Preservation Of Axons Research Articles

Sphingosine-1-Phosphate Receptor Antagonism Enhances Proliferation and Migration of Engrafted Neural Progenitor Cells in a Model of Viral-Induced Demyelination

The oral drug FTY720 affects sphingosine-1-phosphate (S1P) signaling on targeted cells that bear the S1P receptors S1P1, S1P3, S1P4, and S1P5. We examined the effect of FTY720 treatment on the biology of mouse neural progenitor cells (NPCs) after transplantation in a viral model of demyelination. Intracerebral infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV) resulted in an acute encephalomyelitis, followed by demyelination similar in pathology to the human demyelinating disease, multiple sclerosis. We have previously reported that intraspinal transplantation of mouse NPCs into JHMV-infected animals resulted in selective colonization of demyelinated lesions, preferential differentiation into oligodendroglia accompanied by axonal preservation, and increased remyelination. Cultured NPCs expressed transcripts for S1P receptors S1P1, S1P2, S1P3, S1P4, and S1P5. FTY720 treatment of cultured NPCs resulted in increased mitogen-activated protein kinase phosphorylation and migration after exposure to the chemokine CXCL12. Administration of FTY720 to JHMV-infected mice resulted in enhanced migration and increased proliferation of transplanted NPCs after spinal cord engraftment. FTY720 treatment did not improve clinical disease, diminish neuroinflammation or the severity of demyelination, nor increase remyelination. These findings argue that FTY720 treatment selectively increases NPC proliferation and migration but does not either improve clinical outcome or enhance remyelination after transplantation into animals in which immune-mediated demyelination is initiated by the viral infection of the central nervous system.

A nutrient combination designed to enhance synapse formation and function improves outcome in experimental spinal cord injury

Spinal cord injury leads to major neurological impairment for which there is currently no effective treatment. Recent clinical trials have demonstrated the efficacy of Fortasyn® Connect in Alzheimer's disease. Fortasyn® Connect is a specific multi-nutrient combination containing DHA, EPA, choline, uridine monophosphate, phospholipids, and various vitamins. We examined the effect of Fortasyn® Connect in a rat compression model of spinal cord injury. For 4 or 9weeks following the injury, rats were fed either a control diet or a diet enriched with low, medium, or high doses of Fortasyn® Connect. The medium-dose Fortasyn® Connect-enriched diet showed significant efficacy in locomotor recovery after 9weeks of supplementation, along with protection of spinal cord tissue (increased neuronal and oligodendrocyte survival, decreased microglial activation, and preserved axonal integrity). Rats fed the high-dose Fortasyn® Connect-enriched diet for 4weeks showed a much greater enhancement of locomotor recovery, with a faster onset, than rats fed the medium dose. Bladder function recovered quicker in these rats than in rats fed the control diet. Their spinal cord tissues showed a smaller lesion, reduced neuronal and oligodendrocyte loss, decreased neuroinflammatory response, reduced astrocytosis and levels of inhibitory chondroitin sulphate proteoglycans, and better preservation of serotonergic axons than those of rats fed the control diet. These results suggest that this multi-nutrient preparation has a marked therapeutic potential in spinal cord injury, and raise the possibility that this original approach could be used to support spinal cord injured patients.

Proteolipid protein modulates preservation of peripheral axons and premature death when myelin protein zero is lacking.

Protein zero (P0) is the major structural component of peripheral myelin. Lack of this adhesion protein from Schwann cells causes a severe dysmyelinating neuropathy with secondary axonal degeneration in humans with the neuropathy Dejerine-Sottas syndrome (DSS) and in the corresponding mouse model (P0(null)-mice). In the mammalian CNS, the tetraspan-membrane protein PLP is the major structural myelin constituent and required for the long-term preservation of myelinated axons, which fails in hereditary spastic paraplegia (SPG type-2) and the relevant mouse model (Plp(null)-mice). The Plp-gene is also expressed in Schwann cells but PLP is of very low abundance in normal peripheral myelin; its function has thus remained enigmatic. Here we show that the abundance of PLP but not of other tetraspan myelin proteins is strongly increased in compact peripheral myelin of P0(null)-mice. To determine the functional relevance of PLP expression in the absence of P0, we generated P0(null)*Plp(null)-double-mutant mice. Compared with either single-mutant, P0(null)*Plp(null)-mice display impaired nerve conduction, reduced motor functions, and premature death. At the morphological level, axonal segments were frequently non-myelinated but in a one-to-one relationship with a hypertrophic Schwann cell. Importantly, axonal numbers were reduced in the vital phrenic nerve of P0(null)*Plp(null)-mice. In the absence of P0, thus, PLP also contributes to myelination by Schwann cells and to the preservation of peripheral axons. These data provide a link between the Schwann cell-dependent support of peripheral axons and the oligodendrocyte-dependent support of central axons.

