Journal of the Neurological Sciences

To investigate the cerebral glucose metabolism of subjects who had a Clinical Dementia Rating (CDR) of 0.5, we studied 40 subjects whose CDR was 0.5 and 40 age-matched healthy subjects. Cerebral glucose image of each subject was obtained by [18F]-2-fluoro-deoxy-D-glucose (FDG) positron emission tomography (PET). The anatomically standardized images were produced with NEUROSTAT. Then, the two groups were compared with the Statistical Parametric Mappings (SPM) 99. A comparison with the SPM 99 revealed that relative cerebral glucose metabolism was lower in the posterior cingulate gyri and parietal lobules in the CDR 0.5 group than in the healthy subjects group. These findings are very similar to those in patients with probable Alzheimer's disease (AD) and suggest that the majority of subjects with CDR 0.5 are suffering from very mild AD or at least a prodromal state of AD.

C-C chemokine receptor 2 (CCR2) is one of the key players involved in the transmigration of mononuclear cells into the central nervous system (CNS) and subsequent development of multiple sclerosis (MS). The aim of the current study was to analyse the association of CCR2 +190 G/A (rs1799864) polymorphism with susceptibility to MS and its influence on the age at onset, severity and neurological disability in MS. CCR2 genotyping was carried out by a polymerase chain reaction with restriction fragment length polymorphism (PCR-RFLP) in 301 MS patients and 342 healthy controls. Logistic regression analysis suggested a marginally significant association between MS and rs1799864 A allele (AA+GA vs. GG, P=0.047, OR=1.50, 95% CI=1.00-2.25), however, after stratification of study groups for the presence of HLA-DRB1*15:01 risk allele, this association could be found in HLA-DRB1*15:01-negative individuals only (AA+GA vs. GG, P=0.014, OR=1.84, 95% CI=1.13-2.98). Furthermore, there was no association between CCR2 polymorphism and clinical features of MS. In conclusion, our results suggest that CCR2 +190 G/A polymorphism may increase the susceptibility to MS, but its action seems to be restricted to individuals who do not possess the major risk allele HLA-DRB1*15:01. Copyright © 2015 Elsevier B.V. All rights reserved.

Homocysteine (Hcy) has been recognized as a risk factor for atherosclerosis. White matter hyperintensity (WMH) on MRI has been regarded as a hallmark for cerebral small vascular disease. The study is to investigate the relationship between plasma Hcy level and WMH on a hospital-based cohort of Taiwanese stroke patients. A total of 352 consecutive stroke patients (64.7+/-11.2 years) were included. Severity of WMH was semi-quantitatively evaluated with a scoring system. The top WMH score tertile was defined as severe white matter change (sv-WMH). Associations between Hcy tertile levels and sv-WMH were examined, adjusting for demographics and atherosclerosis risk factors. Subjects in the top Hcy tertile (>10.25 micromol/L) had higher WMH scores and prevalence of sv-WMH than those in the middle and in the bottom tertile. The adjusted odds ratio of having sv-WMH was 2.04 (95% confidence interval 1.20-3.47, p=0.008) for the top Hcy level tertile than for the lower two tertiles combined. Hcy is a risk factor for cerebral white matter lesion in stroke patients. Even mild hyperhomocysteinemia can significantly increase severity of cerebral microangiopathy.

To describe the evolution of imaging characteristics of solitary cerebral cysticercal lesions (SCCL) on serial MRI, and to study the effect of treatment with albendazole. Randomised controlled prospective trial. 123 patients with new-onset seizures and SCCL on contrast MRI were randomised to treatment with albendazole and followed with up to five serial MRIs. 81 patients (M - 41, F - 40) with mean age of 19.6+/-11.7years and 4 or 5 serial MRI were included in the analysis. Analysis was performed on 356 MRI's. Scolex was seen in 61.9% of patients in postcontrast T1 sequence in the first MRI study, and there was a significant drop in visibility from the next scan onwards. Cyst contents were initially T1-hypointense and T2-hyperintense with inversion on FLAIR in 30.8% and later scans showed T2-hypointensity. Cyst wall characteristics changed significantly from initially T2-hypointensity to later hyperintense rim. Initial scan revealed perilesional oedema in 98.5%, which is resolved by the second scan. Around 17.5% showed subtle perilesional T2-hyperintensity in follow-up scans. Enhancement pattern changed significantly from ring to disc, and later to non-enhancement. Initially, 69.7% lesions were in colloid-vesicular stage. Lesions moved through subsequent stages of cyst degeneration: time needed for this process is described. Imaging characteristics, both on the first and on subsequent scans, did not differ between albendazole and control groups. Evolution of SCCL follows a predictable sequence corresponding to morphologic stages described earlier, taking over a year to complete. Contrast enhancement decreases as degeneration progresses, but some calcific lesions continue to enhance. Albendazole therapy may hasten resolution of inflammation around the lesion but affects neither the morphology of the cysticercus nor the process of degeneration and subsequent healing.

Genetic analyses indicate that HLA complex genes can be involved in susceptibility to autoimmune myasthenia gravis (MG). Various HLA alleles serve as genetic elements that either predispose to or protect against MG. This study investigates the probable relationship between HLA-DQ allele polymorphisms and MG cases in northern China. The HLA-DQA1 and DQB1 alleles were determined by polymerase chain reaction/sequence-specific primers (PCR-SSP) in 84 MG patients, and the results were compared to 293 healthy controls. Our findings indicate that DQ A1*0401(P=0.008, OR: 2.5, 95%CI: 1.24-3.07) and B1*0301(P=0.000, OR: 2.29, 95%CI: 1.48-3.54) were the most frequent allele; the frequencies of DQA1*0103(P=0.000, OR:0.24, 95%CI 0.13-0.49) and DQB1*0601(P=0.001, OR:0.40, 95%CI 0.22-0.50) were significantly decreased in MG patients compared with healthy controls. Patients with thymomatous MG were positively associated with DQA1 *0401(P=0.011, OR:4.57, 95% CI 1.40-14.90) and DQB1 *0604 (P=0.001, OR:4.01, 95% CI 1.65-9.73) as compared to MG patients without thymoma. Different genetic mechanisms may exist between MG patients with thymoma and those without thymoma. The HLA-DQ associations in MG subgroups suggest that disease heterogeneity may be influenced by different genes or alleles.

We have studied effects of TRH analogue, TA-0910 (3-methyl-(s)-5,6-dihydroorotyl-L-histidyl-L-prolinamide) (from Tanabe, Osaka, Japan) on explanted ventral and dorsal spinal cord cultures from 13- and 14-day-old rat embryos. TA-0910-treated cultures had significantly increased neurite outgrowth with cultures of ventral spinal cord, but not with cultures of dorsal spinal cord. The effect was dose-dependent. A possible role for TRH in amyotrophic lateral sclerosis remains to be defined.

