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The study of human individual differences has matured significantly, in the last decade or so owing, in part, to the notable advances in neuroimaging techniques. There are three major domains of inquiry within individual differences research: personality, creativity, and intelligence. Each has a discrete, testable definition (a new definition for intelligence is offered: rapid and accurate problem solving), and each has been associated with distinct brain regions and interactive networks. Here, we outline commonalities between these constructs, which appear to conform to two major axes: exploratory behavior and restraint. These axes, in turn, conform largely to two major brain networks dedicated to novelty generation (i.e. default mode network — DMN), and refinement of ideas (i.e. cognitive control network — CCN). Thus, human individual differences represent the expression of adaptive behaviors leading to exploratory and/or restrained action arising from brain structure and function.

Glioblastoma multiforme (GBM), the most common malignant brain tumor, universally carries a poor prognosis. Despite aggressive multimodality treatment, the median survival is ~18–20 months, depending on molecular subgroups. A long history of observations suggests antitumor effects of bacterial infections against malignant tumors. The present review summarizes and critically analyzes the clinical data providing evidence for or against the survival benefit of post-operative bacterial infections in GBM patients. Furthermore, we explore the probable underlying mechanism(s) from basic science studies on the topic. There are plausible explanations from immunobiology for the mechanism of the “favorable effect” of bacterial infections in GBM patients. However, available clinical literature does not provide a definitive association between postoperative bacterial infection and prolonged survival in GBM patients. The presently available, single-/multi-center and national database retrospective case-control studies on the topic provide conflicting results. A prospective randomized study on the subject is clearly not possible. Immunobiology literature supports development of genetically modified bacteria as part of multimodal regimen against GBM.

OBJECTIVE Greater extent of resection (EOR) is associated with longer overall survival in patients with high-grade gliomas (HGGs). 5-Aminolevulinic acid (5-ALA) can increase EOR by improving intraoperative visualization of contrast-enhancing tumor during fluorescence-guided surgery (FGS). When administered orally, 5-ALA is converted by glioma cells into protoporphyrin IX (PPIX), which fluoresces under blue 400-nm light. 5-ALA has been available for use in Europe since 2010, but only recently gained FDA approval as an intraoperative imaging agent for HGG tissue. In this first-ever, to the authors’ knowledge, multicenter 5-ALA FGS study conducted in the United States, the primary objectives were the following: 1) assess the diagnostic accuracy of 5-ALA–induced PPIX fluorescence for HGG histopathology across diverse centers and surgeons; and 2) assess the safety profile of 5-ALA FGS, with particular attention to neurological morbidity. METHODS This single-arm, multicenter, prospective study included adults aged 18–80 years with Karnofsky Performance Status (KPS) score > 60 and an MRI diagnosis of suspected new or recurrent resectable HGG. Intraoperatively, 3–5 samples per tumor were taken and their fluorescence status was recorded by the surgeon. Specimens were submitted for histopathological analysis. Patients were followed for 6 weeks postoperatively for adverse events, changes in the neurological exam, and KPS score. Multivariate analyses were performed of the outcomes of KPS decline, EOR, and residual enhancing tumor volume to identify predictive patient and intraoperative variables. RESULTS Sixty-nine patients underwent 5-ALA FGS, providing 275 tumor samples for analysis. PPIX fluorescence had a sensitivity of 96.5%, specificity of 29.4%, positive predictive value (PPV) for HGG histopathology of 95.4%, and diagnostic accuracy of 92.4%. Drug-related adverse events occurred at a rate of 22%. Serious adverse events due to intraoperative neurological injury, which may have resulted from FGS, occurred at a rate of 4.3%. There were 2 deaths unrelated to FGS. Compared to preoperative KPS scores, postoperative KPS scores were significantly lower at 48 hours and 2 weeks but were not different at 6 weeks postoperatively. Complete resection of enhancing tumor occurred in 51.9% of patients. Smaller preoperative tumor volume and use of intraoperative MRI predicted lower residual tumor volume. CONCLUSIONS PPIX fluorescence, as judged by the surgeon, has a high sensitivity and PPV for HGG. 5-ALA was well tolerated in terms of drug-related adverse events, and its application by trained surgeons in FGS for HGGs was not associated with any excess neurological morbidity.

Primary brain tumours often occur near eloquent regions, affecting language, motor and memory capacity, with awake mapping and tailored resection designed to preserve higher cognitive functioning. The effects of such tumours on subcortical structures, including the thalamus and basal ganglia, have been largely unexplored, in spite of the known importance of such structures to higher cognitive functioning. We sought to explore the effects of volume changes of subcortical structures on cognition, in 62 consecutive patients diagnosed with primary brain tumour and cavernous malformations, referred to our neurosurgical practice. We found right caudate to be highly predictive of intelligence, left pallidum of total neuropsychological function and right hippocampus of mood. Our study is the largest of its kind in exploring subcortical substrates of higher cognition in consecutive patients with brain tumours. This research supports prior literature, showing subcortical structures to be related to higher cognitive functioning, particularly measures of memory and executive functioning implicated in fronto-subcortical circuits. Furthermore, involvement of right mesial temporal structures in mood, further strengthens the central role of Papez circuit in emotional quality of cognition. Attention to subcortical integrity is likely to be important in discussing postsurgical cognitive outcome with patients and their families., We explored subcortical volume changes on cognition in 62 consecutive patients diagnosed with brain tumour and cavernous malformations. Right caudate volume predicted intelligence; left pallidum volume predicted total neuropsychological function; right hippocampus volume predicted mood. This research supports prior literature implicating fronto-subcortical circuits structural integrity in higher cognitive functioning., Graphical Abstract Graphical Abstract

