Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study.

Background: Demyelination of cerebral white matter is thought to drive neuronal degeneration and permanent neurological disability in individuals with multiple sclerosis. Findings from brain MRI studies, however, support the possibility that demyelination and neuronal degeneration can occur independently. We aimed to establish whether post-mortem brains from patients with multiple sclerosis show pathological evidence of cortical neuronal loss that is independent of cerebral white-matter demyelination.

JC Polyomavirus Abundance and Distribution in Progressive Multifocal Leukoencephalopathy (PML) Brain Tissue Implicates Myelin Sheath in Intracerebral Dissemination of Infection.

Over half of adults are seropositive for JC polyomavirus (JCV), but rare individuals develop progressive multifocal leukoencephalopathy (PML), a demyelinating JCV infection of the central nervous system. Previously, PML was primarily seen in immunosuppressed patients with AIDS or certain cancers, but it has recently emerged as a drug safety issue through its association with diverse immunomodulatory therapies. To better understand the relationship between the JCV life cycle and PML pathology, we studied autopsy brain tissue from a 70-year-old psoriasis patient on the integrin alpha-L inhibitor efalizumab following a ~2 month clinical course of PML.

Development of an Arthroscopic Joint Capsule Injury Model in the Canine Shoulder.

Background: The natural history of rotator cuff tears can be unfavorable as patients develop fatty infiltration and muscle atrophy that is often associated with a loss of muscle strength and shoulder function. To facilitate study of possible biologic mechanisms involved in early degenerative changes to rotator cuff muscle and tendon tissues, the objective of this study was to develop a joint capsule injury model in the canine shoulder using arthroscopy.

Methods: Arthroscopic surgical methods for performing a posterior joint capsulectomy in the canine shoulder were first defined in cadavers.

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

Background: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis.

TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models.

Variants in triggering receptor expressed on myeloid cells 2 (TREM2) confer high risk for Alzheimer's disease (AD) and other neurodegenerative diseases. However, the cell types and mechanisms underlying TREM2's involvement in neurodegeneration remain to be established. Here, we report that TREM2 is up-regulated on myeloid cells surrounding amyloid deposits in AD mouse models and human AD tissue.

Microglial derived tumor necrosis factor-α drives Alzheimer's disease-related neuronal cell cycle events.

Massive neuronal loss is a key pathological hallmark of Alzheimer's disease (AD). However, the mechanisms are still unclear. Here we demonstrate that neuroinflammation, cell autonomous to microglia, is capable of inducing neuronal cell cycle events (CCEs), which are toxic for terminally differentiated neurons.

Tuberculous radiculomyelitis presenting in a toddler with lower extremity weakness and seizure.

Tuberculous radiculomyelitis is an uncommon but serious complication of tuberculosis that can lead to considerable morbidity and mortality. We present the case of a 21-month-old male Congolese refugee diagnosed with tuberculous radiculomyelitis who presented with gradual motor and speech regression, and likely an infection-related seizure 2 months before diagnosis.

Hippocampal demyelination and memory dysfunction are associated with increased levels of the neuronal microRNA miR-124 and reduced AMPA receptors.

Objective: Hippocampal demyelination, a common feature of postmortem multiple sclerosis (MS) brains, reduces neuronal gene expression and is a likely contributor to the memory impairment that is found in >40% of individuals with MS. How demyelination alters neuronal gene expression is unknown.

Methods: To explore whether loss of hippocampal myelin alters expression of neuronal microRNAs (miRNAs), we compared miRNA profiles from myelinated and demyelinated hippocampi from postmortem MS brains and performed validation studies.

A rare corticotroph-secreting tumor with coexisting prolactin and growth hormone staining cells.

Pituitary adenomas can express and secrete different hormones. Expression of pituitary hormones in nonneoplastic pituitary cells is regulated by different transcription factors. Some pituitary adenomas show plurihormonal expression.

Clinically feasible MTR is sensitive to cortical demyelination in MS.

Objective: Presently there is no clinically feasible imaging modality that can effectively detect cortical demyelination in patients with multiple sclerosis (MS). The objective of this study is to determine if clinically feasible magnetization transfer ratio (MTR) imaging is sensitive to cortical demyelination in MS.

Methods: MRI were acquired in situ on 7 recently deceased patients with MS using clinically feasible sequences at 3 T, including relatively high-resolution T1-weighted and proton density-weighted images with/without a magnetization transfer pulse for calculation of MTR.

Cortical remyelination: a new target for repair therapies in multiple sclerosis.

Objective: Generation and differentiation of new oligodendrocytes in demyelinated white matter is the best described repair process in the adult human brain. However, remyelinating capacity falters with age in patients with multiple sclerosis (MS). Because demyelination of cerebral cortex is extensive in brains from MS patients, we investigated the capacity of cortical lesions to remyelinate and directly compared the extent of remyelination in lesions that involve cerebral cortex and adjacent subcortical white matter.

A technical approach to dissecting and assessing cadaveric veins pertinent to chronic cerebrospinal venous insufficiency in multiple sclerosis.

Objective: To establish a detailed technical procedure for studying the anatomical correlates of chronic cerebrospinal venous insufficiency in cadavers of multiple sclerosis and control subjects, and to present our findings of the normal anatomic venous structures, with reference to previous descriptions from the literature.

