No associations between five polymorphisms in COMT gene and migraine.

OBJECTIVES: The pathophysiology of migraine headaches is not clearly understood yet. The dopaminergic system has been hypothesized to be involved in migraine pathogenesis. The aim of this study was to investigate catechol-O-methyltransferase (COMT) polymorphisms and chronic headaches. We analyzed five single nucleotide polymorphisms (SNPs) in COMT. MATERIALS & METHODS: The study population consisted of 71 patients with migraine with aura, 152 patients with migraine without aura, 86 patients with tension-type headache, and 191 healthy controls. The selected polymorphic markers included one causing His62His (rs4633) and two non-synonymous SNPs, Ala72Ser and Val158Met (rs6267, rs4680 respectively). Two other non-polymorphic SNPs (rs6270, rs740602) were examined. RESULTS: We found no significant differences in any genotypes, allele frequencies, or haplotypes among the patient groups and controls. CONCLUSIONS: Our results indicate that the five polymorphisms in COMT have no association with migraineurs in Western Japan. The possibility that segments elsewhere in the gene may contain a mutation responsible for modifying the expression of COMT or the activity of the enzyme is important. We cannot conclusively exclude the entire COMT gene from being involved in migraine pathogenesis.

Epidemiological study of acute encephalitis in Tottori Prefecture, Japan.

BACKGROUND AND PURPOSE: To conduct an epidemiological survey of acute encephalitis focusing on non-herpetic acute limbic encephalitis (NHALE) in Tottori Prefecture, western area of Japan. METHODS: A questionnaire survey on the annual number of patients aged 16 years or more with acute encephalitis from 2001 to 2005 was undertaken in 2006. RESULTS: During the study period, 49 patients were diagnosed with acute encephalitis. The subtype of acute encephalitis was as follows: 10 patients with herpes simplex encephalitis (HSE), 12 patients with NHALE, 4 patients with paraneoplastic encephalitis, 2 patients with encephalitis associated with collagen disease, one patient with viral encephalitis other than HSE, 20 patients with encephalitis with unknown causes. The service-based incidence rate of acute encephalitis was 19.0 per million person-years. The incidence rate of NHALE subtype was 4.7 per million person-years. CONCLUSIONS: Our epidemiological survey indicated an estimated 550 patients would develop NHALE per year in Japan, suggesting that NHALE may not be a rare disorder.

Pramipexole safely replaces ergot dopamine agonists with either rapid or slow switching.

This prospective, open-label, multicentre study examined the efficacy and safety of rapidly (overnight) or slowly (after 2 weeks of concomitant usage) switching patients with Parkinson's disease (PD) from conventional ergot dopamine agonists (DAs) to the non-ergot DA, pramipexole. Fifty-nine early-to-advanced PD patients with motor symptoms that were inadequately controlled by ergot DAs were enrolled. Patients were switched from ergot derivatives to pramipexole and evaluated every 2 weeks for 12 weeks by Hoehn and Yahr staging, Unified Parkinson's Disease Rating Scale (UPDRS) and a modified Epworth Sleepiness Scale (mESS). The UPDRS III subscores and total UPDRS scores significantly improved, independent of switching method. Adverse events, all of which were mild, occurred in 29.2% of patients. No sudden onset of excessive daytime sleepiness or significant worsening in mESS was seen. Switching patients with PD from ergot DA to pramipexole, using either a slow or rapid switching method, appeared to be well tolerated and effective, although further dose adjustment may be necessary in some patients after the switch.

Microarray analysis of differentially expressed fetal genes in placental tissue derived from early and late onset severe pre-eclampsia.

