A multicenter, single-arm, phase II clinical trial of adrenomedullin in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of hereditary cerebral small vessel disease (SVD), currently lacks disease-modifying treatments. Adrenomedullin (AM), a vasoactive peptide with angiogenic, vasodilatory, anti-inflammatory, and anti-oxidative properties, shows potential effects on the neuro-glial-vascular unit. Objective: The AdrenoMedullin for CADASIL (AMCAD) study aims to assess the efficacy and safety of AM in patients with CADASIL. Sample size: Overall, 60 patients will be recruited. Methods: The AMCAD is a multicenter, investigator-initiated, single-arm phase II trial. Patients with a confirmed CADASIL diagnosis, based on NOTCH3 genetic testing, will receive an 8-h AM treatment (15 ng/kg/min) for 14 days following a baseline assessment (from day 1 to day 14). Follow-up evaluations will be performed on days 15, 28, 90, and 180. Study outcomes: The primary endpoint is the cerebral blood flow change rate in the frontal cortex, evaluated using arterial spin labeling magnetic resonance imaging, from baseline to day 28. Summary statistics, 95% confidence intervals, and a one-sample t-test will be used for analysis. Conclusion: The AMCAD study aims to represent the therapeutic potential of AM in patients with CADASIL, addressing an unmet medical need in this challenging condition. Clinical Trial Registration: jRCT 2,051,210,117 (https://jrct.niph.go.jp/en-latest-detail/jRCT2051210117).

Efficacy and Safety of Cilostazol in Mild Cognitive Impairment: A Randomized Clinical Trial.

Importance: Recent evidence indicates the efficacy of ß-amyloid immunotherapy for the treatment of Alzheimer disease, highlighting the need to promote ß-amyloid removal from the brain. Cilostazol, a selective type 3 phosphodiesterase inhibitor, promotes such clearance by facilitating intramural periarterial drainage. Objective: To determine the safety and efficacy of cilostazol in mild cognitive impairment. Design, Setting, and Participants: The COMCID trial (A Trial of Cilostazol for Prevention of Conversion from Mild Cognitive Impairment to Dementia) was an investigator-initiated, double-blind, phase 2 randomized clinical trial. Adult participants were registered between May 25, 2015, and March 31, 2018, and received placebo or cilostazol for up to 96 weeks. Participants were treated in the National Cerebral and Cardiovascular Center and 14 other regional core hospitals in Japan. Patients with mild cognitive impairment with Mini-Mental State Examination (MMSE) scores of 22 to 28 points (on a scale of 0 to 30, with lower scores indicating greater cognitive impairment) and Clinical Dementia Rating scores of 0.5 points (on a scale of 0, 0.5, 1, 2, and 3, with higher scores indicating more severe dementia) were enrolled. The data were analyzed from May 1, 2020, to December 1, 2020. Interventions: The participants were treated with placebo, 1 tablet twice daily, or cilostazol, 50 mg twice daily, for up to 96 weeks. Main Outcomes and Measures: The primary end point was the change in the total MMSE score from baseline to the final observation. Safety analyses included all adverse events. Results: The full analysis set included 159 patients (66 [41.5%] male; mean [SD] age, 75.6 [5.2] years) who received placebo or cilostazol at least once. There was no statistically significant difference between the placebo and cilostazol groups for the primary outcome. The least-squares mean (SE) changes in the MMSE scores among patients receiving placebo were -0.1 (0.3) at the 24-week visit, -0.8 (0.3) at 48 weeks, -1.2 (0.4) at 72 weeks, and -1.3 (0.4) at 96 weeks. Among those receiving cilostazol, the least-squares mean (SE) changes in MMSE scores were -0.6 (0.3) at 24 weeks, -1.0 (0.3) at 48 weeks, -1.1 (0.4) at 72 weeks, and -1.8 (0.4) at 96 weeks. Two patients (2.5%) in the placebo group and 3 patients (3.8%) in the cilostazol group withdrew owing to adverse effects. There was 1 case of subdural hematoma in the cilostazol group, which may have been related to the cilostazol treatment; the patient was successfully treated surgically. Conclusions and Relevance: In this randomized clinical trial, cilostazol was well tolerated, although it did not prevent cognitive decline. The efficacy of cilostazol should be tested in future trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02491268.

