Alpha-mannosidosis: characterization of CNS pathology and correlation between CNS pathology and cognitive function.

Alpha-mannosidosis (AM) (OMIM 248500) is a rare lysosomal storage disease. The understanding of the central nervous system (CNS) pathology is limited. This study is the first describing the CNS pathology and the correlation between the CNS pathology and intellectual disabilities in human AM. Thirty-four patients, aged 6-35 years, with AM were included. Data from 13 healthy controls were included in the analysis of the magnetic resonance spectroscopy (MRS). Measurements of CNS neurodegeneration biomarkers in cerebrospinal fluid (CSF), CSF-oligosaccharides, and performance of cerebral magnetic resonance imaging (MRI) and MRS were carried out. On MRI, 5 of 10 patients had occipital white matter (WM) signal abnormalities, and 6 of 10 patients had age-inappropriate myelination. MRS demonstrated significantly elevated mannose complex in gray matter and WM. We found elevated concentrations of tau-protein, glial fibrillary acidic protein and neurofilament light protein in 97 patients, 74% and 41% of CSF samples, respectively. A negative correlation between CSF-biomarkers and cognitive function and CSF-oligosaccharides and cognitive function was found. The combination of MRS/MRI changes, elevated concentrations of CSF-biomarkers and CSF-oligosaccharides suggests gliosis and reduced myelination, as part of the CNS pathology in AM. Our data demonstrate early neuropathological changes, which may be taken into consideration when planning initiation of treatment.

Administration of sulfatide to ameliorate type I diabetes in non-obese diabetic mice.

The endogenous glycosphingolipid sulfatide is a ligand for CD1d-restricted type II natural killer T (NKT) lymphocytes. Through the action of these cells,sulfatide treatment has been shown to modulate the immune response in mouse models for autoimmune diseases, infections and tumour immunity. Sulfatide exists naturally in different organs including the pancreas, where sulfatide colocalizes with insulin within the Langerhans islet b-cells, targets for the immune destruction in type 1 diabetes (T1D). Human T1D patients, but not patients with type 2 diabetes nor healthy individuals, have autoantibodies against sulfatide in serum, suggesting that sulfatide induces an immune response in the natural course of T1D in humans. Here, we investigate sulfatide as an autoantigen and a modulator of autoimmune disease in the murine model forT1D, the non-obese diabetic (NOD) mice. We demonstrate that aged NOD mice displayed serum autoantibody reactivity to sulfatide; however, this reactivity did not correlate with onset of T1D. Repeated administration of sulfatide did not result in an increase in serum reactivity to sulfatide. Moreover, a multidose sulfatide treatment of female NOD mice initiated at an early (5 weeks of age),intermediate (8 weeks of age) or late (12 weeks of age) phase of T1D progression did not influence the incidence of disease. Thus, we demonstrate that a fraction of NOD mice develop autoantibody reactivity to sulfatide; however, we fail to demonstrate that sulfatide treatment reduces the incidence of T1D in this mouse strain.

Enzyme replacement therapy for alpha-mannosidosis: 12 months follow-up of a single centre, randomised, multiple dose study.

