Multicenter, Open-Label, Prospective Study Shows Safety and Therapeutic Benefits of a Defined Ginkgo Biloba Extract for Adults with Major Neurocognitive Disorder.

The safety and therapeutic effects of Gingko biloba extract EGb 761® to treat cognitive decline have been demonstrated in numerous clinical trials. However, trials in Indian populations have been lacking. This open-label, multicenter, single-arm, phase IV trial enrolled 150 patients aged ≥50 years with major neurocognitive disorder due to Alzheimer's disease, major vascular neurocognitive disorder, or mixed forms of both according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria and a Mini-Mental State Examination (MMSE) score of 12-24. Patients took 120 mg EGb 761® twice daily for 18 weeks. Therapeutic effects were assessed by CERAD constructional praxis and recall of constructional praxis (CERAD CP, CERAD recall of CP), Trail-Making Test (TMT), Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD), Clinical Global Impressions (CGI) scale, and 11-point box scales for tinnitus and vertigo. Safety assessment was based on the occurrence of adverse events as well as changes in clinical, laboratory, and functional parameters. After 18 weeks, significant improvements compared to baseline were found in constructional praxis (CERAD CP, p < 0.0001), memory (CERAD recall of CP, p < 0.0001), speed and executive functioning (TMT A, p < 0.0001; TMT B, p < 0.0001), and behavioral symptoms (BEHAVE-AD, p < 0.0001). Forty-five adverse events were reported in 33 (22.0%) patients in total, including ten presumed adverse drug reactions in 9 (6.0%) patients. Headache and diarrhea of mild-to-moderate severity were the most frequent events. Two serious adverse events, both considered unrelated to the study drug, occurred in 2 (1.3%) patients. This study confirmed the favorable safety profile and suggested therapeutic benefits of EGb 761® in Indian patients with major neurocognitive disorder.

Chowdhury D ，Roy AK ，Reddy VR ，Gupta YK ，Nigam P ，Hoerr R ... -  《-》

Ginkgo biloba extract for age-related macular degeneration.

Evans JR 《Cochrane Database of Systematic Reviews》

Galantamine for dementia due to Alzheimer's disease and mild cognitive impairment.

