Relationship Between Amyloid Positivity and Sleep Characteristics in the Elderly With Subjective Cognitive Decline.

Background and Purpose: Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive decline in cognition and performance of daily activities. Recent studies have attempted to establish the relationship between AD and sleep. It is believed that patients with AD pathology show altered sleep characteristics years before clinical symptoms appear. This study evaluated the differences in sleep characteristics between cognitively asymptomatic patients with and without some amyloid burden. Methods: Sleep characteristics of 76 subjects aged 60 years or older who were diagnosed with subjective cognitive decline (SCD) but not mild cognitive impairment (MCI) or AD were measured using Fitbit® Alta HR, a wristwatch-shaped wearable device. Amyloid deposition was evaluated using brain amyloid plaque load (BAPL) and global standardized uptake value ratio (SUVR) from fluorine-18 florbetaben positron emission tomography. Each component of measured sleep characteristics was analyzed for statistically significant differences between the amyloid-positive group and the amyloid-negative group. Results: Of the 76 subjects included in this study, 49 (64.5%) were female. The average age of the subjects was 70.72±6.09 years when the study started. 15 subjects were classified as amyloid-positive based on BAPL. The average global SUVR was 1.598±0.263 in the amyloid-positive group and 1.187±0.100 in the amyloid-negative group. Time spent in slow-wave sleep (SWS) was significantly lower in the amyloid-positive group (39.4±13.1 minutes) than in the amyloid-negative group (49.5±13.1 minutes) (p=0.009). Conclusions: This study showed that SWS is different between the elderly SCD population with and without amyloid positivity. How SWS affects AD pathology requires further research.

A Longitudinal Study on Memory Enhancement in Subjective Cognitive Decline Patients: Clinical and Neuroimaging Perspectives.

BACKGROUND: Subjective cognitive decline (SCD) refers to the self-reported persistent cognitive decline despite normal objective testing, increasing the risk of dementia compared to cognitively normal individuals. OBJECTIVE: This study aims to investigate the attributes of SCD patients who demonstrated memory function improvement. METHODS: In this prospective study of SCD, a total of 120 subjects were enrolled as part of a multicenter cohort study aimed at identifying predictors for the clinical progression to mild cognitive impairment or dementia (CoSCo study). All subjects underwent 18F-florbetaben PET and brain MRI scans at baseline and annual neuropsychological tests. At the 24-month follow-up, we classified SCD patients based on changes in memory function, the z-score of the Seoul verbal learning test delayed recall. RESULTS: Of the 120 enrolled patients, 107 successfully completed the 24-month follow-up assessment. Among these, 80 patients (74.8%) with SCD exhibited memory function improvements. SCD patients with improved memory function had a lower prevalence of coronary artery disease at baseline and performed better in the trail-making test part B compared to those without improvement. Anatomical and biomarker analysis showed a lower frequency of amyloid PET positivity and larger volumes in the left and right superior parietal lobes in subjects with improved memory function. CONCLUSIONS: Our prospective study indicates that SCD patients experiencing memory improvement over a 24-month period had a lower amyloid burden, fewer cardiovascular risk factors, and superior executive cognitive function. Identifying these key factors associated with cognitive improvement may assist clinicians in predicting future memory function improvements in SCD patients.

Retrospective Analysis of the Clinical Characteristics of Patients with Breast Cancer Treated with Telomerase Peptide Immunotherapy Combined with Cytotoxic Chemotherapy.

