Search

Background and purposeWe previously reported the usefulness of iodine-123 metaiodobenzylguanidine (123I-MIBG) myocardial scintigraphy for differentiation of dementia with Lewy bodies (DLB) from Alzheimer’s disease (AD) in a cross-sectional multicentre study. The aim of this study was, by using reassessed diagnosis after 3-year follow-up, to evaluate the diagnostic accuracy of 123I-MIBG scintigraphy in differentiation of probable DLB from probable AD.MethodsWe undertook 3-year follow-up of 133 patients with probable or possible DLB or probable AD who had undergone 123I-MIBG myocardial scintigraphy at baseline. An independent consensus panel made final diagnosis at 3-year follow-up. Based on the final diagnosis, we re-evaluated the diagnostic accuracy of 123I-MIBG scintigraphy performed at baseline.ResultsSixty-five patients completed 3-year follow-up assessment. The final diagnoses were probable DLB (n=30), possible DLB (n=3) and probably AD (n=31), and depression (n=1). With a receiver operating characteristic curve analysis of heart-to-mediastinum (H/M) ratios for differentiating probable DLB from probable AD, the sensitivity/specificity were 0.77/0.94 for early images using 2.51 as the threshold of early H/M ratio, and 0.77/0.97 for delayed images using 2.20 as the threshold of delayed H/M ratio. Five of six patients who were diagnosed with possible DLB at baseline and with probable DLB at follow-up had low H/M ratio at baseline.ConclusionsOur follow-up study confirmed high correlation between abnormal cardiac sympathetic activity evaluated with 123I-MIBG myocardial scintigraphy at baseline and the clinical diagnosis of probable DLB at 3-year follow-up. Its diagnostic usefulness in early stage of DLB was suggested.Trial registration numberUMIN00003419.

Background In Japan, selegiline has been approved for combination therapy with levodopa for Parkinson disease (PD). We conducted a trial of selegiline monotherapy for early PD. Methods In this 12-week controlled phase III trial, a total of 292 subjects were randomized to receive placebo (n = 146) (full analysis set 140) or selegiline (n = 146) (full analysis set 139). The primary outcome measure was the change in the Unified Parkinson Disease Rating Scale part I + II + III total score from baseline to the final visit. Other secondary measures and a safety profile were evaluated. Results Selegiline monotherapy reduced the primary outcome measure by -6.26 ± 7.86 compared with the placebo -3.14 ± 6.98 (mean ± SD, P = 0.0005 by analysis of covariance). There was no significant difference in the number of adverse events between the 2 groups (P > 0.05). Conclusions Selegiline monotherapy reduced the total Unified Parkinson Disease Rating Scale part I + II + III score and was well tolerated in Japanese patients with early PD.

OBJECTIVES The aim of this open-label study was to investigate the long-term safety and efficacy of selegiline as monotherapy in Japanese patients with early Parkinson disease (PD). METHODS We conducted a 56-week prospective study in patients with early PD (N = 134) who had previously completed the randomized, double-blind, placebo-controlled phase III trial of selegiline monotherapy for 12 weeks. In the present study, dosing was titrated from 2.5 to 10 mg/d in increments of 2.5 mg/d for 2 weeks. From the seventh week, the dosage was maintained at 10 mg/d until week 56. The primary outcome was any change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score (part I + II + III) from baseline. Secondary outcomes, including changes in the UPDRS subscores and safety profile, were also evaluated. RESULTS Ninety-one (67.9%) patients completed the 56-week study. Treatment with selegiline significantly reduced total UPDRS score from week 4 (mean ± SD, -2.62 ± 3.83; P < 0.0001) to week 56 (-3.39 ± 9.27; P < 0.01). The peak effect was seen at week 20 (-5.79 ± 5.57; P < 0.0001). In addition, we found similar improvements in the UPDRS parts II and III scores. The incidence rate of adverse drug reactions was 44.3% (58 patients) and did not increase during the period of 10 mg selegiline administration. CONCLUSIONS Long-term monotherapy with selegiline (10 mg/d) was effective and well tolerated in patients with early PD in this 56-week study.

Summary Background Identification of causative genes in mendelian forms of Parkinson's disease is valuable for understanding the cause of the disease. We did genetic studies in a Japanese family with autosomal dominant Parkinson's disease to identify novel causative genes. Methods We did a genome-wide linkage analysis on eight affected and five unaffected individuals from a family with autosomal dominant Parkinson's disease (family A). Subsequently, we did exome sequencing on three patients and whole-genome sequencing on one patient in family A. Variants were validated by Sanger sequencing in samples from patients with autosomal dominant Parkinson's disease, patients with sporadic Parkinson's disease, and controls. Participants were identified from the DNA bank of the Comprehensive Genetic Study on Parkinson's Disease and Related Disorders (Juntendo University School of Medicine, Tokyo, Japan) and were classified according to clinical information obtained by neurologists. Splicing abnormalities of CHCHD2 mutants were analysed in SH-SY5Y cells. We used the Fisher's exact test to calculate the significance of allele frequencies between patients with sporadic Parkinson's disease and unaffected controls, and we calculated odds ratios and 95% CIs of minor alleles. Findings We identified a missense mutation ( CHCHD2 , 182C>T, Thr61Ile) in family A by next-generation sequencing. We obtained samples from a further 340 index patients with autosomal dominant Parkinson's disease, 517 patients with sporadic Parkinson's disease, and 559 controls. Three CHCHD2 mutations in four of 341 index cases from independent families with autosomal dominant Parkinson's disease were detected by CHCHD2 mutation screening: 182C>T (Thr61Ile), 434G>A (Arg145Gln), and 300+5G>A. Two single nucleotide variants (−9T>G and 5C>T) in CHCHD2 were confirmed to have different frequencies between sporadic Parkinson's disease and controls, with odds ratios of 2·51 (95% CI 1·48–4·24; p=0·0004) and 4·69 (1·59–13·83, p=0·0025), respectively. One single nucleotide polymorphism (rs816411) was found in CHCHD2 from a previously reported genome-wide association study; however, there was no significant difference in its frequency between patients with Parkinson's disease and controls in a previously reported genome-wide association study (odds ratio 1·17, 95% CI 0·96–1·19; p=0·22). In SH-SY5Y cells, the 300+5G>A mutation but not the other two mutations caused exon 2 skipping. Interpretation CHCHD2 mutations are associated with, and might be a cause of, autosomal dominant Parkinson's disease. Further genetic studies in other populations are needed to confirm the pathogenicity of CHCHD2 mutations in autosomal dominant Parkinson's disease and susceptibility for sporadic Parkinson's disease, and further functional studies are needed to understand how mutant CHCHD2 might play a part in the pathophysiology of Parkinson's disease. Funding Japan Society for the Promotion of Science; Japanese Ministry of Education, Culture, Sports, Science and Technology; Japanese Ministry of Health, Labour and Welfare; Takeda Scientific Foundation; Cell Science Research Foundation; and Nakajima Foundation.

