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1.
Eur J Neurol ; 14(3): 248-54, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17355543

ABSTRACT

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.


Subject(s)
Hydrocephalus, Normal Pressure/cerebrospinal fluid , Hydrocephalus, Normal Pressure/physiopathology , Nerve Fibers, Myelinated/metabolism , Neurofilament Proteins/cerebrospinal fluid , Wallerian Degeneration/cerebrospinal fluid , Wallerian Degeneration/diagnosis , Adult , Aged , Aged, 80 and over , Axons/metabolism , Axons/pathology , Biomarkers/analysis , Biomarkers/cerebrospinal fluid , Brain/metabolism , Brain/pathology , Brain/physiopathology , Cerebrospinal Fluid Pressure/physiology , Cerebrospinal Fluid Proteins/analysis , Cerebrospinal Fluid Proteins/metabolism , Cerebrospinal Fluid Shunts , Down-Regulation/physiology , Female , Humans , Hydrocephalus, Normal Pressure/surgery , Lateral Ventricles/pathology , Lateral Ventricles/physiopathology , Lateral Ventricles/surgery , Magnetic Resonance Imaging , Male , Middle Aged , Nerve Fibers, Myelinated/pathology , Predictive Value of Tests , Treatment Outcome , Wallerian Degeneration/physiopathology
2.
Diabetologia ; 48(10): 1957-62, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16143863

ABSTRACT

Mammalian tissues express beta-isoforms of glycosphingolipids and, among these, sulfatide (sulphated galactosylceramide) is present in the beta cells, and it is here that the short fatty acid chain (C16) isoform is predominately found. In vitro studies have shown that sulfatide preserves insulin crystals and facilitates insulin monomerisation under certain biochemical conditions. It also activates beta cell potassium channels and moderates insulin secretion. Anti-sulfatide antibodies are seen in type 1 diabetes, and immunological presentation of glycosphingolipids by the non-classical CD1 molecules has recently been reported. It is via this mechanism that alpha-galactosylceramide and sulfatide are able to influence the innate immune system and inhibit autoimmunity, possibly through regulatory natural killer T cells. Administration of sulfatide substantially reduces the incidence of diabetes in non-obese diabetic mice and prevents antigen-induced experimental autoimmune encephalomyelitis in wild-type mice. Sulfatide has specific anti-inflammatory properties, increasing the number of CD3+CD25+ regulatory T cells and reducing production of several cytokines, including TNF-alpha. Patients with type 2 diabetes have low serum concentrations of sulfatide, and some animal models of type 2 diabetes have low pancreatic expression of C16:0 sulfatide; administration of this increases insulin secretion and improves first-phase insulin response in Zucker fatty rats. Glycosphingolipids in general, and sulfatide in particular, appear relevant to both type 1 and type 2 diabetes.


Subject(s)
Diabetes Mellitus, Type 1/physiopathology , Diabetes Mellitus, Type 2/physiopathology , Insulin-Secreting Cells/physiology , Sulfoglycosphingolipids/metabolism , Animals , Humans , Insulin-Secreting Cells/metabolism
3.
Diabet Med ; 22(9): 1190-8, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16108848

ABSTRACT

AIMS: The glycosphingolipid sulfatide (sulfated galactosyl-ceramide) increases exocytosis of beta-cell secretory granules, activates K(ATP)-channels and is thereby able to influence insulin secretion through its presence in the islets. A closely related compound, sulfated lactosylceramide (sulf-lac-cer), is present in the islets during fetal and neonatal life when, as in Type 2 diabetes, insulin is secreted autonomically without the usual first phase response to glucose. The aim was to examine whether serum concentrations of these glycolipids are associated with Type 2 diabetes. METHODS: A case-control study, comprising 286 women and 283 men, was designed using a population-based sample of patients with Type 2 diabetes and a population survey. RESULTS: Low serum concentrations of sulfatide were associated with Type 2 diabetes, independent of traditional risk factors for diabetes in a sex-specific analysis: odds ratio (OR) 2.1 (95% confidence interval 1.1, 3.9) in men, and 2.3 (1.2, 4.3) in women, comparing the lowest and the highest tertiles. Type 2 diabetes was also associated with detectable amounts of sulf-lac-cer in serum: OR 1.7 (0.9, 3.4) in men, and 7.6 (3.8, 15.2) in women. After adjustment for confounding from other diabetes risk factors, these associations remained basically unchanged. The connections between sulfatide and Type 2 diabetes, and sulf-lac-cer and Type 2 diabetes were independent of each other. Insulin resistance (HOMA-IR) was negatively correlated with sulfatide concentration and positively correlated with sulf-lac-cer (both P < 0.0001, independently). CONCLUSIONS: We report a new, robust and highly significant independent association between Type 2 diabetes and serum concentrations of sulfatide in both sexes, and sulf-lac-cer in females. The associations were also independent of other known diabetes risk factors.


