Cerebral Spinal Fluid levels of Cytokines are elevated in Patients with Metachromatic Leukodystrophy.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease resulting from a deficiency of arylsulfatase A causing an accumulation of cerebroside sulfate, a lipid normally abundant in myelin. Sulfatide accumulation is associated with progressive demyelination and a clinical presentation in severe disease forms that is dominated by motor manifestations. Cerebral inflammation may contribute to the pathophysiology of MLD. To date, cytokine levels in the cerebral spinal fluid of MLD patients have not previously been reported. The objective of this study was to evaluate the concentration of inflammatory cytokines in the CSF of patients with MLD and to compare these levels to unaffected controls. Of 22 cytokines evaluated, we documented significant elevations of MCP-1, IL-1Ra, IL-8, MIP-1b and VEGF in the MLD patients compared to unaffected controls. The elevated cytokines identified in this study may play a significant role in the pathophysiology of MLD. Better understanding of the inflammatory and neurodegenerative process of MLD may lead to improved targeted therapies.

Fatal Myocarditis Associated With HHV-6 Following Immunosuppression in Two Children.

Fatal myocarditis is a rare complication in immunosuppressed children. Recent reports have linked human herpesvirus 6 (HHV-6) infection, typically a benign infection in childhood, with myocarditis. HHV-6 can reactivate during periods of immunosuppression. Here, we report 2 cases in which children were immunosuppressed, one for treatment of Evans syndrome and the other post hematopoietic stem cell transplantation, who developed rapid and fatal HHV-6-associated myocarditis. These cases suggest that HHV-6 infection should be considered as an etiology of myocarditis in immunosuppressed patients regardless of correlating blood levels. Early treatment of HHV-6 in patients with myocarditis could improve morbidity and mortality.

Early-life iron deficiency anemia alters the development and long-term expression of parvalbumin and perineuronal nets in the rat hippocampus.

Early-life iron deficiency anemia (IDA) alters the expression of critical genes involved in neuronal dendritic structural plasticity of the hippocampus, thus contributing to delayed maturation of electrophysiology, and learning and memory behavior in rats. Structural maturity in multiple cortical regions is characterized by the appearance of parvalbumin-positive (PV(+)) GABAergic interneurons and perineuronal nets (PNNs). Appearance of PV(+) interneurons and PNNs can serve as cellular markers for the beginning and end of a critical developmental period, respectively. During this period, the system progresses from an immature yet highly plastic condition, to a more mature and efficient state that is however less flexible and may exhibit poorer potential for recovery from injury. To test if fetal-neonatal IDA alters parvalbumin (PV) mRNA expression, protein levels, and the number of PV(+) interneurons and PNNs in the male rat hippocampus, pregnant dams were given an iron-deficient (ID) diet (3 mg iron/kg chow) from gestational day 2 to postnatal day (P) 7 and then placed on an iron-sufficient (IS) diet (198 mg/kg) for the remainder of the experiment. On this regimen, formerly ID animals become fully iron-replete by P56. Minimal levels of PV (mRNA and protein), PV(+) interneurons, and PNNs were found in IS and ID P7 rats. By P15, and continuing through P30 and P65, ID rats had reduced PV mRNA expression and protein levels compared to IS controls. While there were no differences in the number of PV(+) neurons at either P30 or P65, the percentage of PV(+) cells surrounded by PNNs was slightly greater in ID rats as compared to IS controls. The lower levels of these acknowledged critical period biomarkers in the ID group are consistent with studies that demonstrate later maturation of the acutely ID hippocampus and lower plasticity in the adult formerly ID hippocampus. The findings provide additional potential cellular bases for previously described electrophysiologic and behavioral abnormalities found during and following early-life IDA.

Cerebrospinal fluid matrix metalloproteinases are elevated in cerebral adrenoleukodystrophy and correlate with MRI severity and neurologic dysfunction.

BACKGROUND: X-linked adrenoleukodystrophy results from mutations in the ABCD1 gene disrupting the metabolism of very-long-chain fatty acids. The most serious form of ALD, cerebral adrenoleukodystrophy (cALD), causes neuroinflammation and demyelination. Neuroimaging in cALD shows inflammatory changes and indicates blood-brain-barrier (BBB) disruption. We hypothesize that disruption may occur through the degradation of the extracellular matrix defining the BBB by matrix metalloproteinases (MMPs). MMPs have not been evaluated in the setting of cALD. METHODOLOGY/PRINCIPAL FINDINGS: We used a multiplex assay to correlate the concentration of MMPs in cerebrospinal fluid and plasma to the severity of brain inflammation as determined by the ALD MRI (Loes) score and the neurologic function score. There were significant elevations of MMP2, MMP9, MMP10, TIMP1, and total protein in the CSF of boys with cALD compared to controls. Levels of MMP10, TIMP1, and total protein in CSF showed significant correlation [p<0.05 for each with pre-transplant MRI Loes Loes scores (R(2) = 0.34, 0.20, 0.55 respectively). Levels of TIMP1 and total protein in CSF significantly correlated with pre-transplant neurologic functional scores (R(2) = 0.22 and 0.48 respectively), and levels of MMP10 and total protein in CSF significantly correlated with one-year post-transplant functional scores (R(2) = 0.38 and 0.69). There was a significant elevation of MMP9 levels in plasma compared to control, but did not correlate with the MRI or neurologic function scores. CONCLUSIONS/SIGNIFICANCE: MMPs were found to be elevated in the CSF of boys with cALD and may mechanistically contribute to the breakdown of the blood-brain-barrier. MMP concentrations directly correlate to radiographic and clinical neurologic severity. Interestingly, increased total protein levels showed superior correlation to MRI score and neurologic function score before and at one year after transplant.