Allen L. Ho

From the Cover: Neutralization of terminal differentiation in gliomagenesis.

An immature state of cellular differentiation—characterized by stem cell–like tendencies and impaired differentiation—is a hallmark of cancer. Using glioblastoma multiforme (GBM) as a model system, we sought to determine whether molecular determinants that drive cells toward terminal differentiation are also genetically targeted in carcinogenesis and whether neutralizing such genes also plays an active role to reinforce the impaired differentiation state and promote malignancy. To that end, we screened 71 genes with known roles in promoting nervous system development that also sustain copy number loss in GBM through antineoplastic assay and identified A2BP1 (ataxin 2 binding protein 1, Rbfox1), an RNA-binding and splicing regulator that is deleted in 10% of GBM cases. Integrated in silico analysis of GBM profiles to elucidate the A2BP1 pathway and its role in glioma identified myelin transcription factor 1-like (Myt1L) as a direct transcriptional regulator of A2BP1. Reintroduction of A2BP1 or Myt1L in GBM cell lines and glioma stem cells profoundly inhibited tumorigenesis in multiple assays, and conversely, shRNA-mediated knockdown of A2BP1 or Myt1L in premalignant neural stem cells compromised neuronal lineage differentiation and promoted orthotopic tumor formation. On the mechanistic level, with the top-represented downstream target TPM1 as an illustrative example, we demonstrated that, among its multiple functions, A2BP1 serves to regulate TPM1’s alternative splicing to promote cytoskeletal organization and terminal differentiation and suppress malignancy. Thus, in addition to the activation of self-renewal pathways, the neutralization of genetic programs that drive cells toward terminal differentiation may also promote immature and highly plastic developmental states that contribute to the aggressive malignant properties of GBM.

Effect of Vascular Anatomy on the Formation of Basilar Tip Aneurysms

BACKGROUND The pathogenesis of intracranial aneurysms is multifactorial and includes genetic, environmental, and anatomic influences. Hemodynamic stress plays a particular role in the formation of intracranial aneurysms, which is conditioned by the geometry and morphology of the vessel trees. OBJECTIVE To identify image-based morphological parameters that correlated with the formation of basilar artery tip aneurysms (BTAs) in a location-specific manner. METHODS Morphological parameters obtained from computed tomographic angiographies of 33 patients with BTAs and 33 patients with aneurysms at other locations were evaluated with Slicer, an open-source image analysis software, to generate 3-dimensional models of the aneurysms and surrounding vascular architecture. We examined the diameters and vessel-to-vessel angles of the main vessels at the basilar bifurcation in patients with and without BTAs. To control for genetic and other risk factors, only patients with at least 1 aneurysm were included. Univariate and multivariate analyses were performed to determine statistical significance. RESULTS Sixty-six patients (33 with BTAs, 33 with other aneurysms) who were evaluated from 2008 to 2013 were analyzed. Multivariate logistic regression revealed that a larger angle between the posterior cerebral arteries (odds ratio, 1.04; P = 1.42 × 10(-3)) and a smaller basilar artery diameter (odds ratio, 0.23; P = .02) were most strongly associated with BTA formation after adjustment for other morphological and clinical variables. CONCLUSION Larger posterior cerebral artery angles and smaller basilar artery diameters are associated with the formation of basilar tip aneurysms. These parameters are easily measurable by the clinician and will aid in screening strategies in high-risk patients.

Stereotactic laser ablation of the splenium for intractable epilepsy

Partial or complete corpus callosotomies have been applied, traditionally via open surgical or radiosurgical approaches, for the treatment of epilepsy in patients with multifocal tonic, atonic, or myoclonic seizures. Minimally invasive methods, such as MRI-guided laser interstitial thermal ablation (MTLA), are being employed to functionally remove or ablate seizure foci in the treatment of epilepsy. This therapy can achieve effectiveness similar to that of traditional resection, but with reduced morbidity compared with open surgery. Here, we present a patient with a history of prior partial corpus callosotomy who continued to suffer from medically refractory epilepsy with bisynchronous onset. We report on the utilization of laser ablation of the splenium in this patient to achieve full corpus callosotomy. Adequate ablation of the splenial remnant was confirmed by postoperative MRI imaging, and at four-month follow-up, the patients seizure frequency had dropped more than 50%. This is the first reported instance of laser ablation of the splenium to achieve full corpus callosotomy following a previous unsuccessful anterior callosotomy in a patient with intractable generalized epilepsy.