Subject(s)
Antigens, CD/blood , Diabetes Mellitus, Type 2/blood , Galactosylceramides/blood , Lactosylceramides/blood , Sulfoglycosphingolipids/blood , Case-Control Studies , Diabetes Mellitus, Type 2/epidemiology , Female , Humans , Insulin Resistance/physiology , Male , Middle Aged , Population Surveillance/methods , Risk Factors , Sex Distribution , Sweden/epidemiology
4.
Immunol Lett ; 91(2-3): 205-11, 2004 Feb 15.
Article in English | MEDLINE | ID: mdl-15019291

ABSTRACT

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.


Subject(s)
Blood Cells/metabolism , Chemokines/metabolism , Cytokines/metabolism , Galactosylceramides/metabolism , Sulfoglycosphingolipids/metabolism , Adult , Animals , Cells, Cultured , Chemokines/blood , Cytokines/blood , Female , Humans , Male , Middle Aged , Swine
5.
Eur J Neurol ; 11(1): 17-23, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14692883

ABSTRACT

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.


Subject(s)
Biomarkers/cerebrospinal fluid , Cerebral Aqueduct/pathology , Cerebrospinal Fluid/physiology , Hydrocephalus/cerebrospinal fluid , Hydrocephalus/physiopathology , Age Factors , Aged , Constriction, Pathologic/complications , Constriction, Pathologic/physiopathology , Constriction, Pathologic/surgery , Female , Humans , Hydrocephalus/etiology , Male , Middle Aged , Treatment Outcome
6.
Neurobiol Aging ; 24(5): 707-14, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12885578

ABSTRACT

Normal pressure hydrocephalus (NPH) is associated with periventricular white matter lesions and demyelination. The aim of the present study was to examine the cerebrospinal fluid (CSF) levels of tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine mediating myelin damage, in patients with NPH. TNF-alpha levels were analyzed by ELISA and measured before and after shunt operation in 35 patients with NPH. The levels of this cytokine were related to the symptomatology and to magnetic resonance imaging (MRI) verified white matter lesions. They were also related to intrathecal levels of sulfatide, a marker for white matter degradation and to levels of neurofilament, a marker for neuronal degeneration. The preoperative levels of TNF-alpha were increased in the CSF of NPH patients compared to controls, and correlated to the levels of sulfatide. The intrathecal TNF-alpha levels were higher in NPH patients with impairment of wakefulness than in those without this symptom. The preoperative TNF-alpha levels were significantly correlated to the improvement of psychometrical test scores, and of wakefulness and to the overall improvement of the patients following shunt operation. Importantly, shunt operation led to complete disappearance of intrathecal TNF-alpha. We conclude that NPH is correlated with intrathecal TNF-alpha production being reversed following shunt operation in parallel with the clinical improvement. The positive correlation between preoperative TNF-alpha and sulfatide levels in the CSF suggest that intrathecal TNF-alpha may contribute to the damage of the white matter known to occur in patients with NPH.


Subject(s)
Hydrocephalus, Normal Pressure/cerebrospinal fluid , Tumor Necrosis Factor-alpha/cerebrospinal fluid , Adult , Aged , Aged, 80 and over , Brain/pathology , Brain/physiopathology , Brain Mapping , Case-Control Studies , Cerebrospinal Fluid Shunts , Enzyme-Linked Immunosorbent Assay/methods , Female , Gait , Humans , Hydrocephalus, Normal Pressure/metabolism , Hydrocephalus, Normal Pressure/surgery , Magnetic Resonance Imaging/instrumentation , Magnetic Resonance Imaging/methods , Male , Mental Status Schedule , Middle Aged , Psychometrics/methods , Psychomotor Performance , Sulfoglycosphingolipids/cerebrospinal fluid , Tumor Necrosis Factor-alpha/metabolism
7.
Dement Geriatr Cogn Disord ; 15(4): 207-11, 2003.
Article in English | MEDLINE | ID: mdl-12626853

