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Recently, the focus of Alzheimer’s disease (AD) research has shifted from the clinical stage to the preclinical stage. We, therefore, aimed to develop a cognitive composite score that can detect the subtle cognitive differences between the amyloid positive (Aβ+) and negative (Aβ−) status in cognitively normal (CN) participants. A total of 423 CN participants with Aβ positron emission tomography images were recruited. The multiple-indicators multiple-causes model found the latent mean difference between the Aβ+ and Aβ− groups in the domains of verbal memory, visual memory, and executive functions. The multivariate analysis of covariance (MANCOVA) showed that the Aβ+ group performed worse in tests related to the verbal and visual delayed recall, semantic verbal fluency, and inhibition of cognitive inference within the three cognitive domains. The Preclinical Amyloid Sensitive Composite (PASC) model we developed using the result of MANCOVA and the MMSE presented a good fit with the data. The accuracy of the PASC score when applied with age, sex, education, and APOE ε4 for distinguishing between Aβ+ and Aβ− was adequate (AUC = 0.764; 95% CI = 0.667–0.860) in the external validation set (N = 179). We conclude that the PASC can eventually contribute to facilitating more prevention trials in preclinical AD.

National dementia plans were applied in dementia support centers established in Seoul, Korea between 2007 and 2009. However, the annual incidence rates of dementia in Seoul have not been reported. We investigated this annual incidence and the characteristics of incident cases from 2003 to 2018. The customized research database of the Korean National Health Insurance Services was used. The annual crude and age-standardized incidence of dementia patients and their characteristics were analyzed. This study analyzed 108,596 incident dementia cases aged ≥60 years. The incidence rate increased from 2003 to 2011, including a rapid increment from 2007 to 2011. From 2011 to 2018, the crude (age-standardized) incidence per 105 person-years decreased from 641.51 (577.12) to 448.26 (361.23). The proportion of incident dementia cases was highest in the highest income group every year. However, the proportion of incident dementia cases in the lowest income group increased from 10.4% in 2003 to 25.8% in 2011. The annual incidence rate of dementia showed a sharp increase immediately after 2007, the year dementia support centers began to be introduced, and then stabilized after 2011. The characteristics of incident dementia cases have changed, including the proportion in the low-income group.

Visuospatial dysfunction is a common symptom in patients with Alzheimer's disease (AD). To more focus on copying processes rather than on finally completed figures, we conceptually split the copying processes into three stages: visuoperceptual function, visuoconstructional function, and working memory function. We constructed perceptual and working spaces to investigate the different stages of copying, and then, we compared the number and duration of fixations and saccades and the number of switches across the two spaces. We used eye-tracking glasses to assess eye-tracking metrics in patients with early-onset AD (EOAD), patients with late-onset AD (LOAD), and normal control (NC) participants while they copied the simplified Rey–Osterrieth complex figure test (RCFT). Regarding eye metrics on the perceptual space, the number and duration of fixations were greater in both groups of patients with AD than in the NC participants group (number: EOAD vs. NC: p < 0.001, LOAD vs. NC: p = 0. 003/ duration: EOAD vs. NC: p < 0.001, LOAD vs. NC: p < 0.001). On the working space, the number and duration of fixations were greater in the patients with EOAD than in the patients with LOAD and NC participants (number: EOAD vs. LOAD: p = 0. 007, EOAD vs. NC: p = 0. 001/duration: EOAD vs. LOAD: p = 0. 008, EOAD vs. NC: p = 0. 002). The number of saccades and switching was higher in patients with EOAD than in NC participants (p < 0.001). The eye-tracking metrics from the simplified RCFT correlated with the neuropsychological test scores. Patients with EOAD and LOAD achieved the same level of performance at the simplified and original RCFT scores. However, patients with EOAD than LOAD showed a greater number and duration of fixations on the working space and more frequent switching between the perceptual and working spaces, which may reflect more cognitive efforts to achieve the same level of performance.