Background: Clinical features, pathogenesis, and treatment of Parkinson's disease (PD) are reviewed as there has been progress in these areas. Summary: PD is a systemic disease of the nervous system as the initial symptom is related to disturbance of the autonomic nervous system, such as constipation or nocturia. Then, the disease progresses to the brain stem involving the nuclei in the pons and the substantia nigra, and inducing sleep and wakefulness disturbances, affect problems such as anxiety and depression, and motor problems when the disease process has reached the substantia nigra. Furthermore, the disease has an effect on the nucleus basalis of Meynert, the amygdaloid complex and the cerebrum manifesting cognitive impairment. The olfactory pathway is also frequently involved. Key Messages: For the treatment of PD, younger patients without dementia should be treated with a nonergot dopamine agonist first and then with levodopa if necessary. Elderly patients or those with dementia should be treated with levodopa. However, after 5 years of levodopa treatment, many patients with PD develop wearing off. Drugs for the treatment of wearing-off symptoms are reviewed. Many of the patients with wearing-off symptoms develop dyskinesia, and amantadine is so far the only drug that can ameliorate dyskinesia. Because of this situation, a new method of treatment is warranted, such as RNA interaction, according to the author's opinion. Recent progress in this field is also reviewed. i 2014 S. Karger AG, Basel

Rotigotine, a non-ergot dopamine receptor agonist, offers potential for continuous dopaminergic stimulation that could avoid the fluctuations observed with traditional treatments. We conducted a randomized, double-blind, placebo-controlled trial in Japanese patients with advanced Parkinson’s disease (PD) to investigate the efficacy and safety of rotigotine. Inclusion criteria included the presence of motor complications, such as wearing off, on–off, delayed-on/no-on, any circumstances that could interfere with levodopa dose escalation because of side effects, or declining levodopa efficacy. The enrolled patients received once-daily applications of rotigotine transdermal patches or matched placebo patches. A total of 174 patients were randomly assigned to rotigotine (87 patients) or placebo (87 patients). The full analysis set included 172 patients (86 for the rotigotine group and 86 for the placebo group). The maximum maintenance dose of rotigotine was set at 16 mg/24 h. The changes in unified PD rating scale Part III scores from baseline to the end of the trial were −10.1 ± 9.0 (mean ± standard deviation) in the rotigotine group and −4.4 ± 7.4 in the placebo group (p < 0.001). There was a significantly greater reduction in the off-time (p = 0.014) in the rotigotine group. Rotigotine was well tolerated, with serious adverse events being reported in only three patients in each group. Rotigotine at doses of up to 16 mg/24 h is efficacious and safe in Japanese patients with advanced PD.

Background We conducted a randomized, double-blind, placebo-controlled trial to determine the safety and efficacy of transdermal rotigotine at doses up to 16 mg/24 hours in patients with early stage Parkinson's disease (PD) in Japan. Methods Patients received once-daily rotigotine 2 to 16 mg/24 hours (mean dose, 12.8 mg/24 hours; n = 82) or placebo (n = 90) for 12 weeks. The primary endpoint was the change in Unified Parkinson's Disease Rating Scale (UPDRS) part II (activities of daily living) and part III (motor function) scores from baseline to the end of treatment. Results The mean (± standard deviation) changes in UPDRS part II and III scores were −8.4 ± 9.7 in the rotigotine group and −4.1 ± 8.2 in the placebo group and were significantly different (P = 0.002). More patients in the rotigotine group than in the placebo group had a ≥20% score reduction. No serious drug-related adverse events were reported. Conclusions Rotigotine at doses up to 16 mg/24 hours was well tolerated and improved function in patients with early stage PD. © 2013 International Parkinson and Movement Disorder Society

Long-term levodopa treatment causes motor complications such as wearing-off and dyskinesias in Parkinson’s disease (PD).1 Various therapeutic approaches have been developed to overcome these difficulties while maintaining adequate therapeutic levodopa levels. However, the complications and dopaminergic side effects of long-term levodopa treatment are not yet fully resolved.2 Istradefylline, a selective adenosine A2A receptor antagonist, is considered nondopaminergic because of the lack of effects on dopamine receptors and dopamine-metabolizing enzymes. Istradefylline is a new antiparkinsonian drug that can be added as a new treatment option to current PD therapy.3,4 In experimental parkinsonian animals, istradefylline, when used in combination with levodopa, exhibits an additive effect on motor control without worsening levodopa-induced dyskinesia.6–9 All10–14 but 115 of the previous studies showed a significant decrease in OFF time. A phase 2b Japanese study showed reduction in daily OFF time16; it is the purpose of this study to confirm our previous results.