ABSTRACT

OBJECTIVES: Subcortical vascular dementia (SVD) is associated with white matter lesions and demyelination. The aim of the present study was to examine the cerebrospinal fluid (CSF) levels of TNF-alpha, a proinflammatory cytokine mediating myelin damage, in SVD patients. The intrathecal TNF-alpha levels were related to the clinical symptoms of dementia, as well as to intrathecal levels of sulfatide, a marker of white matter degradation, and of neurofilament, a marker of neuronal degeneration. METHODS: CSF levels of TNF-a, sulfatide and neurofilament were all analyzed by immunoenzymatic procedures in 17 patients with SVD and in 26 healthy controls. RESULTS: The intrathecal concentration of TNF-alpha was significantly increased in SVD patients compared to healthy controls (p = 0.0001). The intrathecal levels of TNF-alpha were significantly correlated (r = 0.6, p = 0.02) to the levels of sulfatide, but not to the levels of neurofilament, (r = 0.08, NS). CONCLUSIONS: We have demonstrated intrathecal production of TNF-alpha in SVD patients. The correlation between TNF-a and sulfatide levels in the CSF suggests that this apoptosis-inducing cytokine leads to the death of oligodendrocytes, thereby contributing to white matter degeneration, a hallmark of SVD.


Subject(s)
Brain/metabolism , Dementia, Vascular/cerebrospinal fluid , Sulfoglycosphingolipids/cerebrospinal fluid , Tumor Necrosis Factor-alpha/cerebrospinal fluid , Aged , Aged, 80 and over , Apoptosis , Brain/pathology , Case-Control Studies , Dementia, Vascular/immunology , Dementia, Vascular/pathology , Female , Humans , Male , Neurons/pathology
8.
Acta Neurol Scand ; 105(6): 417-26, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12027829

ABSTRACT

OBJECTIVES: To analyse the diagnostic and prognostic value of periventricular hyperintensity (PVH) and deep white matter hyperintensity (DWMH) magnetic resonance imaging (MRI) changes and their relation to symptoms and cerebrospinal fluid (CSF) markers of demyelination (sulphatide) and axonal degeneration [neurofilament triplet protein (NFL)] in a large series of patients with normal pressure hydrocephalus (NPH) and Binswanger disease (BD). MATERIALS AND METHODS: PVH and DWMH were determined by a semi-automatic segmentation method on T2-weighted images in 29 patients with NPH and 17 patients with BD. CSF analyses, psychometric testing and quantification of balance, gait and continence were performed in all patients and also postoperatively in NPH patients. RESULTS: No MRI variable could identify NPH or BD patients. Abundant PVH and DWMH preoperatively correlated with improvement in gait, balance and psychometric performance after shunt surgery (P < 0.05). CSF sulphatide correlated positively with the amount of DWMH (P < 0.05) while NFL was correlated to both PVH and DWMH (P < 0.05). Abundant PVH correlated with poor psychometric performance while DWMH correlated with gait disturbance (P < 0.05). Postoperative reduction in PVH correlated with improvement in gait, balance and psychometric performance. CONCLUSION: In spite of a refined quantification method, NPH and BD patients exhibited similar MRI changes. MRI had a predictive value in NPH patients. DWMH might relate to demyelination and PVH to neuronal axonal dysfunction. NPH and BD share the major part of symptoms and MRI changes, indicating a common pathophysiological pattern, and we raise the question of how to treat BD patients.


Subject(s)
Axons/pathology , Dementia, Vascular/pathology , Demyelinating Diseases/pathology , Hydrocephalus, Normal Pressure/pathology , Aged , Aged, 80 and over , Dementia, Vascular/cerebrospinal fluid , Demyelinating Diseases/cerebrospinal fluid , Female , Humans , Hydrocephalus, Normal Pressure/cerebrospinal fluid , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Middle Aged , Predictive Value of Tests , Sulfoglycosphingolipids/cerebrospinal fluid
9.
Gene Ther ; 9(1): 53-63, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11850723

ABSTRACT

Arylsulfatase A (ASA) knockout mice represent an animal model for the lysosomal storage disease metachromatic leukodystrophy (MLD). Stem cell gene therapy with bone marrow overexpressing the human ASA cDNA from a retroviral vector resulted in the expression of high enzyme levels in various tissues. Treatment partially reduces sulfatide storage in livers exceeding 18 ng ASA/mg tissue, while complete reduction was observed in livers exceeding 50 ng ASA/mg tissue. This corresponds to about 80% and 200% of normal enzyme activity. Similar values seem to apply for kidney. A partial correction of the lipid metabolism was detectable in the brain where the galactoerebroside/sulfatide ratio, which is diminished in ASA-deficient mice, increased upon treatment. This partial correction was accompanied by amelioration of neuropathology; axonal cross-sectional areas, which are reduced in deficient mice, were significantly increased in the saphenic and sciatic nerve but not in the optic nerve. Behavioral tests suggest some improvement of neuromotor abilities. The gene transfer did not delay the degeneration occurring in the acoustic ganglion of ASA-deficient animals. The limited success of the therapy appears to be due to the requirement of unexpected high levels of ASA for correction of the metabolic defect.


