Safety, Tolerability, and Pharmacokinetics of the Novel Adenosine A2A Antagonist/Inverse Agonist KW-6356 Following Single and Multiple Oral Administration in Healthy Volunteers.

KW-6356 is an adenosine A2A receptor-selective antagonist and inverse agonist. We conducted 2 studies: study 6356-001 (no NCT number), a randomized, double-blind, placebo-controlled phase 1 trial of single ascending (1, 3, 10 mg) and multiple (6 mg once daily) oral doses of KW-6356 in healthy Japanese subjects; and study 6356-004 (NCT03830528), including a randomized, double-blind, placebo-controlled phase 1 trial of single ascending (21, 42, 60 mg) and multiple (24 mg once daily) oral doses of KW-6356, and a phase 1 open-label trial of multiple oral doses (6 mg once daily) of KW-6356 in healthy Japanese and White subjects, to evaluate the safety, tolerability, and pharmacokinetics of KW-6356. KW-6356 was well tolerated after administration of single doses of up to 60 mg and multiple doses of up to 24 mg once daily for 14 days. The pharmacokinetics of KW-6356 were linear after a single dose of up to 60 mg KW-6356. The mean terminal elimination half-life of KW-6356 ranged from 18.4 to 43.1 hours following administration of single doses of 1-60 mg. There was no clear difference in the safety or pharmacokinetics of KW-6356 between healthy Japanese and White subjects.

Breast reconstruction in a patient with an implanted deep brain stimulator.

Deep brain stimulators (DBSs) are sometimes used to treat refractory movement disorders such as Parkinson's disease. When DBSs are implanted in a subcutaneous pocket in the chest region, breast reconstruction becomes a challenge because monopolar electrocautery can lead to DBS dysfunction or brain tissue damage caused by heat. We report a patient with a DBS who underwent one-stage implant-based breast reconstruction. We switched off the DBS before surgery and used monopolar electromagnetic cautery with minimum power settings to undermine the subcutaneous pocket for the breast implant. The DBS was switched back on immediately after completion of the surgery. The patient's postoperative recovery was uneventful with the DBS fully functional.

Identification of novel SNORD118 mutations in seven patients with leukoencephalopathy with brain calcifications and cysts.

BACKGROUND: Leukoencephalopathy with brain calcifications and cysts (LCC) is neuroradiologically characterized by leukoencephalopathy, intracranial calcification, and cysts. Coats plus syndrome is also characterized by the same neuroradiological findings together with defects in retinal vascular development. Indeed, LCC and Coats plus were originally considered to be the same clinical entity termed cerebroretinal microangiopathy with calcifications and cysts, but evidence suggests that they are genetically distinct. Mutations in CTS telomere maintenance complex component 1 (CTC1) and small nucleolar RNA, C/D box 118 (SNORD118) genes have been found to cause Coats plus and LCC, respectively. MATERIALS AND METHODS: Eight unrelated families with LCC were recruited. These patients typically showed major neuroradiological findings of LCC with no signs of extra-neurological manifestations such as retinal abnormality, gastrointestinal bleeding, or hematological abnormalities. SNORD118 was examined by Sanger sequencing in these families. RESULTS: Seven out of eight probands carry compound heterozygous mutations, suggesting that SNORD118 mutations are the major cause of LCC. We identified a total of eight mutation, including four that were novel. Some of the variants identified in this study present heterozygously in public databases with an extremely rare frequency (<0.1%). CONCLUSION: Biallelic SNORD118 mutations were exclusively found in most unrelated families with LCC.

Validity of single tract microelectrode recording in subthalamic nucleus stimulation.

In surgery for subthalamic nucleus (STN) deep brain stimulation (DBS), precise implantation of the lead into the STN is essential. Physiological refinement with microelectrode recording (MER) is the gold standard for identifying STN. We studied single tract MER findings and surgical outcomes and verified our surgical method using single tract MER. The number of trajectories in MER and the final position of lead placement were retrospectively analyzed in 440 sides of STN DBS in 221 patients. Bilateral STN DBS yielded marked improvement in the motor score, dyskinesia/fluctuation score, and reduced requirement of dopaminergic medication in this series. The number of trajectories required to obtain sufficient activity of the STN was one in 79.0%, two in 18.2%, and three or more in 2.5% of 440 sides. In 92 sides requiring altered trajectory, the final direction of trajectory movement was posterior in 73.9%, anterior in 13.0%, lateral in 5.4%, and medial in 4.3%. In 18 patients, posterior moves were required due to significant brain shift with intracranial air caused by outflow of CSF during the second side procedure. Sufficient STN activity is obtained with minimum trajectories by proper targeting and precise interpretation of MER findings even in the single tract method. Anterior-posterior moves rather than medial-lateral moves should be attempted first in cases with insufficient recording of STN activity.

Temporary deterioration of executive function after subthalamic deep brain stimulation in Parkinson's disease.