Purpose: Telomerase activation, a critical step in cancer progression, occurs in approximately 95% of breast cancer cases. Telomerase is an attractive therapeutic target for breast cancer owing to its unique expression pattern. GV1001, a telomerase-derived peptide, is loaded onto human leukocyte antigen (HLA) class II antigen-presenting cells and binds to CD4+ T cell activating immune responses. This study aimed to evaluate the effectiveness and safety of co-administration of GV1001 and cytotoxic chemotherapy in patients with heavily-treated metastatic breast cancer. Patients and methods: We analyzed 63 patients with breast cancer who received both GV1001 and cytotoxic chemotherapy. The GV 1001 administration methods involves 0.56 mg intradermal injection three times during the first week, one time at weeks 2, 3, 4, and 6, and then once every 28 days. The primary endpoint of this study was quality of life according to EORTC QLO-C30 and EQ-5D, while the secondary endpoint was the antitumor response according to RECIST 1.1, progression-free survival, overall survival, and toxicity profile. Results: In 34 patients with HR+ breast cancer evaluable for tumor response, the disease control rate (DCR) and overall response rate (ORR) were 58.8% and 26.4%, respectively. The DCR and ORR were 66.6% and 28.5% in 21 patients with HER-2+ and 50% and 25% in patients with triple-negative breast cancer (TNBC), respectively. The median progression free survival was 10.4, 8.7, and 5.6 months in HR+, HER-2+, TNBC, respectively. The overall survival was 19.7, 13.2, and 9.4 months for patients with HR+, HER-2+, and TNBC, respectively. Most patients had an improved quality of life with statistically significant differences in some variables. The patients in this study experienced no additional toxicities other than the cytotoxic chemotherapy-associated side effects. Conclusion: GV1001 is a relatively safe anticancer vaccine for patients with heavily-treated breast cancer and can to improve the quality of life.

Impacts of baseline biomarkers on cognitive trajectories in subjective cognitive decline: the CoSCo prospective cohort study.

BACKGROUND: Subjective cognitive decline (SCD) is a risk factor for Alzheimer's disease (AD); however, the rates of cognitive decline are variable according to underlying pathologies and biomarker status. We conducted an observational study and aimed to investigate baseline characteristics and biomarkers related with cognitive declines in SCD. Our study also assessed whether SCD participants showed different cognitive and biomarker trajectories according to baseline amyloid deposition. METHODS: This study is a part of a longitudinal cohort study conducted in multi-centers in South Korea between 2018 and 2021. Individuals (≥ 60 years old) with persistent cognitive complaint despite of normal cognitive functions were eligible for the study. All participants underwent neuropsychological tests, florbetaben PET scans, plasma amyloid markers, and brain MRI scans. Annual follow-up evaluations included neuropsychological tests and assessments for clinical progressions. Regional brain volumetry and amyloid burden represented by PET-based standardized uptake value ratio (SUVR) were measured. We compared cognitive and brain atrophic changes over 24 months between amyloid positive-SCD (Aß + SCD) and amyloid negative-SCD (Aß-SCD) groups. Baseline factors associated with cognitive outcomes were investigated. RESULTS: A total of 120 participants with SCD were enrolled and 107 completed follow-up evaluations. Aß + SCD participants (n = 20, 18.5%) were older and more frequently APOE4 carriers compared with Aß-SCD participants (n = 87). Baseline cognitive scores were not different between the two groups, except the Seoul Verbal Learning Test (SVLT) scores showing lower scores in the Aß + SCD group. After 24 months, plasma amyloid markers were higher, and regional volumes (entorhinal, hippocampal, and pallidum) were smaller in the Aß + SCD participants compared with Aß-SCD participants adjusted by age, sex, and baseline volumes. SVLT delayed recall and controlled oral word association test (COWAT) scores indicated more declines in Aß + SCD participants. Baseline left entorhinal volumes were related to verbal memory decline, while baseline frontal volumes and global SUVR values were related to frontal functional decline. CONCLUSION: Aß + SCD participants showed more cognitive decline and medial temporal atrophic changes during 24 months. Baseline neurodegeneration and amyloid burden were related with future cognitive trajectories in SCD. TRIAL REGISTRATION: This study was registered at CRIS (KCT0003397).

Clinical Significance of Physical Frailty in Subjects With Subjective Cognitive Decline: A Prospective Study With Amyloid PET Data.