The effects of the specific dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), were studied on the kinetics of [3H]mazindol binding to striatal membranes of C57 black mice. This radioligand was used to label dopamine uptake sites and when administered in vivo, MPTP caused an irreversible, non-competitive inhibition of mazindol binding, consistent with damage to dopaminergic terminals. This effect was abolished by pretreatment with pargyline, a MAOB inhibitor, suggesting that oxidation of MPTP to the pyridinium moiety, MPP+, is a necessary step for toxicity when mazindol binding is used as an end point. In keeping with these findings, pretreatment of mice with mazindol protected against the dopamine-depleting effects of MPTP in vivo. This data suggests that MPTP exerts its toxic effects via MPP+ which is concentrated intraneuronally via the dopamine uptake system. During this process the neurotoxin irreversibly inactivates the dopamine uptake sites.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a parkinsonian state in monkeys and humans and a marked 3,4-dihydroxyphenylethylamine (dopamine) depletion in mouse striatum. In this study, we found that pretreatment with 3-(10,11,-dihydro-5H-dibenzo-[a,d]-cycloheptan-5-ylidene)-1-ethyl- 2- methylpyrrolidine (piroheptine), an anticholinergic drug which also inhibits dopamine uptake completely prevented loss of striatal dopamine in MPTP-treated mice. Trihexyphenidyl partially protected against the neurotoxicity of MPTP. However, clomipramine, a selective 5-hydroxytryptamine uptake inhibitor, did not prevent the loss of striatal dopamine. Piroheptine is another agent which was found to prevent MPTP neurotoxicity.

When the regional effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on brain dopamine uptake sites in C57 Black mice were studied using [3H]mazindol autoradiography, marked regional differences in effect were seen: the mesolimbic system was less affected than the nigrostriatal tract and within each system the effect was more severe in the terminal fields of the striatum than in the cells of origin. Within the striatum itself there was inhomogeneity of effect, with relative sparing of the dorsomedial aspect compared to the remainder. Complete recovery of [3H]mazindol binding to striatal membranes occurred over 12 months, while dopamine levels recovered more slowly. This supports the concept that MPTP has a highly selective effect within dopaminergic systems and that the initial effect is more pronounced on distal terminals compared to cell bodies. The possibility that recovery of mazindol binding with time may be associated with terminal regrowth needs to be investigated further.

Idiopathic Parkinson's disease (PD) may possibly be caused by one or more unidentified neurotoxins present in the environment, or formed endogenously, which progressively damage dopaminergic nigrostriatal neurons. N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is an experimental neurotoxin which produces biochemical and neuropathological changes in humans, lower primates and mice that closely resemble those found in PD. Because the mechanisms of neuronal damage in both idiopathic PD and in the MPTP model of PD may involve free radical formation in the substantia nigra, antioxidants might protect dopaminergic neurons. Previously, we found that both alpha-tocopherol and beta-carotene partially protected mice against MPTP. However, in the experiments described in this paper, neither alpha-tocopherol nor beta-carotene, each administered in massive doses, had any demonstrable protective effect for dopaminergic nigrostriatal neurons in marmosets injected with low doses of MPTP. Without more knowledge about the identity of the neurotoxin(s) causing idiopathic PD, and their mechanism of action, it is not possible at this time to predict whether these 2 antioxidants might be clinically useful in preventing or ameliorating PD.

Long-term effects of MPTP on striatal dopamine (DA) content and the influence of aging on the recovery were investigated in mice. Male C57BL/6J mice, young (2-month-old) and mature (10-month-old), were used. Two different dosage schedules of MPTP, i.e., 4 doses subcutaneous injections of 20 mg/kg each, and 4 doses subcutaneous injections of 40 mg/kg each, were given to both young and mature mice at 12-h intervals. Assays of striatal DA and 3,4-dihydroxyphenylacetic acid (DOPAC) content were performed 1 week, 1 month, 2 months, and 3 months after the last injection of MPTP. MPTP produced a marked reduction (-75% to -80%) of striatal DA content in both young and mature mice 1 week after the last injection of MPTP. In young mice, the striatal DA content showed a partial recovery in the subsequent stages studied. In contrast, no apparent recovery occurred in mature mice until as long as 3 months after the last injection. The results suggest that mice have a capacity for partial recovery of the striatal DA contents which was depleted by MPTP, and this capacity for recovery appears to be impaired in mature mice.

The right common carotid artery was surgically exposed under general anaesthesia in 6 cynomolgus monkeys and MPTP (0.5-2.2 mg/kg) directly infused. This produced a hemiparkinsonian syndrome in the contralateral limbs which responded to treatment with both levodopa and apomorphine. These drugs also precipitated dose-dependent contralateral rotation which reached a peak 2 weeks after MPTP infusion. A massive depletion of large, presumably dopaminergic cells was found from the ipsilateral substantia nigra pars compacta. Three animals receiving chronic therapy with apomorphine developed choreoathetoid movements of the limbs and the face contralateral to the infusion 2 weeks after the commencement of treatment. The severity of the dyskinesia gradually increased and after 4 weeks peak-dose hemiballistic movements were seen. Levodopa and the selective D-2 and D-1 dopamine agonists LY-171555 and SKF 38393 also reversed parkinsonian features and produced contralateral rotation and peak-dose dyskinesia. This unilateral model of parkinsonism in the primate will be of value in the elucidation of the mechanisms by which chronic levodopa or dopamine agonist therapy enhance involuntary movements in parkinsonism.

Motor function was assessed by use of a swim test in C57 Black mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Thirty minutes after the last MPTP injection significant motor impairment was observed while striatal dopamine was reduced to 13.9% of control levels. At 24 h and 7 days post MPTP injection dopamine levels were still reduced to 17.3% and 26.4% of control values but swimming abilities of the mice were unimpaired. Histofluorescence of catecholaminergic neurons confirmed the presence of catecholamine depletion but showed little evidence of neuronal destruction. The use of MPTP as a non-invasive means of nigrostriatal dopamine depletion in rodents and higher animals allows a re-evaluation of the role of the dopaminergic system in the modulation of movement.

There is an unmet need to develop specific biomarkers for multiple sclerosis (MS) to aid in the diagnosis, improve the management of patients and the monitoring of the effectiveness of treatment. We have screened serum from patients with relapsing-remitting MS (RRMS, n = 107) against a library of glycans on a glycan chip, and have found significantly higher levels of IgM anti-Glc(alpha1,4)Glc(alpha) antibodies (anti-Galpha4Galpha antibodies) than in patients suffering from other neurological diseases (OND, n = 50, p < 0.0001), and other autoimmune diseases (OAD, n = 27, p = 0.02). No significant differences were found relative to patients having primary progressive MS (n = 16). No significant differences were detected between the levels of IgM anti-Galpha4Galpha antibodies in sera from patients with RRMS in relapsing versus remitting state, and in patients treated with immunotherapy versus untreated patients. To test whether the highly significant difference in the levels of IgM anti-Galpha4Galpha between RRMS and OND group is due to general increase in IgM levels, we have measured total serum IgM in a subgroup of 62 MS and 48 OND patients. Although the total IgM was significantly lower in the OND than the RRMS group (p = 0.0007), analysis of covariance (ANCOVA) reveled no statistically significant relationship to the covariate (total IgM). Furthermore, following normalizing the values to total IgM the difference in the levels of IgM anti-Galpha4Galpha between the MS and OND groups was found highly significant (p < < 0.0001). The present findings support further assessment of serum anti-Galpha4Galpha antibodies as a potential biomarker for MS, which may confirm disease diagnosis and aid in its management.