Fluorescence guided surgery (FGS) with five-aminolevulinic acid (5-ALA) is expected to revolutionize neurosurgical care of patients with high-grade gliomas (HGG). After the recent landmark FDA approval, this optical agent is now available to neurosurgeons in the United States. This review is designed to highlight the evidence for the use of 5-ALA in recurrent HGG surgery for the neurosurgical community. The manuscript was prepared in accordance with the PRISMA guidelines. Intra-operatively, a strong fluorescent signal is highly correlated with the presence of cellular tumor in recurrent HGG, giving it a high positive predictive value (PPV). Similar to what is observed in primary HGG surgery, false-negative results can occur if tumor cells do not emit fluorescence. In addition, false-positive fluorescence signals in tissues devoid of tumor cells can be observed more frequently in recurrent HGG compared to the primary setting. However, these areas overwhelmingly contain reactive/regressive tissue, resection of which is unlikely to cause functional deficits. The safety profile of 5-ALA is similarly favorable in primary and recurrent HGG. 5-ALA FGS is a powerful adjunct in the resection of recurrent HGG with a high PPV and favorable safety profile. It is therefore the authors’ opinion to routinely employ this fluorescent agent as a standard of care.

Background Recurrence rates for atypical and anaplastic meningiomas range between 9% and 50% after gross total resection and between 36% and 83% after subtotal resection. Optimal treatment of recurrent meningiomas exhibiting atypical/anaplastic histology is complicated because they are often refractory to both surgery and radiation. Objective To evaluate clinical determinants of recurrence and treatment-specific outcomes in patients with recurrent meningiomas exhibiting atypical/anaplastic histology at our institution. Methods A cohort study was conducted using clinical data of all patients treated for meningiomas with atypical/anaplastic histology at first recurrence between January 1985 and July 2014 at a tertiary cancer center. Predictors of second recurrence were analyzed using competing risks regression models. Results Nine hundred eighteen patients with meningioma were screened, of whom 60 (55% female) had recurrent disease with atypical/anaplastic histology at a median age of 58.1 yr at diagnosis. The median follow-up from the time of first recurrence was 36.7 mo, with 32 (53%) patients alive at last follow-up. There was no effect of extent of resection at first recurrence on time to a subsequent recurrence. Inclusion of radiation as primary or adjuvant therapy at first recurrence reduced the risk of progression or subsequent recurrence compared to surgery alone (P = .07). Conclusion Treatment of recurrent meningiomas with atypical/anaplastic histology remains challenging. Our data, from one of the largest cohorts, suggest better tumor control with the addition of radiation and challenges the importance of extent of resection at first recurrence. A multicenter effort is needed to confirm these findings and propose treatment guidelines.

Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to SLC1A1, which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of Slc1a1 loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in (i) locomotor activity, (ii) stereotypy, and (iii) immediate early gene induction in the dorsal striatum following amphetamine administration. Further, Slc1a1-STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCD-like grooming behavior. This reduced grooming is accompanied by reduced dopamine D1 receptor binding in the dorsal striatum of Slc1a1-STOP mice. Slc1a1-STOP mice also exhibit reduced extracellular dopamine concentrations in the dorsal striatum both at baseline and following amphetamine challenge. Viral-mediated restoration of Slc1a1/EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine-induced locomotion and stereotypy in Slc1a1-STOP mice, consistent with an impact of EAAT3 loss on presynaptic dopaminergic function. Collectively, these findings indicate that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors.

Extracranial meningioma metastases (EMM) occur in 0.1% of intracranial meningioma patients and are more commonly seen in those with atypical and anaplastic histologies. While the lungs and pleura are the most common site of EMM, intraspinal and vertebral EMM also occur and are not well described in the literature. Although the presence of EMM can worsen prognosis, no standard of care has been established for EMM management. All patients treated for recurrent atypical/anaplastic meningiomas between January 1985 and July 2014 at Memorial Sloan Kettering Cancer Center were screened for intraspinal and vertebral EMM. Of these patients, 2 were identified as having recurrent meningioma complicated by vertebral or intraspinal EMM. A review of the literature was also conducted. The PubMed database was screened for intraspinal and vertebral EMM cases reported in the literature from 1985 to 2015. Nineteen articles were identified from the literature and included 24 individual cases with a total of 34 vertebral or intraspinal EMM. Forty-two percent (10/24) of patients with vertebral or intraspinal EMM had WHO Grade I tumors. Furthermore, 25% (6/24) of vertebral and intraspinal EMM occurred after the primary tumor but prior to any recurrence. This paper highlights that vertebral and intraspinal EMM can occur in patients with WHO Grade I meningiomas and can occur before tumor recurrence. This challenges the notion that EMM are seen primarily in high-grade atypical and anaplastic meningiomas.

While the behavior of “being musically creative”— improvising, composing, songwriting, etc.—is undoubtedly a complex and highly variable one, recent neuroscientific investigation has offered significant insight into the neural underpinnings of many of the creative processes contributing to such behavior. A previous study from our research group (Bashwiner et al., 2016), which examined two aspects of brain structure as a function of creative musical experience, found significantly increased cortical surface area or subcortical volume in regions of the default-mode network, a motor planning network, and a “limbic” network. The present study sought to determine how these regions coordinate with one another and with other regions of the brain in a large number of participants (n ​= ​218) during a task-neutral period, i.e., during the “resting state.” Deriving from the previous study’s results a set of eleven regions of interest (ROIs), the present study analyzed the resting-state functional connectivity (RSFC) from each of these seed regions as a function of creative musical experience (assessed via our Musical Creativity Questionnaire). Of the eleven ROIs investigated, nine showed significant correlations with a total of 22 clusters throughout the brain, the most significant being located in bilateral cerebellum, right inferior frontal gyrus, midline thalamus (particularly the mediodorsal nucleus), and medial premotor regions. These results support prior reports (by ourselves and others) implicating regions of the default-mode, executive, and motor-planning networks in musical creativity, while additionally—and somewhat unanticipatedly—including a potentially much larger role for the salience network than has been previously reported in studies of musical creativity.

