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Introduction and objectives Rett Syndrome (RTT) is a neurodevelopmental disorder caused by Methyl CpG Binding Protein 2 (MECP2) gene mutations. Previous studies of MeCP2 in the human brain showed variable and inconsistent mosaic-pattern immunolabelling, which has been interpreted as a reflection of activation-state variability. We aimed to study post mortem MeCP2 and BDNF (MeCP2 target) degradation and brain region-specific detection in relation to RTT pathophysiology. Methods We investigated MeCP2 and BDNF stabilities in non-RTT human brains by immunohistochemical labelling and compared them in three brain regions of RTT and controls. Results In surgically excised samples of human hippocampus and cerebellum, MeCP2 was universally detected. There was no significantly obvious difference between males and females. However, post mortem delay in autopsy samples had substantial influence on MeCP2 detection. Immunohistochemistry studies in RTT patients showed lower MeCP2 detection in glial cells of the white matter. Glial fibrillary acidic protein (GFAP) expression was also reduced in RTT brain samples without obvious change in myelin basic protein (MBP). Neurons did not show any noticeable decrease in MeCP2 detection. BDNF immunohistochemical detection showed an astroglial/endothelial pattern without noticeable difference between RTT and controls. Conclusions Our findings indicate that MeCP2 protein is widely expressed in mature human brain cells at all ages. However, our data points towards a possible white matter abnormality in RTT and highlights the importance of studying human RTT brain tissues in parallel with research on animal and cell models of RTT.

Hypochondroplasia, achondroplasia, and thanatophoric dysplasia are related at the molecular level, all caused by fibroblast growth factor receptor 3 (FGFR3) gene mutations. They differ in severity. FGFR3 has critical roles in fibroblast growth factor (FGF) signalling pathways during bone growth and cerebral cortical development. Mutations of the FGFR3 gene lead to constitutive activation of FGFR3. The well-described brain malformation in thanatophoric dysplasia is characterized by gross abnormalities of temporal lobe patterning and severe dysplasia of the hippocampus. Experimental models suggest that increased proliferation, abnormal migration, and decreased apoptosis are involved. However, reports of the brain findings in hypochondroplasia are based solely on radiologic imaging.We present the neuropathology of a 44 year-old man with hypochondroplasia, epilepsy, and significant intellectual disability. The temporal lobes are enlarged, prominent fissures traverse the inferior temporal surface, and the hippocampus is abnormally folded. Microscopically, the dentate gyrus is variably small or thin and is located near the edge of a gyrus. Ammon’s horn is displaced and meandering. Subicular-like clusters are profuse. Complex gyri resemble microgyria. White matter forms a subpial border in some gyri. In summary: medial temporal lobe dysgenesis.This individual also had many autistic features including stereotypies and head banging. The latter could explain another surprising set of brain abnormalities unrelated to the presumed FGFR3-related syndrome.LEARNING OBJECTIVESThis presentation will enable the learner to:1.Summarize current theories on the pathogenesis of FGFR3-related cortical malformation2.Describe the brain abnormalities in hypochondroplasia3.Identify the neuropathology resulting from head banging

We describe the presentation and six-year follow up of a child with nemaline myopathy due to a de novo mutation in the skeletal muscle α-actin gene ( ACTA1 ) characterized by dramatic improvement during the early childhood years. The presentation in this female patient was infantile-onset weakness in the facial, bulbar, respiratory and neck flexor muscles. A six-year follow-up revealed continued progressive improvement in her muscle strength. Based upon the histopathologic and ultrastructural features of nemaline rod disease, ACTA1 was sequenced. This revealed a mutation in exon 4 of ACTA1 (c.557A>G). Our report further expands the phenotypic spectrum associated with ACTA1 mutations. Although it is difficult to infer any genotype–phenotype correlation, this report stimulates the discussion regarding the pathophysiologic mechanism of the clinical improvement seen in some patients with ACTA1 mutations.

Glutaric acidaemia type I (GA I) is caused by the deficiency of glutaryl-CoA dehydrogenase, resulting in accumulation of glutaric acid (GA) and 3- hydroxyglutaric acid (3-OH-GA) in blood and cerebrospinal fluid (CSF). Neuropathological changes with onset in childhood consist of severe neuronal loss in the caudate and putamen. An animal model is necessary to test possible intervention strategies, and prior reports suggested that GA or 3-OH-GA could be used to create specific neuron loss in adult rats. Adult, 3-week-old and 2-week-old rats received intrastriatal injections of GA and 3-OH-GA at a range of doses. High concentrations caused necrotic lesions in striatum. Low concentrations caused white-matter axonal damage and small areas of neuron loss. Injection of lipopolysaccharide prior to administration of 3-OH-GA was not associated with enhanced neuronal loss. Our findings contradict prior claims and we conclude that the simple model of a single GA or 3-OH-GA injection into rat brain does not replicate the neuropathological findings in humans.

A neurological syndrome involving progressive action tremor with ataxia, cognitive decline and generalized brain atrophy has been described recently in some adult males with pre-mutation alleles of the fragile X syndrome (FXS) fragile X mental retardation gene (FMR1). Neurohistological studies have now been performed on the brains of four elderly premutation carriers, not reported previously, who displayed the neurological phenotype. Eosinophilic, intranuclear inclusions were present in both neuronal and astrocytic nuclei of the cortex in all four individuals. Systematic analysis of the brains of two of these carriers demonstrated the presence of the intranuclear inclusions throughout the cerebrum and brainstem, being most numerous in the hippocampal formation. The cerebellum displayed marked dropout of Purkinje cells, Purkinje axonal torpedoes and Bergmann gliosis. Intranuclear inclusions were absent from Purkinje cells, although they were present in a small number of neurones in the dentate nucleus and diffusely in cerebellar astrocytes. The presence of inclusions in the brains of all four FXS carriers with the neurological findings provides further support for a unique clinical entity associated with pre-mutation FMR1 alleles. The origin of the inclusions is unknown, although elevated FMR1 mRNA levels in these pre-mutation carriers may lead to the neuropathological changes.