Previous studies have developed several cognitive composites in preclinical Alzheimer disease (AD). However, more sensitive measures to track cognitive changes and therapeutic efficacy in preclinical AD are needed considering the diverse sociocultural and linguistic backgrounds. This study developed a composite score that can sensitively detect the amyloid-β (Aβ)-related cognitive trajectory of preclinical AD using Korean data.A total of 196 cognitively normal participants who underwent amyloid positron emission tomography were followed-up with neuropsychological assessments. We developed the Longitudinal Amyloid Cognitive Composite in Preclinical AD (LACPA) using the linear mixed-effects model (LMM) and z scores. The LMM was also used to investigate the longitudinal sensitivity of the LACPA and the association between time-varying brain atrophy and the LACPA.Considering the group-time interaction effects of each subtest, the Seoul Verbal Learning Test-Elderly version immediate recall/delayed recall/recognition, the Korean Trail Making Test B Time, and the Korean Mini-Mental State Examination were selected as components of the LACPA. The LACPA exhibited a significant group-time interaction effect between the Aβ+ and Aβ- groups (t = -3.288, p = 0.001). Associations between time-varying LACPA and brain atrophy were found in the bilateral medial temporal, right lateral parietal, and right lateral frontal regions, and hippocampal volume.The LACPA may contribute to reduction in time and financial burden when monitoring Aβ-related cognitive decline and therapeutic efficacy of the disease-modifying agents specifically targeting Aβ in secondary prevention trials.

BACKGROUND Frontal behavioral impairment (FrBI) is commonly observed in various degenerative diseases and refers to various behavioral symptoms. OBJECTIVE We investigated the effects of the presence of FrBI on cortical thickness, and the longitudinal neuropsychological changes in people in the predementia stage. METHODS A total of 794 individuals completed neuropsychological tests and the Frontal Behavioral Inventory (FBI) Questionnaire, and underwent magnetic resonance (MR) scanning. Participants were analyzed and grouped into non-FrBI (FBI = 0) or FrBI (FBI≥1). Cortical thickness was measured on MR images using a surface-based method. RESULTS In total, 281 people with subjective cognitive decline (SCD) and 513 with amnestic mild cognitive impairment (aMCI) were assessed for FrBI. Relative to people without FrBI, those with FrBI presented reduced cortical thickness in the frontal, anterior temporal and lateral parietal regions (p

Background Although few studies have shown that risk factors for Alzheimer’s disease (AD) are associated with cognitive decline in AD, not much is known whether the impact of risk factors differs between early-onset AD (EOAD, symptom onset Methods We followed-up 193 EOAD and 476 LOAD patients without known autosomal dominant AD mutation for 32.3 ± 23.2 months. Mixed-effects model analyses were performed to evaluate the effects of APOE ε4, low education, hypertension, diabetes, dyslipidemia, and obesity on cognitive trajectories. Results APOE ε4 carriers showed slower cognitive decline in general cognitive function, language, and memory domains than APOE ε4 carriers in EOAD but not in LOAD. Although patients with low education showed slower cognitive decline than patients with high education in both EOAD and LOAD, the effect was stronger in EOAD, specifically in frontal-executive function. Patients with hypertension showed faster cognitive decline than did patients without hypertension in frontal-executive and general cognitive function in LOAD but not in EOAD. Patients with obesity showed slower decline in general cognitive function than non-obese patients in EOAD but not in LOAD. Conclusions Known risk factors for AD were associated with slower cognitive decline in EOAD but rapid cognitive decline in LOAD.

Additional file 1: Table S1. The number of 18F-flutemetamol uptake regions in cognitively unimpaired, amnestic mild cognitive impairment, and Alzheimer's disease dementia at baseline. Fig. S1. Scatter plot and regression line showing a significant correlation between the number of 18F-flutemetamol uptake regions and global SUVR.