Subject(s)
Cerebroside-Sulfatase/genetics , Genetic Therapy/methods , Hematopoietic Stem Cell Transplantation , Leukodystrophy, Metachromatic/therapy , Animals , Antibodies/blood , Behavior, Animal , Brain/metabolism , Central Nervous System/metabolism , Cerebroside-Sulfatase/blood , Cerebroside-Sulfatase/immunology , Female , Genetic Vectors , Liver/metabolism , Male , Mice , Mice, Knockout , Models, Animal , Retroviridae/genetics , Sulfoglycosphingolipids/metabolism , Transduction, Genetic
10.
Autoimmunity ; 34(1): 9-17, 2001.
Article in English | MEDLINE | ID: mdl-11681495

ABSTRACT

Sulfatide (3'sulfogalactosylceramide) is a glycosphingolipid present within the nervous system and in the islets of Langerhans. Anti-sulfatide antibodies have been observed in both pre-diabetic and newly diagnosed type 1 diabetic patients. The aim of this study was to test in vivo, the therapeutic effect of sulfatide on the development of diabetes in the NOD mouse. In four separate experiments diabetogenic splenocytes from newly diabetic NOD mice were injected iv into 7-8 week old irradiated (700R) female NOD mice (4-10 million cells/mouse). Each experiment consisted of four treatment groups to which the mice were randomly divided: 1) sulfatide; 2) galactosylceramide (the precursor to sulfatide without sulfate); 3) GM1, a glycosphingolipid negatively charged as sulfatide but with a different sugar composition; and 4) phosphate buffered saline (PBS). The mice received 100 microg glycosphingolipid iv on the day of cell transfer and 1-3 times thereafter at four day intervals, and were screened for diabetes three times a week the next 52 days. Among all the 35 sulfatide-treated mice 54% became diabetic compared to 93 % of 43 PBS-treated animals (p < 0.00001). Correspondingly, galactosylceramide reduced diabetes incidence to 52% (25 mice, p < 0.00001). On the other hand, 86% of GM1-treated mice (n=28) became diabetic indicating that no effect was obtained by this glycosphingolipid. In two experiments in which less spleen cells were transferred (4-5 mill.) and glycosphingolipids were given 4 times, 35% of the sulfatide-treated animals (n = 17) developed diabetes compared to 85% of PBS-treated mice (n = 20, p < 0.001). A robust proliferative response to sulfatide, but none to GM1, was observed when spleen cells were rechallenged with glycosphingolipid in vitro. Thus, like insulin and GAD, sulfatide is able to prevent diabetes in NOD mice.


Subject(s)
Diabetes Mellitus, Type 1/prevention & control , Galactosylceramides/pharmacology , Sulfoglycosphingolipids/pharmacology , Adoptive Transfer , Animals , Autoantigens/administration & dosage , Autoantigens/chemistry , Autoimmunity , Carbohydrate Sequence , Diabetes Mellitus, Type 1/etiology , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/pathology , Female , G(M1) Ganglioside/chemistry , G(M1) Ganglioside/immunology , G(M1) Ganglioside/pharmacology , Galactosylceramides/chemistry , Galactosylceramides/immunology , Humans , Islets of Langerhans/immunology , Islets of Langerhans/pathology , Lymphocyte Activation , Mice , Mice, Inbred NOD , Molecular Sequence Data , Spleen/cytology , Spleen/immunology , Sulfoglycosphingolipids/chemistry , Sulfoglycosphingolipids/immunology
11.
Glycobiology ; 11(6): 473-9, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11445552

