Clinico-radiological features of subarachnoid hyperintensity on diffusion-weighted images in patients with meningitis.

AIM: To investigate the clinical and radiological features of meningitis with subarachnoid diffusion-weighted imaging (DWI) hyperintensity. MATERIALS AND METHODS: The clinical features, laboratory data, and radiological findings, including the number and distribution of subarachnoid DWI hyperintense lesions and other radiological abnormalities, of 18 patients seen at five institutions were evaluated. RESULTS: The patients consisted of eight males and 10 females, whose ages ranged from 4 months to 82 years (median 65 years). Causative organisms were bacteria in 15 patients, including Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus agalactiae, Staphylococcus aureus, Klebsiella pneumoniae, and Listeria monocytogenes. The remaining three were fungal meningitis caused by Cryptococcus neoformans. Subarachnoid DWI hyperintense lesions were multiple in 16 of the 18 cases (89%) and predominantly distributed around the frontal lobe in 16 of the 18 cases (89%). In addition to subarachnoid abnormality, subdural empyema, cerebral infarction, and intraventricular empyema were found in 50, 39, and 39%, respectively. Compared with paediatric patients, adult patients with bacterial meningitis tended to have poor prognoses (7/10 versus 1/5; p = 0.1). CONCLUSION: Both bacterial and fungal meningitis could cause subarachnoid hyperintensity on DWI, predominantly around the frontal lobe. This finding is often associated with poor prognosis in adult bacterial meningitis.

Brain malformations caused by retroviral vector-mediated gene transfer of hippocampal cholinergic neurostimulating peptide precursor protein into the CNS via embryonic mice ventricles.

Hippocampal cholinergic neurostimulating peptide precursor protein (HCNP-pp) is a unique multifunctional protein, being not only the precursor of HCNP, which promotes the phenotype development of septo-hippocampal cholinergic neurons, but also the binding protein of phosphatidylethanolamine, ATP, Raf-1 kinase (known as "Raf-1 kinase inhibitory factor" in peripheral organs), and serine protease. We obtained a high-titer retroviral vector harboring HCNP-pp cDNA by the use of a modified packaging cell line and centrifugation, and by injecting it into embryonic mouse ventricles, we investigated the function of its gene product within the central nervous system (CNS). We found that efficient transduction into hippocampal pyramidal neurons can be achieved by injecting the vector into embryonic brain ventricles on embryonic day 14 (E14). Three days after receiving the intraventricular injection of the high-titer HCNP-pp retrovirus vector on E14, the tissues around the ventricles showed an overexpression of HCNP-pp. This was accompanied by a reduced amount of activated MEK and Erk (as analyzed by histochemical and Western blot methods), suggesting that HCNP-pp also regulates the MAP-kinase cascade within the CNS. Surprisingly, mouse brains that received the HCNP-pp retroviral vector showed massive malformation of the hippocampus and cerebellum when examined 30 days after birth. This shows that strictly regulated HCNP-pp gene expression is necessary for the normal development of the mouse brain, and that the moderate overexpression achieved by retroviral vector-mediated gene transfer is sufficient to cause severe abnormality of entire brain structures.

Age-dependent changes in HCNP-related antigen expression in the human hippocampus.

Hippocampal cholinergic neurostimulating peptide (HCNP), originally purified from the young rat hippocampus, enhances the cholinergic phenotype development of the medial septal nucleus in vitro. In this study, we examined the HCNP-antigen distribution and the age-related changes in the number of positive cells in the hippocampus (obtained at autopsy from 74 subjects with no known neurological disorders). Immunohistochemical assay revealed that the immunopositive cells were GABAergic neurons and oligodendrocytes. They were first identified in the fetus at around 25 to 30 weeks and their number increased rapidly with advancing postconceptional age to reach maximal at the perinatal stage and in early postnatal life; it then decreased to the adult level by 10 years old. These results suggest that HCNP-related antigen may play important roles in the development and/or differentiation of the human hippocampus.

