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Abstract 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 (Aβ + SCD) and amyloid negative-SCD (Aβ-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. Aβ + SCD participants (n = 20, 18.5%) were older and more frequently APOE4 carriers compared with Aβ-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 Aβ + SCD group. After 24 months, plasma amyloid markers were higher, and regional volumes (entorhinal, hippocampal, and pallidum) were smaller in the Aβ + SCD participants compared with Aβ-SCD participants adjusted by age, sex, and baseline volumes. SVLT delayed recall and controlled oral word association test (COWAT) scores indicated more declines in Aβ + 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 Aβ + 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).

Abstract Several programs are widely used for clinical and research purposes to automatically quantify the degree of amyloid deposition in the brain using positron emission tomography (PET) images. Given that very few studies have investigated the use of Heuron, a PET image quantification software approved for clinical use, this study aimed to compare amyloid deposition values quantified from 18F-flutemetamol PET images using PMOD and Heuron. Amyloid PET data obtained from 408 patients were analysed using each quantitative program; moreover, the standardized uptake value ratios (SUVRs) of target areas were obtained by dividing the standardized uptake value (SUV) of the target region by the SUV of cerebellar grey matter as a reference. Compared with PMOD, Heuron yielded significantly higher SUVRs for all target areas (paired sample t-test, p

Abstract 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 Aβ PET scan. We developed EEG-ML algorithm to detect brain Aβ pathology among subjective cognitive decline (SCD) or mild cognitive impairment (MCI) population, and validated it with Aβ PET. 19-channel resting-state EEG and Aβ PET were collected from 311 subjects: 196 SCD(36 Aβ +, 160 Aβ −), 115 MCI(54 Aβ +, 61Aβ −). 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 Aβ +, 43 Aβ −). Limited to SCD, 92.3% sensitivity, 75.0% specificity, 81.1% accuracy (13 Aβ +, 24 Aβ −). 90% sensitivity, 78.9% specificity and 84.6% accuracy for MCI (20 Aβ +, 19 Aβ −). Similar trends of EEG power have been observed from the group comparison between Aβ + and Aβ −, 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.

Abstract 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.

BackgroundThe SoUth Korean study to PrEvent cognitive impaiRment and protect BRAIN health through lifestyle intervention in at-risk elderly people (SUPERBRAIN) is a part of the World-Wide Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (WW-FINGERS) network. This study aimed to demonstrate the effects of the SUPERBRAIN-based multidomain intervention with nutritional supplements in amyloid positive emission tomography (PET) proven early symptomatic Alzheimer’s disease patients.MethodsForty-six participants who were diagnosed with mild cognitive impairment or mild dementia and were positive in the amyloid PET study randomized into three groups: group A, the multidomain intervention with nutritional supplements; group B, nutritional supplements only; and a control group. The primary outcome was a change in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total scale index score after an 8-week intervention. Secondary outcomes, including gut microbiome data, were also analyzed.ResultsThe RBANS total scale index score improved significantly in group A compared with group B (p

Abstract Introduction This study aimed to determine the efficacy of combining plasma phosphorylated tau (p‐tau)181, amyloid beta (Aβ)42/Aβ40, neurofilament light (NfL), and apolipoprotein E (APOE) genotypes for detecting positive amyloid positron emission tomography (PET), which is little known in the Asian population, in two independent cohorts. Methods Biomarkers were measured using a single‐molecule array (Simoa) in a cohort study (Asan). All participants underwent amyloid PET. Significant changes in the area under the curve (AUC) and Akaike Information Criterion values were considered to determine the best model. The generalizability of this model was tested using another cohort (KBASE‐V). Results In the Asan cohort, after adjusting for age and sex, p‐tau181 (AUC = 0.854) or APOE ε4 status (AUC = 0.769) distinguished Aβ status with high accuracy. Combining them or adding NfL and Aβ42/40 improved model fitness. The best‐fit model included the plasma p‐tau181, APOE ε4, NfL and Aβ42/40. The models established from the Asan cohort were tested in the KBASE‐V cohort. Additionally, in the KBASE‐V cohort, these three biomarker models had similar AUC in cognitively unimpaired (AUC = 0.768) and mild cognitive impairment (MCI) (AUC = 0.997) participants. Conclusions Plasma p‐tau181 showed a high performance in determining Aβ‐PET positivity. Adding plasma NfL and APOE ε4 status improved the model fit without significant improvement in AUC.

Background and purposeThe 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.MethodsThe 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.ResultsAmong 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).ConclusionThe 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.