Dementia leads to progressive cognitive decline, and represents a significant health and societal burden. Its prevalence is growing, with Alzheimer's disease as the leading cause. There is no cure for Alzheimer's disease, but there are regulatory-approved pharmacological interventions, such as galantamine, for symptomatic relief. This review updates the 2006 version. To assess the clinical effects, including adverse effects, of galantamine in people with probable or possible Alzheimer's disease or mild cognitive impairment, and to investigate potential moderators of effect. We systematically searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register on 14 December 2022 using the term 'galantamine'. The Register contains records of clinical trials identified from major electronic databases (including CENTRAL, MEDLINE, and Embase), trial registries, grey literature sources, and conference proceedings. We manually searched reference lists and collected information from US Food and Drug Administration documents and unpublished trial reports. We imposed no language restrictions. We included double-blind, parallel-group, randomised controlled trials comparing oral galantamine with placebo for a treatment duration exceeding four weeks in people with dementia due to Alzheimer's disease or with mild cognitive impairment. Working independently, two review authors selected studies for inclusion, assessed their quality, and extracted data. Outcomes of interest included cognitive function, change in global function, activities of daily living, functional disability, behavioural function, and adverse events. We used a fixed-effect model for meta-analytic synthesis, and presented results as Peto odds ratios (OR) or weighted mean differences (MD) with 95% confidence intervals. We used Cochrane's original risk of bias tool (RoB 1) to assess the risk of bias in the included studies. We included 21 studies with a total of 10,990 participants. The average age of participants was 74 years, and 37% were male. The studies' durations ranged from eight weeks to two years, with 24 weeks being the most common duration. One newly included study assessed the effects of galantamine at two years, and another newly included study involved participants with severe Alzheimer's disease. Nineteen studies with 10,497 participants contributed data to the meta-analysis. All studies had low to unclear risk of bias for randomisation, allocation concealment, and blinding. We judged four studies to be at high risk of bias due to attrition and two due to selective outcome reporting. Galantamine for dementia due to Alzheimer's disease We summarise only the results for galantamine given at 8 to 12 mg twice daily (total galantamine 16 mg to 24 mg/day), assessed at six months. See the full review for results of other dosing regimens and assessment time points. There is high-certainty evidence that, compared to placebo, galantamine improves: cognitive function, as assessed with the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) (MD-2.86, 95% CI -3.29 to -2.43; 6 studies, 3049 participants; minimum clinically important effect (MCID) = 2.6- to 4-point change); functional disability, as assessed with the Disability Assessment for Dementia (DAD) scale (MD 2.12, 95% CI 0.75 to 3.49; 3 studies, 1275 participants); and behavioural function, as assessed with the Neuropsychiatric Inventory (NPI) (MD -1.63, 95% CI -3.07 to -0.20; 2 studies, 1043 participants) at six months. Galantamine may improve global function at six months, as assessed with the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus) (OR 1.58, 95% CI 1.36 to 1.84; 6 studies, 3002 participants; low-certainty evidence). Participants who received galantamine were more likely than placebo-treated participants to discontinue prematurely (22.7% versus 17.2%) (OR 1.41, 95% CI 1.19 to 1.68; 6 studies, 3336 participants; high-certainty evidence), and experience nausea (20.9% versus 8.4%) (OR 2.89, 95% CI 2.40 to 3.49; 7 studies, 3616 participants; high-certainty evidence) during the studies. Galantamine reduced death rates at six months: 1.3% of participants in the galantamine groups had died compared to 2.3% in the placebo groups (OR 0.56, 95% CI 0.33 to 0.96; 6 studies, 3493 participants; high-certainty evidence). Galantamine for mild cognitive impairment We summarise results, assessed at two years, from two studies that gave participants galantamine at 8 to 12 mg twice daily (total galantamine 16 mg to 24 mg/day). Compared to placebo, galantamine may not improve cognitive function, as assessed with the expanded ADAS-cog for mild cognitive impairment (MD -0.21, 95% CI -0.78 to 0.37; 2 studies, 1901 participants; low-certainty evidence) or activities of daily living, assessed with the Alzheimer's Disease Cooperative Study - Activities of Daily Living scale for mild cognitive impairment (MD 0.30, 95% CI -0.26 to 0.86; 2 studies, 1901 participants; low-certainty evidence). Participants who received galantamine were probably more likely to discontinue prematurely than placebo-treated participants (40.7% versus 28.6%) (OR 1.71, 95% CI 1.42 to 2.05; 2 studies, 2057 participants) and to experience nausea (29.4% versus 10.7%) (OR 3.49, 95% CI 2.75 to 4.44; 2 studies, 2057 participants), both with moderate-certainty evidence. Galantamine may not reduce death rates at 24 months compared to placebo (0.5% versus 0.1%) (OR 5.03, 95% CI 0.87 to 29.10; 2 studies, 2057 participants; low-certainty evidence). Results from subgroup analysis and meta-regression suggest that an imbalance in discontinuation rates between galantamine and placebo groups, together with the use of the 'last observation carried forward' approach to outcome assessment, may potentially bias cognitive outcomes in favour of galantamine. Compared to placebo, galantamine (when given at a total dose of 16 mg to 24 mg/day) slows the decline in cognitive function, functional ability, and behaviour at six months in people with dementia due to Alzheimer's disease. Galantamine probably also slows declines in global function at six months. The changes observed in cognition, assessed with the ADAS-cog scale, were clinically meaningful. Gastrointestinal-related adverse events are the primary concerns associated with galantamine use in people with dementia, which may limit its tolerability. Although death rates were generally low, participants in the galantamine groups had a reduced risk of death compared to those in the placebo groups. There is no evidence to support the use of galantamine in people with mild cognitive impairment.

Lim AWY ，Schneider L ，Loy C 《Cochrane Database of Systematic Reviews》

Randomized, Double-Blind, Placebo-Controlled Trial on the Efficacy, Safety and Tolerability of Modified-Release Methylphenidate (MPH-MR) in Chinese Children and Adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD).

The efficacy and safety of modified-release methylphenidate (MPH-MR) in the treatment of attention-deficit/hyperactivity disorder (ADHD) have been shown in both pediatric and adult Caucasian patients. The objective of this study was to assess the efficacy and safety of MPH-MR in Chinese children and adolescents with ADHD. MICCA was a randomized, double-blind, placebo-controlled trial conducted at 19 sites in China from September 2018 to July 2021. The study enrolled children and adolescents aged 6 to < 18 years with a primary diagnosis of ADHD according to the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-5). Patients were randomized 1:1 to once-daily MPH-MR (10-60 mg) or placebo. The study included an up-titration phase of up to 5 weeks and a dose maintenance phase of 4 weeks. The primary efficacy endpoint was the change in the ADHD Rating Scale-IV (ADHD-RS-IV) total score from baseline to the end of the maintenance phase (EoM). Secondary endpoints included the change from baseline to EoM in Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) total score, and Clinical Global Impression-Improvement (CGI-I) scores at EoM. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs. A total of 221 patients were randomized (MPH-MR: n = 110; placebo: n = 111). The change in the ADHD-RS-IV total score from baseline to EoM was significantly greater for MPH-MR versus placebo, with a least squares (LS) mean (95% confidence interval [CI]) treatment difference of - 4.6 (- 6.92, - 2.30) (p < 0.001). The mean (95% CI) treatment difference for the WFIRS-P total score change from baseline to EoM also significantly favored MPH-MR over placebo (- 6.46 [- 10.57, - 2.34]; p = 0.002). The CGI-I score at EoM was significantly lower in the MPH-MR group compared to the placebo group (2.2 vs 2.5; p = 0.002). Treatment-emergent adverse events were reported for 74 (67.3%) patients in the MPH-MR group and 55 (49.1%) patients in the placebo group. Most TEAEs were mild to moderate in severity. The most common TEAEs for MPH-MR were decreased appetite, nausea and upper respiratory tract infection. Treatment-emergent adverse events leading to study drug discontinuation/study withdrawal were reported in 4 (3.6%) patients in the MPH-MR group and 1 (0.9%) patient in the placebo group. No clinically relevant changes in vital signs were observed during the study. Modified-release methylphenidate was superior to placebo in improving ADHD symptoms and functioning in Chinese pediatric patients with ADHD. Modified-release methylphenidate had a good safety and tolerability profile. Trial Registration http://www.chinadrugtrials.org.cn/ Identifier: CTR20180056 (registered on 21 May 2018).

