published_or_final_version / Community Medicine / Master / Master of Public Health

HIV-associated sensory neuropathy (HIV-SN) is a common complication associated with human immunodeficiency virus (HIV)-infection. A common symptom of HIV-SN is pain. Variation at specific loci within certain candidate genes has been suggested to alter susceptibility to developing HIV-SN as well as the susceptibility to developing pain and the intensity of the pain experienced. Few studies, however, have been conducted in individuals of black African ancestry. The aim of the current research was to conduct an in-depth study, in a black Southern African population, of genes previously associated with susceptibility to developing HIV-SN (TNFA and surrounding genes and IL12B) and variations in pain susceptibility and intensity (GCH1, KCNS1, IL1B, IL6, CCL2 and CCR2) in other neuropathic pain states. Single nucleotide polymorphisms (SNPs) identified in the literature were supplemented with population appropriate tagSNPs to improve assessment of the genes in an African population. Genotyping of previously collected deoxyribonucleic acid (DNA) samples was carried out using a GoldenGate assay with VeraCode microbeads and data were read on an Illumina BeadXpress Reader. Data were statistically analysed to assess the association of the genetic variants with susceptibility to developing HIV-SN and pain and variability of pain intensity in those patients with painful HIV-SN. Although some SNPs and haplotypes in the genes investigated associated with HIV-SN susceptibility (TNFA region), pain susceptibility (TNFA region, IL12B, KCNS1, IL6 and CCR2) or pain intensity (TNFA region, KCNS1, IL1B and IL6), none of the results were consistent with that which has been found in previous studies in non-African populations. Reasons for this may be that associations are population-specific or model-specific. Limitations of the study included the use of a relatively small sample, the method of sampling (convenience sampling), genotyping failure and tagging inefficiency in some instances, and the fact that there is no Southern African population dataset to use for tagSNP selection. My findings emphasise the importance of conducting genetic association studies in separate ethnic groups.

The purpose of this study was to examine the relative risk of psychiatric disorders occurring in patients diagnosed with neurological disorders. This study separately computed the relative risk ratios for identified psychiatric disorder (i.e., anxiety, mood disorders, somatization, schizophrenia, alcohol abuse, and antisocial personality disorder) on seven of the more common neurological disorders (i.e., brain tumor, closed head injury, stroke, dementia, multiple sclerosis, cerebral palsy, and Parkinson's disease). The six psychiatric disorders were chosen based on the epidemiological catchment area (ECA) research (Robins & Reigier 1991) and provided the control group of psychiatric disorders in the general population by which comparisons were made to the neurological care setting. The neurological disorders were included based on the frequency of referrals to a neuropsychological practice. Further, this study provided an overall relative risk ratio of psychiatric disorders for all seven neurological disorders considered together.Participants in this study included a sample of 367 consecutive referrals to a neurology practice in the Midwest. All of the 376 subjects were diagnosed with a neurological disorder. Two hundred forty-six of the subjects were diagnosed with a neurological disorder and no psychiatric disorder. One hundred twenty-one of the subjects were diagnosed with both a neurological and a psychiatric disorder. The MMPI2 was used in the assessment and diagnosis of psychiatric disorders. The control group, represented by the ECA study, was composed of 19,640 participants.Relative risk estimates were made using cross products ratio. Significance of the risk ratio was tested using Chi-square Continuity Correction values. Power analysis was conducted using Fisher's Exact Test.The results of the analysis suggested that patients with neurological disorders are more likely to present with psychiatric disorders compared to the general population. The overall relative risk for this study revealed that patients were 1.669 times more likely to have a comorbid psychiatric disorder following the diagnosis of a neurological disorder. Additionally, three individual disorders had relative risk ratios suggesting an increase in psychiatric disorders above the risk in the general population. These three conditions included stroke (RR = 3.038), dementia (RR = 2.762), and multiple sclerosis (RR = 3.617). / Department of Educational Psychology

The purpose of the study was to investigate a possible connection between alpha-l-antitrypsin (A1AT) deficiency and familial epilepsy and mental retardation of possible congenital or genetic origin.The individuals were genotyped by using a two dimensional cross-electrophoretic procedure. The electrophoretic procedure involved isoelectric focusing on an acid-starch gel followed by immunoelectrophoresis. The control and experimental groups were then statistically compared to population norms by using the chi-square test. The 0.05 level of significance was established as the critical probability level for the nonacceptance of a connection.ResultsOf the 49 individuals in the control group, 46 had, a protease inhibitor (Pi) genotype of PiMM 1 , and there was 1 each of the Pi MF, Pi MS, and Pi Mz genotypes. Of the 50individuals in the familial epilepsy experimental group, 43 were genotyped as PiMM, 2 as PiMS, and 5 as PIMF. Of the 16 individuals in the mental retardation experimental group, 14 were genotyped as PiMM, 1 as PiMS, and 1 as PiMF.The probability of reoccurrence for the various groups were: control - 0.3 to 0.5; familial epilepsy - 0.3 to 0.5; and mental retardation - 0.7 to 0.8.Conclusions1. The applicability of starch gel electrophoresis in a clinical setting is questionable because of cost, length of time required, and difficulty in handling.2. The control group demonstrated no statistical variation in the 1AT frequency from general population norms.3. The familial epilepsy experimental group showed no statistical evidence linking it to abnormal A1AT genotypes.4. The mental retardation experimental group demonstrated no statistical evidence linking it to abnormal A.1 AT genotypes.