BACKGROUND: Alpha-mannosidosis (OMIM 248500) is a rare lysosomal storage disease (LSD) caused by alpha-mannosidase deficiency. Manifestations include intellectual disabilities, facial characteristics and hearing impairment. A recombinant human alpha-mannosidase (rhLAMAN) has been developed for weekly intravenous enzyme replacement therapy (ERT). We present the preliminary data after 12 months of treatment. METHODS: This is a phase I-II study to evaluate safety and efficacy of rhLAMAN. Ten patients (7-17 y) were treated. We investigated efficacy by testing motor function (6-minutes-Walk-Test (6-MWT), 3-min-Stair-Climb-Test (3-MSCT), The Bruininks-Oseretsky Test of Motor Proficiency (BOT2), cognitive function (Leiter-R), oligosaccharides in serum, urine and CSF and Tau- and GFA-protein in CSF. RESULTS: Oligosaccharides: S-, U- and CSF-oligosaccharides decreased 88.6% (CI -92.0 -85.2, p < 0.001), 54.1% (CI -69.5- -38.7, p < 0,001), and 25.7% (CI -44.3- -7.1, p < 0.05), respectively. Biomarkers: CSF-Tau- and GFA-protein decreased 15%, p < 0.009) and 32.5, p < 0.001 respectively. Motor function: Improvements in 3MSCT (31 steps (CI 6.8-40.5, p < 0.01) and in 6MWT (60.4 m (CI -8.9 -51.1, NS) were achieved. Cognitive function: Improvement in the total Equivalence Age of 4 months (0.34) was achieved in the Leiter R test (CI -0.2-0.8, NS). CONCLUSIONS: These data suggest that rhLAMAN may be an encouraging new treatment for patients with alpha-mannosidosis.The study is designed to continue for a total of 18 months. Longer-term follow-up of patients in this study and the future placebo-controlled phase 3 trial are needed to provide greater support for the findings in this study.

Altered distribution of the gangliosides GM1 and GM2 in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder where ß-amyloid tends to aggregate and form plaques. Lipid raft-associated ganglioside GM1 has been suggested to facilitate ß-amyloid aggregation; furthermore, GM1 and GM2 are increased in lipid rafts isolated from cerebral cortex of AD cases. AIM/METHOD: The distribution of GM1 and GM2 was studied by immunohistochemistry in the frontal and temporal cortex of AD cases. Frontotemporal dementia (FTD) was included as a contrast group. RESULTS: The distribution of GM1 and GM2 changes during the process of AD (n = 5) and FTD (n = 3) compared to controls (n = 5). Altered location of the GM1-positive small circular structures seems to be associated with myelin degradation. In the grey matter, the staining of GM1-positive plasma membranes might reflect neuronal loss in the AD/FTD tissue. The GM1-positive compact bundles were only visible in cells located in the AD frontal grey matter, possibly reflecting raft formation of GM1 and thus a pathological connection. Furthermore, our results suggest GM2 to be enriched within vesicles of pyramidal neurons of the AD/FTD brain. CONCLUSION: Our study supports the biochemical finding of ganglioside accumulation in cellular membranes of AD patients and shows a redistribution of these molecules.

Gamma-secretase-dependent amyloid-beta is increased in Niemann-Pick type C: a cross-sectional study.

OBJECTIVE: Niemann-Pick disease type C (NPC) is an inherited disorder characterized by intracellular accumulation of lipids such as cholesterol and glycosphingolipids in endosomes and lysosomes. This accumulation induces progressive degeneration of the nervous system. NPC shows some intriguing similarities with Alzheimer disease (AD), including neurofibrillary tangles, but patients with NPC generally lack amyloid-ß (Aß) plaques. Lipids affect γ-secretase-dependent amyloid precursor protein (APP) metabolism that generates Aß in vitro, but this has been difficult to prove in vivo. Our aim was to assess the effect of altered lipid constituents in neuronal membranes on amyloidogenic APP processing in humans. METHODS: We examined Aß in CSF from patients with NPC (n = 38) and controls (n = 14). CSF was analyzed for Aß(38), Aß(40), Aß(42), α-cleaved soluble APP, ß-cleaved soluble APP, total-tau, and phospho-tau. RESULTS: Aß release was markedly increased in NPC, with a shift toward the Aß(42) isoform. Levels of α- and ß-cleaved soluble APP were similar in patients and controls. Patients with NPC had increased total-tau. Patients on treatment with miglustat (n = 18), a glucosylceramide synthase blocker, had lower Aß(42) and total-tau than untreated patients. CONCLUSION: Increased CSF levels of Aß(38), Aß(40), and Aß(42) and unaltered levels of ß-cleaved soluble APP are consistent with increased γ-secretase-dependent Aß release in the brains of patients with NPC. These results provide the first in vivo evidence that neuronal lipid accumulation facilitates γ-secretase-dependent Aß production in humans and may be of relevance to AD pathogenesis.

