review of all patients who underwent preoperative spinal angiography (regardless of whether tumor embolization was performed) at our institution (from 2002 to 2012) for primary and metastatic cervical spinal tumors. Tumor vascularity was graded from 0 (tumor blush equal to the normal adjacent vertebral body) to 3 (intense tumor blush with arteriovenous shunting). Tumors were considered "hypervascular" if they had a tumor vascular grade from 1 to 3. Embolic materials included particles, liquid embolics, and detachable coils. The main embolization technique was superselective catheterization of an arterial tumor feeder followed by injection of embolic material. This technique could be used alone or supplemented with occlusion of dangerous anastomoses of the vertebral artery as needed to prevent inadvertent embolization of the vertebrobasilar system. In cases when superselective catheterization of the tumoral feeder was not feasible, embolization was performed from a proximal catheter position after occlusion of branches supplying areas other than the tumor ("flow diversion"). RESULTS: A total of 47 patients with 49 cervical spinal tumors were included in this study. Of the 49 total tumors, 41 demonstrated increased vascularity (vascularity score > 0). The most common tumor pathology in our series was renal cell carcinoma (RCC) (N = 16; 32.7% of all tumors) followed by thyroid carcinoma (N = 7; 14.3% of all tumors).Tumor embolization was undertaken in 25 hypervascular tumors resulting in complete, near-complete, and partial embolization in 36.0% (N = 9), 44.0% (N = 11), and 20.0% (N = 5) of embolized tumors, respectively. We embolized 42 tumor feeders in 25 tumors. The most commonly embolized tumor feeders were branches of the vertebral artery (19.0%; N = 8), the deep cervical artery (19.0%; N = 8), and the ascending cervical artery (19.0%; N = 8). Sixteen hypervascular tumors were not embolized because of minimal hypervascularity (8/16), unacceptably high risk of spinal cord or vertebrobasilar ischemia (4/16), failed superselective catheterization of tumor feeder (3/16), and cancellation of surgery (1/16). Vertebral artery occlusion was performed in 20% of embolizations. There were no new post-procedure neurological deficits or any serious adverse events. Estimated blood loss data from this cohort show a significant decrease in operative blood loss for embolized tumors of moderate and significant hypervascularity. CONCLUSIONS: Preoperative embolization of cervical spinal tumors can be performed safely and effectively in centers with significant experience and a standardized approach.

Meningoencephalitis associated with passive immunization of a transgenic murine model of Alzheimer's amyloidosis.

Immunization against the Abeta peptide reverses the pathologic and behavioral manifestations of Alzheimer's disease in murine models. Since active immunization is associated with an autoimmune meningoencephalitis in a subset of humans, passive transfer of anti-Abeta immunoglobulin is being pursued as a potentially safer alternative. We have identified cases of meningoencephalitis subsequent to peripheral and intracerebral passive immunization of Tg2576 mice. The vasocentric mononuclear infiltrate localized only to brain regions affected by Abeta amyloid deposits suggesting that the inflammatory reaction was Abeta specific. This report indicates that current passive immunization in humans should proceed with careful regard for autoimmune complications.

Multi-institutional neurosurgical training initiative at a tertiary referral center in Mwanza, Tanzania: where we are after 2 years.

BACKGROUND: The paucity of neurosurgical care in East Africa remains largely unaddressed. A sustained investment in local health infrastructures and staff training is needed to create an independent surgical capacity. The Madaktari organization has addressed this issue by starting initiatives to train local general surgeons and assistant medical officers in basic neurosurgical procedures. We report illustrative cases since beginning of the program in Mwanza in 2009 and focus on the most recent training period. METHODS: A multi-institutional neurosurgical training program and a surgical database was created at a tertiary referral center in Mwanza, Tanzania. We collected clinical data on consecutive patients who underwent a neurosurgical procedure between September 9th and December 1st, 2011. All procedures were performed by a local surgeon under the supervision of a visiting neurosurgeon. Since the inception of the training initiative, comprehensive multidisciplinary training courses in Tanzania and an annual visiting fellowship for East African surgeons to travel to a major U.S. medical center have been established. RESULTS: At initial visits infrastructure and feasibility of complex case scenarios was assessed. Surgeries for brain tumors and complex spinal cases were performed. During the 3-month training period, 62 patients underwent surgery. Pediatric hydrocephalus comprised 52% of patients, 11% suffered from meningomyelocelia, and 6% presented with an encephalocele. A total of 24% of patients were treated for trauma-related conditions, representing 75% of the adult patients. A total of 10% of patients had surgery because of traumatic spine injury, and 15% of operations were on patients with severe head injury. A total of 6% of patients presented with degenerative spine disease. One patient sustained a fatal perioperative complication. At the end of the training period, the local general surgeon was able to perform all basic neurosurgical cases independently. CONCLUSIONS: Neurosurgical care in Tanzania needs to address a diverse, unique disease burden. We found that local surgeons could be enabled to safely perform basic cranial and spinal neurosurgical procedures through immersive, 1-on-1 on-site collaborations, multidisciplinary courses, and educational visiting fellowships.