Muscarinic cholinergic and glutamatergic reciprocal regulation of expression of hippocampal cholinergic neurostimulating peptide precursor protein gene in rat hippocampus.

Hippocampal cholinergic neurostimulating peptide, an undecapeptide originally isolated from the hippocampus of young rats, enhances acetylcholine synthesis in rat medial septal nucleus in vitro. Hippocampal cholinergic neurostimulating peptide is derived from the N-terminal region of its 21-kmol.wt precursor protein. The highest expression of the hippocampal cholinergic neurostimulating peptide precursor protein messenger RNA is in hippocampal pyramidal neurons. In an in vitro rat hippocampal slice, preparation in which electrical stimulation could be delivered to the Schaffer collateral-CA1 pyramidal cell synapse, semi-quantitative non-radioisotopic in situ hybridization, demonstrated that expression of the hippocampal cholinergic neurostimulating peptide precursor protein messenger RNA is regulated by neuronal activity. Selective inhibition with pharmacological agents revealed that the constitutive hippocampal cholinergic neurostimulating peptide precursor protein messenger RNA level can be up-regulated by D-(-)-2-amino-5-phosphono-valeric acid, and that activity-dependent transcription can be inhibited by tetrodotoxin, nifedipine, 6-cyano-7-nitroquinoxaline-2,3-dione, and scopolamine, but not by mecamylamine. These results indicate that septal cholinergic neurons and hippocampal glutamatergic neurons exert a reciprocal influence over the expression of hippocampal cholinergic neurostimulating peptide precursor protein messenger RNA in the hippocampus, and that the activity-dependent and constitutive expressions of hippocampal cholinergic neurostimulating peptide precursor protein messenger RNA may be regulated by different routes, involving calcium influx via L-type Ca(2+) channels and N-methyl-D-aspartate receptors.

Intramedullary hemorrhage caused by arteriovenous malformation: a case of mixed lateral and medial medullary syndrome.

A 48-year-old man with no known risk factor for cerebrovascular disease, other than cigarette smoking, experienced the sudden onset of a mixed lateral and medial medullary syndrome. Computed tomography scan failed to show any definite abnormality. Magnetic resonance imaging scans revealed hemorrhage restricted to the left dorsolateral medulla. Angiography showed abnormal arteries originating from the left vertebral artery with small niduses located on the surface of the medulla and contralateral cerebellum. Small brain-stem hemorrhages are a contraindication to thrombolytic or anticoagulant therapy, and therefore must be recognized in the acute stage.

Hepatitis B virus infection among residents of a nursing home for the elderly: seroepidemiological study and molecular evolutionary analysis.

A seroepidemiological study of HBV infection was carried out to investigate the seroprevalence of hepatitis B surface antigen (HBsAg) and the transmission routes of hepatitis B virus (HBV) infection among residents of a nursing home for the elderly. HBV serum markers were examined in 119 residents and 71 healthcare workers in the institution, as also in 1330 healthy subjects from the same geographical area, as the control group. HBsAg was detected in 6 (5%), 0 and 20 (1.5%) residents, healthcare workers and healthy subjects, respectively. Four residents (A-D) who had HBV-DNA in the serum were studied by molecular evolutionary analysis. The strains derived from residents A, B and D were clustered together within a close range of evolutionary distances. Residents B and D, who were not positive for HBsAg at the time of admission to the institution, subsequently became HBsAg-positive asymptomatic carriers. These results suggested intrainstitutional transmission of HBV in the nursing home for the elderly, and confirmed that the source of transmission of HBV to residents B and D was resident A who was positive for HBsAg. Residents in a nursing home for the elderly should be considered as being a high-risk group for HBV infection, and vaccination against HBV of these groups is recommended.

[An autopsy case of corticobasal degeneration without prominent cortical pathology--an imitator of progressive supranuclear palsy].