BACKGROUND AND PURPOSE: Physical frailty is known to be closely associated with cognitive impairment and to be an early sign of Alzheimer's disease. We aimed to understand the characteristics of physical frailty and define factors associated with physical frailty in subjects with subjective cognitive decline (SCD) by analyzing amyloid data. METHODS: We prospectively enrolled subjects with SCD from a cohort study to identify predictors for the clinical progression to mild cognitive impairment or dementia from SCD (CoSCo). All of the subjects underwent brain magnetic resonance imaging, and brain amyloid positron-emission tomography (PET) to detect amyloid beta plaques. Self-reported exhaustion, handgrip strength, and gait speed were used to measure physical frailty. RESULTS: Of 120 subjects with SCD, 26 (21.7%) were amyloid-positive in PET. Female (odds ratio [OR]=3.79, p=0.002) and amyloid-PET-positive (OR=3.80, p=0.008) subjects with SCD were at high risks of self-reported exhaustion. Amyloid PET positivity (OR=3.22, p=0.047) and high burden from periventricular white-matter hyperintensity (OR=3.34, 95% confidence interval=1.18-9.46, p=0.023) were significantly associated with a weaker handgrip. The subjects with SCD with self-reported exhaustion and weaker handgrip presented with lower cognitive performance in neuropsychological tests, especially for information processing speed and executive function. Subjects with a slower gait performed worse in visual memory function tests. CONCLUSIONS: Amyloid PET positivity was associated with a higher risk of self-reported exhaustion and weaker handgrip in subjects with SCD. The subjects with SCD and physical frailty also performed worse in neuropsychological tests.

PET-validated EEG-machine learning algorithm predicts brain amyloid pathology in pre-dementia Alzheimer's disease.

Developing reliable biomarkers is important for screening Alzheimer's disease (AD) and monitoring its progression. Although EEG is non-invasive direct measurement of brain neural activity and has potentials for various neurologic disorders, vulnerability to noise, difficulty in clinical interpretation and quantification of signal information have limited its clinical application. There have been many research about machine learning (ML) adoption with EEG, but the accuracy of detecting AD is not so high or not validated with Aß PET scan. We developed EEG-ML algorithm to detect brain Aß pathology among subjective cognitive decline (SCD) or mild cognitive impairment (MCI) population, and validated it with Aß PET. 19-channel resting-state EEG and Aß PET were collected from 311 subjects: 196 SCD(36 Aß +, 160 Aß -), 115 MCI(54 Aß +, 61Aß -). 235 EEG data were used for training ML, and 76 for validation. EEG features were standardized for age and sex. Multiple important features sets were selected by 6 statistics analysis. Then, we trained 8 multiple machine learning for each important features set. Meanwhile, we conducted paired t-test to find statistically different features between amyloid positive and negative group. The best model showed 90.9% sensitivity, 76.7% specificity and 82.9% accuracy in MCI + SCD (33 Aß +, 43 Aß -). Limited to SCD, 92.3% sensitivity, 75.0% specificity, 81.1% accuracy (13 Aß +, 24 Aß -). 90% sensitivity, 78.9% specificity and 84.6% accuracy for MCI (20 Aß +, 19 Aß -). Similar trends of EEG power have been observed from the group comparison between Aß + and Aß -, and between MCI and SCD: enhancement of frontal/ frontotemporal theta; attenuation of mid-beta in centroparietal areas. The present findings suggest that accurate classification for beta-amyloid accumulation in the brain based on QEEG alone could be possible, which implies that QEEG is a promising biomarker for beta-amyloid. Since QEEG is more accessible, cost-effective, and safer than amyloid PET, QEEG-based biomarkers may play an important role in the diagnosis and treatment of AD. We expect specific patterns in QEEG could play an important role to predict future progression of cognitive impairment in the preclinical stage of AD. Further feature engineering and validation with larger dataset is recommended.

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.

Development of a home-based cognitive test for cognitive monitoring in subjective cognitive decline with high risk of Alzheimer's disease.

BACKGROUND AND PURPOSE: Subjective cognitive decline (SCD) indicates a self-perceived persistent cognitive worsening despite of normal performance in standard neuropsychological tests. Owing to its heterogeneity and potential risk of Alzheimer's disease, baseline biomarkers to predict cognitive decline are important. In the present study, we developed a home-based cognitive test (HCT) to monitor cognitive changes regularly without visiting hospitals. This study aims to compare cognitive and biomarker trajectories during a 48-month period between amyloid positive SCD and amyloid negative SCD subjects. METHODS: Data will be collected from a prospective observational cohort study conducted in South Korea. Eighty participants with SCD aged ≥ 60 years are eligible for the study. All participants undergo annual neuropsychological tests and neurological examinations, bi-annual brain MRI scans and plasma amyloid markers, and baseline florbetaben Positron Emission Tomography scans. The amyloid burden and regional volumes will be measured. Cognitive and biomarker changes will be compared between the amyloid-positive SCD and amyloid negative SCD groups. Validation would be performed to assess reliability and feasibility of HCT. CONCLUSIONS: This study would suggest a perspective on SCD in terms of cognitive and biomarker trajectories. Baseline characteristics and biomarker status might affect faster cognitive decline and future biomarker trajectories. In addition, HCT could be an alternative option of in-person neuropsychological tests to track cognitive changes without visiting hospitals.