We have investigated inositol 1,4,5-trisphosphate (InsP3) metabolism in cerebellar membranes of normal humans and patients with dominant ataxia ('C' kindred), and also in cerebellar microsomes of Lurcher mutant mouse (a suggested model for cerebellar ataxia). Various [3H]InsP3 metabolites formed were separated by HPLC using 3 successive convex gradients of 1.7 M ammonium formate, pH 3.7. [3H]InsP3 metabolism was rapid and in 15- and 45-day-old control mice cerebella about 50% of [3H]InsP3 was metabolized within 20 s. In 15-day-old Lurcher mice the rate of [3H]InsP3 metabolism was significantly low (40% of normal). [3H]InsP3 metabolism was almost absent in 45-day-old Lurcher mice cerebellar microsomes. The decreased [3H]InsP3 metabolism was consistent with decreased recovery of the various inositol polyphosphates formed. Similarly, in cerebellar membranes of human patients with olivopontocerebellar atrophy (OPCA) a significant decrease in [3H]InsP3 metabolism was observed when compared with normal controls. These data suggest that altered phosphoinositide turnover may be associated with the onset of neuronal degeneration in human OPCA.

Fatiguability is a determining characteristic of different muscle fibre types. An important aspect, indirectly related to fatiguability, gluconeogenesis, was investigated by observing fructose-1,6-diphosphatase (FDP) activity in experimental models prepared in rabbits by cross-reinnervation of the fatigue-resistant m.soleus (postural muscle) and the highly fatiguable m.flexor digitorum longus (fast muscle -- m.fdl). The resultant reprogramming of the m. soleus was associated with greatly intensified FDP activity. Changes in the m.fdl 6-9 months after cross-reinnervation indicated a shift in the opposite direction. The study adds some data on the much neglected state of fatiguability to the otherwise much explored field of alien reinnervation.

A 25-year-old woman with a non-familial congenital nonprogressive myopathy was found to have atypical core-like lesions in type 1 muscle fibers. Typical core lesions (approximately 13 micrometers in diameter) and smaller, PAS positive (4.1 micrometers in diameter) atypical core were associated with a predominant type 1 fibre myopathy. A specific deficiency of fructose 1, 6-diphosphatase was found with normal values for nine other muscle glycolytic and mitochondrial marker enzymes. The data provide evidence for a specific muscle enzyme deficiency in a patient with atypical central core disease.

Post-mortem concentrations of carbamazepine (CBZ) and its anticonvulsive metabolite carbamazepine-10,11-epoxide (CE) were determined in different lesions of the cerebral cortex and in the serum (total and free) from 13 epileptic patients. Twenty cortical specimens were obtained from the superior frontal gyrus, the temporopolar region and the neocerebellum. The cortical samples showed various pathological changes characterized by augmented glial cells, fibre gliosis or ulegyria as well as abundant corpora amylacea or encephalitic signs of viral type besides neuronal depletion. The CBZ and CE concentrations in the 20 cortical lesions were not significantly decreased when compared to the control specimens of 32 epileptic patients without essential histopathological alterations of the specified cortical areas (p < 0.05). A comparable result had been found in our former study on phenytoin (PHT) and phenobarbital (PB). Six patients with cortical lesions of the present series had already been included in this PHT/PB study. Five of these patients revealed unchanged CBZ and CE as well as PHT and PB concentrations. Only in one neocerebellar specimen the CE concentration was just above the upper 95% confidence limit of the control group. But, most probably this finding has no further relevance. The results greatly favour the nonspecific binding of CBZ and CE to cerebral tissue constituents.

The competitive N-methyl-D-aspartate antagonist MDL-100,453 has been shown to attenuate ischemic cell damage when administered after permanent focal cerebral ischemia. The aim of the present study was to measure the dose-response of cerebral infarcted volume to the agent administered 30 min after permanent middle cerebral artery occlusion and to test whether short-term infusion of this drug reduces ischemic cell damage. Thirty-five Sprague-Dawley rats were randomly assigned to 4 groups: low dose group, a bolus of 12.4 mg/kg MDL-100,453 followed by infusion of 31.7 mg/kg/h MDL-100,453; middle and high dose groups, bolus and infusion doses increased to 24.8 mg/kg, 63.3 mg/kg/h and 49.6 mg/kg, 126.7 mg/kg/h, respectively; and control group, saline used for bolus and infusion. Middle cerebral artery occlusion (MCAO) was induced by insertion of intraluminal suture. The infusion was accomplished by a microprocessor controlled pump connected to a jugular vein, which delivered drug or saline over a period of 9 h. Infarct volume was calculated using 2,3,5-triphenyltetrazolium chloride staining 24 h after MCAO. The infarct volumes were significantly reduced in both middle (46%) and high (52%) dose groups compared with the saline group (p < 0.05). No reduction of infarct volume was found in the low dose group. A statistically significant (p < 0.05), but poor inverse correlation existed between the average blood level of MDL-100,453 and infarct volume. We demonstrated that a short-term (9 h) intravenous administration of an appropriate dose of MDL-100,453 beginning 30 min after MCAO significantly reduces ischemic lesion volume at 24 h after onset of permanent focal cerebral ischemia.

1.(1) 1000 intracranial space-occupying lesions (ICSOL) were analysed and compared with other series reported from different parts of the world. Of these 881 were biopsy specimens.2.(2) 252 were from children under 15 years. In contrast to the paediatric neoplasms in Zulch's (1957) series which constitute only 8% of the total, a higher proportion was observed in the present series (16.8% of the neoplasms).3.(3) The average age for all the ICSOL was found to be 27.1 years and for neoplasms 30.9 years, which is nearly a decade lower than that found in Zulch's series.4.(4) 21.5% of all ICSOL and 46.4% of ICSOL in children were tuberculomas. The percentages for all tumour entities were calculated separately for 1000 ICSOL and for 768 neoplasms. On the basis of the total, the percentage for most brain tumours was much lower than the figures given in other series from countries where the incidence of tuberculoma is very low. When the neoplasms alone were considered, the percentages of all tumour entities reached a level comparable to that reported by others. This difference became more evident in paediatric material, where, for instance, the percentage of gliomas went up from 40.1% of total ICSOL to 78.3% of true neoplasms.5.(5) The low average age of ICSOL (27.1 years) was partly due to the inclusion of tuberculomas. They were also responsible for the high proportion (20%) of ICSOL in the first decade. Their presence had raised the proportion of infratentorial lesions from under 33% in neoplasms to over 37% in ICSOL, and had lowered the male preponderance from 67% in neoplasms to 62% in ICSOL.6.(6) 56.5% of all tuberculomas were in females, but in the first decade of life 59% of affected individuals were male; the preponderance of the female sex was manifested from the 2nd decade onwards, especially after puberty.7.(7) The histological features of tuberculoma including those of the rare cystic change and abscess are discussed. Other unusual tuberculous space-occupying lesions are mentioned.8.(8) The presence or absence of a correlation between the incidence of tuberculoma and that of tuberculous meningitis is pointed out.9.(9) The other granulomas (gumma and fungal granuloma), constituting only 0.5% of ICSOL, are described briefly.10.(10) A high incidence (1.2%) of non-neoplastic cysts was noted.11.(11) A comparatively low incidence of meningiomas (13.1% of neoplasms) was observed, but parenchymal vasoformative tumours seemed proportionately high (5.1% of neoplasms).12.(12) The gliomas, Schwannomas, pituitary adenomas and congenital tumours which constituted 48.2%, 9.9%, 8.7% and 7.7% of neoplasms respectively, were comparable to those in other series.13.(13) Unusual skull tumours constituted 0.65% of all neoplasms.14.(14) When the autopsy specimens alone (119) were considered, the metastatic lesions formed about 11%, while of the entire series they comprised only 5.2%.