Background We report neuropathologic findings in a patient with homozygous deletions of exons 2 to 4 of parkin. Results Although the absence of Lewy bodies has been considered a neuropathologic characteristic of parkin mutation, here we report a pathologic finding with the presence of Lewy bodies. Methods The patient was a 72-year-old woman with onset of the disease at age 61. Her autopsy revealed marked decrease in melanized neurons in the substantia nigra and the locus coeruleus. Lewy bodies were found in the substantia nigra, the locus coeruleus, the dorsal motor nucleus of the vagus, the basal nucleus of Meynert, the amygdaloid nucleus, and the sympathetic nerve bundles in the myocardium. Conclusions Only 3 previous case reports described Lewy body formation in patients carrying parkin mutations. The distribution of Lewy bodies in our patient appeared to be reminiscent of sporadic Parkinson's disease. © 2013 Movement Disorder Society

Early-onset Parkinson’s disease (PD) denotes onset of the disease below the age of 40 years. Patients tend to have a slower disease progression, an increased rate of dystonia, an increased rate of dyskinesias in response to L-3,4-dihydroxyphenylalanine and a lower rate of dementia compared with those in late-onset PD. Early-onset PD patients may experience more social and psychosocial conflict compared with late-onset patients and these factors would contribute to greater impairment of quality of life. Unemployment due to disability or early retirement may be causes for these conflicts. We have to take these factors into account whenever we institute drug therapy in early-onset PD. There is no randomized controlled study on early-onset PD; however, we may make a reasonable decision by considering the data on PD in general and clinical characteristics of early-onset patients. The management of motor and non-motor symptoms of early-onset PD patients is reviewed here.

The objectives of this study were to evaluate the efficacy of istradefylline at an oral dose of 20 mg or 40 mg once daily for 12 weeks in Parkinson's disease (PD) patients with motor complications on levodopa therapy based on the change in the daily OFF time compared with placebo and to assess the safety at these doses. A total of 363 subjects were randomly assigned to receive 20 mg/day istradefylline (n = 119), 40 mg/day istradefylline (n = 125), or placebo (n = 119). The primary outcome variable was the change from baseline at endpoint in daily OFF time based on patients' ON/OFF diaries. At endpoint, the daily OFF time reduced from baseline by 1.31 hours for 20 mg/day istradefylline (P = 0.013 as compared to the placebo), 1.58 hours for 40 mg/day istradefylline (P < 0.001), and 0.66 hours for placebo; istradefylline significantly reduced the daily OFF time compared with placebo. The UPDRS Part III subscale score (ON state) reduced by 5.7 at endpoint in both istradefylline groups and 3.7 in the placebo group (P = 0.006 for 20 mg/day and P = 0.006 for 40 mg/day group as compared with placebo). The most commonly reported drug-related treatment emergent adverse event (TEAE) was dyskinesia, which occurred in 2.5% (3/119) of subjects receiving placebo, 8.5% (10/118) receiving 20 mg/day istradefylline, and 6.4% (8/125) receiving 40 mg/day istradefylline. We conclude that istradefylline at 20 mg and 40 mg once daily is effective in relieving wearing-off fluctuations of PD patients. In addition, istradefylline was well tolerated at both doses.

SNCA duplication is a recognized cause of familial Parkinson's disease (PD). We aimed to explore the genetic and clinical variability in the disease manifestation. Molecular characterization was performed using real-time PCR, SNP arrays, and haplotype analysis. We further studied those patients who were found to harbor SNCA duplication with olfactory function tests, polysomnography, and PET. We identified four new families and one sporadic patient with SNCA duplication. Eleven symptomatic patients from these four families presented with parkinsonism, of which three subsequently developed dementia. The lifetime estimate of overall penetrance was 43.8%. FDG-PET study of symptomatic patients showed hypometabolism in the occipital lobe, whereas asymptomatic carriers of SNCA duplication demonstrated normal glucose metabolism. Symptomatic patients showed abnormal olfactory function and polysomnography and asymptomatic carriers showed normal results. The clinical features of SNCA duplication include parkinsonism with or without dementia. Asymptomatic carriers displayed normal test results with the eldest individual aged 79 years; thus, even a carrier of SNCA duplication may escape the development of PD. This difference in age-associated penetrance may be due to the genetic background or environmental exposures. Further studies of SNCA duplication carriers will help identify disease-modifiers and may open novel avenues for future treatment.

Dropped head syndrome (DHS) associated with parkinsonism is not frequent, but it markedly reduces the activities of daily living and is refractory. To elucidate the mechanism and treatment of DHS associated with parkinsonism, we assessed 28 parkinsonian patients with DHS (2 men and 26 women) by examining their clinical features and cervical-muscle-needle and surface electromyographic (EMG) recordings. We also evaluated the effects of lidocaine, muscle afferent block (MAB; 1% lidocaine mixed with ethanol), and botulinum toxin injected into the bilateral sternocleidomastoid muscles (SCMs), which were considered to be the affected muscles. In some patients, DHS occurred after the initiation or loading of dopamine agonists (less common after pergolide than cabergoline and pramipexole). Improvement was noted after a reduction in the dopamine agonist dose in some patients, and loading of l-dopa in others. Needle EMG revealed no evidence for weakness of the dorsal neck muscles. Surface EMG showed a gradual increase in SCMs activity upon passive head lifting. Lidocaine injection into SCMs markedly improved DHS, but the effect was temporary. The effect of botulinum toxin and MAB was not satisfactory. Whereas DHS could have a heterogeneous etiology, dopamine receptor sensitivity may play a role in its pathogenesis. For the treatment of DHS in parkinsonian patients, an increase in the dosage of l-dopa and a decrease in that of the dopamine agonist should be considered. Lidocaine injection (lidocaine test) could be useful for determining the most affected muscle before using botulinum toxin or MAB. Further studies are needed to examine the outcome of such treatments that include GPi-DBS.