204. Treatment with Modified Erythropoietin Gene Therapy Is Neuroprotective in a Mouse Model of Induced Ocular Hypertension

Gene delivery of modified EPO attenuates glaucomatous pathology of retinal ganglion cells in the induced model of ocular hypertension. Pre-treatment with EPO gene therapy provides more robust preservation of RGC axons than EPO gene therapy commenced at onset of hypertension. Delayed gene therapy preserves axon transport significantly, however, which may be due to delayed therapy preserving normal function of surviving RGC axons while failing to attenuate early axon loss.

A single dose of a neuron-binding human monoclonal antibody improves brainstem NAA concentrations, a biomarker for density of spinal cord axons, in a model of progressive multiple sclerosis.

BackgroundIntracerebral infection of susceptible mouse strains with Theiler’s murine encephalomyelitis virus (TMEV) results in chronic demyelinating disease with progressive axonal loss and neurologic dysfunction similar to progressive forms of multiple sclerosis (MS). We previously showed that as the disease progresses, a marked decrease in brainstem N-acetyl aspartate (NAA; metabolite associated with neuronal integrity) concentrations, reflecting axon health, is measured. We also demonstrated stimulation of neurite outgrowth by a neuron-binding natural human antibody, IgM12. Treatment with either the serum-derived or recombinant human immunoglobulin M 12 (HIgM12) preserved functional motor activity in the TMEV model. In this study, we examined IgM-mediated changes in brainstem NAA concentrations and central nervous system (CNS) pathology.Findings1H-magnetic resonance spectroscopy (MRS) showed that treatment with HIgM12 significantly increased brainstem NAA concentrations compared to controls in TMEV-infected mice. Pathologic analysis demonstrated a significant preservation of axons in the spinal cord of animals treated with HIgM12.ConclusionsThis study links drug efficacy of slowing deficits with axon preservation and NAA concentrations in the brainstem in a model of progressive MS. HIgM12-mediated changes of NAA concentrations in the brainstem are a surrogate marker of axon injury/preservation throughout the spinal cord. This study provides proof-of-concept that a neuron-reactive human IgM can be therapeutic and provides a biomarker for clinical trials.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0303-y) contains supplementary material, which is available to authorized users.

How Klingler's dissection permits exploration of brain structural connectivity? An electron microscopy study of human white matter.

The objective of this study is to explore histological and ultrastructural changes induced by Klingler's method. Five human brains were prepared. First, the effects of freezing-defrosting on white matter were explored with optical microscopy on corpus callosum samples of two brains; one prepared in accordance with the description of Klingler (1956) and the other without freezing-defrosting. Then, the combined effect of formalin fixation and freezing-defrosting was explored with transmission electron microscopy (EM) on samples of cingulum from one brain: samples from one hemisphere were fixed in paraformaldehyde-glutaraldehyde (para/gluta), other samples from the other hemisphere were fixed in formalin; once fixed, half of the samples were frozen-defrosted. Finally, the effect of dissection was explored from three formalin-fixed brains: one hemisphere of each brain was frozen-defrosted; samples of the corpus callosum were dissected before preparation for scanning EM. Optical microscopy showed enlarged extracellular space on frozen samples. Transmission EM showed no significant alteration of white matter ultrastructure after formalin or para/gluta fixation. Freezing-defrosting created extra-axonal lacunas, larger on formalin-fixed than on para/gluta-fixed samples. In all cases, myelin sheaths were preserved, allowing maintenance of axonal integrity. Scanning EM showed the destruction of most of the extra-axonal structures after freezing-defrosting and the preservation of most of the axons after dissection. Our results are the first to highlight the effects of Klingler's preparation and dissection on white matter ultrastructure. Preservation of myelinated axons is a strong argument to support the reliability of Klingler's dissection to explore the structure of human white matter.