We describe an autopsy case of parkinsonism with bradykinesia, muscle rigidity, and dementia as major symptoms. The patient had developed bradykinesia at the age of 62, and then muscle rigidity, a parkinsonian posture, bradylalia, and dementia gradually appeared. Neurological examination revealed rigidity in the neck and limbs, with motion and speech being generally slow. He lacked involuntary movements including alien hand, tremor, chorea, and dystonia. Vertical gaze palsy, both upward and downward was noted, but other cranial nerves were intact. He was diagnosed as suffering from PSP clinically based on vertical gaze palsy, bradykinesia, instability on standing and gait, and dementia. Levodopa was only transiently effective. Within three years he became bed-ridden and in a state of akinetic mutism. At age 65 he died from pneumonia. Neuropathology revealed severe neuronal degeneration and gliosis in the substantia nigra. Because atrophy of the tegmentum of brainstem, dentate nuclei, inferior olivary nuclei was very mild and Alzheimer neurofibrillary tangles in the brainstem were relatively few, PSP was ruled out. Cortical neuronal degeneration was not apparent, but in the deep layer of cingulate gyrus, frontal lobe, and insula, there were several ballooned neurons. Gallyas-Braak silver staining showed no tuft-shaped astrocytes, specific for PSP, but it disclosed astrocytic plaques in the basal ganglia and the cerebral cortex. At present, astrocytic plaques are recognized as a hallmark of corticobasal degeneration (CBD), along with ballooned neurons in the cerebral cortex. The present case thus illustrates that CBD has a wide spectrum and may include cases in which degeneration of cerebral cortex is very mild.

Hippocampal cholinergic neurostimulating peptides (HCNP).

Neuronal development and differentiation require a variety of cell interactions. Diffusible molecules from target neurons play an important part in mediating such interactions. Our early studies used explant culture technique to examine the factors that enhance the differentiation of septo-hippocampal cholinergic neurons, and they revealed that several components resident in the hippocampus are involved in the differentiation of presynaptic cholinergic neurons in the medial septal nucleus. One of these components, originally purified from young rat hippocampus, is a novel undecapeptide (hippocampal cholinergic neurostimulating peptide; HCNP); this enhances the production of ChAT, but not of AchE. Later experiments revealed that: (1) a specific receptor appears to mediate this effect; (2) NGF and HCNP act cooperatively to regulate cholinergic phenotype development in the medial septal nucleus in culture; and (3) these two molecules differ both in their mechanism of release from the hippocampus and their mechanism of action on cholinergic neurons. The amino acid sequence deduced from base sequence analysis of cloned HCNP-precursor protein cDNA shows that HCNP is located at the N-terminal domain of its precursor protein. The 21 kDa HCNP precursor protein shows homology with other proteins, and it functions not only as an HCNP precursor, but also as a binding protein for ATP, opioids and phosphatidylethanolamine. The distribution and localization of HCNP-related components and the expression of their mRNAs support the notion that the precursor protein is multifunctional. In keeping with its multiple functions, the multiple enhancers and promoters found in the genomic DNA for HCNP precursor protein may be involved in the regulation of its gene in a variety of cells and at different stages of development. Furthermore, several lines of evidence obtained from studies of humans and animal models suggest that certain types of memory and learning disorders are associated with abnormal accumulation and expression of HCNP analogue peptide and/or its precursor protein mRNA in the hippocampus.

[A case of sarcoid meningoencephalitis with an isolated supratentorial lesion].