Background: MS is common in people of northern European ethnicity who live in northern geographic areas; however, MS is rarely identified among aboriginal peoples living in the same areas. Objectives: To determine the prevalence, clinical features, HLA type, and viral infections associated with MS among aboriginals in Manitoba, Canada. Methods: A retrospective study was performed in which the clinical features of all aboriginal patients with MS together with HLA type and human herpesvirus-6, HIV-1, human T-cell lymphotropic virus-1, and endogenous retrovirus associated with MS (MSRV) infections were analyzed and compared with results from nonaboriginal patients with MS. Results: Seven aboriginals with MS were identified with a period prevalence among aboriginals of 40:100,000. Clinical features included relapsing–remitting (n = 6) or primary progressive (n = 1) phenotypes with aggressive disease courses and frequent involvement of optic nerves and spinal cord (n = 5) compared with nonaboriginal patients. Autopsy of one patient showed necrosis and eosinophil infiltrates in a cervical spinal cord lesion and a demyelinated optic nerve. Analysis of HLA alleles at the DRB1 and DQB1 loci indicated that the HLA types detected were common in aboriginals, but there were no HLA alleles previously associated with the development of MS. Analysis of the copy number of MRSV did not show differences among aboriginals and nonaboriginals with or without MS. Conclusions: Aboriginals of Algonkian background are at increased risk for an aggressive type of MS, resembling neuromyelitis optica, which is resistant to conventional MS treatments and occurs independently of HLA alleles previously associated with MS.

We examined whether following a hypoxic–ischemic insult in young animals there are long-lasting functional deficits that correlate either to histological tissue damage or to potential compensatory plasticity changes. Four-week-old rats were subjected to an episode of cerebral hypoxia–ischemia (right carotid artery occlusion + 30 min of hypoxia) or a sham operation. In hypoxic–ischemic animals there were gross neurological deficits 1, 24, and 48 h postinsult with recovery by 1 week. Behavioral deficits were observed in both the acquisition and the performance of a response duration differentiation test and a fine motor control test (staircase test) 3 months after the hypoxia–ischemia. Functional magnetic resonance imaging studies demonstrated less activation in the sensory–motor cortex of hypoxic–ischemic animals in response to left vs right forepaw stimulation 4 months postinsult. Histological assessment delineated striatal, cortical, and hippocampal damage in the hypoxic–ischemic hemisphere and a reduction in cortical thickness, bilaterally. GFAP immunoreactivity was increased in injured striatum and cortex. Neurofilament heavy chain (NF200) immunoreactivity was normally most intense in white matter and decreased in areas of ipsilateral cortical damage. Synaptophysin immunoreactivity was reduced around areas of infarction and somewhat increased in adjacent undamaged striatum and in layer IV of parietal cortex. The histological damage or chronic degenerative changes could account for much of the variance in functional outcome detected with sensitive behavioral tests so that overall the compensatory or plasticity changes evident within the juvenile brain are rather modest.

A personal perspective on the study of experimental models of hydrocephalus is offered. Many animal models are available; each has its own advantages and disadvantages. Detailed study of more than one model is needed to clarify the pathogenesis of hydrocephalus-induced brain damage in the immature nervous system. Further information is needed about the mechanism of axonal injury in periventricular tissue, changes in the extracellular compartment, water dynamics within brain tissue, the role of neurotrophic factors in hydrocephalus, and the sites of injury in chronic ‘arrested’ hydrocephalus. Insight into the multifactorial nature of the brain damage may allow us to develop supplemental pharmacologic therapies, which could protect the brain and promote recovery in the pre- and postshunt period.

Background and Purpose —Tumor necrosis factor-α (TNF-α) expression is increased in brain after cerebral ischemia, although little is known about its abundance and role in intracerebral hemorrhage (ICH). A TNF-α–specific antisense oligodeoxynucleotide (ORF4-PE) was used to study the extent to which TNF-α expression influenced neurobehavioral outcomes and brain damage in a collagenase-induced ICH model in rat. Methods —Male Sprague-Dawley rats were anesthetized, and ICH was induced by intrastriatal administration of heparin and collagenase. Immediately before or 3 hours after ICH induction, ORF4-PE was administered directly into the site of ICH. TNF-α mRNA and protein levels were measured by reverse transcriptase–polymerase chain reaction and immunoblot analyses. Cell death was measured by terminal deoxynucleotidyl transferase–mediated uridine 5′triphosphate-biotin nick end labeling (TUNEL). Neurobehavioral deficits were measured for 4 weeks after ICH. Results —ICH induction (n=6) elevated TNF-α mRNA and protein levels ( P P P P P P Conclusions —These results indicate a pathogenic role for TNF-α during ICH and demonstrate that reducing TNF-α expression using antisense oligodeoxynucleotides is neuroprotective.

Feline immunodeficiency virus (FIV) is a lentivirus that causes immune suppression and neurological disease in cats. Among animal viruses, individual viral strains have been shown to be neurovirulent, but the role of viral strain specificity among lentiviruses and its relationship to systemic immune suppression in the development of neurological disease remains uncertain. To determine the extent to which different FIV strains caused neurological disease, FIV V1CSF and Petaluma were compared in ex vivo assays and in vivo. Both viruses infected and replicated in macrophage and mixed glial cell cultures at similar levels, but V1CSF induced significantly greater neuronal death than Petaluma in a neurotoxicity assay. V1CSF-infected animals showed significant neurodevelopmental delay compared to the Petaluma-infected and uninfected animals. Magnetic resonance spectroscopy studies of frontal cortex revealed significantly reducedN-acetyl aspartate/creatine ratios in the V1CSF group compared to the other groups. Cyclosporin A treatment of Petaluma-infected animals caused neurodevelopmental delay and reducedN-acetyl aspartate/creatine ratios in the brain. Reduced CD4+ and CD8+ cell counts were observed in the V1CSF-infected group compared to the uninfected and Petaluma-infected groups. These findings suggest that neurodevelopmental delay and neuronal injury is FIV strain specific but that systemic immune suppression is also an important determinant of FIV-induced neurovirulence.

