A Multinational, Multicenter, Randomized, Double-Blind, Active Comparator, Phase III Clinical Trial to Evaluate the Efficacy and Safety of Donepezil Transdermal Patch in Patients With Alzheimer's Disease.

BACKGROUND AND PURPOSE: Oral administration of cholinesterase inhibitors is often associated with adverse gastrointestinal effects, and so developing an alternative administration route, such as transdermal, is urgently needed. The primary objective of this study was to determine the efficacy and safety of the IPI-301 donepezil transdermal patch compared with donepezil tablets (control) in mild-to-moderate probable Alzheimer's disease (AD). METHODS: This prospective, randomized, double-blind, double-dummy, two-arm parallel, multicenter trial included 399 patients, among whom 303 completed the trial. For randomization, the patients were stratified based on previous treatment and donepezil dose; patients in each stratum were randomized to the test and control groups at a 1:1 ratio. RESULTS: The difference between the control group and the IPI-301 group, quantified as the Hodges-Lehmann estimate of location shift, was 0.00 (95% confidence interval: -1.00 to 1.33), with an upper limit of less than 2.02. The change in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) score differed significantly between the IPI-301 and control groups (p=0.02). However, the changes in the full-itemized ADCS-ADL scores at week 24 did not differ significantly between the two groups. There were no differences between the two groups regarding the scores for the Clinician Interview-Based Impression of Change (p=0.9097), Mini-Mental State Examination (p=0.7018), Neuropsychiatric Inventory (p=0.7656), or Clinical Dementia Rating (p=0.9990). Adverse events, vital signs, and laboratory test results were comparable between the two groups. CONCLUSIONS: IPI-301 was safe and efficacious in improving cognitive function in patients with mild-to-moderate AD.

fNIRS-based functional connectivity estimation using semi-metric analysis to study decision making by nursing students and registered nurses.

This study aims to investigate the generalizability of the semi-metric analysis of the functional connectivity (FC) for functional near-infrared spectroscopy (fNIRS) by applying it to detect the dichotomy in differential FC under affective and neutral emotional states in nursing students and registered nurses during decision making. The proposed method employs wavelet transform coherence to construct FC networks and explores semi-metric analysis to extract network redundancy features, which has not been considered in conventional fNIRS-based FC analyses. The trials of the proposed method were performed on 19 nursing students and 19 registered nurses via a decision-making task under different emotional states induced by affective and neutral emotional stimuli. The cognitive activities were recorded using fNIRS, and the emotional stimuli were adopted from the International Affective Digitized Sound System (IADS). The induction of emotional effects was validated by heart rate variability (HRV) analysis. The experimental results by the proposed method showed significant difference (FDR-adjusted p = 0.004) in the nursing students' cognitive FC network under the two different emotional conditions, and the semi-metric percentage (SMP) of the right prefrontal cortex (PFC) was found to be significantly higher than the left PFC (FDR-adjusted p = 0.036). The benchmark method (a typical weighted graph theory analysis) gave no significant results. In essence, the results support that the semi-metric analysis can be generalized and extended to fNIRS-based functional connectivity estimation.

Role of Fluid Biomarkers and PET Imaging in Early Diagnosis and its Clinical Implication in the Management of Alzheimer's Disease.

Clinical diagnosis of Alzheimer's disease (AD) is based on symptoms; however, the challenge is to diagnose AD at the preclinical stage with the application of biomarkers and initiate early treatment (still not widely available). Currently, cerebrospinal fluid (CSF) amyloid-ß 42 (Aß42) and tau are used in the clinical diagnosis of AD; nevertheless, blood biomarkers (Aß42 and tau) are less predictive. Amyloid-positron emission tomography (PET) imaging is an advancement in technology that uses approved radioactive diagnostic agents (florbetapir, flutemetamol, or florbetaben) to estimate Aß neuritic plaque density in adults with cognitive impairment evaluated for AD and other causes of cognitive decline. There is no cure for AD to date-the disease progression cannot be stopped or reversed; approved pharmacological agents (donepezil, galantamine, and rivastigmine; memantine) provide symptomatic treatment. However, the disease-modifying therapies are promising; aducanumab and CAD106 are in phase III trials for the early stages of AD. In conclusion, core CSF biomarkers reflect pathophysiology of AD in the early and late stages; the application of approved radiotracers have potential in amyloid-PET brain imaging to detect early AD.