Objective Neuropsychological test-specific neural substrates in subcortical vascular cognitive impairment (SVCI) are expected to differ from those in Alzheimer’s disease-related cognitive impairment (ADCI) but the details are unclear. To determine neural substrates related to cerebral small vessel disease, we investigated the correlations between cognitive dysfunctions measured by standardized neuropsychological tests and cortical thickness in a large sample of participants with amyloid negative (Aβ (−)) SVCI. Methods One hundred ninety-eight participants with Aβ (−) SVCI were recruited from the memory clinic between November 2007 to August 2018. To acquire neural substrates, we performed linear regression using the scores of each neuropsychological test as a predictor, cortical thickness as an outcome, and age, sex, education years, intracranial volume and white matter hyperintensity (WMH) as confounders. Results Poor performances in each neuropsychological test were associated with cortical atrophy in certain brain regions regardless of WMH. Especially, not the medial temporal but the frontal and posterior cingulate regions with cortical atrophy were mainly associated with memory impairment. Poor performance in animal fluency was more likely to be associated with cortical atrophy in the left hemisphere, while poor performance in the visuospatial memory test was more likely to be associated with cortical atrophy in the right hemisphere. Conclusions Our findings suggested that cortical atrophy was an important factor of cognitive impairment in Aβ (−) SVCI regardless of WMH. Furthermore, our findings might give clinicians a better understanding of specific neural substrates of neuropsychological deficits in patients with SVCI.

BACKGROUND The Rey-Osterrieth Complex Figure Test (RCFT) is a neuropsychological test that is widely used to assess visual memory and visuoconstructional deficits in patients with cognitive impairment, including Alzheimer disease (AD). Patients with AD have an increased tendency for exhibiting extraordinary behaviors in the RCFT for selecting the drawing area, organizing the figure, and deciding the order of images, among other activities. However, the conventional scoring system based on pen and paper has a limited ability to reflect these detailed behaviors. OBJECTIVE This study aims to establish a scoring system that addresses not only the spatial arrangement of the finished drawing but also the drawing process of patients with AD by using digital pen data. METHODS A digital pen and tablet were used to copy complex figures. The stroke patterns and kinetics of normal controls (NCs) and patients with early-onset AD (EOAD) and late-onset AD (LOAD) were analyzed by comparing the pen tip trajectory, spatial arrangement, and similarity of the finished drawings. RESULTS Patients with AD copied the figure in a more fragmented way with a longer pause than NCs (EOAD: P=.045; LOAD: P=.01). Patients with AD showed an increased tendency to draw the figures closer toward the target image in comparison with the NCs (EOAD: P=.005; LOAD: P=.01) Patients with AD showed the lower accuracy than NCs (EOAD: P=.004; LOAD: P=.002). Patients with EOAD and LOAD showed similar but slightly different drawing behaviors, especially in space use and in the initial stage of drawing. CONCLUSIONS The digitalized complex figure test evaluated copying performance quantitatively and further elucidated the patients’ ongoing process during copying. We believe that this novel approach can be used as a digital biomarker of AD. In addition, the repeatability of the test will delineate the process of executive functions and constructional organization abilities with disease progression.

BACKGROUND Most clinical trials focus on amyloid-β positive (Aβ+) amnestic mild cognitive impairment (aMCI), but screening failures are high because only a half of patients with aMCI are positive on Aβ PET. Therefore, it becomes necessary for clinicians to predict which patients will have Aβ biomarker. OBJECTIVE We aimed to compare clinical factors, neuropsychological (NP) profiles, and apolipoprotein E (APOE) genotype between Aβ+ aMCI and Aβ-aMCI and to develop a clinically useful prediction model of Aβ positivity on PET (PET-Aβ+) in aMCI using a nomogram. METHODS We recruited 523 aMCI patients who underwent Aβ PET imaging in a nation-wide multicenter cohort. The results of NP measures were divided into following subgroups: 1) Stage (Early and Late-stage), 2) Modality (Visual, Verbal, and Both), 3) Recognition failure, and 4) Multiplicity (Single and Multiple). A nomogram for PET-Aβ+ in aMCI patients was constructed using a logistic regression model. RESULTS PET-Aβ+ had significant associations with NP profiles for several items, including high Clinical Dementia Rating Scale Sum of Boxes score (OR 1.47, p = 0.013) and impaired memory modality (impaired both visual and verbal memories compared with visual only, OR 3.25, p = 0.001). Also, presence of APOEɛ4 (OR 4.14, p < 0.001) was associated with PET-Aβ+. These predictors were applied to develop the nomogram, which showed good prediction performance (C-statistics = 0.79). Its prediction performances were 0.77/0.74 in internal/external validation. CONCLUSIONS The nomogram consisting of NP profiles, especially memory domain, and APOEɛ4 genotype may provide a useful predictive model of PET-Aβ+ in patients with aMCI.