Anterior cervical discectomy and fusion with a zero-profile integrated plate and spacer device: a clinical and radiological study: Clinical article.

OBJECT: Anterior cervical plating decreases the risk of pseudarthrosis following anterior cervical discectomy and fusion (ACDF). Dysphagia is a common complication of ACDF, with the anterior plate implicated as a potential contributor. A zero-profile, stand-alone polyetheretherketone (PEEK) interbody spacer has been postulated to minimize soft-tissue irritation and postoperative dysphagia, but studies are limited. The object of the present study was to determine the clinical and radiological outcomes for patients who underwent ACDF using a zero-profile integrated plate and spacer device, with a focus on the course of postoperative prevertebral soft-tissue thickness and the incidence of dysphagia. METHODS: Using a surgical database, the authors conducted a retrospective analysis of all patients who had undergone ACDF between August 2008 and October 2011. All patients received a Zero-P implant (DePuy Synthes Spine). The Neck Disability Index (NDI) and visual analog scale (VAS) scores for arm and neck pain were documented. Dysphagia was determined using the Bazaz criteria. Prevertebral soft-tissue thickness, spinal alignment, and subsidence were assessed as well. RESULTS: Twenty-two male and 19 female consecutive patients, with a mean age of 58.4 ± 14.68, underwent ACDF (66 total operated levels) in the defined study period. The mean clinical follow-up in 36 patients was 18.6 ± 9.93 months. Radiological outcome in 37 patients was assessed at a mean follow-up of 9.76 months (range 7.2-19.7 months). There were significant improvements in neck and arm VAS scores and the NDI following surgery. The neck VAS score improved from a median of 6 (range 0-10) to 0 (range 0-8; p < 0.001). The arm VAS score improved from a median of 2 (range 0-10) to 0 (range 0-7; p = 0.006). Immediate postoperative dysphagia was experienced by 58.4% of all patients. Complete resolution was demonstrated in 87.8% of affected patients at the latest follow-up. The overall median Bazaz score decreased from 1 (range 0-3) immediately postoperatively to 0 (range 0-2; p < 0.001) at the latest follow-up. Prevertebral soft-tissue thickness significantly decreased across all levels from a mean of 15.8 ± 4.38 mm to 10.1 ± 2.93 mm. Postoperative lordosis was maintained at the latest follow-up. Mean subsidence from the immediate postoperative to the latest follow-up was 4.1 ± 4.7 mm (p < 0.001). Radiographic fusion was achieved in 92.6% of implants. No correlation was found between prevertebral soft-tissue thickness and Bazaz dysphagia score. CONCLUSIONS: A zero-profile integrated plate and spacer device for ACDF surgery produces clinical and radiological outcomes that are comparable to those for nonintegrated plate and spacer constructs. Chronic dysphagia rates are comparable to or better than those for previously published case series.

The transplanum transtuberculum approaches for suprasellar and sellar-suprasellar lesions: avoidance of cerebrospinal fluid leak and lessons learned.

OBJECTIVE: To present a large series of patients and examine the learning curve of the endonasal endoscopic transplanum, transtuberculum approach for primarily suprasellar or sellar-suprasellar tumors. METHODS: We identified 122 patients who underwent 126 surgeries using the transplanum, transtuberculum approach. Extent of resection was determined with volumetric analysis of magnetic resonance imagings. Results concerning vision, endocrine function, and complications were noted. RESULTS: Average tumor volume was 14 cm(3). The most frequent pathologies were pituitary macroadenoma (51.6%), craniopharyngioma (20.6%), and meningioma (15.9%). A total of 73% patients presented with visual compromise. Rates of gross total resection (GTR) and near total resection for the group as a whole were 58.1% and 13.7%, and for the patients in whom GTR was intended (n = 90), rates of GTR and near total resection were 77.5% and 12.5% for a total of 90%. Extent of resection in this group was 97.6%. Vision improved in 52.4% and deteriorated in 4.8%. Favorable endocrine outcome occurred in 63.5%. The cerebrospinal fluid leak rate was 3.1% for the series as a whole. It improved from 6.3% in the first half of the series to 0 in the second half. Leak rates varied with technique from 11% (fat graft only) to 4.2% (gasket seal only) to 1.8% (fat plus nasoseptal flap) to 0 (gasket plus nasoseptal flap). The rate of other complications was 14.3% in the first half of the series and 1.6% in the second half. There was one infection (0.8%). CONCLUSIONS: The endonasal endoscopic transtuberculum transplanum approach is a safe and effective minimal access approach to midline pathology in the suprasellar cistern.