The glycolipid sulfatide protects insulin-producing cells against cytokine-induced apoptosis, a possible role in diabetes.

AIMS/HYPOTHESIS: Cytokine-induced apoptosis is recognised as a major cause of the decline in ß-cell mass that ultimately leads to type 1 diabetes mellitus. Interleukin-1ß, interferon-γ and tumour necrosis factor-α in conjunction initiate a series of events that lead to ß-cell apoptosis; important among these is NO production. The glycosphingolipid sulfatide is present in ß-cells in the secretory granules in varying amounts and is secreted together with insulin. We now investigate whether sulfatide is able to protect insulin-producing cells against the pro-apoptotic effect of interleukin-1ß, interferon-γ and tumour necrosis factor-α. METHODS: INS-1E cells and genuine rat islets were incubated for 24 h exposed to interleukin-1ß, interferon-γ and tumour necrosis factor-α with or without sulfatide. The production of NO was monitored and the number of apoptotic cells was determined using terminal deoxynucleotidyl transferase-mediated dUTP Nick-End labelling and caspase-3/7 activity assays. In addition, the amount of iNOS mRNA was determined using real-time quantitative polymerase chain reaction. RESULTS: Cytokine-induced apoptosis was reduced to 27% of cytokine-treated controls with 30 µmol/L sulfatide treatment (p < 0.01). Likewise, sulfatide in concentrations of 3-30 µmol/L decreased NO production in a dose-dependent manner to 19-40% of cytokine-treated controls (overall p = 0.0007). The level of iNOS mRNA after cytokine exposure was reduced to 55% of cytokine-treated controls with 30 µmol/L of sulfatide. CONCLUSIONS/INTERPRETATION: In the present study, we report the ability of sulfatide to significantly reduce apoptosis, cellular leakage and NO production in insulin-producing cells. Data suggest this is not due to induction of ß-cell rest. Our findings indicate a possible implication for sulfatide in the pathogenesis of diabetes.

Mucopolysaccharidosis type III (Sanfilippo disease) in Sweden: clinical presentation of 22 children diagnosed during a 30-year period.

AIM: The aim of this study was to present the natural clinical course in children and adolescents with MPS III diagnosed during a 30-year period in Sweden. METHODS: The patients were identified from metabolic laboratory records between 1975 and 2004. Patient data were assessed from interviews of parents and by clinical examination and records from the patients. RESULTS: A total of 15 children, 68%, with MPS IIIA were diagnosed at a median age of 6.8 years (range 1.2-18.9 years). One boy had MPS IIIB and five children MPS IIIC, diagnosed at ages between 1.9 and 11.6 years. In one child the type was not determined. The median age of children with type IIIA who had deceased was 16.2 years (range 10.4-31.2 years). Ten individuals with MPS III are alive at ages between 5 and 29 years. In four families, two children were affected. CONCLUSION: In 22 Swedish children with Sanfilippo disease an early normal development followed by a delay in speech and an appearance of behaviour problems was found in most children during the early preschool period. Mental retardation was diagnosed in almost all individuals before starting school. Early diagnosis is important in this devastating, progressive disorder, not only for genetic counselling but also for participation in future treatments.

Elevated cerebrospinal fluid levels of prostaglandin E2 and 15-(S)-hydroxyeicosatetraenoic acid in multiple sclerosis.

OBJECTIVE: To test the hypothesis that the arachodinic acid metabolites prostaglandin E2 (PGE2) and 15-(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in cerebrospinal fluid (CSF) are elevated and reflect neuroinflammation and degenerative changes in multiple sclerosis (MS). PATIENTS AND METHODS: We measured PGE2 and 15(S)-HETE concentrations, as well as markers of axonal and astroglial injury in CSF from 46 MS patients, 46 healthy siblings and 50 controls. RESULTS: We found elevated levels of both PGE2 and 15(S)-HETE in MS compared with the control and sibling groups. Siblings had lower PGE2 levels and higher 15(S)-HETE levels than controls. There were no correlations between either PGE2 or 15(S)-HETE and clinical scores of MS severity or biochemical markers of axonal or astroglial injury. CONCLUSION: These data suggest no direct involvement of PGE2 and 15(S)-HETE in the MS disease process. Rather, the elevated levels reflect a general up-regulation of arachidonic acid metabolism and neuroinflammation.