GGF2 is neuroprotective in a rat model of cavernous nerve injury-induced erectile dysfunction.

Erectile dysfunction is a major complication of radical prostatectomy, commonly associated with penile neuropathy. In animal models of peripheral nerve injury, glial growth factor-2 (GGF2), a member of the neuregulin family of growth factors, has neuroprotective and neurorestorative properties, but this potential has not been established after cavernous nerve (CN) injury. The effectiveness of GGF2 in preserving axonal integrity and recovering erectile function in a rat model of radical prostatectomy-associated CN injury. Adult male Sprague-Dawley rats underwent bilateral CN crush injury (BCNI) or sham surgery. Rats were administered GGF2 (0.5, 5, or 15 mg/kg) or vehicle subcutaneously 24 hour pre and 24-hour post-BCNI, and once weekly for 5 weeks. Erectile function was assessed in response to electrical stimulation of the CN. CN survival was assessed by fluorogold retrograde axonal tracing in major pelvic ganglia (MPG). Unmyelinated axons in the CNs were quantitated by electron microscopy. Erectile function recovery, CN survival, and unmyelinated CN axon preservation in response to GGF2 treatment following BCNI. Erectile function was decreased (P < 0.05) after BCNI, and it was improved (P < 0.05) by all doses of GGF2. The number of fluorogold-labeled cells in the MPG was reduced (P < 0.05) by BCNI and was increased (P < 0.05) by GGF2 (0.5 and 5 mg/kg). The percentage of denervated Schwann cells in the BCNI group was higher (P < 0.05) than that in the sham-treated group and was decreased (P < 0.05) in the GGF2-treated (5 mg/kg) BCNI group. In the BCNI + GGF2 (5 mg/kg) group, the unmyelinated fiber histogram demonstrated a rightward shift, indicating an increased number of unmyelinated axons per Schwann cell compared with the BCNI group. GGF2 promotes erectile function recovery following CN injury in conjunction with preserving unmyelinated CN fibers. Our findings suggest the clinical opportunity to develop GGF2 as a neuroprotective therapy for radical prostatectomy.

Activation of Nuclear Receptors RAR, RXR, and LXR Does Not Reduce Cuprizone-Induced Demyelination in Mice

Experiments with animal models of multiple sclerosis have shown that the expression of retinoid X receptors (RXR) increases during demyelination and that RXR is involved in the regulation of remyelination. After ligand binding RXRs form heterodimeric transcription factors with other nuclear receptor (NR) families including the retinoic acid receptors (RAR) and liver X receptors (LXR). We tested whether activation of these nuclear receptor complexes reduces pathological demyelination using the cuprizone mouse model. Cuprizone, which causes oligodendrocyte degeneration, was given for three weeks as a food additive. For the activation of nuclear receptors mice were treated with daily i.p. injections of agonists for RXR (9-cis RA), RAR (all-trans RA), and LXR (T0901317). Myelin status, oligodendrocyte survival, astrogliosis, microglial activation, and axon density were monitored with immunohistochemistry and evaluated quantitatively. Three weeks of cuprizone feeding caused severe demyelination and significantly raised the number of Iba1 immunoreactive microglia cells in the caudal corpus callosum. This increase of microglia activity was reduced with 9-cis RA treatment but was enhanced with all-trans RA and was not affected by T0901317. Nuclear receptor activation did not influence the degree of demyelination, oligodendrocyte survival, astrogliosis, or axonal preservation. We conclude that RXR activation, although affecting Iba1-positive microglia, does not protect oligodendrocytes from cuprizone toxicity and does not induce compensatory mechanisms in the initial phase of demyelination.

Acute optic neuritis: a clinical paradigm for evaluation of neuroprotective and restorative strategies?