In the South Korean study to prevent cognitive impairment and protect BRAIN health through lifestyle intervention in at-risk elderly people (SUPERBRAIN), we evaluated the impact of a 24-week facility-based multidomain intervention (FMI) and home-based MI (HMI) on white matter integrity. Among 152 participants, aged 60–79 years without dementia but with ≥1 modifiable dementia risk factor, 19 FMI, 20 HMI, and 16 controls underwent brain MRI at baseline and 24 weeks. Between the intervention and control groups, we compared changes in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) at regions-of-interest (ROI) including the cingulum cingulate gyrus (CgC), cingulum hippocampus (CgH), superior longitudinal fasciculus (SLF), as well as the uncinate fasciculus (UF). In addition, correlations between total and standard scores cognitive domains of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) or serum brain-derived neurotrophic factor (BDNF) and changes in brain image measures were evaluated at a statistical significance level of p

Alzheimer’s disease (AD) is closely related to neurodegeneration, leading to dementia and cognitive impairment, especially in people aged > 65 years old. The detection of biomarkers plays a pivotal role in the diagnosis and treatment of AD, particularly at the onset stage. Field-effect transistor (FET)-based sensors are emerging devices that have drawn considerable attention due to their crucial ability to recognize various biomarkers at ultra-low concentrations. Thus, FET is broadly manipulated for AD biomarker detection. In this review, an overview of typical FET features and their operational mechanisms is described in detail. In addition, a summary of AD biomarker detection and the applicability of FET biosensors in this research field are outlined and discussed. Furthermore, the trends and future prospects of FET devices in AD diagnostic applications are also discussed.

Abstract Background Neurofilament light chain (NFL) level has been suggested as a blood-based biomarker for neurodegeneration in dementia. However, the association between baseline NFL levels and cognitive stage transition or cortical thickness is unclear. This study aimed to investigate whether baseline NFL levels are associated with cognitive stage transition or cortical thickness in mild cognitive impairment (MCI) and cognitively unimpaired (CU) participants. Methods This study analyzed data on participants from the independent validation cohort of the Korea Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE-V) study. Among the participants of KBASE-V study, 53 MCI and 146 CU participants who were followed up for ≥ 2 years and had data on the serum NFL levels were eligible for inclusion in this study. Participants were classified into three groups according to baseline serum NFL levels of low, middle, or high. Results The Kaplan–Meier analysis showed association between the serum NFL tertiles and risk of cognitive stage transition in MCI (P = 0.002) and CU (P = 0.028) participants, analyzed separately. The same is true upon analysis of MCI and CU participants together (P < 0.001). In MCI participants, the highest serum NFL tertile and amyloid-beta positivity were independent predictors for cognitive stage transition after adjusting for covariates. For CU participants, only amyloid-beta positivity was identified to be an independent predictor. Conclusion The study shows that higher serum NFL tertile levels correlate with increased risk of cognitive stage transition in both MCI and CU participants. Serum NFL levels were negatively correlated with the mean cortical thickness of the whole-brain and specific brain regions.

Background and purposeSex differences in cerebral microbleeds (CMBs) are not well-known. We aimed to assess the impact of sex on the progression of CMBs.MethodsThe 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.ResultsA 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].ConclusionThe progression of CMB over 2 years was significantly greater in women than in men.

Abstract Background Given that tau accumulation, not amyloid-β (Aβ) burden, is more closely connected with cognitive impairment in Alzheimer’s disease (AD), a detailed understanding of the tau-related characteristics of cognitive function is critical in both clinical and research settings. We investigated the association between phosphorylated tau (p-Tau) level and cognitive impairment across the AD continuum and the mediating role of medial temporal lobe (MTL) atrophy. We also developed a prediction model for abnormal tau accumulation. Methods We included participants from the Gwangju Alzheimer’s Disease and Related Dementia Cohort in Korea, who completed cerebrospinal fluid analysis and clinical evaluation, and corresponded to one of three groups according to the biomarkers of A and T profiles based on the National Institute on Aging and Alzheimer’s Association research framework. Multiple linear and logistic regression analyses were performed to examine the association between p-Tau and cognition and to develop prediction models. Receiver operating characteristic curve analysis was performed to examine the discrimination ability of the models. Results Among 185 participants, 93 were classified as A-T-, 23 as A+T-, and 69 as A+T+. There was an association between decreased visuospatial delayed memory performance and p-Tau level (B = − 0.754, β = − 0.363, p < 0.001), independent of other relevant variables (e.g., Aβ). MTL neurodegeneration was found to mediate the association between the two. Prediction models with visuospatial delayed memory alone (area under the curve [AUC] = 0.872) and visuospatial delayed memory and entorhinal thickness (AUC = 0.921) for abnormal tau accumulation were suggested and they were validated in an independent sample (AUC = 0.879 and 0.891, respectively). Conclusion It is crucial to identify sensitive cognitive measures that capture subtle cognitive impairment associated with underlying pathological changes. Preliminary findings from the current study might suggest that abnormal tau accumulation underlies episodic memory impairment, particularly visuospatial modality, in the AD continuum. Suggested models are potentially useful in predicting tau pathology, and might be utilized practically in the field.