The Seoul Neuropsychological Screening Battery (SNSB) for Comprehensive Neuropsychological Assessment.

The Seoul Neuropsychological Screening Battery (SNSB) is known as a representative comprehensive neuropsychological evaluation tool in Korea since its first standardization in 2003. It was the main neuropsychological evaluation tool in the Clinical Research Center for Dementia of South Korea, a large-scale multi-center cohort study in Korea that was started in 2005. Since then, it has been widely used by dementia clinicians, and further solidified its status as a representative dementia evaluation tool in Korea. Many research results related to the SNSB have been used as a basis for the diagnosis and evaluation of patients in various clinical settings, especially, in many areas of cognitive assessment, including dementia evaluation. The SNSB version that was updated in 2012 provides psychometrically improved norms and indicators through a model-based standardization procedure based on a theoretical probability distribution in the norm's development. By providing a score for each cognitive domain, it is easier to compare cognitive abilities between domains and to identify changes in cognitive domain functions over time. Through the development of the SNSB-Core, a short form composed of core tests, which also give a composite score was provided. The SNSB is a useful test battery that provides key information on the evaluation of early cognitive decline, analysis of cognitive decline patterns, judging the severity of dementia, and differential diagnosis of dementia. This review will provide a broad understanding of the SNSB by describing the test composition, contents of individual subtests, characteristics of standardization, analysis of the changed standard score, and related studies.

Study Design and Baseline Results in a Cohort Study to Identify Predictors for the Clinical Progression to Mild Cognitive Impairment or Dementia From Subjective Cognitive Decline (CoSCo) Study.

Background and Purpose: Subjective cognitive decline (SCD) refers to the self-perception of cognitive decline with normal performance on objective neuropsychological tests. SCD, which is the first help-seeking stage and the last stage before the clinical disease stage, can be considered to be the most appropriate time for prevention and treatment. This study aimed to compare characteristics between the amyloid positive and amyloid negative groups of SCD patients. Methods: A cohort study to identify predictors for the clinical progression to mild cognitive impairment (MCI) or dementia from subjective cognitive decline (CoSCo) study is a multicenter, prospective observational study conducted in the Republic of Korea. In total, 120 people aged 60 years or above who presented with a complaint of persistent cognitive decline were selected, and various risk factors were measured among these participants. Continuous variables were analyzed using the Wilcoxon rank-sum test, and categorical variables were analyzed using the χ2 test or Fisher's exact test. Logistic regression models were used to assess the predictors of amyloid positivity. Results: The multivariate logistic regression model indicated that amyloid positivity on PET was related to a lack of hypertension, atrophy of the left temporal lateral and entorhinal cortex, low body mass index, low waist circumference, less body and visceral fat, fast gait speed, and the presence of the apolipoprotein E ε4 allele in amnestic SCD patients. Conclusions: The CoSCo study is still in progress, and the authors aim to identify the risk factors that are related to the progression of MCI or dementia in amnestic SCD patients through a two-year follow-up longitudinal study.

Electroencephalography for Early Detection of Alzheimer's Disease in Subjective Cognitive Decline.