A rare case of sarcoid meningoencephalitis with no systemic lesion is reported here. A 58-year old man was admitted experiencing dull headache and speech disturbance. He had never received a diagnosis of systemic sarcoidosis. On admission, neurological examination revealed dysarthria, a defect of the right-side visual field and accelerated right Achilles tendon reflex. A T2-weighted MRI showed a high-intensity signal in the white matter of the left parieto-occipital lobe surrounded by severe brain edema with a mass effect. The meninges around the lesion were enhanced by gadolinium, but no enhancement was observed in the basal portion. Angiotensin-converting enzyme (ACE) activities of cerebrospinal fluid (CSF) and serum were within normal range. The level of interleukin-6 in the CSF was slightly elevated. Chest X ray films and chest CT revealed no abnormal lesions. Whole body gallium scanning showed a hot region only in the intracranial lesion. A brain biopsy was performed. Histological examination revealed typical granuloma of sarcoidosis accompanied by microvasculitis and epithelioid cell granuloma without caseous necrosis. Oral administration of prednisolone improved all symptoms and MRI findings. These observations suggest that release of cytokines from macrophages and epithelioid cells, as well as disruption of the blood-brain barrier due to microvasculitis, are involved in the mechanism responsible for producing lesions of sarcoid meningoencephalitis.

Neuronal distribution and subcellular localization of HCNP-like immunoreactivity in rat small intestine.

A novel peptide, hippocampal cholinergic neurostimulating peptide (HCNP), originally purified from young rat hippocampus, affects the development of specific cholinergic neurons of the central nervous system in vitro. In this study, HCNP-like-immunoreactive nerve processes and nerve cell bodies were identified by electron microscopic immunocytochemistry in the rat small intestine. Labeled nerve processes were numerous in the circular muscle layer and around the submucosal blood vessels. In the submucosal and myenteric plexuses, some HCNP-like-immunopositive nerve cell bodies and nerve fibers were present. The reaction product was deposited on the membranes of various subcellular organelles, including the rough endoplasmic reticulum, Golgi saccules, ovoid electron-lucent synaptic vesicles in axon terminals associated with submucosal and myenteric plexuses, and the outer membranes of a few mitochondria. The synaptic vesicles of HCNP-like positive terminals were 60-85 nm in diameter. The present data provide immunocytochemical evidence that HCNP-like-positive nerve cell bodies and nerve fibers are present in the submucosal and myenteric plexuses of the rat small intestine. An immunohistochemical light microscopic study using mirror-image sections revealed that in both the submucosal and myenteric ganglia, almost all choline acetyltransferase (ChAT)-immunoreactive neurons were also immunoreactive for HCNP. These observations suggest (i) that HCNP proper and/or HCNP precursor protein is a membrane-associated protein with a widespread subcellular distribution, (ii) that HCNP precursor protein may be biosynthesized within neurons localized in the rat enteric nervous system, and (iii) that HCNP proper and/or HCNP precursor protein are probably stored in axon terminals.

Increased expression of hippocampal cholinergic neurostimulating peptide-related components and their messenger RNAs in the hippocampus of aged senescence-accelerated mice.

Hippocampal cholinergic neurostimulating peptide stimulates cholinergic phenotype development by inducing choline acetyltransferase in the rat medial septal nucleus in vitro. Adult senescence-accelerated-prone mice/8, a substrain of the senescence-accelerated-prone mouse, show a remarkable age-accelerated deterioration in learning and memory. We cloned mouse hippocampal cholinergic neurostimulating peptide precursor protein complementary DNA. The deduced amino acid sequence showed that the neurostimulating peptide itself is the same as that found in the rat. In situ hybridization revealed that the highest expression of the precursor protein messenger RNA was in hippocampal pyramidal neurons. Compared with a strain of senescence-accelerated-resistant mouse (control mouse), adult senescence-accelerated-prone mice/8 showed increased expression of both the precursor messenger RNA and the neurostimulating peptide-related immunodeposits in the hippocampal CA1 field. The deposits were intensely and diffusely precipitated in neuropils throughout the strata oriens and radiatum in senescence-accelerated-prone mice/8, but not in control mice. The neurostimulating peptide content in the hippocampus was higher in senescence-accelerated-prone mice/8 than in control mice, while its precursor protein itself was not different between the two strains. Furthermore, our previous and present data show that the medial septal and hippocampal choline acetyltransferase activity was significantly lower in senescence-accelerated-prone mice/8 than in control mice. The data suggest that, in hippocampal neurons in adult senescence-accelerated-prone mice/8, the production of hippocampal cholinergic neurostimulating peptide precursor protein in neuronal somata, which is associated with an increased expression of its messenger RNA in the CA1 field, occurs as a consequence of low activity in their presynaptic cholinergic neurons. This is followed by accelerated processing to generate bioactive peptide and transport to its functional fields. However, certain mechanisms reduce the release of the peptide and lead to its accumulation in the neuropil. These disturbances of the septohippocampal cholinergic system might be the biochemical mechanism underlying the characteristic deterioration of senescence-accelerated-prone mice/8.

