CSF opening pressure in children with optic nerve head edema.

BACKGROUND: We previously reported that an abnormal CSF opening pressure (OP) in children was greater than 28 cm H(2)O. Since elevated intracranial pressure can cause optic nerve head edema (ONHE), we would expect that most patients with ONHE would have an OP greater than 28 cm H(2)O. This study describes the range of OP for children with ONHE and compared them to age-matched controls without ONHE. METHODS: Case subjects were children (1-18 years of age) enrolled in a prospective study of CSF OP that demonstrated ONHE at time of lumbar puncture and that the ONHE later resolved. Patients with ONHE secondary to infectious, inflammatory, or ischemic conditions were excluded. Control subjects from the same study, but without ONHE, were matched to cases. RESULTS: Of the 472 subjects enrolled in the study, 41 OP measurements were obtained from 33 patients with ONHE who did not have any exclusionary criteria and matched to 41 control subjects without ONHE. Case subjects had a significantly higher OP (mean, 41.4 cm H(2)0; range, 22-56) than control subjects (mean, 18.9 cm H(2)O; range, 9-29; p < 0.01). Forty of 41 (97.6%) case subjects and 2 of 41 (4.8%) control subjects had OP measures >28 cm H(2)O. CONCLUSIONS: Children with ONHE not related to infectious, inflammatory, or ischemic causes typically have an OP >28 cm H(2)O, significantly higher than age-matched controls without ONHE. This study provides further support to our previously published findings that suggests an abnormal OP in children is typically above 28 cm H(2)O.

Immunization-induced inflammatory infiltration of the central nervous system in transgenic mice expressing a microbial antigen in astrocytes.

Transgenic mice expressing a defined microbial antigen from central nervous system (CNS) cell type-specific promoters can be utilized to investigate the consequences of induction of peripheral immune responses to foreign antigens produced by different CNS cell types. Immunization of mice expressing beta-galactosidase (beta-gal) in astrocytes with this protein resulted in antigen-dependent infiltration of the CNS by mononuclear cells, principally CD4+ T lymphocytes and monocyte/macrophages. The perivascular and intraparenchymal infiltrates, which were located predominantly in the hippocampal formation and cerebellum, the areas of highest beta-gal expression, were associated with astrocytosis, microgliosis, and a generalized increase in blood-brain barrier permeability. The resemblance of these pathological changes to aspects of human immune inflammatory CNS disorders, e.g. multiple sclerosis, suggests that an initiating step in the process by which such complex diseases are produced could be the induction of peripheral immune responses to antigens expressed in astrocytes.

Increased central nervous system production of extracellular matrix components and development of hydrocephalus in transgenic mice overexpressing transforming growth factor-beta 1.

A number of important neurological diseases, including HIV-1 encephalitis, Alzheimer's disease, and brain trauma, are associated with increased cerebral expression of the multifunctional cytokine transforming growth factor-beta 1 (TGF-beta 1). To determine whether overexpression of TGF-beta 1 within the central nervous system (CNS) can contribute to the development of neuropathological alterations, a bioactive form of TGF-beta 1 was expressed in astrocytes of transgenic mice. Transgenic mice with high levels of cerebral TGF-beta 1 expression developed a severe communicating hydrocephalus, seizures, motor incoordination, and early runting. While unmanipulated heterozygous transgenic mice from a low expressor line showed no such alterations, increasing TGF-beta 1 expression in this line by injury-induced astroglial activation or generation of homozygous offspring did result in the abnormal phenotype. Notably, astroglial overexpression of TGF-beta 1 consistently induced a strong upmodulation of the extracellular matrix proteins laminin and fibronectin in the CNS, particularly in the vicinity of TGF-beta 1-expressing perivascular astrocytes, but was not associated with obvious CNS infiltration by hematogenous cells. While low levels of extracellular matrix protein expression may assist in CNS wound repair and regeneration, excessive extracellular matrix deposition could result in the development of hydrocephalus. As an effective inducer of extracellular matrix components, TGF-beta 1 may also contribute to the development of other neuropathological alterations, eg, the formation of amyloid plaques in Alzheimer's disease.

Protection against HIV-1 gp120-induced brain damage by neuronal expression of human amyloid precursor protein.

