Use of catechol‐O‐methyltransferase inhibition to minimize L‐3,4‐dihydroxyphenylalanine‐induced dyskinesia in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐lesioned macaque

L‐3,4‐dihydroxyphenylalanine (L‐DOPA)‐induced dyskinesia is a complication of dopaminergic treatment in Parkinson's disease. Lowering the L‐DOPA dose reduces dyskinesia but also reduces the antiparkinsonian benefit. A therapy that could enhance the antiparkinsonian action of low‐dose L‐DOPA (LDl) without exacerbating dyskinesia would thus be of considerable therapeutic benefit. This study assessed whether catechol‐O‐methyltransferase (COMT) inhibition, as an add‐on to LDl, might be a means to achieve this goal. Cynomolgus macaques were administered 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine. Dyskinesia was established by chronic treatment with L‐DOPA. Two doses of L‐DOPA were identified – high‐dose L‐DOPA (LDh), which provided good antiparkinsonian benefit but was compromised by disabling dyskinesia, and LDl, which was sub‐threshold for providing significant antiparkinsonian benefit, without dyskinesia. LDh and LDl were administered in acute challenges in combination with vehicle and, for LDl, with the COMT inhibitor entacapone (5, 15 and 45 mg/kg). The duration of antiparkinsonian benefit (ON‐time), parkinsonism and dyskinesia were determined. The ON‐time after LDh was ～170 min and the ON‐time after LDl alone (～98 min) was not significantly different to vehicle (～37 min). In combination with LDl, entacapone significantly increased the ON‐time (5, 15 and 45 mg/kg being ～123, ～148 and ～180 min, respectively). The ON‐time after LDl/entacapone 45 mg/kg was not different to that after LDh. However, whereas the percentage ON‐time that was compromised by disabling dyskinesia was ～56% with LDh, it was only ～31% with LDl/entacapone 45 mg/kg. In addition to the well‐recognized action of COMT inhibition to reduce wearing‐OFF, the data presented suggest that COMT inhibition in combination with low doses of L‐DOPA has potential as a strategy to alleviate dyskinesia.     

Perampanel,a selective,noncompetitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor antagonist,as adjunctive therapy for refractory partial‐onset seizures: Interim results from phase III,extension study 307

Purpose: To evaluate safety, tolerability, and seizure outcome data during long‐term treatment with once‐daily adjunctive perampanel (up to 12 mg/day) in patients with refractory partial‐onset seizures. Methods: Study 307 was an extension study for patients completing the double‐blind phase of three pivotal phase III trials (studies 304, 305, and 306). The study consisted of two phases: an open‐label treatment phase (including a 16‐week blinded conversion period and a planned 256‐week maintenance period) and a 4‐week follow‐up phase. Patients were blindly titrated during the conversion period to their individual maximum tolerated dose (maximum 12 mg/day). Adverse events (AEs) were monitored throughout the study and seizure frequency recorded. The interim data cutoff date for analyses was December 1, 2010. Key Findings: In total, 1,218 patients were enrolled in the study. At the interim cutoff date, 1,186 patients were in the safety analysis set; 1,089 (91.8%) patients had >16 weeks of exposure to perampanel, 580 (48.9%) patients had >1 year of exposure, and 19 (1.6%) patients had >2 years of exposure. At the interim analysis, 840 (70.8%) patients remained on perampanel treatment. The large majority of patients (n = 1,084 [91%]) were titrated to 10 mg or 12 mg/day. Median (range) duration of exposure was 51.4 (1.1–128.1) weeks. Treatment‐emergent AEs were reported in 87.4% of patients. The most frequent were dizziness (43.9%), somnolence (20.2%), headache (16.7%), and fatigue (12.1%). Serious AEs were reported in 13.2% of patients. In the intent‐to‐treat analysis set (n = 1,207), the frequency of all seizures decreased over the first 26 weeks of perampanel treatment in patients with at least 26 weeks of exposure to perampanel (n = 1,006 [83.3%]); this reduction was maintained in patients with at least 1 year of exposure (n = 588 [48.7%]). The overall median percent changes in seizure frequency in patients included in each 13‐week interval of perampanel treatment were ?39.2% for weeks 14–26 (n = 1,114), ?46.5% for weeks 40–52 (n = 731), and ?58.1% for weeks 92–104 (n = 59). Overall responder rates in patients included in each 13‐week interval of perampanel treatment were 41.4% for weeks 14–26 (n = 1,114), 46.9% for weeks 40–52 (n = 731), and 62.7% for weeks 92–104 (n = 59). During the blinded conversion period, the reduction in seizure frequency in patients previously randomized to placebo (?42.4%, n = 369) was similar to that in patients previously randomized to perampanel (?41.5%, n = 817). Significance: Consistent with pivotal phase III trials, these interim results demonstrated that perampanel had a favorable tolerability profile in patients with refractory partial‐onset seizures over the longer term. The decrease in seizure frequency was consistent and maintained in those patients over at least 1 year of perampanel exposure.     