Assessing Neural Compensation With Visuospatial Working Memory Load Using Near-Infrared Imaging.

Alzheimer's disease is characterized by the progressive deterioration of cognitive abilities particularly working memory while mild cognitive impairment (MCI) represents its prodrome. It is generally believed that neural compensation is intact in MCI but absent in Alzheimer's disease. This study investigated the effects of increasing task load as a means to induce neural compensation through a novel visual working memory (VSWM) task using functional near-infrared spectroscopy (fNIRS). The bilateral prefrontal cortex (PFC) was explored due to its relevance in VSWM and neural compensation. A total of 31 healthy controls (HC), 12 patients with MCI and 18 patients with mild Alzheimer's disease (mAD) were recruited. Although all groups showed sensitivity in terms of behavioral performance (i.e. score) towards increasing task load (level 1 to 3), only in MCI load effect on cortical response (as measured by fNIRS) was significant. At lower task load, bilateral PFC activation did not differ between MCI and HC. Neural compensation in the form of hyperactivation was only noticeable in MCI with a moderate task load. Lack of hyperactivation in mAD, coupled with significantly poorer task performance across task loads, suggested the inability to compensate due to a greater degree of neurodegeneration. Our findings provided an insight into the interaction of cognitive load theory and neural compensatory mechanisms. The experiment results demonstrated the feasibility of inducing neural compensation with the proposed VSWM task at the right amount of cognitive load. This may provide a promising avenue to develop an effective cognitive training and rehabilitation for dementia population.

Lurasidone in the treatment of schizophrenia: Results of a double-blind, placebo-controlled trial in Asian patients.

INTRODUCTION: To evaluate efficacy and safety of lurasidone for the treatment of Asian patients with schizophrenia. METHODS: Patients with schizophrenia from Japan, South Korea, Malaysia, and Taiwan were randomly assigned to 6 weeks of double-blind treatment with 40 or 80 mg/d of lurasidone or placebo. The primary efficacy measure was change from baseline to week 6 on the Positive and Negative Syndrome Scale (PANSS) total score. Efficacy was evaluated using a mixed-model repeated-measures (MMRM) analysis in the modified intention-to-treat (mITT) population. RESULTS: On the basis of the analysis for the mITT population, the estimated difference score for lurasidone 40 and 80 mg/d vs placebo was -4.8 (P = 0.050) and -4.2 (P = 0.080). For the full intention-to-treat (ITT) population, the difference score for lurasidone 40 and 80 mg/d vs placebo was -5.8 (P = 0.017) and -4.2 (P = 0.043). The most frequent adverse events in the lurasidone 40 and 80 mg/d and placebo groups, respectively, were akathisia (7.3%, 10.4%, 3.3%), somnolence (6.0%, 2.6%, 0.7%), and vomiting (6.0%, 5.8%, 2.0%). The proportion of patients experiencing clinically significant weight gain (≥7%) was 5.3% for lurasidone 40 mg/d, 1.3% for 80 mg/d, and 1.4% for placebo. End point changes in metabolic parameters and prolactin were comparable for both lurasidone groups and placebo. CONCLUSIONS: In the ITT (but not the mITT) population, treatment with lurasidone was associated with significant improvement in the PANSS total score in patients with schizophrenia. Lurasidone was generally well tolerated with minimal impact on weight and metabolic parameters.

Visualizing Hyperactivation in Neurodegeneration Based on Prefrontal Oxygenation: A Comparative Study of Mild Alzheimer's Disease, Mild Cognitive Impairment, and Healthy Controls.