To investigate the frequency of cardiac valve regurgitation related with low dose dopamine agonists in patients with Parkinson's disease (PD), echocardiograms were analyzed in 527 consecutive PD patients (448 patients treated with dopamine agonists, 79 patients never treated with dopamine agonists as age-matched controls). The frequency of mild or above mild regurgitation of the aortic valve (AR) was significantly higher in the cabergoline group (13.7%, P < 0.05) compared with the controls (2.5%). Odds ratio adjusted by age and sex for AR was significantly higher in the cabergoline group (OR, 6.45; 95% CI, 1.46-28.60; P = 0.01): odds ratio was significantly higher in patients treated with higher daily doses (OR, 14.41; 95% CI, 3.08-67.38; P = 0.0007) and higher cumulative doses (OR, 15.29; 95% CI, 3.19-73.18; P = 0.0006). No statistical difference was identified in the frequency of the tricuspid and mitral regurgitation. None of the other dopamine agonist groups including pergolide gave higher frequency or higher odds ratio compared with the controls. None of our patients showed severe regurgitation or was operated for valvular heart disease. The question as to whether or not longer duration of low dose dopamine agonist treatment would yield the same results needs further studies.

There is evidence that α-synuclein gene ( SNCA ) point mutations and gene multiplications play a pivotal role in the development of Lewy bodies (LBs) and Lewy neuritic (LN) pathology. Dysregulation of the production/degradation of the α-synuclein protein, a major component of LBs and LNs, is speculated to result in its accumulation and produce the neuropathological features of SNCA -related neurodegeneration.1 The identification of SNCA multiplications in families with parkinsonism suggests that SNCA gene dosage may play a role in the onset of Parkinson disease (PD).2 Most patients with SNCA triplication develop cognitive and autonomic dysfunction in early stage of the disease.3,4 However, three families with SNCA duplication have been reported with symptoms more reminiscent of typical PD.5,6 Interestingly, a recent study reported that one triplication (a Swedish-American pedigree) and one duplication pedigree have a common ancestor.7 As a common mechanism of multiplications, the area including the SNCA-MMRN1 locus could play a role in multiple copy numbers. Another multiplication family has been reported also to have the rearrangement change in the same region indicating the SNCA-MMRN1 locus may be fragile.2,5–7 With regard to clinical aspects, patients with SNCA duplication tend to have milder symptoms compared to those with triplication.5–7 The onset of disease in SNCA duplication patients occurs approximately 15 years later (50 years of age) than that of SNCA triplication families (35 years of age). These features suggest that differences in genetic copy numbers could influence the clinical features of PD. Recently, we identified two families of Japanese origin with SNCA duplications.8 One patient from Family B (named as B-1) developed severe parkinsonism and dementia. These findings indicate that SNCA duplication also causes PD with dementia (PDD). Three copies of the locus SNCA-MMRN1 were identified in the two duplication families. The length of …

This article reviews the current situation regarding the treatment of Parkinson's disease (PD). How to apply the various therapeutic options to treat PD appears to be internationally agreed, but the currently available treatment methods are said to be all symptomatic ones. However, some of these may have marginal disease modifying effects. In addition, there are many investigational interventions aiming at modification of the disease processes; some of these interesting strategies are reviewed here. Regarding the currently available drugs, dopamine agonists may delay the loss of dopamine transporters in the striatum and even L-dopa may have some neuroprotective effects. Monoamine oxidase B inhibitors and coenzyme Q10 may also be disease modifying. Recently, a more systemic approach to finding disease modifying drugs has been initiated in the United States which has revealed that creatine and minocycline might have a small disease modifying effect. Although the disease modifying effect of each drug is small, eventually it may be possible to find more potent drugs for PD using this approach. Another important issue is to exchange specialists' “know-how” on the management of various problems arising from long-term L-dopa treatment such as disabling dyskinesia. Although it has not been proven by controlled clinical trials, giving small amounts of liquid L-dopa in frequent doses may be helpful in reducing the severity of dyskinesia and wearing off phenomenon.

Objectives Istradefylline is a selective adenosine A2A receptor antagonist. We evaluated the safety and efficacy of istradefylline administered once daily for 52 weeks in Parkinson disease (PD) patients experiencing wearing-off symptoms on levodopa therapy. Methods This was a phase 3, multicenter, open-label, long-term study in PD patients experiencing wearing-off who had previously completed a double-blind placebo-controlled clinical study of istradefylline in Japan. Istradefylline was administered for 52 weeks at a starting dosage of 20 mg/d, with or without dosage adjustment up to 40 mg/d. Safety was assessed using the incidence of treatment-emergent adverse events, and efficacy was assessed as the change in the daily off time. Results A total of 308 patients were included in this study. The most frequently reported treatment-emergent adverse events were nasopharyngitis (24.4%) and dyskinesia (21.4%). The mean change in the daily off time from day 1 was -0.65 hour in week 2, fluctuating between -0.71 and -0.04 hour until week 52 in patients who had previously taken placebo in the preceding double-blind study. The off time reduction from baseline of the double-blind study remained at similar levels between weeks 2 and 52 in patients who had previously taken istradefylline 20 and 40 mg/d in the preceding double-blind study. Conclusions This study showed that istradefylline treatment was well tolerated and produced a sustained reduction in off time in levodopa-treated PD patients over a 52-week period.

We report on a male patient with Pick disease who had shown severe white matter atrophy and dilatation of the lateral ventricle in the frontal lobe from an early stage. Upon admission to our hospital 2 years after disease onset, the patient showed apathy, and MRI revealed severe atrophy of the cortex and white matter of the frontal lobe. He died at age 74, 11 years after disease onset. Autopsy revealed severe atrophy of the frontal and temporal lobes, severe loss of white matter in the frontal lobe, dilatation of the lateral ventricles, and cortical thinning. Histopathological examination showed severe loss of myelinated fibers in the frontal white matter and severe neuronal loss with gliosis in the frontal and temporal cortices. Many Pick bodies were seen. Our patient had a rare case of Pick disease predominantly affecting the frontal lobe with severe involvement of the white matter from an early stage. This case suggests that myelinated fibers in the white matter as well as cerebral neurons are primarily affected in Pick disease.