Functional and behavioral disturbances associated with hydrocephalus may be due in part to altered neurotransmitter function in the brain. Hydrocephalus was induced in adult rabbits by injection of silicone oil into the cisterna magna. These and controls were killed 3 days, 1 and 4 weeks post-injection. Tissue concentrations of norepinephrine, epinephrine, serotonin, dopamine, and the metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) levels were determined in fifteen brain regions using HPLC. There were decreases in hypothalamic and medullary dopamine, transient decreases in basal ganglia serotonin, increases in thalamic noradrenaline, and increases in hypothalamic and thalamic epinephrine. Changes in the primary neurotransmitters may be attributable to damage of their axonal projection systems. Metabolite concentrations increased in the cerebrum. Reduced clearance of extracellular fluid which accompanies cerebrospinal fluid stasis may explain the accumulation of metabolites.

We hypothesized that hydrocephalus in young animals could cause a delay in myelination. Hydrocephalus was induced in 3-week-old rats by injecting kaolin into the cisterna magna. Ventricular size was assessed by magnetic resonance imaging. After 1 to 4 weeks, rats were either sacrificed, or treated by diversionary shunting of cerebrospinal fluid and then sacrificed 3 to 4 weeks later. Samples of corpus callosum/supraventricular white matter, fimbria, medulla, and spinal cord were assayed for myelin-related enzyme activities including p-nitrophenylphosphorylcholine phosphocholine phosphodiesterase (PNPCP), glycerophosphocholine phosphocholine phosphodiesterase (GPCP), and 2',3'-cyclic neucleotide 3'-phosphodiesterase (CNPase), and the oligodendrocyte enzyme UDP-galactose, ceramide galactosyltransferase (CGa1T). Myelin basic protein (MBP) and proteolipid protein (PLP) were assayed in cerebrum by immunoblots and Northern blot. The corpus callosum was processed for electron microscopy and myelin thickness to axon diameter ratios were quantified. One week after induction of hydrocephalus, CGa1T and GPCP activity were reduced in the corpus callosum there was less MBP and PLP in the cerebrum, and myelin sheaths around axons greater than 0.4 micron in diameter were abnormally thin. With persistent hydrocephalus, the corpus callosum became thinned, axons were lost, and myelin-related enzyme activities and proteins were decreased. Treatment of hydrocephalus at 1 week largely prevented the damage while shunting at 4 weeks failed to restore the injured white matter. Early reduction in CGa1T activity in the medulla and spinal cord suggest that oligodendrocyte production of myelin was reduced, even before irreversible damage occurred in the corticospinal tracts. We conclude that hydrocephalus in the immature rat brain delays myelination, but compensatory myelination is possible if treatment is instituted prior to the development of axonal injury. Possible mechanisms of oligodendrocyte impairment are discussed.

Background:The cortical changes resulting from chronic hydrocephalus in adults are not well defined.Methods:Retrospective analysis of twenty-one patients (age 64-88 years) with a clinical diagnosis of “normal pressure hydrocephalus” who underwent cortical biopsy at the time of intracranial pressure monitoring or shunt insertion, and eight patients who were biopsied but not shunted. Eleven brains (age 26-92 years), seven from patients who could be considered to have “normal pressure hydrocephalus”, were also examined following autopsy. Age- and sex-matched control brains with small ventricles and no history of dementia were compared to the hydrocephalic brains. Senile plaques and neurofibrillary tangles were assessed semiquantitatively and a non-parametric statistical analysis was employed.Results:Five biopsies exhibited both senile plaques and rare neurofibrillary tangles, while two had only neurofibrillary tangles. Neurofibrillary tangles were more prevalent in hydrocephalic brains than in controls. There was no difference in the prevalence of senile plaques between the two groups. Grumose bodies in the substantia nigra were identified in five autopsy brains, a prevalence higher than in control brains.Conclusions:These pathological features are not specific for hydrocephalus; however, they suggest that long-standing ventriculomegaly is associated with degenerative brain changes in sites beyond the periventricular white matter. The presence of senile plaques in cortical biopsies from hydrocephalic patients does not appear to be a contraindication to shunting; however a prospective study in patients undergoing intracranial pressure monitoring would better address the issue.

We investigated whether the neuroprotection provided by dexamethasone against neonatal hypoxic-ischemic damage can be inhibited by a glucocorticoid antagonist and whether corticosterone, the endogenous glucocorticoid in the rat, also provides protection. Rats (6 days old) were treated with either vehicle (0.1 ml/10 g), corticosterone (3.5-80 mg/kg, s.c.) or dexamethasone alone or in combination with RU38486 (20-80 mg/kg, s.c.) 15 min prior to dexamethasone (0.1 mg/kg, i.p.). At 7 days of age, cerebral hypoxia-ischemia was produced by right carotid artery ligation under anesthesia and subsequent exposure to 2 h of hypoxia. Damage was quantified from brains perfusion-fixed and processed 2 days later. The reduction in somatic growth, thymus weight and the relatively elevated blood glucose levels at the end of hypoxia-ischemia were inhibited by RU38486. The protective effect of dexamethasone was also prevented by RU38486 (P < 0.001). Similar to pre-treatment with dexamethasone, administration of corticosterone (40-80 mg/kg) markedly reduced the extent of infarction compared to vehicle-treated controls (P < 0.0001). Thus, the endogenous glucocorticoid in the rat also provides protection against hypoxic-ischemic damage. RU38486 inhibits the beneficial effects of dexamethasone demonstrating that the neuroprotection observed with dexamethasone is a glucocorticoid receptor-mediated effect.

Background The boundary separating the posterior columns of the spinal cord is formed by the lateral margins of the neural groove approximating to form the neural canal. In anatomy texts this line is usually drawn as continuous, uniform, centered, and straight. It is universally termed posterior or dorsal, median “septum.” Methods Sections from the cervical and lumbar enlargements and the mid-thoracic region were examined from 35 human autopsy specimens from 20 weeks gestation to 70 years with no history of spinal cord disease or trauma. They were stained with Masson's trichrome, and by immunohistochemistry for collagen types 1 and 4, and for glial fibrillary acidic protein (GFAP). Results One or more variations were found in the position character, shape, or extent of the line at one or more levels in every case. There was no midline staining for collagen other than that associated with blood vessels. There is intense immunoreactivity for GFAP from 20 weeks gestation to 35 weeks diminishing thereafter. When the posterior columns are separated the “septum” divides. Conclusion In the absence of any collagen this line of separation is more akin to a raphe than a septum. Inasmuch as there is an immediately adjacent subarachnoid posterior median septum it would be advantageous to re-name this intraspinal structure “dorsal” or “posterior” median raphe. © 1996 Wiley-Liss, Inc.

