Pathways In Spinal Cord Research Articles

Complex Inflammation mRNA-Related Response in ALS Is Region Dependent.

Inflammatory changes are analyzed in the anterior spinal cord and frontal cortex area 8 in typical spinal-predominant ALS cases. Increased numbers of astrocytes and activated microglia are found in the anterior horn of the spinal cord and pyramidal tracts. Significant increased expression of TLR7, CTSS, and CTSC mRNA and a trend to increased expression of IL10RA, TGFB1, and TGFB2 are found in the anterior lumbar spinal cord in ALS cases compared to control cases, whereas C1QTNF7 and TNFRSF1A mRNA expression levels are significantly decreased. IL6 is significantly upregulated and IL1B shows a nonsignificant increased expression in frontal cortex area 8 in ALS cases. IL-6 immunoreactivity is found in scattered monocyte-derived macrophages/microglia and TNF-α in a few cells of unknown origin in ALS cases. Increased expression and abnormal distribution of IL-1β occurred in motor neurons of the lumbar spinal cord in ALS. Strong IL-10 immunoreactivity colocalizes with TDP-43-positive inclusions in motor neurons in ALS cases. The present observations show a complex participation of cytokines and mediators of the inflammatory response in ALS consistent with increased proinflammatory cytokines and sequestration of anti-inflammatory IL-10 in affected neurons.

Pain and spinal cord imaging measures in children with demyelinating disease.

Pain is a significant problem in diseases affecting the spinal cord, including demyelinating disease. To date, studies have examined the reliability of clinical measures for assessing and classifying the severity of spinal cord injury (SCI) and also to evaluate SCI-related pain. Most of this research has focused on adult populations and patients with traumatic injuries. Little research exists regarding pediatric spinal cord demyelinating disease. One reason for this is the lack of reliable and useful approaches to measuring spinal cord changes since currently used diagnostic imaging has limited specificity for quantitative measures of demyelination. No single imaging technique demonstrates sufficiently high sensitivity or specificity to myelin, and strong correlation with clinical measures. However, recent advances in diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) measures are considered promising in providing increasingly useful and specific information on spinal cord damage. Findings from these quantitative imaging modalities correlate with the extent of demyelination and remyelination. These techniques may be of potential use for defining the evolution of the disease state, how it may affect specific spinal cord pathways, and contribute to the management of pediatric demyelination syndromes. Since pain is a major presenting symptom in patients with transverse myelitis, the disease is an ideal model to evaluate imaging methods to define these regional changes within the spinal cord. In this review we summarize (1) pediatric demyelinating conditions affecting the spinal cord; (2) their distinguishing features; and (3) current diagnostic and classification methods with particular focus on pain pathways. We also focus on concepts that are essential in developing strategies for the detection, monitoring, treatment and repair of pediatric myelitis.

Activity-Based Restorative Therapies after Spinal Cord Injury: Inter-institutional conceptions and perceptions.

This manuscript is a review of the theoretical and clinical concepts provided during an inter-institutional training program on Activity-Based Restorative Therapies (ABRT) and the perceptions of those in attendance. ABRT is a relatively recent high volume and intensity approach toward the restoration of neurological deficits and decreasing the risk of secondary conditions associated with paralysis after spinal cord injury (SCI). ABRT is guided by the principle of neuroplasticity and the belief that even those with chronic SCI can benefit from repeated activation of the spinal cord pathways located both above and below the level of injury. ABRT can be defined as repetitive-task specific training using weight-bearing and external facilitation of neuromuscular activation. The five key components of ABRT are weight-bearing activities, functional electrical stimulation, task-specific practice, massed practice and locomotor training which includes body weight supported treadmill walking and water treadmill training. The various components of ABRT have been shown to improve functional mobility, and reverse negative body composition changes after SCI leading to the reduction of cardiovascular and other metabolic disease risk factors. The consensus of those who received the ABRT training was that ABRT has much potential for enhancement of recovery of those with SCI. Although various institutions have their own strengths and challenges, each institution was able to initiate a modified ABRT program.

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.

PKC/MEK inhibitors suppress oxaliplatin-induced neuropathy and potentiate the antitumor effects.