Creative cognition, as measured through divergent thinking (DT), offers insight into one’s ability to generate novel ideas. Relatively little work has been done exploring the relationship between creative idea generation tasks and white matter integrity via fractional anisotropy (FA). Our previous work has shown that higher scores on DT tasks were related to reduced fractional anisotropy (FA) within the left hemisphere anterior thalamic radiation (Jung et al., 2010). However, Takeuchi et al., 2010, found positive correlations with FA and DT tasks in the prefrontal cortex and genu of the corpus callosum. The present study assessed subjects studying or working in science, technology, engineering and mathematics (STEM; N ​= ​178) for correlations in white matter FA, as related to a measure of DT. Healthy normal subjects aged (16–32 years, mean age ​= ​22.0 ​± ​3.8; F ​= ​89/178). Three idea generation DT measures were scored by three raters (α ​= ​0.71) using the consensual assessment technique, from which a composite creativity index (CCI) was derived. We found that CCI was inversely related to FA (all p ​

Importance Cerebral cavernous malformations (CCMs) are vascular lesions of the brain that may lead to hemorrhage, seizures, and neurologic deficits. Most are linked to loss-of-function mutations in 1 of 3 genes, namely CCM1 (originally called KRIT1), CCM2 (MGC4607), or CCM3 (PDCD10), that can either occur as sporadic events or are inherited in an autosomal dominant pattern with incomplete penetrance. Familial forms originate from germline mutations, often have multiple intracranial lesions that grow in size and number over time, and cause an earlier and more severe presentation. Despite active preclinical research on a few pharmacologic agents, clinical translation has been slow. Open surgery and, in some cases, stereotactic radiosurgery remain the only effective treatments, but these options are limited by lesion accessibility and are associated with nonnegligible rates of morbidity and mortality. Observations We discuss the limits of CCM management and introduce findings from in vitro and in vivo studies that provide insight into CCM pathogenesis and indicate molecular mechanisms as potential therapeutic targets. These studies report dysregulated cellular pathways shared between CCM, cardiovascular diseases, and cancer. They also suggest the potential effectiveness of proper drug repurposing in association with, or as an alternative to, targeted interventions. Conclusions and relevance We propose methods to exploit specific molecular pathways to design patient-tailored therapeutic approaches in CCM, with the aim to alter its natural progression. In this scenario, the lack of effective pharmacologic options remains a critical barrier that poses an unfulfilled and urgent medical need.

Highlights • Overlap with respiratory and neurological symptoms in the COVID-19 population. • Obtain early head imaging in COVID-19 patients with a poor neurological exam. • COVID-19 patients can develop CVAs and may benefit from neurosurgical interventions., Background Patients undergoing cardiopulmonary stabilization in the intensive care unit for novel coronavirus (COVID-19) are often sedated, placing timely assessment of a neurological decline at risk. Case description Here, we present two cases of COVID-19 infected young patients transferred to our facility in a cardio-pulmonary crisis, with a poor neurological exam. While there was significant delay in obtaining brain imaging in the first patient, the second patient had timely recognition of her ischemic infarct, underwent emergent surgery, and is now doing well. Conclusions These cases highlight the importance of early head imaging in COVID-19 patients with a poor neurological exam. While lungs remain the primary target of COVID-19, these cases alert the medical community to suspect involvement of the central nervous system, since there may be life-saving surgical interventions available.

Leptomeningeal carcinomatosis (LMC) is a rare complication of cancer that often presents at an advanced stage after obvious metastasis of a primary cancer or locally advanced disease. We present an uncommon case of LMC secondary to pancreatic carcinoma presenting with headache, unilateral VII nerve palsy, and lower extremity weakness. Initial cerebrospinal fluid (CSF) studies were concerning for chronic aseptic meningitis but negative for malignant cells; the diagnosis of tuberculous meningitis was erroneously evoked. Three lumbar punctures were required to capture malignant cells. The diagnosis of LMC was based on CSF examination with cytology/immunohistochemistry and leptomeningeal enhancement on MRI. Post mortem autopsy revealed advanced and diffusely metastatic pancreatic adenocarcinoma. This patient demonstrates that solid tumors can present with leptomeningeal spread that often confuses the treating physician. Fungal or tuberculous meningitis can mimic LMC in the absence of neoplastic signs and negative CSF cytology. This event is exceedingly rare in pancreatic cancer. If the index of suspicion is high, repeat CSF sampling can increase the sensitivity of detection of malignant cells and thus result in the correct diagnosis.

GABAergic interneuron hypofunction is hypothesized to underlie hippocampal dysfunction in schizophrenia. Here, we use the cyclin D2 knockout (Ccnd2(-/-)) mouse model to test potential links between hippocampal interneuron deficits and psychosis-relevant neurobehavioral phenotypes. Ccnd2(-/-) mice show cortical PV(+) interneuron reductions, prominently in hippocampus, associated with deficits in synaptic inhibition, increased in vivo spike activity of projection neurons, and increased in vivo basal metabolic activity (assessed with fMRI) in hippocampus. Ccnd2(-/-) mice show several neurophysiological and behavioral phenotypes that would be predicted to be produced by hippocampal disinhibition, including increased ventral tegmental area dopamine neuron population activity, behavioral hyperresponsiveness to amphetamine, and impairments in hippocampus-dependent cognition. Remarkably, transplantation of cells from the embryonic medial ganglionic eminence (the major origin of cerebral cortical interneurons) into the adult Ccnd2(-/-) caudoventral hippocampus reverses these psychosis-relevant phenotypes. Surviving neurons from these transplants are 97% GABAergic and widely distributed within the hippocampus. Up to 6 mo after the transplants, in vivo hippocampal metabolic activity is lowered, context-dependent learning and memory is improved, and dopamine neuron activity and the behavioral response to amphetamine are normalized. These findings establish functional links between hippocampal GABA interneuron deficits and psychosis-relevant dopaminergic and cognitive phenotypes, and support a rationale for targeting limbic cortical interneuron function in the prevention and treatment of schizophrenia.