This review summarizes the current scientific literature concerning the ependymal lining of the cerebral ventricles of the brain with an emphasis on selective barrier function and protective roles for the common ependymal cell. Topics covered include the development, morphology, protein and enzyme expression including reactive changes, and pathology. Some cells lining the neural tube are committed at an early stage to becoming ependymal cells. They serve a secretory function and perhaps act as a cellular/axonal guidance system, particularly during fetal development. In the mature mammalian brain ependymal cells possess the structural and enzymatic characteristics necessary for scavenging and detoxifying a wide variety of substances in the CSF, thus forming a metabolic barrier at the brain-CSF interface.

Pretreatment with the synthetic glucocorticoid dexamethasone prevents hypoxic-ischemic brain damage in 7-day-old neonatal rats. We presently characterize the response further by examining the effect of varying the age, the glucocorticoid, and the time of injection and by examining whether fasting can influence the response. Rats (n = 193) were randomized to one of 16 different treatment groups and subjected to hypoxia-ischemia (right carotid artery occlusion +8% O2 which was 3 h in duration for 7-day, 1 h for 2-week, and 30 min for 1-month-old animals). The brains were subsequently perfusion fixed and the area of infarction was measured from hematoxylin- and eosin-stained sections. Time dependence studies demonstrated that treatment with 0.1 mg/kg intraperitoneal dexamethasone 4 h prior to hypoxia reduced infarct size compared to vehicle-treated animals whereas pretreatment at either 48 h or 4 days was ineffective. Dexamethasone pretreatment (4 h) also provided neuroprotection against 4 h of hypoxia-ischemia. Fasted animals which received dexamethasone had reduced blood glucose levels yet markedly less damage than controls. Another glucocorticoid, methylprednisolone (0.7 mg/kg), also reduced infarction. In 2-week-old animals the area of infarction was reduced by pretreatment with dexamethasone, whereas in 1-month-old animals dexamethasone was ineffective. The results suggest that a glucocorticoid-mediated response intervenes in events leading to neuronal death in young animals but not older animals once myelination and synaptogenesis are complete.

Haemorrhagic brain damage is frequently encountered as a complication of premature birth. Much less frequently, multifocal petechial haemorrhage is identified in asphyxiated term newborns. Our goal was to develop an experimental rat model to reproduce this pattern of brain damage.Neonatal rat pups were exposed to a 24-h period of 10% or 8% hypoxia followed by a single dose of phenylephrine. Acute and subacute changes, as well as long-term outcomes, were investigated by histology, brain magnetic resonance imaging and behavioural assessment. Immunostaining for vascular endothelial growth factor and caveolin-1 was performed in the rat brains as well as in a 17-day human case.Small foci of haemorrhage were identified in almost all regions of the rat brain subjected to hypoxia plus phenylephrine, but not hypoxia alone. Exposure to 8% hypoxia was associated with more haemorrhagic foci than 10% hypoxia. With rare exceptions, the blood deposits were too small to be detected by magnetic resonance imaging. Altered immunohistochemical detection of vascular endothelial growth factor and caveolin-1 in the child and the rat model suggests a role for blood-brain barrier compromise. There were no clear behavioural changes and no residual morphological abnormalities in the 78-day follow-up of the rats.We conclude that transient hypoxia, in a dose-dependent manner, can weaken the vasculature and predispose to brain haemorrhage in the situation of labile blood pressure. Persistent hypoxia is likely to be important in the genesis of permanent severe brain damage.

Brothers are reported with an apparently new constellation of manifestations including Dandy-Walker complex (DWC), migrational brain disorder, macrocephaly, and facial anomalies. The first brother presented at birth, the second was detected prenatally with DWC and the pregnancy terminated. Fetal brain histopathology showed DWC associated with brainstem dysgenesis. Inheritance is likely autosomal or X-linked recessive. An extensive review of the differential diagnosis of DWC is provided.

A 41-year-old woman with a history of birth injury to the brachial plexus suffered several delayed episodes of neurological deterioration. Magnetic resonance imaging studies revealed a syrinx extending from the conus medullaris into the brainstem and rostrally into both internal capsules. She died of an acute exacerbation of chronic respiratory failure. Autopsy demonstrated syringomyelia and syringobulbia with cavity extension bilaterally along the corticospinal tracts into the internal capsules. Islands of glial tissue in the subarachnoid space around the medulla caused obstruction of the subarachnoid space at the foramen magnum. These were probably the result of birth injury to the cerebellum. A detailed clinico-pathological correlation is provided to explain her neurological deficits. The pathogenesis of syrinx formation is discussed in terms of a late manifestation of birth trauma.

(2001). New models for analysing hydrocephalus and disorders of CSF volume transmission. British Journal of Neurosurgery: Vol. 15, No. 3, pp. 281-283.

An 8.5-year-old female presented with multiple episodes of aseptic meningitis and was found to have a cystic lesion in the prepontine region. Microscopic examination revealed a respiratory-type epithelium with squamous metaplasia. Like its normal analogue in the respiratory tract, the epithelium of these intracranial cysts can undergo squamous metaplasia when chronically irritated. The ultrastructural and immunohistochemical characteristics of the transition from ciliated epithelium to squamous metaplasia are described.

A 2.5-year-old girl with Crouzon's disease, hydrocephalus, and a lumboperitoneal shunt died as a result of chronic tonsillar herniation (acquired Chiari 'malformation'). The possible synergistic role of the cranial dysmorphism and the lumboperitoneal shunt in the development of this anomaly is discussed. The literature is reviewed and it is argued that if hydrocephalus occurs in infants in whom cephalocranial disproportion is likely to develop, then it is inadvisable to insert a lumboperitoneal shunt.