What makes the acute optic neuritis model unique in an era of trials for neuroprotective and myelin repair agents? Acute optic neuritis (AON) is a common, and often the earliest manifestation of central nervous system (CNS) inflammatory demyelinating disorders like multiple sclerosis (MS) and neuromyelitis optica (NMO). It affects at least half the patients with MS and is the presenting feature in 15–20% of patients. Vision loss in AON secondary to NMO tends to be more severe with less potential for recovery and greater axonal degeneration, as measured by optical coherence tomography (OCT) (Bennett et al., 2014). Several unique features of the afferent visual pathway (AVP) make the AON model an ideal system to study disease pathogenesis and evaluate potential neuroprotective and myelin repair strategies.

Chronic exercise confers neuroprotection in experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an autoimmune disease that affects the CNS, resulting in accumulated loss of cognitive, sensory, and motor function. This study evaluates the neuropathological effects of voluntary exercise in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Two groups of C57BL/6J mice were injected with an emulsion containing myelin oligodendrocyte glycoprotein and then randomized to housing with a running wheel or a locked wheel. Exercising EAE mice exhibited a less severe neurological disease score and later onset of disease compared with sedentary EAE animals. Immune cell infiltration and demyelination in the ventral white matter tracts of the lumbar spinal cord were significantly reduced in the EAE exercise group compared with sedentary EAE animals. Neurofilament immunolabeling in the ventral pyramidal and extrapyramidal motor tracts displayed a more random distribution of axons and an apparent loss of smaller diameter axons, with a greater loss of fluorescence immunolabeling in the sedentary EAE animals. In lamina IX gray matter regions of the lumbar spinal cord, sedentary animals with EAE displayed a greater loss of α-motor neurons compared with EAE animals exposed to exercise. These findings provide evidence that voluntary exercise results in reduced and attenuated disability, reductions in autoimmune cell infiltration, and preservation of axons and motor neurons in the lumbar spinal cord of mice with EAE.

Analysis of pathological characteristics of acute and chronic cerebral tumefactive demyelinating lesions

To summarize the clinical features, neuroimaging findings and pathological characteristics of pathologically confirmed tumefactive demyelinating lesions (TDL). The clinical features, neuroimaging findings and pathological characteristics were retrospectively collected and analyzed for 58 patients with pathologically confirmed TDLs.For pathological studies, a combination of hematoxylin and eosin staining, myelin staining (Luxol fast blue/periodic acid-Schiff or immunohistochemistry for myelin basic protein), macrophage-specific marker (immunohistochemistry for KiM1P or CD68) and staining for axons (Bielschowski silver impregnation or immunohistochemistry for neurofilament protein) were employed. The mean age of onset was 6-56 (36 ± 13) years. The onsets were acute (n = 21, 36%), subacute (n = 27, 46.5%) and chronic (n = 10, 17.5%). The diagnoses of TDL were confirmed by repeat biopsy and pathological examinations (n = 2, 3.4%).In acute phase, the plaques of lesions were characterized by massive demyelination with relatively axonal preservation associated with prominent reactive astrocytosis and profound infiltrates of macrophages.In plaques of chronic lesions, demyelinated lesions with relative axonal preservation and sharply defined margins were major findings. And myelin-laden macrophages accumulated at the edges of plaques and stayed relatively inactive with densely gliotic center and processbearing astrocytosis. TDL is a distinct entity of demyelinating disease.Even though it is often misdiagnosed as neoplasm in brain, bilateral brain involvements and multiple lesions are more common in TDL. The pathological features of TDL are important for the early diagnosis of this disease and helpful for differentiating with brain tumors and central nervous system vasculitis.

Delayed administration of a bio-engineered zinc-finger VEGF-A gene therapy is neuroprotective and attenuates allodynia following traumatic spinal cord injury.