International audience; Structural plasticity in the adult brain is essential for adaptive behavior. We have found a remarkable anatomical plasticity in the basal ganglia of adult mice that is regulated by dopamine D2 receptors (D2Rs). By modulating neuronal excitability, striatal D2Rs bidirectionally control the density of direct pathway collaterals in the globus pallidus that bridge the direct pathway with the functionally opposing indirect pathway. An increase in bridging collaterals is associated with enhanced inhibition of pallidal neurons in vivo and disrupted locomotor activation after optogenetic stimulation of the direct pathway. Chronic blockade with haloperidol, an antipsychotic medication used to treat schizophrenia, decreases the extent of bridging collaterals and rescues the locomotor imbalance. These findings identify a role for bridging collaterals in regulating the concerted balance of striatal output and may have important implications for understanding schizophrenia, a disease involving excessive activation of striatal D2Rs that is treated with D2R blockers.

More patients are surviving long-term following a cancer diagnosis and as such are at risk for second malignancies. As the most common primary brain tumor, glioblastoma (GBM) will not infrequently occur in this population. No study has examined the incidence of prior cancer (PC) in patients harboring GBM. Here we evaluate the epidemiological features, as well as the molecular and clinical characteristics of GBM as a second cancer. Utilizing a web-based cancer data management system at our institution, we identified 2164 patients harboring GBM from 2007 to 2014. We collected baseline demographic, molecular, and clinical data. Univariate analysis was performed to compare the cohort of GBM patients with and without PC diagnosis. Survival differences were analyzed with Kaplan–Meier and log-rank testing. A Cox-proportional hazards model was fit for multivariable analysis. 170 patients (7.9%) harboring GBM had a PC diagnosis. The median interval between diagnoses was 79 months. The most common pathologies were breast (18.8%) and prostate (18.8%) cancer. Patients with a PC were older at the time of GBM diagnosis than those without PC (66 vs. 59 years, p

Object Fenestration of the lamina terminalis (FLT) during aneurysm surgery for subarachnoid hemorrhage can, in theory, improve CSF circulation from the lateral and third ventricles to the cortical subarachnoid space, which may, in turn, decrease the incidence of hydrocephalus and vasospasm. However, the actual effects of FLT on CSF circulation have been difficult to determine, due to confounding factors. In addition, it is unclear whether the lamina terminalis remains functionally patent when the brain resumes its normal position. The goal of this study was to assess the functional patency of the fenestrated lamina terminalis in patients who underwent surgery for ruptured aneurysms. Methods This prospective study included 15 patients who underwent surgical clipping of ruptured anterior circulation aneurysms, with FLT performed during surgery. On postoperative Day 1, the external ventricular drain of each patient was closed, and 1 ml of Omnipaque 300, an iodine based contrast agent, was injected intraventricularly, accompanied by cranial maneuvering designed to position the contrast agent adjacent to the lamina terminalis. Three to 5 minutes after cranial maneuvering, the flow of contrast agent into the basal cisterns was assessed with CT imaging. Flow was verified by an increase in Hounsfield units in a prespecified “region of interest” within the basal cisterns on the CT scan. This procedure was performed using a standardized protocol designed in consultation with the Department of Radiology and approved by the institutional review board. One patient who underwent endoscopic third ventriculostomy was recruited as a positive control to validate the technique, and 1 patient who underwent aneurysm clipping but not FLT was recruited as a negative control. Results Seventeen patients consented to study participation. In the 15 patients who underwent aneurysm clipping and FLT, and the negative control patient who underwent aneurysm clipping but not FLT, the contrast agent followed the normal ventricular pathway from the lateral ventricles into the fourth ventricle, and did not appear in the basal cisterns. In the positive control patient, the contrast agent robustly and immediately filled the basal cisterns. Conclusions Fenestration of the lamina terminalis did not result in functional patency of the lamina terminalis when performed as part of surgical clipping for ruptured aneurysms.

Maximum two-dimensional (2D) diameter has been used to define giant pituitary adenoma (GPA) surgery outcomes as has volume using an ellipsoid approximation of volumetrics. Cross sectional length can be measured in several different planes. We sought to compare the accuracy of different 2D cross sectional measurements with the 3D volumetric measurements for predicting GPA surgery outcomes.Retrospective analysis was performed on a prospectively collected database. Tumors with3 cm diameter were identified and classified based on maximal cross sectional measurements in three separate co-axial planes, i.e. transverse (TV), antero-posterior (AP) and cranio-caudal (CC). Volume was calculated using both MRI-guided volumetrics and an ellipsoid approximation (TV × AP × CC/2). Univariate and multivariate analysis was used to evaluate the relationship between cross sectional and volumetric data and extent of resection (EOR).In 62 subjects, median tumor volume using 3D volumetrics was 13.74 cm(3), which was overestimated by 16 % by the ellipsoid calculation (p = 0.0029), particularly for tumors20 cm(3). Gross total resection (GTR) was 46.7 % and median EOR was 99.57 %. At 22-month follow-up, visual and anterior pituitary functions were stable (90 %) or improved (87 %). Pre-operative tumor volume10 cm(3) (p = 0.02) and Knosp grade 3-4 (p = 0.04) were independent predictors of EOR. Knosp grade 3-4 (p 0.0001), TV measurement4 cm (p = 0.007) and maximum cross sectional length4 cm (p = 0.04) were predictors of not achieving GTR. Only TV measurement (p = 0.02) predicted permanent diabetes insipidis. The smallest significant thresholds for predicting decreased GTR were TV measurement25 mm, AP measurement35 mm and volume19 cm(3).We propose a new volumetric threshold of 20 cm(3) as most accurate for predicting GTR in the EEA era. CC measurement is the least useful predictor. Cavernous sinus invasion remains the best predictor of incomplete resection.