We report an autopsy case of a boy who, following drowning at the age of 15 years, was found to have severe occult hydrocephalus and a cavernous angioma compressing the lumen of the superior sagittal sinus. We speculate that the cause of hydrocephalus was increased intrasinus pressure with impaired drainage of cerebrospinal fluid.

Krabbe disease, a disorder caused by the deficiency of lysosomal galactosylceramidase, is typically associated with cerebral white matter degeneration, cortical sparing, accumulation of macrophages ("globoid cells"), and ultrastructural needle-shaped inclusions. Two sisters presented with progressive neurological deterioration beginning before the age of 2.5 years. The first, who died at the age of 9 years, exhibited profound destruction of cerebral white matter with sparing of subcortical fibers but no globoid cells. The brain of the second, who died at the age of 15 years and who had a proven galactosylceramidase deficiency, exhibited white matter destruction, previously undescribed circumscribed spongiform cortical degeneration (postcentral, inferior temporal, cingulate), and cerebellar atrophy, but no globoid cells. The peripheral nerve biopsies from both girls exhibited typical needle-shaped inclusions in Schwann cells. These observations confirm the rare reports that Krabbe disease is not always associated with globoid cells in the brain. Psychosine, which accumulates in the brain, might be toxic to cortical neurons following prolonged survival. The reason for the regional susceptibility in the cerebral cortex is unknown.

Hydrocephalus-induced damage is dependent on the rate and magnitude of ventricular dilatation, the proximity to the ventricle, and the developmental stage at which the disturbance occurs. It is mediated through a combination of mechanical, ischemic, and metabolic-toxic disturbances. Developmental processes, including myelin production, can be impaired. Periventricular axons are the primary target, however. The potential for reversal of damage by shunting diminishes as the duration and severity of hydrocephalus increases. Ancillary pharmacologic means for preventing hydrocephalus-induced brain damage are worth pursuing.

Inactivating mutations of the gene encoding parkin are responsible for autosomal recessive juvenile parkinsonism (AR-JP). However, little information is known about the function and distribution of parkin. We generated antibodies to two different peptides of parkin. By Western blot analysis and immunohistochemistry, we found that parkin is a 50-kd protein that is expressed in neuronal processes and cytoplasm of selected neurons in the basal ganglia, midbrain, cerebellum, and cerebral cortex. Unlike ubiquitin and alpha-synuclein, parkin labeling was not found in Lewy bodies of four sporadic Parkinson disease brains. Parkin was colocalized with actin filaments but not with microtubules in COS1 kidney cells and nerve growth factor-induced PC12 neurons. These results point to the importance of the cytoskeleton and associated proteins in neurodegeneration.

Object. It can be inferred from data published in the literature that brain compression occurs in the early stages of acute hydrocephalus and that drainage of extracellular waste products is impaired. The authors hypothesized that compression of the cortex would alter water distribution and retard the diffusion of fluid in the hydrocephalic brain.Methods. Proton diffusion, blood perfusion, and T1 and T2 relaxation times were determined in adult rat brain by using magnetic resonance imaging prior to, and 1 and 8 days after induction of hydrocephalus by kaolin injection. Five anatomical regions of interest were studied. The striatum, dorsal cortex, and lateral cortex exhibited decreased T2 and apparent diffusion coefficient (ADC) values but no change in perfusion. Examination of white matter revealed an initial decrease in ADC followed by a significant increase. The T2 relaxation times increased and perfusion decreased progressively between 1 and 8 days after induction of hydrocephalus.Conclusions. Acute experimental hydrocephalus causes compression of gray matter, perhaps associated with reduction in total water, which impairs diffusion of water in the tissue. White matter compression and hypoperfusion precede the development of edema. These findings have importance for understanding the neurochemical changes that occur in hydrocephalic brains.

Hydrocephalus is associated with brain compression and accumulation of neurotransmitter waste products in the brain and cerebrospinal fluid. We postulated that the extracellular compartment is compressed and specifically hypothesized that extracellular fluid tracer movement through brain would differ between control and hydrocephalic rats. Gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) was injected into the cerebral cortex of 4-week-old rats, 7-11 days after induction of hydrocephalus by kaolin injection into the cisterna magna. The movement of this soluble paramagnetic compound was followed over successive timed intervals from 20 min to 180 min with T1-weighted magnetic resonance imaging. Non-hydrocephalic controls exhibited greater spread of the tracer and greater change in T1-weighted signal intensity in the ipsilateral cortex than hydrocephalic animals. Hydrocephalic animals exhibited preferential accumulation of tracer in edematous white matter. Gd-DTPA penetrated the lateral ventricles within 30 min in both control and hydrocephalic rats. The results suggest that there is a relative impairment of extracellular fluid movement through the cerebral cortex of young hydrocephalic rats.

Alzheimer's Disease is a neurodegenerative disorder marked by progressive cognitive decline. AD presents with many of thesame clinical symptoms as senile dementia, but the diagnosis of AD must be confirmed by post-mortem examination of themorphological and histopathologicat features of the brain. The two classical lesions found in the cortical and hippocampalregions of the brain are the f-amyloid-bearing neuritic plaques and the intraneuronal neurofibrillary tangles (NFTs). A3peptide aggregates are typically found in the plaque core and paired-helical filaments (PHFs) of hyperphosphorylated tau inthe damaged NFT-containing neurons. The pathogenesis of AD is unclear and the prevailing arguments appear to reside intwo camps; those who believe A peptide causes the neurodegeneration and those who believe that the aberrant tau proteinleads to neuronal dysfunction. Although histochemistry can reveal these classical lesions ofAD, discrete structural changes atthe subcellular or molecular level may be beyond the detection limitations of the subjective staining process. Therefore wesought to utilize synchrotron FuR microspectroscopy to compare Alzheimer's diseased hippocampus to that of control in theattempt to localize plaques and tangles so that the molecular substructure ofthe tissue could be evaluated. After spectroscopicanalysis tissue staining confirmed the presence of A3 peptide (3-sheet conformation) within regions of diffuse plaque.Presence ofA3 peptide was also detected in regions where staining was inconclusive. Moreover, an unusual IR signature wasfound for some pyramidal neurons in the CAl and CA2 field of an AD hippocampus that did not stain as classical tangles