Although seizures have been described in hypocalcemia, myoclonus has been rarely reported. We report the first case of a patient with hypocalcemic cortical myoclonus due to hypoparathyroidism following a previous thyroidectomy. The patient was an 84-year-old woman who presented with multifocal myoclonus, which was predominant in the upper extremities, neck, jaw, and facial muscles. Electrophysiological studies revealed enlarged somatosensory evoked potentials, cortical reflexes evoked by peripheral nerve stimulation, and a cerebral potential preceding myoclonic jerks determined by jerk-locked averaging. All these findings were consistent with cortical myoclonus. The myoclonic state disappeared as serum calcium level became normal. Hypocalcemia should be considered in patients who had had a thyroidectomy, even if it was performed more than 10 years previously.

This study was designed to investigate the neuroprotective effect of intrinsic and extrinsic erythropoietin (EPO) against hypoxia/ischemia, and determine the optimal time-window with respect to the EPO-induced neuroprotection. Experiments were conducted using primary mixed neuronal/astrocytic cultures and neuron-rich cultures. Hypoxia (2%) induces hypoxia-inducible factor-1alpha (HIF-1alpha) activity followed by strong EPO expression in mixed cultures and weak expression in neuron-rich cultures as documented by both western blot and RT-PCR. Immunoreactive EPO was strongly detected in astrocytes, whereas EPOR was only detected in neurons. Neurons were significantly damaged in neuron-rich cultures but were distinctly rescued in mixed cultures. Application of recombinant human EPO (rhEPO) (0.1 U/mL) within 6 h before or after hypoxia significantly increased neuronal survival compared with no rhEPO treatment. Application of rhEPO after onset of reoxygenation achieved the maximal neuronal protection against ischemia/reperfusion injury (6 h hypoxia followed 24 h reoxygenation). Our results indicate that HIF-1alpha induces EPO gene released by astrocytes and acts as an essential mediator of neuroprotection, prove the protective role of intrinsic astrocytic-neuronal signaling pathway in hypoxic/ischemic injury and demonstrate an optimal therapeutic time-window of extrinsic rhEPO in ischemia/reperfusion injury in vitro. The results point to the potential beneficial effects of HIF-1alpha and EPO for the possible treatment of stroke.

Background : The purpose of this study was to assess the prevalence of impaired glucose tolerance (IGT) and insulin resistance in stroke patients without previously known diabetes by performing a 75g oral glucose tolerance test (75g OGTT).Methods : We recruited 203 stroke patients (atherothrombotic infarction (ATI) ; 42.2%, lacunar infarction (LI) ; 29.6%, cardioembolic infarction (CE) ; 11.3%, cerebral hemorrhage (Hem) ; 11.8%, transient ischemic attack ; 3.9%, others; 1.2%). 75g OGTT was used to evaluate the disorders of glucose metabolism. We investi-gated the relationships between the incidence of IGT and insulin resistance using HOMA-R and stroke sub-types.Results : The disorders of glucose metabolism were present in 62.7% of patients without previously known diabetes. Diabetes and IGT were diagnosed in 38% and 28%, respectively, of patient with ATI. IGT was observed 35% with a single risk factor (hypertension or hyperlipidemia) and 65% with two risk factors (both of hypertension and hyperlipidemia). HOMA-R was markedly higher level in patients with ATI than with another stoke subtypes.Conclusions : A screening by 75g OGTT was useful for diagnosis of the disorders of glucose metabolism in patients with no prior history of diabetes. Insulin resistance might be an important role for the progression of atherosclerosis in patients with ATI.

tional cases under the same eponym, but the case reported in 1913 was later identifi ed to be adrenoleukodystrophy, and the 1924 case subacute sclerosing panencephalitis. The diagnostic criteria of ‘true’ Schilder’s disease have been proposed in 1986 [1] . There should be large (at least 3 ! 2 cm) bilateral plaques in the centrum semiovale of the cerebral hemispheres with histological characteristics identical to MS. Here, we report the fi rst case of elderly onset Schilder’s disease confi rmed by auDear Sir, Schilder’s disease or myelinoclastic diffuse sclerosis is a rare form of primary demyelinating disease, which is now considered to be a variant of multiple sclerosis (MS) [1, 2] . In 1912, Schilder described a case of a 14-year-old girl who had signs of mental deterioration associated with an increased intracranial pressure. She died after 19 weeks of her illness, and autopsy revealed large areas of sharply demarcated plaques of demyelination in both hemispheres [3] . Subsequently, Schilder reported two addiReceived: June 13, 2005 Accepted: January 10, 2006 Published online: April 21, 2006

We report a long-term outcome on a large cohort of Japanese patients with Parkinson's disease (PD). A total of 1,768 (793 men, 975 women) consecutive patients visited our clinic from 1 January 1989 to 31 December 2002. Among them, 1,183 patients (531 men, 652 women) came to our clinic within 5 years from the onset of disease and at the Hoehn & Yahr Stage III or less at the first visit. Long-term outcome was evaluated in this subcohort of the patients. We examined the duration to reach Stage III, IV, and V, and the duration to develop wearing off and dyskinesia. Time to reach Stage III was slightly but significantly shorter in women, in that 23.8% of men and 35.3% of women reached Stage III by the end of the 5th year; 49.7% of men and 63.3% of women reached Stage III by the end of the 10th year, and 88.9% of men and 79.9% of women by the end of the 15th year (P < 0.001). Also, durations to develop wearing off and dyskinesia were shorter in women compared to men. These data suggest that the disease progression may be slightly faster for women. Young-onset patients showed significantly longer duration to reach Stage III, IV, and V but shorter duration to develop wearing off and dyskinesia. Not many studies are available in the literature on the long-term outcome of PD, and our data would be useful as a reference.