Oxaliplatin is a key drug commonly used in colorectal cancer treatment. Despite high clinical efficacy, its therapeutic application is limited by common, dose-limiting occurrence of neuropathy. As usual symptomatic neuropathy treatments fail to improve the patients' condition, there is an urgent need to advance our understanding of the pathogenesis of neuropathy to propose effective therapy and ensure adequate pain management. Oxaliplatin-induced neuropathy was recently reported to be associated with protein kinase C (PKC) activation. It is unclear, however, whether PKC inhibition can prevent neuropathy. In our current studies, we found that a PKC inhibitor, tamoxifen, inhibited oxaliplatin-induced neuropathy via the PKC/extracellular signal-regulated kinase (ERK)/c-Fos pathway in lumbar spinal cords (lumbar segments 4-6). Additionally, tamoxifen was shown to act in synergy with oxaliplatin to inhibit growth in tumor cells-implanted mice. Moreover, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, PD0325901, suppressed oxaliplatin-induced neuropathy and enhanced oxaliplatin efficacy. Our results indicate that oxaliplatin-induced neuropathy is associated with PKC/ERK/c-Fos pathway in lumbar spinal cord. Additionally, we demonstrate that disruption of this pathway by PKC and MEK inhibitors suppresses oxaliplatin-induced neuropathy, thereby suggesting that PKC and MEK inhibitors may be therapeutically useful in preventing oxaliplatin-induced neuropathy and could aid in combination antitumor pharmacotherapy.

Focal Hand Dystonia as a Sign of Demyelinating Attack in Multipl Sclerosis: 'Report of Three Cases’

Ad dress for Cor res pon den ce/Ya z›fl ma Ad re si: Ozge Ocek MD, Izmir Bozyaka Training and Research Hospital, Clinic of Neurology, Izmir, Turkey Phone: +90 232 342 66 60 E-mail: ozge_giray@yahoo.com Re cei ved/Ge lifl Ta ri hi: 28.09.2013 Ac cep ted/Ka bul Ta ri hi: 06.02.2014 Although it is known that dystonia is a basal ganglia disease, dystonic symptoms have been observed in association with lesions of various sites located in sensory and motor pathways. We report three cases of paroxysmal focal hand dystonia, which may be due to the damage of the somatosensorial pathways in the cervical spinal cord. We suggest that the dystonia in our patients may be related to these active demyelinating cervical plaques. Two female and one male patients with definite relapsing remitting Multiple sclerosis (MS) between the ages of 22 to 45 were admitted with serious disability while using their right hands. In all three cases abnormal posture in the right hand and involuntary sustained contractions together with minor choreiform movements of the fingers were observed. Cervical MRI showed contrast-enhancing demyelinating lesions at the level of C2-3 in all patients. One of the patient’s cranial MRI revealed also two new contrast-enhancing plaques on the neighbourhood of right posterior lateral ventricle and parietal cortex. No new or enhancing lesion was detected in the basal ganglia; indicating that the cervical spinal cord lesions were responsible for hand dystonia. In one of the patients, the right median somatosensory evoked potential response was absent in accordance with the clinical symptom. All three patients were treated with 1 gr. intravenous methylprednisolone per day for 5-10 days. Approximately one month later, clinical symptoms have been completely disappeared and control cervical MRI revealed resolution of the active lesions in all. (Turkish Journal of Neurology 2014; 20:141-143)

Erythropoietin activates the phosporylated cAMP [adenosine 3′5′ cyclic monophosphate] response element-binding protein pathway and attenuates delayed paraplegia after ischemia-reperfusion injury

Paraplegia remains a devastating complication of complex aortic surgery. Erythropoietin (EPO) has been shown to prevent paraplegia after ischemia reperfusion, but the protective mechanism remains poorly described in the spinal cord. We hypothesized that EPO induces the CREB (cAMP [adenosine 3'5' cyclic monophosphate] response element-binding protein) pathway and neurotrophin production in the murine spinal cord, attenuating functional and cellular injury. Adult male mice were subjected to 4 minutes of spinal cord ischemia via an aortic and left subclavian cross-clamp. Experimental groups included EPO treatment 4 hours before incision (n = 7), ischemic control (n = 7), and shams (n = 4). Hind-limb function was assessed using the Basso motor score for 48 hours after reperfusion. Spinal cords were harvested and analyzed for neuronal viability using histology and staining with a fluorescein derivative. Expression of phosphorylated (p)AKT (a serine/threonine-specific kinase), pCREB, B-cell lymphoma 2, and brain-derived neurotrophic factor were determined using immunoblotting. By 36 hours of reperfusion, EPO significantly preserved hind-limb function after ischemia-reperfusion injury (P < .01). Histology demonstrated preserved cytoarchitecture in the EPO treatment group. Cords treated with EPO expressed significant increases in pAKT (P = .021) and pCREB (P = .038). Treatment with EPO induced expression of both of the neurotrophins, B-cell lymphoma 2, and brain-derived neurotrophic factor, beginning at 12 hours. Erythropoietin-mediated induction of the CREB pathway and production of neurotrophins is associated with improved neurologic function and increased neuronal viability following spinal cord ischemia reperfusion. Further elucidation of EPO-derived neuroprotection will allow for expansion of adjunct mechanisms for spinal cord protection in high-risk thoracoabdominal aortic intervention.

