Influence of Preoperative COVID-19 Vaccination on Outcomes After Coronary Artery Bypass Grafting-A Propensity Score-Matched Analysis.

BACKGROUND: Reports of intravascular thrombosis and cardiac complications have raised concerns about the safety of COVID-19 vaccinations, particularly in patients with high cardiovascular risk. Herein, we aimed to analyze the impact of preoperative COVID-19 vaccination on outcomes after coronary artery bypass grafting (CABG). METHODS AND RESULTS: Among 520 patients who underwent isolated CABG from 2020 to 2022, 481 patients (mean±SD age: 67±11 years, 86 women) whose COVID-19 vaccination status could be confirmed were included. A total of 249 patients who had not received any COVID-19 vaccine before CABG (never vaccinated group) and 214 patients who had completed primary vaccination (fully vaccinated group) were subjected to 1:1 propensity score matching, and 156 pairs of patients were matched. There was no significant difference in early mortality between the 2 groups after matching. After matching, overall survival (P=0.930) and major adverse cardiovascular and cerebrovascular event-free survival (P=0.636) did not differ between the 2 groups. One-year graft patency also did not differ significantly between the 2 groups; all patent grafts in 85/104 patients (82%) and 62/73 patients (85%) in the never vaccinated and fully vaccinated groups, respectively (P=0.685). Subgroup analysis showed equivalent overall and major adverse cardiovascular and cerebrovascular event-free survival among AstraZeneca and Pfizer vaccine recipients and between those with ≤30 days versus >30 days from vaccination to CABG. CONCLUSIONS: Despite the very high cardiovascular risk for patients undergoing CABG, COVID-19 vaccination did not affect major outcomes after CABG. Therefore, there is no reason for patients with coronary artery disease requiring CABG to avoid preoperative COVID-19 vaccination.

Angiotensin-converting enzyme insertion/deletion gene polymorphism and the progression of cerebral microbleeds.

Background and purpose: The angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism has been studied as a genetic candidate for cerebral small vessel disease (CSVD). However, no previous study has evaluated the relationship between the ACE I/D polymorphism and cerebral microbleed (CMB), an important CSVD marker. We evaluated the association between ACE I/D polymorphisms and 2-year changes in CMBs. Methods: The CHALLENGE (Comparison Study of Cilostazol and Aspirin on Changes in Volume of Cerebral Small Vessel Disease White Matter Changes) database was analyzed. Of 256 subjects, 186 participants who underwent a 2-year follow-up brain scan and ACE genotyping were included. Our analysis was conducted by dividing the ACE genotype into two groups (DD vs. ID/II) under the assumption of the recessive effects of the D allele. A linear mixed-effect model was used to compare the 2-year changes in the number of CMBs between the DD and combined ID/II genotypes. Results: Among 186 patients included in this study, 24 (12.9%) had the DD genotype, 91 (48.9%) had the ID genotype, and 71 (38.2%) had the II genotype. Baseline clinical characteristics and cerebral small vessel disease markers were not different between the two groups (DD vs. ID/II) except for the prevalence of hypertension (DD 66.7% vs. ID/II 84.6%; p = 0.04). A multivariate linear mixed-effects model showed that the DD carriers had a greater increase in total CMB counts than the ID/II carriers after adjusting for the baseline number of CMBs, age, sex, and hypertension (estimated mean of difference [standard error (SE)] = 1.33 [0.61]; p = 0.03). When we performed an analysis of cases divided into deep and lobar CMBs, only lobar CMBs were significantly different between the two groups (estimated mean of difference [SE] = 0.94 [0.42]; p = 0.02). Conclusion: The progression of CMBs over 2 years was greater in the ACE DD carriers compared with the combined II/ID carriers. The results of our study indicate a possible association between the ACE I/D polymorphism and CMB. A study with a larger sample size is needed to confirm this association.

Effects of GV1001 on Language Dysfunction in Patients With Moderate-to-Severe Alzheimer's Disease: Post Hoc Analysis of Severe Impairment Battery Subscales.