An unusual course of progressive multifocal leukoencephalopathy in a patient with idiopathic CD4+ T lymphocytopenia.

A case is reported of idiopathic CD4+T lymphocytopenia with progressive multifocal leukoencephalopathy and cervical lymph node tuberculosis. A 57 year old Japanese man presented with cervical lymphadenopathy and progressive neurological deficits, and six months later he developed akinetic mutism. He had a persistent severely depressed number of circulating CD4+T lymphocytes in the absence of human immunodeficiency virus infection. T1 weighted MRI showed a diffuse decreased signal intensity limited to the white matter without mass effect. A brain biopsy specimen had a morphology similar to that of progressive multifocal leukoencephalopathy. Polyomavirus antigen was detected in the brain lesion, and viral DNA was identified in nucleated blood cells and urine. Unusually this serious medical condition has lasted for more than three years without remission. To our knowledge this is the first patient with CD4+T lymphocytopenia with progressive multifocal leukoencephalopathy, suggesting that similar opportunistic infections should be considered even in previously normal people.

NMDA receptor activation enhances the release of a cholinergic differentiation peptide (HCNP) from hippocampal neurons in vitro.

Hippocampal cholinergic neurostimulating peptide (HCNP) is a novel undecapeptide purified from the hippocampus of young rats. The peptide stimulates cholinergic phenotype development in the rat medial septal nucleus in vitro. Here, we have focused on the mechanism of release of the peptide from the hippocampus, by applying tissue culture techniques. Quantitation of HCNP in the culture supernatant after chemical stimulation was carried out by RIA, and by a combination of HPLC and RIA. We found that the N-methyl-D-aspartate (NMDA) receptor specifically mediates release of the deacetylated form of HCNP from the culture. Our results suggest that during the early development of hippocampal neurons, the peptide is released by NMDA receptor activation, and that it may be involved in mediating the effect of activity-dependent cues on developing septal cholinergic neurons.

High levels of hippocampal cholinergic neurostimulating peptide (HCNP) in the CSF of some patients with Alzheimer's disease.

Hippocampal cholinergic neurostimulating peptide (HCNP), originally purified from the hippocampus of young rats, enhances the cholinergic development of rat medial septal nuclei in vitro. This report concerns the determination of the HCNP content of the cerebrospinal fluid (CSF) of 173 clinically, and of 22 clinico-pathologically defined patients. A radioimmunoassay was used throughout. The HCNP level was relatively uniform among the clinically defined patients; for almost all non-Alzheimer's patients, the level fell within the range delimited by +/- 2 SD of the mean for all patients taken together, and none of them had a level above this range. By contrast, the early-onset Alzheimer's disease patients could be divided on the basis of their HCNP level into two groups, one with high levels (markedly above the mean +/- 2SD range), and the other with levels similar to those of the other patients. The analysis of the CSF samples obtained postmortem revealed that Group I Alzheimer-type dementia (ATD) patients with clinico-pathologically established diagnoses had a strikingly higher level of HCNP than patients with either Group II ATD or cerebral vascular disease. These results suggest that HCNP is involved in certain pathophysiological alterations associated with dementia, and that its determination may be useful in patient evaluation. Copyright 1998 Lippincott Williams & Wilkins

Mechanism of expression of the rat HCNP precursor protein gene.