Telomerase expression in amyotrophic lateral sclerosis (ALS) patients.

Telomerase and telomeric complex have been linked to a variety of disease states related to neurological dysfunction. In amyotrophic lateral sclerosis (ALS) patients, telomerase activity, as human telomerase reverse transcriptase (hTERT) expression, has not been characterized yet. Here, for the first time, we characterized telomerase and related pathway in blood sample and spinal cord from ALS patients compared with healthy controls. We found that hTERT expression level was significantly lower in ALS patients and was correlated either to p53 mRNA expression or p21 expression, pointing out the hypothesis that telomerase inhibition could be a pathogenetic contributor to neurodegeneration in ALS. As a consequence of the reduced telomerase activity, we identified shorter telomeres in leukocytes from sporadic ALS patients compared with healthy control group.

Spinal cord stimulation exerts analgesia effects in chronic constriction injury rats via suppression of the TLR4/NF-κB pathway

Spinal cord stimulation (SCS) is an established method for treating chronic neuropathic pain. However, the mechanisms underlying the pain relieving effect of SCS on neuropathic pain remain unclear. Evidence shows that the toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signal transduction pathway plays a key role in chronic neuropathic pain. We investigated changes in the TLR4/NF-κB pathway and downstream pro-inflammatory cytokine expression in L4-6 spinal cord following SCS. Neuropathic pain was induced through chronic constriction injury (CCI) of the sciatic nerve in rats. Mechanical withdrawal threshold (MWT) was assessed before surgery and on days 1, 4, 7, and 14 after CCI. During days 11-14, the nerve-injured rats were treated with SCS for 30min per day. Compared with the control group, the CCI rats displayed a significantly decreased MWT. After SCS for 3 days, the expression of TLR4/NF-κB and the levels of interleukin(IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in the spinal cord were lower in the SCS group compared to those in the CCI and sham spinal cord stimulation (S-SCS) groups. These results indicate that SCS could effectively attenuate neuropathic pain in CCI rats by inhibiting the activation of the TLR4/NF-κB signaling pathway and by inhibiting the up-regulation of pro-inflammatory cytokines in the spinal cord.

Attenuation of neuropathic pain by saikosaponin a in a rat model of chronic constriction injury.

Despite immense advances in the treatment strategies, the effective treatment of patients suffering from neuropathic pain remains challenging. Saikosaponin a possesses anti-inflammatory activity. However, the role of saikosaponin a in neuropathic pain is still unclear. Therefore, the objective of this study was to investigate the effects of saikosaponin a on neuropathic pain. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve in rats. After CCI, rats were administered saikosaponin a (6.25, 12.50 and 25.00 mg/kg intraperitoneal, once daily) for 14 days. Mechanical withdrawal threshold and thermal withdrawal latency were assessed before surgery and on days 1, 3, 7, and 14 after CCI. Our results showed that CCI significantly decreased mechanical withdrawal threshold and thermal withdrawal latency on days 1, 3, 7 and 14, as compared with sham groups, however, saikosaponin a reversed this effects. In addition, saikosaponin a inhibited CCI-induced the levels of TNF-α, IL-1β, IL-2 in spinal cord. Western blot analysis demonstrated that saikosaponin a reduced the elevated expression of p-p38 mitogen-activated protein kinase (MAPK) and NF-κB in the spinal cord induced by CCI. These results suggest that saikosaponin a could effectively attenuate neuropathic pain in CCI rats by inhibiting the activation of p38 MAPK and NF-κB signaling pathways in spinal cord.

Activation of the cAMP-PKA signaling pathway in rat dorsal root ganglion and spinal cord contributes toward induction and maintenance of bone cancer pain.

