Galantamine Response Associates with Agitation and the Prefrontal Cortex in Patients with Alzheimer's Disease.

Behavioral and psychological symptoms of dementia (BPSD) occur in up to 80% of AD patients and represent one of the largest factors contributing to caregiver burden. To analyze the effect of galantamine on BPSD and caregiver burden, we treated a total of 50 patients with mild AD for 12 weeks and evaluated them using the Neuropsychiatric Inventory (NPI) and Japanese version of the Zarit Caregiver Burden Interview (ZBI). We also performed regional cerebral blood flow single photon emission computed tomography (rCBF SPECT) at baseline using three-dimensional sterotatic surface projections. Total NPI and ZBI scores did not significantly change after 12-week galantamine treatment. To identify the characteristics of patients who showed improvement after galantamine treatment, we divided patients into two groups, those with and those without sub-items on the NPI. Patients with aggression showed improvement in ZBI scores (p < 0.05). A comparison of rCBF SPECT between these two groups indicated that patients with aggression exhibited increased rCBF in the right prefrontal cortex compared with those without aggression. In a patient with aggression, 20-month treatment with galantamine inhibited increases in the rCBF area in the right prefrontal lobe. These results suggest that galantamine response may be related to aggression and dysfunction of the prefrontal cortex.

Recapitulation of Clinical Individual Susceptibility to Drug-Induced QT Prolongation in Healthy Subjects Using iPSC-Derived Cardiomyocytes.

To predict drug-induced serious adverse events (SAE) in clinical trials, a model using a panel of cells derived from human induced pluripotent stem cells (hiPSCs) of individuals with different susceptibilities could facilitate major advancements in translational research in terms of safety and pharmaco-economics. However, it is unclear whether hiPSC-derived cells can recapitulate interindividual differences in drug-induced SAE susceptibility in populations not having genetic disorders such as healthy subjects. Here, we evaluated individual differences in SAE susceptibility based on an in vitro model using hiPSC-derived cardiomyocytes (hiPSC-CMs) as a pilot study. hiPSCs were generated from blood samples of ten healthy volunteers with different susceptibilities to moxifloxacin (Mox)-induced QT prolongation. Different Mox-induced field potential duration (FPD) prolongation values were observed in the hiPSC-CMs from each individual. Interestingly, the QT interval was significantly positively correlated with FPD at clinically relevant concentrations (r > 0.66) in multiple analyses including concentration-QT analysis. Genomic analysis showed no interindividual significant differences in known target-binding sites for Mox and other drugs such as the hERG channel subunit, and baseline QT ranges were normal. The results suggest that hiPSC-CMs from healthy subjects recapitulate susceptibility to Mox-induced QT prolongation and provide proof of concept for in vitro preclinical trials.

Utility of time-resolved three-dimensional magnetic resonance digital subtraction angiography without contrast material for assessment of intracranial dural arterio-venous fistula.

BACKGROUND: Intracranial dural arteriovenous fistula (DAVF) is an arteriovenous shunting disease of the dura. Magnetic resonance angiography (MRA) is expected to be a safer alternative method in evaluation of DAVF, compared with invasive intra-arterial digital subtraction angiography (IADSA). PURPOSE: To evaluate the diagnostic use of time-spatial labeling inversion pulse (Time-SLIP) three-dimensional (3D) magnetic resonance digital subtraction angiography (MRDSA) without contrast material in six patients with DAVF. MATERIAL AND METHODS: Images for 3D time-of-flight MRA, which has been a valuable tool for the diagnosis of DAVF but provide little or less hemodynamic information, and Time-SLIP 3D MRDSA, were acquired for each patient. The presence, side, and grade of the disease were evaluated according to IADSA. RESULTS: In all patients, the presence and side of the DAVF were correctly identified by both 3D time-of-flight MRA and Time-SLIP 3D MRDSA. Cortical reflux present in a patient with a grade 2b DAVF was not detected by Time-SLIP 3D MRDSA, when compared with IADSA findings. CONCLUSION: Time-SLIP 3D MRDSA provides hemodynamic information without contrast material and is a useful complementary tool for diagnosis of DAVF.