OBJECTIVE: Selective impairment of executive function has been shown in Parkinson's Disease (PD) patients undergoing Deep Brain Stimulation (DBS) of the Subthalamic Nucleus (STN). However, some patients experience difficulties in daily life, such as dissension in interpersonal relationships or a loss of lifestyle balance, in the short term after surgery. Our hypothesis is that these difficulties might be related to executive dysfunction. To elucidate the involvement of executive dysfunction in these difficulties, we assessed motor and executive function in the short term and long term after surgery. METHODS: We examined motor function and executive function in 30 patients who underwent bilateral STN-DBS for medically refractory PD. Patients were evaluated for executive function 1 month before surgery, 1 month after surgery, and 12 months after surgery using the Trail Making Test (TMT), the Modified Stroop Color Word Interference Test (MST) and tests of Verbal Fluency (VF). RESULTS: TMT-B, TMT (B/A), MST-B, VF-phonemic and VF-semantic scores were significantly poorer 1 month after STN-DBS. TMT-B, TMT (B/A) and VF-phonemic recovered to preoperative levels by 12 months after surgery. A reduction in dopaminergic medication 1 month after surgery was significantly correlated with deterioration of TMT (B/A). CONCLUSION: Temporary deterioration of executive function may occur in the short term after STN-DBS, whereas motor function is usually improved. PD patients undergoing STN-DBS should be managed during this period to better predict temporary executive dysfunction. Excessive reduction of dopaminergic medication after surgery might, at least in part, result in this deterioration of executive function.

Complications of subthalamic nucleus stimulation in Parkinson's disease.

Subthalamic nucleus deep brain stimulation (STN-DBS) is effective for medically refractory Parkinson's disease. We retrospectively analyzed complications in 180 consecutive patients who underwent bilateral STN-DBS. Surgery-related complications were symptomatic intracerebral hemorrhage in 2, chronic subdural hematoma in 1, and transient deterioration of medication-induced psychosis in 2 patients. Device-related complications involved device infection in 5, skin erosion in 5, and implantable pulse generator malfunction in 2 patients. All of these patients required surgical repair. Surgery and device-related complications could be reduced with increased surgical experience and the introduction of new surgical equipment and technology. Treatment or stimulation-related complications were intractable dyskinesia/dystonia in 11, problematic dysarthria in 7, apraxia of eyelid opening (ALO) in 11, back pain in 10, and restless leg syndrome in 6 patients. Neuropsychiatric complications were transient mood changes in some, impulse control disorder in 2, severe depression related to excessive reduction of dopaminergic medications in 2, rapid progression of dementia in 1, and suicide attempts in 2 patients. Most complications were mild and transient. Dysarthria and ALO were the most frequent permanent sequelae after STN-DBS. Treatment-related adverse events may be caused not only by the effect of stimulation effect but also excessive reduction of dopaminergic medication, or progression of the disease. In conclusion, STN-DBS seems to be a relatively safe procedure. Although serious complications with permanent sequelae are rare, significant incidences of adverse effects occur. Physicians engaged in this treatment should have a comprehensive understanding of the probable complications and how to avoid them.

Subthalamic nucleus stimulation for Parkinson disease with severe medication-induced hallucinations or delusions.

OBJECT: Subthalamic nucleus deep brain stimulation (STN DBS) improves cardinal motor symptoms of Parkinson disease (PD) and reduces antiparkinsonian medication. Therefore, STN DBS seems to be well indicated for patients suffering from medication-induced psychotic symptoms. However, there are few available data dealing with the effect of STN DBS in this kind of patient. The authors studied the effect of STN DBS in patients with PD and severe medication-induced hallucinations or delusions. METHODS: The authors retrospectively reviewed the clinical course of 10 patients who suffered from severe medication-induced hallucinations or delusions and underwent bilateral STN DBS. Patients whose preoperative thought disorder score (Unified Parkinson's Disease Rating Scale Part I, item 2) was 3 or more were enrolled in this study. All patients underwent cognitive function examination and brain perfusion SPECT preoperatively to exclude dementia with Lewy bodies. RESULTS: Subthalamic nucleus DBS yielded significant improvement of motor function in all patients. In 8 patients, psychotic symptoms completely disappeared with significant reduction of dopaminergic medication. In 2 patients, hallucinations and delusions deteriorated immediately after surgery despite complete withdrawal of antiparkinsonian medication. However, these psychotic symptoms completely disappeared after a few months with administration of antipsychotics, and no recurrence was observed afterward in either patient. CONCLUSIONS: Subthalamic nucleus DBS is a good treatment option for patients with PD who are suffering severe medication-induced hallucinations or delusion. However, vigilance is needed, because temporary deterioration of psychotic symptoms may occur after surgery.

Predictive factors affecting early deterioration of axial symptoms after subthalamic nucleus stimulation in Parkinson's disease.

Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment option for medically refractory Parkinson's disease (PD). However, some patients show deterioration of axial symptoms within a short time after surgery. We studied 43 patients who underwent bilateral STN-DBS and investigated predictive factors affecting early deterioration of axial symptoms. Among 43 patients, 16 patients showed obvious deterioration of axial symptoms within three years of surgery. Multiple logistic regression analysis indicated that the significant independent variables related to early deterioration of axial symptoms were rapidly progressive short duration of the disease and advanced age at surgery. These results suggest that patients with rapidly progressing PD, who need early surgical intervention, tend to show early deterioration of axial symptoms after STN-DBS.