Background and Purpose: The efficacy and safety of GV1001 have been demonstrated in patients with moderate-to-severe Alzheimer's disease (AD). In this study, we aimed to further demonstrate the effectiveness of GV1001 using subscales of the Severe Impairment Battery (SIB), which is a validated measure to assess cognitive function in patients with moderate-to-severe AD. Methods: We performed a post hoc analysis of data from a 6 month, multicenter, phase 2, randomized, double-blind, placebo-controlled trial with GV1001 (ClinicalTrials.gov, NCT03184467). Patients were randomized to receive either GV1001 or a placebo for 24 weeks. In the current study, nine subscales of SIB-social interaction, memory, orientation, language, attention, praxis, visuospatial ability, construction, and orientation to name- were compared between the treatment (GV1001 1.12 mg) and placebo groups at weeks 12 and 24. The safety endpoints for these patients were also determined based on adverse events. Results: In addition to the considerable beneficial effect of GV1001 on the SIB total score, GV1001 1.12 mg showed the most significant effect on language function at 24 weeks compared to placebo in both the full analysis set (FAS) and per-protocol set (PPS) (p=0.017 and p=0.011, respectively). The rate of adverse events did not differ significantly between the 2 groups. Conclusions: Patients with moderate-to-severe AD receiving GV1001 had greater language benefits than those receiving placebo, as measured using the SIB language subscale.

Effect of internet-based vs. in-person multimodal interventions on patients with mild to moderate Alzheimer's disease: a randomized, cross-over, open-label trial.

Objective: We aimed to investigate the effect of internet-based and in-person cognitive interventions on cognition, mood, and activities of daily living (ADL) on patients with mild to moderate Alzheimer's disease (AD) and examine whether internet-based intervention is as effective as the in-person intervention. Methods: We recruited 52 patients with probable mild AD, of whom 42 completed the trial. We randomly divided participants into intervention and control groups at a 1:1 ratio and statistically compared the neuropsychological test results of the two groups. In addition, patients in the intervention group were randomly assigned to a 4 weeks internet-based or in-person intervention, with subsequent crossover to the other group for 4 weeks. We statistically analyzed and compared the neuropsychological test scores between internet-based and in-person interventions. Results: Compared with the control group, the intervention group (internet-based and in-person) showed significantly improved profile in cognition (p < 0.001), depression (p < 0.001), anxiety (p < 0.001) and ADL (p < 0.001). In addition, the effect of the internet-based intervention on cognition (p = 0.918) and depression (p = 0.282) was not significantly different from that of the in-person intervention. However, in the Beck anxiety inventory (p = 0.009) and Seoul instrumental activity of daily living (p = 0.023), in-person intervention was more effective than internet-based intervention. Conclusion: This study suggests that both types of cognitive intervention (in-person and internet-based) may be viable supplementary treatments along with approved pharmacological therapy. In terms of anxiety and ADL, the effect of the in-person interventions may be more effective than the-internet based interventions.

A Multicentre, Randomised, Open-Label, Prospective Study to Estimate the Add-On Effects Of Memantine as Ebixa® Oral Pump (Solution) on Language in Patients with Moderate to Severe Alzheimer's Disease Already Receiving Donepezil (ROMEO-AD).

