Neurology Commons^™

Neuroangiogenesis: A Vascular Basis For Alzheimer's Disease And Cognitive Decline During Aging, Charles T. Ambrose

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Angiogenesis directs development of the brain's microcirculation during antenatal and postnatal development, but its role later in life is less well recognized. I contend that during senescence a reduced cerebral capillary density accounts in part for the vascular cognitive impairment observed in many older persons and possibly for some forms of Alzheimer's disease. I propose that neuroangiogenesis is essential throughout adult life for maintaining the microcirculation of the cerebral cortex and elsewhere in the brain and that it commonly declines with old age. To support this hypothesis I have examined the neurological literature for relevant studies on cerebral capillary density …

Mir-128 Inhibits Tumor Growth And Angiogenesis By Targeting P70s6k1., Zhu-Mei Shi, Jing Wang, Zhiping Yan, Yong-Ping You, Chong-Yong Li, Xu Qian, Yu Yin, Peng Zhao, Ying-Ying Wang, Xie-Feng Wang, Ming-Na Li, Ling-Zhi Liu, Ning Liu, Bing-Hua Jiang

Kimmel Cancer Center Faculty Papers

MicroRNAs are a class of small noncoding RNAs that function as critical gene regulators through targeting mRNAs for translational repression or degradation. In this study, we showed that miR-128 expression levels were decreased in glioma, and identified p70S6K1 as a novel direct target of miR-128. Overexpression of miR-128 suppressed p70S6K1 and its downstream signaling molecules such as HIF-1 and VEGF expression, and attenuated cell proliferation, tumor growth and angiogenesis. Forced expression of p70S6K1 can partly rescue the inhibitory effect of miR-128 in the cells. Taken together, these findings will shed light to the role and mechanism of miR-128 in regulating …

Macrophage Imbalance (M1 Vs. M2) And Upregulation Of Mast Cells In Wall Of Ruptured Human Cerebral Aneurysms: Preliminary Results., David Hasan, Nohra Chalouhi, Pascal Jabbour, Tomoki Hashimoto

Department of Neurosurgery Faculty Papers

BACKGROUND: M1 and M2 cells are two major subsets of human macrophages that exert opposite effects on the inflammatory response. This study aims to investigate the role of macrophage M1/M2 imbalance and mast cells in the progression of human cerebral aneurysms to rupture.

METHODS: Ten patients with cerebral aneurysms (five ruptured and five unruptured) underwent microsurgical clipping. During the procedure, a segment of the aneurysm dome was resected and immunostained with monoclonal antibodies for M1 cells (anti-HLA DR), M2 cells (anti-CD 163), and mast cells (anti-tryptase clone AA). A segment of the superficial temporal artery (STA) was also removed and …

Functional Recovery Of Untreated Human Immunodeficiency Virus-Associated Guillain-Barré Syndrome: A Case Report, Adam L. Schreiber, John W. Norbury Iii, Eduardo A. De Sousa

Department of Rehabilitation Medicine Faculty Papers

HIV-associated Guillain-Barré Syndrome is a well-documented phenomenon, typically occurring at seroconversion. GBS may result in functional impairment treated with a combination of medications, plasmapheresis, and rehabilitation. The quantified functional recovery of HIV-associated GBS with or without HIV treatment is not well-described. Utilizing serial FIM scoring, we describe a patient’s recovery from HIV-associated GBS after treatment with IVIg and acute inpatient rehabilitation without HIV treatment.

Strain-Dependent Variation In The Early Transcriptional Response To Cns Injury Using A Cortical Explant System, David J. Graber, Brent T. Harris, William F. Hickey

Dartmouth Scholarship

While it is clear that inbred strains of mice have variations in immunological responsiveness, the influence of genetic background following tissue damage in the central nervous system is not fully understood. A cortical explant system was employed as a model for injury to determine whether the immediate transcriptional response to tissue resection revealed differences among three mouse strains. Immunological mRNAs were measured in cerebral cortex from SJL/J, C57BL/6J, and BALB/cJ mice using real time RT-PCR. Freshly isolated cortical tissue and cortical sections incubated in explant medium were examined. Levels of mRNA, normalized to β-actin, were compared using one way analysis …

