ICP-MS Multi-Elemental Analysis of the Human Meninges Collected from Sudden Death Victims in South-Eastern Poland.

Metals perform many important physiological functions in the human body. The distribution of elements in different tissues is not uniform. Moreover, some structures can be the site of an accumulation of essential or toxic metals, leading to multi-directional intracellular damage. In the nervous system, these disorders are especially dangerous. Metals dyshomeostasis has been linked to a variety of neurological disorders which end up leading to permanent injuries. The multi-elemental composition of the human brain is still the subject of numerous investigations and debates. In this study, for the first time, the meninges, i.e., the dura mater and the arachnoid, were examined for their elemental composition by means of inductively coupled plasma mass spectrometry (ICP-MS). Tissue samples were collected post mortem from those who died suddenly as a result of suicide (n = 20) or as a result of injuries after an accident (n = 20). The interactions between 51 elements in both groups showed mainly weak positive correlations, which dominated the arachnoid mater compared to the dura mater. The study showed differences in the distribution of some elements within the meninges in the studied groups. The significant differences concerned mainly metals from the lanthanide family (Ln), macroelements (Na, K, Ca, Mg), a few micronutrients (Co), and toxic cadmium (Cd). The performed evaluation of the elemental distribution in the human meninges sheds new light on the trace metals metabolism in the central nervous system, although we do not yet fully understand the role of the human meninges.

In vitro meningeal permeation of MnFe2O4 nanoparticles.

MnFe2O4 nanoparticles (NPs) are commonly produced in some occupational settings and may reach high concentration in activities such as arc-welding or ferroalloy metallurgy. Manganese is an essential cofactor in enzyme activities but it has been demonstrated that long-term exposure to excessive levels can lead to "manganism", a neurodegenerative disease resembling Parkinson features. Inhaled NPs deposit partially in pharynx and nasopharynx and may reach the central nervous system through the olfactory nerve, which is completely enveloped by the meningeal membranes throughout its course from the nasal cavity to the olfactory bulb or through the trigeminal nerves. This study investigated in vitro the transmeningeal absorption of 50 nm MnFe2O4NPs, using excised porcine meninges mounted on Franz diffusion cells. We tested two donor solutions: the first containing MnFe2O4NPs (2.0 g/L) and the second obtained by the ultrafiltration of the first one, in order to test only the NPs water soluble fraction. Each experiment was carried separately for 4 h. Results showed that no Mn flux permeation through the meninges occurred, since only trace of the metal was found in receivers solutions of cells exposed to MnFeNPs (5.5 ±â€¯2.2 ng/cm2), ultrafiltered solution (3.5 ±â€¯1.5 ng/cm2) and blank cells. (2.1 ±â€¯0.6 ng/cm2) (mean and SE). Differences did not reach the statistical significance. Our study shows - for the first time - that MnFe2O4NPs penetrate the meningeal membrane in a negligible amount, thus making unlikely the hypothesis of a transcellular and paracellular absorption through the olfactory nerve but not excluding the hypothesis of an active intraneuronal absorption.

Preparation of Amyloid Fibrils Seeded from Brain and Meninges.

Seeding of amyloid fibrils into fresh solutions of the same peptide or protein in disaggregated form leads to the formation of replicate fibrils, with close structural similarity or identity to the original fibrillar seeds. Here we describe procedures for isolating fibrils composed mainly of ß-amyloid (Aß) from human brain and from leptomeninges, a source of cerebral blood vessels, for investigating Alzheimer's disease and cerebral amyloid angiopathy. We also describe methods for seeding isotopically labeled, disaggregated Aß peptide solutions for study using solid-state NMR and other techniques. These methods should be applicable to other types of amyloid fibrils, to Aß fibrils from mice or other species, tissues other than brain, and to some non-fibrillar aggregates. These procedures allow for the examination of authentic amyloid fibrils and other protein aggregates from biological tissues without the need for labeling the tissue.

[Meningioangiomatosis: a clinicopathological study of five cases].