Background and Purpose: Early detection of subjective cognitive decline (SCD) due to Alzheimer's disease (AD) is important for clinical research and effective prevention and management. This study examined if quantitative electroencephalography (qEEG) could be used for early detection of AD in SCD. Methods: Participants with SCD from 6 dementia clinics in Korea were enrolled. 18F-florbetaben brain amyloid positron emission tomography (PET) was conducted for all the participants. qEEG was performed to measure power spectrum and source cortical activity. Results: The present study included 95 participants aged over 65 years, including 26 amyloid PET (+) and 69 amyloid PET (-). In participants with amyloid PET (+), relative power at delta band was higher in frontal (p=0.025), parietal (p=0.005), and occipital (p=0.022) areas even after adjusting for age, sex, and education. Source activities of alpha 1 band were significantly decreased in the bilateral fusiform and inferior temporal areas, whereas those of delta band were increased in the bilateral cuneus, pericalcarine, lingual, lateral occipital, precuneus, posterior cingulate, and isthmus areas. There were increased connections between bilateral precuneus areas but decreased connections between left rostral middle frontal area and bilateral frontal poles at delta band in participants with amyloid PET (+) showed. At alpha 1 band, there were decreased connections between bilateral entorhinal areas after adjusting for covariates. Conclusions: SCD participants with amyloid PET (+) showed increased delta and decreased alpha 1 activity. qEEG is a potential means for predicting amyloid pathology in SCD. Further longitudinal studies are needed to confirm these findings.

The Effect of Hearing Loss on Cognitive Function in Subjective Cognitive Decline.

INTRODUCTION: Subjective cognitive decline (SCD) is a self-reported cognitive decline without objective cognitive impairment. The relationship between audiometric hearing loss (HL) and cognitive function has not been reported in SCD. The purpose of this study was to investigate whether HL affects cognition-related indexes in SCD individuals. METHODS: This is a cross-sectional study that used the baseline data of a multicenter cohort study that monitors clinical progression from SCD to dementia. Individuals aged ≥60 years who reported cognitive decline but had no objective cognitive impairment on comprehensive neuropsychological tests were recruited. Participants were grouped into the normal-hearing (NH) and bilateral HL groups. The demographics, clinical characteristics, dementia biomarkers, global cognition, questionnaire scores, neuropsychological test scores, and segmental brain volumes from MRI were compared between the groups. RESULTS: Of a total of 120 participants, one hundred and two had NH (n = 57) or bilateral HL (n = 45). There were no group differences in the demographic and clinical data except the age. The biomarkers, global cognition, and questionnaire scores were not different between the groups. The HL group performed worse (the z-score of -0.06) in the Stroop Color Word Test than the NH group (0.27) (p = 0.025). Brain volumetric analysis revealed that the HL group had reduced gray matter volumes in four brain subregions: left temporal pole, left caudal middle frontal gyrus, left hippocampus, and right isthmus of the cingulate gyrus. CONCLUSION: In SCD, HL exerted an adverse effect on cognitive function, primarily frontal executive function tested in the Stroop task. HL was also related to gray matter volume reductions in brain subregions, although causality needs further investigation. This study may provide evidence for a potential link between hearing and cognition in SCD, an emerging clinical entity.

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.

Automated brain volumetric program measuring regional brain atrophy in diagnosis of mild cognitive impairment and Alzheimer's disease dementia.

A quantitative analysis of brain volume can assist in the diagnosis of Alzheimer's disease (AD) which is ususally accompanied by brain atrophy. With an automated analysis program Quick Brain Volumetry (QBraVo) developed for volumetric measurements, we measured regional volumes and ratios to evaluate their performance in discriminating AD dementia (ADD) and mild cognitive impairment (MCI) patients from normal controls (NC). Validation of QBraVo was based on intra-rater and inter-rater reliability with a manual measurement. The regional volumes and ratios to total intracranial volume (TIV) and to total brain volume (TBV) or total cerebrospinal fluid volume (TCV) were compared among subjects. The regional volume to total cerebellar volume ratio named Standardized Atrophy Volume Ratio (SAVR) was calculated to compare brain atrophy. Diagnostic performances to distinguish among NC, MCI, and ADD were compared between MMSE, SAVR, and the predictive model. In total, 56 NCs, 44 MCI, and 45 ADD patients were enrolled. The average run time of QBraVo was 5 min 36 seconds. Intra-rater reliability was 0.999. Inter-rater reliability was high for TBV, TCV, and TIV (R = 0.97, 0.89 and 0.93, respectively). The medial temporal SAVR showed the highest performance for discriminating ADD from NC (AUC = 0.808, diagnostic accuracy = 80.2%). The predictive model using both MMSE and medial temporal SAVR improved the diagnostic performance for MCI in NC (AUC = 0.844, diagnostic accuracy = 79%). Our results demonstrated QBraVo is a fast and accurate method to measure brain volume. The regional volume calculated as SAVR could help to diagnose ADD and MCI and increase diagnostic accuracy for MCI.

