A defined method for differentiating human iPSCs into midbrain dopaminergic progenitors that safely restore motor deficits in Parkinson's disease.

Background: Parkinson's disease (PD) is a progressive neurodegenerative condition that primarily affects motor functions; it is caused by the loss of midbrain dopaminergic (mDA) neurons. The therapeutic effects of transplanting human-induced pluripotent stem cell (iPSC)-derived mDA neural progenitor cells in animal PD models are known and are being evaluated in an ongoing clinical trial. However, However, improvements in the safety and efficiency of differentiation-inducing methods are crucial for providing a larger scale of cell therapy studies. This study aimed to investigate the usefulness of dopaminergic progenitor cells derived from human iPSCs by our previously reported method, which promotes differentiation and neuronal maturation by treating iPSCs with three inhibitors at the start of induction. Methods: Healthy subject-derived iPS cells were induced into mDA progenitor cells by the CTraS-mediated method we previously reported, and their proprieties and dopaminergic differentiation efficiency were examined in vitro. Then, the induced mDA progenitors were transplanted into 6-hydroxydopamine-lesioned PD model mice, and their efficacy in improving motor function, cell viability, and differentiation ability in vivo was evaluated for 16 weeks. Results: Approximately ≥80% of cells induced by this method without sorting expressed mDA progenitor markers and differentiated primarily into A9 dopaminergic neurons in vitro. After transplantation in 6-hydroxydopamine-lesioned PD model mice, more than 90% of the engrafted cells differentiated into the lineage of mDA neurons, and approximately 15% developed into mature mDA neurons without tumour formation. The grafted PD model mice also demonstrated significantly improved motor functions. Conclusion: This study suggests that the differentiation protocol for the preparation of mDA progenitors is a promising option for cell therapy in patients with PD.

Mesial Frontal Lobe Infarction Presenting as Pisa Syndrome.

Pisa syndrome is usually seen in patients with Alzheimer's disease treated with a cholinesterase inhibitor, dementia with Lewy bodies, Parkinson's disease, or atypical parkinsonism including multiple system atrophy. An 86-year-old woman presented with an acute onset of lateral flexion of her trunk to the left side, i.e., Pisa syndrome. She also showed left hemiparesis predominantly in her lower extremity. Her diffusion-weighted magnetic resonance images showed acute infarction in the right premotor area and supplementary motor area. Clopidogrel (75 mg daily) was prescribed. After two weeks from the onset of symptoms, her Pisa syndrome improved. The pathophysiology of Pisa syndrome has not yet been fully understood, but different mechanisms have been assumed. In this patient, it is possible that the infarction in her unilateral frontal lobe impaired the information processing from the temporoparietal cortex to the frontal lobe, including the premotor area and supplementary motor area for anticipatory postural control.

Clinical Characterization of Definite Autoimmune Limbic Encephalitis: A 30-case Series.

Objective Limbic encephalitis (LE) is an inflammatory condition of the limbic system that has an acute or subacute onset. Several types of antibodies are related to the onset of LE, including anti-N-methyl D-aspartate receptor (NMDAR) antibodies and voltage-gated potassium channel (VGKC)-complex antibodies. However, the characteristics and prevalence of LE remain unclear, especially in Asian cohorts, due to the rarity. We aimed to survey their characteristics. Materials and Methods Data of 30 cases clinically defined as "definite autoimmune LE" (based on the standard criteria) were retrospectively collected. These patients were categorized into four subtypes: NMDAR (+) (n=8), VGKC (+) (n=2), antibodies related to paraneoplastic syndrome (n=2), and an antibody-negative group (uncategorized) (n=18). Results LE is rare in Japan, and affected only 30 of 16,759 hospital patients (0.2%) over a ten-year period. The NMDAR (+) group showed distinctive symptoms, while the other three groups had similar indications. Brain MRI indicated significant medial temporal lobe atrophy at one year follow up after discharge. The prevalence of cognitive dysfunction as a complication was 64% (9/14). First-line immunotherapy resulted in a good outcome. A drastic improvement was seen from 4.0±1.1 to 1.1+ on the modified Rankin Scale. A good treatment outcome was observed in all groups (NMDAR, VGKC, and uncategorized), suggesting the importance of an early clinical diagnosis and the early initiation of treatment. Furthermore, we reviewed 26 cases that were clinically diagnosed as definitive autoimmune LE in previous case reports. Conclusion Our findings show that the establishment of a clinical diagnosis based on the clinical criteria of definitive autoimmune LE is important for the initiation of immunotherapy.