Although it has been well documented that pre-eclampsia is caused by a combination of maternal and fetal susceptibility genes, little is known about the precise etiology of this complicated disorder. To investigate how the expression of fetal genes contributes to the mechanisms underlying the progression of this disease, we have analyzed differentially expressed genes using placentas from 13 normal pregnancies and 14 pregnancies with severe pre-eclampsia. We performed genome-wide expression profiling using high-density oligonucleotide microarrays, followed by validation using real-time PCR. Among the 47,000 genes that were screened in the microarray, 137 genes were found to be differentially expressed between normal and pre-eclamptic tissues. Among these candidates, 70 were up-regulated and 67 were down-regulated. The up-regulated genes included leptin and inhibin A, which are well-known biological markers for pre-eclampsia, as well as FLT1, which was recently proved to be tightly linked with the etiology of this disease. Gene ontology analysis further revealed several biological processes that could be associated with the development of pre-eclampsia, including response to stress, host-pathogen interactions, lipid metabolism, and carbohydrate metabolism. Analyses of biological mechanisms highlighted some important pathways that may be involved in this disorder, such as the TGF-beta and CEBPA-related pathways. Furthermore, when our present subjects were classified as either severe cases of early onset or late onset pre-eclampsia, the expression of 11 genes could be correlated with the severity of this disorder. These genes may therefore prove to be novel biological markers by which the severity of this condition could be predicted. Our data are likely to be a useful future resource in the elucidation of the disease-process and in the identification of novel markers for pre-eclampsia.

Perfusion MR Imaging Using a 3D Pulsed Continuous Arterial Spin-Labeling Method for Acute Cerebral Infarction Classified as Branch Atheromatous Disease Involving the Lenticulostriate Artery Territory.

BACKGROUND AND PURPOSE: Branch atheromatous disease is a stroke subtype considered a risk factor for early neurologic deterioration. Meanwhile, crossed cerebellar diaschisis is thought to be influenced by the degree and location of supratentorial perfusion abnormalities and is associated with the clinical outcome in the case of an ischemic stroke. In this article, our aim was to clarify the utility of using a whole-brain 3D pulsed continuous arterial spin-labeling method as an imaging biomarker for predicting neurologic severity in branch atheromatous disease. MATERIALS AND METHODS: Twenty-three patients with branch atheromatous disease in the lenticulostriate artery territory were enrolled. All patients underwent MR imaging, including DWI, 3D-TOF-MRA, and 3D-arterial spin-labeling. We measured the asymmetry index of CBF in the affected area (branch atheromatous disease), the asymmetry index of the contralateral cerebellar hemisphere (crossed cerebellar diaschisis), and the DWI infarct volume in the lenticulostriate artery territory. We also compared each parameter with the initial NIHSS score with the Pearson correlation coefficient. RESULTS: Among the 23 patients, we found no correlation between NIHSS score and the asymmetry index of CBF in the affected area (branch atheromatous disease) (r = -0.027, P = .724), whereas the asymmetry index of the contralateral cerebellar hemisphere (crossed cerebellar diaschisis) and DWI infarct volumes were significantly correlated with NIHSS score (r = 0.515, P = .012; r = 0.664, P = .001, respectively). CONCLUSIONS: In patients with branch atheromatous disease, 3D-arterial spin-labeling can detect crossed cerebellar diaschisis, which is correlated with the degree of neurologic severity.

Gene expression profile in rat renal isografts from brain dead donors.

BACKGROUND: Brain death (BD) and the subsequent ischemia/reperfusion (I/R) injury have cardinal implications for the pathogenesis of kidney transplantation (Tx). However, the precise mechanistic pathway of BD and the subsequent I/R injury are unknown. In this study, we performed genome-wide analysis for differential gene expression in kidney isografts from BD donors. Their gene expressions were compared with those from living sources. METHODS: Kidneys from BD rats were engrafted and their gene expressions were compared with those from living controls. Donors were intubated, and mechanically ventilated for 6 hours. Grafts were harvested 6 hours after BD, and 1 hour after engraftment. The expression profile of approximately 20,500 genes was analyzed. RESULTS: Gene expression of chemokines (Scya2 and Gro1), cytokines (IL-1 and -6) and adhesion molecules (E- and P-selectin and ICAM-1) were upregulated in the BD kidneys and 1 hour after engraftment. An antiapoptotic gene (Birc2), IkappaB-zeta, and protective gene (HO-1) were also upregulated. Other upregulated genes included oncogenes (lipocalin2, Bcl3, and CCAAT/enhancer binding protein delta), Calgranulin B, DEXRAS1, insulin-like growth factor binding protein-1, inhibin beta-B-subunit gene, IgG Fc receptor, and FK 506 binding protein 5. We also observed downregulation of the genes Amphiphsin, Jagged 1, Pace 4, Slc15a2, Kcnn2, and gap junction membrane channel protein alpha5 only in kidneys from BD donors. CONCLUSIONS: This is the first demonstration of global gene expression analysis using the rat brain-death isograft model. These results provide new insights for the detection of novel target genes for treatment and prognosis of grafts from brain-dead and extended marginal donors.