Anticonvulsant and proconvulsant actions of 2‐deoxy‐d‐glucose

Purpose: 2‐Deoxy‐d ‐glucose (2‐DG), a glucose analog that accumulates in cells and interferes with carbohydrate metabolism by inhibiting glycolytic enzymes, has anticonvulsant actions. Recognizing that severe glucose deprivation can induce seizures, we sought to determine whether acute treatment with 2‐DG can promote seizure susceptibility by assessing its effects on seizure threshold. For comparison, we studied 3‐methyl‐glucose (3‐MG), which like 2‐DG accumulates in cells and reduces glucose uptake, but does not inhibit glycolysis. Methods: Mice were treated with 2‐DG or 3‐MG and the seizure threshold determined in the 6‐Hz test, the mouse electroshock seizure threshold (MEST) test, and the intravenous pentylenetetrazol (i.v. PTZ) or kainic acid (i.v. KA) seizure threshold tests. 2‐DG was also tested in fully amygdala‐kindled rats. Results: 2‐DG (125–500 mg/kg, i.p., 30 min before testing) significantly elevated the seizure threshold in the 6‐Hz seizure test. 2‐DG (250–500 mg/kg) decreased the threshold in the MEST and i.v. PTZ and i.v. KA tests. 3‐MG had no effect on seizure threshold in the 6‐Hz test but, like 2‐DG, decreased seizure threshold in the i.v. PTZ test. 2‐DG (250 and 500 mg/kg, i.p., 30 min before testing) had no effect on amygdala‐kindled seizures. Conclusions: Although 2‐DG protects against seizures in the 6‐Hz seizure test, it promotes seizures in some other models. The proconvulsant action may relate to reduced glucose uptake, whereas the anticonvulsant action may require inhibition of glycolysis and shunting of glucose metabolism through the pentose phosphate pathway.     

Novel D3 dopamine receptor‐preferring agonist D‐264: Evidence of neuroprotective property in Parkinson's disease animal models induced by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine and lactacystin