INTRODUCTION: This multicentre, randomised, open-label, and prospective study aimed to evaluate the effectiveness of memantine (memantine solution) on speech function in patients with moderate to severe Alzheimer's disease (AD) who were already on donepezil therapy. METHODS: Participants were divided into two groups: the drug trial group was administered donepezil + memantine (memantine solution), while the control group was administered only donepezil. Patients in the test group were required to increase the dose of memantine by 5 mg/day per week for the first 4 weeks and were maintained at 20 mg/day until the end of the trial. RESULTS: Of the 188 participants, 24 dropped out, and 164 completed the final research process. As the primary outcome, K-WAB showed an increase in scores in both groups compared to baseline scores; however, the difference was not statistically significant (P = 0.678). After 12 weeks, the donepezil treatment group had higher K-MMSE and lower CDR-SB scores than the donepezil and memantine combination group, indicating better cognitive and functional status. However, this effect was not sustained for 24 weeks. Patients who were assigned to receive only donepezil had Relevant Outcome Scale for AD (ROSA) scores that were higher by an average of 4.6 points compared to the donepezil and memantine combination group. The NPI-Q index improved compared to baseline values in both groups. CONCLUSIONS: Although several clinical studies have reported significant improvements in speech function after the administration of memantine, clinical studies on speech function improvement in patients with Alzheimer's disease are still insignificant. There are no studies on the effect of donepezil and memantine in combination treatment on language function in the moderate and severe stages of AD. Therefore, we investigated the effect of memantine (memantine solution) on speech function in patients with moderate to severe AD who were administered donepezil at a stable dose. Although the efficacy of the combination therapy was not superior to that of donepezil monotherapy alone, memantine was effective in improving behavioural symptoms in patients with moderate or severe AD.

White Matter Lesions Predominantly Located in Deep White Matter Represent Embolic Etiology Rather Than Small Vessel Disease.

Background and Purpose: We investigated the correlation between the deep distribution of white matter hyperintensity (WMH) (dWMH: WMH in deep and corticomedullary areas, with minimal periventricular WMH) and a positive agitated saline contrast echocardiography result. Methods: We retrospectively recruited participants with comprehensive dementia evaluations, an agitated saline study, and brain imaging. The participants were classified into two groups according to WMH-distributions: dWMH and dpWMH (mainly periventricular WMH with or without deep WMH.) We hypothesized that dWMH is more likely associated with embolism, whereas dpWMH is associated with small-vessel diseases. We compared the clinical characteristics, WMH-distributions, and positive rate of agitated saline studies between the two groups. Results: Among 90 participants, 27 and 12 met the dWMH and dpWMH criteria, respectively. The dWMH-group was younger (62.2±7.5 vs. 78.9±7.3, p<0.001) and had a lower prevalence of hypertension (29.6% vs. 75%, p=0.008), diabetes mellitus (3.7% vs. 25%, p=0.043), and hyperlipidemia (33.3% vs. 83.3%, p=0.043) than the dpWMH-group. Regarding deep white matter lesions, the number of small lesions (<3 mm) was higher in the dWMH-group(10.9±9.7) than in the dpWMH-group (3.1±6.4) (p=0.008), and WMH was predominantly distributed in the border-zones and corticomedullary areas. Most importantly, the positive agitated saline study rate was higher in the dWMH-group than in the dpWMH-group (81.5% vs. 33.3%, p=0.003). Conclusions: The dWMH-group with younger participants had fewer cardiovascular risk factors, showed more border-zone-distributions, and had a higher agitated saline test positivity rate than the dpWMH-group, indicating that corticomedullary or deep WMH-distribution with minimal periventricular WMH suggests embolic etiologies.

Resting Heart Rate and Cognitive Decline: A Meta-Analysis of Prospective Cohort Studies.

BACKGROUND AND PURPOSE: Several previous meta-analyses have identified an association between cognitive decline and heart rate variability, which reflects autonomic nerve activity. This systematic review and meta-analysis investigated the impact of increased resting heart rate (RHR) on the incidence of cognitive decline, including dementia. METHODS: The PubMed, Embase, and PsycInfo databases were searched for relevant prospective cohort studies published before April 18, 2022. A methodological quality assessment of the included studies was conducted using the Newcastle-Ottawa Scale. Summary estimates of the incidence of cognitive decline, including dementia, were generated using a random-effects model. Potential publication bias was evaluated using Begg's funnel plots and Egger's regression tests. RESULTS: The meta-analysis included 7 prospective cohort studies comprising 53,621 participants. A weak significant association was observed between RHR and the risk of cognitive decline, although the analysis indicated high heterogeneity among the studies (relative risk=1.18, 95% confidence interval=1.04-1.33, I²=82.5%). Significant associations were determined between RHR and all combined types of dementia except for Alzheimer's disease and mild cognitive impairment. There was also a dose-response association between increased RHR and cognitive decline. The meta-estimate of the cognitive decline risk associated with a 10 beat-per-minute increase in RHR was 1.06, and it was 1.10 for dementia. CONCLUSIONS: This study found that a higher RHR was associated with an increased cognitive decline risk. Due to study limitations such as publication bias and high heterogeneity, additional studies are required to validate this finding. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42021282912.