ABSTRACT

Sulfatide is a glycolipid that has been associated with insulin-dependent diabetes mellitus. It is present in the islets of Langerhans and follows the same intracellular route as insulin. However, the role of sulfatide in the beta cell has been unclear. Here we present evidence suggesting that sulfatide promotes the folding of reduced proinsulin, indicating that sulfatide possesses molecular chaperone activity. Sulfatide associates with insulin by binding to the insulin domain A8--A10 and most likely by interacting with the hydrophobic side chains of the dimer-forming part of the insulin B-chain. Sulfatide has a dual effect on insulin. It substantially reduces deterioration of insulin hexamer crystals at pH 5.5, conferring stability comparable to those in beta cell granules. Sulfatide also mediates the conversion of insulin hexamers to the biological active monomers at neutral pH, the pH at the beta-cell surface. Finally, we report that inhibition of sulfatide synthesis with chloroquine and fumonisine B1 leads to inhibition of insulin granule formation in vivo. Our observations suggest that sulfatide plays a key role in the folding of proinsulin, in the maintenance of insulin structure, and in the monomerization process.


Subject(s)
Insulin/chemistry , Proinsulin/metabolism , Protein Folding , Sulfoglycosphingolipids/pharmacology , Animals , Crystallography , Humans , Insulin/biosynthesis , Models, Molecular , Proinsulin/drug effects , Protein Conformation , Swine
12.
Eur Neurol ; 45(1): 38-42, 2001.
Article in English | MEDLINE | ID: mdl-11150839

ABSTRACT

Primary and metastatic brain tumours may result in an altered exposure of normal cellular components to the immune system inducing an immune response measurable in autoantibodies. One potential immunogenic molecule is sulphatide, the major acidic glycolipid in myelin. Thirty-eight sera from 31 patients with primary and metastatic brain tumours have, therefore, been analyzed for the presence of antisulphatide antibodies by an ELISA performed on thin layer chromatography plates. Twenty-eight of the thirty-eight sera (74%) showed a positive antibody titre to sulphatide. The antibody titres were significantly higher (p < 0.01) in sera from patients with primary brain tumours than in sera from those with metastases. The study lends support to the possibility that antisulphatide antibodies could contribute to tissue damage and this might facilitate the invasive growth in primary brain tumours by demyelination. However, the pathogenic significance of these autoantibodies remains to be further elucidated.


Subject(s)
Antibodies, Neoplasm/blood , Brain Neoplasms/blood , Myelin Sheath/immunology , Sulfoglycosphingolipids/immunology , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Myelin Sheath/chemistry , Sulfoglycosphingolipids/chemistry
13.
J Neurol Sci ; 182(2): 117-21, 2001 Jan 01.
Article in English | MEDLINE | ID: mdl-11137516

ABSTRACT

Cerebrospinal fluid from 39 healthy individuals showed evidence for increasing blood-CSF barrier permeability with age, and confirmed that haptoglobins are more sensitive but less predictive markers of barrier permeability than total protein. Haptoglobin (Hp) species were identified by polyacrylamide gel electrophoresis followed by immunoblotting. Hp 1-1 (35 A, 85 kDa) was detected in all (9/9) subjects who exhibited this phenotype. Hp 2-1 (42 A, 120 kDa) was detected in 53% (8/15) of subjects in whom Hp 2-1 was the phenotype. Hp 2-2 (54 A, 160 kDa) was detected in only 20% (3/15) of subjects who exhibited this phenotype. The likelihood of detecting any haptoglobin species corresponded to the molecular size and the consequent resistance offered by the barrier. Among younger subjects aged < or =45 years, a significant difference in incidence occurred between the two smaller species Hp 1-1 and Hp 2-1. However, among those aged >45, the significant difference in incidence was between the two larger species Hp 2-1 and Hp 2-2. The incidence of detection among those with Hp 2-1 phenotypes was higher in the older age group. The increased likelihood of detecting haptoglobins with age is in keeping with the notion that barrier function is compromised by age, and also indicates that Hp 2-1 and Hp 2-2 are sensitive markers of barrier function. The appreciable incidence of haptoglobins in normal CSF, even of the larger species, suggests reservation in assuming that their presence signifies barrier damage.