OBJECTIVE: To investigate the clinicopathologic characteristics of meningioangiomatosis (MA). METHODS: Five cases of MA were evaluated morphologically by HE and immunohistochemistry on formalin-fixed paraffin-embedded tissue. Clinical information was also obtained. The literature was reviewed. The clinical pathology and biological behavior of MA were discussed. RESULTS: Five cases of MA were reported, arising in three males and two females, with an age range of 16 to 26 years at diagnosis. All five subjects had intractable seizure disorders, and the duration of illness ranged from 8 months to 18 years. The lesions were resected from the frontal lobe in four patients, and from the temporal lobe in one. All the lesions were confined to the cortex, firm in consistency, without capsules and had poor blood supply. There was focal involvement of the overlying leptomeninges. Microscopically, they showed characteristic features of MA, such as proliferating microvessels with perivascular cuffs of spindle-cell within the cortex. Some had numerous calcifications, others showed acidophilic granular bodies. The cells were positive for EMA and vimentin by immunohistochemistry, and for reticulin by histochemical staining. CONCLUSIONS: MA is a rare, benign hamartomatous lesion of the central nervous system. It usually presents as plaque-like or nodular mass in the cerebral cortex and the overlying leptomeninges, consisting of meningovascular proliferation and leptomeningeal calcification. In some cases the lesion may show perivascular proliferation of elongated spindle-shaped cells. MA usually affects children and young adults, and is located in the frontal or temporal lobes with variable involvement of the overlying leptomeninges. Clinically, most of sporadic cases have a long history of intractable seizures despite multiantiepileptic drugs. MA has also been reported to coexist with arteriovenous malformations,meningiomas and other tumorous lesions.

Senile plaques and cerebral amyloid angiopathy in an aged California sea lion (Zalophus californianus).

Senile plaques (SPs) and cerebral amyloid angiopathy (CAA) consisting of ß-amyloid (Aß) are major features in the brain of Alzheimer's disease (AD) patients and elderly humans and animals. In this study, we report the finding of SPs and CAA in an aged sea lion (30 years), which is the first demonstration of AD-related pathological changes in a marine animal. Histologically, SPs were observed at the cerebral cortex, most frequently at the frontal lobe, with two morphologically different types: the small round type and the large granular type. Only the small round SPs were positive for Congo red staining. The SPs were equally immunoreactive to Aß40 and Aß42 and were mainly composed of Aß with an N-terminal pyroglutamate residue at position 3. Amyloid depositions at vessel walls were noted at the meninges and within the parenchyma. Interestingly, double immunofluorescence staining for Aß40 and Aß42 showed that the two subtypes were deposited segmentally in different parts of the vessel walls. The lesions observed in the sea lion suggest that Aß deposition is widely present in various animal species, including marine mammals; however, the peculiar deposits similar to cotton wool plaques and the specific pattern of CAA are characteristic features of this animal.

Distribution and pharmacokinetics of double-radiolabeled endotoxin in the rat brain and peripheral organs.

The endotoxin, lipopolysaccharide (LPS), of Salmonella typhimurium was biosynthetically labeled with (3)H and (14)C incorporated into the fatty acyl chains and glucosamine residues, respectively. The radio-labeled LPS was isolated from the bacteria and then injected into Sprague-Dawley rats. The distribution of (14)C and (3)H-LPS in plasma and other organs was determined following intraperitoneal (IP) doses of (14)C and (3)H-LPS (200 µg/kg). Plasma concentrations of both fatty acyl chains and glucosamine residues were biphasic, with a relatively rapid decay followed by a slow decline for 48 h. Similar biphasic results were found in the peripheral organs (kidney and heart) and brain barrier tissues (meninges and choroid plexus). In other brain tissues (brain stem, caudate nucleus, hypothalamus, frontal cortex, cerebellum and hippocampus), the glucosamine residue was biphasic, whereas the fatty acyl chains showed accumulation. Highest concentrations of LPS were found in the plasma, spleen and the liver. In addition, in the liver, sustained elevations of (14)C-glucosamine and (3)H-fatty acyl chains were observed. This indicates LPS accumulation in the liver. By contrast, the spleen showed biphasic decay of glucosamine residues and accumulation of fatty acyl chains. In the brain barrier tissues, peak LPS concentrations were significantly reduced (about 70%) and were further reduced (about 95%) in other brain tissues. The high elevation of LPS in the spleen is considered indicative of an immune response. Our findings highlight the potential significant role of lipid A as shown with the sustained elevation of (3)H-fatty acyl chains in the brain.