Long-term patency of bilateral internal thoracic artery Y composite coronary artery bypass grafts-determinants and impact on survival.

Background: Bilateral internal thoracic artery Y-composite grafting with sequential anastomoses is a well-established strategy for multi-arterial coronary artery bypass grafting. This study investigated the factors affecting long-term patency of bilateral internal thoracic artery Y-composite grafts and their influence on survival. Methods: Patients who underwent coronary artery bypass grafting using bilateral internal thoracic artery Y-composite grafts due to triple-vessel disease were included. In total, 415 cases (2003-2020) with at least 1 postoperative coronary computed tomography or angiography examination were enrolled. Through a retrospective review of medical records and computed tomography, risk factors for graft events (string sign or occlusion) were analysed, and the influence of string sign or occlusion in the initial postoperative computed tomography on long-term survival was evaluated. Results: Patients' mean age was 66±9 years and 324 were male (78%). The mean number of anastomoses from bilateral internal thoracic artery grafts was 4.0±0.9. The mean follow-up duration was 8.0±4.0 years (interquartile range: 4.8-11.5 years). Beating-heart surgery negatively affected the patency of grafts to the left circumflex and right coronary artery territories (P=0.015 and P=0.030, respectively), but in the left anterior descending territory, the graft patency did not differ (P=0.053). Non-severe (<90%) native-vessel stenosis was a risk factor for poor patency in the left anterior descending, left circumflex, and right coronary artery territories (P<0.001 for all). Twenty-four of the 104 nonvisible or narrowed grafts (23%) on early imaging later became widely patent. Occlusion of the grafts or the string sign within postoperative 1 year did not have a negative impact on long-term survival (P=0.421). Conclusions: The patency rate was suboptimal in case of non-severe target-vessel stenosis (<90%). The beating-heart technique may negatively influence the patency of anastomoses to the left circumflex and right coronary artery territories. Compromised graft patency observed on initial computed tomography did not lead to worse survival.

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.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase IIb Clinical Study to Evaluate the Safety and Efficacy of DHP1401 in Patients with Mild to Moderate Alzheimer's Disease Treated with Donepezil: DHP1401 Randomized Trial in Mild to Moderate Alzheimer's Disease (DRAMA).

BACKGROUND: Preclinical studies in transgenic models of Alzheimer's disease (AD) suggest that DHP1401 has neuroprotective and memory-enhancing effects. OBJECTIVE: To evaluate the efficacy and safety of DHP1401 in AD patients treated with donepezilMethods:Methods: In a double-blind study, patients with mild-to-moderate AD were randomized (1:1:1) to receive a twice daily total dose of 500 mg or 1000 mg DHP1401 or placebo for 24 weeks. Tolerability and safety were monitored at baseline and weeks 12 and 24. RESULTS: total of 180 patients were randomized to Active 1 (500 mg: n = 62), Active 2 (1000 mg: n = 53), and control groups (n = 65) in 16 sites in Korea. There was no significant difference in the Alzheimer's Disease Assessment Scale (ADAS-cog) score, the primary efficacy endpoint, from baseline. However, in the subgroup with mild AD patients (MMSE, 20-26) who received the high dose of DHP1401 and the group that received donepezil 5 mg, the ADAS-cog scores improved. MMSE and K-TMT-e type B were significant in both active groups at week 24. The most frequently observed symptom was dizziness (2.78%), and the most commonly observed reactions were related to metabolism and nutrition disorders (5.00%). No remarkable adverse events were observed for 24 weeks. CONCLUSION: Although the effectiveness of DHP1401 was not proved to be superior as the primary efficacy endpoint, the secondary endpoints, MMSE and K-TMT-e type B, showed significant beneficial effects. Also, the subgroups showed that ADAS-cog scores significantly were improved. DHP1401 could be proven beneficial for the AD treatment by further clinical trials.