The g.1170C>T polymorphism of the 5' untranslated region of the human alpha-galactosidase gene is associated with decreased enzyme expression--evidence from a family study.

Subnormal leukocyte α-galactosidase (α-Gal) activity was found during evaluation of an adolescent male with cryptogenic cerebrovascular small-vessel disease. The only molecular abnormality found was the g.1170C>T single-nucleotide polymorphism (SNP) in the 5' untranslated region of exon 1 in the α-Gal gene (GLA). Historically, this polymorphism has been considered to be biologically neutral. To test the hypothesis that the g.1170T allele might be associated with lower α-Gal expression, we genotyped GLA exon 1 and measured leukocyte and plasma α-Gal in the parents, brother and sister of the index case. The g.1170T allele co-segregated with a subnormal leukocyte α-Gal activity in the three siblings. Although plasma enzyme activities were within the normal range in all five relatives, the ranking of their values suggested a dosage effect of the g.1170T allele. Western blotting assays of leukocyte protein extracts showed that the relative expression of α-Gal in both the patient and his sister was significantly lower than in sex-matched hemizygous or homozygous controls for the g.1170C allele, either normalized to the ß-actin immunoblot expression or standardized to a known amount of recombinant human α-Gal. These family data, in combination with results from a recent GLA SNP screening study among healthy Portuguese individuals, suggest that the g.1170C>T SNP may be co-dominantly associated with a relatively decreased GLA expression at the transcription and/or translation level. Larger population studies are needed to confirm these findings and to test the hypothesis that the GLA g.1170C>T may contribute to the multifactorial risk of ischaemic small-vessel cerebrovascular disease.

Effect of single-nucleotide polymorphisms of the 5' untranslated region of the human α-galactosidase gene on enzyme activity, and their frequencies in Portuguese caucasians.

BACKGROUND: The α-galactosidase gene (GLA) has three single-nucleotide polymorphisms in the 5' untranslated region of exon 1, respectively g.1150G>A, g.1168G>A, g.1170C>T. The g.1150A allele is associated with increased plasma α-galactosidase (α-Gal) activity in hemizygotes, while the others are regarded as biologically neutral. The primary goal of this investigation was to test the hypothesis, raised by a clinical observation and results of a family study, that the g.1170T allele polymorphism is associated with lower α-Gal expression. SUBJECTS AND METHODS: Plasma and leukocyte α-Gal activities were assayed in unrelated healthy young adults of both sexes, who had been genotyped for GLA exon 1, and enzyme activity values in carriers of any of the polymorphisms were compared to those of individuals with the standard genotype; GLA exon 1 was genotyped in males who had α-Gal activity in dried blood spots lower than 2 SD below the cohort average. RESULTS AND CONCLUSIONS: Mean α-Gal leukocyte activity was ∼ 25% higher in subjects with the g.1170C or CC genotype than in those with the alternative genotypes (p < 0.05). The frequency of the g.1170T allele in subjects with low α-Gal activity in dried blood spots was 4-fold higher (p < 0.05) than in the general population. As in hemizygotes, the g.1150A heterozygote identified in this study had plasma α-Gal activity more than 2-fold above the normal mean. The g.1168A allele did not affect enzyme activity. Surprisingly, females with the standard GLA exon 1 genotype had significantly higher plasma α-Gal activity than genetically comparable males.