The objective of this study was to explore the role of cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) signaling in the development of bone cancer pain in rats. Female Sprague-Dawley rats (N=48) were divided randomly into four groups: sham (n=8), tumor cell implantation (TCI) (n=16), TCI+saline (n=8), and TCI+PKA inhibitor (n=16). Bone cancer-induced pain behaviors - thermal hyperalgesia and mechanical allodynia - were tested at postoperative days -3, -1, 1, 3, 5, 7, 10, and 14. A PKA inhibitor, Rp-cAMPS (1 mmol/l/20 μl), was injected intrathecally on postoperative days 3, 4, and 5 (early phase) or 7, 8, and 9 postoperative days (late phase). The expression of PKA mRNA in dorsal root ganglia (DRG) was detected by reverse transcription-PCR. The concentration of cAMP and activity of PKA in DRG and spinal cord were measured by enzyme-linked immunosorbent assay. TCI treatment induced significant pain behaviors, manifested as thermal hyperalgesia and mechanical allodynia. Spinal administration of the PKA inhibitor Rp-cAMPS during the early phase and late phase significantly delayed or reversed, respectively, TCI-induced thermal hyperalgesia and mechanical allodynia. TCI treatment also led to obvious tumor growth and bone destruction. The level of PKA mRNA in the DRG, as well as the concentration of cAMP and the activity of PKA, in both the DRG and spinal cord were significantly increased after TCI treatment (P<0.01). We conclude that the inhibition of the cAMP-PKA signaling pathway may reduce bone cancer pain.

Encoding of forelimb forces by corticospinal tract activity in the rat.

In search of a solution to the long standing problems encountered in traditional brain computer interfaces (BCI), the lateral descending tracts of the spinal cord present an alternative site for taping into the volitional motor signals. Due to the convergence of the cortical outputs into a final common pathway in the descending tracts of the spinal cord, neural interfaces with the spinal cord can potentially acquire signals richer with volitional information in a smaller anatomical region. The main objective of this study was to evaluate the feasibility of extracting motor control signals from the corticospinal tract (CST) of the rat spinal cord. Flexible substrate, multi-electrode arrays (MEA) were implanted in the CST of rats trained for a lever pressing task. This novel use of flexible substrate MEAs allowed recording of CST activity in behaving animals for up to three weeks with the current implantation technique. Time-frequency and principal component analyses (PCA) were applied to the neural signals to reconstruct isometric forelimb forces. Computed regression coefficients were then used to predict isometric forces in additional trials. The correlation between measured and predicted forces in the vertical direction averaged across six animals was 0.67 and R2 value was 0.44. Force regression in the horizontal directions was less successful, possibly due to the small amplitude of forces. Neural signals above and near the high gamma band made the largest contributions to prediction of forces. The results of this study support the feasibility of a spinal cord computer interface (SCCI) for generation of command signals in paralyzed individuals.

Active learning: hands‐on activities add pizzazz to lecture‐based anatomy courses (721.10)

Educating students in the field of anatomy has been a challenge for decades. Bringing a “dead” science to “life” has been problematic for even the greatest of educators. We have examined several different group activities and approaches to teaching anatomy that incorporated a variety of teaching activities designed to keep the learning process engaging, stimulating, and self‐motivating. Developing novel approaches for the group activities in a lecture based class is essential for student engagement. Group activities that we have successfully implemented include the incorporation of clinically relevant video clips, which students assess and discuss as a group, construction of organs out of modeling clay and/or other craft supplies, using fabric muscles made of felt to attach to a skeleton which helped reinforce their understanding of muscle attachments, using yarn to depict the passageway of nerves in the brachial plexus and spinal cord tracts, and other approaches. The level of student satisfaction increased 23% and the majority of students felt that these activities enhanced their learning with an average of 4.74 out of 5 on the Likert scale. Moreover, grades increased 12% compared to another section of the same class where these techniques were not employed. Engaging teams of students is of great importance for understanding difficult concepts, retention of knowledge in anatomical sciences and student satisfaction.

Curcumin modulates TLR4/NF-κB inflammatory signaling pathway following traumatic spinal cord injury in rats