Inflammatory cells are postulated to mediate some of the brain damage following ischemic stroke. Intracerebral hemorrhage is associated with more inflammation than ischemic stroke. We tested the sulfated polysaccharide fucoidan, which has been reported to reduce inflammatory brain damage, in a rat model of intracerebral hemorrhage induced by injection of bacterial collagenase into the caudate nucleus. Rats were treated with seven day intravenous infusion of fucoidan (30 micrograms h-1) or vehicle. The hematoma was assessed in vivo by magnetic resonance imaging. Motor behavior, passive avoidance, and skilled forelimb function were tested repeatedly for six weeks. Fucoidan-treated rats exhibited evidence of impaired blood clotting and hemodilution, had larger hematomas, and tended to have less inflammation in the vicinity of the hematoma after three days. They showed significantly more rapid improvement of motor function in the first week following hemorrhage and better memory retention in the passive avoidance test. Acute white matter edema and eventual neuronal loss in the striatum adjacent to the hematoma did not differ between the two groups. Investigation of more specific anti-inflammatory agents and hemodiluting agents are warranted in intracerebral hemorrhage.

Experiments in rodents and marmoset monkeys indicate that granule neurons of the dentate gyrus may be renewable throughout the entire life of the animal. Whether this occurs in larger primates remains a matter of contention. However, a recent study of brain samples from five adult humans who had been injected with the thymidine analog bromodeoxyuridine indicates that new neurons might indeed be produced in the dentate gyrus. In this study, hippocampus specimens removed from 18 adult humans for treatment of epilepsy were examined. The cell cycle marker Ki67, which is expressed from late G1 to M phase, was demonstrated by immunohistochemistry, and H2b/H3/H4 histone mRNAs, which are expressed during S phase, were demonstrated by in situ hybridization. Only 0.17% of cells in the subgranular layer, the site of neuronal progenitor cells, were Ki67 immunoreactive but the identity of these could not be proven. Although the histone in situ hybridization technique was shown to work in human fetal brain, no M phase cells could be demonstrated in the hippocampus. The generation of new granule neurons in the human hippocampus must occur at a very slow rate. The approaches used in this study are likely unsuitable for studying cell populations with low turnover rate. Further work is needed to determine the fate of newly generated cells in the dentate gyrus. This information is of importance to our understanding of the mechanisms of learning and memory.

Object. The origin of chronic communicating hydrocephalus following subarachnoid hemorrhage (SAH) is not well understood. Fibrosis of the arachnoid villi has been suggested as the cause for obstruction of cerebrospinal fluid (CSF) flow, but this is not well supported in the literature. The goal of this study was to determine the relationship between blood, inflammation, and cellular proliferation in arachnoid villi after SAH.Methods. Arachnoid villi from 50 adult patients were sampled at autopsy. All specimens were subjected to a variety of histochemical and immunohistochemical stains. The 23 cases of SAH consisted of patients in whom an autopsy was performed 12 hours to 34 years post-SAH. Fifteen cases were identified as moderate-to-severe SAH, with varying degrees of hydrocephalus. In comparison with 27 age-matched non-SAH controls, the authors observed blood and inflammation within the arachnoid villi during the 1st week after SAH. Greater mitotic activity was also noted among arachnoid cap cells. The patient with chronic SAH presented with ventriculomegaly 2 months post-SAH and exhibited remarkable arachnoid cap cell accumulation.Conclusions. The authors postulate that proliferation of arachnoidal cells, triggered by the inflammatory reaction or blood clotting products, could result in obstruction of CSF flow through arachnoid villi into the venous sinuses. This does not exclude the possibility that SAH causes generalized fibrosis in the subarachnoid space.

Spinocerebellar ataxia type 2 (SCA2) is caused by expansion of a CAG trinucleotide repeat located in the coding region of the human SCA2 gene. The SCA2 gene product, ataxin-2, is a basic protein with two domains (Sm1 and Sm2) implicated in RNA splicing and protein interaction. However, the wild-type function of ataxin-2 is yet to be determined. To help clarify the function of ataxin-2, we produced antibodies to three antigenic peptides of ataxin-2 and analyzed the expression pattern of ataxin-2 in normal and SCA2 adult brains and cerebellum at different developmental stages. These studies revealed that (1) both wild-type and mutant forms of ataxin-2 were synthesized; (2) the wild-type ataxin-2 was localized in the cytoplasm in specific neuronal groups with strong labeling of Purkinje cells; (3) the level of ataxin-2 increased with age in Purkinje cells of normal individuals; and (4) ataxin-2-like immunoreactivity in SCA2 brain tissues was more intense than in normal brain tissues, and intranuclear ubiquitinated inclusions were not seen in SCA2 brain tissues.

In the past few years, although significant efforts have been made to assess flow distribution during retrograde cerebral perfusion with microspheres, dye, or hydrogen clearance, flow distribution in real time is still undefined. We used MR perfusion imaging to monitor flow distribution in the brain during and after deep hypothermic circulatory arrest (DHCA) with antegrade or retrograde cerebral perfusion (ACP or RCP).Thirteen pigs were divided into 2 groups and exposed to 120 minutes of either RCP (n = 7) or ACP (n = 6) at 15 degrees C, followed by 60 minutes of cardiopulmonary bypass (CPB) at 37 degrees C. During DHCA, the brain was perfused antegradely through the common carotid artery or retrogradely through the superior vena cava at pressures of 60 to 70 mm Hg and 20 to 25 mm Hg in the ACP and RCP groups, respectively. Esophageal temperature was monitored continuously. MR perfusion images were acquired every 30 minutes before, during, and after DHCA. The brain was perfusion-fixed with formaldehyde solution for histopathology at the completion of each experiment. During initial normothermic CPB, MR perfusion imaging showed a nearly uniform distribution of flow in the brain. The same pattern was maintained with a significant increase in regional cerebral blood volume during ACP and reperfusion in the ACP group. RCP provided little or no detectable blood distribution to the brain, resulting in poor reperfusion of many areas of the brain on reflow with CPB at 37 degrees C. The total area suffering poor reperfusion was significantly higher in the RCP group than the ACP group. Histopathology showed no morphological changes in any area of the brain in the ACP group, whereas varying severity of neuronal damage was observed in different regions of the brain in the RCP group.ACP preserves uniform blood distribution and normal morphology of brain tissue after prolonged DHCA. RCP provides very little blood to the tissue of the brain. A 120-minute period of RCP results in abnormal flow distribution and neuronal damage during reperfusion. The damage resulting from shorter periods of RCP remains to be assessed.