Down syndrome (DS) is caused by the triplication of ∼240 protein-coding genes on chromosome 21 and is the most prevalent form of developmental disability. This condition results in abnormalities in many organ systems, as well as in intellectual retardation. Many previous efforts to understand brain dysfunction in DS have indicated that cognitive deficits are coincident with reduced synaptic plasticity and decreased neuronal proliferation. One therapeutic strategy for optimizing the microenvironment for neuronal proliferation and synaptic plasticity in the brain is the use of neurotrophins to restore the homeostasis of the brain biochemical milieu. Here, we show that peripheral administration of Peptide 6, an 11-mer corresponding to an active region of ciliary neurotrophic factor, amino acid residues 146 to 156, can inhibit learning and memory impairments in Ts65Dn mice, a trisomic mouse model of DS. Long-term treatment with Peptide 6 enhanced the pool of neural progenitor cells in the hippocampus and increased levels of synaptic proteins crucial for synaptic plasticity. These findings suggest a therapeutic potential of Peptide 6 in promoting functional neural integration into networks, thereby strengthening biologic substrates of memory processing.

Study Design. This is a single case-based report. Objective. We report the first case of epithelioid trophoblastic tumor (ETT) presenting as primary metastasis to the spine. Summary of Background Data. ETT is an extremely rare form of gestational trophoblastic neoplasm with less than 100 cases reported in the literature. A 36-year-old, postpartum woman presented with severe low back pain and was found to have a contrast-enhancing lesion in lower thoracic spine subsequently confirmed as ETT. Methods. The patient data, history, clinical examination findings, laboratory, and histopathology data and imaging studies were retrospectively reviewed and findings reported. A literature search using Pubmed and Cochrane database was conducted. Result. We described the first case of an ETT to present as a primary metastasis to the spine. Conclusion. This first report of metastasis of ETT to the spine adds significant new information to the growing literature of this rare and newly identified tumor. It also alerts the neurosurgeon into considering the diagnosis with appropriate clinical presentation. As more number of cases of nervous system involvement with this tumor are reported, crucial information on prognostic factors and treatment regimens will emerge.

Development of neurotrophic peptidergic drugs that can mimic neurotrophins and promote neurogenesis and maturation of newborn cells into mature functional neurons represents an exciting therapeutic opportunity for treatment of Alzheimer disease and other learning and memory disorders as well as enhancing cognition of normal individuals. Here we report the design of a peptidergic compound, Ac-DGGLAG-NH2, called P21, when administered peripherally, enhanced learning as well as both short-term and spatial reference memories of normal adult C57Bl6 mice. P21 induced enhancement of neurogenesis and maturation of newly born neurons in the granular cell layer and subgranular zone of the dentate gyrus.

In light of the clinical evidence implicating dopamine in schizophrenia, and the prominent hypotheses put forth regarding alterations in dopaminergic transmission in this disease, molecular imaging has been used to examine multiple aspects of the dopaminergic system. Here we review the imaging methods used and compare the findings across the different molecular targets. Findings have converged to suggest early dysregulation in the striatum, especially in the rostral caudate, manifesting as excess synthesis and release. Recent data showed deficit extending to most cortical regions, and even to other extrastriatal subcortical regions not previously considered to be “hypodopaminergic” in schizophrenia. These findings yield a new topography for the dopaminergic dysregulation in schizophrenia. In this review we discuss the dopaminergic innervation within the individual projection fields to provide a topographical map of this dual dysregulation and explore potential cellular and circuit based mechanisms for brain region-dependent alterations in dopaminergic parameters. This refined knowledge is essential to better guide translational studies and efforts in early drug development.

Background Spine and nonspine skeletal metastases occur in more than 80% of patients with prostate cancer. Objective To examine the characteristics of the patient population undergoing surgery for the treatment of prostate cancer metastatic to the spine. Methods A retrospective chart review was performed on all patients treated at our institution from June 1993 to August 2014 for surgical management of metastatic spine disease from prostate cancer. Results During the study period, 139 patients with 157 surgical lesions underwent surgery for metastatic spine disease. Decompression for high-grade epidural spinal cord compression was required for 126 patients with 143 lesions. Preoperatively, 69% had a motor deficit and 21% were nonambulatory, with 32% due to motor weakness. At surgery, 87% of patients had hormone-refractory prostate cancer (HRPC) and 61% failed prior radiation. Median overall survival for HRPC patients was 6.6 mo (95% confidence interval [CI]: 5.6-8.6) while the median overall survival for hormone-sensitive patients was 16.3 mo (95% CI: 4.0-26.6). Conclusion The majority of patients undergoing surgery for prostate cancer metastases to the spine were refractory to hormone therapy, indicating that patients with hormone-sensitive prostate cancer are unlikely to develop symptomatic spinal cord compression or spinal instability. A significant number of HRPC patients presented with neurological deficits attributable to spinal cord compression. Vigilant monitoring for the development of signs and symptoms of epidural spinal cord compression and spinal instability in hormone-refractory patients is recommended. Surgical decision making may be affected by the much shorter postoperative survival for HRPC patients as compared to patients with hormone-sensitive cancer.

Glutamate toxicity through NMDA receptor channels has long been central to the understanding of acute neuronal injury. Recent studies implicate similar events in chronic neurodegenerative diseases. Here, we analyze some of the most intriguing evidence for NMDA receptor-mediated cellular dysfunction and propose a mechanism by which hyperactive NMDA receptors might lead to neurofibrillary degeneration in Alzheimer's disease.

The activity of protein phosphatase (PP)-2A, which regulates tau phosphorylation, is compromised in Alzheimer disease brain. Here we show that the transient transfection of PC12 cells with inhibitor-2 (I2PP2A) of PP2A causes abnormal hyperphosphorylation of tau at Ser396/Ser404 and Ser262/Ser356. This hyperphosphorylation of tau is observed only when a sub-cellular shift of I2PP2A takes place from the nucleus to the cytoplasm and is accompanied by cleavage of I2PP2A into a 20 kDa fragment. Memantine, an un-competitive inhibitor of N-methyl-D-aspartate receptors, inhibits this abnormal phosphorylation of tau and cell death and prevents the I2PP2A-induced inhibition of PP2A activity in vitro. These findings demonstrate novel mechanisms by which I2PP2A regulates the intracellular activity of PP2A and phosphorylation of tau, and by which Memantine modulates PP2A signaling and inhibits neurofibrillary degeneration.