BackgroundCurcumin, a polyphenolic compound extracted from the plant turmeric, has protective effects on spinal cord injury (SCI) through attenuation of inflammatory response. This study was designed to detect whether curcumin modulates toll-like receptor 4 (TLR4) and the nuclear factor-kappa B (NF-κB) inflammatory signaling pathway in the injured rat spinal cord following SCI.MethodsAdult male Sprague–Dawley rats were subjected to laminectomy at T8–T9 and compression with a vascular clip. There were three groups: (a) sham group; (b) SCI group; and (g) SCI + curcumin group. We measured TLR4 gene and protein expression by real-time polymerase chain reaction and western blot analysis; NF-κB activity by electrophoretic mobility shift assay, inflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6 levels by enzyme-linked immunosorbent assay, hindlimb locomotion function by Basso, Beattie, and Bresnahan rating, spinal cord edema by wet/dry weight method, and apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) analysis.ResultsThe results showed that SCI induced the up-regulation of TLR4, NF-κB, and inflammatory cytokines in the injured rat spinal cord. Treatment with curcumin following SCI markedly down-regulated the levels of these agents related to the TLR4/NF-κB inflammatory signaling pathway. Administration of curcumin also significantly ameliorated SCI induced hind limb locomotion deficits, spinal cord edema, and apoptosis.ConclusionsPost-SCI curcumin administration attenuates the TLR4/NF-κB inflammatory signaling pathway in the injured spinal cord, and this may be a mechanism whereby curcumin improves the outcome following SCI.

Promising Advances in Targeted Cellular Based Therapies: Treatment Update in Spinal Cord Injury

Spinal Cord Injury (SCI) affects approximately 10,000 people per year in North America. Over the last twenty years, significant advances have been made in the understanding the pathophysiology of traumatic spinal cord injuries. In addition there have been concurrent advances in embryonic stem cells (ESCs) and the various pathways of their differentiation into neural stem cells (NSCs) and progenitors. It is hoped that these advancing fields can be merged. The administration of ESCs and NSC cells will reconstitute the architecture of the injured spinal cord as well as spinal cord tracts. Thus, this would result in improved anatomical recovery and plasticity allowing for improved neurologic function and locomotion. The authors provide a brief overview of recent publications to illustrate the various approaches to the treatment of SCI with cellular based therapies, including both pluripotent stem cells and neural-committed lineages. Considerable advances have been made in the field. While there is a growing body of laboratory evidence in the literature to support translating cellular therapies into the clinical setting, there are no definitive answers on the efficacy of cellular based therapies in the clinical setting. A variety of cellular therapies have been implemented in novel clinical trials including OECs, fetal-derived NSCs, and Schwann cells. Further refinement of these methods should be made in the future to limit patient morbidity.

Stroke Recovery after Unilateral Posterior Spinal Artery Stroke: A Case Report

Background and Purpose: The present report details the acute history and functional recovery of a patient with a rare ischemic infarction of the posterior spinal artery affecting the right posterior column and descending lateral motor tracts in the uppermost cervical spinal cord. Summary of Case: The patient presented with significant unilateral sensory ataxia and hemiparesis. We monitored the patient’s recovery for six months using standard clinical assessments and novel robotic measures of sensorimotor impairment. Conclusion: There are challenges in accurately monitoring stroke recovery, in particular sensory recovery. This case highlights the potential for new robotic assessment tools.

A case report of conjoined twin(PYGOPAGUS) separation

We report successful separation of PYGOPAGUS twins. Meticulous planning and multidisciplinary approach are the core aspects in the management of Pygopagus conjoined twins. Early elective separation versus delayed separation of the conjoined twins improves the survival from 40% to 80% . Preoperative assessment of sickle cell disease, cross-circulation and organ sharing between twins proved valuable for planning sedation and analgesia and allowing detailed scripting of the complex anesthetic induction sequence, airway management, complex neurological monitoring and post operative intensive care related issues. Fusion of lower back, spinal cord , nerve roots , and rectal and genitourinary tract was a major surgical challenge related to potentially adverse neurological outcomes, bladder /bowel dysfunction and intact long term survival. Post operative critical care issues such as pain , prone ventilation, sickle cell sequalae, cerebrospinal fluid leak and meningitis, wound infection and colostomy care, nutrition, and other potential complications are discussed in detail in this report. We emphasize the role of pediatric intensive care, preoperative planning with multidisciplinary team, and staged surgical intervention and a good postoperative care in the successful management of complicated variants.