Following spinal cord injury (SCI) there are drastic changes that occur in the spinal microvasculature, including ischemia, hemorrhage, endothelial cell death and blood-spinal cord barrier disruption. Vascular endothelial growth factor-A (VEGF-A) is a pleiotropic factor recognized for its pro-angiogenic properties; however, VEGF has recently been shown to provide neuroprotection. We hypothesized that delivery of AdV-ZFP-VEGF – an adenovirally delivered bio-engineered zinc-finger transcription factor that promotes endogenous VEGF-A expression – would result in angiogenesis, neuroprotection and functional recovery following SCI. This novel VEGF gene therapy induces the endogenous production of multiple VEGF-A isoforms; a critical factor for proper vascular development and repair. Briefly, female Wistar rats – under cyclosporin immunosuppression – received a 35 g clip-compression injury and were administered AdV-ZFP-VEGF or AdV-eGFP at 24 hours post-SCI. qRT-PCR and Western Blot analysis of VEGF-A mRNA and protein, showed significant increases in VEGF-A expression in AdV-ZFP-VEGF treated animals (p<0.001 and p<0.05, respectively). Analysis of NF200, TUNEL, and RECA-1 indicated that AdV-ZFP-VEGF increased axonal preservation (p<0.05), reduced cell death (p<0.01), and increased blood vessels (p<0.01), respectively. Moreover, AdV-ZFP-VEGF resulted in a 10% increase in blood vessel proliferation (p<0.001). Catwalk™ analysis showed AdV-ZFP-VEGF treatment dramatically improves hindlimb weight support (p<0.05) and increases hindlimb swing speed (p<0.02) when compared to control animals. Finally, AdV-ZFP-VEGF administration provided a significant reduction in allodynia (p<0.01). Overall, the results of this study indicate that AdV-ZFP-VEGF administration can be delivered in a clinically relevant time-window following SCI (24 hours) and provide significant molecular and functional benefits.

Neuroprotective dimethyl fumarate synergizes with immunomodulatory interferon beta to provide enhanced axon protection in autoimmune neuroinflammation

IntroductionDespite recent advances in development of treatments for multiple sclerosis, there is still an unmet need for more effective and also safe therapies. Based on the modes of action of interferon-beta (IFN-β) and dimethyl fumarate (DMF), we hypothesized that anti-inflammatory and neuroprotective effects may synergize in experimental autoimmune encephalomyelitis (EAE). MethodsEAE was induced in C57BL/6 mice by immunization with MOG35–55-peptide. Murine IFN-β was injected s.c. every other day at 10.000IU, and DMF was provided at 15mg/kg by oral gavage twice daily. Control mice received PBS injections and were treated by oral gavage with the vehicle methylcellulose. Mice were scored daily by blinded observers and histological, FACS and cytokine studies were performed to further elucidate the underlying mechanism of action. ResultsCombination therapy significantly ameliorated EAE disease course in comparison to controls and monotherapy with IFN-β. Histological analyses showed a significant effect on axon preservation with almost twice as much axons present in inflamed lesions as compared to control. Remarkably, the effect on axonal preservation was more pronounced under combination therapy than with both monotherapies. Neither monotherapy nor combination therapy demonstrated modulation of cytokines and frequency of antigen presenting cells. DiscussionCombination of IFN-β and DMF resulted in greater beneficial effects with improved tissue protection as compared to the respective monotherapies. Further combination studies of these safe therapies in human disease are warranted.

Targeting Insulin-Like Growth Factor 1 Leads to Amelioration of Inflammatory Demyelinating Disease

In patients with multiple sclerosis (MS) and in mice with experimental autoimmune encephalomyelitis (EAE), proliferating autoreactive T cells play an important role in the pathogenesis of the disease. Due to the importance of these myelin-specific T cells, these cells have been therapeutic targets in a variety of treatments. Previously we found that Lenaldekar (LDK), a novel small molecule, could inhibit exacerbations in a preclinical model of MS when given at the start of an EAE exacerbation. In those studies, we found that LDK could inhibit human T cell recall responses and murine myelin responses in vitro. In these new studies, we found that LDK could inhibit myelin specific T cell responses through the insulin-like growth factor-1 receptor (IGF-1R) pathway. Alteration of this pathway led to marked reduction in T cell proliferation and expansion. Blocking this pathway could account for the observed decreases in clinical signs and inflammatory demyelinating disease, which was accompanied by axonal preservation. Our data indicate that IGF-1R could be a potential target for new therapies for the treatment of autoimmune diseases where autoreactive T cell expansion is a requisite for disease.