Cerebrospinal fluid tau and amyloid beta42 protein in patients with myotonic dystrophy type 1.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is associated with brain morphology changes including neurofibrillary degeneration. METHODS: We have examined cerebrospinal fluid (CSF) markers indicative of neuronal degeneration and amyloidogenesis; total tau (T-tau), phosphorylated tau (P-tau) and beta amyloid 1-42 (Abeta42), in 32 patients with DM1. RESULTS AND CONCLUSIONS: Associations between CSF markers and CTG repeat expansion size, brain MRI findings, and neuropsychological test results were analysed. As compared with matched controls Abeta42 was significantly decreased (P = 0.001), whilst levels of T-tau were increased (P < 0.001). No difference was found between measures considering P-tau levels. At present the clinical implications of these findings is unclear, because of an overlap between CSF values of DM1 patients and healthy controls, but also regarding modest associations between CSF markers and other measures. However notably, the Tau pathology, as seen in DM1, differs from Alzheimers disease, considering the lack of increased levels of P-tau.

Non-neurological surgery results in a neurochemical stress response.

There is a paucity of studies assessing changes in measures of human neurotransmission during stressful events, such as surgery. Thirty-five patients without any neurological disorders undergoing knee replacements with spinal bupivacaine anaesthesia and propofol sedation had cerebrospinal fluid (CSF) drawn from a spinal catheter before, three hours after and the morning after surgery. The CSF concentrations of the dopamine metabolite homovanillinic acid (HVA) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), which are related to the activity of the dopaminergic and serotonergic systems of the brain, increased sharply during surgery and reached 188% and 166% of their initial concentrations on the morning after the intervention (p < 0.0001). The CSF concentrations of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglucol (MHPG) increased modestly (non-significantly) during and after surgery. The HVA/5-HIAA ratios initially increased but returned to the initial level during the night after surgery. We conclude that non-neurological surgery, in this case to the lower limb, is accompanied by a marked central nervous stress response in spite of a spinal blockade.

Late cerebral graft versus host reaction in a bone marrow transplanted girl with Hurler (MPS I) disease.

A girl with Hurler disease (MPS IH) underwent allogeneic stem cell transplantation at 13 months of age with her one HLA-B antigen mismatch mother as donor. The procedure was complicated by cerebral hemorrhage and a ventricular-peritoneal shunt device was inserted. Mild GVH reactions were rapidly reversed. One year after transplantation ventriculitis was suspected and the shunt was replaced by a ventricular drainage catheter. Antibiotics had no effect and graft-versus-host disease (GVHD) was diagnosed. All symptoms were reversed by prednisolone and cyclosporine. Increased albumin and pleocytosis in the cerebrospinal fluid (CSF) normalized concomitantly. Electron microscopy of the CSF sediment showed debris consisting of numerous complex aggregates of thin lamellae and electron dense fragments with a tight lamellar texture. Biochemical analysis of the CSF sediment proved that the debris contained galactosylceramide and sulfatide. The electron microscopic and biochemical findings were interpreted to represent stripping of central myelin as a result of subacute GVHD in the central nervous system and its desquamation from the brain parenchyma into the ventricular CSF through the post-hemorrhage defect. From reversal of the GVHD at 2 years of age until follow-up at 10 years of age the clinical condition remained stable with no recurrence or deterioration.

The earliest MR imaging and proton MR spectroscopy abnormalities in adult-onset Krabbe disease.

BACKGROUND: Adult-onset Krabbe disease is an uncommon form of leukodystrophy. Its magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) manifestations are not well documented. AIM OF THE STUDY: To describe early MR findings in adult-onset Krabbe disease. MATERIALS AND METHODS: A 28-year-old woman who had spastic paraparesis and a 5-year history of gait problems underwent MRI of the brain and cervical spine. Proton MRS was performed at 1.5 T using a short echo time. Metabolites were analyzed in the areas of MR signal abnormalities and normal-appearing brain. Six healthy volunteers were examined as controls. RESULTS: MRI revealed changes in the upper corticospinal tracts, splenium and, minimally, adjacent to the atria of the lateral ventricles. MRS showed decreased creatine, choline, N-acetylaspartate and glutamate and probably elevated lactate in the upper corticospinal tract but not in the normal-appearing frontal lobe. The spinal cord was thin. Laboratory tests verified Krabbe disease. CONCLUSIONS: These results indicate early involvement of the upper corticospinal tract in adult-onset Krabbe disease. The cases reported earlier had imaging changes indicating a more advanced disease or no MR findings. Thinning of the spinal cord is a new finding in Krabbe disease.