Segmental and restricted localization pattern of Fras1 in the developing meningeal basement membrane in mouse.

The Fras1/Frem family of extracellular matrix proteins consists of Fras1 and its structurally related proteins, Frem1 (Fras1-related extracellular matrix protein 1), Frem2 and Frem3. These are co-localized in embryonic epithelial basement membranes (BMs), where they contribute to epithelial-mesenchymal adhesion. Although Fras1 localization pattern in epithelial BMs has been well defined, it has not yet been comprehensively studied in the central nervous system. Here, we demonstrate the immunohistochemical profile of Fras1 in the developing mouse brain and reveal an exclusively meningeal BM protein deposition. Interestingly, Fras1 displays a segmental localization pattern, which is restricted to certain regions of the meningeal BM. Frem2 protein displays a similar localization pattern, while Frem3 is rather uniformly distributed throughout the meningeal BM. Fras1 and Frem2 proteins are detected in regions of the BM that underlie organizing centers, such as the roof plate (RP) of diencephalon, midbrain and hindbrain, and the RP-derived structures of telencephalon (choroid plexus and hem). Organizing centers exert their activity via the production of bioactive molecules, which are potential Fras1 ligands. The restricted pattern of Fras1 and Frem2 proteins indicates a molecular compartmentalization of the meningeal BM that could reflect, yet unspecified, functional and structural differences.

Autoradiographic evidence for the transmeningeal diffusion of muscimol into the neocortex in rats.

Electrophysiological and behavioral studies have demonstrated that muscimol administered through the cranial meninges can prevent focal neocortical seizures. It was proposed that transmeningeal muscimol delivery can be used for the treatment of intractable focal neocortical epilepsy. However, it has not been proved that muscimol administered via the transmeningeal route can penetrate into the neocortex. The purpose of the present study was to solve this problem by using combined autoradiography-histology methods. Four rats were implanted with epidural cups over the parietal cortices. A 50 µL mixture of [³H] muscimol and unlabeled muscimol with a final concentration of 1.0mM was delivered through each cup on the dura mater. After a 1-hour exposure, the muscimol solution was removed and replaced with formalin to trap the transmeningeally diffused molecules. Then the whole brain was fixed transcardially, sectioned, with the sections subjected to autoradiography and thionine counterstaining. Results showed that (1) [³H] muscimol diffused through the meninges into the cortical tissue underlying the epidural cup in all rats. (2) [³H] muscimol-related autoradiography grains were distributed in all six neocortical layers. (3) [³H] muscimol-related autoradiography grains were localized to the cortical area underneath the epidural delivery site and were absent in the cerebral cortical white matter and other brain structures. This study provided evidence that muscimol can be delivered via the transmeningeal route into the neocortical tissue in a spatially controlled manner. The finding further supports the rationale of using transmeningeal muscimol for the treatment of intractable focal neocortical epilepsy.

Heparan sulfate niche for cell proliferation in the adult brain.