Abstract Accumulating evidence indicates that amyloid-beta (Aβ) deposition and biogenic aldehyde accumulation contribute to the pathogenesis of neurodegenerative diseases. Human aldehyde dehydrogenase 2 (ALDH2) metabolizes biogenic aldehydes produced in the brain to prevent damage. However, r671G>A, a single nucleotide polymorphism of ALDH2, causes aldehyde accumulation and decreased ALDH2 activity. We aimed to investigate whether Aβ deposition and rs671 polymorphism have an interaction effect on cortical thickness (CTh). We grouped 179 participants in the Biobank Innovations for chronic Cerebrovascular disease With ALZheimer's disease Study as follows: amyloid (–) [A(–)] and amyloid (+) [A(+)] groups based on the Aβ deposition degree; A-carrier (AC) and GG (GG) groups based on the presence/absence of the rs671 A allele; and their combinations, i.e., A(–)AC, A(–)GG, A(+)AC, and A(+)GG groups. A multiple regression analysis identified nine regions of interest. Compared with the A(–)GG group, the A(–)AC group showed thinner CTh in all regions. There were no significant differences between the A(+)AC and A(+)GG groups. We observed an interaction effect of amyloid deposition and rs671 polymorphism on CTh. The CTh in the A(–) group appeared to be strongly influenced by rs671 polymorphism, which could have contributed to cortical thinning and biogenic aldehyde accumulation in the AC group. Additionally, CTh in the A(+) group appeared to be strongly influenced by amyloid deposition.

Quantitative electroencephalography (QEEG) has proven useful in predicting the response to various treatments, but, until now, no study has investigated changes in functional connectivity using QEEG following a lifestyle intervention program. We aimed to investigate neurophysiological changes in QEEG after a 24-week multidomain lifestyle intervention program in the SoUth Korean study to PrEvent cognitive impaiRment and protect BRAIN health through lifestyle intervention in at-risk elderly people (SUPERBRAIN). Participants without dementia and with at least one modifiable dementia risk factor, aged 60–79 years, were randomly assigned to the facility-based multidomain intervention (FMI) (n = 51), the home-based multidomain intervention (HMI) (n = 51), and the control group (n = 50). The analysis of this study included data from 44, 49, and 34 participants who underwent EEG at baseline and at the end of the study in the FMI, HMI, and control groups, respectively. The spectrum power and power ratio of EEG were calculated. Source cortical current density and functional connectivity were estimated by standardized low-resolution brain electromagnetic tomography. Participants who received the intervention showed increases in the power of the beta1 and beta3 bands and in the imaginary part of coherence of the alpha1 band compared to the control group. Decreases in the characteristic path lengths of the alpha1 band in the right supramarginal gyrus and right rostral middle frontal cortex were observed in those who received the intervention. This study showed positive biological changes, including increased functional connectivity and higher global efficiency in QEEG after a multidomain lifestyle intervention.Clinical trial registration[https://clinicaltrials.gov/ct2/show/NCT03980392] identifier [NCT03980392].

Abstract Background Genome-wide association studies (GWAS) have identified a number of genetic variants for Alzheimer’s disease (AD). However, most GWAS were conducted in individuals of European ancestry, and non-European populations are still underrepresented in genetic discovery efforts. Here, we performed GWAS to identify single nucleotide polymorphisms (SNPs) associated with amyloid β (Aβ) positivity using a large sample of Korean population. Methods One thousand four hundred seventy-four participants of Korean ancestry were recruited from multicenters in South Korea. Discovery dataset consisted of 1190 participants (383 with cognitively unimpaired [CU], 330 with amnestic mild cognitive impairment [aMCI], and 477 with AD dementia [ADD]) and replication dataset consisted of 284 participants (46 with CU, 167 with aMCI, and 71 with ADD). GWAS was conducted to identify SNPs associated with Aβ positivity (measured by amyloid positron emission tomography). Aβ prediction models were developed using the identified SNPs. Furthermore, bioinformatics analysis was conducted for the identified SNPs. Results In addition to APOE, we identified nine SNPs on chromosome 7, which were associated with a decreased risk of Aβ positivity at a genome-wide suggestive level. Of these nine SNPs, four novel SNPs (rs73375428, rs2903923, rs3828947, and rs11983537) were associated with a decreased risk of Aβ positivity (p