Zheng Y ，Liu H ，Wang X ，Li H ，Ruhmann M ，Mayer A ，Dangel O ，Ammer R ... -  《-》

The Turkish validity and reliability of Addenbrooke's Cognitive Examination III.

Addenbrooke's Cognitive Examination III (ACE-III) was developed as a screening tool for cognitive disorders. Many countries have proven the cultural adaptation, reliability and validity of ACE-III. To make cultural adaptations of ACE-III for the Turkish population and to examine its validity and reliability. First, ACE-III was translated and adapted into Turkish (ACE-III-TR), then its validity and reliability were examined. The study included 234 people: 93 with dementia (78 Alzheimer's disease (AD) and 15 frontotemporal dementia (FTD)), 46 with mild cognitive impairment (MCI) and 95 healthy. Two blinded speech and language therapists rated the ACE-III-TR simultaneously for interrater validity. The same practitioner retested the same participants 2 weeks later for test-retest reliability. The construct validity of the culturally adapted test was assessed by analysing subsection correlations with the ACE-III-TR total score. The association between the Mini-Mental State Examination (MMSE) total score, relevant subsections and ACE-III-TR total score was examined for criterion validity. Intergroup differences for healthy, MCI and dementia were studied for ACE-III-TR subsections and total score, and cut-off scores were calculated for total score with sensitivity and specificity in differential diagnosis. Attention, memory and ACE-III-TR total scores showed a statistically significant difference between the three groups of dementia, MCI and healthy (p < 0.001). Statistically significant positive correlations ranging from 0.571 to 0.929 were found between ACE-III-TR subsections and total scores (p < 0.05). A highly significant positive correlation was found between MMSE total score and ACE-III-TR total score (r = 0.870). Between the second and first measurements, positive, moderately significant correlations were found for all subsections and ACE-III-TR total (ICC = 0.508-0.784, r = 0.477-0.646). A high level of agreement was found between two raters for all ACE-III-TR subsections and the ACE-III-TR total score (alpha = 0.9296-0.99995). The total ACE-III-TR cut-off score was 79.5 for healthy and MCI and 69.5 for MCI and mild stage dementia. This study found that ACE-III-TR is a sensitive and specific screening test for the diagnosis of MCI and dementia that has high validity and reliability. ACE-III-TR was found to be a valid and reliable tool in dementia, including AD and FTD, and in mild, moderate and advanced dementia. By providing a more comprehensive assessment of a person's cognitive profile, it can help the clinician make a differential diagnosis of MCI and dementia. ACE-III-TR may be useful in monitoring the progression of cognitive deficits in clinical practice, research studies and therapy follow-up processes. What is already known on the subject ACE was used as a screening tool to detect MCI and to differentiate AD from FTD. ACE was revised by Hsieh et al. in 2013 and updated as ACE-III, which has the advantages of assessing five cognitive domains, not requiring the use of additional materials, and providing an effective and sensitive measurement in a short time. However, the validity and reliability study of the ACE-III in Turkish has not been conducted. What this study adds to the existing knowledge This study demonstrates the validity and reliability of the Turkish ACE-III (ACE-III-TR), which is a sensitive and specific screening test for the diagnosis of MCI and dementia. What are the practical and clinical implications of this work? The ACE-III-TR can provide clinicians and patients with a quick and brief general cognitive screening, indicating both the patient's overall cognitive profile and the measures of each of the assessed domains. By providing a more comprehensive assessment of a person's cognitive profile, it can help the clinician make a differential diagnosis of MCI and dementia. ACE-III-TR may be useful in monitoring the progression of cognitive deficits in clinical practice, research studies and therapy follow-up processes.

Parlak MM ，Bizpınar Munis Ö ，Köse A ，Yıldırım C ，Ülker CA ... -  《-》