In adulthood, new neurons and glial cells are generated from stem cells in restricted zones of the brain, namely the olfactory bulb (OB), rostral migratory stream (RMS), subventricular zone (SVZ) of the lateral ventricle, sub-callosum zone (SCZ) and sub-granular layer (SGL) of the dentate gyrus. What makes these zones germinal? We previously reported that N-sulfated heparan sulfates (N-sulfated HS) present in specialized extracellular matrix structures (fractones) and vascular basement membranes bind the neurogenic factor FGF-2 (fibroblast growth factor-2) next to stem cells in the anterior SVZ of the lateral ventricle, the most neurogenic zone in adulthood. To determine to which extent cell proliferation is associated with N-sulfated HS, we mapped N-sulfated HS and proliferating cells by immunohistochemistry throughout the adult mouse brain. We found that cell proliferation is associated with N-sulfated HS in the OB, RMS, the whole germinal SVZ, and the SCZ. Cell proliferation was weakly associated with N-sulfated HS in the SGL, but the SGL was directly connected to a sub-cortical N-sulfated HS+ extension of the meninges. The NS-sulfated HS+ structures were blood vessels in the OB, RMS and SCZ, and primarily fractones in the SVZ. N-sulfated HS+ fractones, blood vessels and meninges formed a continuum that coursed along the OB, SVZ, RMS, SCZ and SGL, challenging the view that these structures are independent germinal entities. These results support the possibility that a single anatomical system might be globally responsible for mitogenesis and ultimately the production of new neurons and glial cells in the adult brain.

Abundant extracellular myelin in the meninges of patients with multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS) myelin debris has been observed within MS lesions, in cerebrospinal fluid and cervical lymph nodes, but the route of myelin transport out of the brain is unknown. Drainage of interstitial fluid from the brain parenchyma involves the perivascular spaces and leptomeninges, but the presence of myelin debris in these compartments has not been described. AIMS: To determine whether myelin products are present in the meninges and perivascular spaces of MS patients. METHODS: Formalin-fixed brain tissue containing meninges from 29 MS patients, 9 non-neurological controls, 6 Alzheimer's disease, 5 stroke, 5 meningitis and 7 leucodystrophy patients was investigated, and immunohistochemically stained for several myelin proteins [proteolipid protein (PLP), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase)]. On brain material from MS patients and (non)neurological controls, PLP immunostaining was used to systematically investigate the presence of myelin debris in the meninges, using a semiquantitative scale. RESULTS: Extensive extracellular presence of myelin particles, positive for PLP, MBP, MOG and CNPase in the leptomeninges of MS patients, was observed. Myelin particles were also observed in perivascular spaces of MS patients. Immunohistochemical double-labelling for macrophage and dendritic cell markers and PLP confirmed that the vast majority of myelin particles were located extracellularly. Extracellular myelin particles were virtually absent in meningeal tissue of non-neurological controls, Alzheimer's disease, stroke, meningitis and leucodystrophy cases. CONCLUSIONS: In MS leptomeninges and perivascular spaces, abundant extracellular myelin can be found, whereas this is not the case for controls and other neurological disease. This may be relevant for understanding sustained immunogenicity or, alternatively, tolerogenicity in MS.

[Therapeutic effect of a new recombinant immunotoxin mMIP-1alpha-DT390 on experimental autoimmune encephalomyelitis].

OBJECTIVE: To evaluate the therapeutic effect of a new recombinant immunotoxin mMIP-1alpha-DT390 on experimental autoimmune encephalomyelitis (EAE). METHODS: EAE was induced in the low-sensitive strain C57BL/6 mice with intraperitoneal injection of myelin basic protein (MBP) to simulate the human disease multiple sclerosis, followed by intramuscular injection of cationic liposome carrying the plasmid DNA SRalpha-mMIP-1alpha-DT390 in the leg muscle to elicit resistance to EAE development. The mice were then examined daily for clinical signs of EAE by an observer blind to the treatment protocol. For immunohistochemistry the mice were anesthetized and perfused with sterile PBS and paraformaldehyde, and the cerebrum, cerebellum, medulla and spinal cord were removed for preparation of serial sections. The mononuclear cells (MNCs) from the EAE mouse spleens were prepared for three-color flow cytometry analysis of the surface markers with appropriate antibodies following the BD Pharmingen cytokine staining protocol. RESULTS: EAE model was successfully established by active MBP immunization in C57BL/6 mice. Administration of the immunotoxin mMIP-1alpha-DT390 significantly delayed the disease onset and lowered the mean clinical score for EAE as compared with the control mice. Immunohistochemistry demonstrated much less CCR5(+) infiltrating cells in the central nervous system in mMIP-1alpha-DT390-treated mice than in the control. The treatment also eliminated reactive T cells in the periphery blood without affecting the number of B cells. CONCLUSION: The immunotoxin mMIP-1alpha-DT390 can attenuate the disease activity of EAE in mice, suggesting its potential use in the treatment of other autoimmune disorders.