Balance and Gait Improvements of Postoperative Rehabilitation in Patients with Parkinson's Disease Treated with Subthalamic Nucleus Deep Brain Stimulation (STN-DBS).

BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a surgical treatment to reduce the "off" state motor symptoms of Parkinson's disease (PD). Postural instability is one of the major impairments, which induces disabilities of activities of daily living (ADLs). The effectiveness of STN-DBS for postural instability is unclear, and the effect of rehabilitation following STN-DBS has remained uncertain. OBJECTIVE: The purpose of this study was to examine changes in balance ability, gait function, motor performance, and ADLs following 2 weeks of postoperative rehabilitation in PD patients treated with STN-DBS. METHODS: Sixteen patients were reviewed retrospectively from February 2016 to March 2017. All patients were tested in their "on" medication state for balance and gait performance using the Mini-Balance Evaluation Systems Test (Mini-BESTest) and the Timed "Up and Go" (TUG) test before the operation, after the operation, and during the discharge period. The UPDRS motor score (UPDRS-III) and Barthel Index (BI) were assessed before the operation and during the discharge period. Rehabilitation focused on muscle strengthening with stretching and proactive balance training. Friedman's test and the post hoc Wilcoxon's signed-rank test were used to analyze the balance assessments, and ANOVA and the post hoc Tukey's test were used to analyze gait performance. The significance level was p < 0.05. RESULTS: During the discharge period, the Mini-BESTest and TUG were significantly improved compared with the preoperative and postoperative periods (p < 0.05). There were no differences between preoperative and postoperative periods in the Mini-BESTest (p=0.12) and TUG (p=0.91). The BI and motor sections of the UPDRS did not differ significantly between the preoperative and postoperative periods (p=0.45, p=0.22). CONCLUSION: The results of this study suggest that postoperative rehabilitation improves balance and gait ability in patients with PD treated with STN-DBS.

A Randomized Crossover Pilot Study of Telemedicine Delivered via iPads in Parkinson's Disease.

BACKGROUND: We investigated the feasibility and safety of a video-based telemedicine system, delivered via a tablet, in Parkinson's disease (PD). METHODS: In a randomized, crossover, open-label pilot trial, we compared a telemedicine period (regular visits every two months with intermediate video calls via an iPad mini) with a control period (regular visits every two months), both lasting 6 months. We included 10 patients diagnosed with PD according to the British Brain Bank criteria, aged 20-75 years. The primary outcome was the PD questionnaire summary index (PDQ-39 SI). Secondary outcomes included the Hoehn and Yahr Stage and scores on the Unified PD Rating Scale (UPDRS) part I-IV, Beck Depression Inventory (BDI), and visual analog scale for satisfaction. RESULTS: Both study periods were completed by 10 patients with PD. Friedman's test revealed that there were no significant differences between the two periods in primary and secondary outcomes (p > 0.05). With respect to visual analog scale scores for satisfaction, participants indicated high satisfaction with the telemedicine system. The number of extra hospital visits and phone calls did not differ between the periods. There were no adverse events or side effects. CONCLUSIONS: We observed that a telemedicine system delivered via a tablet could successfully be used by patients as a part of their care. Further studies investigating the use of telemedicine to replace in-person visits are warranted. This trial is registered with UMIN000015536.

Dopamine transporter imaging predicts motor responsiveness to levodopa challenge in patients with Parkinson's disease: A pilot study of DATSCAN for subthalamic deep brain stimulation.