Serum cadmium is associated with hepatic steatosis and fibrosis: Korean national health and nutrition examination survey data IV-VII.

ABSTRACT: Although cadmium (Cd) is correlated with elevated levels of hepatic amino transferases, its influence on the degree of liver steatosis and fibrosis are unknown yet. We aimed to investigate the associations between the serum level of Cd and degree of liver steatosis/fibrosis.Clinical data were obtained from Korean National Health and Nutrition Examination Surveys IV-VII. Alanine aminotransferase (ALT) elevation was defined as ≥ 33 IU/L for men and ≥ 25 IU/L for women. Significant steatosis was defined as a hepatic steatosis index ≥ 36, while significant fibrosis was defined as a fibrosis index (FIB-4) ≥ 2.67 and as an aspartate aminotransferase and platelet ratio index ≥ 0.7. Adjusted odds ratios and 95% confidence intervals were calculated after adjustment.The levels of serum Cd were assessable in 15,783 subjects. The serum cadmium concentrations were significantly associated with ALT elevation, significant liver steatosis and fibrosis. Multivariate logistic regression analysis demonstrated serum Cd level in the forth quartile had a positive correlation with ALT elevation, hepatic steatosis index ≥ 36, FIB-4 ≥ 2.67 and aspartate aminotransferase-to-platelet ratio ≥ 0.7 using the first quartile of serum Cd level as the reference, (adjusted odds ratios 1.90, 1.26, 1.73, and 2.53, respectively; P values <.001).The serum level of Cd was associated with liver steatosis and fibrosis. The evaluation of serum Cd may help for assessing an unexplained liver steatosis and fibrosis, and further prospective studies are needed to confirm our findings.

Cilostazol Versus Aspirin on White Matter Changes in Cerebral Small Vessel Disease: A Randomized Controlled Trial.

BACKGROUND AND PURPOSE: Cerebral small vessel disease is characterized by progressive cerebral white matter changes (WMCs). This study aimed to compare the effects of cilostazol and aspirin on changes in WMC volume in patients with cerebral small vessel disease. METHODS: In a multicenter, double-blind, randomized controlled trial, participants with moderate or severe WMCs and at least one lacunar infarction detected on brain magnetic resonance imaging were randomly assigned to the cilostazol and aspirin groups in a 1:1 ratio. Cilostazol slow release (200 mg) or aspirin (100 mg) capsules were administered once daily for 2 years. The primary outcome was the change in WMC volume on magnetic resonance images from baseline to 2 years. Secondary imaging outcomes include changes in the number of lacunes or cerebral microbleeds, fractional anisotropy, and mean diffusivity on diffusion tensor images, and brain atrophy. Secondary clinical outcomes include all ischemic strokes, all ischemic vascular events, and changes in cognition, motor function, mood, urinary symptoms, and disability. RESULTS: Between July 2013 and August 2016, 256 participants were randomly assigned to the cilostazol (n=127) and aspirin (n=129) groups. Over 2 years, the percentage of WMC volume to total WM volume and the percentage of WMC volume to intracranial volume increased in both groups, but neither analysis showed significant differences between the groups. The peak height of the mean diffusivity histogram in normal-appearing WMs was significantly reduced in the aspirin group compared with the cilostazol group. Cilostazol significantly reduced the risk of ischemic vascular event compared with aspirin (0.5 versus 4.5 cases per 100 person-years; hazard ratio, 0.11 [95% CI, 0.02-0.89]). CONCLUSIONS: There was no significant difference between the effects of cilostazol and aspirin on WMC progression in patients with cerebral small vessel disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01932203.