[Development of the Japanese version of the 16-Item Informant Questionnaire on Cognitive Decline for the Elderly (J-IQCODE 16) for the Diagnosis of Prestroke Dementia].

The 16-Item Informant Questionnaire on Cognitive Decline for the Elderly (IQCODE 16) has been frequently used to diagnose prestroke dementia, an important determinant of stroke prognosis. We developed the Japanese version of the IQCODE 16 (J-IQCODE 16) using standardized translation methods. We applied the J-IQCODE 16 to 102 patients with stroke (19 with prestroke dementia diagnosed with DSM-5) admitted to the stroke care unit in our hospital. The cohort was randomly divided into a derivation cohort and a validation cohort containing 51 patients each. In the derivation cohort, the median J-IQCODE 16 score was 3.06, and the area under the receiver operating characteristic curve for prestroke dementia was 0.96, with an optimal cutoff value of 3.25 determined using the Youden index. When applied this cut-point to the validation cohort, the sensitivity and specificity of the J-IQCODE 16 for prestroke dementia were 90% and 85%, respectively. The J-IQCODE 16 is considered useful for the diagnosis of prestroke dementia.

Comparing Pathological Risk Factors for Dementia between Cognitively Normal Japanese and Americans.

The Alzheimer's Disease Neuroimaging Initiative showed that Japanese had significantly lower brain Aß burden than Americans among a cognitively normal population. This cross-sectional study aimed to compare vascular disease burden, Aß burden, and neurodegeneration between cognitively normal elderly Japanese and Americans. Japanese and American participants were matched for age (±4-year-old), sex, and Apolipoprotein E (APOE) genotype. Brain vascular disease burden and brain Aß burden were measured using white matter lesions (WMLs) and 11C-labeled Pittsburgh Compound B (PiB) retention, respectively. Neurodegeneration was measured using hippocampal volumes and cortical thickness. A total of 95 Japanese and 95 Americans were recruited (50.5% men, mean age = 82). Compared to Americans, Japanese participants had larger WMLs, and a similar global Aß standardized uptake value ratio (SUVR), cortical thickness and hippocampal volumes. Japanese had significantly lower regional Aß SUVR in the anterior ventral striatum, posterior cingulate cortex, and precuneus. Cognitively normal elderly Japanese and Americans had different profiles regarding vascular disease and Aß burden. This suggests that multiple risk factors are likely to be involved in the development of dementia. Additionally, Japanese might have a lower risk of dementia due to lower Aß burden than Americans. Longitudinal follow-up of these cohorts is warranted to ascertain the predictive accuracy of these findings.

Associations of equol-producing status with white matter lesion and amyloid-ß deposition in cognitively normal elderly Japanese.

INTRODUCTION: Equol, a metabolite of a soy isoflavone transformed by the gut microbiome, is anti-oxidant and anti-amyloidogenic. We assessed the associations of equol with white matter lesion normalized to total brain volume (WML%) and amyloid beta (Aß) deposition. METHODS: From 2016 to 2018, 91 cognitively normal elderly Japanese aged 75 to 89 underwent brain magnetic resonance imaging and positron emission tomography using 11C-Pittsburgh compound-B. Serum equol was measured using stored samples from 2008 to 2012. Equol producers were defined as individuals with serum levels >0. Producers were further divided into high (> the median) and low (≤ the median) producers. RESULTS: The median (interquartile range) WML% was 1.10 (0.59 to 1.61); 24.2% were Aß positive, and 51% were equol producers. Equol-producing status (non-producers, low and high) was significantly inversely associated with WML%: 1.19, 0.89, and 0.58, respectively (trend P < .01). Equol-producing status was not associated with Aß status. DISCUSSION: A randomized-controlled trial of equol targeting WML volume is warranted.

Effects of soy isoflavones on cognitive function: a systematic review and meta-analysis of randomized controlled trials.

