Functional central nervous system myelin repair in an adult mouse model of demyelination caused by proteolipid protein overexpression.

Two types of interventions to remyelinate the adult demyelinated central nervous system were investigated in heterozygous transgenic mice overexpressing the proteolipid protein gene. 1) A cocktail of trophic factors, "TS1," was directed toward the activation of the endogenous pool of neural progenitors to increase the number of myelinating oligodendrocytes (OL) in the brain. 2) A combinatorial approach in which OL progenitors were coinjected with TS1 into the corpus callosum of wild-type and He4e transgenic mice that displayed hindlimb paralysis. The levels of locomotor ability in these mice were evaluated after a single treatment. The data showed that a single administration of either one of the interventions had similar therapeutic effects, alleviating the symptoms of demyelination and leading to the recovery of hindlimb function. Histological and immunofluorescent examination of brain sections showed extensive remyelination that was sufficient to reverse hindlimb paralysis in transgenic mice. When the interventions were administered prior to hindlimb paralysis, He4e mice were able to walk up to 1 year of age without paralysis.

Direct neural fate specification from embryonic stem cells: a primitive mammalian neural stem cell stage acquired through a default mechanism.

Little is known about how neural stem cells are formed initially during development. We investigated whether a default mechanism of neural specification could regulate acquisition of neural stem cell identity directly from embryonic stem (ES) cells. ES cells cultured in defined, low-density conditions readily acquire a neural identity. We characterize a novel primitive neural stem cell as a component of neural lineage specification that is negatively regulated by TGFbeta-related signaling. Primitive neural stem cells have distinct growth factor requirements, express neural precursor markers, generate neurons and glia in vitro, and have neural and non-neural lineage potential in vivo. These results are consistent with a default mechanism for neural fate specification and support a model whereby definitive neural stem cell formation is preceded by a primitive neural stem cell stage during neural lineage commitment.

GM1b is a new member of antigen for serum antibody in Guillain-Barré syndrome.

Serum antibody from some patients with Guillain-Barré syndrome recognized an antigen of a minor component in human brain monosialoganglioside fraction. We purified that antigen, which migrated at a position slightly lower than that of GM1 on a thin-layer chromatogram (TLC), by using Iatrobeads column chromatography and preparative TLC. Structural analyses, including fast atom bombardment mass spectrometry, showed it to be GM1b. An enzyme-linked immunosorbent assay (ELISA) using purified GM1b showed that anti-GM1b antibody was present in 22 of 104 cases tested. No anti-GM1b antibody was present in the sera from control patients with other diseases or from the normal controls. Four sera recognized only GM1b among the 11 ganglioside antigens tested. The other 18 sera had antibodies to other antigens, most of which shared no terminal epitope with GM1b. Eight of nine sera samples with anti-GalNAc-GD1a antibody also had anti-GM1b antibody. Antibody to a minor monosialoganglioside, GM1b, was found to be a useful diagnostic marker for Guillain-Barré syndrome. Further study is needed to determine whether this antibody plays a role in the pathogenetic mechanism of the syndrome.

A novel ganglioside, 9-O-acetyl GD1b, is recognized by serum antibodies in Guillain-Barré syndrome.

A hitherto undescribed ganglioside was detected in a crude ganglioside fraction of bovine brain using an IgM M-protein binding to Gal beta 1, 3GalNAc residue. We purified and identified it as 9-O-acetyl GD1b based on results of alkali treatment that yielded GD1b and results of fast atom bombardment-mass and gas chromatography-mass spectrometries. 9-O-acetyl GD1b was also found to be present in human peripheral nerve tissue. The reactivities of the serum antibodies from patients with Guillain-Barré syndrome to 9-O-acetyl GD1b, GD1b, and GM1 were determined by ELISA and TLC immunostaining. Nineteen of 85 serum samples from Guillain-Barré syndrome patients had antibodies that bound to 9-O-acetyl GD1b: 14 of the positive samples also reacted with GM1 and GD1b, three reacted with GM1 but not with GD1b, one with GD1b but not with GM1, and one with neither GM1 nor GD1b. These results show that a subset of patients with Guillain-Barré syndrome had antibodies that react with 9-O-acetyl GD1b; therefore, this ganglioside can serve as a target antigen against the antibodies present in Guillain-Barré syndrome.

Degeneration of rabbit sensory neurons induced by passive transfer of anti-GD1b antiserum.