Functional and behavioral disturbances associated with hydrocephalus may be due in part to altered neurotransmitter function in the brain. Hydrocephalus was induced in adult rabbits by injection of silicone oil into the cisterna magna. These and controls were killed 3 days, 1 and 4 weeks post-injection. Tissue concentrations of norepinephrine, epinephrine, serotonin, dopamine, and the metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) levels were determined in fifteen brain regions using HPLC. There were decreases in hypothalamic and medullary dopamine, transient decreases in basal ganglia serotonin, increases in thalamic noradrenaline, and increases in hypothalamic and thalamic epinephrine. Changes in the primary neurotransmitters may be attributable to damage of their axonal projection systems. Metabolite concentrations increased in the cerebrum. Reduced clearance of extracellular fluid which accompanies cerebrospinal fluid stasis may explain the accumulation of metabolites.

The motor and cognitive dysfunction associated with hydrocephalus remains a clinical problem in children. We hypothesized that young rats with hydrocephalus should exhibit similar dysfunction and that the dysfunction should be reversible by shunting. Hydrocephalus was induced in 3-week-old rats by injection of kaolin into the cisterna magna. Rats were assessed by T2-weighted images obtained with a 7-T magnetic resonance device and by repeated behavioral testing including ability to traverse a narrow beam and ability to find a hidden platform in a water pool. Some of the rats underwent a shunting procedure 1 or 4 weeks after kaolin injection. Magnetic resonance images were used to measure ventricle size. They clearly demonstrated increased signal in periventricular white matter, which corresponded to increased brain water content. A flow-void phenomenon was observed in the cerebral aqueduct. Ability to traverse the beam did not correlate with the degree of ventriculomegaly. Ability to swim to the hidden platform demonstrated a progressive impairment of learning function which may have been accentuated by motor disability. When rats were shunted after 1 week, the behavioral dysfunction was prevented. Late shunting after 4 weeks was associated with gradual recovery of the behavioral disability which was not complete after 4 weeks. We conclude that early shunting is superior to late shunting with regard to behavioral dysfunction. High-resolution MR imaging shows features in hydrocephalic rats similar to those found in hydrocephalic humans.

Cerebro-oculo-facial-skeletal (COFS) syndrome is a rare autosomal recessive disorder with microcephaly, severe mental retardation, and death in childhood. The pathogenesis is unknown. Neuropathological features of 8 children with COFS syndrome are presented. Seven of the children, ranging in age from 36 weeks gestation to 5 years 8 months, are of North American aboriginal background from Manitoba, Canada. The eighth child is a 3-year-old Caucasian male. In all children there was severe microencephaly and mild ventriculomegaly. Cerebral myelination appeared to be delayed in one infantile case. Swollen ubiquitinated granular cells appeared in the white matter shortly after birth. Older children displayed cortical neuron loss, patchy or diffuse absence of myelin and gliosis in the white matter, and pericapillary and parenchymal mineralization in the globus pallidus and to a lesser extent the putamen and cerebral cortex. The cerebellum of older children exhibited severe degenerative changes involving the internal granular layer and Purkinje cell layer. The neuropathological changes, previously not well documented, suggest that COFS syndrome is associated with a degenerative process that begins in utero and affects many brain cell types. Similarities to Cockayne syndrome are discussed.

Background:Transtentorial herniation of large cerebral fragments is a rare phenomenon.Method:Case StudyResults:Examination of the brain of a 35-year-old male showed massive intracerebral hemorrhage resulting in displacement of basal ganglia components into the fourth ventricle.Conclusions:Sufficiently rapid intracerebral bleeding can dissect fragments of cerebrum and displace them long distances across the tentorial opening.

The boundary separating the posterior columns of the spinal cord is formed by the lateral margins of the neural groove approximating to form the neural canal. In anatomy texts this line is usually drawn as continuous, uniform, centered, and straight. It is universally termed posterior or dorsal, median "septum".Sections from the cervical and lumbar enlargements and the mid-thoracic region were examined from 35 human autopsy specimens from 20 weeks gestation to 70 years with no history of spinal cord disease or trauma. They were stained with Masson's trichrome, and by immunohistochemistry for collagen types 1 and 4, and for glial fibrillary acidic protein (GFAP).One or more variations were found in the position character, shape, or extent of the line at one or more levels in every case. There was no midline staining for collagen other than that associated with blood vessels. There is intense immunoreactivity for GFAP from 20 weeks gestation to 35 weeks diminishing thereafter. When the posterior columns are separated the "septum" divides.In the absence of any collagen this line of separation is more akin to a raphé than a septum. Inasmuch as there is an immediately adjacent subarachnoid posterior median septum it would be advantageous to re-name this intraspinal structure "dorsal" or "posterior" median raphé.

Brain damage due to an episode of cerebral hypoxia/ischemia remains a major problem in the human infant, providing impetus for the testing of potential neuroprotective agents in animal models. Although these animal models do not mirror the human pathology exactly (e.g., with respect to regions vulnerable to damage), they usually have the histological characteristics of gray matter hypoxic/ischemic injury in the human. An important factor in comparing models directly is the stage of development of the brain at birth, which varies widely between species. Approaches to prevent or treat cerebral hypoxic/ischemic damage in neonates have paralleled those in adults. However, most of these results should be interpreted cautiously, since neonatal rat models with little concurrent physiological monitoring are often used. As in adults, moderate hypothermia during the insult or a preconditioning stress prior to the insult has prevented hypoxic/ ischemic brain damage. Different from adults is the demonstration that pretreatment with moderate doses of glucocorticoids or hyperglycemia during the hypoxic/ ischemic insult protects the brain against infarction. Partial protection, primarily in neonatal rats, has also been produced by pretreatment with voltage-sensitive calcium channel antagonists, free radical scavengers, growth factors, gangliosides, anticonvulsants, antiinflammatory agents, and nitric oxide synthase inhibitors. Posttreatment has been effective with a few agents. The most consistent has been the protective effect observed with glutamate receptor antagonists administered before but also up to 4 h after the insult. The effects of most of these therapies on blood glucose, body temperature, and/or the systemic circulation should be measured and the protective effects confirmed in larger species prior to considering clinical applications.