Alzheimer's disease-like neurofibrillary pathology is neither seen in rodents nor in transgenic animals expressing the disease causing mutant human APP or mutant human presenilins. Whether the absence of this pathology is due to inability of the murine tau to self assemble into filaments or due to some other factors is not understood. In this study, we compared recombinant murine and human taus in their ability to form filaments by AD-like hyperphosphorylation in vitro. Human and murine taus, 0N4R, were generated as recombinant proteins and phosphorylated with rat brain extract as a source of protein kinases. We found that murine tau could be hyperphosphorylated to similar stoichiometry and manner as human tau. Upon hyperphosphorylation, murine tau was able to self polymerize into bundles of paired helical filament- and straight filament-like morphology. The filaments obtained from self assembly of murine tau closely resembled those formed from identically treated human tau. Moreover, like human tau, 60-70% of murine tau aggregated on hyperphosphorylation.

Traumatic brain injury (TBI) is a risk factor for Alzheimer disease (AD), a neurocognitive disorder with similar cellular abnormalities. We recently discovered a small molecule (Peptide 6) corresponding to an active region of human ciliary neurotrophic factor, with neurogenic and neurotrophic properties in mouse models of AD and Down syndrome.To describe hippocampal abnormalities in a mouse model of mild to moderate TBI and their reversal by Peptide 6.TBI was induced in adult C57Bl6 mice using controlled cortical impact with 1.5 mm of cortical penetration. The animals were treated with 50 nmol/d of Peptide 6 or saline solution for 30 days. Dentate gyrus neurogenesis, dendritic and synaptic density, and AD biomarkers were quantitatively analyzed, and behavioral tests were performed.Ipsilateral neuronal loss in CA1 and the parietal cortex and increase in Alzheimer-type hyperphosphorylated tau and A-β were seen in TBI mice. Compared with saline solution, Peptide 6 treatment increased the number of newborn neurons, but not uncommitted progenitor cells, in dentate gyrus by 80%. Peptide 6 treatment also reversed TBI-induced dendritic and synaptic density loss while increasing activity in tri-synaptic hippocampal circuitry, ultimately leading to improvement in memory recall on behavioral testing.Long-term treatment with Peptide 6 enhances the pool of newborn neurons in the dentate gyrus, prevents neuronal loss in CA1 and parietal cortex, preserves the dendritic and synaptic architecture in the hippocampus, and improves performance on a hippocampus-dependent memory task in TBI mice. These findings necessitate further inquiry into the therapeutic potential of small molecules based on neurotrophic factors.

Background Multimodal intracranial monitoring in the neurosurgical patient requires insertion of probes through multiple craniostomies. Objective To report our 5-year experience with a novel device allowing multimodal monitoring though a single twist-drill hole. Methods All devices (Hummingbird Synergy, Innerspace) were placed at the Kocher point between 2008 and 2013 at our institution. An independent clinical research nurse prospectively collected data on all bedside placements. Placement accuracy was graded on computed tomography scan as grade 1 (ipsilateral frontal horn or third ventricle), grade 2 (contralateral lateral ventricle), and grade 3 (anywhere else). Infection was monitored with serial cerebrospinal fluid samples. Results Two hundred seventy-five devices (198 at bedside, 77 in operating room) were placed in patients with spontaneous subarachnoid hemorrhage (49%), traumatic brain injury (47%), and others (4%) for a median duration of 6 days. A junior (postgraduate year 1-2), midlevel (postgraduate year 3-4), or senior resident (postgraduate year 5-6) placed 39%, 32%, and 29% of the devices, respectively. Ninety-two percent of all devices placed were draining cerebrospinal fluid, ie, were grade 1 (75%) or 2 (17%). Placement accuracy did not vary with level of training. Complications included hemorrhage (10%) and infection (4%), with 1 patient requiring intraparenchymal hematoma evacuation and a second requiring abscess drainage. These rates were lower than reported in the literature for standard external ventricular drains. Conclusion Hummingbird Synergy is a novel single-port access device for multimodal intracranial monitoring that can be placed safely at the bedside or in the operating room with placement accuracy and has a complication profile similar to or better than that for standard external ventricular drains.

Association study of two interleukin-1 gene loci with essential hypertension in a Pakistani Pathan population

Radiation exposure to patients and personnel remains a major concern in the practice of interventional radiology, with minimal literature available on exposure to the forehead and cranium.In this study, we measured cranial radiation exposure to the patient, operating interventional neuroradiologist, and circulating nurse during neuroangiographic procedures. We also report the effectiveness of wearing a 0.5 mm lead equivalent cap as protection against radiation scatter.24 consecutive adult interventional neuroradiology procedures (six interventional, 18 diagnostic) were prospectively studied for cranial radiation exposures in the patient and personnel. Data were collected using electronic detectors and thermoluminescent dosimeters.Mean fluoroscopy time for diagnostic and interventional procedures was 8.48 (SD 2.79) min and 26.80 (SD 6.57) min, respectively. Mean radiation exposure to the operator's head was 0.08 mSv, as measured on the outside of the 0.5 mm lead equivalent protective headgear. This amounts to around 150 mSv/year, far exceeding the current deterministic threshold for the lens of the eye (ie, 20 mSv/year) in high volume centers performing up to five procedures a day. When compared with doses measured on the inside of the protective skullcap, there was a statistically significant reduction in the amount of radiation received by the operator's skull.Our study suggests that a modern neurointerventional suite is safe when equipped with proper protective shields and personal gear. However, cranial exposure is not completely eliminated with existing protective devices and the addition of a protective skullcap eliminates this exposure to both the operator and support staff.