Parkinson's disease (PD), a progressive neurodegenerative movement disorder, is known to be caused by diverse pathological conditions resulting from dysfunction of the ubiquitin‐proteasome system (UPS), mitochondria, and oxidative stress leading to preferential nigral dopamine (DA) neuron degeneration in the substantia nigra. In the present study, we evaluated the novel D3 receptor‐preferring agonist D‐264 in a mouse model of PD to evaluate its neuroprotective properties against both the nigrostriatal dopaminergic toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐ and the proteasome inhibitor lactacystin‐induced dopaminergic degeneration. C57BL/6 male mice either were given MPTP by intraperitoneal injection twice per day for 2 successive days at a dose 20 mg/kg or were microinjected with lactacystin bilaterally (1.25 μg/side) into the medial forebrain bundle (MFB). Pretreatment with D‐264 (1 mg/kg and 5 mg/kg, intraperitoneally, once per day), started 7 days before administration of MPTP or lactacystin. We found that D‐264 significantly improved behavioral performance, attenuated both MPTP‐ and lactacystin‐induced DA neuron loss, and blocked proteasomal inhibition and microglial activation in the substantia nigra (SN). Furthermore, D‐264 treatment was shown to increase the levels of brain‐derived neurotrophic factor (BDNF) and glial cell line‐derived factor (GDNF) in MPTP‐ and lactacystin‐treated mice, possibly indicating, at least in part, the mechanism of neuroprotection by D‐264. Furthermore, pretreatment with the D3 receptor antagonist U99194 significantly altered the effect of neuroprotection conferred by D‐264. Collectively, our study demonstrates that D‐264 can prevent neurodegeneration induced by the selective neurotoxin MPTP and the UPS inhibitor lactacystin. The results indicate that D‐264 could potentially serve as a symptomatic and neuroprotective treatment agent for PD. © 2010 Wiley‐Liss, Inc.     

Pre‐hospital notification reduced the door‐to‐needle time for iv t‐PA in acute ischaemic stroke

Background and purpose: Intrahospital delay is the most serious obstacle in thrombolysis in acute ischaemic stroke (AIS). We implemented the pre‐hospital notification system from the emergency medical information system in our metropolitan area to reduce intrahospital delay. Methods: From October 2007, we implemented a 24‐h hotline system between our stroke center and the Korean Emergency Medical Information System in Busan. We compared processing times and clinical outcomes amongst patients after using intravenous tissue type plasminogen activator (iv t‐PA) with and without the hotline system. Results: After the pre‐hospital notification system was implemented, the rate of iv t‐PA use increased from 6.5% to 14.3%. Time of onset in patients with pre‐hospital notification was much longer than in patients without (121.5 ± 34.8 min vs. 74.7 ± 38.5 min, P < 0.01) notification but door‐to‐needle time was significantly reduced (28.9 ± 11.4 min vs. 47.7 ± 22.8 min, P < 0.01). However, there were no significant differences in 90‐day clinical outcomes between the two groups. Conclusions: The pre‐hospital notification system reduced intrahospital processing times which led to increased iv t‐PA use after AIS. However, the improvement of clinical outcomes in thrombolysis might require organization of not only intrahospital processes but of outside processes such as the early recognition and rapid dispatch of patients with suspected AIS.     

MLK3‐MKK3/6‐P38MAPK cascades following N‐methyl‐D‐aspartate receptor activation contributes to amyloid‐β peptide‐induced apoptosis in SH‐SY5Y cells

Amyloid‐β peptide (Aβ) has been implicated in the development of Alzheimer's disease (AD), but the underlying molecular mechanisms remain unclear. The present study explores the proapoptosis signaling evoked by N‐methyl‐D‐aspartate (NMDA) receptors in Aβ neurotoxicity. Oligomeric Aβ25–35 incubation resulted in significant apoptosis of neuronal SH‐SY5Y cells. Preadministration of the potent NMDA receptor antagonist MK801 promoted neuronal survival. Both NVP‐AAM077 and Ro25–6981, GluN2A‐ and GluN2B‐subunit‐selective NMDA receptor antagonists, respectively, showed effects similar to those of MK801, supporting a critical role of GluN2A‐ or GluN2B‐containing NMDA receptors in Aβ neurotoxicity. Exposure to oligomeric Aβ25–35 increased the phosphorylation (activation) of mixed‐lineage kinase 3 (MLK3), dual‐specific mitogen‐activated protein kinase kinase 3/6 (MKK3/6), and P38 mitogen‐activated protein kinase (P38MAPK) in SH‐SY5Y cells. Inhibition of P38MAPK activation by SB239063 had a neuroprotective effect. K252a attenuated the phosphorylation of MLK3, MKK3/6, and P38MAPK but also partially prevented SH‐SY5Y cells apoptosis. MK801, NVP‐AAM077, and Ro25–6981, abrogated the MLK3‐MKK3/6‐P38MAPK activation induced by oligomeric Aβ25–35. These results suggest that the activation of GluN2A‐ or GluN2B‐containing NMDA receptors is responsible for the activation of MLK3‐MKK3/6‐P38MAPK cascades, which contributes to Aβ‐mediated cell apoptosis. © 2014 Wiley Periodicals, Inc.     