Background Sex effects on the progression of Alzheimer's disease (AD) have received less attention than other demographic factors, including onset age and education. Objective The aim of this study was to investigate whether sex affected cortical thinning in the disease progression of AD. Methods We prospectively recruited 36 patients with early-stage AD and 14 people with normal cognition. All subjects were assessed with magnetic resonance imaging at baseline, Year 1, Year 3, and Year 5. We performed cortical thickness analyses using surface-based morphometry on magnetic resonance imaging. Results Women with AD showed more rapid cortical thinning in the left dorsolateral frontal cortex, left superior temporal gyrus, bilateral temporo-parietal association cortices, bilateral anterior cingulate gyri, bilateral medial frontal cortices, and bilateral occipital cortices over 5 years than men with AD, even though there was no difference in cortical thickness at baseline. In contrast, there were no regions of significantly more rapid atrophy in men with AD. Conclusions Our findings suggest that women deteriorate faster than men in the progression of AD.

Background and purpose Biomarker changes in cognitively impaired patients with small vessel disease are largely unknown. The rate of amyloid/lacune progression, cortical thinning and cognitive decline were evaluated in subcortical vascular mild cognitive impairment (svMCI) patients. Methods Seventy-two svMCI patients were divided into early stage (ES-svMCI, n = 39) and late stage (LS-svMCI, n = 33) according to their Clinical Dementia Rating Sum of Boxes score. Patients were annually followed up with neuropsychological tests and brain magnetic resonance imaging for 3 years, and underwent a second [11 C] Pittsburgh compound B (PiB) positron emission tomography scan within a mean interval of 32.4 months. Results There was no difference in the rate of increase in PiB uptake or lacune number between the ES-svMCI and LS-svMCI. However, LS-svMCI showed more rapid cortical thinning and cognitive decline than did the ES-svMCI. Conclusions We suggest that, whilst the rate of change in pathological burden did not differ between ES-svMCI and LS-svMCI, cortical thinning and cognitive decline progressed more rapidly in the LS-svMCI.

Background: Recently, the focus of Alzheimer's disease (AD) research has shifted from the clinical and symptomatic stage to the preclinical and asymptomatic stage. However, studies on the distinctive neuropsychological features of preclinical AD with adjusted measurement errors are insufficient. The present study aimed to investigate the distinctive cognitive features of preclinical AD and develop a cognitive composite model that can sensitively distinguish between the amyloid positive (Aβ+) and amyloid negative (Aβ-) status in cognitively normal (CN) elderly participants. Methods: A total of 423 CN elderly participants with amyloid positron emission tomography (PET) images were recruited. Using the multiple-indicator multiple-cause (MIMIC) model, sensitive cognitive domains to the Aβ+ group were found. Then, several cognitive tests were selected to create the cognitive composite model as a result of the multivariate analysis of covariance (MANCOVA). Results: The MIMIC model revealed that the domains of episodic memory (verbal and visual) and executive functions were significantly different between Aβ- and Aβ+ ( p