Large-Scale Chondroitin Sulfate Proteoglycan Digestion with Chondroitinase Gene Therapy Leads to Reduced Pathology and Modulates Macrophage Phenotype following Spinal Cord Contusion Injury

Chondroitin sulfate proteoglycans (CSPGs) inhibit repair following spinal cord injury. Here we use mammalian-compatible engineered chondroitinase ABC (ChABC) delivered via lentiviral vector (LV-ChABC) to explore the consequences of large-scale CSPG digestion for spinal cord repair. We demonstrate significantly reduced secondary injury pathology in adult rats following spinal contusion injury and LV-ChABC treatment, with reduced cavitation and enhanced preservation of spinal neurons and axons at 12 weeks postinjury, compared with control (LV-GFP)-treated animals. To understand these neuroprotective effects, we investigated early inflammatory changes following LV-ChABC treatment. Increased expression of the phagocytic macrophage marker CD68 at 3 d postinjury was followed by increased CD206 expression at 2 weeks, indicating that large-scale CSPG digestion can alter macrophage phenotype to favor alternatively activated M2 macrophages. Accordingly, ChABC treatment in vitro induced a significant increase in CD206 expression in unpolarized monocytes stimulated with conditioned medium from spinal-injured tissue explants. LV-ChABC also promoted the remodelling of specific CSPGs as well as enhanced vascularity, which was closely associated with CD206-positive macrophages. Neuroprotective effects of LV-ChABC corresponded with improved sensorimotor function, evident as early as 1 week postinjury, a time point when increased neuronal survival correlated with reduced apoptosis. Improved function was maintained into chronic injury stages, where improved axonal conduction and increased serotonergic innervation were also observed. Thus, we demonstrate that ChABC gene therapy can modulate secondary injury processes, with neuroprotective effects that lead to long-term improved functional outcome and reveal novel mechanistic evidence that modulation of macrophage phenotype may underlie these effects.

Axonal Preservation in Deep Subcortical White Matter Lesions in the Ageing Brain

Cerebral white matters lesions (WML) are seen in 94% of the population aged 64 and over and are associated with cognitive decline and depression. We used immunohistochemistry and stereological methods on post mortem brain samples derived from the Medical Research Council Cognitive Function and Ageing Study (MRC-CFAS) cohort to investigate the axonal density within deep subcortical lesions. There was no significant difference between the lesional and control white matter, therefore, we conclude that there is axonal preservation within these lesions that are characterized by demyelination.

Two faces of Schwann cell dedifferentiation in peripheral neurodegenerative diseases: pro-demyelinating and axon-preservative functions.

In vertebrates, Schwann cells are glial cells that form a myelin sheath, which produces the saltatory conduction of neural impulses in the peripheral nervous system (Sherman and Brophy, 2005). In the case of abnormal myelin sheath generation due to genetic mutations or myelin sheath destruction by acquired nerve damage induced by inflammation or drugs, problems arise in the peripheral nervous system, leading to muscle atrophy or sensory disorders (Sherman and Brophy, 2005; Jessen and Mirsky, 2008). During the embryonic period, the neural crest cells migrate along with growing peripheral axons. A Schwann cell precursor that has finished migrating and has attached to a growing nerve may wrap around a few or as many as dozens of axons, but ultimately only target a single axon that requires a myelin sheath in response to a certain stimulus (Sherman and Brophy, 2005; Jessen and Mirsky, 2008). In the period of Schwann cell generation, the cell is called Schwann cell progenitor or immature Schwann cell. Subsequently, the Schwann cell begins the process of myelin-related gene expression and wraps the axon with the elongated Schwann cell membrane, which continues throughout the postnatal period to complete the myelin sheath formation (Sherman and Brophy, 2005; Jessen and Mirsky, 2008). The mature myelin sheath will last a lifetime, except when damage, such as nerve injury, occurs. Acute and chronic demyelinating peripheral neuropathies are primary diseases that cause myelin destruction in adults (Jessen and Mirsky, 2008). When a peripheral nerve is physically severed, distal axons are completely degenerated, and the Schwann cells wrapped around the axons directly participate in the degeneration of the myelin sheath, which leads to demyelination (Jessen and Mirsky, 2008). Afterwards, macrophages that migrate from the blood assist in completely removing the degenerated axon and the myelin sheath (Martini et al., 2008). Meanwhile, in inflammatory demyelinating diseases, acute or chronic form of demyelination may occur regardless of axonal damage, and it is considered that demyelination occurs due to local inflammation caused by autoimmune mechanisms, which may attack components of the myelin sheath or junctional regions (Pollard and Armati, 2011).