Imaging studies are necessary prior to subthalamic deep brain stimulation (STN-DBS). Dopamine transporter (DAT) imaging is a powerful tool for visualizing dopamine terminals in the striatum, but its usefulness in STN-DBS is unclear. Here, we retrospectively investigated the relationship between motor symptoms and the specific binding ratio (SBR) on DAT imaging in patients with Parkinson's disease (PD). We included 23 consecutive patients (9 female; 14 male) who were evaluated for DBS eligibility between October 2013 and October 2014 and subsequently received bilateral STN-DBS. Correlation and simple regression analyses were performed on SBR values and clinical parameters before and after surgery. SBR value was negatively correlated with Unified Parkinson's Disease Rating Scale (UPDRS) motor score in the "ON" state before surgery (rs=-0.637, p=0.001) and positively correlated with the reduction of the levodopa equivalent daily dose by surgery (r=0.422, p=0.045). A simple regression analysis revealed that SBR value was positively correlated with UPDRS motor score improvement after levodopa challenge before surgery (p=0.001, R2=0.423). DAT imaging may be useful in STN-DBS candidate selection and the identification of the therapeutic mechanism of STN-DBS in patients with advanced PD and motor symptom fluctuations.

Current Topics in Deep Brain Stimulation for Parkinson Disease.

There is a long history of surgical treatment for Parkinson disease (PD). After pioneering trials and errors, the current primary surgical treatment for PD is deep brain stimulation (DBS). DBS is a promising treatment option for patients with medically refractory PD. However, there are still many problems and controversies associated with DBS. In this review, we discuss current issues in DBS for PD, including patient selection, clinical outcomes, complications, target selection, long-term outcomes, management of axial symptoms, timing of surgery, surgical procedures, cost-effectiveness, and new technology.

Reward-Induced Phasic Dopamine Release in the Monkey Ventral Striatum and Putamen.

In-vivo voltammetry has successfully been used to detect dopamine release in rodent brains, but its application to monkeys has been limited. We have previously detected dopamine release in the caudate of behaving Japanese monkeys using diamond microelectrodes (Yoshimi 2011); however it is not known whether the release pattern is the same in various areas of the forebrain. Recent studies have suggested variations in the dopaminergic projections to forebrain areas. In the present study, we attempted simultaneous recording at two locations in the striatum, using fast-scan cyclic voltammetry (FSCV) on carbon fibers, which has been widely used in rodents. Responses to unpredicted food and liquid rewards were detected repeatedly. The response to the liquid reward after conditioned stimuli was enhanced after switching the prediction cue. These characteristics were generally similar between the ventral striatum and the putamen. Overall, the technical application of FSCV recording in multiple locations was successful in behaving primates, and further voltammetric recordings in multiple locations will expand our knowledge of dopamine reward responses.

A patient with demyelination, laminar cortical necrosis, and rhabdomyolysis associated with hypernatremia.

A 60-year-old man with renal failure and intraabdominal abscess formation probably due to perforation of the colon underwent laparotomy on the sixth hospital day. He developed respiratory infection, deterioration of renal failure, and heart failure resulting in severe respiratory insufficiency after laparotomy. He was placed on mechanical ventilation using sedatives and muscle relaxant and was treated with antibiotics, steroids, and a diuretic. The value of serum sodium jumped from 146 to 164 mEq/L in 2 days. Sodium infusion was discontinued, and hypernatremia decreased. He fell into a coma and demonstrated generalized convulsions after mechanical ventilation was discontinued. His head computed tomography did not indicate any pathologic findings, and his convulsions were not controlled so that he was again placed on mechanical ventilation. The laboratory findings revealed rhabdomyolysis (18936 IU/L) 5 days after the normalization of hypernatremia. Mechanical ventilation and hemodialysis were terminated after the convulsions were controlled and the renal failure improved on the 82nd hospital day. Head magnetic resonance imaging exhibited that multiple hyperintensity lesions in the white matter with linear signal changes in both occipital cortex. He remained unconscious for 6 months. This is the first case that demonstrated demyelination, laminar cortical necrosis, and rhabdomyolysis associated with hypernatremia. Rhabdomyolysis after rapid occurrence of hypernatremia might be a laboratory sign of concomitant demyelination.