目的:悪性腫瘍に伴う脳梗塞の臨床的特徴と凝血学的分子マーカーの有用性について検討した.対象と方法:過去5年間に当院に入院した脳梗塞患者で悪性腫瘍を有した74例(平均71±11才,男53人,女21人)を対象とし,臨床的特徴について検討した.結果:45例(60.8%)が塞栓性,29例(39.2%)が血栓性であった.原発臓器は胃癌が最多で(23%),組織型は腺癌が最多だった(60.8%).対照群と比べ,発症時のD-dimer値が有意に高値だった(D-dimer;9.6±18.7μg/ml vs3.9±6.8μg/ml,p

We screened LRRK2 mutations in exon 41 in 904 parkin-negative Parkinson's disease (PD) patients (868 probands) from 18 countries across 5 continents. We found three heterozygous missense (novel I2012T, G2019S, and I2020T) mutations in LRRK2 exon 41. We identified 11 (1.3%) among 868 PD probands, including 2 sporadic cases and 8 (6.2%) of 130 autosomal dominant PD families. The LRRK2 mutations in exon 41 exhibited relatively common and worldwide distribution. Among the three mutations in exon 41, it has been reported that Caucasian patients with G2019S mutation have a single-founder effect. In the present study, Japanese patients with G2019S were unlikely to have a single founder from the Caucasian patients. In contrast, I2020T mutation has a single-founder effect in Japanese patients. Clinically, patients with LRRK2 mutations had typical idiopathic PD. Notably, several patients developed dementia and psychosis, and one with I2020T had low cardiac 123I-metaiodobenzylguanidine (MIBG) heart/mediastinum ratio, although the ratio was not low in other patients with I2020T or G2019S. Clinical phenotypes including psychosis, dementia, and MIBG ratios are also heterogeneous, similar to neuropathology, in PD associated with LRRK2 mutations. © 2006 Movement Disorder Society

Background and Purpose— Oxidative stress contributes to ischemia/reperfusion neuronal damage in a consecutive 2-phase pattern: an immediate direct cytotoxic effect and subsequent redox-mediated inflammatory insult. The present study was designed to assess the neuroprotective mechanisms of edaravone, a novel free radical scavenger, through antioxidative and anti-inflammatory pathways, from the early period to up to 7 days after ischemia/reperfusion in mice. Methods— Mice were subjected to 60-minute ischemia followed by reperfusion. They were divided into the edaravone group (n=72; with different schedules for first administration) and the vehicle (control) group (n=36). Infarct volume and neurological deficit scores were evaluated at several time points after ischemia. Immunohistochemical analysis for 4-hydroxy-2-nonenal (HNE), 8-hydroxy-deoxyguanosine (8-OHdG), ionized calcium-binding adapter molecule 1 (Iba-1), inducible NO synthase (iNOS), and nitrotyrosine were performed at 24 hours, 72 hours, or 7 days after reperfusion. Result— Edaravone, even when administrated 6 hours after onset of ischemia/reperfusion, significantly reduced the infarct volume (68.10±6.24%; P P P Conclusion— Our results indicated that edaravone exerts an early neuroprotective effect through the early free radicals scavenging pathway and a late anti-inflammatory effect and suggested that edaravone is important for expansion of the therapeutic time window in stroke patients.

Background and Purpose— Neurogenesis has been observed in the dentate gyrus of the adult hippocampus; however, the mechanisms involved in this process are still only partly understood. In this study, we visualized the proliferation, migration, and differentiation of neuronal progenitor cells in the dentate gyrus induced by ischemic stress using improved retroviral vector. Methods— Improved retroviral vector expressing enhanced green fluorescent protein (EGFP) as a transgene was injected into the dentate gyrus of adult Mongolian gerbils. After 48 hours, transient global ischemia (TGI) was induced by bilateral common carotid artery occlusion for 5 minutes using aneurysm clips. The morphological and immunohistological features of newly-generated cells in the dentate gyrus were analyzed at various times thereafter. Results— At 48 hours after viral injection, almost all EGFP-positive dividing cells were found in the subgranule layer (SGL). These cells proliferated and migrated to the granule cell layer (GCL), expressing the developing neuronal markers polysialic acid and doublecortin, and differentiated to neuronal nuclei–positive or calbindin-positive mature granule cells at 30 days after TGI or sham-operation. The number of GFP-positive cells in the GCL was significantly higher ( P Conclusions— We saw neurogenesis in the adult dentate gyrus. Furthermore, we showed that ischemic stress promoted the proliferation and normal development of neurons at this site.

In the present case, a patient in whom limb apraxia and asymmetrical parkinsonism developed suggesting corticobasal degeneration, is reported. Neuropathologic examination revealed numerous tufted astrocytes in the precentral cortex in addition to the characteristic pathologic findings of PSP. Therefore, on the basis of clinicopathologic features, atypical progressive supranuclear palsy was diagnosed. In addition, the brain tissue of the present patient was investigated with an antibody specific for four-repeat tau (4R-tau). In the precentral cortex, numerous tau-positive tufted astrocytes, pretangles, and threads were positive for 4R-tau. Using a confocal microscopy we demonstrated that tufted astrocytes positive for 4R-tau were adjacent to astrocytes positive for GFAP. The present findings suggest that accumulation of four-repeat tau in astrocytes is a degenerative process rather than a reactive process.

We report serum creatine kinase (CK) activity level in patients with Parkinson's disease and controls matched with gender and age. The clinical subjects consist of 84 patients with Parkinson's disease and 257 control subjects. Serum CK level was significantly elevated in parkinsonian patients (117.3+/-65.0 units/l) compared to that of the controls (85.1+/-33.2 units/l) (p

We reviewed literature on malignant syndrome occurring in patients with Parkinson's disease (PD) during the course of drug therapy. Clinical features were high fever, marked rigidity, consciousness disturbance, autonomic dysfunction, and elevation of serum creatine kinase. The clinical features were essentially similar to those of neuroleptic malignant syndrome. The immediate triggering event was, most often, discontinuation or reduction of anti-parkinsonian drugs, particularly of levodopa. But no anti-parkinsonian drug was the exception to the induction of malignant syndrome. Serious complications were severe pneumonia, disseminated intravascular coagulation, and acute renal failure. Early treatment with intravenous fluid infusion and external body cooling are essential for good recovery. Bromocriptine and dantrolene sodium were used frequently. It has been claimed that they are effective; however, randomized controlled studies are needed to explicitly prove the efficacy of these drugs in malignant syndrome associated with PD.