Tract‐based spatial statistics analysis of diffusion‐tensor imaging data in pediatric‐ and adult‐onset multiple sclerosis

Background: White matter (WM) microstructure may vary significantly in pediatric‐onset (PO) and adult‐onset (AO) patients with multiple sclerosis (MS), a difference that could be explained by the effects of an inherent plasticity in the affected pediatric brains early in the disease, and a phenomenon that does not occur later in life. This hypothesis would support the observation that disease progression is much slower in POMS compared to AOMS patients. Objectives: To examine WM microstructure in the brain of adults with POMS and AOMS, using tract based spatial statistics (TBSS) analysis of diffusion‐tensor imaging (DTI). Methods: Adults with relapsing‐remitting (RR) POMS, who were diagnosed before age of 18 years (n = 16), were compared with age‐matched (AOA, n = 23) and disease duration‐matched (AOD, n = 22) RR patients who developed MS after the age of 18 years. Scans were analyzed using the FSL software package (Oxford, UK) and statistics were performed using TBSS to evaluate WM microstructure between groups based on the mean fractional anisotropy (FA) values obtained from the DTI. Results: Widespread cortical and deep WM area differences characterized by increased FA values were seen in the AOAMS compared with POMS group (P < 0.05, TFCE corrected). Significantly increased FA values of posterior WM areas were detected in the AODMS compared with POMS group (P < 0.05, TFCE corrected). Conclusion: Increased FA values in WM areas of the AOMS compared with the POMS patients suggest that diffuse WM microstructure changes are more attributable to age of onset than a simple function of disease duration and age. Hum Brain Mapp 35:53–60, 2014. © 2012 Wiley Periodicals, Inc.     

Cognitive impairment in rapid‐onset dystonia‐parkinsonism

Rapid‐onset dystonia‐parkinsonism (RDP) is caused by mutations in the ATP1A3 gene. This observational study sought to determine if cognitive performance is decreased in patients with RDP compared with mutation‐negative controls. We studied 22 familial RDP patients, 3 non‐motor‐manifesting mutation‐positive family members, 29 mutation‐negative family member controls in 9 families, and 4 unrelated RDP patients, totaling 58 individuals. We administered a movement disorder assessment, including the Burke‐Fahn‐Marsden Dystonia Rating Scale (BFMDRS) and the Unified Parkinson's Disease Rating Scale (UPDRS) and a cognitive battery of memory and learning, psychomotor speed, attention, and executive function. The cognitive battery was designed to evaluate a wide range of functions; recognition memory instruments were selected to be relatively pure measures of delayed memory, devoid of significant motor or vocal production limitations. Comparisons of standardized cognitive scores were assessed both with and without controlling for psychomotor speed and similarly for severity of depressive symptoms. A majority of RDP patients had onset of motor symptoms by age 25 and had initial symptom presentation in the upper body (face, mouth, or arm). Among patients, the BFMDRS (mean ± SD, 52.1 ± 29.5) and UPDRS motor subscore (29.8 ± 12.7) confirmed dystonia‐parkinsonism. The affected RDP patients performed more poorly, on average, than mutation‐negative controls for all memory and learning, psychomotor speed, attention, and executive function scores (all P ≤ 0.01). These differences persisted after controlling for psychomotor speed and severity of depressive symptoms. Impaired cognitive function may be a manifestation of ATP1A3 mutation and RDP. © 2014 International Parkinson and Movement Disorder Society     