Pathophysiology of X-linked adrenoleukodystrophy

Currently the molecular basis for the clinical heterogeneity of X-linked adrenoleukodystrophy (X-ALD) is poorly understood. The genetic bases for all different phenotypic variants of X-ALD are mutations in the gene encoding the peroxisomal ATP-binding cassette (ABC) transporter, ABCD1 (formerly adrenoleukodystrophy protein, ALDP). ABCD1 transports CoA-activated very long-chain fatty acids from the cytosol into the peroxisome for degradation. The phenotypic variability is remarkable ranging from cerebral inflammatory demyelination of childhood onset, leading to death within a few years, to adults remaining pre-symptomatic through more than five decades. There is no general genotype–phenotype correlation in X-ALD. The default manifestation of mutations in ABCD1 is adrenomyeloneuropathy, a slowly progressive dying-back axonopathy affecting both ascending and descending spinal cord tracts as well as in some cases, a peripheral neuropathy. In about 60% of male X-ALD patients, either in childhood (35–40%) or in adulthood (20%), an initial, clinically silent, myelin destabilization results in conversion to a devastating, rapidly progressive form of cerebral inflammatory demyelination. Here, ABCD1 remains a susceptibility gene, necessary but not sufficient for inflammatory demyelination to occur. Although the accumulation of very long-chain fatty acids appears to be essential for the pathomechanism of all phenotypes, the molecular mechanisms underlying these phenotypes are fundamentally different. Cell autonomous processes such as oxidative stress and energy shortage in axons as well as non-cell autonomous processes involving axon–glial interactions seem pertinent to the dying-back axonopathy. Various dynamic mechanisms may underlie the initiation of inflammation, the altered immune reactivity, the propagation of inflammation, as well as the mechanisms leading to the arrest of inflammation after hematopoietic stem cell transplantation. An improved understanding of the molecular mechanisms involved in these events is required for the development of urgently needed therapeutics.

Consequences of perinatal bisphenol A exposure in a mouse model of multiple sclerosis

Multiple sclerosis (MS) is a complex disease influenced by genetic and environmental contributing factors. Endocrine disrupting compounds (EDCs) such as bisphenol A (BPA) affect gene expression and hormone-regulated systems throughout the body. We investigated the effects of BPA on Theiler’s-virus induced demyelination (TVID), a mouse model of MS. Perinatal BPA exposure, combined with viral infection, resulted in a decreased level of viral antibodies, accelerated the onset of TVID symptoms, increased inflammation in both the spinal cord and digestive tract, and amplified immune-related gene expression changes induced by viral infection. These results demonstrate the effect of BPA on the trajectory of TVID, and illustrate how multiple factors collectively influence autoimmune disease.

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL): Assessment of the involved white matter tracts by MRI

Background and purposeLeukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is a recently identified autosomal recessive disorder with early onset of symptoms and slowly progressive pyramidal, cerebellar and dorsal column dysfunction. LBSL is characterized by distinct white matter abnormalities and selective involvement of brainstem and spinal cord tracts. The purpose of this study is to assess the imaging features of the involved white matter tracts in cases of LBSL by MRI. Patients and methodsWe retrospectively reviewed the imaging features of the selectively involved white matter tracts in sixteen genetically proven cases of leukoencephalopathy with brainstem and spinal cord involvement and elevated brain lactate (LBSL). All patients presented with slowly progressive cerebellar sensory ataxia with spasticity and dorsal column dysfunction. MRI of the brain and spine using 1.5T machine and proton magnetic resonance spectroscopy (1H MRS) on the abnormal white matter were done to all patients. The MRI and MRS data sets were analyzed according to lesion location, extent, distribution and signal pattern as well as metabolite values and ratios in MRS. Laboratory examinations ruled out classic leukodystrophies. ResultsIn all cases, MRI showed high signal intensity in T2-weighted and FLAIR images within the cerebral subcortical, periventricular and deep white matter, posterior limbs of internal capsules, centrum semiovale, medulla oblongata, intraparenchymal trajectory of trigeminal nerves and deep cerebellar white matter. In the spine, the signal intensity of the dorsal column and lateral cortico-spinal tracts were altered in all patients. The subcortical U fibers, globi pallidi, thalami, midbrain and transverse pontine fibers were spared in all cases. In 11 cases (68.8%), the signal changes were inhomogeneous and confluent whereas in 5 patients (31.2%), the signal abnormalities were spotty. MRI also showed variable signal abnormalities in the sensory and pyramidal tracts in addition to the brainstem and cerebellar connections. Proton MRS showed consistent elevation of the lactate within the abnormal white matter. ConclusionDistinct MRI findings in the form of selective affection of subcortical and deep white matter tracts of the brain (involving the posterior limb of internal capsules and sparing the subcortical U fibers), dorsal column and lateral cortico-spinal tracts of the spinal cord should lead to the diagnosis of LBSL supported by the presence of lactate peak in 1H MRS. The disease can be confirmed by the analysis of the disease gene DARS2.