In the SoUth Korean study to PrEvent cognitive impaiRment and protect BRAIN health through lifestyle intervention in at-risk elderly people (SUPERBRAIN), we evaluated the impact of multidomain lifestyle intervention on regional homogeneity (ReHo) in resting-state functional brain magnetic resonance imaging (MRI) data. Of 152 participants aged 60–79 years without dementia assigned to either facility-based multidomain intervention (FMI), home-based MI, or controls, we analyzed 56 scanned MRIs at baseline and 24 weeks. ReHo values from regions with significant longitudinal changes were compared between the intervention and control groups and their correlations with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) or serum brain-derived neurotrophic factor (BDNF) were evaluated. ReHo values in the left medial orbitofrontal gyrus and right superior parietal lobule were increased [p = 0.021, correlated positively with serum BDNF changes (r = 0.504, p = 0.047)] and decreased [p = 0.021, correlated negatively with changes in the total (r = −0.509, p = 0.044) and attention (r = −0.562, p = 0.023). RBANS], respectively, in the participants assigned to the FMI group than those of the controls. Our results suggest that facility-based group preventive strategies may have cognitive benefits through neuroplastic changes in functional processing circuits in the brain areas which play a crucial role in the adaptive learning and internally directed cognition.

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease associated with a complex genetic etiology. Besides the apolipoprotein E ε4 (APOE ε4) allele, a few dozen other genetic loci associated with AD have been identified through genome-wide association studies (GWAS) conducted mainly in individuals of European ancestry. Recently, several GWAS performed in other ethnic groups have shown the importance of replicating studies that identify previously established risk loci and searching for novel risk loci. APOE-stratified GWAS have yielded novel AD risk loci that might be masked by, or be dependent on, APOE alleles. We performed whole-genome sequencing (WGS) on DNA from blood samples of 331 AD patients and 169 elderly controls of Korean ethnicity who were APOE ε4 carriers. Based on WGS data, we designed a customized AD chip (cAD chip) for further analysis on an independent set of 543 AD patients and 894 elderly controls of the same ethnicity, regardless of their APOE ε4 allele status. Combined analysis of WGS and cAD chip data revealed that SNPs rs1890078 (P = 6.64E−07) and rs12594991 (P = 2.03E−07) in SORCS1 and CHD2 genes, respectively, are novel genetic variants among APOE ε4 carriers in the Korean population. In addition, nine possible novel variants that were rare in individuals of European ancestry but common in East Asia were identified. This study demonstrates that APOE-stratified analysis is important for understanding the genetic background of AD in different populations.

Abstract Background Our previous studies showed that GV1001 has various protective effects against β-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

Abstract Background The presence of ß-amyloid (Aß) in the brain can be identified using amyloid PET. In clinical practice, the amyloid PET is interpreted based on dichotomous visual rating, which renders focal Aß accumulation be read as positive for Aß. However, the prognosis of patients with focal Aß deposition is not well established. Thus, we investigated cognitive trajectories of patients with focal Aß deposition. Methods We followed up 240 participants (112 cognitively unimpaired [CU], 78 amnestic mild cognitive impairment [aMCI], and 50 Alzheimer’s disease (AD) dementia [ADD]) for 2 years from 9 referral centers in South Korea. Participants were assessed with neuropsychological tests and 18F-flutemetamol (FMM) positron emission tomography (PET). Ten regions (frontal, precuneus/posterior cingulate (PPC), lateral temporal, parietal, and striatum of each hemisphere) were visually examined in the FMM scan, and participants were divided into three groups: No-FMM, Focal-FMM (FMM uptake in 1–9 regions), and Diffuse-FMM. We used mixed-effects model to investigate the speed of cognitive decline in the Focal-FMM group according to the cognitive level, extent, and location of Aß involvement, in comparison with the No- or Diffuse-FMM group. Results Forty-five of 240 (18.8%) individuals were categorized as Focal-FMM. The rate of cognitive decline in the Focal-FMM group was faster than the No-FMM group (especially in the CU and aMCI stage) and slower than the Diffuse-FMM group (in particular in the CU stage). Within the Focal-FMM group, participants with FMM uptake to a larger extent (7–9 regions) showed faster cognitive decline compared to those with uptake to a smaller extent (1–3 or 4–6 regions). The Focal-FMM group was found to have faster cognitive decline in comparison with the No-FMM when there was uptake in the PPC, striatum, and frontal cortex. Conclusions When predicting cognitive decline of patients with focal Aß deposition, the patients’ cognitive level, extent, and location of the focal involvement are important.