CONTEXT: The results of preclinical and observational studies support the beneficial effect of soy isoflavones on cognition. OBJECTIVE: This review aimed to evaluate the effects of soy isoflavones on cognition in adults. DATA SOURCES: The PUBMED, EMBASE, Ovid Medline, Cochrane Library, and clinicaltrials.gov databases were searched. STUDY SELECTION: Two researchers independently screened 1955 records, using the PICOS criteria: participants were adults; intervention was dietary sources with soy isoflavones or isolated soy isoflavones; comparator was any comparator; outcome was cognitive function; study type was randomized controlled trials (RCTs). A third researcher was consulted to resolve any discrepancies. Sixteen RCTs were included and their quality assessed. DATA EXTRACTION: Information on study design, characteristics of participants, and outcomes was extracted. PRISMA guidelines were followed. DATA ANALYSIS: A random-effects meta-analysis was used to pool estimates across studies. In the 16 RCTs (1386 participants, mean age = 60 y), soy isoflavones were found to improve overall cognitive function (standardized mean difference [SMD], 0.19; 95% confidence interval [CI], 0.07-0.32) and memory (SMD, 0.15; 95%CI, 0.03-0.26). CONCLUSION: The results showed that soy isoflavones may improve cognitive function in adults. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42018082070.

Effect of S-equol and Soy Isoflavones on Heart and Brain.

BACKGROUND: Observational studies in Asia show that dietary intake of soy isoflavones had a significant inverse association with coronary heart disease (CHD). A recent randomized controlled trial (RCT) of soy isoflavones on atherosclerosis in the US, however, failed to show their benefit. The discrepancy may be due to the much lower prevalence of S-equol producers in Westerners: Only 20-30% of Westerners produce S-equol in contrast to 50-70% in Asians. S-equol is a metabolite of dietary soy isoflavone daidzein by gut microbiome and possesses the most antiatherogenic properties among all isoflavones. Several short-duration RCTs documented that soy isoflavones improves arterial stiffness. Accumulating evidence shows that both atherosclerosis and arterial stiffness are positively associated with cognitive decline/dementia. Therefore, potentially, soy isoflavones, especially S-equol, are protective against cognitive decline/dementia. METHODS/RESULTS: This narrative review of clinical and epidemiological studies provides an overview of the health benefits of soy isoflavones and introduces S-equol. Second, we review recent evidence on the association of soy isoflavones and S-equol with CHD, atherosclerosis, and arterial stiffness as well as the association of atherosclerosis and arterial stiffness with cognitive decline/ dementia. Third, we highlight recent studies that report the association of soy isoflavones and S-equol with cognitive decline/dementia. Lastly, we discuss the future directions of clinical and epidemiological research on the relationship of S-equol and CHD and dementia. CONCLUSIONS: Evidence from observational studies and short-term RCTs suggests that S-equol is anti-atherogenic and improves arterial stiffness and may prevent CHD and cognitive impairment/ dementia. Well-designed long-term (≥ 2years) RCTs should be pursued.

The parenting attitudes and the stress of mothers predict the asthmatic severity of their children: a prospective study.

OBJECTIVE: To examine relationships between a mother's stress-related conditions and parenting attitudes and their children's asthmatic status. METHODS: 274 mothers of an asthmatic child 2 to 12 years old completed a questionnaire including questions about their chronic stress/coping behaviors (the "Stress Inventory"), parenting attitudes (the "Ta-ken Diagnostic Test for Parent-Child Relationship, Parent Form"), and their children's disease status. One year later, a follow-up questionnaire was mailed to the mothers that included questions on the child's disease status. RESULTS: 223 mothers (81%) responded to the follow-up survey. After controlling for non-psychosocial factors including disease severity at baseline, multiple linear regression analysis followed by multiple logistic regression analysis found chronic irritation/anger and emotional suppression to be aggravating factors for children aged < 7 years; for children aged 7 and over, the mothers' egocentric behavior was a mitigating factor while interference was an aggravating factor. CONCLUSIONS: Different types of parental stress/coping behaviors and parenting styles may differently predict their children's asthmatic status, and such associations may change as children grow.