Plasma homocysteine and MTHFR C677T genotype in levodopa-treated patients with PD.

Plasma homocysteine and cysteine levels were measured in 90 patients with PD with the MTHFR C677T (T/T) genotype. The authors found that the levels of homocysteine-a possible risk factor for vascular disease-were elevated by 60% in levodopa-treated patients with PD, with the most marked elevation occurring in patients with the T/T genotype. Cysteine levels in subjects with PD did not differ from levels in control subjects. In the T/T genotype patients, homocysteine and folate levels were inversely correlated. Increased homocysteine might be related to levodopa, MTHFR genotype, and folate in PD.

Antineuronal antibodies in acute cerebellar ataxia following Epstein-Barr virus infection.

A 29-year-old man developed acute cerebellar ataxia following Epstein-Barr virus infection. Serum IgG and IgM antibodies reacted with both nuclear and cytoplasmic elements of neurons. Western blot revealed IgG binding to the 34- and 29-kd bands and IgM binding to the 44-, 37-, and 29-kd bands. The IgM reactivity gradually reduced. There was no identifiable neoplasm and the ataxia gradually improved. These findings suggest a role for autoimmune mechanisms in the pathogenesis of acute cerebellar ataxia.

A multi-center, double-blind study on slow-release bromocriptine in the treatment of Parkinson's disease.

We report on the clinical efficacy of a slow-release formulation of bromocriptine studied in a multi-center, double-blind trial using standard bromocriptine as the control. We randomly allocated enrolled patients (N = 243) to either the slow-release or normal bromocriptine group. Sixty of them were de novo patients. The maintenance dose of slow-release bromocriptine was 14.2 +/- 0.7 mg/d and that of standard bromocriptine 13.5 +/- 0.7 mg/d (mean +/- SE). The slow-release formulation was taken twice and the standard three times a day. Forty-one percent of the patients treated with the slow-release bromocriptine and 32% of the patients treated with the standard bromocriptine showed moderate or marked improvement in the global improvement rating. There were no serious side effects, and the frequency of vomiting and epigastric discomfort was lower in the patients treated with the slow-release bromocriptine. Clinical efficacies for tremor, rigidity, akinesia, and gait disturbance were comparable between the two drugs tested. The slow-release bromocriptine seems to be a valuable drug for the treatment of Parkinson's disease with less severe side effects than regular bromocriptine.

Association of anti-GM2 antibodies in Guillain-Barré syndrome with acute cytomegalovirus infection.

We examined serum anti-cytomegalovirus (CMV) and anti-ganglioside antibodies by ELISA in 51 patients with Guillain-Barré syndrome (GBS), and titers were compared with those from 47 normal and 74 disease controls. Three GBS patients with IgM anti-CMV antibodies had high titers of IgM and IgG anti-GM2 antibodies. The other GBS patients without IgM anti-CMV antibodies, and the normal and disease controls except one of 6 non-GBS patients with acute CMV infections had no anti-GM2 antibodies. The titers of anti-GM2 antibodies decreased on absorption with CMV-infected cells. These findings suggest that anti-GM2 antibodies are associated with acute CMV infections in GBS patients.

The homozygous C677T mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for migraine.