Predictive Scale for Amyloid PET Positivity Based on Clinical and MRI Variables in Patients with Amnestic Mild Cognitive Impairment.

The presence of amyloid-ß (Aß) deposition is considered important in patients with amnestic mild cognitive impairment (aMCI), since they can progress to Alzheimer's disease dementia. Amyloid positron emission tomography (PET) has been used for detecting Aß deposition, but its high cost is a significant barrier for clinical usage. Therefore, we aimed to develop a new predictive scale for amyloid PET positivity using easily accessible tools. Overall, 161 aMCI patients were recruited from six memory clinics and underwent neuropsychological tests, brain magnetic resonance imaging (MRI), apolipoprotein E (APOE) genotype testing, and amyloid PET. Among the potential predictors, verbal and visual memory tests, medial temporal lobe atrophy, APOE genotype, and age showed significant differences between the Aß-positive and Aß-negative groups and were combined to make a model for predicting amyloid PET positivity with the area under the curve (AUC) of 0.856. Based on the best model, we developed the new predictive scale comprising integers, which had an optimal cutoff score ≥ 3. The new predictive scale was validated in another cohort of 98 participants and showed a good performance with AUC of 0.835. This new predictive scale with accessible variables may be useful for predicting Aß positivity in aMCI patients in clinical practice.

Subtle Cognitive Deficits Are Associated with Amyloid-ß Positivity, but Not Severity of Self-Reported Decline: Results from the CoSCo Study.

INTRODUCTION: Subjective cognitive decline (SCD) can be considered as the preclinical manifestation of Alzheimer's disease (AD). The National Institute on Aging and the Alzheimer's Association criteria for preclinical AD proposed that subtle cognitive changes appear along with AD biomarkers in the late stage of preclinical AD. The objective of this study was to explore whether subtle cognitive impairment (SCI) in individuals with SCD is associated with brain amyloid-ß (Aß) status and SCD severity. METHODS: One hundred twenty individuals with SCD (mean age: 70.87 ± 6.10 years) were included in this study. SCI was defined as performance ≤ -1.0 SD on at least two neuropsychological tests. Participants underwent an amyloid positron emission tomography, which was assessed visually and quantitatively using standardized uptake value ratio (SUVR). The severity of SCD was assessed using two self-reported questionnaires: the SCD questionnaire based on the SCD-plus features and the Korean-Everyday Cognition (K-ECog) scale. RESULTS: SCD individuals with SCI (n = 25) had more Aß positivity than the SCD only group (n = 95) (44% vs. 15.79%; p = 0.002). In addition, the SCI group had a higher global SUVR than the SCD only group (p = 0.048). For self-reported questionnaires, there were no differences in SCD questionnaire total scores and K-ECog global and cognitive domain-specific scores between two groups. CONCLUSIONS: In SCD individuals, SCI was associated with higher Aß positivity, but not with the severity of self-reported cognitive decline, compared to the SCD only group. These results suggest that the recognition of objectively defined subtle cognitive deficits may contribute to the early identification of AD in SCD.

Survival in Korean Patients with Frontotemporal Dementia Syndrome: Association with Behavioral Features and Parkinsonism.

We investigated the survival time of each clinical syndrome of frontotemporal dementia (FTD) and the impacts of behavioral and motor features on survival of FTD. A total of 216 patients with FTD [82 behavioral variant FTD (bvFTD), 78 semantic variant primary progressive aphasia (svPPA), 43 non-fluent/agrammatic variant PPA (nfvPPA), 13 FTD-motor neuron disease (MND)] were enrolled from 16 centers across Korea. Behaviors and parkinsonism were assessed using the Frontal Behavioral Inventory and Unified Parkinson's Disease Rating Scale Part III, respectively. The Kaplan-Meier method was used for the survival analysis and the Cox proportional hazards model was applied for analysis of the effect of behavioral and motor symptoms on survival, after controlling vascular risk factors and cancer. An overall median survival of FTD was 12.1 years. The survival time from onset was shortest for FTD-MND and longest for svPPA. The median survival time of patients with bvFTD was unavailable but likely comparable to that of patients with nfvPPA. In the bvFTD group, negative behavioral symptoms and akinetic rigidity were significantly associated with survival. In the nfvPPA group, the presence of dysarthria had a negative impact on survival. These findings provide useful information to clinicians planning for care.