Scalp‐recorded high‐frequency oscillations in childhood sleep‐induced electrical status epilepticus

Because high‐frequency oscillations (HFOs) may affect normal brain functions, we examined them using electroencephalography (EEG) in epilepsy with continuous spike‐waves during slow‐wave sleep (CSWS), a condition that can cause neuropsychological regression. In 10 children between 6 and 9 years of age with epilepsy with CSWS or related disorders, we investigated HFOs in scalp EEG spikes during slow‐wave sleep through temporal expansion of the EEG traces with a low‐cut frequency filter at 70 Hz as well as through time‐frequency power spectral analysis. HFOs (ripples) concurrent with spikes were detected in the temporally expanded traces, and the frequency of the high‐frequency peak with the greatest power in each patient’s spectra ranged from 97.7 to 140.6 Hz. This is the first report on the detection of HFOs from scalp EEG recordings in epileptic patients. We speculate that epileptic HFOs may interfere with higher brain functions in epilepsy with CSWS.     

Autopsied case of non‐plaque‐type dura mater graft‐associated Creutzfeldt‐Jakob disease presenting with extensive amyloid‐β deposition

We present an autopsied case of non‐plaque‐type dura mater graft‐associated Creutzfeldt‐Jakob disease (dCJD) with extensive amyloid‐β (Aβ) deposition in the brain. A 39‐year‐old Japanese woman presented with memory disturbance and abnormal behavior. The patient had a history of craniotomy with dura matter‐graft transplant for a head injury which occurred when she was 19 years old. Magnetic resonance imaging (MRI) showed hyperintensities in the cerebral cortex and striatum on diffusion‐weighted images, particularly on the dura mater‐grafted right side. Her clinical symptoms, including rapidly progressing cognitive impairment, myoclonus, and periodic sharp wave complexes on electroencephalogram, could not be distinguished from typical sporadic CJD cases. The patient died 11 months after symptom onset, and pathological investigations showed extensive spongiform degeneration with prion protein (PrP) deposition without Kuru plaques; these observations were essentially the same as those of typical sporadic CJD cases. Furthermore, Aβ immunohistochemistry showed extensive diffuse staining in the cerebral neocortex, plaque‐type deposition, positive staining in the pia mater, and cerebral amyloid angiopathy. Although the MRI findings suggested that the pathological involvement originated from the dura mater‐grafted right side, the PrP and Aβ depositions showed no apparent regionalization and laterality. Tau‐pathology including neurofibrillary tangles was hardly identified. The proteins phosphorylated α‐synuclein and phosphorylated transactivation response DNA‐binding protein 43 kDa were not detected on immunostaining. Although this report describes only one case, various speculations were made based on detailed clinical and pathological observations in conjunction with previous reports of dCJD. In particular, this report provides significant insight into the characteristics and progression of dCJD pathology and its relationship with Aβ pathology.     

LGI‐1 antibody encephalitis in a seven‐year‐old girl

LGI‐1 antibody encephalitis is a rare autoimmune limbic encephalitis which has been reported predominantly in adults. Seizures in LGI‐1 antibody encephalitis exhibit significant semiological variability. Faciobrachial dystonic seizures are characteristically seen in this condition and have so far been described only in adults. Other seizure types have also been reported. We describe the case of a seven‐year‐old girl with LGI‐1 limbic encephalitis who presented with acute new‐onset seizures, and rapidly deteriorated over the course of a few weeks with very frequent seizures and encephalopathy, becoming non‐verbal and non‐ambulatory. The electroclinical presentation of this child with LGI‐1 encephalitis makes this case unique and further highlights the importance of a high index of suspicion for diagnosis in young children. Early diagnosis can lead to prompt and appropriate treatment with immunotherapy, and potential harmful treatments such as pharmacological coma can be avoided. To the best of our knowledge, this is the youngest case ever reporter. [Published with video sequences]