Background: Argatroban is a selective thrombin inhibitor used for the treatment of atherothrombotic infarction. We evaluated its therapeutic effect using coagulation markers in 30 patients with cardioembolic infarction and 30 patients with atherothrombotic infarction during the immediate period after ischemic stroke. Methods: Argatroban therapy was initiated within 24 hours of the onset of stroke and the course was followed until 7 days after the start of treatment. Neurological evaluation was performed using the Hemispheric Stroke Scale (HSS). We also monitored the serial changes in activated partial thromboplastin time, prothrombin time, thrombin-antithrombin complex (TAT), and prothrombin fragments 1 + 2 (F1 + 2). Results: Both groups of patients showed significant improvement of HSS after 7 days of argatroban therapy (p < 0.05). Hemorrhagic infarction developed in 8 of patients with cardioembolic infarction, but no worsening of symptoms was noted in any of these patients. There was no significant prolongation of activated partial thromboplastin time or prothrombin time after 7 days, while levels of both TAT and F1 + 2 were significantly decreased from day 2. Conclusion: The decrease in TAT and F1 + 2 during argatroban therapy suggested improvement of hypercoagulability, which might explain how this drug prevents the recurrence of both ATI and CEI in the acute stage. Our findings also suggested that TAT and F1 + 2 might be useful indices for evaluation of argatroban efficacy.

We describe clinical characteristics of 10 patients (five families) with familial hemifacial spasm, with reviews of 13 patients hitherto reported in the literature. There is no clear difference in clinical manifestations between sporadic and familial hemifacial spasms. There is no definite inheritance pattern, but may be autosomal dominant with low penetrance. The ages of onset of familial hemifacial spasm are variable, but occasionally can occur at early years of life. There is a left-side predominance with respect to the affected side of cases with familial hemifacial spasm. Similar to sporadic hemifacial spasm, vascular decompression was effective, suggesting that vascular compression is involved in generating hemifacial spasm even in the familial cases. Familial hemifacial spasm may not be a rare disorder, but may possibly be overlooked. Clarifying the role of genetic susceptibility in pathophysiological mechanisms underlying hemifacial spasm is an important approach toward better understanding of the pathogenesis of cranial rhizopathies.

Leucine-rich repeat kinase 2 (LRRK2) is a causative gene of autosomal dominant familial Parkinson's disease (PD). We screened for LRRK2 mutations in 3 frequently reported exons (31, 41, and 48) in our cohort of 871 Japanese patients with PD (430 with sporadic PD and 441 probands with familial PD). Direct sequencing analysis of LRRK2 revealed 1 proband (0.11%) with a p.R1441G mutation, identified for the first time in Asian countries, besides frequently reported substitutions including, the p.G2019S mutation (0.11%) and p.G2385R variant (11.37%). Several studies have suggested that the LRRK2 p.R1441G mutation, which is highly prevalent in the Basque country, is extremely rare outside of northern Spain. Further analysis of family members of the proband with the p.R1441G mutation revealed that her mother and first cousin shared the same mutation and parkinsonism. Haplotype analysis revealed a different haplotype from that of the original Spanish families. Our patients demonstrated levodopa-responsive parkinsonism with intrafamilial clinical heterogeneity. This is the first report of familial PD because of the LRRK2 p.R1441G mutation in Asia.

We report a patient who showed pathological features of both multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) at autopsy. The clinical features included severe cerebellar ataxia, autonomic failure, and rigid-akinetic parkinsonism. The clinical diagnosis was MSA. Pathological examination showed severe neuronal loss with gliosis in the putamen, substantia nigra, inferior olive, and the pontine nucleus, and numerous glial cytoplasmic inclusions. In addition, moderate neuronal loss with gliosis was observed in the globus pallidus and subthalamic nucleus, and neurofibrillary tangles and tufted astrocytes were seen in the basal ganglia and the brain stem. These findings indicate that the patient had both MSA and PSP. Double-labeling immunofluorescence in the brain stem showed alpha-synuclein immunoreactivity localized in the oligodendrocytes and phosphorylated tau immunoreactivity in the neurons and the glia. Co-existence of synucleinopathy and tauopathy is rare.

Background and Purpose —Lipid and lipoprotein abnormalities have been implicated in the pathogenesis of ischemic cerebrovascular disease and atherosclerosis. Lipoprotein lipase (LPL) plays an important role in plasma lipoprotein metabolism. Several studies have recently reported the presence of a relationship between Ser447Stop mutation of LPL and coronary artery disease. Other polymorphisms ( Hin dIII and Pvu II) of the LPL gene have already been shown to correlate significantly with dyslipidemia. We investigated whether these polymorphisms are associated with increased risk of ischemic cerebrovascular disease (CVD). Methods —We recruited 177 CVD patients (atherothrombotic infarction, n=71; cardioembolic infarction, n=30; lacunar infarction, n=76) and 177 healthy control subjects. Subjects were genotyped for the Ser447Stop mutation and for Hin dIII/ Pvu II restriction fragment length polymorphisms of the LPL gene, and the findings were investigated for associations with the clinical subtypes of CVD and with lipid levels. Results —The Ser447Stop mutation correlated significantly with CVD (0.107 versus 0.158; P =0.035). For the CG+GG versus CC genotype, the odds ratio between control subjects and CVD patients with atherothrombotic infarction was 0.42 (95% CI, 0.18 to 0.99) ( P =0.046). Serum HDL cholesterol and triglyceride levels did not correlate significantly with the Ser447Stop genotype. Hin dIII polymorphism correlated significantly with CVD (0.234 versus 0.169; P =0.031), but the frequency of Pvu II polymorphism was not significantly different between groups. Conclusions —Our results suggest that the Ser447Stop mutation of the LPL gene is a novel genetic marker for low risk of atherothrombotic cerebral infarction.