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.

Machine Learning to Predict Brain Amyloid Pathology in Pre-dementia Alzheimer's Disease Using QEEG Features and Genetic Algorithm Heuristic.

The use of positron emission tomography (PET) as the initial or sole biomarker of ß-amyloid (Aß) brain pathology may inhibit Alzheimer's disease (AD) drug development and clinical use due to cost, access, and tolerability. We developed a qEEG-ML algorithm to predict Aß pathology among subjective cognitive decline (SCD) and mild cognitive impairment (MCI) patients, and validated it using Aß PET. We compared QEEG data between patients with MCI and those with SCD with and without PET-confirmed beta-amyloid plaque. We compared resting-state eyes-closed electroencephalograms (EEG) patterns between the amyloid positive and negative groups using relative power measures from 19 channels (Fp1, Fp2, F7, F3, Fz, F4, F8, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6, O1, O2), divided into eight frequency bands, delta (1-4 Hz), theta (4-8 Hz), alpha 1 (8-10 Hz), alpha 2 (10-12 Hz), beta 1 (12-15 Hz), beta 2 (15-20 Hz), beta 3 (20-30 Hz), and gamma (30-45 Hz) calculated by FFT and denoised by iSyncBrain®. The resulting 152 features were analyzed using a genetic algorithm strategy to identify optimal feature combinations and maximize classification accuracy. Guided by gene modeling methods, we treated each channel and frequency band of EEG power as a gene and modeled it with every possible combination within a given dimension. We then collected the models that showed the best performance and identified the genes that appeared most frequently in the superior models. By repeating this process, we converged on a model that approximates the optimum. We found that the average performance increased as this iterative development of the genetic algorithm progressed. We ultimately achieved 85.7% sensitivity, 89.3% specificity, and 88.6% accuracy in SCD amyloid positive/negative classification, and 83.3% sensitivity, 85.7% specificity, and 84.6% accuracy in MCI amyloid positive/negative classification.

The Influence of Amyloid Burden on Cognitive Decline over 2 years in Older Adults with Subjective Cognitive Decline: A Prospective Cohort Study.

BACKGROUND: Subjective cognitive decline (SCD) is a self-perceived cognitive worsening without objective cognitive impairment. Due to its heterogeneity and potential risk of Alzheimer's disease (AD), baseline biomarkers to predict progression are clinically important. In the present study, cognitive trajectories during a 24-month period were compared between amyloid-positive SCD (A+SCD) and amyloid-negative SCD (A-SCD) subjects, and biomarkers associated with memory decline were investigated. METHODS: Data from a prospective cohort study in Korea between 2016 and 2019 were analyzed. SCD subjects ≥50 years of age were eligible. All participants underwent neuropsychological tests, brain magnetic resonance imaging, and florbetaben positron emission tomography scans. Amyloid burden and regional volumes were measured. Cognitive changes corrected for age were compared between A+SCD and A-SCD groups. Biomarkers associated with memory decline were assessed. RESULTS: Forty-seven SCD subjects (69.9 ± 6.7 years, mini-mental state examination (MMSE) score 27.5) were enrolled, and 31 completed at least 1 annual follow-up (mean follow-up: 24.7 months). Baseline characteristics except age, hippocampal atrophy, and white matter hyperintensities were similar between A+SCDs (n = 12, 25.6%) and A-SCDs (n = 35). A+SCD subjects showed greater decline in the verbal memory function compared with the A-SCD subjects after adjustment for age. MMSE scores decreased more in the A+SCD (1.1 in the A+SCD; 0.55 in the A-SCD), although it was not statistically significant. Amyloid burden and baseline memory score were associated with memory decline. CONCLUSIONS: Within SCD, A+SCD subjects showed faster memory decline compared with the A-SCD subjects and amyloid burden might be associated with future memory decline in SCD.