Acute Effects Of A Selective Cannabinoid-2 Receptor Agonist On Neuroinflammation In A Model Of Traumatic Brain Injury., Melanie B Elliott, Ronald F Tuma, Peter S Amenta, Mary F Barbe, Jack I Jallo

Department of Neurosurgery Faculty Papers

Proposed therapeutic strategies for attenuating secondary traumatic brain injury (TBI) include modulation of acute neuroimmune responses. The goal of this study was to examine the acute effects of cannabinoid-2 receptor (CB(2)R) modulation on behavioral deficits, cerebral edema, perivascular substance P, and macrophage/microglial activation in a murine model of TBI. Thirty male C57BL/6 mice underwent sham surgery, or cortical contusion impact injury (CCI). CCI mice received vehicle or the CB(2)R agonist 0-1966 at 1 and 24 h after injury. Performance on the rotarod, forelimb cylinder, and open-field tests were evaluated before and at 48 h after sham or CCI surgery. Cerebral …

Multiple Courses Of Stereotactic Re-Irradiation In Recurrent Oligodendroglioma: A Case Report., Shannon Fogh, Charles Glass, David W Andrews, Maria Werner-Wasik

Department of Radiation Oncology Faculty Papers

INTRODUCTION: High grade gliomas are an insidious disease associated with an extremely poor prognosis. The role of re-irradiation for recurrent gliomas is unclear but several retrospective studies have indicated mild toxicity and modest outcomes with this regimen. With subsequent progression, it is unclear what options remain and more radiotherapy is rarely offered for fear of surpassing normal central nervous system tissue tolerance and causing significant side effects without significant benefit.

CASE PRESENTATION: In this report, we describe a 37-year-old Caucasian male initially diagnosed with a grade IV oligodendroglioma, who received multiple courses of re-irradiation and experienced a survival of 10 …

A Test Of The Role Of The Medial Temporal Lobe In Single-Word Decoding., Karol Osipowicz, Tyler Rickards, Atif Shah, Ashwini Sharan, Michael Sperling, Waseem Kahn, Joseph Tracy

Department of Neurology Faculty Papers

The degree to which the MTL system contributes to effective language skills is not well delineated. We sought to determine if the MTL plays a role in single-word decoding in healthy, normal skilled readers. The experiment follows from the implications of the dual-process model of single-word decoding, which provides distinct predictions about the nature of MTL involvement. The paradigm utilized word (regular and irregularly spelled words) and pseudoword (phonetically regular) stimuli that differed in their demand for non-lexical as opposed lexical decoding. The data clearly showed that the MTL system was not involved in single word decoding in skilled, native …

Ms4a4b, A Cd20 Homologue In T Cells, Inhibits T Cell Propagation By Modulation Of Cell Cycle., Hui Xu, Yaping Yan, Mark S Williams, Gregory B Carey, Jingxian Yang, Hongmei Li, Guang-Xian Zhang, Abdolmohamad Rostami

Department of Neurology Faculty Papers

MS4a4B, a CD20 homologue in T cells, is a novel member of the MS4A gene family in mice. The MS4A family includes CD20, FcεRIβ, HTm4 and at least 26 novel members that are characterized by their structural features: with four membrane-spanning domains, two extracellular domains and two cytoplasmic regions. CD20, FcεRIβ and HTm4 have been found to function in B cells, mast cells and hematopoietic cells respectively. However, little is known about the function of MS4a4B in T cell regulation. We demonstrate here that MS4a4B negatively regulates mouse T cell proliferation. MS4a4B is highly expressed in primary T cells, natural …

White Matter Diffusion Alterations In Normal Women At Risk Of Alzheimer's Disease, Charles D. Smith, Himachandra Chebrolu, Anders H. Andersen, David A. Powell, Mark A. Lovell, Shuling Xiong, Brian T. Gold