Systemic infusion of high-titer anti-GD1b antiserum to two rabbits pre-inoculated with keyhole limpet hemocyanin and Freund's complete adjuvant was performed. The two rabbits had low-titer anti-GD1b antibody in sera. Although no apparent clinical signs were observed, pathological examinations showed vacuolar degeneration with macrophage infiltration in a few axons in the dorsal columns of the spinal cords from the two rabbits. No such pathological changes were observed in the other two pre-inoculated rabbits infused with normal rabbit sera. Anti-GD1b antibody therefore may cause degeneration in rabbit sensory neurons with central axons extending to the dorsal column.

Rabbit experimental sensory ataxic neuropathy: anti-GD1b antibody-mediated trkC downregulation of dorsal root ganglia neurons.

We previously reported experimental sensory neuropathy in rabbit induced by the immunization of ganglioside GD1b. The major pathological change in diseased rabbits was degeneration of primary sensory neurons with central axons extending to the dorsal column of the spinal cord. The loss of primary sensory neurons that mediate proprioceptive sensation prompted us to investigate the expression of trkC in dorsal root ganglia (DRG) because this type of neuron is thought depend mainly on neurotrophin-3-mediated trkC signaling. Northern blotting analysis revealed markedly reduced expression of trkC in DRG of diseased rabbits in acute phase. This result together with the absence of lymphocytic infiltration in DRG of diseased rabbits at any stage suggests the anti-GD1b antibody-mediated downregulation of trkC expression could be one of the pathogenesis of this experimental sensory ataxic neuropathy.

Double mutations at codon 180 and codon 232 of the PRNP gene in an apparently sporadic case of Creutzfeldt-Jakob disease.

Several polymorphisms of the prion protein gene are associated with the occurrence of familial Creutzfeldt-Jakob disease. We described a 84-year-old Japanese man with neuropathologically verified Creutzfeldt-Jakob disease of apparently sporadic type. His clinical presentation was atypical in point of a very late age at onset and absence of periodic synchronous discharge on electroencephalography. The patient carried double hitherto undescribed mutations of the prion protein gene; at codon 180 on one allele and at codon 232 on another. The mutation at codon 180 abolishes the Tth111I cutting site, which may be misunderstood to represent codon 178 mutation on routine restriction fragment length polymorphism study.

PET analysis of a case of cerebrotendinous xanthomatosis presenting hemiparkinsonism.

We describe a 34-year-old Japanese woman presenting gait difficulty and Achilles tendon swelling. The patient was diagnosed as having cerebrotendinous xanthomatosis (CTX) based on the high serum cholestanol level and diminished enzymatic activity of 27-hydroxylase of fibroblasts from her skin. Her clinical presentation was atypical regarding the presence of hemiparkinsonism and absence of apparent cataract, dementia, and cerebellar ataxia. Although MRI studies could not detect any abnormality in the basal ganglia or midbrain, PET analysis using [18F]-6-fluoro-L-dopa revealed reduced uptake of dopamine into the putamen, suggesting the impairment of presynaptic dopaminergic neurons.

Cerebellar ataxia and polyneuropathy in a patient with IgM M-protein specific to the Gal(beta 1-3)GalNAc epitope.

A 79-year-old man with sensory dominant polyneuropathy, cerebellar ataxia, and palatal myoclonus had serum IgM M-protein that specifically bound to GM1, GD1b, and asialo-GM1. IgM with the same specificity was detected in his cerebrospinal fluid. Results of immunohistochemical studies showed specific binding of this monoclonal IgM to the cerebellar granular layer, dentate nucleus, inferior olive, and gray matter of the cerebrum and spinal cord. Monoclonal antibody GGR12, monospecific to GD1b, had an immunostaining distribution similar to that of the patient's IgM M-protein. The binding of M-protein may be associated with the development of cerebellar ataxia and palatal myoclonus in this patient.

Elevated serum interleukin-6 in POEMS syndrome reflects the activity of the disease.

In patients with POEMS syndrome, which often accompanies plasma cell dyscrasia, the roles of interleukin-6 (IL-6) and other acute phase cytokines are unknown. Serum IL-6, interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) were measured by the enzyme-linked immunosorbent assay technique in 16 patients with POEMS syndrome and in patients with other neurological diseases (OND) as control. Serum IL-6 was more frequently detected and higher in active POEMS than in stable POEMS or in OND patients. No sample was positive for IL-1 beta. TNF-alpha was positive in 3 out of 7 active POEMS patients, but its significance was not definite. Serum IL-6 levels in POEMS patients reflected the disease activity but not the severity of accompanying plasma cell dyscrasia.

Portal-systemic encephalopathy and hypothalamic hypothyroidism: effect of thyroid hormone on ammonia metabolism.