In our continuing pathological analysis of 1000 intracranial space-occupying lesions (ICSOL), Part 4 deals with 118 additional lesions falling into 3 categories.Sixty-seven pituitary adenomas included 60 of the chromophobe variety, and 7 of the eosinophil variety: the latter patients were of significantly younger age and all had acromegaly. Malignant and haemorrhagic forms of the former tumour type are stressed.Forty tumours of developmental origin included 14 craniopharyngiomas, 12 chordomas, 11 epidermoids and 3 pineal atypical teratomas; 9 of these were in children, mainly the craniopharyngiomas. Intra-sellar and cystic forms of this tumour are stressed. The different locations and histological variations of the chordoma, especially chondroid and pseudochondroid features and malignant transformation within the general framework of a mucinous cell tumour are stressed. This is contrasted with the constant histological composition of the intracranial epidermoid in different situations. The high incidence of these 2 unusual tumours in our material remains unexplained. The two-celled character and mosaicism of the pineal atypical teratoma are stressed.Eleven unusual non-neoplastic cysts, 3 parasitic and 8 possibly developmental, are presented as unusual ICSOL. The former included 2 hydatid cysts and 1 intraventricular cyst probably due to the rarer Coenurus cerebralis.The 8 “developmental” cysts are described and discussed in some detail, in an age group extending from 5 months to 46 years. Six of these appeared to be congenital arachnoid cysts, as evidenced by the history and histology, and were found in both supra- and infra-tentorial locations. Another appeared to be truly porencephalic with an ependymal component. The eighth was an intracerebellar non-neoplastic glial cyst of dubious origin.

Two hundred and twenty-five tumours, of our original series of 1000 intracranial space-occupying lesions (ICSOL), are presented with emphasis on their histological features. They consisted of A: 47 vascular tumours and hamartomas, B: 100 meningiomas and C: 78 cranial nerve-sheath tumours.The lowest average age (26 years) was seen in cases of group A tumours, and the highest average age (40 years) in cases of group B tumours.Of the 17 hamartomas, 5 were cerebellar including 1 in a 3-month-old infant. They consisted of capillary haemangiomas (9) and venous angiomas (8). Five of the former were of the small capillary type, 3 of the large cavernous variety, and 1 showed slight endothelial proliferation.Of the 18 haemangioblastomas, all with a typical structure of vacuolated cells, 17 were cerebellar and 1 was cerebral.Of the 7 intracranial haemangiopericytomas, 1 showed angiomatous areas in addition to the typical neoplastic component. This consisted of elongated ill-defined cells with fusiform nuclei around newly-formed vascular channels with an intact endothelial lining, and with vascular and pericellular reticulin. Three of the 7 showed endotheliomatous areas as well, all these having an attachment to the dura.The 3 haemangioendotheliomas were intracerebral and were characterized histologically by greater cellular and nuclear pleomorphism than the haemangiopericytomas and by a break in the integrity of the lining of their proliferated capillaries (intraluminal growth).The 2 “vascular sarcomas” showed bizarre cellular proliferation and evidence of malignancy around newly-formed vascular channels.The angioblastic meningiomas (8) of the second group, when considered along with the “tumours” of the first group, constituted a higher proportion (5.5%) of all ICSOL than reported in any other series. The histological hall-mark of this type of meningioma was an extreme pleomorphism of cell and nucleus around newly-formed blood vessels, at least in parts of the tumour.The 12 fibroblastic (not merely fibrous) meningiomas included 1 intraventricular tumour in a 2-year-old boy. Nine of the meningiomas were infratentorial, including 7 of the 70 of transitional type.All 76 Schwannomas were of the acoustic nerve. In 1 unusual case of neurofibrosarcoma, the primary tumour appeared to arise from the fifth nerve with multiple dural and pulmonary metastases.The 1 case of von Recklinghausen's disease, with a history of 23 years, showed intracranial and spinal Schwannomas and meningiomas of various types.

1.(1) In continuation of our first paper (Dasturet al. 1968) on the overall analysis of 1000 intracranial space-occupying lesions, this paper analyses in detail 370 gliomas which constituted 37.1% of the former but 48.2% of the 768 true neoplasms in this series. The average age for gliomas was 27 years, much younger than that of any reported series.2.(2) Astrocytomas comprise 60.5% of gliomas. They have been classified into grades I, II, III and IV according to the degree of cellular anaplasia (Kernohan's method). Benign astrocytomas (grades I and II together) comprise 39.3% and the malignant (grades III and IV together) 60.7%. The average age for the former was 26 years, for the latter 35 years, and for the whole group 31.5 years.3.(3) Of the total number of gliomas 27.3% (101) occurred in children under 15 years of age, a figure comparable with Japanese data but much higher than the figures reported from the West. Of these 41.5% were astrocytomas, of which nearly 70% were benign in contrast to 39% in the total material. Similarly, while two-thirds of all the total gliomas were supratentorial, two-thirds of the gliomas in childhood were infratentorial. Cerebellar astrocytoma was mainly responsible for these two features.4.(4) Vascular and perivascular changes in astrocytomas were stressed and a case of combined astrocytoma and vascular sarcoma is described. The youngest age at onset (4 years) and longest survival (4 years) were observed in a boy with malignant astrocytoma.5.(5) Ependymomas constituted the second most frequent type of glial tumour in both our total (14%) and paediatric (24%) material, being comparable to the incidence in Japan; but the proportion of our fourth ventricular ependymomas in children was higher than in Japan, and much higher than in any Western series.6.(6) The medulloblastomas, almost equalling the proportion of ependymomas among children, were divided into the 3 histological subtypes of classical (49%), transitional (24%) and desmoplastic (27%) tumours. There was no significant age difference between the former, and the latter which was characterised by hemispheric location, surface extension and profuse reticulin in the fibroblastic part of the tumour. The histogenesis of the medulloblastoma is discussed.7.(7) The optic nerve gliomas and neuro-hypophyseal gliomas were characterised by a common pattern of piloid astrocytoma. The former were all seen in children. The 4 latter constituted an unusually large proportion (1.1%) and occurred at all ages, and 1 of them showed excessive Rosenthal bodies.8.(8) Four of the 7 pineal tumours appeared gliomatous with the pattern either of a pineocytoma or pineoblastoma. They are not very frequent tumours, thus contrasting with the findings in Japan.9.(9) The choroid plexus papilloma also appears to be a tumour of childhood. One case with anaplastic change is described.10.(10) Two cases of ganglioglioma were found. Both were seen in children, and were slow-growing, with astrocytic elements predominating. One case showed oligodendroglia and calcospherites.11.(11) A most unusual medullo-epithelioma with a rich fibrovascular stroma is described.12.(12) The effect of X-irradiation on a glioma is demonstrated through an unusual case of olfactory neuroblastoma which showed extensions into the frontal lobes and the naso-pharynx. An ependymoma operated on four times is also described to show the lack of cellular and nuclear outline which may result from irradiation.13.(13) Cerebral reticulosis with its typical large mononuclear cells and cellular reticulin is demonstrated through the oldest case of our series, a man aged 76 years.