Subject(s)
Biomarkers/cerebrospinal fluid , Capillary Permeability/physiology , Haptoglobins/cerebrospinal fluid , Adolescent , Adult , Age Factors , Aged , Female , Haptoglobins/genetics , Humans , Male , Middle Aged , Phenotype , Reference Values , Sex Factors
14.
J Neuroimmunol ; 112(1-2): 129-38, 2001 Jan 01.
Article in English | MEDLINE | ID: mdl-11108941

ABSTRACT

Guillain-Barré syndrome (GBS) is an acute inflammatory disease affecting myelin and axons of the peripheral nervous system (PNS). GBS is considered to be caused by breakdown of tolerance to autoantigens of the PNS. The involvement of cytokines in GBS and in relation to treatment with high dose intravenous immunoglobulin (IvIg) is incompletely known. We studied the temporal profiles of IL-10 and IFN-gamma-secreting blood mononuclear cells (MNC) over the course of GBS, using enzyme-linked immunospot (ELISPOT) assays. Pretreatment levels of blood MNC spontaneously secreting IL-10 were higher in the acute phase of GBS than in control patients with aseptic meningitis, other neurological diseases, diabetic neuropathy and healthy subjects. Levels of IFN-gamma-secreting blood MNC were not increased over the course of GBS. Patients treated with IvIg had lower numbers of IL-10-secreting MNC compared to untreated patients. High levels of IL-10-secreting MNC correlated with serum anti-ganglioside IgM antibody levels, and with neurophysiological signs of axonal damage. The present data suggests that IFN-gamma is not involved in GBS pathogenesis, and IL-10 being up-regulated in the early phase of GBS and associated with axonal damage, may have a pathogenetic role in GBS.


Subject(s)
Guillain-Barre Syndrome/immunology , Interferon-gamma/biosynthesis , Interleukin-10/biosynthesis , Adult , Aged , Female , Gangliosides/immunology , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Leukocytes, Mononuclear/metabolism , Male , Middle Aged
15.
Neuropathol Appl Neurobiol ; 27(6): 451-64, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11903928

ABSTRACT

This work describes the in vivo expression and distribution of glioma-associated gangliosides (GD3, GM2, 3'-isoLM1) in a novel human brain tumour nude rat xenograft model. In this model, the tumours, which are established directly from human glioblastoma biopsies, show extensive infiltrative growth within the rat brain. This model therefore provides an opportunity to study ganglioside expression not only within the macroscopic tumour, but also in brain areas with tumour cell infiltration. The ganglioside expression was studied by confocal microscopy of immunostained brain sections using antiganglioside monoclonal antibodies. Xenografts from four human glioblastoma multiformes were established in rats and the brains removed after 3-4 months. Ganglioside GD3 was expressed in the tumour parenchyma while ganglioside 3'-isoLM1 was more abundantly expressed in the periphery of the tumour associated with areas of tumour cell invasion. GM2 expression was only seen in one tumour, where it was located within the main tumour mass. Double staining with a pan antihuman monoclonal antibody (3B4) and the antiganglioside monoclonal antibodies confirmed that the ganglioside expression was associated with tumour cells. This work supports the concept of different biological roles for individual gangliosides and indicates that antibodies or ligands directed against GD3 and 3'-isoLM1 might be complementary when applied in the treatment of human glioblastomas.


Subject(s)
Brain Neoplasms/metabolism , Gangliosides/analysis , Glioblastoma/metabolism , Animals , Antibodies, Monoclonal , Antigens, Tumor-Associated, Carbohydrate/analysis , Antigens, Tumor-Associated, Carbohydrate/biosynthesis , Brain Injuries/metabolism , Brain Neoplasms/chemistry , Disease Models, Animal , Fluorescent Antibody Technique , Gangliosides/biosynthesis , Gangliosides/immunology , Glioblastoma/chemistry , Humans , Microscopy, Confocal , Neoplasm Transplantation , Rats , Rats, Nude , Transplantation, Heterologous , Wounds, Stab/metabolism
16.
J Alzheimers Dis ; 3(5): 435-442, 2001 Oct.
Article in English | MEDLINE | ID: mdl-12214028

ABSTRACT

The protein clusterin has been suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Its expression is increased in brain regions affected by AD pathology, and to elucidate if there is a concomitant increase of clusterin also in the cerebrospinal fluid (CSF) in different neurological disorders, CSF samples from patients with AD, vascular dementia (VAD), Parkinson's disease (PD), and controls were analysed. Also longitudinal (five occasions) samples from patients with acute stroke were analysed, to follow any degenerative/regenerative phase after acute brain damage. However, there were no changes in CSF-clusterin levels from patients in AD, VAD, PD or acute stroke, as compared to controls. The increase of clusterin in brain tissue is suggested to reflect a regenerative response process, which here is shown not to be followed by a concomitant increase in the CSF. Thus, CSF-clusterin can not be used as an indicator or a diagnostic marker for AD.