Fusion of intraoperative three-dimensional rotational angiography and flat-panel detector computed tomography for cerebrovascular neuronavigation.

OBJECTIVE: We introduce a technique that uses intraoperative flat-panel detector computed tomography (FD-CT) and three-dimensional rotational angiography (3D-RA) acquired in the hybrid operative suite to provide full neuronavigation capabilities during cerebrovascular surgery without the use of preoperative imaging studies. METHODS: An Artis Zeego FD system (Siemens AG, Forchheim, Germany), mounted on a robotic C-arm was used during the clipping of an aneurysm to acquire intraoperative FD-CT and 3D-RA images. These images were then fused via the use of BrainLab iPlan 3.0 software and sent to a Vector Vision Sky neuronavigation system (NNS; BrainLAB, Heimstetten, Germany) to provide intraoperative image guidance. RESULTS: The use of intraoperative FD-CT and 3D-RA with a NNS allowed for accurate visualization of the vascular anatomy and localization of pathology. In a case of a patient harboring two aneurysms, one that was surgically clipped and a second that was treated endovascularly, the 3D-RA clearly showed neck remnants at both aneurysms. Use of the NNS assisted in further clip placement for obliteration of these neck remnants. CONCLUSIONS: Hybrid operating suites equipped with FD-CT, 3D-RA, and NNS capabilities can be used to provide intraoperative 3D image guidance during cerebrovascular surgery with excellent accuracy and without the need for preoperative angiography. Furthermore, this technique required less than 15 minutes for image acquisition and utilizes digitally subtracted angiographic images that are superior to conventional CT or MRI for the imaging of cerebrovascular pathology.

Balloon-assisted coil embolization of intracranial aneurysms is not associated with increased periprocedural complications.

BACKGROUND: The balloon-assisted coil embolization (BACE) technique represents an effective tool for the treatment of complex wide-necked intracranial aneurysms; however, its safety is a matter of debate. This study presents the authors' institutional experience regarding the safety of the BACE technique. METHODS: 428 consecutive patients with 491 intracranial aneurysms (274 acutely ruptured and 217 unruptured) treated with conventional coil embolization (CCE) or with BACE were retrospectively reviewed. All procedure-related adverse events were reported, regardless of clinical outcome. Thromboembolic events, intraprocedural aneurysm ruptures, device-related complications, morbidity and mortality were compared between the CCE and BACE groups. RESULTS: The total rate of procedural and periprocedural adverse events was 9.6% (47/491 embolizations). Thromboembolic events, intraprocedural aneurysmal rupture and device-related complications occurred in 2.4%, 3.9% and 3.3% of procedures, respectively. The risk of thromboembolic events and device-related problems was similar between the CCE and BACE groups. A trend towards a higher risk of intraprocedural aneurysm rupture was observed in the BACE group (not statistically significant). The total cumulative morbidity and mortality for both groups was 2.6% (11/428 patients) and there was no statistically significant difference in the morbidity, mortality and cumulative morbidity and mortality rates between the two groups. CONCLUSION: In this series of patients with acutely ruptured and unruptured aneurysms, the BACE technique allowed treatment of aneurysms with unfavorable anatomic characteristics without increasing the incidence of procedural complications.

Preoperative embolization of hypervascular thoracic, lumbar, and sacral spinal column tumors: technique and outcomes from a single center.