We describe a 53-year-old woman with portal-systemic encephalopathy and altered thyroid function. Endocrinological studies revealed low levels of free thyroid hormone with an inappropriately low level of thyroid-stimulating hormone that responded to bolus injection of thyrotropin-releasing hormone with a normal but somewhat delayed pattern. On the diagnosis of hypothalamic hypothyroidism, she was treated with levothyroxine sodium. Thyroid hormone replacement improved not only the symptoms of hypothyroidism but the hyperammonemia and consciousness disturbance, which suggested a hitherto undescribed possibility that hypothyroidism may be an exacerbation factor of hyperammonemia and portal-systemic encephalopathy.

[Gerstmann-Sträussler-Scheinker disease with heterozygous codon change at prion protein codon 129].

A 53-year-old male was admitted to our hospital for progressive dementia and gait disturbance which had started at the age of 48. Examination indicated dementia, dysarthria, dysphagia, bilateral pyramidal signs, apraxia of the limbs, and extrapyramidal signs such as fine finger tremors, and rigidity of limbs. There were no cerebellar signs or myoclonus. His mother and elder brother showed similar symptoms and died at the ages of 53 and 50, respectively. EEG was normal. CT and MRI showed mild brain atrophy, but no cerebellar atrophy. T2 weighted image indicated low intensity areas covering bilateral caudate nuclei and putamina. A heterozygous amino acid change from methionine to valine was noted at codon 129 of the prion protein of the patient as well as in one of his son. The most likely diagnosis was Gerstmann-Sträussler-Scheinker (GSS) disease without cerebellar atrophy. GSS may include a broad spectrum of brain pathology. Whether the codon change is associated with pathology without cerebellar atrophy is a problem that awaits further investigation.

[A case of portal-systemic encephalopathy presenting characteristic MR images in globus pallidus, hypothalamus, corpus callosum, pontine base, and middle cerebellar peduncle].

A 53-year-old woman developed symptoms of slow speech, mild dementia, increased deep tendon reflex, ataxic gait, flapping tremor, and dystonic posture during two years. She had liver cirrhosis and hyperammonemia, which suggested a diagnosis of portal-systemic encephalopathy. MR T1-weighted images showed increased signal intensity in globus pallidus, internal capsule, substantia innominata, and a part of hypothalamus. T2-weighted images revealed abnormal findings as follows: high intense area in middle cerebellar peduncle, and low signal intensity of corpus callosum and pontine base. This is the first report about MRI abnormalities in substantia innominata, corpus callosum, and pontine base in a patient with portal-systemic encephalopathy.

[The role of interleukin-6 in Crow-Fukase syndrome].

We measured serum interleukin-6 (IL-6) levels in 14 patients with Crow-Fukase syndrome. Five out of 14 patients with Crow-Fukase syndrome showed high serum IL-6 levels above 10 pg/ml, which was statistically significant in comparison with control subjects with other neurological diseases. Serial studies of serum IL-6 levels in two patients revealed the increase before the exacerbation of clinical symptoms of edema, and pleural or cardiac effusion, and the fall after the treatment by high dose pulsed methylprednisolone. We suggest that serum IL-6 level appears to be a useful marker to predict its exacerbation. Also we performed immunohistochemical study on cutaneous angioma from three Crow-Fukase syndrome patients using anti-IL-6 antibody. The cytoplasm of endothelial cells of cutaneous angioma from two patients was positively stained, which might imply the abnormality of endothelial cells in Crow-Fukase syndrome.

[A case of Crow-Fukase syndrome with increased serum interleukin-6].

We experienced a 47-year-old Japanese female with polyneuropathy, edema, hypertrichosis, hyperpigmentation, and white nail, which were diagnostic as having Crow-Fukase syndrome. Laboratory and radiological evaluation showed neither plasma cell dyscrasia nor monoclonal gammopathy. Increased factor VIII activity and thrombocytosis, which suggested thrombotic tendency, were observed at the exacerbation of clinical symptoms. In her third exacerbation, she presented marked cyanosis in her right foot, and angiography confirmed narrowing of arteries at the ankle. Increased serum interleukin-6 was also observed, and the production of interleukin-6 by endothelial cells of cutaneous angioma was shown. Possible role of interleukin-6 in Crow-Fukase syndrome was discussed.

[The effect of anticholinergic drugs on 123I-IMP SPECT in Parkinson's disease].