Cyclooxygenase-2 (COX-2) was reported to be induced in the infarcted human brain. Spreading depression (SD) is thought to play a role in this induction. In this study, we correlated the expression of SD-associated genes with COX-2 production in brains after SD. Rats were divided into 3 groups: rats that did not undergo SD (group I saline controls, n=7), rats that underwent unilateral SD as a result of KCl application (group II, n=9), and rats that were pretreated with the selective COX-2 inhibitor, JTE-522 3 h before the induction of SD (group III, n=7). The expression of the SD-associated genes, S-100A9, and mitogen-activated proteinkinase phosphatase (cpg21) was analyzed 2 h later using a cDNA array. In group II, COX-2 and cpg21 mRNA expression, as determined by RT-PCR, were significantly upregulated in the hemisphere undergoing SD. While the expression of S-100A9 mRNA was bilaterally upregulated in these animals, this expression was significantly reduced in group III, and was accompanied by reduced bilateral production of PGE(2). Thus, the bilateral induction of expression of the S-100A9 gene in response to SD was associated with COX-2 activation.

We prospectively examined the effect of arundic acid (AA; ONO-2506) on S-100beta, an astrocyte-derived protein, in a phase I acute stroke study. Subjects with acute ischemic stroke were randomized to daily infusion of AA or placebo for 7 days. Serum S-100beta levels were assayed pre-infusion on Days 1-7 and post-infusion on Days 1, 3, and 7, and correlated with National Institutes of Health Stroke Scale (NIHSS). Samples were obtained from 86 subjects (46 AA, 40 placebo). Increase in S-100beta protein level from baseline was less in the AA cohort than in the placebo cohort at 7 (p=0.0471; t-test) and 12 (p=0.0095)-hours post-infusion on Day 3. Baseline NIHSS correlated with maximal S-100beta levels between Days 1 and 3 in the AA (r=0.51; p=0.0003) and placebo (r=0.41; p=0.0084) cohorts and in the pooled aggregate (n=86; r=0.46; p<0.0001). The same correlations were observed between Day 10 NIHSS and Day 1-3 maximum serum S-100beta levels. Treatment with AA was associated with lower serum levels of S-100beta after acute ischemic stroke. Our results showing correlation between S-100beta and NIHSS indicate that this protein is a clinically relevant marker of neurological deficit in acute stroke.

The resolution of an intracerebral hemorrhage can be measured by the occurrence of hemosiderin. Extravasation of blood elicits a cellular reaction in the adjacent surviving tissue where the lesion activates resident microglia and attracts many more phagocytes from the blood stream. The signals for this migration into the perifocal reactive zone are not fully understood but it is likely that proteins in the coagulated blood contribute to cellular activation. In order to study the role of plasma proteins in the pathogenesis of the perifocal reactive zone, intracerebral injections of either autologous whole blood (0.1 ml) or an equal volume of washed autologous red blood cells (RBC) in lactated Ringer's solution were made in adult rabbits. The amount of total iron was the same (30 micrograms). The cellular responses to the injections were studied by iron histochemistry and immunocytochemistry for ferritin, the ferritin repressor protein (FRP), the glial fibrillary acidic protein (GFAP), and the complement receptor CR3. Experimental hematomas resolved much more slowly after the injection of whole blood than after the injection of RBC. Qualitative microglial and astrocytic responses were quite similar. However, at 48 h, iron- and ferritin-reactive microglia were more numerous following the injection of whole blood. After injections of either type, ferritin-immunoreactive cells were more abundant than iron-positive cells. This observation implied that the biosynthesis of holoferritin protein and iron incorporation proceeded independently. Expression of CR3 on the surface of microglia was much more prominent after whole blood, suggesting a role of inactivated complement 3b in the attraction of additional phagocytes. Conversion to hemosiderin began at 5 days after the injection of either blood or RBC. The lesions caused initial destruction of astrocytes in the perifocal zone as judged by GFAP- and FRP-immunoreactivity. However, at 5 days, astrocytic processes reentered the perifocal zone and intermingled with microglia and macrophages. It is proposed that this contact between astrocytes and microglia reversed the uncoupling of ferritin biosynthesis and iron incorporation and initiated the storage of iron and formation of hemosiderin.

Previous studies assessing the magnetic resonance imaging (MRI) correlates of cognitive dysfunction in multiple sclerosis (MS) achieved conflicting results. Diffusion tensor (DT)-MRI provides metrics that are sensitive to the macro- and microscopic MS lesion load with increased specificity to the more destructive aspects of MS pathology than conventional imaging. We performed an exploratory study to assess the magnitude of the correlation between quantities derived from DT-MRI and measures of cognitive impairment in patients with relapsing-remitting (RR) MS.T2, T1, DT-MRI scans of the brain and an extensive battery of neuropsychological tests (exploring language, complex reasoning, attention and memory) were obtained from 34 RRMS patients. We measured T2 and T1 lesion volumes (LV) and brain volume. Average lesion mean diffusivity (D) and fractional anisotropy (FA) were calculated. D and FA histograms from the brain tissue (BT), the normal-appearing brain tissue (NABT), the normal-appearing white matter (NAWM) and the normal-appearing gray matter (NAGM) were also obtained. Nine patients (26.5%) were found to be cognitively impaired. Moderate correlations were found between symbol digit modalities test, verbal fluency test and 10/36 spatial recall test scores and T2 LV, T1 LV and average lesion, WBT, NABT, NAWM and NAGM values (r values ranging from -0.30 to -0.53). No correlations were found between any of the neuropsychological test scores and brain volume, average lesion FA and WBT FA.DT-MRI provides quantitative metrics that seem to reflect the severity of language, attention and memory deficits in patients with RRMS. This study also suggests that the extent and the intrinsic nature of the macroscopic lesions as well as the damage of the NAWM and NAGM all contribute to the neuropsychological deficits of RRMS patients.

Tumor-related seizures are a well-known presenting symptom of primary brain tumors, particularly low-grade gliomas (LGGs). The objective of the present study was to investigate the possible correlation between tumor-related seizures and molecular genetic profile in Chinese patients with LGGs. A series of 103 LGGs, including 27 oligodendrogliomas, 41 oligoastrocytomas and 35 astrocytomas, was analyzed by denaturing high-performance liquid chromatography (DHPLC) for 1p and 19q status, with particular emphasis on correlations with tumor-related seizures. Most oligodendrogliomas and oligoastrocytomas had LOH 1p and LOH 19q, which were rarely seen in combination in astrocytomas (p<0.001). LOH 1p and LOH 19q were also closely associated (p=0.022). The majority of patients with LGGs presented with seizures at disease onset (68.9% of all patients). The most common seizure type was secondary generalized seizures (81.7% of patients with seizures). Patients without LOH 19q were more likely to present with seizures (p=0.033), particularly secondary generalized seizures (p=0.005), than those with this alteration. The current study presented an update on studies on tumor-related seizures and molecular genetic profile, and brought forward putative candidate genes for secondary generalized seizures on chromosome 19q, based on the assumption that common molecular genetic pathways may exist for glioma development and tumor-related seizures.

The formation of focal granular enlargements within axons (axonal spheroids or "torpedoes"; neuroaxonal dystrophy) is a well known phenomenon occurring in a variety of neurological diseases. The relative susceptibility of different types of neurons to this kind of axonal pathology, however, is largely unknown. An immunocytochemical study directed at localizing glutamic acid decarboxylase (GAD), the synthetic enzyme for the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), in various CNS regions in feline models of lysosomal storage disorders has revealed vast numbers of axonal spheroids containing this enzyme. In some storage diseases (GM1 and GM2 gangliosidosis), GAD-immunoreactive spheroids were a common occurrence in many brain regions, whereas in other disorders these structures were more limited in distribution (alpha-mannosidosis), or were absent (mucopolysaccharidosis type I). Axonal spheroids unreactive for GAD were encountered in large numbers in subcortical white matter in GM2 gangliosidosis, but were infrequently observed in the other diseases. The incidence and distribution of GAD-immunoreactive spheroids in the various diseases under study were found to correlate closely with the type and degree of neurological deficits exhibited by affected animals. This study indicates that the neuroaxonal dystrophy occurring in some types of storage disorders commonly involves axons of GABAergic neurons and suggests that a resulting defect in neurotransmission in inhibitory circuits may be an important factor underlying brain dysfunction in this family of diseases.

