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Presenilin 1 (PSEN1) is a part of the gamma secretase complex with several interacting substrates, including amyloid precursor protein (APP), Notch, adhesion proteins and beta catenin. PSEN1 has been extensively studied in neurodegeneration, and more than 300 PSEN1 mutations have been discovered to date. In addition to the classical early onset Alzheimer’s disease (EOAD) phenotypes, PSEN1 mutations were discovered in several atypical AD or non-AD phenotypes, such as frontotemporal dementia (FTD), Parkinson’s disease (PD), dementia with Lewy bodies (DLB) or spastic paraparesis (SP). For example, Leu113Pro, Leu226Phe, Met233Leu and an Arg352 duplication were discovered in patients with FTD, while Pro436Gln, Arg278Gln and Pro284Leu mutations were also reported in patients with motor dysfunctions. Interestingly, PSEN1 mutations may also impact non-neurodegenerative phenotypes, including PSEN1 Pro242fs, which could cause acne inversa, while Asp333Gly was reported in a family with dilated cardiomyopathy. The phenotypic diversity suggests that PSEN1 may be responsible for atypical disease phenotypes or types of disease other than AD. Taken together, neurodegenerative diseases such as AD, PD, DLB and FTD may share several common hallmarks (cognitive and motor impairment, associated with abnormal protein aggregates). These findings suggested that PSEN1 may interact with risk modifiers, which may result in alternative disease phenotypes such as DLB or FTD phenotypes, or through less-dominant amyloid pathways. Next-generation sequencing and/or biomarker analysis may be essential in clearly differentiating the possible disease phenotypes and pathways associated with non-AD phenotypes.

Postoperative delirium (POD) is a frequent complication in older people undergoing general anesthesia surgery. We investigated the potential link between Alzheimer’s disease and POD by comparing plasma amyloid-beta oligomer levels (measured using the multimer detection system, MDS-OAβ) in patients who developed POD after general anesthesia surgery with those who did not. A total of 104 eligible participants were screened daily for delirium for three days postoperatively. After propensity score matching based on the ApoE4 allele, the final analysis included 31 patients with POD and 31 without POD. In the ICU, patients with delirium underwent immediate assessment with the Korean version of the Delirium Rating Scale-98 (K-DRS-98) and plasma MDS-OAβ levels. The control group (those without POD) received the same tests on the third postoperative day. Patients with POD had significantly higher MDS-OAβ values compared to those without POD. Within the POD group, MDS-OAβ values positively correlated with K-DRS-98 scores (both severity and total scores). These findings suggest an association between POD in older people undergoing general anesthesia surgery and elevated plasma amyloid oligomer levels. To definitively establish causality, further prospective studies are necessary.

Alzheimer's disease (AD), the most common form of dementia, is characterized by progressive cognitive decline. To address this, we conducted a randomized, double-blinded, sham-controlled study to investigate the therapeutic potential of transcranial direct current stimulation (tDCS) on patients with amyloid positron emission tomography (PET)- positive AD. Participants already undergoing pharmacological treatment and testing positive for amyloid PET were divided into Active-tDCS (  = 8) and Sham-tDCS (  = 8) groups. For 12 weeks, participants or their caregivers administered daily bi-frontal tDCS (YMS-201B+, Ybrain Inc., Seongnam, Korea) at home (2 mA, 30 min). Pre- and post-intervention assessments included neuropsychological tests and blood sample measurements for oligomerized beta-amyloid. The Active-tDCS group demonstrated significant improvements in cognitive domains such as language abilities, verbal memory, and attention span and in frontal lobe functions compared to the Sham-tDCS group. Furthermore, the Active-tDCS group showed a marked reduction in post-intervention plasma Aβ oligomerization tendency level, suggesting changes in pivotal AD-associated biomarkers. Our results emphasize the potential therapeutic benefits of tDCS for mild AD patients with amyloid PET positivity and stress the urgency for broader research, considering the global challenges of dementia and the need to pursue innovative therapeutic strategies.