Previous investigations showed that fragments of fetal rabbit brain tronsplanted into striatum of neonatal shiverer mouse give rise to cells that migrate through host tissue and differentiate into astroglia and oligodendroglia within 2 weeks. We studied the integration of transplanted astroglia at the ultrastructural level using pre-embedding labeling with a monoclonal antibody which recognizes an epitope -associated with rabbit but not mouse glial fibrillary acidic protein. The morphology of early migrating donor cells does not distinguish them from cells -arising in host germinal matrix. Once the cells complete their migration they integrate into host brain in a structurally normal manner. Transplanted astroglia form perivascular foot plates with host capillaries. They also send extensive processes into the neuropil where intimate contacts with neurons and synaptic structures are formed. Oligodendroglia send processes to nearby axons where they form normal-appearing myelin. During the rejection process, which may begin at 4 weeks, donor astroglia show evidence of reaction with increased intermediate filament content. Donor cells are attacked by leukocytes, including eosinophils, and subsequently degenerate. We conclude that crossspecies transplantation of glial cells can result in entirely normal structural integration into host brain

There are many reports in experimental animals indicating that microglia are activated in the dentate gyrus and hippocampus following hypoxic-ischaemic brain injury. The hippocampi of brains removed at autopsy from 178 children were studied retrospectively and the quantity of microglia in the polymorphous layer of the dentate gyrus was assessed. Up to the age of 8-9 months, patients with proven hypoxic or hypotensive episodes due to perinatal asphyxia, congenital heart defects, or chronic pulmonary dysfunction often had a dense infiltrate of microglial cells. A comparable microglial infiltrate was seen in most children dying under circumstances consistent with sudden infant death syndrome. Children under 9 months of age dying of other acute causes, for example trauma or sepsis either suddenly or with survival of less than 4 days in the intensive care unit, had significantly fewer microglia. After the age of 9 months a dense microglial infiltrate was never seen regardless of the cause of death. We conclude that the presence of abundant microglia in the polymorphous layer of the dentate gyrus of human infants is a marker of chronic illness or mild hypoxic-ischaemic brain injury which takes several days to develop.

✓ The metabolic changes in neonatal hydrocephalus that lead to permanent brain injury are not clearly defined, nor is the extent to which these changes can be prevented by a cerebrospinal fluid shunt. To clarify these processes, cerebral glucose utilization was examined using [14C]2-deoxyglucose autoradiography in 1-month-old kittens, kaolin-induced hydrocephalic littermates, and hydrocephalic kittens in which a ventriculoperitoneal shunt had been inserted 10 days after kaolin injection. The hydrocephalic kittens showed thinning of the cerebral mantle and an anterior-to-posterior gradient of enlargement of the ventricular system, with a ventricle:brain ratio of 24% for the frontal and 35% for the occipital horns compared with control (< 0.5%) and shunted (< 5%) animals. White matter in hydrocephalic animals was edematous. Myelination was delayed in the periventricular region and in the cores of the cerebral gyri. Glucose utilization in hydrocephalic and shunted animals was unchanged from control animals in all gray-matter regions examined. However, in hydrocephalic animals, the frontal white matter exhibited a significant increase in glucose utilization (25 µmol • 100 gm−1 • min−1) in the cores of gyri compared with normal surrounding white-matter values (14.8 µmol • 100 gm−1 • min−1). Very low values (mean 4 µmol • 100 gm−1 • min−1) were found in areas corresponding to severe white-matter edema, and these areas were surrounded by a halo of increased activity (24 µmol • 100 gm−1 • min−1). In contrast, cytochrome oxidase activity in white matter was homogeneous. Shunting resulted in restoration of the cerebral mantle thickness, a return to normal levels of glucose utilization in the white matter, and an improvement in myelination. It is suggested that the areas of increased glucose utilization seen in the white matter represent anaerobic glycolysis which, if untreated, progresses to infarction. The pattern of this increased glucose utilization matches that of expected myelination and, during this period of high energy demand, white matter may be susceptible to the hypoperfusion associated with hydrocephalus.

✓ It has recently been reported that pretreatment with a single dose of dexamethasone (0.1 mg/kg) 24 hours before hypoxia in 7-day-old rat pups is protective against an hypoxic-ischemic insult (unilateral carotid artery occlusion followed by 3 hours of hypoxia in 8% O2). The authors now examine whether pretreatment 6 hours before insult is equally effective and compare other agents potentially suitable for prophylaxis in neonatal hypoxia-ischemia, including the calcium antagonists flunarizine (30 mg/kg pretreatment), nimodipine (0.5 mg/kg pretreatment), and the 21-aminosteroid U-74389F (10 mg/kg pre- and posttreatment). For each active agent, there was also a vehicle-treated control group. Comparison of the mean area of ipsilateral infarction on brain coronal sections showed that there was no statistically significant difference between the various control groups (mean area of infarction 66% ± 4%). Pretreatment with dexamethasone 6 hours prior to hypoxia offered complete protection with no infarction. A beneficial effect was seen following pretreatment with flunarizine (mean area of infarction 33.6% ± 7.8%), although this degree of damage was still significantly different from that seen with dexamethasone pretreatment. Pretreatment with nimodipine or U-74389F offered no protection (mean area of infarction 77.5% ± 4% and 59% ± 10%, respectively). Unlike findings in adult animals and clinical studies, the current studies show that dexamethasone may have a role in the treatment of neonatal hypoxia-ischemia and deserves reappraisal.