The subject of our studies included 105 muscles from 31 cases; all cases had been subjected to detailed electromyographic examination before death, and histological studies could be made on the whole of the muscles and the spinal cords corresponding to them at autopsy. Histochemical methods were not applied. The diagnostic significance of EMG and muscle biopsy was investigated by making a comparison between the findings obtained by EMG and histological findings in muscles and spinal cords. The results are as follows: 1.(1) All 25 muscles that were histologically found to contain groups of small fibres showed neurogenic changes in the EMG. However, among the muscles showing neurogenic changes in the EMG, some had no distinctly discernible groups of small fibres and contained only muscle fibres of different sizes, or scattered small fibres. These pathological findings in muscle could also be interpreted as neurogenic because the anterior horn cells of the corresponding spinal segments showed some morbid changes.2.(2) In a considerable number of the muscles having groups of small fibres, the groups were localized in small areas of the muscle bellies, and therefore, they might quite easily have been missed on sampling by muscle biopsy.3.(3) The wider the range of the groups of small fibres, the more marked the decrease in the number of action potentials in maximum contractions, and the more grave was the muscular wasting, clinically.4.(4) All the anterior horns of the spinal cords corresponding to the muscles with neurogenic changes, both in the EMG and in the histopathology, presented some abnormal findings in serial sections.5.(5) Degeneration of isolated muscle fibres, if scattered, had little influence on the EMG, and myopathic changes were not revealed by the EMG until muscle fibre degeneration had become diffuse in the muscle atrophy due to disuse or ageing.

The time-course of degeneration/regeneration was investigated in leg muscles throughout the life of the mdx mutant mouse, which is a biochemical homologue of Duchenne muscular dystrophy (DMD). In young and adult mice (up to 52 weeks old), muscle fibre necrosis was compensated by a vigorous regeneration, but in old mdx mice (65-104 weeks) this regeneration slightly declined, while the necrotic process persisted. Body and muscles weights declined strikingly after 52 weeks. Life span of mdx mutants was reduced in comparison with the control C57BL/10 animals. Immunostaining of old mdx muscles showed clusters of dystrophin-positive fibres. Muscle fibres in old mdx mice showed great variation in size, many being atrophied or split. Endomysial fibrosis became increasingly conspicuous, and there was some accumulation of adipose tissue. These progressive degenerative changes of old mdx mice resemble those found in DMD and imply that basic pathological similarities between the murine and human diseases previously observed in diaphragm of mdx mice may be extended to other skeletal muscles.

Citicoline (CDP-choline or cytidine 5'-diphosphocholine) has been used as a therapeutic agent in combination with levodopa in the treatment of Parkinson's disease (PD). The present study examines the effects of citicoline by using validated in vivo and in vitro models. Citicoline reduces the cytotoxic effect of 6-hydroxydopamine (6-OHDA)-treated human dopaminergic SH-SY5Y neuroblastoma cells as measured cellular redox activity with 3-[4.5-dimethylthiazol-2-yl]-2.5-diphenyltetrazolium bromide (MTT) and increases the levels of reduced glutathione (GSH), a major antioxidant agent. Moreover, citicoline (500 mg/kg i.p.) administered for 7 days ameliorates functional behaviour by significantly reducing the number of apomorphine-induced contralateral rotations in 6-OHDA rats. Finally, citicoline significantly attenuates substantia nigra (SN) dopaminergic cell dropout and tyrosine hydroxylase immunoreactivity in the ipsilateral striatum in rats injected intrastriatally with 6-hydroxydopamine (6-OHDA).

A case was reported of variant Gerstmann-Sträussler-Scheinker disease (GSS) carrying codon 105 mutation (Pro to Leu) with codon 129 polymorphism (Met/Val) of the prion protein (PrP) gene. The male patient had developed clumsiness of the right hand at age 42, and subsequently exhibited slowly progressive spastic paraparesis, ataxia, dysarthria, memory disturbance and apraxia. Myoclonus or periodic synchronous discharge was not observed. He died at age 53. The cerebral cortex and white matter showed atrophy, which was prominent in the frontal regions. There were numerous amyloid plaques throughout the cerebral cortex, which were reactive with the antibody to PrP, but not to beta/A 4 peptide. PrP immunostaining also revealed many amorphous deposits in the deep cortical layers, where neuronal loss and glial proliferation was evident. The cerebellum was almost intact, except a few amyloid plaques in the white matter. This variant GSS with codon 105 mutation has been found in four pedigrees, only in Japan up to the present, and the clinicopathological phenotype is summarized as follows: (1) onset at age 38-48, with a duration of 7-11 years, (2) prominent spastic paraparesis, associated with dementia and ataxia, (3) numerous amyloid plaques in the cerebral cortex, (4) amorphous PrP deposits with neuronal loss in the deep cortical layers, and (5) minor change of cerebellum.

One hundred and five (105) cases of muscle weakness were reviewed in order to evaluate the reliability of clinical diagnosis, quantitative EMG, and muscle histochemistry in neuromuscular disorders. Patients were grouped into 3 categories: group I, disorders which could be diagnosed by clinical observation alone (38 patients); group II, disorders in which the EMG and biopsy were necessary for delineation (63 patients); disorders in which it was not possible to make a diagnosis because the clinical and laboratory studies were contradictory (4 patients). In group I, only one patient showed an inconsistency between clinical and laboratory data. In group II, the EMG and biopsy were concordant in all but 4 cases of Kugelberg-Welander syndrome with neuropathic EMG and myopathic biopsy. In group III, 4 patients had a myopathic EMG and neuropathic biopsy.The overall concordance of EMG and histochemistry was greater than 90%. The laboratory studies also discerned 2 different categories of disease, “neuropathic” and “myopathic”. The consistency in EMG and histochemistry correlation suggests that a true division between neuropathic and myopathic disorders exists.

A 70-year-old Japanese man with amyloid polyneuropathy associated with a Val 107 transthyretin (TTR) mutation is reported. The patient presented with carpal tunnel syndrome, cardiomyopathy, bulbar palsy, dysphonia and polyneuropathy. DNA analysis of the TTR gene revealed a point mutation responsible for substitution of valine for isoleucine at position 107 of the TTR molecule. Taken together with reports of patients with the same TTR variant, Val 107 TTR mutation is probably associated with a clinical phenotype characterized by carpal tunnel syndrome, cardiomyopathy, bulbar palsy and dysphonia. This case implies a worldwide distribution of the Val 107 TTR mutation with a common clinical phenotype, despite different ethnic background.