Expression of the HIV-1 envelope protein gp120 in brains of transgenic (tg) mice induces extensive neurodegeneration (Toggas, S. M., E. Masliah, E. M. Rockenstein, G. F. Rall, C. R. Abraham, and L. Mucke. 1994. Nature [Lond.]. 367:188-193.). To further analyze the pathogenesis of gp120-induced neurotoxicity and to assess the neuroprotective potential of human amyloid precursor proteins (hAPPs) in vivo, different hAPP isoforms were expressed in neurons of gp120/hAPP-bigenic mice: hAPP751, which contains a Kunitz-type protease inhibitor domain, or hAPP695, which lacks this domain. Bigenic mice overexpressing hAPP751 at moderate levels showed significantly less neuronal loss, synapto-dendritic degeneration, and gliosis than singly tg mice expressing gp120 alone. In contrast, higher levels of hAPP695 expression in bigenic mice failed to prevent gp120-induced brain damage. These data indicate that hAPP can exert important neuroprotective functions in vivo and that the efficiency of this protection may depend on the hAPP isoform expressed and/or on the level of neuronal hAPP expression. Hence, molecules that mimic beneficial APP activities may be useful in the prevention/treatment of HIV-1-associated nervous system damage and, perhaps, also of other types of neural injury.

Indicator expression directed by regulatory sequences of the glial fibrillary acidic protein (GFAP) gene: in vivo comparison of distinct GFAP-lacZ transgenes.

An increase in the expression of the glial fibrillary acidic protein (GFAP) gene by astrocytes appears to constitute a crucial component of the brain's response to injury because it is seen in many different species and features prominently in diverse neurological diseases. Previously, we have used a modified GFAP gene (C-339) to target the expression of beta-galactosidase (beta-gal) to astrocytes in transgenic mice (Mucke et al.; New Biol 3:465-474 1991). To determine to what extent the in vivo expression of GFAP-driven fusion genes is influenced by intragenic GFAP sequences, the E. coli lacZ reporter gene was either placed downstream of approximately 2 kb of murine GFAP 5' flanking region (C-259) or ligated into exon 1 of the entire murine GFAP gene (C-445). Transgenic mice expressing C-259 versus C-445 showed similar levels and distributions of beta-gal activity in their brains. Exclusion of intragenic GFAP sequences from the GFAP-lacZ fusion gene did not diminish injury-induced upmodulation of astroglial beta-gal expression or increase beta-gal expression in non-astrocytic brain cells. These results demonstrate that 2 kb of murine GFAP 5' flanking region is sufficient to restrict transgene expression primarily to astrocytes and to mediate injury-responsiveness in vivo. This sequence therefore constitutes a critical target for mediators of reactive astrocytosis. While acute penetrating brain injuries induced focal increases in beta-gal expression around the lesion sites in C-259, C-445, and C-339 transgenic mice, infection of C-339 transgenic mice with scrapie led to a widespread upmodulation of astroglial beta-gal expression. Hence, GFAP-lacZ transgenic mice can be used to monitor differential patterns of astroglial activation in vivo. These and related models should facilitate the assessment of strategies aimed at the in vivo manipulation of GFAP expression and astroglial activation.

Synaptotrophic effects of human amyloid beta protein precursors in the cortex of transgenic mice.

The amyloid precursor protein (APP) is involved in Alzheimer's disease (AD) because its degradation products accumulate abnormally in AD brains and APP mutations are associated with early onset AD. However, its role in health and disease appears to be complex, with different APP derivatives showing either neurotoxic or neurotrophic effects in vitro. To elucidate the effects APP has on the brain in vivo, cDNAs encoding different forms of human APP (hAPP) were placed downstream of the neuron-specific enolase (NSE) promoter. In multiple lines of NSE-hAPP transgenic mice neuronal overexpression of hAPP was accompanied by an increase in the number of synaptophysin immunoreactive (SYN-IR) presynaptic terminals and in the expression of the growth-associated marker GAP-43. In lines expressing moderate levels of hAPP751 or hAPP695, this effect was more prominent in homozygous than in heterozygous transgenic mice. In contrast, a line with several-fold higher levels of hAPP695 expression showed less increase in SYN-IR presynaptic terminals per amount of hAPP expressed than the lower expressor lines and a decrease in synaptotrophic effects in homozygous compared with heterozygous offspring. Transgenic mice (2-24 months of age) showed no evidence for amyloid deposits or neurodegeneration. These findings suggest that APP may be important for the formation/maintenance of synapses in vivo and that its synaptotrophic effects may be critically dependent on the expression levels of different APP isoforms. Alterations in APP expression, processing or function could contribute to the synaptic pathology seen in AD.