Fenestration of the lamina terminalis (FLT) during aneurysm surgery for subarachnoid hemorrhage can, in theory, improve CSF circulation from the lateral and third ventricles to the cortical subarachnoid space, which may, in turn, decrease the incidence of hydrocephalus and vasospasm. However, the actual effects of FLT on CSF circulation have been difficult to determine, due to confounding factors. In addition, it is unclear whether the lamina terminalis remains functionally patent when the brain resumes its normal position. The goal of this study was to assess the functional patency of the fenestrated lamina terminalis in patients who underwent surgery for ruptured aneurysms.This prospective study included 15 patients who underwent surgical clipping of ruptured anterior circulation aneurysms, with FLT performed during surgery. On postoperative Day 1, the external ventricular drain of each patient was closed, and 1 ml of Omnipaque 300, an iodine based contrast agent, was injected intraventricularly, accompanied by cranial maneuvering designed to position the contrast agent adjacent to the lamina terminalis. Three to 5 minutes after cranial maneuvering, the flow of contrast agent into the basal cisterns was assessed with CT imaging. Flow was verified by an increase in Hounsfield units in a prespecified "region of interest" within the basal cisterns on the CT scan. This procedure was performed using a standardized protocol designed in consultation with the Department of Radiology and approved by the institutional review board. One patient who underwent endoscopic third ventriculostomy was recruited as a positive control to validate the technique, and 1 patient who underwent aneurysm clipping but not FLT was recruited as a negative control.Seventeen patients consented to study participation. In the 15 patients who underwent aneurysm clipping and FLT, and the negative control patient who underwent aneurysm clipping but not FLT, the contrast agent followed the normal ventricular pathway from the lateral ventricles into the fourth ventricle, and did not appear in the basal cisterns. In the positive control patient, the contrast agent robustly and immediately filled the basal cisterns.Fenestration of the lamina terminalis did not result in functional patency of the lamina terminalis when performed as part of surgical clipping for ruptured aneurysms.

A therapeutic strategy against cognitive disorders like A lzheimer's disease is to take advantage of the regenerative ability of the brain and the properties of neurotrophic fact ors to shift the balance from neurodegeneration to neurogenesis and neuronal plasticity. Although the ciliary neurotrophic fa ctor (CNTF) has some of the required neuroprotective characteristics, its clinical use, due to its side effects, i.e., anorexia, skele tal muscle loss, hyperalgesia, cramps, and muscle pain, has not materialized. In the present study, we report that Peptide 6c (GDDL) that corresponds to CNTF amino acid residues 147-150, enhances the dentate gyrus neurogenesis and neuronal plasticity, and improves cognition without weight loss or any other apparent side effects in mice. Normal adult C57Bl6 mice received subcutaneous implants of extended release depot pellets containing vehicle or Peptide 6c for 30 days of continuous dosing. Dentate gyrus neurogenesis was assessed by stereological analysis of cells expressing neuronal markers, doublecortin and NeuN, and BrdU uptake. We found that Peptide 6c significantly increased early neuron al commitment, differentiation, and survival of newborn progenitor cells. These newborn neurons were functionally integrated into the hippocampal network, since basal expression of c-fos was enhanced and neuronal plasticity was increased, as reflected by higher expression of MAP2a,b and synaptophysin. Consequently, Peptide 6c treatment improved encoding of hippocampal- dependent information in a spatial reference memory task in mice. Overall, these findings demonstrated the therapeutic potential of Peptide 6c for regeneration of the brain and improvement of cognition.

Pharmacological enhancement of hippocampal neurogenesis is a therapeutic approach for improvement of cognition in learning and memory disorders such as Alzheimer's disease. Here we report the development of an 11-mer peptide that we designed based on a biologically active region of the ciliary neurotrophic factor. This peptide, Peptide 6, induced proliferation and increased survival and maturation of neural progenitor cells into neurons in the dentate gyrus of normal adult C57BL6 mice. Furthermore, Peptide 6 increased the MAP2 and synaptophysin immunoreactivity in the dentate gyrus. Thirty-day treatment of the mice with a slow release bolus of the peptide implanted subcutaneously improved reference memory of the mice in Morris water maze. Peptide 6 has a plasma half life of over 6 h, is blood-brain barrier permeable, and acts by competitively inhibiting the leukemia inhibitory factor signaling. The fact that Peptide 6 is both neurogenic and neurotrophic and that this peptide is effective when given peripherally, demonstrates its potential for prevention and treatment of learning and memory disorders.

Two groups of tau, 3R- and 4R-tau, are generated by alternative splicing of tau exon 10. Normal adult human brain expresses equal levels of them. Disruption of the physiological balance is a common feature of several tauopathies. Very early in their life, individuals with Down syndrome (DS) develop Alzheimer-type tau pathology, the molecular basis for which is not fully understood. Here, we demonstrate that Dyrk1A, a kinase encoded by a gene in the DS critical region, phosphorylates alternative splicing factor (ASF) at Ser-227, Ser-234, and Ser-238, driving it into nuclear speckles and preventing it from facilitating tau exon 10 inclusion. The increased dosage of Dyrk1A in DS brain due to trisomy of chromosome 21 correlates to an increase in 3R-tau level, which on abnormal hyperphosphorylation and aggregation of tau results in neurofibrillary degeneration. Imbalance of 3R- and 4R-tau in DS brain by Dyrk1A-induced dysregulation of alternative splicing factor-mediated alternative splicing of tau exon 10 represents a novel mechanism of neurofibrillary degeneration and may help explain early onset tauopathy in individuals with DS.