Molecular basis of intervertebral disc degeneration.

Intervertebral disc (IVD) degeneration is a disease of the discs connecting adjoining vertebrae in which structural damage leads to degeneration of the disc and surrounding area. Degeneration of the disc is considered to be a normal process of aging, but can accelerate faster than expected or be precipitated by other factors. The scientific community has come a long way in understanding the biological basis and interpreting the lifestyle implications of IVD degeneration. Of all the diseases of the intervertebral disc, degeneration is the most common and has earned much attention due to its diversity in presentation and potential multiorgan involvement. We will provide a brief overview of the anatomic, cellular, and molecular structure of the IVD, and delve into the cellular and molecular pathophysiology surrounding IVD degeneration. We will then highlight some of the newest developments in stem cell, protein, and genetic therapy for IVD degeneration.

Clinical evaluation of concussion: the evolving role of oculomotor assessments.

Sports-related concussion is a change in brain function following a direct or an indirect force to the head, identified in awake individuals and accounting for a considerable proportion of mild traumatic brain injury. Although the neurological signs and symptoms of concussion can be subtle and transient, there can be persistent sequelae, such as impaired attention and balance, that make affected patients particularly vulnerable to further injury. Currently, there is no accepted definition or diagnostic criteria for concussion, and there is no single assessment that is accepted as capable of identifying all patients with concussion. In this paper, the authors review the available screening tools for concussion, with particular emphasis on the role of visual function testing. In particular, they discuss the oculomotor assessment tools that are being investigated in the setting of concussion screening.

Deep Brain Stimulation for Obesity

Obesity is now the third leading cause of preventable death in the US, accounting for 216,000 deaths annually and nearly 100 billion dollars in health care costs. Despite advancements in bariatric surgery, substantial weight regain and recurrence of the associated metabolic syndrome still occurs in almost 20-35% of patients over the long-term, necessitating the development of novel therapies. Our continually expanding knowledge of the neuroanatomic and neuropsychiatric underpinnings of obesity has led to increased interest in neuromodulation as a new treatment for obesity refractory to current medical, behavioral, and surgical therapies. Recent clinical trials of deep brain stimulation (DBS) in chronic cluster headache, Alzheimer’s disease, and depression and obsessive-compulsive disorder have demonstrated the safety and efficacy of targeting the hypothalamus and reward circuitry of the brain with electrical stimulation, and thus provide the basis for a neuromodulatory approach to treatment-refractory obesity. In this study, we review the literature implicating these targets for DBS in the neural circuitry of obesity. We will also briefly review ethical considerations for such an intervention, and discuss genetic secondary-obesity syndromes that may also benefit from DBS. In short, we hope to provide the scientific foundation to justify trials of DBS for the treatment of obesity targeting these specific regions of the brain.

Sports-related brain injuries: connecting pathology to diagnosis

Brain injuries are becoming increasingly common in athletes and represent an important diagnostic challenge. Early detection and management of brain injuries in sports are of utmost importance in preventing chronic neurological and psychiatric decline. These types of injuries incurred during sports are referred to as mild traumatic brain injuries, which represent a heterogeneous spectrum of disease. The most dramatic manifestation of chronic mild traumatic brain injuries is termed chronic traumatic encephalopathy, which is associated with profound neuropsychiatric deficits. Because chronic traumatic encephalopathy can only be diagnosed by postmortem examination, new diagnostic methodologies are needed for early detection and amelioration of disease burden. This review examines the pathology driving changes in athletes participating in high-impact sports and how this understanding can lead to innovations in neuroimaging and biomarker discovery.

Smoking and Intracranial Aneurysm Morphology.