The existing literature on preoperative spine tumor embolization is limited in size of patient cohorts and diversity of tumor histologies. This report presents our experience with preoperative embolization of hypervascular thoracic, lumbar, and sacral spinal column tumors in the largest series to date. We conducted a retrospective review of 228 angiograms and 188 pre-operative embolizations for tumors involving thoracic, lumbar and sacral spinal column. Tumor vascularity was evaluated with conventional spinal angiography and was graded from 0 (same as normal adjacent vertebral body) to 3 (severe tumor blush with arteriovenous shunting). Embolic materials included poly vinyl alcohol (PVA) particles and detachable platinum coils and rarely, liquid embolics. The degree of embolization was graded as complete, near-complete, or partial. Anesthesia records were reviewed to document blood loss during surgery. Renal cell carcinoma (44.2%), thyroid carcinoma (9.2%), and leiomyosarcoma (6.6%) were the most common tumors out of a total of 40 tumor histologies. Hemangiopericytoma had the highest mean vascularity (2.6) of all tumor types with at least five representative cases followed by renal cell carcinoma (2.0) and thyroid carcinoma (2.0). PVA particles were used in 100% of cases. Detachable platinum coils were used in 51.6% of cases. Complete, near-complete, and partial embolizations were achieved in 86.1%, 12.7%, and 1.2% of all cases, respectively. There were no new post-procedure neurologic deficits or other complications with long-term morbidity. The mean intra-operative blood loss for the hypervascular tumors treated with pre-operative embolization was 1745 cc. Preoperative embolization of hypervascular thoracic, lumbar, and sacral spine tumors can be performed with high success rates and a high degree of safety at high volume centers.

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.

Spreading depolarization: a possible new culprit in the delayed cerebral ischemia of subarachnoid hemorrhage.

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease with a high mortality and morbidity rate. Gradual improvements have been made in the reduction of mortality rates associated with the disease during the last 30 years. However, delayed cerebral ischemia (DCI), the major delayed complication of SAH, remains a significant contributor to mortality and morbidity despite substantial research and clinical efforts. During the last several years, the predominant role of cerebral vasospasm, the long-accepted etiologic factor behind DCI, has been questioned. It is now becoming increasingly clear that the pathophysiology underlying DCI is multifactorial. Cortical spreading depression is emerging as a likely factor in this complex web of pathologic changes after SAH. Understanding its role after SAH and its relationship with the other pathologic processes such as vasospasm, microcirculatory dysfunction, and microemboli will be vital to the development of new therapeutic approaches to reduce DCI and improve the clinical outcome of the disease.

Management of acute cervical compression fractures in two patients with osteogenesis imperfecta.

STUDY DESIGN: We report 2 cases of acute cervical compression fracture in patients with osteogenesis imperfecta (OI). In case 1, a 15-year-old girl with an acute C6 compression fracture and additional fractures of the posterior elements underwent a C6 corpectomy and instrumented posterior fusion. In case 2, a 46-year-old man with a C7 compression fracture was managed nonoperatively. OBJECTIVE: To illustrate a subset of possible acute subaxial cervical fractures in OI patients and to describe the feasibility of performing a combined anterior/posterior cervical decompression and fusion in an OI patient. SUMMARY OF BACKGROUND DATA: OI is a rare genetic collagen disorder that is characterized by bone fragility and ligamentous laxity. Spinal complications associated with this disease included scoliosis, thoracolumbar compression fractures, and other spinal fractures, cervical spondyloptosis, and basilar invagination. There is limited literature that addresses the management of acute cervical spine fractures in OI patients. METHODS: In case 1, the patient was initially treated with a Minerva brace. Nonoperative management was abandoned when a progressive kyphotic deformity developed. A C6 corpectomy and placement of a fibular strut allograft was followed by a C4-C7 posterior fusion with sublaminar wiring and rods. In case 2, the patient was managed nonoperatively with a rigid cervical collar alone. RESULTS: In case 1, the patient made a prompt recovery, and on 12-month follow-up has maintained alignment. In case 2, the patient maintained normal alignment without need for surgical intervention. CONCLUSION: A combined anterior/posterior decompression and fusion of the subaxial cervical spine is feasible in the fragile OI population. Moreover, certain isolated compression fractures of the subaxial cervical spine in this same patient population may be managed nonoperatively.

Endonasal endoscopic resection of an os odontoideum to decompress the cervicomedullary junction: a minimal access surgical technique.

STUDY DESIGN: We report the case of a 50 year-old woman with os odontoideum and posterior atlantoaxial subluxation, who underwent an occipitocervical fusion followed by endonasal endoscopic anterior decompression of the cervicomedullary junction (CMJ). OBJECTIVE: To describe the feasibility of performing endonasal endoscopic anterior decompression of CMJ pathology in conjunction with occipitocervical fusion in 1 operative setting. SUMMARY OF BACKGROUND DATA: The recommended management of symptomatic atlantoaxial instability secondary to os odontoideum with irreducible ventral compression is occipitocervical fusion with anterior decompression. The traditional method for anterior decompression of CMJ abnormalities is the transoral approach. The endonasal endoscopic approach is an emerging minimal access technique that reduces the potential morbidity of the transoral approach. METHODS: The patient underwent an occipitocervical fusion and anterior decompression in 1 operative setting. Occiput to C5 fusion was first undertaken in the prone position. After a wake-up test, the patient was flipped into a supine position for the endonasal endoscopic procedure. Anterior decompression was achieved by resecting the anterior arch of C1 and the os odontoideum with the aid of frameless stereotactic navigation. RESULTS: The patient tolerated the procedure well and was extubated on the first postoperative day. Liquids were started that afternoon and advanced to a regular diet on the second postoperative day. The patient was discharged to rehabilitation after a short postoperative stay. Postoperative imaging demonstrated excellent decompression of the anterior CMJ pathology. At 3-month follow-up, the patient showed clear improvements in hand strength and ability to ambulate. CONCLUSION: The endonasal endoscopic approach to the CMJ provides an effective and minimally invasive alternative for anterior decompression of irreducible CMJ pathology.