17.
Infection ; 28(3): 143-8, 2000.
Article in English | MEDLINE | ID: mdl-10879637

ABSTRACT

BACKGROUND: Loss of synapses and neurons is a common finding in HIV-1 infection. Since the in vivo infection of neurons by HIV-1 is limited, indirect factors are likely to contribute to the pathogenesis. PATIENTS AND METHODS: We have analyzed cerebrospinal fluid (CSF) and serum samples from 25 HIV-1-infected individuals (nine with and 16 without CNS complications) and 19 HIV-negative controls with aseptic meningitis or viral encephalitis, for the presence of antibodies directed against the neuron-associated gangliosides GM1, GD1a and GD1b. RESULTS: Positive antibody titers to > or =1 of the gangliosides were found in 13/25 HIV-1-infected patients in CSF and in 17/25 in serum. Significant correlations were found between the presence and titers of CSF antibodies against GM1, GD1a, and GD1b. Six out of nine patients with, and 3/16 without neurological complications (p < 0.05) had positive CSF titers of > or = 1 of the ganglioside antibodies combined with negative serum titers, indicating intrathecal antibody production. In contrast, only 1/19 controls had detectable anti-ganglioside antibodies in the CSF. CONCLUSION: The results should be interpreted with caution and CSF anti-ganglioside antibody production might be a part of a non-specific intrathecal polyclonal immunoactivation. Nevertheless, autoantibodies directed against neuron-associated gangliosides might be involved in the neuropathogenesis in HIV-1 disease.


Subject(s)
Antibodies/cerebrospinal fluid , Encephalitis, Viral/cerebrospinal fluid , Gangliosides/immunology , HIV Infections/cerebrospinal fluid , HIV-1 , Adult , Antibodies/blood , Autoantibodies/blood , Autoantibodies/cerebrospinal fluid , Encephalitis, Viral/etiology , Enzyme-Linked Immunosorbent Assay , Female , G(M1) Ganglioside/immunology , HIV Infections/blood , HIV Infections/complications , Humans , Immunoglobulin G/blood , Immunoglobulin G/cerebrospinal fluid , Immunoglobulin M/blood , Immunoglobulin M/cerebrospinal fluid , Lactones/immunology , Male , Middle Aged , Neurons/chemistry
18.
J Neurol Neurosurg Psychiatry ; 69(1): 74-81, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10864607

ABSTRACT

OBJECTIVES: To examine the CSF concentrations of molecules reflecting demyelination, neuronal and axonal degeneration, gliosis, monoaminergic neuronal function, and aminergic and peptidergic neurotransmission in a large series of patients with normal pressure hydrocephalus (NPH) or subcortical arteriosclerotic encephalopathy (SAE), to elucidate pathogenic, diagnostic, and prognostic features. METHODS: CSF concentrations of glycosphingolipid (sulfatide), proteins (neurofilament triplet protein (NFL), glial fibrillary acidic protein (GFAP)), neuropeptides (vasoactive intestinal peptide (VIP), 4-aminobutyric acid (GABA)), and monoamines (homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA), 4-hydroxy-3-methoxyphenylglycol (HMPG)) were analysed in 43 patients with NPH and 19 patients with SAE. The diagnoses of NPH and SAE were based on strict criteria and patients with NPH were subsequently operated on. Twelve clinical variables, psychometric tests measuring perceptual speed, accuracy, learning, and memory and a psychiatric evaluation were performed in all patients and before and after a shunt operation in patients with NPH. RESULTS: The CSF sulfatide concentration was markedly increased in patients with SAE (mean 766, range 300-3800 nmol/l) compared with patients with NPH (mean 206, range 50-400 nmol/l) (p<0.001). 5-HIAA, GABA, and VIP in CSF were higher in patients with SAE than in patients with NPH. The patients with NPH with cerebrovascular aetiology had higher sulfatide concentrations and a poorer outcome after shunt surgery than patients with NPH with other aetiologies. CONCLUSIONS: The pathogenesis of the white matter changes in NPH and SAE is different and ischaemic white matter changes can be a part of the NPH state. The markedly increased CSF sulfatide concentrations in patients with SAE indicate ongoing demyelination as an important pathophysiological feature of SAE. The CSF sulfatide concentration distinguished between patients with SAE and those with NPH with a sensitivity of 74% and a specificity of 94%, making it an important diagnostic marker.