Neurology Faculty Publications

Increased white matter mean diffusivity and decreased fractional anisotropy (FA) has been observed in subjects diagnosed with mild cognitive impairment (MCI) and Alzheimer's disease (AD). We sought to determine whether similar alterations of white matter occur in normal individuals at risk of AD. Diffusion tensor images were acquired in 42 cognitively normal right-handed women with both a family history of dementia and at least one apolipoprotein E4 allele. These were compared with images from 23 normal women without either AD risk factor. Group analyses were performed using tract-based spatial statistics. Reduced FA was observed in the fronto-occipital and inferior temporal …

Multiport Minimally Invasive Skull Base Surgery: How Many Ports Are Too Many?, Yaron A. Moshel, Theodore H. Schwartz

Department of Neurosurgery Faculty Papers

Surgical access to the ventral skull base has evolved considerably over the past several years with the introduction of minimally invasive endoscopic and endoscope-assisted approaches. The accompanying manuscript by Ciporen et al. demonstrates an addition to this growing body of literature in their description of the feasibility of multiportal endoscopic approaches to the skull base, particularly the precaruncular transorbital approach, in a series of cadaver dissections. Similar to laparoscopic abdominal surgery, which utilizes multiple small ports to improve visualization and manipulation, they envision a modular combination of approaches that allows an endoscope to be placed in one port and surgery …

Progressive Changes In Microglia And Macrophages In Spinal Cord And Peripheral Nerve In The Transgenic Rat Model Of Amyotrophic Lateral Sclerosis, David J. Graber, William F. Hickey, Brent T. Harris

Dartmouth Scholarship

The role of neuroinflammation in motor neuron death of amyotrophic lateral sclerosis (ALS) is unclear. The human mutant superoxide dismutase-1 (hmSOD1)-expressing murine transgenic model of ALS has provided some insight into changes in microglia activity during disease progression. The purpose of this study was to gain further knowledge by characterizing the immunological changes during disease progression in the spinal cord and peripheral nerve using the more recently developed hmSOD1 rat transgenic model of ALS. Using immunohistochemistry, the extent and intensity of tissue CD11b expression in spinal cord, lumbar nerve roots, and sciatic nerve were evaluated in hmSOD1 rats that were …

Interaction Of The Mu-Opioid Receptor With Gpr177 (Wntless) Inhibits Wnt Secretion: Potential Implications For Opioid Dependence., Jay Jin, Saranya Kittanakom, Victoria Wong, Beverly A S Reyes, Elisabeth J Van Bockstaele, Igor Stagljar, Wade Berrettini, Robert Levenson

Department of Neurosurgery Faculty Papers

BACKGROUND: Opioid agonist drugs produce analgesia. However, long-term exposure to opioid agonists may lead to opioid dependence. The analgesic and addictive properties of opioid agonist drugs are mediated primarily via the mu-opioid receptor (MOR). Opioid agonists appear to alter neuronal morphology in key brain regions implicated in the development of opioid dependence. However, the precise role of the MOR in the development of these neuronal alterations remains elusive. We hypothesize that identifying and characterizing novel MOR interacting proteins (MORIPs) may help to elucidate the underlying mechanisms involved in the development of opioid dependence. RESULTS: GPR177, the mammalian ortholog of Drosophila …

Mitochondrial Mislocalization Underlies Abeta42-Induced Neuronal Dysfunction In A Drosophila Model Of Alzheimer's Disease., Kanae Iijima-Ando, Stephen A Hearn, Christopher Shenton, Anthony Gatt, Lijuan Zhao, Koichi Iijima

Department of Biochemistry and Molecular Biology Faculty Papers

The amyloid-beta 42 (Abeta42) is thought to play a central role in the pathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms by which Abeta42 induces neuronal dysfunction and degeneration remain elusive. Mitochondrial dysfunctions are implicated in AD brains. Whether mitochondrial dysfunctions are merely a consequence of AD pathology, or are early seminal events in AD pathogenesis remains to be determined. Here, we show that Abeta42 induces mitochondrial mislocalization, which contributes to Abeta42-induced neuronal dysfunction in a transgenic Drosophila model. In the Abeta42 fly brain, mitochondria were reduced in axons and dendrites, and accumulated in the somata without severe mitochondrial …

Human Amniotic Fluid Stem Cells Do Not Differentiate Into Dopamine Neurons In Vitro Or After Transplantation In Vivo., Angela E Donaldson, Jingli Cai, Ming Yang, Lorraine Iacovitti