Chapter 7 - Infections and multiple sclerosis

Multiple sclerosis is a chronic inflammatory condition of unknown cause. Increasing evidence suggests that the disease develops as a result of interactions between the environment and the immune system in genetically susceptible individuals. It has long been recognized that infections may serve as environmental triggers for the disease, and a large number of pathogens have been proposed to be associated with multiple sclerosis. Here, we detail the historical basis linking infections to multiple sclerosis and review the epidemiology of the disease, which suggests a possible relationship with infectious agents. We also describe pathophysiologic studies in animals and other human demyelinating diseases that have demonstrated a variety of mechanisms by which infectious agents may induce chronic, relapsing central nervous system disease with myelin damage and relative preservation of axons, similar to multiple sclerosis. In addition, we discuss recent studies in individuals with multiple sclerosis indicating enhanced immune responses to infectious antigens, though not consistently demonstrating evidence for ongoing infection. Taken together, these studies suggest a role for infectious agents in the development of multiple sclerosis. Conclusive evidence, however, remains lacking.

Sustained Neuroprotection From a Single Intravitreal Injection of PGJ2in a Rodent Model of Anterior Ischemic Optic Neuropathy

Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common cause of sudden optic nerve-related vision loss in persons older than 50 in the United States. There currently is no treatment for this disorder. We previously showed that systemic administration of 15-deoxy, delta (12, 14) prostaglandin J2 (PGJ2) is neuroprotective in our rodent model of AION (rAION). In this study, we determined if a single intravitreal (IVT) injection of PGJ2 is neuroprotective after rAION, and if this method of administration is toxic to the retina, optic nerve, or both. TOXICITY was assessed after a single IVT injection of PGJ2 in one eye and PBS in the contralateral eye of normal, adult Long-Evans rats. EFFICACY was assessed by inducing rAION in one eye and injecting either PGJ2 or vehicle immediately following induction, with the fellow eye serving as naïve control. Visual evoked potentials (VEPs) and ERGs were performed before induction and at specific intervals thereafter. Animals were euthanized 30 days after induction, after which immunohistochemistry, transmission electron microscopy, and quantitative stereology of retinal ganglion cell (RGC) numbers were performed. IVT PGJ2 did not alter the VEP or ERG compared with PBS-injected control eyes, and neither IVT PGJ2 nor PBS reduced overall RGC numbers. IVT PGJ2 preserved VEP amplitude, reduced optic nerve edema, and resulted in significant preservation of RGCs and axons in eyes with rAION. A single IVT injection of PGJ2 is nontoxic to the retina and optic nerve and neuroprotective when given immediately after rAION induction.

Plaque-like demyelination in acute disseminated encephalomyelitis (ADEM) – an autopsy case report

The pattern of demyelination in the scant autopsy literature on acute disseminated encephalomyelitis (ADEM) is described as perivenous sleeves. We report an unusual neuropathological presentation of ADEM, also known as postinfectious or perivenous encephalomyelitis. A 19-yearold female patient presented with headache and myalgias, followed by subacute onset of lethargy, confusion, left hemiparesis and dysphasia after an interval of 4 - 5 days. On MRI, extensive subcortical white matter lesions were seen and a diagnosis of ADEM was made after other causes were excluded. The patient received intravenous methylprednisolone and plasma exchange. Neurological symptoms remained stable over the length of the hospital stay (1 month). The patient passed away due to non-neurologic causes. On autopsy, the brain showed extensive, confluent, plaque-like demyelinating lesions with a striking selectivity for the subcortical white matter sparing the U-fibers. No lesions were discernible in the cortex, the deep grey matter, the cerebellum, the spinal cord or the optic nerves on LFB-stained sections. Only one lesion extended to the periventricular area in the right occipital lobe. Some lesions had a scalloped border and foci of inhomogeneous demyelination, suggestion coalescence of smaller lesions. Histologically, all lesions were of the same age, coupling near complete demyelination with relative preservation of axons, along with scant perivascular lymphohistiocytic cuffing, dense infiltration by foamy macrophages, and prominent gliosis. The morphology of individual demyelinating< lesions is indistinguishable from the lesions in a new onset case of multiple sclerosis (MS) and adds to the autopsy literature on overlapping neuropathological findings in ADEM and multiple sclerosis.