Induction of the antimicrobial peptide CRAMP in the blood-brain barrier and meninges after meningococcal infection.

Antimicrobial peptides are present in most living species and constitute important effector molecules of innate immunity. Recently, we and others have detected antimicrobial peptides in the brain. This is an organ that is rarely infected, which has mainly been ascribed to the protective functions of the blood-brain barrier (BBB) and meninges. Since the bactericidal properties of the BBB and meninges are not known, we hypothesized that antimicrobial peptides could play a role in these barriers. We addressed this hypothesis by infecting mice with the neuropathogenic bacterium Neisseria meningitidis. Brains were analyzed for expression of the antimicrobial peptide CRAMP by immunohistochemistry in combination with confocal microscopy. After infection, we observed induction of CRAMP in endothelial cells of the BBB and in cells of the meninges. To explore the functional role of CRAMP in meningococcal disease, we infected mice deficient of the CRAMP gene. Even though CRAMP did not appear to protect the brain from invasion of meningococci, CRAMP knockout mice were more susceptible to meningococcal infection than wild-type mice and exhibited increased meningococcal growth in blood, liver, and spleen. Moreover, we could demonstrate that carbonate, a compound that accumulates in the circulation during metabolic acidosis, makes meningococci more susceptible to CRAMP.

Meningeal involvement in Wegener's granulomatosis is associated with localized disease.

Meningeal involvement is a rare occurrence in Wegener's Granulomatosis (WG). A Medline search uncovered only 48 previously reported cases. Here we describe the clinical features of meningeal involvement in WG and to evaluate the association with systemic disease extension. Through a systematic literature review of papers concerning meningeal involvement in WG, we collected and analysed data about sex, age, disease extension, symptoms, cerebrospinal fluid examination, imaging, ANCA and histology about previously reported patients. Headache is almost always the first symptom of meningeal involvement in WG. Later in the course of the disease other abnormalities may develop. Among them cranial nerve palsy, seizures and encephalopathy are the most frequent. Diagnosis is obtained by neuroimaging, which may disclose two distinct patterns of meningeal thickening: diffuse or focal. 62.9% of patients tests positive for ANCA. Histology typically shows necrotizing granulomatosis. Meningeal involvement is by far more frequent in the setting of localized WG. Meningitis is a rare complication of WG. It usually develops in patients with localized disease who are more likely to have destructive lesions of the upper airways. It may be recognized by a constellation of clinical and radiological findings and by histological signs of necrotizing granulomatosis, with little or no vasculitis.

Oculoleptomeningeal amyloidosis in a large kindred with a new transthyretin variant Tyr69His.

OBJECTIVE: To describe the clinical, radiologic, and pathologic findings of a kindred with oculoleptomeningeal amyloidosis and a newly associated transthyretin mutation. BACKGROUND: Transthyretin (TTR) amyloidosis can present in the form of oculoleptomeningeal amyloidosis. Clinical features include dementia, seizures, stroke-like episodes, subarachnoid hemorrhage, ataxia, myelopathy, deafness, radiculopathy, and ocular amyloidosis. Eight TTR mutations associated with oculoleptomeningeal amyloidosis have been described. METHODS: Fourteen individuals from a kindred with oculoleptomeningeal amyloidosis were examined clinically and radiologically. Analysis of the TTR gene was performed. Neuropathologic examination was obtained on the index patient. RESULTS: Affected individuals had vitreous amyloid, radiculopathy, seizures, stroke-like episodes, encephalopathy, and dementia. Severely affected individuals died by the end of the fifth decade. Leptomeningeal enhancement on contrast MRI and elevated CSF protein were the defining features on investigations. Sequencing of exon 3 in the TTR gene found a base pair substitution at codon 69. This resulted in heterozygosity for normal tyrosine and variant histidine (ATTR Tyr69His) in affected family members. Domino liver transplantation was attempted as treatment for one family member. CONCLUSIONS: The ATTR Tyr69His mutation is associated with oculoleptomeningeal amyloidosis. Expression of the genotype is variable. This has implications for treatment of affected individuals and counseling of family members. Efficacy of liver transplantation in patients with oculoleptomeningeal amyloidosis remains unknown. The authors advocate the investigation of liver transplantation in patients with severe symptoms due to oculoleptomeningeal amyloidosis.