Farber Institute for Neuroscience Faculty Papers

Although embryonic stem (ES) cells can generate dopamine (DA) neurons that are potentially useful as a cell replacement therapy in Parkinson's disease (PD), associated ethical and practical concerns remain major stumbling blocks to their eventual use in humans. In this study, we examined human amniotic fluid stem (hAFS) cells derived from routine amniocenteses for their potential to give rise to DA neurons in vitro and following transplantation into the 6-hydroxydopamine-lesioned rat brain. We show that undifferentiated hAFS cells constitutively expressed mRNAs and proteins typical of stem cells but also cell derivatives of all three germ layers, including neural progenitors/neurons (nestin, …

Dynamic Mechanical (Brush) Allodynia In Cluster Headache: A Prevalence Study In A Tertiary Headache Clinic., Michael J Marmura, Muhammad Abbas, Avi Ashkenazi

Department of Jefferson Headache Center Papers and Presentations

Cutaneous allodynia (CA) has been described in migraine and has been related to treatment failure. There are little data about the incidence of CA in other primary headache syndromes such as cluster headache (CH). The objectives of this study are to evaluate the prevalence of dynamic mechanical (brush) allodynia (BA) in CH patients attending a tertiary headache clinic, and to assess its relation to disease characteristics. Adult patients with episodic or chronic CH were recruited. We obtained demographic data and data on disease characteristics through a structured questionnaire, and tested the patients for brush allodynia BA by applying a 4 …

The Efficacy Of Surgical Decompression Before 24 Hours Versus 24 To 72 Hours In Patients With Spinal Cord Injury From T1 To L1--With Specific Consideration On Ethics: A Randomized Controlled Trial., Vafa Rahimi-Movaghar, Soheil Saadat, Alexander R Vaccaro, Seyed Mohammad Ghodsi, Mohammad Samadian, Arya Sheykhmozaffari, Seyed Mohammad Safdari, Bahram Keshmirian

Department of Neurosurgery Faculty Papers

BACKGROUND: There is no clear evidence that early decompression following spinal cord injury (SCI) improves neurologic outcome. Such information must be obtained from randomized controlled trials (RCTs). To date no large scale RCT has been performed evaluating the timing of surgical decompression in the setting of thoracolumbar spinal cord injury. A concern for many is the ethical dilemma that a delay in surgery may adversely effect neurologic recovery although this has never been conclusively proven. The purpose of this study is to compare the efficacy of early (before 24 hours) verse late (24-72 hours) surgical decompression in terms of neurological …

Interrelation Of Inflammation And App In Sibm: Il-1 Beta Induces Accumulation Of Beta-Amyloid In Skeletal Muscle., Jens Schmidt, Konstanze Barthel, Arne Wrede, Mohammad Salajegheh, Mathias Bähr, Marinos C Dalakas

Department of Neurology Faculty Papers

Distinct interrelationships between inflammation and beta-amyloid-associated degeneration, the two major hallmarks of the skeletal muscle pathology in sporadic inclusion body myositis (sIBM), have remained elusive. Expression of markers relevant for these pathomechanisms were analysed in biopsies of sIBM, polymyositis (PM), dermatomyositis (DM), dystrophic and non-myopathic muscle as controls, and cultured human myotubes. By quantitative PCR, a higher upregulation was noted for the mRNA-expression of CXCL-9, CCL-3, CCL-4, IFN-gamma, TNF-alpha and IL-1 beta in sIBM muscle compared to PM, DM and controls. All inflammatory myopathies displayed overexpression of degeneration-associated markers, yet only in sIBM, expression of the mRNA of amyloid precursor …

Spinal Cord Stimulation: An Update., Steven Falowski, Amanda Celii, Ashwini Sharan

Department of Neurosurgery Faculty Papers

Spinal cord stimulation has been used in the treatment of many chronic pain disorders since 1967. In this update, the indications for spinal cord stimulation are reviewed with attention to recent publications. A focused review of the literature on abdominal and visceral pain syndromes is also provided. Furthermore, the technology has evolved from the use of monopolar electrodes to complex electrode arrays. Similarly, the power source has changed from a radio frequency-driven system to a rechargeable impulse generator. These topics are covered, along with a short discussion of implant technique. Finally, we include a review of complications of such therapy. …