Sex differences in the progression of cerebral microbleeds in patients with concomitant cerebral small vessel disease.

Background and purpose: Sex differences in cerebral microbleeds (CMBs) are not well-known. We aimed to assess the impact of sex on the progression of CMBs. Methods: The CHALLENGE (Comparison Study of Cilostazol and Aspirin on Changes in Volume of Cerebral Small Vessel Disease White Matter Changes) database was analyzed. Out of 256 subjects, 189 participants with a follow-up brain scan were included in the analysis. The linear mixed-effect model was used to compare the 2-year changes in the number of CMBs between men and women. Results: A total of 65 men and 124 women were analyzed. There were no significant differences in the prevalence (70.8 vs. 71.8%; P = 1.000) and the median [interquartile range (IQR)] number of total CMBs [1 (0-7) vs. 2 (0-7); P = 0.810] at baseline between men and women. The median (IQR) increase over 2 years in the number of CMBs was statistically higher in women than in men [1 (0-2) vs. 0 (0-1), P = 0.026]. The multivariate linear mixed-effects model showed that women had a significantly greater increase in the number of total, deep, and lobar CMBs compared to men after adjusting for age and the baseline number of CMBs [estimated log-transformed mean of difference between women and men: 0.040 (P = 0.028) for total CMBs, 0.037 (P = 0.047) for deep CMBs, and 0.047 (P = 0.009) for lobar CMBs]. Conclusion: The progression of CMB over 2 years was significantly greater in women than in men.

Effects of Body Weight on the Safety of High-Dose Donepezil in Alzheimer's Disease: Post hoc Analysis of a Multicenter, Randomized, Open-Label, Parallel Design, Three-Arm Clinical Trial.

BACKGROUND: Donepezil 23 mg is considered for Alzheimer's disease (AD) to optimize cognitive benefits; however, increased adverse events (AEs) can negatively influence drug adherence. We investigated whether body weight (BW) differs based on the presence of AEs, and which baseline factors were relevant to the safety of high-dose donepezil. METHODS: This study was a post hoc analysis of a multicenter randomized trial between 2014 and 2016. We included patients with moderate to severe AD treated with 10 mg/day of donepezil, and the daily dose was escalated to 23 mg with/without dose titration. Dose titration indicates 15 mg/day of donepezil before escalation or 10 mg and 23 mg/day on alternate days before escalation during the first 4 weeks. The patients were divided into 2 groups based on occurrence of AEs of special interest (AESIs) to compare baseline characteristics. We also assessed relationships between BW and AESIs. RESULTS: Among the 160 participants in the safety population, the baseline BWs differed between the AESI (+) (n = 67) and AESI (-) (n = 93) groups. Baseline BW was inversely correlated with the occurrence of AESIs (p = 0.020), and this relationship was prominent in the no-dose titration group (p = 0.009) but absent in the dose-titration groups (p > 0.05). CONCLUSIONS: BW is the most important factor that correlated with cholinergic AEs. Hence, stepwise dose titration should be considered, particularly in patients with low BW, to minimize the inverse relationship between BW and the occurrence of AEs ("Clinicaltrials.gov" No. NCT02550665 registered on September 15, 2015).

Efficacy and safety of GV1001 in patients with moderate-to-severe Alzheimer's disease already receiving donepezil: a phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial.