Stromal cell-derived factor 1 is secreted by meningeal cells and acts as chemotactic factor on neuronal stem cells of the cerebellar external granular layer.

The cerebellar external granular layer (EGL) is an unusually long-lasting neural proliferative zone positioned immediately beneath the pial surface. Its position and stability critically depend on meningeal cells, as their selective destruction leads to its rapid dispersal, creating massive cortical ectopia. Similar ectopias have recently been described as a side effect of deficiency for stromal cell-derived factor 1 (SDF-1), a chemoattractant for haematopoietic precursor cell migration. Here we show that SDF-1 is present in meningeal cells in vivo and in vitro, where it is secreted in functionally relevant concentrations into the medium. Correspondingly, the SDF-1 receptor (termed CXCR4) can be demonstrated on stem cells of the external granular layer, but is absent on postmitotic cells commencing their final inward migration. We show that SDF-1 is concentrated by heparan sulphate proteoglycans highly expressed in the EGL in a laminar fashion, which thus might act to locally restrict SDF-1 action to the EGL in a kind of step gradient. In vitro, SDF-1 chemotactically attracts neuronal cells isolated from the external, but not from the internal granular layer, in a Boyden chamber assay in concentrations found in meningeal cell-conditioned medium. Selective removal of SDF-1 from conditioned media by immunoprecipitation abolishes their chemoattractive action, which can be reconstituted again by the addition of recombinant SDF-1. Meningeal cells are thus an important source for the expression of SDF-1 during brain development, which--comparable to its role in haematopoiesis--appears to be a key factor attracting precursor cells to their proliferative compartment.

Dynamics of brain-derived proteins in cerebrospinal fluid.

BACKGROUND: The recent theory of blood-cerebrospinal fluid (CSF) barrier function and dysfunction connects molecular flux and CSF flow rate. A reduced CSF flow rate is sufficient to account for the observed hyperbolic relation between different blood-derived protein concentrations in CSF in cases of a blood-CSF barrier dysfunction. METHODS: The dynamics of brain-derived proteins in CSF are investigated with reference to the CSF flow rate measured by CSF/serum albumin concentration quotient. RESULTS: Proteins from neurons or glial cells, tau protein, neuron-specific enolase, S-100 protein, all enter CSF primarily in the ventricular and cisternal space. Their concentration between normal ventricular and lumbar CSF is decreasing (in contrast to blood-derived proteins), and in the case of pathologically decreasing CSF flow rate, the concentration in lumbar CSF remains invariantly constant. Concentrations of the primarily leptomeningeal proteins, beta-trace protein and cystatin C, increase between normal ventricular and lumbar CSF, and in the case of pathologically decreased CSF flow rate they increase linearly in lumbar CSF (concentrations of blood-derived proteins increase non-linearly). CONCLUSIONS: A satisfactory physiological explanation can now be given for the dynamics of proteins in CSF consisting of both brain- and blood-derived fractions (transthyretin, soluble intercellular adhesion molecule (s-ICAM)), as well as the disputed decrease of leptomeningeal protein concentrations (beta-trace protein, cystatin C) in cases of bacterial meningitis is also explained. The biophysical treatment of dynamics in the ventricular and lumbar CSF extends the new theory and shows that CSF flow rate is the most relevant parameter for understanding the pathological changes of both blood- and brain-derived proteins in CSF. The impact on diagnosis of neuro-degenerative diseases is discussed.