Background: Cognitive performance is relatively well preserved during early cognitive impairment owing to compensatory mechanisms. Methods: We explored functional near-infrared spectroscopy (fNIRS) alongside a semantic verbal fluency task (SVFT) to investigate any compensation exhibited by the prefrontal cortex (PFC) in Mild Cognitive Impairment (MCI) and mild Alzheimer's disease (AD). In addition, a group of healthy controls (HC) was studied. A total of 61 volunteers (31 HC, 12 patients with MCI and 18 patients with mild AD) took part in the present study. Results: Although not statistically significant, MCI exhibited a greater mean activation of both the right and left PFC, followed by HC and mild AD. Analysis showed that in the left PFC, the time taken for HC to achieve the activation level was shorter than MCI and mild AD (p = 0.0047 and 0.0498, respectively); in the right PFC, mild AD took a longer time to achieve the activation level than HC and MCI (p = 0.0469 and 0.0335, respectively); in the right PFC, HC, and MCI demonstrated a steeper slope compared to mild AD (p = 0.0432 and 0. 0107, respectively). The results were, however, not significant when corrected by the Bonferroni-Holm method. There was also found to be a moderately positive correlation (R = 0.5886) between the oxygenation levels in the left PFC and a clinical measure [Mini-Mental State Examination (MMSE) score] in MCI subjects uniquely. Discussion: The hyperactivation in MCI coupled with a better SVFT performance may suggest neural compensation, although it is not known to what degree hyperactivation manifests as a potential indicator of compensatory mechanisms. However, hypoactivation plus a poorer SVFT performance in mild AD might indicate an inability to compensate due to the degree of structural impairment. Conclusion: Consistent with the scaffolding theory of aging and cognition, the task-elicited hyperactivation in MCI might reflect the presence of compensatory mechanisms and hypoactivation in mild AD could reflect an inability to compensate. Future studies will investigate the fNIRS parameters with a larger sample size, and their validity as prognostic biomarkers of neurodegeneration.

Country variations in depressive symptoms profile in Asian countries: Findings of the Research on Asia Psychotropic Prescription (REAP) studies.

INTRODUCTION: This study was to assess differences in the symptom profile of depressive illness across various countries/territories in Asia. The study was a part of the Research on Asia Psychotropic Prescription project. The participating countries/territories include China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, Singapore, Taiwan, and Thailand. METHODS: The pattern of depressive symptoms in 1,400 subjects with depressive disorder from 42 psychiatric centers in 10 Asian countries/territories was assessed. We collected information on socio-demographic and clinical characteristics with a standardized protocol and data collection procedure. RESULTS: The most common presentations of depressive symptoms were persistent sadness, loss of interest, and insomnia. Similar findings were found regardless of the region, country, or its income level. Patients with depressive disorder from high-income countries presented significantly more with vegetative symptom cluster (P < 0.05), while those from the upper middle-income countries had significantly more with both mood (P < 0.001) and cognitive symptom clusters (P < 0.01). In lower middle-income countries, patients with depressive symptoms had significantly less mood symptom cluster (P < 0.001) but significantly more cognitive symptom cluster (P < 0.05). DISCUSSION: This study demonstrates that in Asia, despite variations in the initial symptom reported by the patients, across different countries/territories, core depressive symptoms remain the same. Variations have been found in presentation of depressive symptoms with regards to the level of income of countries. Physical or vegetative symptoms were reported more by centers in higher income countries, while depressive cognition and suicidal thoughts/acts were more frequently reported from lower income countries.

Social support and burden among caregivers of patients with dementia in Malaysia.

This study aims to examine selected factors of dementia patients and their caregivers that were associated with the burden of family caregivers. This cross sectional study involves face-to-face interview with family caregivers of patients with dementia. Participants were recruited through convenient sampling from geriatric and psychiatry outpatient clinics from three government hospitals, one university hospital, one rural health centre and Alzheimer Disease caregivers' support groups. 70 caregivers took part in the study. Measures included patient and caregiver demographic variables and caregiver burden using the Zarit Burden Interview (ZBI). Caregiver burden was found to be significantly associated with both ethnicity and informal support. Chinese caregivers were found to have a higher level of burden compared to Indians and Malays. Informal support, in particular assistance from family members, was significantly associated with a lower burden perceived by the caregivers. However, the study shows that formal support such as assistance from maids and private nurses did not alleviate the burden of caregivers. Results highlighted the importance of improving the coping skills in burdened caregivers particularly among family members with dementia relatives. Interventions should be designed for specific needs of caregivers of different ethnicities.