Subject(s)
Dementia, Vascular/diagnosis , Hydrocephalus, Normal Pressure/diagnosis , Sulfoglycosphingolipids/cerebrospinal fluid , Adult , Aged , Aged, 80 and over , Brain/pathology , Dementia, Vascular/cerebrospinal fluid , Diagnosis, Differential , Female , Humans , Hydrocephalus, Normal Pressure/cerebrospinal fluid , Magnetic Resonance Imaging , Male , Middle Aged , Nerve Tissue Proteins/cerebrospinal fluid , Neuropsychological Tests , Prognosis , Reference Values
19.
J Neurosci Res ; 60(4): 531-42, 2000 May 15.
Article in English | MEDLINE | ID: mdl-10797556

ABSTRACT

We have studied the cellular distribution of gangliosides GD1b, GD3 and GM1 in rat cerebellum by immunostaining, using monoclonal antibodies and confocal microscopy. Antibodies against astroglial, neuronal and synaptic vesicle associated molecules were used for colocalization analyses. In the gray matter, the anti-GD1b antibody stained thin strands in the molecular layer (ML), interpreted as Bergman glia fibers based on colocalized staining with anti-glial fibrillary acidic protein (GFAP). The neuropil in the granule (GL) and Purkinje (PL) cell layers was also anti-GD1b positive. The anti-GD3 antibody stained the ML, the neuropil in the GL and PL and also the granule and Purkinje cell bodies, appearing intracytoplasmically and vesicle associated. Anti-GD1b and anti-GD3 staining in the GL glomeruli were colocalized with anti-synaptophysin staining. The anti-GM1 antibody stained cell bodies in the ML but they could not be characterized in colocalization experiments. The GL and PL were not stained with the anti-GM1 antibody. In the white matter, different staining patterns were seen for the gangliosides, the anti-GM1 staining being the most intense. This study shows cellular layer and cell type specific associations of the investigated gangliosides and localization of GD1b and GD3 at synaptic sites, warranting further studies on their role in synaptic mechanisms.


Subject(s)
Cerebellum/metabolism , G(M1) Ganglioside/metabolism , Gangliosides/metabolism , Animals , Astrocytes/metabolism , Cerebellum/cytology , Fluorescent Antibody Technique, Indirect , Immunohistochemistry , Microscopy, Confocal , Nerve Fibers/metabolism , Neuropil/metabolism , Purkinje Cells/metabolism , Rats , Rats, Sprague-Dawley
20.
Neurochem Res ; 25(4): 511-7, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10823584

ABSTRACT

Apolipoprotein E (apoE) is a protein involved in transport of lipids and has been implicated to play an important role in regeneration after nerve injury. Determination of apoE in cerebrospinal fluid (CSF) thus have a potential interest when studying different forms of brain damage and as a marker of ongoing regenerative processes in the brain. However, previous studies on CSF-ApoE in Alzheimer's disease (AD) have given inconclusive results. Such inconsistent results might be related to confounding factors interfering with sample handling and/or analyses, which have not been fully elucidated. We therefore examined different potential confounding factors for analyses of apoE in CSF and also developed a new enzyme linked immunosorbent assay (ELISA). The hydrophobic character of ApoE resulted in adsorption to different types of test tubes commonly used for collection of CSF at lumbar puncture, resulting in falsely low levels. This makes CSF handling critical, especially if samples are taken in different types of tubes, or is transferred to new tubes. Taking this confounding factors in consideration and analysing patient and control CSF handled in the same way and using the new ELISA, we could confirm our previous finding of reduced levels of ApoE in AD, (3.4 +/- 1.3 mg/l) compared with controls (4.5 +/- 2.7 mg/l) (p = 0.045). Both in the AD and in the control group, higher levels of CSF-ApoE was found in individuals possessing the ApoE4 alleles. Our results support that CSF-ApoE is reduced in AD, and that handling of CSF is a critical factor, which may explain the discrepant results from previous studies. Differences in the amount of patients and controls possessing the ApoE4 allele included might also increase the variance between different studies.


Subject(s)
Alzheimer Disease/cerebrospinal fluid , Apolipoproteins E/cerebrospinal fluid , Enzyme-Linked Immunosorbent Assay/methods , Aged , Alleles , Analysis of Variance , Antibody Specificity , Apolipoprotein E4 , Apolipoproteins E/chemistry , Apolipoproteins E/genetics , Female , Gene Frequency , Humans , Male , Middle Aged , Polysorbates/chemistry , Polystyrenes/chemistry , Protein Binding , Reproducibility of Results , Specimen Handling , Temperature
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