Distribution of estramustine-binding protein during postnatal development of rat brain.

Estramustine-binding protein (EMBP) is expressed in several types of brain tumors, such as astrocytoma, ependymoma, and meningioma. It binds the cytotoxic drug estramustine with high affinity and is suggested to cause accumulation of the drug in EMBP-expressing tumor cells. In this study, the spatial distribution of EMBP in normal rat brain was studied with immunohistochemistry. Brains from male and female rats of different ages were used. EMBP was found in the cytoplasm of ependymal cells, in the leptomeninges, mainly the arachnoid, and in scattered neurons. Moreover, staining was seen in nuclei of choroid plexus cells, in the granular cell layer in the cerebellum, and in a few scattered endothelial cells. The nuclear staining was more frequent in younger animals. No obvious difference in EMBP expression between male and female rats was observed. The expression of EMBP in rat brain was confirmed with nested RT-PCR. Future studies are justified to elucidate the role of EMBP-like proteins in CNS and in brain tumors.

Meningeal nodules in teratoma of the testis.

A case of a 52-year-old man with a mature adult teratoma is reported. Beside histologically mature tissues, this teratoma contained large areas of a meningiomatous proliferation in close proximity of a peripheral nerve and glial tissue. These meningiomatous proliferations were mostly seen in the peripheral parts of the teratoma surrounding the rest of teratomatous elements and were immunohistochemically EMA-positive and S-100 protein- and cytokeratin-negative. Identical meningothelial proliferations are well known in the skin and adjacent soft tissues of the scalp, where they have variously been called sequestrated meningoceles, meningeal hamartoma, cutaneous meningiomas, rudimentary meningocele, hamartoma of the scalp with ectopic meningothelial elements, or cutaneous heterotopic meningeal nodules.

Gene transfer of extracellular superoxide dismutase increases superoxide dismutase activity in cerebrospinal fluid.

BACKGROUND AND PURPOSE: Copper-zinc superoxide dismutase (CuZnSOD) is expressed intracellularly, while extracellular SOD (EC-SOD) is released from cells. The purpose of this study was to determine whether gene transfer of CuZnSOD increases SOD activity predominantly in tissues, and gene transfer of EC-SOD increases SOD activity in cerebrospinal fluid (CSF). We also determined whether heparin or dextran sulfate releases EC-SOD into CSF. METHODS: We injected recombinant adenoviruses expressing EC-SOD (AdEC-SOD), CuZnSOD (AdCuZnSOD), or beta-galactosidase (Adbeta-gal) into the cisterna magna of rabbits. RESULTS: Total SOD activity in CSF was 39+/-11 U/mL (mean+/-SE) before virus injection. Three days later, total SOD activity in CSF increased to 148+/-22 U/mL after AdEC-SOD and 92+/-10 U/mL after AdCuZnSOD (P:<0.05 versus AdEC-SOD), with no change after Adbeta-gal (49+/-5 U/mL). EC-SOD protein was detected in CSF after AdEC-SOD but not AdCuZnSOD or Adbeta-gal. Injection of heparin or dextran sulfate into the cisterna magna increased total SOD activity 27-fold and 32-fold over basal values, respectively, in CSF of rabbits that received AdEC-SOD. In contrast to effects in CSF, total SOD activity in basilar artery and meninges was significantly higher after AdCuZnSOD and tended to be higher after AdEC-SOD than after Adbeta-gal. CONCLUSIONS: -We have developed a method for intracranial gene transfer of CuZnSOD and EC-SOD. After gene transfer, CuZnSOD was expressed mainly in tissues, and EC-SOD was released into the CSF, especially after injection of heparin or dextran sulfate. Gene transfer of different isoforms of SOD may be useful in studies of cerebral vascular physiology and pathophysiology.