Methods: This study examined the internal jugular veins (IJVs), the brachiocephalic veins, and the azygos vein from 20 cadavers (10 control and 10 multiple sclerosis). These veins were exposed, isolated by clamps from the rest of the venous system, flushed with water, and then injected with fluid silicone from the superior ends of both IJVs.

Identification of VHY/Dusp15 as a regulator of oligodendrocyte differentiation through a systematic genomics approach.

Multiple sclerosis (MS) is a neuroinflammatory disease characterized by a progressive loss of myelin and a failure of oligodendrocyte (OL)-mediated remyelination, particularly in the progressive phases of the disease. An improved understanding of the signaling mechanisms that control differentiation of OL precursors may lead to the identification of new therapeutic targets for remyelination in MS. About 100 mammalian Protein Tyrosine Phosphatases (PTPs) are known, many of which are involved in signaling both in health and disease.

An unusual form of superficially disseminated glioma in children: report of 3 cases.

Three children, aged 4, 5, and 9 years, had an insidious onset of ataxia. Magnetic resonance imaging (MRI) showed hydrocephalus and countless foci of high T2 signal coating the cerebellum, basilar cisterns, brainstem, and fourth ventricle. Similar lesions were present in the spinal cord.

Demyelination causes synaptic alterations in hippocampi from multiple sclerosis patients.

Objective: Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system. Although the clinical impact of gray matter pathology in MS brains is unknown, 30 to 40% of MS patients demonstrate memory impairment. The molecular basis of this memory dysfunction has not yet been investigated in MS patients.

Interobserver and intraobserver reproducibility in focal cortical dysplasia (malformations of cortical development).

Purpose: Malformations of cortical development (MCD) (cortical dysplasias) are well-recognized causes of intractable epilepsy. Although a histologic classification system for MCD has been proposed by Palmini et al. (Neurology; 2004; 62:S2), studies to date have not assessed reproducibility.

NG2-positive glia in the human central nervous system.

Cells that express the NG2 chondroitin sulfate proteoglycan and platelet-derived growth factor receptor alpha (NG2 glia) are widespread in the adult human cerebral cortex and white matter and represent 10-15% of non-neuronal cells. The morphology and distribution of NG2 glia are similar to, but distinct from, both microglia and astrocytes. They are present as early as 17 weeks gestation and persist throughout life.

Beta4 tubulin identifies a primitive cell source for oligodendrocytes in the mammalian brain.

We have identified a novel population of cells in the subventricular zone (SVZ) of the mammalian brain that expresses beta4 tubulin (betaT4) and has properties of primitive neuroectodermal cells. betaT4 cells are scattered throughout the SVZ of the lateral ventricles in adult human brain and are significantly increased in the SVZs bordering demyelinated white matter in multiple sclerosis brains. In human fetal brain, betaT4 cell densities peak during the latter stages of gliogenesis, which occurs in the SVZ of the lateral ventricles.

Imaging correlates of leukocyte accumulation and CXCR4/CXCL12 in multiple sclerosis.

Objective: To compare leukocyte accumulation and expression of the chemokine receptor/ligand pair CXCR4/CXCL12 in magnetic resonance imaging-defined regions of interest (ROIs) in brains from patients with chronic multiple sclerosis. We studied the following ROIs: normal-appearing white matter (NAWM); regions abnormal only on T2-weighted images (T2 only); and regions abnormal on T2- and T1-weighted images with an abnormal magnetization transfer ratio (T2/T1/MTR).

Design: Case-control study.

Neurogenesis in the chronic lesions of multiple sclerosis.

Subcortical white matter in the adult human brain contains a population of interneurons that helps regulate cerebral blood flow. We investigated the fate of these neurons following subcortical white matter demyelination. Immunohistochemistry was used to examine neurons in normal-appearing subcortical white matter and seven acute and 59 chronic demyelinated lesions in brains from nine patients with multiple sclerosis and four controls.

Solitary Nocardia farcinica brain abscess in an immunocompetent adult mimicking metastatic brain tumor: rapid diagnosis by pyrosequencing and successful treatment.

Background: Nocardia brain abscess carries a higher morbidity and mortality rate than other bacterial cerebral abscesses, with reported mortality rates of 55% and 20% in immunocompromised and immunocompetent patients, respectively. To prevent a delay in diagnosis and treatment, an aggressive therapeutic approach is required. In the present study, a rapid and accurate molecular diagnostic approach using pyrosequencing (PS), a semiautomated molecular genotyping method of nucleotide sequencing-by-synthesis, was performed.

Inflammatory progressive multifocal leukoencephalopathy in human immunodeficiency virus-negative patients.

Objective: Inflammatory progressive multifocal leukoencephalopathy (iPML) with enhancing magnetic resonance imaging (MRI) lesions and leukocyte infiltration occurs in human immunodeficiency virus (HIV)-infected individuals after highly active antiretroviral therapy (HAART) treatment. MRI diagnostic criteria for PML suggest that iPML does not occur in HIV-negative individuals.

Methods: We studied pathologically proved PML (12 by biopsy, 9 with MRI, 32 at autopsy).

Neutrophilic myositis: an extra-intestinal manifestation of ulcerative colitis.

Myositis of the skeletal muscle is rarely seen as an extraintestinal manifestation of inflammatory bowel disease. We report a case of a 36-year-old man with ulcerative colitis who developed 3 episodes of steroid responsive myositis in a 4-month period. He presented with a blistering rash followed by pain and massive swelling in the right shoulder and lower extremities, with marked elevation in muscle enzymes.