Increased homocysteine levels are associated with various pathological conditions in humans, including stroke and cardiovascular disorders. Homocysteine acts as an excitatory amino acid in vivo and may influence the threshold of migraine headache. Frosst et al. [1995] reported an association between the homozygous C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and serum homocysteine levels. This study was designed to determine the prevalence of the MTHFR mutation in Japanese patients with migraine and tension-type headache (TH). Seventy-four patients with migraine headaches (22 with aura and 52 without aura), 47 with THs, and 261 normal controls were recruited. Genotyping of MTHFR C677T polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism. We detected that the incidence of the homozygous transition (T/T) in migraine sufferers (20.3%) was significantly higher than that in controls (9.6%). Moreover, the frequency of the T/T genotype in individuals with migraine headaches with aura was remarkably high (40.9%). The MTHFR T allele was more frequent in the migraine group than in the control group. Our results support the conclusion that the MTHFR gene, causing mild hyperhomocysteinemia may be a genetic risk factor for migraine. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:762-764, 2000.

Somatosensory evoked potential recovery in myotonic dystrophy.

OBJECTIVE: To evaluate recovery functions of the sensory cortex using somatosensory evoked potentials (SEPs) elicited by paired stimuli of the median nerve in patients with myotonic dystrophy (MD). SUBJECTS/METHODS: Twelve MD patients were enrolled in the present investigation. Five patients with facioscapulohumeral muscular dystrophy (FSH) and 12 healthy volunteers were studied as control groups. SEP was recorded from the hand sensory area contralateral to the median nerve stimulated at the wrist. Single pulse or paired-pulse stimuli at various interstimulus intervals (ISIs) (10, 20, 40, 60, 80, 100, 150, 200 and 300 ms) were given. Recovery functions of N9, N20onset-N20peak, N20-P25 and P25-N33 components were studied. RESULTS: Conventional SEPs to a single stimulus were normal in the latency and amplitude in all the patients. Recovery functions of both N9 and N20o-N20p components were normal in the patients. In contrast, in MD patients, disinhibited or hyperexcitable recovery pattern was observed in recovery curves of the N20-P25 or P25-N33 components, whereas those were normal in FSH patients. CONCLUSIONS: Disinhibited cortical excitability (or hyperexcitability) is present in the sensory cortex in patients with myotonic dystrophy. This may reflect cortical pathology or functional alteration of the sensory cortex in MD.

Amyloid beta protein deposition in patients with frontotemporal lobar degeneration: relationship to age and apolipoprotein E genotype.

Amyloid beta protein (Abeta) deposition was investigated in the frontal cortex of 54 autopsy cases of frontotemporal lobar degeneration (FTLD) using methenamine silver staining, and immunohistochemistry employing the monoclonal end-specific antibodies BC05 and BA27 to visualize deposits containing Abeta(42(43)) and Abeta(40), respectively. Abeta was detected in 14 (26%) patients, nearly always in the form of diffuse Abeta(42(43)) containing plaques though some cored, neuritic plaques with trace amounts of Abeta(40) were occasionally seen. The 14 patients showing Abeta deposits were significantly older at onset of illness than those 40 patients without Abeta. It was only possible to genotype 46/54 cases, 16 of whom bore at least one copy of the Apolipoprotein E (APOE) epsilon4 allele, giving an allele frequency of 20%. Possession of APOE epsilon4 allele was significantly associated with deposition of Abeta such that 10/16 epsilon4 allele bearers had Abeta deposits. Eight of these ten patients showed only mild to moderate amounts of Abeta, but in two patients, one homozygous and one heterozygous for epsilon4 allele, there was extensive neuritic plaque and neurofibrillary tangle formation. In contrast, only few non-epsilon4 allele bearers (4/30) showed minor Abeta deposits. When stratifying for APOE epsilon4 allele, both bearers and non-bearers of epsilon4 allele with Abeta deposits had a significantly later age at onset than their respective groups without Abeta deposits. We conclude that the likelihood of Abeta deposition, as a secondary and coincidental feature unrelated to the primary pathological process, within the brains of individuals with FTLD will be high if patients have a sufficiently late onset of illness or happen to be a bearer of the APOE epsilon4 allele. Indeed 9/14 patients with Abeta deposits studied here had an onset of illness after 55 years of age and bore APOE epsilon4 allele.