Short-Wavelength Light Sensitivity Of Circadian, Pupillary, And Visual Awareness In Humans Lacking An Outer Retina, Farhan H. Zaidi, Joseph T. Hull, Stuart N. Peirson, Katharina Wulff, Daniel Aeschbach, Joshua J. Gooley, George C. Brainard, Kevin Gregory-Evans, Joseph F. Rizzo Iii, Charles A. Czeisler, Russell G. Foster, Merrick J. Moseley, Steven W. Lockley

Department of Neurology Faculty Papers

As the ear has dual functions for audition and balance, the eye has a dual role in detecting light for a wide range of behavioral and physiological functions separate from sight. These responses are driven primarily by stimulation of photosensitive retinal ganglion cells (pRGCs) that are most sensitive to short-wavelength ( approximately 480 nm) blue light and remain functional in the absence of rods and cones. We examined the spectral sensitivity of non-image-forming responses in two profoundly blind subjects lacking functional rods and cones (one male, 56 yr old; one female, 87 yr old). In the male subject, we found …

Developing "Human Functioning And Rehabilitation Research" From The Comprehensive Perspective., Gerold Stucki, Jan Dietrich Reinhardt, Gunnar Grimby, John Melvin

Department of Rehabilitation Medicine Faculty Papers

With the International Classification of Functioning, Disability and Health (ICF) the World Health Organization (WHO) has prepared the ground for a comprehensive understanding of Human Functioning and Rehabilitation Research, integrating the biomedical perspective on impairment with the social model of disability. This poses a number of old and new challenges regarding the enhancement of adequate research capacity. Here we will summarize approaches to address these challenges with respect to 3 areas: the organization of Human Functioning and Rehabilitation Research into distinct scientific fields, the development of suitable academic training programmes and the building of university centres and collaboration networks.

Meeting Report: The Role Of Environmental Lighting And Circadian Disruption In Cancer And Other Diseases, Richard G. Stevens, David E. Blask, George C. Brainard, Johnni Hansen, Steven W. Lockley, Ignacio Provencio, Mark S. Rea, Leslie Reinlib

Department of Neurology Faculty Papers

Light, including artificial light, has a range of effects on human physiology and behavior and can therefore alter human physiology when inappropriately timed. One example of potential light-induced disruption is the effect of light on circadian organization, including the production of several hormone rhythms. Changes in light-dark exposure (e.g., by nonday occupation or transmeridian travel) shift the timing of the circadian system such that internal rhythms can become desynchronized from both the external environment and internally with each other, impairing our ability to sleep and wake at the appropriate times and compromising physiologic and metabolic processes. Light can also have …

Cephalalgiaphobia: A Possible Specific Phobia Of Illness., Mario F P Peres, Juliane P P Mercante, Vera Z Guendler, Felipe Corchs, Marcio A Bernik, Eliova Zukerman, Stephen Silberstein

Department of Jefferson Headache Center Papers and Presentations

Psychiatric comorbidity, mainly anxiety and depression, are common in chronic migraine (CM). Phobias are reported by half of CM patients. Phobic avoidance associated with fear of headache or migraine attack has never been adequately described. We describe 12 migraine patients with particular phobic-avoidant behaviours related to their headache attacks, which we classified as a specific illness phobia, coined as cephalalgiaphobia. All patients were women, mean age 42, and all had a migraine diagnosis (11 CM, all overused acute medications). Patients had either a phobia of a headache attack during a pain-free state or a phobia of pain worsening during mild …

Dissociation Of Automatic And Strategic Lexical-Semantics: Functional Magnetic Resonance Imaging Evidence For Differing Roles Of Multiple Frontotemporal Regions, Brian T. Gold, David A. Balota, Sara J. Jones, David K. Powell, Charles D. Smith, Anders H. Andersen