Postoperative delirium (POD) is common in older adults and has been linked to Alzheimer's disease (AD). Plasma amyloid-β oligomers (AβOs) may clarify this relationship. We evaluated whether preoperative AβO burden is associated with POD severity. In this single-center prospective pilot study, we enrolled 22 patients aged ≥65 years undergoing hip or knee arthroplasty under general anesthesia. Blood was drawn preoperatively and postoperatively to quantify oligomerized amyloid-β using the multimer detection system (MDS-Oaβ). POD was assessed with the Korean version of the Delirium Rating Scale-98 (K-DRS-98). Group comparisons and correlations examined associations between MDS-Oaβ and POD. Eleven of 22 patients developed POD. Those with POD were older and had higher preoperative MDS-Oaβ than those without POD (0.81 vs 0.56 ng/mL). There was no significant perioperative change in MDS-Oaβ, suggesting surgery or anesthesia did not alter the plasma Aβ oligomerization tendency. Within the POD group, preoperative MDS-Oaβ correlated with both K-DRS-98 severity and total scores. In this pilot cohort, higher preoperative AβO burden was associated with the occurrence and severity of POD, while perioperative factors did not measurably affect AβO levels. These findings support a potential mechanistic link between AD-related pathology and POD. Given the small sample ( =22), estimates are imprecise and hypothesis-generating; validation in larger, multicenter studies is required before clinical application.

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.

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  < 0.05). These were not significantly observed in group 2. Among the secondary endpoints, only the NPI score showed significantly better improvement in group 2 than in group 3 at week 12; however, there were no other significant differences between the groups. Although the ADCS-ADL and CDR-SOB scores showed a pattern similar to SIB scores, a statistically significant result was not found. Adverse events were similar across all three groups. Conclusions The results indicate that GV1001 1.12 mg met the primary endpoint of a statistically significant difference. GV1001 was well tolerated without safety concerns. This study warrants a larger clinical trial. Trial registration ClinicalTrials.gov NCT03184467 . Registered on June 12, 2017.

Alzheimer’s disease (AD) is the most common cause of dementia and accounts for approximately 60–80% of total dementia patients. Currently, accurate diagnosis for AD relies on cerebrospinal fluid (CSF) sampling or a positron emission tomography (PET) scan, methods that cannot be done in primary care centers where most people go with cognitive complaints. This Limitation calls for the urgent need to develop blood-related diagnostic tests that could facilitate early detection and enable timely treatment. Recent CSF proteomic research categorized AD into five molecular subtypes with discrete Genetic risk profiles. Subtypes 1–3, namely neuronal hyperplasticity, innate immune activation, and RNA dysregulation, were characterized by more classical AD-related changes, like accumulation of amyloid/tau and synaptic and immune dysfunction, respectively. On the contrary, non-traditional AD mechanisms in subtypes 4–5 were choroid plexus (CP) dysfunction and blood–brain barrier (BBB) dysfunction, emphasizing clearance deficits in association with brain barrier dysfunction. The unchanged tau levels later may be explained by an alternate disease mechanism (clearance dysfunction). These subtypes included BBB and CP dysfunction. Biomarker identification based on the mechanism of disease progression would increase the precision of diagnoses, allowing for tailored interventions and aiding in the creation of novel therapies for subtypes that might not react favorably to conventional amyloid/tau-targeting strategies. Finding biomarkers specific to each subtype would aid in patient classification, resulting in more individualized therapy as opposed to a “one-size-fits-all” strategy. The present review emphasized the importance of identifying blood-based biomarkers (BBMs) related to brain barrier dysfunction from CSF studies and personalized treatment strategies to streamline the diagnostic workup, and may be utilized in standard clinical practice for the early detection of AD.

The pathophysiology of transient global amnesia (TGA) is not fully understood. Previous studies using single photon emission computed tomography (SPECT) have reported inconclusive results regarding cerebral perfusion. This study was conducted to identify the patterns of regional cerebral blood flow (rCBF) in TGA patients via longitudinal SPECT analysis. An association between the observed SPECT patterns and a pathophysiological mechanism was considered. Based on the TGA registry database of Seoul National University Bundang Hospital, 22 TGA patients were retrospectively identified. The subjects underwent initial Tc-99m-ethyl cysteinate dimer (ECD) SPECT within 4 days of an amnestic event and underwent follow-up scans approximately 6 months later. The difference in ECD uptake between the two scans was measured via voxel-based whole brain analysis, and the quantified ECD uptake was tested using a paired t-test. The TGA patients had significantly decreased cerebral perfusion at the left precuneus (P<0.001, uncorrected) and at the left superior parietal and inferior temporal gyrus according to the voxel-based whole brain analysis (P<0.005, uncorrected). A difference in the quantified ECD uptake between the 2 scans was also found at the left precuneus among the 62 cortical volumes of interest (P = 0.018, Cohen's d = -0.25). We identified left hemispheric lateralized hypoperfusion that may be related to posterior medial network disruption. These findings may be a contributing factor to the pathophysiology of TGA.