A comparison of tau protein in cerebrospinal fluid between corticobasal degeneration and progressive supranuclear palsy.

Many clinical and pathological discussions have been focused on the difficulty of differential diagnosis between corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) in recent years. This study was conducted to evaluate the usefulness of tau proteins in cerebrospinal fluid (CSF) for the differentiation of these two diseases. Subjects consisted of 10 patients with CBD (four males and six females with a mean age of 67.9+/-5.8 years), 12 patients with PSP (eight males and four females with a mean age of 62.6+/-5.8 years) and 36 control subjects (CTL) (16 males and 20 females with a mean age of 65.8+/-9.9 years). The CBD group included patients with probable CBD, while all the patients in the PSP group satisfied the diagnostic criteria developed by the National Institute of Neurological Disorders and Stroke and Society for PSP (NINDS-SPSP). CSF tau proteins were measured with the sandwich ELISA method (Innogenetics, Belgium). The CSF tau protein level was 320.1+/-86.5 pg/ml in the CBD group, 151.5+/-52.7 pg/ml in the PSP group and 128.7+/-91.7 pg/ml in the CTL group. Significant differences were noted in tau protein levels between the CBD group and both the PSP group (P<0.001) and the CTL group (P<0.005). We suggested that the measurement of CSF tau proteins may be useful for the differentiation between CBD and PSP.

Extrapyramidal system involvement in motor neuron disease.

Three cases of motor neuron disease (MND), in which neuropathological findings were atypical, are reported. The first case manifested widespread and severe degeneration of the spinal cord, as in spinal fibrosis. Case 2 revealed severe degeneration of the pyramidal tract with many spheroids, which made it difficult to differentiate from primary amyotrophic lateral sclerosis. The last case revealed degeneration of the nigro-pallido-luysian system, even though no clinical manifestation of extrapyramidal and/or cerebellar symptoms had been noted throughout the clinical course. In MND, degeneration might occur in various locations other than the motor system.

Kinesin and cytoplasmic dynein in spinal spheroids with motor neuron disease.

Kinesin and cytoplasmic dynein are two major molecular motors responsible for fast axonal transport. As visualized by immunohistochemistry with monoclonal antibodies, both motors were found to be distributed throughout the cell bodies, dendrites and axons of motor neurons in normal human spinal cords. Large axonal swellings, spheroids, in the spinal cords of patients with motor neuron disease showed massive accumulation of kinesin co-localized with highly phosphorylated neurofilaments. Of 114 spheroids in five spinal cords, 87% were stained heavily with the three anti-kinesin antibodies used in this study. Cytoplasmic dynein was scarce or absent in most of the spheroids. These findings suggest that kinesin selectively accumulates in the spheroids of motor neuron axons, causing disturbance of the machinery for anterograde fast axonal transport in motor neuron disease.

Effects of artefacts on scanning laser polarimetry of retinal nerve fibre layer thickness measurement.