Neuroscience Faculty Publications

Behavioral research has demonstrated three major components of the lexical-semantic processing system: automatic activation of semantic representations, strategic retrieval of semantic representations, and inhibition of competitors. However, these component processes are inherently conflated in explicit lexical-semantic decision tasks typically used in functional magnetic resonance imaging (fMRI) research. Here, we combine the logic of behavioral priming studies and the neurophysiological phenomenon of fMRI priming to dissociate the neural bases of automatic and strategic lexical-semantic processes across a series of three studies. A single lexical decision task was used in all studies, with stimulus onset asynchrony or linguistic relationship between prime and …

Spontaneous Intracranial Arterial Dissection In The Young: Diagnosis By Ct Angiography, William C. Robertson, Curtis A. Given

Neurology Faculty Publications

BACKGROUND: Spontaneous carotid artery dissections have been rarely reported in children. Diagnosis has traditionally been confirmed by catheter arteriography. More recently diagnosis has been made by magnetic resonance imaging and magnetic resonance angiography; however the sensitivity of these techniques has yet to be determined. The authors are unaware of reports of carotid dissection confirmed by dynamic computed tomography (computerized tomographic arteriography) in the young.

CASE PRESENTATION: We recently evaluated a fourteen year-old male following the development of transient neurologic symptoms. There was no antecedent illness or trauma. Dynamic computed tomography revealed an intracranial dissection involving the supraclinoid segment of the …

Estrogen Protects Against The Synergistic Toxicity By Hiv Proteins, Methamphetamine And Cocaine, Jadwiga Turchan, Caroline Anderson, Kurt F. Hauser, Qinmiao Sun, Jiayou Zhang, Ying Liu, Phyllis M. Wise, Inna Kruman, William Maragos, Mark P. Mattson, Rosemarie Booze, Avindra Nath

Neurology Faculty Publications

BACKGROUND: Human immunodeficiency virus (HIV) infection continues to increase at alarming rates in drug abusers, especially in women. Drugs of abuse can cause long-lasting damage to the brain and HIV infection frequently leads to a dementing illness. To determine how these drugs interact with HIV to cause CNS damage, we used an in vitro human neuronal culture characterized for the presence of dopaminergic receptors, transporters and estrogen receptors. We determined the combined effects of dopaminergic drugs, methamphetamine, or cocaine with neurotoxic HIV proteins, gp120 and Tat.

RESULTS: Acute exposure to these substances resulted in synergistic neurotoxic responses as measured by …

Global Cns Gene Transfer For A Childhood Neurogenetic Enzyme Deficiency: Canavan Disease., Paola Leone, Christopher G Janson, Scott J Mcphee, Matthew J During

Department of Neurosurgery Faculty Papers

The neurogenetic prototypic disease on which we chose to test our gene therapy strategy is Canavan disease (CD). CD is an autosomal recessive leukodystrophy associated with spongiform degeneration of the brain. At present the disease is uniformly fatal in affected probands. CD is characterized by mutations in the aspartoacylase (ASPA) gene, resulting in loss of enzyme activity. In this review, recent evidence is summarized on the etiology and possible treatments for CD. In particular, we discuss two gene delivery systems representing recent advances in both viral and liposome technology: a novel cationic liposome-polymer-DNA (LPD) complex, DCChol/DOPE-protamine, as well as recombinant …

Basic Fibroblast Growth Factor And Fibroblast Growth Factor Receptor I Are Implicated In The Growth Of Human Astrocytomas., R S Morrison, F Yamaguchi, H Saya, J M Bruner, Alan M. Yahanda Md, Facs, L A Donehower, M Berger

PCI Publications and Projects

Malignant astrocytomas are highly invasive, vascular neoplasms that comprise the majority of nervous system tumors in humans. A strong association has previously been made between malignancy in human astrocytic tumors and increased expression of certain fibroblast growth factor (FGF) family members, including basic and acidic FGF. The influence of endogenous basic FGF on glioblastoma cell growth in vitro was evaluated using basic FGF-specific antisense oligonucleotides. These studies indicated that human glioblastoma cell growth in vitro, can be inhibited by suppressing basic FGF expression. Human astrocytomas also exhibited changes in FGF receptor (FGFR) expression during the course of their progression from …