BACKGROUND Smoking is a well-known independent risk factor for both aneurysm formation and rupture. There is mounting evidence that aneurysm morphology beyond size can have a significant role in aneurysm formation and rupture risk by its effects on aneurysmal hemodynamics. OBJECTIVE To study the variation in aneurysm morphology between smokers and nonsmokers and delineate how changes in these factors might affect aneurysm formation and rupture. METHODS We generated 3-dimensional models of aneurysms and their surrounding vasculature by analyzing preoperative computed tomography angiograms with Slicer software. We then examined the association between smoking status and intrinsic, transitional, and extrinsic aspects of aneurysm morphology in both univariate and multivariate statistical analyses. RESULTS From 2005 to 2013, 199 cerebral aneurysms in never smokers and current smokers were evaluated/treated at a single institution with available computed tomography angiograms (102 in never smokers and 97 in current smokers). Multivariate analysis of current smokers vs never smokers demonstrated that aneurysms in current smokers were significantly associated with multiple aneurysms (odds ratio [OR]: 2.15, P = .03), larger daughter vessel diameters (OR: 3.13, P = .01), larger size ratio (OR: 1.78, P = .01), and location at the basilar apex (OR: 6.26, P = .02). CONCLUSION The differences in aneurysm morphology between smoking and nonsmoking patient populations may elucidate the effects of smoking on aneurysm formation and eventual rupture. We identified several aspects of aneurysm morphology significantly associated with smoking status that may provide the morphological basis for how smoking leads to increased aneurysm rupture.

Neutralization of terminal differentiation in gliomagenesis

An immature state of cellular differentiation—characterized by stem cell–like tendencies and impaired differentiation—is a hallmark of cancer. Using glioblastoma multiforme (GBM) as a model system, we sought to determine whether molecular determinants that drive cells toward terminal differentiation are also genetically targeted in carcinogenesis and whether neutralizing such genes also plays an active role to reinforce the impaired differentiation state and promote malignancy. To that end, we screened 71 genes with known roles in promoting nervous system development that also sustain copy number loss in GBM through antineoplastic assay and identified A2BP1 (ataxin 2 binding protein 1, Rbfox1), an RNA-binding and splicing regulator that is deleted in 10% of GBM cases. Integrated in silico analysis of GBM profiles to elucidate the A2BP1 pathway and its role in glioma identified myelin transcription factor 1-like (Myt1L) as a direct transcriptional regulator of A2BP1. Reintroduction of A2BP1 or Myt1L in GBM cell lines and glioma stem cells profoundly inhibited tumorigenesis in multiple assays, and conversely, shRNA-mediated knockdown of A2BP1 or Myt1L in premalignant neural stem cells compromised neuronal lineage differentiation and promoted orthotopic tumor formation. On the mechanistic level, with the top-represented downstream target TPM1 as an illustrative example, we demonstrated that, among its multiple functions, A2BP1 serves to regulate TPM1’s alternative splicing to promote cytoskeletal organization and terminal differentiation and suppress malignancy. Thus, in addition to the activation of self-renewal pathways, the neutralization of genetic programs that drive cells toward terminal differentiation may also promote immature and highly plastic developmental states that contribute to the aggressive malignant properties of GBM.

Cushing's disease: predicting long-term remission after surgical treatment

Cushings disease (CD) is a state of excess glucocorticoid production resulting from an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. The gold-standard treatment for CD is transsphenoidal adenomectomy. In the hands of an experienced neurosurgeon, gross-total resection is possible in the majority of ACTH-secreting pituitary adenomas, with early postoperative remission rates ranging from 67% to 95%. In contrast to the strong data in support of resection, the clinical course of postsurgical persistent or recurrent disease remains unclear. There is significant variability in recurrence rates, with reports as high as 36% with a mean time to recurrence of 15-50 months. It is therefore important to develop biochemical criteria that define postsurgical remission and that may provide prognosis for long-term recurrence. Despite the use of a number of biochemical assessments, there is debate regarding the accuracy of these tests in predicting recurrence. Here, the authors review the various biochemical criteria and assess their utility in predicting CD recurrence after resection.