Objectives - To obtain a simple and reliable clinical parameter for the diagnosis of multiple sclerosis among patients with neurological diseases. Patients and methods - Heparinized peripheral blood was obtained from patients with multiple sclerosis and those with non-inflammatory neurological diseases and healthy volunteers. A new enzyme immunoassay method determining medullasin levels in human granulocytes was developed by using mouse monoclonal antibody against medullasin. Results - A newly developed enzyme immunoassay method for medullasin can detect as little as 1 ng/ml medullasin and results can be obtained within 2 h. Eighty-five out of 112 patients with multiple sclerosis (75.8%) showed positive results (above means of normals+2 SD) in the medullasin test, while 15.4% (12/78) of patients with non-inflammatory neurological disease had positive results. Conclusion - This newly developed enzyme immunoassay method for medullasin is considered to be a useful paraclinical test for the diagnosis of multiple sclerosis.

The present study examined the postural effects of unilaterally local injection of metabotropic glutamate receptor (mGluR) antagonists into the subthalamic nucleus (STN), in rats with haloperidol-induced parkinsonism. In rats which received unilateral microinjections of (+)-alpha-methyl-4-carboxyphenylglycine (MCPG), a selective, subtype-non-specific antagonist of mGluR, but not the vehicle, into the STN, systemic administration of haloperidol induced ipsiversive dystonic posturing. The severity of the dystonic posturing was dose-dependent. However, subtype-specific antagonists of group I, II, or III mGluRs induced no dystonic posturing. The present findings suggest that the activity of the STN under conditions of dopamine blockade is facilitated by blockade of mGluRs in the STN, suggesting that mGluRs exert inhibitory influence on glutamate release in the STN.

DJ-1 mutations cause autosomal recessive parkinsonism (ARP). Although some reports of DJ-1 mutations have been published, there is lack of information on the prevalence of these mutations in large-scale studies of both familial and sporadic parkinsonism. In this genetic screening study, we analyzed the distribution and frequency of DJ-1 mutations by direct nucleotide sequencing of coding exons and exon-intron boundaries of DJ-1, in 386 parkin-negative parkinsonism patients (371 index cases: 67 probands of autosomal recessive parkinsonism families, 90 probands of autosomal dominant parkinsonism families, 201 patients with sporadic parkinsonism, and 13 with unknown family histories) from 12 countries (Japan 283, China 27, Taiwan 22, Korea 22, Israel 16, Turkey 5, Philippines 2, Bulgaria 2, Greece 2, Tunisia 1, USA 2, Ukraine 1, unknown 1). None had causative mutation in DJ-1, suggesting DJ-1 mutation is very rare among patients with familial and sporadic parkinsonism from Asian countries and those with other ethnic background. This is in contrast to the higher frequencies and worldwide distribution of parkin- and PINK1-related parkinsonism in ARP and sporadic parkinsonism. Thus, after obtaining clinical information, screening for mutations in (1) parkin, (2) PINK1, (3) DJ-1, (4) ATP13A2 should be conducted in that order, in ARP and sporadic parkinsonism, based on their reported frequencies. In addition, haplotype analysis should be employed to check for homozygosity of 1p36, which harbors a cluster of causative genes for ARP such as DJ-1, PINK1 and ATP13A2 in ARP and sporadic parkinsonism, especially in parkinsonism with consanguinity.

This review discusses the etiology and pathogenesis of Parkinson's disease (PD). Mitochondrial respiratory failure and oxidative stress appear to be two major contributors to nigral neuronal death in PD. Complex I deficiency has been reported by several groups and appears to be one of the basic abnormalities responsible for mitochondrial failure. The principal question is whether or not complex I deficiency is primary or secondary. The second question is whether or not complex I deficiency is localized in the nigrostriatal system or is systemically present. It is our impression that complex I deficiency is not the primary cause but that its deficiency appears to be systemic. The primary cause may be the combination of genetic background and potential nigral neurotoxins. Exposure of nigral neurons to a high risk for oxidative damage because of its high dopamine content may be the reason for more pronounced nigral complex I deficiency compared to systemic organs. Oxidative stress and mitochondrial failure produce a vicious cycle in nigral neurons. To explore the genetic risk factors of sporadic PD, studies on familial PD and parkinsonism are important. Recently, an autosomal dominant form of familial PD was found to be caused by point mutations of the alpha-synuclein gene, and an autosomal recessive familial parkinsonism was mapped to the long arm of chromosome 6 near the Mn-SOD gene locus. Information obtained in these familial cases will contribute to the research on sporadic PD.

The present study examined the postural effects of the local application of glutamatergic antagonists unilaterally into the subthalamic nucleus (STN), on haloperidol-induced akinesia in rats. After intracerebral injections of MK-801, a selective antagonist of N -methyl- d -aspartate (NMDA) receptor, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) disodium, a selective α -amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist, or vehicle, unilaterally into the STN, haloperidol was administered systemically and the elicited behaviors were assessed quantitatively. In rats which received injections of MK-801 or CNQX, but not vehicle, unilaterally into the STN, the administration of haloperidol induced contraversive dystonic posturing. The severity of the deviated posturing was dose-dependent. The present findings revealed that the overactivity of the STN under conditions of dopamine blockade is suppressed by interruptions of glutamatergic inputs, mediated via both NMDA or AMPA receptors, to the STN. Therefore, the present study may provide functional evidence in support of a recently proposed hypothesis, that not only disinhibition from the inhibitory globus pallidus efferents but also excitatory glutamatergic inputs to the STN actually contribute to the overactivity of the STN under dopamine-depleted conditions.