Effect of subthalamic deep brain stimulation on postural abnormality in Parkinson disease.

OBJECT: Parkinson disease (PD) is often accompanied by various postural abnormalities such as camptocormia (bent spine) or Pisa syndrome (lateral flexion). The authors studied the effect of subthalamic nucleus deep brain stimulation (STN DBS) on postural abnormality in patients with PD. METHODS: The authors retrospectively reviewed the clinical course of 18 patients who suffered from significant postural abnormality and underwent bilateral STN DBS. Patients whose preoperative posture score (Unified Parkinson's Disease Rating Scale III, item 28) was 2 or more in the "medication-on" state were enrolled in this study. Eight patients were considered to have camptocormia, and 10 patients were considered to have so-called Pisa syndrome. Nine patients showed apparent thoracolumbar spinal deformity on radiography. Most patients had significant motor fluctuations from levodopa. RESULTS: In 13 patients with moderate postural abnormality (score of 2 on item 28), 9 patients improved soon after surgery, but 1 patient relapsed. Two patients improved gradually over a long period after surgery, whereas 2 patients did not improve at all. In 5 patients with severe postural abnormality (score of 3 or 4 on item 28), 2 patients improved slightly in the long-term follow-up period after surgery, but 3 patients did not improve at all. CONCLUSIONS: Postural abnormality in patients with PD could be ameliorated by STN DBS, and therefore surgery should be considered before irreversible spinal deformity develops.

Upregulation of the P2X7 receptor after cryogenic injury to rat brain.

The P2X7 receptor is a member of the P2X family of adenosine triphosphate-gated ion channels. It is expressed in the central nervous system and is associated with several pathological conditions. Here, we examined the expression of P2X7 with immunohistochemistry after cryogenic injury to the rat cortex. One day after cortical cryogenic injury, P2X7 immunoreactive cells were increased in regions surrounding the cold-injured site. These P2X7 positive cells were also immunoreactive for OX42, a microglial marker, and possessed the short, thick processes that are characteristic of activated microglia. These results suggest that the increased local expression of P2X7 may be associated with microglial activation, contributing to detrimental and/or protective functions around the cold-injured site.

Apraxia of eyelid opening after subthalamic deep brain stimulation may be caused by reduction of levodopa.

Apraxia of eyelid opening (ALO) is an infrequent side effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's disease (PD). However, the pathogenesis of ALO after STN DBS is not well understood. We report on two patients who suffered from disabling ALO after bilateral STN DBS. Their ALO improved by resuming the levodopa medication that had been discontinued after the surgery. Although ALO after STN DBS is considered as an adverse effect of STN stimulation, postoperative modification of dopaminergic medication may be a cause of ALO after STN DBS.

Expression of myelencephalon-specific protease after cryogenic lesioning of the rat parietal cortex.

The gene for myelencephalon-specific protease (MSP) is a member of the kallikrein gene family and in rats is expressed mainly in the central nervous system. Its function and alteration in brain injury have not yet been clarified. We examined the expression of MSP after cryogenic injury (CI) using in situ hybridization, immunohistochemistry, and Western blotting. Analysis of MSP mRNA by in situ hybridization revealed a higher level of expression around the cryogenic area than on the contralateral side at 2-7 days after CI, with peak expression occurring 7 days after CI. Immunohistochemical analysis demonstrated expression of MSP protein at 1 day after CI, in the same region in which MSP mRNA was observed, with peak expression again at 7 days after CI, in the area around the lesion. Double immunohistochemical labeling revealed that MSP was expressed mainly in oligodendrocytes. These results suggest that expression of MSP may be related to the turnover of myelin-associated proteins and extracellular matrix proteins after CI. The regulation of active MSP may be important in the physiological or pathological changes involved in remyelination or demyelination.

Expression of myelencephalon-specific protease in transient middle cerebral artery occlusion model of rat brain.

Myelencephalon-specific protease (MSP) is one of the serine proteases and is expressed in the central nervous system of rats. Its function and alternation in brain injury have not yet been clarified. In this study, we investigated the expression of MSP after transient middle cerebral artery occlusion (MCAO) using in situ hybridization and immunohistochemistry. In situ localization of MSP mRNA demonstrated a higher level in the corpus callosum and around the ischemic area from 12 h to 14 days after MCA reperfusion, with the peak of expression coming 3 days after reperfusion in both regions. Immunohistochemically, the expression of protein was found 1 day after reperfusion in the same brain region that was observed for mRNA. The peak was 7 days after reperfusion in both regions. Micro-autoradiography, immunostaining and double immunohistochemical labeling revealed the expression of MSP to be located mainly in the oligodendrocytes. The present results indicate that MSP may be related to the turnover of the myelin-associated proteins and the extracellular matrix proteins after transient MCAO. The activation of MSP may play a role in remodeling processes such as neurite outgrowth and remyelination.