Several reports have suggested that anticholinergics have some associations with mental deterioration in Parkinson's disease (PD). We investigated the effect of anticholinergics on regional cerebral uptake of tracer in PD patients using N-isopropyl p-[I-123] iodoamphetamine SPECT. Sixteen pairs of region of interest (ROI) were located in the cortex, a pair in the basal ganglia, thalamus, and cerebellum. The size of each ROI was about 16 mm x 16 mm. Regional cerebral uptake ratio (rCUR) was calculated by the next equation: rCUR = (total count in an ORI)/(mean of total count in the cerebellar ROIs). The comparison consisted of two parts; (1) 7 PD patients (age 59-76 (65.4 +/- 6.7 mean +/- S.D.)) who had been on chronic anticholinergic therapy underwent SPECT and Wechsler Adult Intelligence Scale (WAIS) twice, for the first time when they were on anticholinergics and second a month after discontinuation of anticholinergics. All but two patients performed significantly better on WAIS after discontinuation than when they were on anticholinergics. The improvement was about 10 points in total IQ. (2) 11 PD patients (age 52-79 (64.5 +/- 8.6 mean +/- S.D.)) on chronic anticholinergic therapy including all but two patients mentioned above (group A) and 25 PD patients (age 52-88 (66.7 +/- 9.8 mean +/- S.D.)) not receiving anticholinergics (group B) also underwent SEPCT. In the comparison (1), at all but two ROIs was the mean rCUR higher after discontinuation than when they were on anticholinergics and the difference was significant at 10 ROIs out of 32 ROIs in the cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

[Adult-onset dementia with abundant neurofibrillary tangles resembling progressive supranuclear palsy].

We described an autopsy case of 79-year-old woman with clinically unclassified senile dementia. The patient developed forgetfulness at the age of 73, and later, persecution mania, apathy and episodic stupor, but no extrapyramidal symptoms. Neuropathological examination revealed severe neuronal loss and gliosis of substantia nigra, moderate neuronal loss and marked grumose degeneration of dentate nucleus, and mild astrocytosis of subthalamic nucleus. Abundant neurofibrillary tangles (NFT) were observed in subthalamic nucleus, globus pallidus, substantia nigra, locus ceruleus, tegmentum of brain stem, pontine nucleus, inferior olive, and dentate nucleus. Gallyas silver impregnation method showed a wide distribution of argyrophilic grains and threads in cerebrum, brain stem and cerebellum. Although absence of clinical and neuropathological hallmarks excluded the diagnosis of progressive supranuclear palsy (PSP), the distribution of NFT and argyrophilic grains in this patient resembled PSP.

[High field magnetic resonance imaging in Wilson's disease].

Magnetic resonance imaging studies on 3 cases with Wilson's disease were performed, using high field magnetic resonance system of 1.5 tesla. All patients had neurological findings of tremor, rigidity, dystonia or dysarthria at onset. Two patients had been treated with D-penicillamine for 14 years and 7 years respectively, and one patient was not treated then. T2-weighted images revealed abnormalities of signal intensity in lenticular nucleus, thalamus, pulvinar, superior colliculus, lateral portion of substantia nigra, midbrain and pontine tegmentum, and cerebral and cerebellar white-matter. Especially noted were following three hitherto undescribed abnormalities; high signal intensity of globus pallidus which normally shows very low signal intensity, restoration of signal intensity of lateral portion of substantia nigra, and marked low signal intensity of pulvinar and superior colliculus.

[Crow-Fukase syndrome].

The association of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes forms a characteristic multisystem syndrome, Crow-Fukase syndrome, or acronym POEMS syndrome. The pathogenesis of the syndrome is still unknown. An M component found in more than three quarters of the patients appears not be the direct cause, because no evidence of deposition or interaction was observed in skin, peripheral nerve or endocrine organs with few exceptions. Solitary or multiple bone lesions, or plasmacytoma, are found in more than half of patients with Crow-Fukase syndrome. The nature of abnormal plasma cells of Crow-Fukase syndrome seems to be distinct from that of multiple myeloma. Substances elaborated by plasmacytoma cells are recently postulated as a pathogenesis of the disorder because of the finding that the Crow-Fukase syndrome may regress after resection or irradiation of solitary plasmacytoma, although a definite conclusion awaits further investigations.

New evidence for the occurrence of a glycolipid-mediated signal transduction system.

Gangliosides have attracted particular attention in the field of brain research, since they were found not only to be abundant in neural tissue but also to have intricate structures in synaptic membranes. A murine neuroblastoma cell line, Neuro2a, expresses negligible amounts of GM3 and b-series gangliosides, but significant amounts of a-series gangliosides (GM1 and GD1a). With the transfection of cDNA encoding GD3 synthase, the de novo synthesis and expression of GD3 and b-series gangliosides occurred, and, furthermore, it induced the growth of axon-like neurites and cholinergic differentiation of Neuro2a cells. On the other hand, with the transfection of an alpha 1,2-fucosyltransferase, the axon-like neurite outgrowth was suppressed and dendrite-like neurites were outgrowth. These observations directly demonstrate the primary importance of the gene expression of a glycosyltransferase, and of the subsequent biosynthesis of gangliosides and their expression on the cell surface for neural cell development and differentiation.