The hippocampal cholinergic neurostimulating peptide (HCNP), isolated from hippocampal tissue of 10- to 12-day-old rats, enhances the in vitro synthesis of acetylcholine in medial septal tissue explants. The HCNP precursor is a 21 kDa protein that binds hydrophobic ligands and Mg-ATP, and is associated with the opioid-binding protein. We employed an HCNP-precursor cDNA as probe to clone the genomic DNA, used for mapping of the exon-intron structure of the gene. We also determined the nucleotide structure of the promoter region of the rat HCNP precursor protein gene. By using S1 mapping and CAT as a reporter, we found multiple promoters that were aligned in the 5' untranslated region. In addition, the presence of several putative enhancer binding sequences were tested by electrophoresis mobility shift assays. Northern blot analysis revealed that the gene is expressed in a variety of rat tissues and various subregions of the brain. These results suggest that HCNP-precursor gene expression is regulated by a general transactivation factor such as SP1, and that the specific presence of the bioactive HCNP in certain tissues results from post-translational events such as proteolytic processing of the precursor protein, which takes place predominantly in the hippocampus of young rats.

Mixed connective tissue disease associated with acute polyradiculoneuropathy.

A rare case of mixed connective tissue disease (MCTD) with acute polyradiculoneuropathy is reported. A 23-year-old woman presented with high body temperature, arthralgia and a headache, and developed gait disturbance two weeks later. She had many clinical features common to patients with MCTD. Her neurological manifestations were diagnosed as acute polyradiculoneuropathy based on the clinical picture, combined with supportive ancillary data, including cerebrospinal fluid (CSF) analysis, electrophysiological evaluation, sural nerve biopsy, peroneus brevis muscle biopsy, and magnetic resonance imaging (MRI). Her neurologic deficits, as well as associated laboratory findings, were improved by corticosteroid therapy.

Hirano bodies and Alzheimer's disease.

Hirano bodies are refractile eosinophilic rod-like structures, initially observed in Guamanian (Chamorro) patients with amyotrophic lateral sclerosis and parkinsonism-dementia complex. Subsequent investigations revealed that Hirano bodies have a distinct topographic distribution in the hippocampus, and that their number increases in the pyramidal layer of Sommer's sector but not in the stratum lacunosum with advancing age. Since patients with Alzheimer's disease (AD) have significantly more Hirano bodies than normal subjects in the same age range, the inclusions appear seem to be of relevance in this disease. Immunohistochemical and electron microscopic studies have demonstrated that the main components of Hirano bodies are abnormal micro-filaments, and that not only molecules associated with cell cytoskeleton, but also some stress-related proteins and growth factors such as beta-amyloid precursor protein, hippocampal cholinergic neurostimulating peptide (HCNP), transforming growth factor beta 3 are present in Hirano bodies. The accumulation of HCNP in Hirano bodies suggests that patients bearing these inclusions may have a disturbance of the septohippocampal cholinergic system, considered to be of importance for le arning and memory formation, and hence be related to the memory impairment of AD.

Possible implication of hippocampal cholinergic neurostimulating peptide (HCNP)-related components in Hirano body formation.

We have previously demonstrated that hippocampal cholinergic neurostimulating peptide (HCNP)-related components accumulate in almost all Hirano bodies in Sommer's sector of the hippocampus of elderly individuals, and that the number of HCNP-positive Hirano bodies is greater in patients with Alzheimer's disease. Although Hirano bodies occur preferentially in the neuronal processes of the stratum pyramidale of the hippocampus, they can be seen occasionally as small inclusions, intermingled with neurofibrillary tangles and in association with senile plaques. Here we show that the small inclusions are also recognized by an anti-HCNP antibody, and by using immunoelectron microscopy demonstrate that these HCNP-positive inclusions, intermingled with tau protein-positive neurofibrillary tangles and beta-amyloid-positive senile plaques are indeed Hirano bodies. These findings strongly suggest that HCNP-related components may be involved in Hirano body formation.