Abstract Background Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarker cutoffs from immunoassays with low interlaboratory variability in diverse ethnic groups are necessary for their use in clinics and clinical trials. With lack of cutoffs from fully automated immunoassay platforms in diverse races, the aim of this study is to evaluate the clinical utility of CSF AD biomarkers from the Lumipulse fully automated immunoassay based on β-amyloid (Aβ) positron emission tomography (PET) status comparing with these from two manual immunoassays, in Koreans. Methods Among 331 Korean participants enrolled from a prospective, 3-year longitudinal observational study of the validation cohort of Korean Brain Aging Study for the Early Diagnosis and Prediction of AD, 139 (29 CN, 58 SCD, 29 MCI, and 23 AD) provided CSF and 271 underwent baseline amyloid PET (n = 128 with overlapping CSF and Aβ-PET, and 143 without CSFs). Three annual cognitive and neuropsychiatric function tests were conducted. Aβ42, Aβ40, total-tau, and phosphorylated-tau181 were measured by Lumipulse fully automated immunoassay and two manual immunoassays (INNO-BIA AlzBio3, INNOTEST). Clinical utility of CSF biomarker cutoffs, based on 128 participants with Aβ-PET, was evaluated. Results Cognitive and neuropsychological scores differed significantly among the groups, with descending performance among CN>SCD>MCI>AD. Biomarker levels among immunoassays were strongly intercorrelated. We determined the Aβ-PET status in a subgroup without CSF (n = 143), and then when we applied CSF biomarker cutoffs determined based on the Aβ-PET status, the CSF biomarkers (cutoffs of 642.1 pg/mL for Aβ42, 0.060 for Aβ42/Aβ40, 0.315 for t-tau/Aβ42, and 0.051 for p-tau/Aβ42, respectively) showed good agreement with Aβ-PET (overall AUC ranges of 0.840–0.898). Use of the Aβ-PET-based CSF cutoffs showed excellent diagnostic discrimination between AD and CN (Aβ42, Aβ42/Aβ40, t-tau/Aβ42, and p-tau/Aβ42) with overall AUC ranges of 0.876–0.952. During follow-up, participants with AD-like CSF signature determined by Aβ-PET-based cutoffs from Lumipulse showed rapid progression of cognitive decline in 139 subjects, after adjustment for potential confounders, compared with those with a normal CSF signature. Conclusion CSF AD biomarkers measured by different immunoassay platforms show strong intercorrelated agreement with Aβ-PET in Koreans. The Korean-specific Aβ-PET-based CSF biomarker cutoffs measured by the Lumipulse assay strongly predicts progression of cognitive decline. The clinical utility of CSF biomarkers from fully-automated immunoassay platforms should be evaluated in larger, more diverse cohorts.

Abstract Background Recently, several studies suggested potential involvements of α-synuclein in Alzheimer’s disease (AD) pathophysiology. Higher concentrations of α-synuclein were reported in cerebrospinal fluid (CSF) of AD patients with a positive correlation towards CSF tau, indicating its possible role in AD. We analyzed the CSF biomarkers to verify whether α-synuclein could be an additional supported biomarker in AD diagnosis. Methods In this cross-sectional study, CSF samples of 71 early-onset AD, 34 late-onset AD, 11 mild cognitive impairment, 17 subjective cognitive decline, 45 Parkinson’s disease, and 32 healthy control (HC) were collected. CSF amyloid-β1-42 (A), total tau (N), and phosphorylated tau181 (T) were measured by commercial ELISA kits, and in-house ELISA kit was developed to quantify α-synuclein. The cognitive assessments and amyloid-PET imaging were also performed. Results CSF α-synuclein manifested a tendency to increase in AD and to decreased in Parkinson’s disease compared to HC. The equilibrium states of total tau and α-synuclein concentrations were changed significantly in AD, and the ratio of total tau/α-synuclein (N/αS) was dramatically increased in AD than HC. Remarkably, N/αS revealed a strong positive correlation with tau phosphorylation rate. Also, the combination of N/αS with amyloid-β1-42/phosphorylated tau181 ratio had the best diagnosis performance (AUC = 0.956, sensitivity = 96%, specificity = 87%). In concordance analysis, N/αS showed the higher diagnostic agreement with amyloid-β1-42 and amyloid-PET. Analysis of biomarker profiling with N/αS had distinctive characteristics and clustering of each group. Especially, among the group of suspected non-Alzheimer’s disease pathophysiology, all A−T+N+ patients with N/αS+ were reintegrated into AD. Conclusions The high correlation of α-synuclein with tau and the elevated N/αS in AD supported the involvement of α-synuclein in AD pathophysiology. Importantly, N/αS improved the diagnostic performance, confirming the needs of incorporating α-synuclein as a biomarker for neurodegenerative disorders. The incorporation of a biomarker group [N/αS] could contribute to provide better understanding and diagnosis of neurodegenerative disorders.