Two parallel pathways have been proposed between the hippocampus and neocortex. Recently, the anterior and posterior hippocampus showed distinct connectivity with different cortical areas in an fMRI study. We investigated whether the two parallel pathways could be confirmed in patients with transient global amnesia (TGA) which is a natural lesion model of a perturbation of the hippocampus. In addition, we evaluated the relationship between the location of the hippocampal lesion and various clinical variables. A consecutive series of 37 patients were identified from the TGA registry database of Seoul National University Bundang Hospital. Based on the location of the diffusion-weighted imaging (DWI) lesion along the anterior-posterior axis of the hippocampus, they were divided into the following three groups: head (n = 15), body (n = 15) or tail (n = 7). To evaluate which cortical regions showed hypoperfusion according to the location of the DWI lesion, their SPECT images were compared between two groups using statistical parametric mapping. We performed hierarchical cluster analysis to group demographic and clinical variables, including the location of the DWI lesion, into clusters. Statistical parametric mapping analyses revealed that more anterior DWI lesions were associated with hypoperfusion of the anterior temporal and frontal areas, whereas more posterior lesions were associated with hypoperfusion of the posterior temporal, parietal, occipital and cerebellar areas. The difference was most prominent between the group of hippocampal lesions on the head and tail. Hierarchical cluster analysis demonstrated that vomiting was related to female gender and hippocampal head lesions, whereas vascular risk factors were related to male gender and hippocampal body lesions. We confirmed the parallel pathways between the hippocampus and neocortex with DWI and SPECT images of patients with TGA. Patients with hippocampal head lesions and body lesions were clustered within different groups of clinical variables.

Background: Hospitalization for severe neuropsychiatric symptoms in Alzheimer’s disease (AD) presents challenges, often requiring environments that ensure safety while addressing therapeutic needs. Traditional closed wards, originally designed for psychiatric conditions like schizophrenia, may not fully address the unique needs of AD patients. This study evaluates the effectiveness of a Specialized Dementia Ward (SDW) tailored for AD patients compared to a General Ward (GW). Methods: A retrospective study compared 51 AD patients in an SDW (February 2018–January 2019) and 40 AD patients in a GW (December 2017–January 2018). Patients met NINCDS-ADRDA criteria, with a Clinical Dementia Rating (CDR) ≤ 2 and a Korean Mini-Mental State Examination (K-MMSE) ≤ 20. Clinical assessments at admission and four weeks included K-MMSE, Resident Assessment Instrument Minimum Data Set Version 2.0 (RAI-MDS), and Neuropsychiatric Inventory Questionnaire (NPI-Q). Psychotropic medication use, length of stay, and discharge destination were also analyzed. Results: No statistically significant differences emerged between SDW and GW groups regarding baseline demographics, cognitive function, ADL, or neuropsychiatric symptoms. At four weeks, both groups exhibited trends toward improved K-MMSE, RAI-MDS, and NPI-Q scores and reduced psychotropic usage, but these did not reach statistical significance. Although mean length of stay was shorter for SDW patients (3.2 vs. 4.9 months; p = 0.078), the difference was not significant. Notably, a significantly higher proportion of SDW patients were discharged home (58.8% vs. 37.5%; p = 0.049). Conclusions: Although clinical outcomes were comparable, the SDW demonstrated advantages in facilitating discharge to home, suggesting that tailored ward environments may better support AD patients. These findings underscore the importance of therapeutic environments in dementia care and highlight the need for further research on specialized dementia ward designs to improve outcomes and patient satisfaction.