BACKGROUND: Our previous studies showed that GV1001 has various protective effects against ß-amyloid and other stressors. Based on these findings, we hypothesized that GV1001 might have beneficial effects in patients with Alzheimer's disease (AD). METHODS: A phase 2, double-blind, parallel-group, placebo-controlled, 6-month randomized clinical trial was performed to evaluate the safety and efficacy of subcutaneously administered GV1001. Between September 2017 and September 2019, 13 centers in South Korea recruited participants. A total of 106 patients were screened, and 96 patients with moderate-to-severe AD were randomized 1:1:1 to the placebo (group 1, n = 31), GV1001 0.56 mg (group 2, n = 33), and 1.12 mg (group 3, n = 32) groups. GV1001 was administered every week for 4 weeks (4 times), followed by every 2 weeks until week 24 (10 times). The primary endpoint was the change in the Severe Impairment Battery (SIB) score from baseline to week 24. The key secondary efficacy endpoints were the change in the Clinical Dementia Rating Sum of Box (CDR-SOB), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI), Mini-Mental State Examination, and Global Deterioration Scale scores. The safety endpoints were also assessed based on adverse events, laboratory test results, vital signs, and other observations related to safety. RESULTS: Group 3 showed less decrease in the SIB score at 12 and 24 weeks compared with group 1 (P < 0.05). These were not significantly observed in group 2. Among the secondary endpoints, only the NPI score showed significantly better improvement in group 2 than in group 3 at week 12; however, there were no other significant differences between the groups. Although the ADCS-ADL and CDR-SOB scores showed a pattern similar to SIB scores, a statistically significant result was not found. Adverse events were similar across all three groups. CONCLUSIONS: The results indicate that GV1001 1.12 mg met the primary endpoint of a statistically significant difference. GV1001 was well tolerated without safety concerns. This study warrants a larger clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT03184467 . Registered on June 12, 2017.

Prediction of amyloid ß PET positivity using machine learning in patients with suspected cerebral amyloid angiopathy markers.

Amyloid-ß(Aß) PET positivity in patients with suspected cerebral amyloid angiopathy (CAA) MRI markers is predictive of a worse cognitive trajectory, and it provides insights into the underlying vascular pathology (CAA vs. hypertensive angiopathy) to facilitate prognostic prediction and appropriate treatment decisions. In this study, we applied two interpretable machine learning algorithms, gradient boosting machine (GBM) and random forest (RF), to predict Aß PET positivity in patients with CAA MRI markers. In the GBM algorithm, the number of lobar cerebral microbleeds (CMBs), deep CMBs, lacunes, CMBs in dentate nuclei, and age were ranked as the most influential to predict Aß positivity. In the RF algorithm, the absence of diabetes was additionally chosen. Cut-off values of the above variables predictive of Aß positivity were as follows: (1) the number of lobar CMBs > 16.4(GBM)/14.3(RF), (2) no deep CMBs(GBM/RF), (3) the number of lacunes > 7.4(GBM/RF), (4) age > 74.3(GBM)/64(RF), (5) no CMBs in dentate nucleus(GBM/RF). The classification performances based on the area under the receiver operating characteristic curve were 0.83 in GBM and 0.80 in RF. Our study demonstrates the utility of interpretable machine learning in the clinical setting by quantifying the relative importance and cutoff values of predictive variables for Aß positivity in patients with suspected CAA markers.

Effect of Integrated Cognitive Intervention Therapy in Patients with Mild to Moderate Alzheimer's Disease.

BACKGROUND AND PURPOSE: The effect of the integrated program comprising cognitive training, art therapy, and music therapy has not been extensively studied in patients with Alzheimer's disease (AD). The present study investigated the effect of integrated cognitive intervention therapy on cognition, and activity of daily life (ADL), and mood in patients with mild to moderate AD. METHODS: In this study, the data of 59 patients who met the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer disease and Related Disorders Association (NINCDS-ADRDS) criteria of probable AD among those who registered at the Centenarian's Good Memory Program in Goyang from September 2014 to August 2019 were collected. We statistically analyzed the scores of Korean version of a Mini-Mental Status Examination (K-MMSE), Korean Dementia Screening Questionnaire-Cognition (KDSQ-C), Geriatric Depression Scale (GDS), Beck Anxiety Inventory (BAI), and Seoul-Instrumental Activities of Daily Living (S-IADL) of the same patients before and after the use of integrated cognitive intervention therapy. RESULTS: K-MMSE slightly increased from 18.7±4.5 to 19.7±5.0 (p<0.001) and KDSQ-C improved from 14.5±7.6 before therapy to 12.6±7.2 after therapy (p=0.001). Mean S-IADL score improved from 17.6±7.6 before therapy to 15.7±9.5 after therapy (p<0.001). Additionally, mean GDS score before the therapy was 5.6±3.5 that improved to 4.2±3.0 after the therapy (p<0.001). Mean BAI score decreased from 8.4±10.3 before therapy to 5.9±8.4 after therapy (p=0.001). CONCLUSIONS: In conclusion, this study demonstrated the possibility that the use of an integrated cognitive therapy improved cognition, ADL, and mood (depression and anxiety) in patients with mild to moderate ADs.