Abstract Background Although amyloid PET of typical Alzheimer’s disease (AD) shows diffuse ß-amyloid (Aß) deposition, some patients show focal deposition. The clinical significance of this focal Aß is not well understood. We examined the clinical significance of focal Aß deposition in terms of cognition as well as Aß and tau cerebrospinal fluid (CSF) levels. We further evaluated the order of Aß accumulation by visual assessment. Methods We included 310 subjects (125 cognitively unimpaired, 125 mild cognitive impairment, and 60 AD dementia) from 9 referral centers. All patients underwent neuropsychological tests and 18F-flutemetamol (FMM) PET. Seventy-seven patients underwent CSF analysis. Each FMM scan was visually assessed in 10 regions (frontal, precuneus and posterior cingulate, lateral temporal, parietal, and striatum of each hemisphere) and was classified into three groups: No-FMM, Focal-FMM (FMM uptake in 1–9 regions), and Diffuse-FMM (FMM uptake in all 10 regions). Results 53/310 (17.1%) subjects were classified as Focal-FMM. The cognitive level of the Focal-FMM group was better than that of Diffuse-FMM group and worse than that of No-FMM group. Among the Focal-FMM group, those who had FMM uptake to a larger extent or in the striatum had worse cognitive levels. Compared to the Diffuse-FMM group, the Focal-FMM group had a less AD-like CSF profile (increased Aß42 and decreased t-tau, t-tau/Aß42). Among the Focal-FMM group, Aß deposition was most frequently observed in the frontal (62.3%) and least frequently observed in the striatum (43.4%) and temporal (39.6%) regions. Conclusions We suggest that focal Aß deposition is an intermediate stage between no Aß and diffuse Aß deposition. Furthermore, among patients with focal Aß deposition, those who have Aß to a larger extent and striatal involvement show clinical features close to diffuse Aß deposition. Further longitudinal studies are needed to evaluate the disease progression of patients with focal Aß deposition.

The use of positron emission tomography (PET) as the initial or sole biomarker of β-amyloid (Aβ) 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 Aβ pathology among subjective cognitive decline (SCD) and mild cognitive impairment (MCI) patients, and validated it using Aβ 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.

Abstract Background Neuropsychological tests (NPTs) are important tools for informing diagnoses of cognitive impairment (CI). However, interpreting NPTs requires specialists and is thus time-consuming. To streamline the application of NPTs in clinical settings, we developed and evaluated the accuracy of a machine learning algorithm using multi-center NPT data. Methods Multi-center data were obtained from 14,926 formal neuropsychological assessments (Seoul Neuropsychological Screening Battery), which were classified into normal cognition (NC), mild cognitive impairment (MCI) and Alzheimer’s disease dementia (ADD). We trained a machine learning model with artificial neural network algorithm using TensorFlow (https://www.tensorflow.org) to distinguish cognitive state with the 46-variable data and measured prediction accuracies from 10 randomly selected datasets. The features of the NPT were listed in order of their contribution to the outcome using Recursive Feature Elimination. Results The ten times mean accuracies of identifying CI (MCI and ADD) achieved by 96.66 ± 0.52% of the balanced dataset and 97.23 ± 0.32% of the clinic-based dataset, and the accuracies for predicting cognitive states (NC, MCI or ADD) were 95.49 ± 0.53 and 96.34 ± 1.03%. The sensitivity to the detection CI and MCI in the balanced dataset were 96.0 and 96.0%, and the specificity were 96.8 and 97.4%, respectively. The ‘time orientation’ and ‘3-word recall’ score of MMSE were highly ranked features in predicting CI and cognitive state. The twelve features reduced from 46 variable of NPTs with age and education had contributed to more than 90% accuracy in predicting cognitive impairment. Conclusions The machine learning algorithm for NPTs has suggested potential use as a reference in differentiating cognitive impairment in the clinical setting.