Ventricular cerebrospinal fluid neurofilament protein levels decrease in parallel with white matter pathology after shunt surgery in normal pressure hydrocephalus.

Normal pressure hydrocephalus (NPH) is characterized by disturbed cerebrospinal fluid (CSF) dynamics and white matter lesions (WML). Although the morphology of these lesions is described, little is known about the biochemistry. Our aim was to explore the relationship between ventricular CSF markers, periventricular WML and postoperative clinical outcome in patients with NPH. We analysed lumbar and ventricular concentrations of 10 CSF markers, 12 clinical symptoms and signs, magnetic resonance imaging (MRI) periventricular white matter hyperintensities (PVH) and ventricular size before and 3 months after shunt surgery in 35 patients with NPH. Higher ventricular CSF neurofilament protein (NFL), an axonal marker, correlated with more extensive PVH. A larger postoperative reduction in NFL correlated with larger reduction in PVH and a more pronounced overall improvement. Albumin ratio, HMPG, NPY, VIP and GD3 increased postoperatively whereas NFL, tau and HVA decreased. Variations in ventricular size were not associated with CSF concentrations of any marker. We conclude that NPH is characterized by an ongoing periventricular neuronal dysfunction seen on MRI as PVH. Clinical improvement after shunt surgery is associated with CSF changes indicating a restitution of axonal function. Other biochemical effects of shunting may include increased monoaminergic and peptidergic neurotransmission, breakdown of blood brain barrier function, and gliosis.

Interaction of cholera toxin with three life-cycle stages of Schistosoma mansoni: adult worm, egg and cercaria.

We have previously reported that there is an immunological cross-reactivity between Schistosoma mansoni and cholera toxin (CT). In this study, using an immunofluorescence technique with anti-CT antibody, we provide further evidence for this cross-reactivity by demonstrating an antigen, localized in the tegument of S. mansoni adult worms which is cross-reactive with a CT antigen. Anti-CT antibodies also reacted with structures in S. mansoni cercariae and eggs. Additionally, CT itself was found to bind strongly to the gut of the adult worm, gut cells of cercaria and the egg shell. The binding of CT to the parasite was blocked when parasite sections were incubated with CT which had been incubated with the ganglioside GM1. Lipid extraction and isolation of gangliosides demonstrated the presence of GM1 in adult worms. For further analysis of CT-binding structures, the possible interaction of CT with two major schistosome gut antigens, circulating cathodic antigen (CCA) and circulating anodic antigen (CAA), was studied. We found that CT blocked the binding of anti-CCA antibody to the gut of adult worms and that anti-CCA blocked the binding of CT to the worm gut. These findings indicate that CT binds to CCA present in the gut of the parasite and thus has, in addition to GM1, a second binding specificity.

Modest phenotypic improvements in ASA-deficient mice with only one UDP-galactose:ceramide-galactosyltransferase gene.

BACKGROUND: Arylsulfatase A (ASA)-deficient mice are a model for the lysosomal storage disorder metachromatic leukodystrophy. This lipidosis is characterised by the lysosomal accumulation of the sphingolipid sulfatide. Storage of this lipid is associated with progressive demyelination. We have mated ASA-deficient mice with mice heterozygous for a non-functional allele of UDP-galactose:ceramide-galactosyltransferase (CGT). This deficiency is known to lead to a decreased synthesis of galactosylceramide and sulfatide, which should reduce sulfatide storage and improve pathology in ASA-deficient mice. RESULTS: ASA-/- CGT+/- mice, however, showed no detectable decrease in sulfatide storage. Neuronal degeneration of cells in the spiral ganglion of the inner ear, however, was decreased. Behavioural tests showed small but clear improvements of the phenotype in ASA-/- CGT+/- mice. CONCLUSION: Thus the reduction of galactosylceramide and sulfatide biosynthesis by genetic means overall causes modest improvements of pathology.