AIMS: To investigate the effects of artefacts on scanning laser polarimetry of the retinal nerve fibre layer. METHODS: Six eyes of six normal volunteers and an artificial nerve fibre layer were examined using the nerve fibre analyser II. The retinal nerve fibre layer thickness (RNFLT) was measured in each of four 90 degree quadrants, superior (S), temporal (T), inferior (I), and nasal (N), at 1.5 disc diameters from the disc margin. Study 1: Measurement in normal eyes. The amount of maximum error in RNFLT measurements was investigated as follows: (1) the intensity setting of the laser beam was changed to be as weak as possible or to be as strong as possible; (2) the intentional offsets of the laser beam axis in relation to the pupil were made in four directions; (3) the eye was rotated by shifting the head 45 or 90 degrees; (4) the right eye was measured by moving it to the left eye position on the head rest. Study 2: Measurements on an artificial nerve fibre layer. The birefringence measurements were confirmed with a plastic disc, which has a radial arrangement of birefringence. The plastic disc with black paper was fixed at the right eye position or the left eye position on the head rest. The retardation of the laser beam by the plastic disc on the black paper was measured. The retardation of the plastic disc was checked by an automatic birefringence evaluation system (ABR-10A, Uniopt Co, Ltd, Shizuoka). RESULTS: Study 1: The effects of the rotated eye and the measurement of the opposite eye position were significant. The eyes rotated 90 degrees showed quite a different pattern in which the thicker and thinner locations of the RNFLT are switched. The nasal RNFLT of the baseline and the 90 degree rotated eye are 41.9 (SD 6.0) microm and 122.5 (11.2) microm, respectively (p<0.0001, Scheffe multiple comparison test). Study 2: The uniform retardation of the plastic disc was observed with the ABR-10A. The NFA detects the retardation of the plastic disc which the retardation map showed as a double humped pattern. CONCLUSIONS: Study 2 indicated that the amount of corneal compensation was not small. The cause of significant influences by the rotated eyes and right eyes measurement in left eye position were thought to be incorrect corneal compensation. To increase the diagnostic ability of SLP, an improved compensation of the cornea is thought to be important.

An autopsied case of juvenile parkinsonism and dementia, with a widespread occurrence of Lewy bodies and spheroids.

An autopsied case of juvenile parkinsonism and dementia is described. The patient is a 48-year-old man who had a ten-year history of parkinsonian syndrome and progressive dementia. Neuropathological examination revealed a widespread occurrence of Lewy bodies and spheroids in the central nervous system. Lewy bodies were found not only in the brain stem and diencephalon, but also in the cerebral cortex. Massive numbers of small spheroids were observed in the globus pallidus, substantia nigra, mamillary bodies and hippocampus. Electron microscopical examination showed that most spheroids were composed of degenerative organelles with only a few neurofilaments, and were different from those of Hallervorden-Spatz disease. There was also marked neuronal loss with gliosis in the CA3-4 of the hippocampus. Some neurofibrillary tangles occurred in the hippocampus, subcortical and brain stem nuclei, but senile plaques were absent. This case may represent an atypical form of pure diffuse Lewy body disease.

Anti-Hu antibody in a patient with Lambert-Eaton myasthenic syndrome and early detection of small cell lung cancer.

We report a patient with Lambert-Eaton myasthenic syndrome (LEMS) and anti-Hu antibody, which was an important clue in detecting small cell lung cancer (SCLC) at the early stage. This patient had no symptoms of anti-Hu associated paraneoplastic neurological syndrome. In LEMS patients in whom conventional tests fail to detect malignancy, anti-Hu antibody should be evaluated to diagnose SCLC at the early stage.

Relationships between anti-ganglioside antibodies and clinical characteristics of Guillain-Barré syndrome.

We studied relationships between anti-ganglioside antibodies and the clinical characteristics of Guillain-Barré syndrome (GBS) using multivariate analysis. Serum anti-ganglioside antibodies were measured by enzyme-linked immunosorbent assay (ELISA) in 42 GBS patients and 47 controls. Relationships between antibodies and 15 clinical characteristics were analyzed using a logistic model. Anti-GM1 antibodies were significantly infrequent in patients with objective sensory disturbance (immunoglobulin G (IgG), p < 0.05, odds ratio = 0.094; immunoglobulin M (IgM), p < 0.01, odds ratio = 0.032) and frequent in patients with prodromal diarrhea (IgG, p < 0.05, odds ratio = 5.759; IgM, p < 0.05, odds ratio = 16.28). The combination of anti-GM1 and anti-GD1b antibodies was frequent in patients with prodromal diarrhea (IgG, p < 0.01, odds ratio = 9.667; IgM, p < 0.01, odds ratio = 14.50). IgG anti-GQ1b antibodies were extremely frequent in patients with ophthalmoplegia (p < 0.01, odds ratio = 102.3), and infrequent in patients with objective sensory disturbance (p < 0.05, odds ratio = 0.023).