Abstract Introduction Oligomeric amyloid-ß is a major toxic species associated with Alzheimer’s disease pathogenesis. Methods used to measure oligomeric amyloid-β in the blood have increased in number in recent years. The Multimer Detection System-Oligomeric Amyloid-β (MDS-OAβ) is a specific method to measure oligomerization tendencies in the blood. The objective of this study was to determine the association between amyloid-ß oligomerization in the plasma and structural changes of the brain. Methods We studied 162 subjects composed of 92 community-based normal healthy subjects, 17 with subjective cognitive decline, 14 with mild cognitive impairment and 39 with Alzheimer’s disease dementia. All subjects underwent MDS-OAβ and three-dimensional T1 magnetic resonance imaging. To determine the structural changes of the brain that are statistically correlated with MDS-OAβ level, we used voxel-based morphometry with corrections for age and total intracranial volume covariates. Results We found brain volume reduction in the bilateral temporal, amygdala, parahippocampal and lower parietal lobe and left cingulate and precuneus regions (family-wise error, p

Emerging nanomaterials providing benefits in sensitivity, specificity and cost-effectiveness are being widely investigated for biosensors in the application of Alzheimer’s disease (AD) diagnosis. Core biomarkers amyloid-beta (Aβ) and Tau have been considered as key neuropathological hallmarks of AD. However, they did not sufficiently reflect clinical severity and therapeutic response, proving the difficulty of the Aβ- and Tau-targeting therapies in clinical trials. In recent years, there has still been a shortage of sensors for non-Aβ-Tau pathophysiological biomarkers that serve as advanced reporters for the early diagnosis of AD, predict AD progression, and monitor the treatment response. Nanomaterial-based sensors measuring multiple non-Aβ-Tau biomarkers could improve the capacity of AD progression characterization and supervised treatment, facilitating the comprehensive management of AD. This is the first review to principally represent current nanobiosensors for non-Aβ-Tau biomarker and that strategically deliberates future perspectives on the merit of non-Aβ-Tau biomarkers, in combination with Aβ and Tau, for the accurate diagnosis and prognosis of AD.

Studies investigating the impact of white matter hyperintensities (WMHs) on the response of acetylcholinesterase inhibitors in patients with Alzheimer's disease (AD) have presented inconsistent results. We aimed to compare the effects of the rivastigmine patch between patients with AD with minimal WMHs and those with moderate WMHs.Three hundred patients with mild to moderate AD were enrolled in this multicenter prospective open-label study and divided into two groups. Group 1 comprised patients with AD with minimal WMHs and group 2 comprised those with moderate WMHs. The patients were treated with a rivastigmine patch for 24 weeks. Efficacy measures were obtained at baseline and after 24 weeks. The primary endpoint was the change in the AD Assessment Scale-Cognitive subscale (ADAS-Cog) from the baseline to the end of the study.Of the 300 patients, there were 206 patients in group 1 and 94 patients in group 2. The intention-to-treat group comprised 198 patients (group 1, n = 136; group 2, n = 46) during the 24-week study period. Demographic factors did not differ between group 1 and group 2. There were no significant differences in change in ADAS-cog between group 1 (-0.62±5.70) and group 2 (-0.23±5.98) after the 24-week rivastigmine patch therapy (p = 0.378). The patients in group 1 had a 0.63-point improvement from baseline on the Frontal Assessment Battery, while group 2 had a 0.16-point decline compared to baseline at the end of the study (p = 0.037). The rates of adverse events (AEs) (42.6 vs. 40.3%) and discontinuation due to AEs (10.3% vs. 4.3%) did not differ between the groups.Although the efficacy and tolerability of rivastigmine patch therapy were not associated with WMH severity in patients with AD, some improvement in frontal function was observed in those with minimal WMHs.ClinicalTrials.gov NCT01380288.

PURPOSE:We investigated the association of the macular ganglion cell-inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (RNFL) thicknesses with disease progression in mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS:We recruited 42 patients with AD, 26 with MCI, and 66 normal elderly controls. The thicknesses of the RNFL and GCIPL were measured via spectral-domain optic coherent tomography in all participants at baseline. The patients with MCI or AD underwent clinical and neuropsychological tests at baseline and once every year thereafter for 2 years. RESULTS:The Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) score exhibited significant negative relationships with the average GCIPL thickness (β = -0.15, p < 0.05) and the GCIPL thickness in the superotemporal, superonasal, and inferonasal sectors. The composite memory score exhibited significant positive associations with the average GCIPL thickness and the GCIPL thickness in the superotemporal, inferonasal, and inferotemporal sectors. The temporal RNFL thickness, the average and minimum GCIPL thicknesses, and the GCIPL thickness in the inferonasal, inferior, and inferotemporal sectors at baseline were significantly reduced in MCI patients who were converted to AD compared to stable MCI patients. The change of CDR-SB from baseline to 2 years exhibited significant negative associations with the average (β = -0.150, p = 0.006) and minimum GCIPL thicknesses as well as GCIPL thickness in the superotemporal, superior, superonasal, and inferonasal sectors at baseline. CONCLUSIONS:Our data suggest that macular GCIPL thickness represents a promising biomarker for monitoring the progression of MCI and AD.