Background Computerized versions of cognitive screening test could have advantages over pencil-and-paper versions by eliminating rater-dependent factors and saving the time required to score the tests and report the results. We developed a computerized cognitive screening test (Inbrain Cognitive Screening Test [Inbrain CST]) that takes about 30 minutes to administer on a touchscreen computer and is composed of neuropsychological tests already shown to be sensitive in detecting early cognitive decline in Alzheimer's disease (AD). The aims of this study were to 1) introduce normative data for Inbrain CST, 2) verify its reliability and validity, 3) assess clinical usefulness, and 4) identify neuroanatomical correlates of Inbrain CST. Methods The Inbrain CST runs on the Microsoft Windows 10 operating system and comprises 7 subtests that encompass 5 cognitive domains: attention, language, visuospatial, memory, and executive functions. First, we recruited 480 cognitively normal elderly people (age 50–90) from communities nationwide to establish normative data for Inbrain CST. Second, we enrolled 97 patients from our dementia clinic (26 with subjective cognitive decline [SCD], 42 with amnestic mild cognitive impairment [aMCI], and 29 with dementia due to AD) and investigated sensitivity and specificity of Inbrain CST for discriminating cognitively impaired patients from those with SCD using receiver operating characteristic (ROC) curve analyses. Third, we compared the Inbrain CST scores with those from another neuropsychological test battery to obtain concurrent validity and assessed test–retest reliability. Finally, magnetic resonance imaging (MRI)-based cortical thickness analyses were performed to provide anatomical substrates for performances on the Inbrain CST. Results First, in the normative sample, the total score on the Inbrain CST was significantly affected by age, years of education, and gender. Second, Inbrain CST scores among the three patient groups decreased in the order of SCD, aMCI, and AD dementia, and the ROC curve analysis revealed that Inbrain CST had good discriminative power for differentiating cognitively impaired patients from those with SCD. Third, the Inbrain CST subtests had high concurrent validity and test–retest reliability. Finally, in the cortical thickness analysis, each cognitive domain score and the total score of Inbrain CST showed distinct patterns of anatomical correlates that fit into the previously known brain–behavior relationship. Conclusion Inbrain CST had good validity, reliability, and clinical usefulness in detecting cognitive impairment in the elderly. Furthermore, it showed neuroanatomical validity through MRI cortical thinning patterns. These results suggest that Inbrain CST is a useful cognitive screening tool with efficiency and validity to detect mild impairments in cognition in clinical settings., Graphical Abstract

Background/Aims: Early detection and intervention may alter the disease course of subcortical vascular cognitive impairment (SVCI). Patients with SVCI have white matter ischemia that disrupts connections between the cortex and subcortical gray matter and therefore manifest various symptoms such as motor disturbances and behavioral/cognitive dysfunction. Reduced vocal loudness, or hypophonia, is one of the common motor symptoms of SVCI, but few studies have systematically investigated it in this patient population. The main purpose of this investigation was to identify neural pathways underlying hypophonia in patients with SVCI. Methods: Eighty-eight patients with SVCI and 21 normal controls performed phonation tasks. Diffusion tensor imaging data from 73 patients were utilized to measure white matter changes associated with hypophonia. Results: Correlational analyses between white matter fractional anisotropy values and the decibel level of the “sustained phonation” task identified the left midbrain cerebral peduncle (corticobulbar tract), external capsule, corona radiata/internal capsule, and bilateral frontal white matter as possible neural correlates for hypophonia. Conclusion: Our results support the notion that hypophonia in SVCI patients might be caused by the impairment of the pyramidal and extrapyramidal systems. This study provides a unique contribution towards understanding the neuropathology of hypophonic features in this population.