Reliability and Validity of a Short Form of the Korean Dementia Screening Questionnaire-Cognition.

BACKGROUND AND PURPOSE: We aimed to determine the reliability and validity of a short form of the Korean Dementia Screening Questionnaire-Cognition (KDSQ-C) as a screening tool for cognitive dysfunction. METHODS: This study recruited 420 patients older than 65 years and their informants from 11 hospitals, and categorized the patients into normal cognition, mild cognitive impairment, and dementia subgroups. The KDSQ-C was completed separately by the patients and their informants. We abstracted three components of the KDSQ-C and combined these components into the following four subscales: KDSQ-C-I (items 1-5, memory domain), KDSQ-C-II (items 1-5 & 11-15, memory domain+activities of daily living), KDSQ-C-III (items 1-5 & 6-10, memory domain+other cognitive domains), and KDSQ-C-IV (items 6-10 & 11-15, other cognitive domains+activities of daily living). The reliability and validity were compared between these four subscales. RESULTS: A receiver operating characteristic (ROC) analysis of questionnaire scores provided by the patients showed that the areas under the ROC curves (AUCs) for the KDSQ-C, KDSQC-I, and KDSQ-C-II for diagnosing dementia were 0.75, 0.72, and 0.76, respectively; the corresponding AUCs for informant-completed questionnaires were 0.92, 0.89, and 0.92, indicating good discriminability for dementia. CONCLUSIONS: A short form of the patient- and informant-rated versions of the KDSQ-C (KDSQ-C-II) is as capable as the 15-item KDSQ-C in screening for dementia.

Self- and informant-reported cognitive functioning and awareness in subjective cognitive decline, mild cognitive impairment, and very mild Alzheimer disease.

OBJECTIVES: The present study examined self-reports and informant reports of cognitive function and discrepancies between the two reporting methods in healthy controls (HC), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and very mild Alzheimer disease (AD) using three questionnaires. METHODS: The study included a total of 300 individuals (mean age: 74.4 ± 5.7 y), including 130 HC, 70 SCD, 51 MCI, and 49 very mild AD patients. Self-ratings and informant ratings of cognitive function were assessed using the Korean Dementia Screening Questionnaire-Cognition (KDSQ-C), AD8, and Subjective Memory Complaints Questionnaire (SMCQ). Awareness of cognitive functioning was measured on the basis of the discrepancy scores between self-reports and informant reports. RESULTS: Group comparisons on questionnaire scores adjusting for age, education, and depressive symptoms showed that self-reports were lowest in HC than other groups, with no differences between SCD and MCI groups. Informant reports were lower in SCD than in MCI, while discrepancy scores were higher in SCD than in MCI (P < .001 for KDSQ-C and SMCQ; P = .076 for AD8). There were no differences in self-reports, informant reports, and discrepancy scores between MCI and AD groups. CONCLUSIONS: These results support the usefulness of informant-reported cognitive functioning to classify MCI among elderly with subjective cognitive complaints. In addition, discrepancies between self-reports and informant reports demonstrate that overestimation and underestimation of cognitive function may serve as a clinical indicator of SCD and MCI across the cognitive continuum, respectively.