Hyperphosphorylated tau has long been proposed as the key molecule disrupting normal neuronal microtubule dynamics and leading to neurofibrillary degeneration in Alzheimer disease. Here we provide a direct evidence of hyperphosphorylated tau-induced disruption of microtubule network. Using Nocodozole-treated and detergent-extracted cells, we created a neuronal environment in mouse embryonic fibroblasts, 3T3 cells, by replacing their cytoplasm with adult rat brain cytosol. By recreating neuronal microtubule network in these cells, we were able to follow the effects of hyperphosphorylated tau on microtubule dynamics in real time. Whereas recombinant human brain tau promoted assembly and bundling of microtubules, abnormally hyperphosphorylated tau isolated from Alzheimer disease brain cytosol (AD P-tau) inhibited the assembly and disrupted preformed microtubule network by sequestering normal brain tau and MAP2. This breakdown of the microtubule network was reversed by treatment of the extracted cells with protein phosphatase-2A. This study, for the first time, provides direct mechanistic insights into the molecular basis of both axonal and dendritic neurodegeneration seen in Alzheimer disease.

The activity of protein phosphatase (PP)-2A, which regulates tau phosphorylation, is compromised in Alzheimer disease brain. Here we show that the transient transfection of PC12 cells with inhibitor-2 (I2PP2A) of PP2A causes abnormal hyperphosphorylation of tau at Ser396/Ser404 and Ser262/Ser356. This hyperphosphorylation of tau is observed only when a sub-cellular shift of I2PP2A takes place from the nucleus to the cytoplasm and is accompanied by cleavage of I2PP2A into a 20 kDa fragment. Memantine, an un-competitive inhibitor of N-methyl-D-aspartate receptors, inhibits this abnormal phosphorylation of tau and cell death and prevents the I2PP2A-induced inhibition of PP2A activity in vitro. These findings demonstrate novel mechanisms by which I2PP2A regulates the intracellular activity of PP2A and phosphorylation of tau, and by which Memantine modulates PP2A signaling and inhibits neurofibrillary degeneration.

Pediatric meningiomas are rare and account for about 1.5% of all intracranial tumors. When compared to adults, intraventricular location of childhood meningiomas is four to ten times as high. Atypical pathology of these lesions is very uncommon and indicates an aggressive nature. They are usually associated with Neurofibromatosis 2 (NF2) or previous cranial irradiation. Here, we present an interesting case of an unusually large, congenital intraventricular meningioma of atypical pathology in a 16 month old child with subsequently diagnosed NF2. A brief review of literature is also presented with this case illustration.

Introduction Radiation exposure to patients and personnel remains a major concern in the practice of interventional radiology. Medical personnel using radiation now account for more than half of all radiation workers exposed to man-made sources of radiation. While scatter radiation exposure to the lens of the eye and regions below the neck have been quantified and minimised using a variety of protective equipment, not much literature is available on exposure to the forehead and cranium. Here, we report cranial radiation exposure to the patient, operating interventional neuroradiologist, and circulating nurse during neuro-angiographic procedures in 24 prospective patients in a modern neuro-interventional suite. We also report the effectiveness of wearing a 0.5mm lead equivalent cap in protection against radiation scatter. Methods Twenty-four consecutive adult interventional neuro-radiology procedures (6 interventional, 18 diagnostic) were prospectively studied for cranial radiation exposures in the patient, interventional radiologist, and circulating nurse at the University of New Mexico Hospital. Radiation exposure data was collected on each case using NAVLAP accredited (National Voluntary Laboratory Accreditation Program) electronic detectors (Instadose™, Mirion Technologies, CA) placed on the temporal scalp facing the radiation source for the operator and nurse (i.e. left temporal scalp of the operator and right temporal scalp of the nurse), while patient exposure was collected using two thermoluminescent dosimeters (TLD-100, Quantaflux, OH) placed on the table top directly under the patients head. The entire study was done by one operator wearing a 0.5mm lead equivalent skullcap (Radpad Protection, Worldwide Innovations & Technologies, Inc., KS). Results The mean fluoroscopy time for diagnostic and interventional procedures was 8.48 (SD 2.79) and 26.80 (SD 6.57) minutes, respectively, while patient cranial radiation exposure was 198.60 mSv for diagnostic and 991.54 mSv in interventional procedures. The mean radiation exposure to the operator’s head was 7.75 mrem (SD 19.62) as measured on the outside of the 0.5 mm lead equivalent protective headgear. This amounts to 0.08mSv per procedure or 150 mSv/year (the deterministic threshold for lens) in high volume centres doing up to 5 procedures a day. When compared to doses measured on the inside of the protective skullcap, there was statistically significant reduction in the amount of radiation received by the operator’s skull (overall means 0.58 + 1.61mrem inside vs 7.75 + 19.62 mrem outside the skull cap). Mean cranial exposure to the circulating nurse was 2.92 + 6.09 mrem. Conclusions Our study suggests that a modern neuro-interventional suite is safe when equipped with proper protective shields and personal gear. However, cranial exposure is not completely eliminated with existing protective devices and the addition of protective skullcap eliminates this exposure to both the operator and support staff. We therefore, strongly suggest routine use of a protective skullcap. Disclosures M. Chohan: None. D. Sandoval: None. C. Murray-Krezan: None. C. Taylor: None.

The past 25 years have seen an explosion of scientific progress into the basic neurobiology of Alzheimer’s disease (AD). Unfortunately, the gap between bench and bedside remains as vast as ever. The scientific community in general and the pharmaceutical industry in particular have invested heavily in just a few areas of therapeutics. The result is quite clear: symptomatic drugs are the best that can be offered to patients with this devastating disease. Despite the seemingly desperate state of affairs, we now see a steady influx of novel, unconventional therapeutic approaches. This special issue of the Journal of Alzheimer’s Disease presents perspectives written by leaders in the field who believe that it is high time for innovation in AD therapeutics. This special issue, “Novel approaches to Alzheimer’s Disease Therapeutics” is divided into two main parts: the first part focuses mainly on preclinical studies and novel agents that are still in the experimental phase, whereas the second part describes current clinical studies and some of the major issues involved. The issue starts off with two novel breakthroughs in AD immunotherapy. Einar Sigurdsson proposes active immunization against tau, while Michal Novak and his group elaborate on passive tau immunization. This is followed by an update on GSK-3 inhibitors by Daniel Perez and Anna Martinez, who leads a major