SEE COHEN DOI101093/AWW183 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Amyloid-β and cerebral small vessel disease are the two major causes of cognitive impairment in the elderly. However, the underlying mechanisms responsible for precisely how amyloid-β and cerebral small vessel disease affect cognitive impairment remain unclear. We investigated the effects of amyloid-β and lacunes on downstream imaging markers including structural network and cortical thickness, further analysing their relative impact on cognitive trajectories. We prospectively recruited a pool of 117 mild cognitive impairment patients (45 amnestic type and 72 subcortical vascular type), from which 83 patients received annual follow-up with neuropsychological tests and brain magnetic resonance imaging for 3 years, and 87 patients received a second Pittsburgh compound B positron emission tomography analysis. Structural networks based on diffusion tensor imaging and cortical thickness were analysed. We used linear mixed effect regression models to evaluate the effects of imaging markers on cognitive decline. Time-varying Pittsburgh compound B uptake was associated with temporoparietal thinning, which correlated with memory decline (verbal memory test, unstandardized β = -0.79, P < 0.001; visual memory test, unstandardized β = -2.84, P = 0.009). Time-varying lacune number was associated with the degree of frontoparietal network disruption or thinning, which further affected frontal-executive function decline (Digit span backward test, unstandardized β = -0.05, P = 0.002; Stroop colour test, unstandardized β = -0.94, P = 0.008). Of the multiple imaging markers analysed, Pittsburgh compound B uptake and the number of lacunes had the greatest association with memory decline and frontal-executive function decline, respectively: Time-varying Pittsburgh compound B uptake (standardized β = -0.25, P = 0.010) showed the strongest effect on visual memory test, followed by time-varying temporoparietal thickness (standardized β = 0.21, P = 0.010) and time-varying nodal efficiency (standardized β = 0.17, P = 0.024). Time-varying lacune number (standardized β = -0.25, P = 0.014) showed the strongest effect on time-varying digit span backward test followed by time-varying nodal efficiency (standardized β = 0.17, P = 0.021). Finally, time-varying lacune number (β = -0.22, P = 0.034) showed the strongest effect on time-varying Stroop colour test followed by time-varying frontal thickness (standardized β = 0.19, P = 0.026). Our multimodal imaging analyses suggest that cognitive trajectories related to amyloid-β and lacunes have distinct paths, and that amyloid-β or lacunes have greatest impact on cognitive decline. Our results provide rationale for the targeting of amyloid-β and lacunes in therapeutic strategies aimed at ameliorating cognitive decline.

Background The Rey-Osterrieth Complex Figure Test (RCFT) is a neuropsychological test that is widely used to assess visual memory and visuoconstructional deficits in patients with cognitive impairment, including Alzheimer disease (AD). Patients with AD have an increased tendency for exhibiting extraordinary behaviors in the RCFT for selecting the drawing area, organizing the figure, and deciding the order of images, among other activities. However, the conventional scoring system based on pen and paper has a limited ability to reflect these detailed behaviors. Objective This study aims to establish a scoring system that addresses not only the spatial arrangement of the finished drawing but also the drawing process of patients with AD by using digital pen data. Methods A digital pen and tablet were used to copy complex figures. The stroke patterns and kinetics of normal controls (NCs) and patients with early-onset AD (EOAD) and late-onset AD (LOAD) were analyzed by comparing the pen tip trajectory, spatial arrangement, and similarity of the finished drawings. Results Patients with AD copied the figure in a more fragmented way with a longer pause than NCs (EOAD: P=.045; LOAD: P=.01). Patients with AD showed an increased tendency to draw the figures closer toward the target image in comparison with the NCs (EOAD: P=.005; LOAD: P=.01) Patients with AD showed the lower accuracy than NCs (EOAD: P=.004; LOAD: P=.002). Patients with EOAD and LOAD showed similar but slightly different drawing behaviors, especially in space use and in the initial stage of drawing. Conclusions The digitalized complex figure test evaluated copying performance quantitatively and further elucidated the patients’ ongoing process during copying. We believe that this novel approach can be used as a digital biomarker of AD. In addition, the repeatability of the test will delineate the process of executive functions and constructional organization abilities with disease progression.

Recent improvements in neuroimaging and molecular markers of Alzheimer’s disease (AD) have aided diagnosis in the early stage of the disease, which greatly increases the chance for successful prevention and treatment. However, the expanding resources for AD diagnosis are unlikely to benefit all elderly due to economic burden. Here, we aimed to develop an inexpensive and sensitive method to detect early-stage AD. A scenario for real-world social event memory test (SEMT) was created and filmed in 360° video. Participants watched the 7-min video through head-mounted display (HMD) and then answered questionnaire about the video. We categorized the SEMT score into recall, recognition, and place-matching scores and compared them to scores on the Mini-Mental State Examination and Seoul Verbal Learning Test. Using the SEMT scores, we built a logistic regression model that discriminated between amyloid positivity and negativity of the participants, with a cross-validation AUC. Furthermore, a classifier was created using support vector machine, which produced 93.8–95.1% sensitivity in classifying individuals into four groups of normal, mild cognitive impairment with or without amyloid, and AD elderly. The high correlation between the SEMT score and amyloid positivity in individuals who experienced virtual social gathering through an HMD opens a new possibility for early diagnosis of AD.