Heat shock proteins (HSPs) have been regarded as cytoprotectants that protect brain cells during the progression of neurodegenerative diseases and from damage resulting from cerebral ischemia. In this study, we assessed the association between plasma HSP 70/27 levels and cognitive decline.Among participants in the community-based cohort study of dementia called the Gwangju Dementia and Mild Cognitive Impairment Study, subjects without cognitive impairment at baseline, who then either remained without impairment (non-conversion group), or suffered mild cognitive impairment (MCI) (conversion group) (non-conversion group, N = 36; conversion group, N = 30) were analyzed.After a five to six year follow-up period, comparison of the plasma HSP 70 and HSP 27 levels of the two groups revealed that only the plasma HSP 70 level was associated with a conversion to MCI after adjustments for age, gender, years of education, follow-up duration, APOE e4, hypertension, and diabetes (repeated measure analysis of variance: F = 7.59, p = 0.008). Furthermore, an increase in plasma HSP 70 level was associated with cognitive decline in language and executive function (linear mixed model: Korean Boston Naming Test, -0.426 [-0.781, -0.071], p = 0.019; Controlled Oral Word Association Test, -0.176 [-0.328, -0.023], p = 0.024; Stroop Test, -0.304 [-0.458, -0.150], p

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) can be caused by a variety of drugs. Dopaminergic drugs might enhance the secretion of the antidiuretic hormone arginine vasopressin by reducing γ-amino butyric acid release through the dopaminergic receptor in supraoptic nucleus. A 75-year-old woman with Parkinson’s disease developed asthenia, delirium, aggravated parkinsonian symptoms, and hypotonic hyponatremia along with the diagnostic criteria for SIADH during dose escalation of pramipexole. After pramipexole withdrawal, these symptoms disappeared, and sodium levels returned to normal values. The serum sodium levels of patients receiving pramipexole should be monitored, especially during dose escalation.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) can be caused by a variety of drugs. Dopaminergic drugs might enhance the secretion of the antidiuretic hormone arginine vasopressin by reducing γ-amino butyric acid release through the dopaminergic receptor in supraoptic nucleus. A 75-year-old woman with Parkinson’s disease developed asthenia, delirium, aggravated parkinsonian symptoms, and hypotonic hyponatremia along with the diagnostic criteria for SIADH during dose escalation of pramipexole. After pramipexole withdrawal, these symptoms disappeared, and sodium levels returned to normal values. The serum sodium levels of patients receiving pramipexole should be monitored, especially during dose escalation.

Purpose: Research on the relationship between diet and dementia among Koreans are lacking. This study investigated the association between dietary habits and dementia progression over 3 years in patients with Alzheimer’s disease dementia (ADD). Materials and Methods: This study included 705 patients with mild-to-moderate ADD. Dietary habits were assessed using the Mini Dietary Assessment Index, comprising 10 questions. Outcome measures included the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB), Seoul-Instrumental Activities of Daily Living, Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI), and neuropsychological test battery (NTB) z-scores, which were evaluated annually over 3 years. Results: In Q10 (eat all food evenly without being picky), the 3-year mean differences in CDR-SB (increases in scores represent worsening) compared to the “rarely” group were -1.86 [95% confidence interval (CI)=-3.64 – -0.09, p=0.039] for the “usually” group and -2.23 (95% CI=-4.40 – -0.06, p=0.044) for the “always” group. In Q7 (add salt or soy sauce to food when eating), the 3-year mean differences in CDR-SB compared to the “always” group were -2.47 (95% CI=-4.70 – -0.24, p=0.030) for the “usually” group and -3.16 (95% CI=-5.36 – -0.96, p=0.005) for the “rarely” group. The “rarely” and “usually” groups in Q7 showed significantly less decline in NTB z-score and CGA-NPI compared to the “always” group. Conclusion: Eating a balanced diet and reducing salt intake were associated with a slower decline in dementia severity, cognition, and behavioral alterations in patients with ADD. [ABSTRACT FROM AUTHOR]

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 2years 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. [ABSTRACT FROM AUTHOR]