Thesis (Ph.D.)--Virginia Commonwealth University, 2008. / Prepared for: Dept. of Anatomy and Neurobiology. Bibliography: leaves 164-205. Also available online via the Internet.

Tolosa-Hunt syndrome is a rare neurological disorder with an incidence of one case per million. It is a granulomatous inflammatory condition that affects the cavernous sinus and is characterized by painful ophthalmoplegia and headaches. We present a 57-year-old male veteran with past medical history of alcohol use disorder, hepatitis c, hypertension and tobacco use who presented with complaints of double vision and headaches for 2 days. The patient also had a history of well controlled cluster headaches treated with sumatriptan. But, he reported that from several days prior to admission, the headaches were getting more frequent, sharp, localized to the left side, and preventing him from sleeping. On physical exam, vitals were stable, the neck was supple, the pupils were equal in size and reactive to light but limited left eye abduction and external rotation were noted. The remainder of physical exam was unremarkable including the remaining cranial nerves. Computerized tomography (CT) head was done which showed no evidence of acute stroke. Magnetic resonance imagining (MRI) brain was performed which showed an asymmetric bulge of the left cavernous sinus which raised suspicion for cavernous sinus inflammation. Systemic high dose steroid trial was given. Patient’s symptoms improved within 72 hours and diagnosis of Tolosa-Hunt Syndrome was confirmed. According to the National Organisation for Rare Disorders (NORD) the average age of onset for this condition is 41 years. The pathogenesis is thought to be inflammation of unknown etiology. The criteria for diagnosis fo Tolosa-Hunt syndrome is given by International Headache Society, which includes: Unilateral headache; MRI or biopsy demonstrating granulomatous inflammation of cavernous sinus, superior orbital fissure or orbit; ipsilateral nerve palsy involving one or more of 3rd, 4th and/or 6th cranial nerves; no alternate diagnosis based on the symptoms; specific history of ipsilateral headache localized to the ipsilateral brow and eye and it should occur 2 week before the oculomotor palsy or along with it. Our patient met all the criteria mentioned above. Ruling out other causes of headache and ophthalmoplegia is important in making the diagnosis. A differential diagnosis includes cavernous sinus thrombosis, stroke, vasculitis, myasthenia gravis, Miller Fisher variant of GBS, multiple sclerosis and idiopathic intracranial hypertension. Currently, inadequate data is available to determine the best route and duration of treatment with steroids. Our patient received oral steroid 100 mg for 3 days followed by slow steroid taper and had improvement in symptoms. Although a rare disorder, it is important to consider Tolosa-Hunt syndrome in the differential diagnosis of patients who presents with headaches and visual changes, especially after ruling out other common causes.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). Neuropathological studies in both human MS and the experimental autoimmune encephalomyelitis (EAE) animal model have shown that endothelial cell (EC) inflammation, associated with focal breakdown of the blood-brain barrier (BBB) and neo-angiogenesis, is prevalent in demyelinating plaques. Neo-angiogenesis and BBB damage contribute to leakage of serum components, infiltration of immune cells into the CNS, neuroinflammation, axonal demyelination, neuronal dysfunction, and disease progression. In Chapter 1, I introduce MS and its pathological hallmarks related to immune and vascular dysfunctions, the clinical course of MS progression, genetic and environmental influences, current treatments, and animal models. Next, I elaborate upon the pathways and processes involved in the development of a functioning CNS vascular system and the BBB. Finally, I discuss what is currently known about the contribution and the underlying mechanisms of neo-angiogenesis in MS and other diseases. While an increase in vessel density has been documented for both MS and EAE lesions, the origin and pathways that drive formation of new, but leaky, blood vessels in EAE are poorly understood. In Chapter 3, I address these questions by performing single-cell RNA-sequencing (scRNA-seq) of 45309 ECs isolated from the spinal cord of control, acute and chronic MOG35-55 EAE mice. Based on expression patterns of blood vessel subtype-specific markers, I identified 23 distinct EC clusters with arterial, capillary, venule, and vein identities in either control or disease states. I performed differential gene expression and gene set enrichment analyses comparing control and disease EC clusters for each vascular subtype to identify which vessels exhibited gene expression profiles indicative of neo-angiogenesis in EAE. I found that molecular signatures of neo-angiogenesis are upregulated specifically in venous ECs during acute and, to a lesser extent, chronic EAE. Consistent with these data, EC proliferation is upregulated in veins in the EAE spinal cord. RNA fluorescent in situ hybridization and immunofluorescence staining confirmed increased expression of key angiogenic markers Egfl7, Ecm1, Serpine1 and Emcn, and the tip cell marker Mcam, with a corresponding increase in vein density, in demyelinating white matter lesions of EAE spinal cords relative to controls. I also assessed changes in expression of some of these markers in human MS tissue and discovered upregulated expression of EGFL7 in cortical white matter lesions of MS patients, concomitant with increased vascular density. In Chapter 4, I examine the signaling pathways that may trigger pathogenic angiogenesis in EAE. I discovered that, in contrast to developmental angiogenesis, VEGF-A and TGF-β signaling may act as the driver of neo-angiogenesis in EAE. To test this hypothesis, I used a humanized VEGF-A blocking antibody, bevacizumab, to block VEGF signaling and found that this treatment ameliorated the MOG35-55 EAE neurological score by reducing expression of several angiogenic markers Egfl7, Ecm1, Serpine1, and Emcn, as confirmed by both in situ hybridization and computational analysis of scRNA-seq data. Immune profiling of spleens and spinal cords by flow cytometry did not show changes in immune cell activation in bevacizumab-treated mice relative to IgG controls, indicating that the protective effects of VEGF blockade are not due to defects in the initiation of the immune response. Finally, in Chapter 5, I summarize the major findings of my dissertation and propose a model for the mechanisms by which neo-angiogenesis contributes to pathology in MS/EAE. I also present several future avenues of research that can be pursued to further our understanding of the molecular and cellular changes underlying pathogenic angiogenesis and its role in MS/EAE. While most current disease-modifying MS therapies aim to reduce inflammation and infiltration of immune cells into the CNS, these findings may lead to development of additional potential therapeutics that may reduce pathogenic neo-angiogenesis in order to alleviate long-term neurological deficits in MS. Additionally, since postcapillary venules and veins are the major sites of immune cell infiltration, BBB damage and neo-angiogenesis in EAE, the findings of this study suggest that development of treatment modalities that target venous ECs with anti-angiogenic compounds may be more effective in inhibiting the growth of pathogenic neovessels than therapies directed against the entire endothelium.