"Gasket-seal" watertight closure in minimal-access endoscopic cranial base surgery.

OBJECTIVE: Transnasal endoscopic cranial base surgery is a novel minimal-access method for reaching the midline cranial base. Postoperative cerebrospinal fluid leak remains a persistent challenge. A new method for watertight closure of the anterior cranial base is presented. METHODS: To achieve watertight closure of the anterior cranial base, autologous fascia lata was used to create a "gasket seal" around a bone buttress, followed by application of a tissue sealant such as DuraSeal (Confluent Surgical, Inc., Waltham, MA). The gasket-seal closure was used to seal the anterior cranial base in a series of 10 patients with intradural surgery for suprasellar craniopharyngiomas (n = 5), planum meningiomas (n = 3), clival chordoma (n = 1), and recurrent iatrogenic cerebrospinal fluid leak (n = 1). Lumbar drains were placed intraoperatively in five patients and remained in place for 3 days postoperatively. RESULTS: After a mean follow-up period of 12 months, there were no cerebrospinal fluid leaks. CONCLUSION: The gasket-seal closure is an effective method for achieving watertight closure of the anterior cranial base after endoscopic intradural surgery.

Targeting amyloid-beta peptide (Abeta) oligomers by passive immunization with a conformation-selective monoclonal antibody improves learning and memory in Abeta precursor protein (APP) transgenic mice.

Passive immunization of murine models of Alzheimer disease amyloidosis reduces amyloid-beta peptide (Abeta) levels and improves cognitive function. To specifically address the role of Abeta oligomers in learning and memory, we generated a novel monoclonal antibody, NAB61, that preferentially recognizes a conformational epitope present in dimeric, small oligomeric, and higher order Abeta structures but not full-length amyloid-beta precursor protein or C-terminal amyloid-beta precursor protein fragments. NAB61 also recognized a subset of brain Abeta deposits, preferentially mature senile plaques, and amyloid angiopathy. Using NAB61 as immunotherapy, we showed that aged Tg2576 transgenic mice treated with NAB61 displayed significant improvements in spatial learning and memory relative to control mice. These data implicated Abeta oligomers as a pathologic substrate for cognitive decline in Alzheimer disease.

Impaired rapid eye movement sleep in the Tg2576 APP murine model of Alzheimer's disease with injury to pedunculopontine cholinergic neurons.

Impaired rapid eye movement sleep (REMS) is commonly observed in Alzheimer's disease, suggesting injury to mesopontine cholinergic neurons. We sought to determine whether abnormal beta-amyloid peptides impair REMS and injure mesopontine cholinergic neurons in transgenic (hAPP695.SWE) mice (Tg2576) that model brain amyloid pathologies. Tg2576 mice and wild-type littermates were studied at 2, 6, and 12 months by using sleep recordings, contextual fear conditioning, and immunohistochemistry. At 2 months of age, REMS was indistinguishable by genotype but was reduced in Tg2576 mice at 6 and 12 months. Choline acetyltransferase-positive neurons in the pedunculopontine tegmentum of Tg2576 mice at 2 months evidenced activated caspase-3 immunoreactivity, and at 6 and 12 months the numbers of pedunculopontine tegmentum choline acetyltransferase-positive neurons were reduced in the Tg2576 mice. Other cholinergic groups involved in REMS were unperturbed. At 12 months, Tg2576 mice demonstrated increased 3-nitrotyrosine immunoreactivity in cholinergic projection sites but not in cholinergic soma. We have identified a population of selectively compromised cholinergic neurons in young Tg2576 mice that manifest early onset REMS impairment. The differential vulnerability of these cholinergic neurons to Abeta injury provides an invaluable tool with which to understand mechanisms of sleep/wake perturbations in Alzheimer's disease.