The -1082G/A polymorphism in IL-10 gene has been extensively investigated for association to Alzheimer's disease (AD), however, results of different studies have been inconsistent. The objective of this study is to assess the relationship of IL-10 -1082G/A polymorphism and AD risk by using meta-analysis. All eligible case-control studies were searched in Pubmed and Embase. Odds ratios (OR) with the 95% confidence intervals (CI) were used to assess the association. A total of 2158 cases and 2088 controls in 12 case-control studies were included. The results indicated that the A allele carriers (AA+AG) had a 27% increased risk of AD, when compared with the homozygote GG (OR=1.27, 95%CI=1.02-1.58 for AA+AG vs. GG). In the subgroup analysis by ethnicity, significant elevated risks were associated with A allele carriers in Europeans (OR=1.27 and 95%CI=1.01-1.59 for AA+AG vs. GG), but not in Asians (OR=1.37 and 95%CI=0.32-5.88 for AA+AG vs. GG). This meta-analysis suggested that the -1082G/A polymorphism of IL-10 gene would be a risk factor for AD. To further evaluate gene-to-gene and gene-to-environmental interactions between polymorphisms of IL-10 gene and AD risk, more studies with large groups of patients are required.

The temporal evolution and spatial distribution of ischemic cell injury was investigated after transient middle cerebral artery (MCA) occlusion. Male Wistar rats (n = 61) were subjected to 2 h of MCA occlusion induced by advancing a nylon monofilament into the right internal carotid artery. Animals were killed after different durations of reperfusion, ranging from 4 to 166 h (n = 6-11 for each group). Neuronal injury and astrocytic reaction were evaluated using hematoxylin and eosin (H & E) and glial fibrillary acidic protein (GFAP) immunohistochemistry, respectively. Eosinophilic neurons were detected at 4 h of reperfusion in the basal ganglia, and at 10 h of reperfusion in the cortex. Focal brain infarct developed by 46 h of reperfusion, both in the cortex and the basal ganglia, and the volume remained constant between 46 and 166 h of reperfusion. Significant differences in astrocytic reaction were detected between the lesion and the periphery of the lesion at reperfusion times from 46 to 166 h; GFAP staining decreased in the core of the lesion and increased in the peripheral areas. Our data suggest that, after 2 h of MCA occlusion, brain tissue progresses from isolated neuronal injury to infarct with a time course dependent on anatomical site; and astrocytic reactivity, expressed by GFAP staining, reflects the outcome of the ischemic injury.

Ciliary neurotrophic factor (CNTF), a multipoietic factor, on a variety of neurons, prevents axotomy-induced motoneuron loss and can improve the outcome of murine motor neuron disease (MND). We carried out a study to determine whether other cytokines rescue spinal motoneurons from axotomy-induced cell death. Unilateral sciatic nerve was transected in neonatal rats. Two doses of recombinant murine cholinergic differentiation factor/leukemia inhibitory factor (CDF/LIF), recombinant rat CNTF, recombinant human granulocyte-colony stimulating factor (G-CSF), recombinant human interleukin-6 (IL-6), recombinant human tumor necrosis factor beta (TNF beta), or vehicle were administered daily for 2 weeks by intraperitoneal injection. After treatment, the number of spinal motoneurons was determined at the level of L4-5 segments. In comparison with vehicle, the higher doses of CDF/LIF, CNTF, and IL-6, and the lower doses of CDF/LIF and IL-6 significantly retarded the loss of motoneurons. G-CSF and TNF beta failed to inhibit motoneuron death. CDF/LIF and IL-6 rescued motoneurons from the retrograde death following axotomy, in a similar manner to CNTF. These results provide evidence that several cytokines may have therapeutic potential in human axonopathy or MND.

To describe residual disability 10years after onset of Guillain-Barré syndrome (GBS) and longitudinal changes from 2weeks after onset until 10years afterwards. The Erasmus GBS Outcome score (EGOS) was applied for predicting prognosis at 2 and 10years. Twenty-nine patients, mean age at onset 49years, were followed prospectively from 2weeks to 10years after GBS onset. Measures included; GBS disability score, EGOS, Barthel Index, Frenchay Activity Index, Sickness Impact Profile (SIP), Overall Neuropathy Limitations Scale (ONLS), Walk-12, and Fatigue Severity Scale. At 10years, the facial paralysis found in 5 participants at 2years was still present, 11 participants (38%) experienced paresthesia, 6 (21%) had limitations in their arms, and 15 (52%) had limitations in walking. Decreased health-related quality of life on comparison to the general population was seen in the physical dimension of SIP at 10years. The median EGOS at 2weeks was 4.5, which correlated highly only with the Barthel Index at 2years and the ONLS arm scale at 10years. The residual disabilities at 1-2years comprised mainly of reduced walking ability, and are still persistent 10years after GBS onset. For some individuals, facial paralysis caused major disability. The EGOS only partly predicted residual disability at 2 and 10years after onset.

Five percent of incident patients with MND in Scotland 1989-1990 had a family history of this disease. This paper assesses the demographic and clinical features of this group.

Machado-Joseph disease (MJD), or hereditary spinocerebellar ataxia type 3, is the most common dominantly inherited ataxia. However, lower urinary tract (LUT) dysfunction in MJD has not been fully delineated. We investigated LUT dysfunction in MJD by clinical-urodynamic observations. In 24 genetically diagnosed MJD, we recruited all 11 patients with LUT symptoms (six men, five women; age, 18-61 [mean 48] years; disease duration, 2-24 [mean 9] years; voiding difficulty, 7, urinary incontinence, 4). Urodynamic studies consisted of uroflowmetry, measurement of post-void residuals and electromyography (EMG)-cystometry. Neurophysiology tests consisted of motor unit potential (MUP) analysis of the sphincter and extremity muscles, tibial nerve somatosensory evoked potentials (SEP) and nerve conduction studies (NCS) of the extremities. Urodynamic abnormalities were seen in all 11 patients studied. Maximum or average flow rate was decreased in five. Post-void residual was noted in three but residual urine volume > 100 ml was noted in only one patient. Maximum urethral closure pressure was low in one and high in one of five patients studied. EMG-cystometry during filling showed detrusor overactivity in five, impaired bladder sensation in four, low compliance detrusor in one, uninhibited sphincter relaxation in one and incompetent urethra in one. Voiding phase abnormalities included detrusor areflexia in three and detrusor-sphincter dyssynergia in two. Bethanechol supersensitivity of the bladder was noted in one of three patients studied. Bulbocavernosus reflex was absent in two of five patients studied. MUP analysis showed neurogenic changes in six of nine sphincter muscles and in all six extremity muscles studied. Five patients had prolonged or absent cortical response in SEP and four had sensory axonal neuropathy in NCS, which were relevant to the impaired bladder sensation. In the present study, a half of MJD patients had LUT symptoms and they showed various urodynamic abnormalities. Detrusor overactivity, impaired bladder sensation, and neurogenic sphincter EMG were common findings, and large post-void residuals were rare. These findings are relevant to central and peripheral nervous system pathology of MJD.