Postural orthostatic tachycardia syndrome (POTS) is a common yet frequently misdiagnosed dysautonomia characterized by a significant increase in heart rate upon standing. POTS patients experience severe fatigue, dizziness, pre-syncope, and a diminished quality of life. The intent of this thesis is to investigate factors contributing to POTS misdiagnosis and develop a proposal for improving diagnostic procedures. The first part of this thesis presents an overview of other frequently misdiagnosed conditions, providing an understanding of the basis for the diagnostic problems in POTS and methods to combat such difficulties. The second part of this thesis details a meta-analysis performed on POTS clinical studies since its classification in 1993, in an attempt to synthesize current knowledge and potential deficits in research. Results show the misdiagnosis rates for POTS are understandably high, as POTS shares many characteristics with other misdiagnosed conditions. Analysis of these conditions demonstrates the need for easier in-clinic diagnostic tests for POTS. The meta-analysis results demonstrate misunderstanding about POTS remains within the scientific community. The final recommendations to reduce POTS misdiagnosis include using a blood pressure/heart rate screening test to identify patients sooner and shifting research efforts from etiology and treatment to prevalence and diagnostic procedures.

published_or_final_version / abstract / Medicine / Doctoral / Doctor of Philosophy

This project consists of three distinct, but sequential studies that explore the psychological factors and neuropathological substrates of metacognition or self-awareness among older adults. Study 1 examines the premorbid, psychological characteristics associated with metamemory—the mainstay of metacognitive research—in a healthy, community-dwelling cohort of older adults. Study 2 builds on these analyses, and examines the psychological characteristics associated with metacognition, more broadly, in a neurologic cohort of older adults with Essential Tremor (ET). Study 3, which utilizes post-mortem evaluations of participants from Study 2, goes beyond premorbid characteristics and examines whether distortions in metacognition are in part attributable to an underlying disease process. Findings demonstrated that psychological characteristics were associated with metacognitive accuracy in a healthy, community-dwelling cohort of older adults, but not among individuals with ET; further, distortions in metacognition among individuals with ET were better attributable to non-ET specific pathologies, such as amyloid β, neurofibrillary tangles, and regional-specific atrophy. This project underscores the importance of employing a biopsychosocial approach to understanding the factors that influence metacognition. Ultimately, by understanding and working effectively with awareness phenomena, there is a strong potential to reduce disability and enhance well-being.