The aim of the study was to explore the therapeutic potential of menopausal hormone therapy (MHT) in women with mild cognitive impairment (MCI).Thirty-seven postmenopausal women (age range: 57-82 y) with multiple-domain, amnestic subtype MCI were randomly assigned to either placebo (n = 18) or MHT (n = 19) for 24 months (percutaneous estradiol [E2] gel [0.1%, 2 mg/d] and oral micronized progesterone [MP4] [100 mg/d]). All participants received donepezil, and apolipoprotein E genotype was determined. The primary endpoint was general cognitive function: Alzheimer's disease Assessment Scale, cognitive subscale, the Korean version of Mini-Mental State Examination (K-MMSE), and the Korean version of the Montreal Cognitive Assessment (MoCA_K) were performed in-person every 6 months.Twenty-one participants (placebo 13, MHT 8) completed the trial (56.8%). Progression rates to dementia were 52.9% (9/17) in the placebo group and 44.4% (8/18) in the MHT group. Within-group analysis showed that all three tests significantly worsened during the trial in the placebo, but not the MHT groups. Analysis adjusted for ε4 allele demonstrated that MHT significantly reduced deterioration of MoCA_K score, a sensitive tool for assessing global cognition in MCI (P = 0.0261). Compared with the control group, both MoCA_K (P = 0.043; mean difference, 3.85; 95% CI, -0.46 to 8.16) and K-MMSE (P = 0.0319; mean difference, 3.26; 95% CI, 0.04-6.48) scores were significantly better at 24 months in the MHT group.Long-term MHT using percutaneous E2 gel and oral MP4 might attenuate cognitive decline in postmenopausal women with MCI.

Background: Dysphagia is a common symptom and an important prognostic factor in Parkinson’s disease (PD). Although cognitive and motor dysfunctions may contribute to dysphagia in patients with PD, any specific association between such problems and swallowing functions is unclear. Here, we examined the potential relationship between cognitive/motor components and swallowing functions in PD. We evaluated the contributions of cognition and motor function to the components of swallowing via video fluoroscopic swallowing (VFS) experiments. Methods: We prospectively enrolled 56 patients without dementia having PD. Parkinson’s disease severity was assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS). All participants received neuropsychological tests covering general mental status, visuospatial function, attention, language, learning and memory, and frontal executive function. The well-validated “modified barium swallow impairment profile” scoring system was applied during VFS studies to quantify swallowing impairments. Finally, correlations between neuropsychological or motor functions and impairment in swallowing components were calculated. Results: The most significant correlations were found between the frontal/executive or learning/memory domains and the oral phase of swallowing, though a minor component of the pharyngeal phase correlated with frontal function as well. Bradykinesia and the UPDRS total score were associated with both the pharyngeal and oral phases. Conclusions: Our findings suggest that cognitive dysfunctions are associated with the oral phase of swallowing in patients with early stage PD while the severity of motor symptoms may be associated with overall swallowing function.

Introduction We conducted a phase 1 clinical trial in nine patients with mild-to-moderate Alzheimer's disease to evaluate the safety and dose-limiting toxicity of stereotactic brain injection of human umbilical cord blood–derived mesenchymal stem cells (hUCB-MSCs). Methods The low- (n = 3) and high-dose (n = 6) groups received a total of 3.0 × 10 6 cells/60 μL and 6.0 × 10 6 cells/60 μL, respectively, into the bilateral hippocampi and right precuneus. Results No patient showed serious adverse events including fever during the 24-month follow-up period. During the 12-week follow-up period, the most common acute adverse event was wound pain from the surgical procedure (n = 9), followed by headache (n = 4), dizziness (n = 3), and postoperative delirium (n = 3). There was no dose-limiting toxicity. Discussion Administration of hUCB-MSCs into the hippocampus and precuneus by stereotactic injection was feasible, safe, and well tolerated. Further trials are warranted to test the efficacy. Clinical Trial Registration ClinicalTrial.gov identifier NCT01297218 and NCT01696591.