Glioma is the most common and lethal primary brain tumors, and is regarded as one of the deadliest of human cancers. To date, a growing number of studies have tested the diagnostic accuracy of microRNAs (miRNAs) in glioma detection and altered levels of characteristic miRNAs have also been identified in glioma. However, there are some conflicting conclusions. Thus, we conducted this meta-analysis to evaluate the overall accuracy of miRNAs in the diagnosis of glioma. A comprehensive literature search was conducted using a combination of keywords. The random effect model was used to calculate the pooled diagnostic parameters. The summary receiver operator characteristic (SROC) curves were plotted to assess the overall diagnostic performance of miRNAs. Subgroup and sensitivity analyses were conducted to analyze the potential sources of heterogeneity. In total, 28 studies from 11 articles covering 1729 patients and 1491 controls were available in this meta-analysis. The pooled sensitivity, specificity, PLR, NLR, DOR, and AUC were 0.87 (95% CI: 0.83-0.91), 0.87 (95% CI: 0.81-0.91), 6.6 (95% CI: 4.5-9.6), 0.15 (95% CI: 0.10-0.21), 45 (95% CI: 23-90), and 0.93 (95% CI: 0.91-0.95), respectively. Subgroup analysis demonstrated that panels of multiple miRNAs could largely improve the diagnostic accuracy. An independent meta-analysis of five included studies was conducted to evaluate the diagnostic efficacy of miR-21 in patients with glioma, with a pooled sensitivity of 0.82, specificity of 0.94, PLR of 13.2, NLR of 0.19, DOR of 69 and AUC of 0.95. This meta-analysis indicated the great potential of miRNAs, especially panels of multiple miRNAs, as promising biomarkers in glioma detection and monitoring. As one of the most representative miRNAs, we also found that a single miR-21 could be a powerful clinical biomarker in glioma diagnosis. Copyright © 2014 Elsevier B.V. All rights reserved.

To use deuterium-substituted [11C](L)-deprenyl PET to depict astrocytosis in vivo in patients with amyotrophic lateral sclerosis (ALS). In human brain, the enzyme MAO-B is primarily located in astrocytes. L-deprenyl binds to MAO-B and autoradiography with 3H-L-deprenyl has been used to map astrocytosis in vitro. Motor neuron loss in ALS is accompanied by astrocytosis and astrocytes may play an active role in the neurodegenerative process. Deuterium-substituted [11C](L)-deprenyl PET provides an opportunity to localize astrocytosis in vivo in the brain of patients with ALS. Deuterium-substituted [11C](L)-deprenyl PET was performed in seven patients with ALS and seven healthy control subjects. Increased uptake rate of [11C](L)-deprenyl was demonstrated in ALS in pons and white matter. This study provides evidence that astrocytosis may be detected in vivo in ALS by the use of deuterium-substituted [11C](L)-deprenyl PET though further studies are needed to determine whether deuterium-substituted [11C](L)-deprenyl binding tracks disease progression and reflects astrocytosis.

The best technical approach to rat middle cerebral artery occlusion (MCAO) using a nylon-monofilament suture remains unsettled, regarding the usefulness of coated or uncoated sutures. Three investigators with different degrees of experience: A, well skilled; B, 2 years of experience; C, a novice with 6 months of experience, each subjected 10 Sprague-Dawley rats to permanent MCAO using low-viscosity silicone-coated sutures with a mean diameter 0.468+/-0.013 mm (mean+/-S.D.) at the tip and 0.361+/-0.013 mm in the body. Post-mortem corrected infarct size 24 h after MCAO was similar among the three investigators: A, 204.7+/-33.2 mm3; B, 212.6+/-42.8, and C, 195.9+/-44.4. The coefficient of variation was 16.2% to 22.7%, and 19.4% for the three investigators. This study suggests that experimental stroke with silicone-coated sutures (Koizumi's method) provides good reproducibility and reliability, among investigators of varying experience.

Although there is increasing evidence for microglial activation after an ischaemic stroke in the infarct core and the peri-infarct region, the "evolution" of the process in stroke patients is poorly known. Using PET and [((11))C]vinpocetine, we measured the regional changes of TSPO in the brain of nine ischaemic stroke patients up to 14weeks after the insult. Already a week after stroke there was an increased radioligand uptake, indicating the up-regulation of TSPO and the presence of activated microglia, in both the ischaemic core and the peri-infarct zone. This increased activation showed a steady decrease with post stroke time. The proportion between %SUV values in the peri-infarct zone and the ischaemic core increased with time. There were no time-dependent TSPO activity changes in other regions, not affected directly by the stroke. The present observations demonstrate that increased regional microglia activation, as a consequence of stroke, can be visualised with PET, using the TSPO molecular imaging biomarker [((11))C]vinpocetine. The evolution of this microglial activation shows a time dependent decrease the gradient of which is different between the peri-infarct zone and the ischaemic core. The findings indicate an increased microglial activation in the peri-stroke region for several weeks after the insult.

We herein report a 12-year-old girl with a basal ganglia germinoma who presented with right-sided hemiparesis after a minor head trauma. Magnetic resonance (MR) imaging revealed a minimally enhanced lesion involving the left putamen, thalamus, and corona radiata. The lesion showed low-signal intensity on T1-, and high intensity on T2- and diffusion-weighted imaging. The MR signal in the adjacent globus pallidum was also low on T2-weighted imaging. MR spectroscopy on the lesion showed a large lactate/lipid/macromolecule peak with a decreased NAA/Cr ratio, but no increase in the Cho/Cr ratio. However, posttraumatic infarction at the territory of lateral lenticulostriate artery was ruled out 1 month later. This was based on progression of the hemiparesis and neuroimaging results, including an increased Cho/Cr ratio and weak uptake on (11)C-methionine positron emission tomography of the basal ganglia lesion. Stereotaxic brain biopsy confirmed the diagnosis of germinoma.

Global aphasia without hemiparesis (GAWH) is a rare stroke syndrome. This study localized the lesion and examined the pathogenic mechanism in Korean patients with GAWH, and investigated whether areas of extensive hypoperfusion existed outside the diffusion-weighted imaging (DWI) lesions seen in these patients. Eleven patients were diagnosed with aphasia using the Western Aphasia Battery. To identify decreased perfusion, which might be functionally relevant to aphasia but not detected by DWI, single photon emission tomography (SPECT) was performed in five patients. To uncover the possible pathogenic mechanisms of ischemic stroke, vascular and cardiologic work-ups were performed in all of the patients. The lesions seen on DWI varied, and included both inferior frontal and superior temporal (three), isolated inferior frontal (four) or superior temporal (one), subcortical (two), and even parieto-occipital (one) lesions. Brain SPECT did not reveal an extensive lesion of the peri-sylvian area outside the DWI lesion in any of the patients, except one with the subcortical lesions. Our results indicate that a single lesion in different locations may be sufficient to produce GAWH, and the lesion profile and stroke mechanism in GAWH are heterogeneous, suggesting that lesions to an area of complex functional anatomy result in aphasia.

Cerebral gliomas may cause a reduction of glucose metabolism in the cerebellum contralateral to the tumor side (crossed cerebellar diaschisis, CCD). We investigated whether CCD is related to tumor localization, histological grade, size and tumor biochemistry. Cerebellar glucose metabolism was measured in 44 glioma patients and 15 healthy subjects using positron emission tomography and [18F]fluorodeoxyglucose (FDG). CCD was determined by calculating an asymmetry index of cerebellar glucose metabolism. Further, the tumor uptake of FDG and [11C]methionine (MET) was also assessed, and was expressed as ratio of normalized tracer uptake in tumor over contralateral cortex (T/C). Frontal lobe tumors were associated with highest CCD values. For these tumors, CCD was higher in malignant (-11.8+/-9.9%) than in low-grade (-4.3+/-4.1%) gliomas (P=0.010). In addition, frontal lobe tumors showed increasing CCD values with increasing size. In tumors of the parietal or temporal lobe, CCD was less marked or absent. T/C ratios of tumor tracer uptake were higher in malignant than in low-grade gliomas, but were not correlated with CCD. Our data indicate that the magnitude of CCD is mainly determined by tumor localization and size, the latter being associated with tumor grade. These findings raise the question whether CCD provides a measure of expansion or progression particularly in low-grade tumors of the frontal lobe.