Beta-galactosylceramide increases and sulfatide decreases cytokine and chemokine production in whole blood cells.

The glycosphingolipid sulfatide and its immediate precursor beta-galactosylceramide (GalCer) are present in the pancreatic beta-cell in equimolar concentrations and may play a role in islet pathology. Previous studies of mononuclear cells have shown that sulfatide tends to decrease and GalCer tends to increase the production of proinflammatory cytokines. In this study we investigated the influence of various isoforms of sulfatide on the production of cyto- and chemokines and tested whether the opposing effects of GalCer and sulfatide could counter one another in competition assays. PHA-, LPS-, or unstimulated whole blood cultures were incubated with 30 microg/ml of native sulfatide (isolated from pig brains), C:16:0 and C:24:0 analogues of sulfatide, or native GalCer preparations. After 24 h, the supernatant levels of proinflammatory cytokines and chemokines were quantitated by ELISA. The general trend was for the sulfatides to lower the production of the cytokines, and for GalCer to increase it. In competition assays, native sulfatide dampened the stimulatory effects of GalCer but did not abolish cytokine release; GalCer, on the other hand, nullified the effect of native sulfatide at a ratio of four sulfatide molecules to one GalCer molecule. C:16:0 sulfatide appeared to have a stronger effect than C:24:0 sulfatide. The C:16:0 analogue decreased IL-1beta, IL-6, TNF-alpha, MIP-1alpha and IL-8 to 3-56% of control values (P < 0.05-0.01), while GalCer increased their production 2- to 10-fold (P < 0.01). In conclusion, sulfatide decreases the in vitro production of proinflammatory cytokines, whereas GalCer has the opposite effect.

Differences in cerebrospinal fluid dynamics do not affect the levels of biochemical markers in ventricular CSF from patients with aqueductal stenosis and idiopathic normal pressure hydrocephalus.

To compare levels of biochemical markers in ventricular cerebrospinal fluid (vCSF) between patients with aqueductal stenosis (AS) and idiopathic normal pressure hydrocephalus (INPH) and relate these results to clinical outcome after surgery. Neurofilament light protein, tau protein, sulfatide, vasoactive intestinal peptide (VIP), neuropeptide PYY (NPY) and CSF/serum albumin ratio were measured in vCSF from 18 consecutive AS and 19 consecutive INPH patients. Clinical outcome was evaluated after surgery by standardized indices. The levels of markers were related to clinical outcome. No differences in any of the markers were found between AS and INPH patients. The concentration of sulfatide and albumin ratio correlated inversely with psychometric improvement, whilst VIP and NPY correlated inversely with improvement in alertness. The similar levels of biochemical markers in vCSF from AS and INPH patients indicate similarities in pathophysiology and turnover rate of vCSF despite differences in CSF dynamics. High albumin ratio and sulfatide concentrations in vCSF in hydrocephalus patients have negative implications for surgical outcome and might indicate concomitant cerebrovascular disorder.

Metachromatic leukodystrophy: consequences of sulphatide accumulation.

UNLABELLED: Metachromatic leukodystrophy is a lysosomal lipid storage disorder. It is caused by mutations in the gene for arylsulphatase A, an enzyme involved in the degradation of the sphingolipid 3'-O-sulphogalactosylceramide (sulphatide). This membrane lipid can be found in various cell types, but in particularly high concentrations in the myelin of the nervous system. Patients suffer from progressive, finally lethal, demyelination due to accumulation of sulphatide. In the nervous system, lipid storage not only affects oligodendrocytes but also neurons and, in addition, leads to astrogliosis and activation of microglia. At the cellular level, lysosomal sulphatide storage also affects the lipid composition of myelin itself and has consequences for the amount and localization of particular myelin membrane-associated proteins. Here we review data, largely based on an arylsulphatase A knock-out mouse model of metachromatic leukodystrophy. CONCLUSION: The knock-out mouse model of metachromatic leukodystrophy has provided insights into the histopathological and cellular consequences of sulphatide storage.