Apolipoprotein E4 (APOE4) is a genetic risk factor for developing Alzheimer's disease (AD). Once AD manifests clinically, however, the effects of APOE4 are less clear. Therefore, we investigated the longitudinal effects of APOE4 on topographical changes in AD patient brain atrophy. We prospectively recruited 35 patients with AD (19 APOE4 carriers and 16 non-carriers), and 14 normal controls, then followed them for five years. We measured hippocampal deformities and cortical thickness. Hippocampal comparison between APOE4 carriers and non-carriers with AD showed carriers had rapid changes in the head and body, while non-carriers had rapid changes in a small portion of the body. Cortical thickness comparison between APOE4 carriers and non-carriers with AD dementia showed carriers had rapid thinning in the lateral frontal, temporal, and parietal regions, while no region showed more rapid cortical thinning in non-carriers than in carriers. These findings underlined the importance of the APOE4 allele for designing and interpreting future treatment trials in patients with AD dementia.

Some patients with frontotemporal dementia (FTD) show an artistic enhancement of musical abilities. However, no patients with FTD, to date, have been reported to be able to learn how to play a musical instrument after disease onset. Herein we describe a patient (J. K.) who had never played any musical instruments premorbidly, but who learned to play the saxophone after being diagnosed with a behavioral variant of FTD. He mastered a repertoire that consisted of 10 pieces of Korean folk songs over a period of three years. Furthermore, his saxophone skills were high enough to outperform other students in his class.

Background: Subcortical vascular dementia (SVaD) is one of the most common dementias, after Alzheimer's disease (AD) dementia. Few survival analyses in SVaD patients have been reported. Methods: The dates and causes of death of 146 SVaD and 725 AD patients were included. We used the Cox proportional hazards model to compare survival between SVaD and AD patients and to explore possible factors related to survival of SVaD patients. Results: The median survival time after the onset of SVaD (109 months) was shorter than that recorded for AD (152 months). The most common cause of death in SVaD was stroke (47.1%). Factors associated with shorter survival in SVaD were late onset, male sex, worse baseline cognition, absence of hypertension and a family history of stroke. Conclusions: Stroke prevention may be important in SVaD treatment because 47.1% of SVaD patients died of stroke. A family history of stroke and absence of hypertension were associated with a shorter survival in SVaD, suggesting the existence of genetic or unknown risk factors.

Motor impersistence, an inability to sustain a certain position or movement, is a motor-intentional disorder, caused more often by right than left hemisphere lesions. Since the right hemisphere is dominant for mediating motor persistence, callosal lesions that disconnect the left hemisphere from the right may induce impersistence of the right upper and lower limbs. After an undiagnosed left callosal infarction, a 65-year-old right-handed man suddenly developed a transient loss of volitional movement of his left leg. Five days after onset, he was admitted to our hospital with signs of callosal disconnection: left-hand agraphia and apraxia, left-hand tactile anomia, failures on cross-replication of hand postures, and intermanual conflict. He had neither weakness nor ataxia of his upper or lower extremities, but when asked to keep his arms or legs extended he could not maintain his right arm and leg in the extended position, suggesting motor impersistence in his dominant limbs. When we examined him 3 months after onset, the motor impersistence had disappeared. In conclusion, motor impersistence of dominant limbs can result from isolated callosal injury that disconnects the left hemisphere from the right hemisphere's frontal-subcortical networks.

Because of repeated failures of clinical trials, the concept of Alzheimer's disease (AD) has been changing rapidly in recent years. As suggested by the National Institute on Aging and the Alzheimer's Association Research Framework, the diagnosis and classification of AD is now based on biomarkers rather than on symptoms, allowing more accurate identification of proper candidates for clinical trials by pathogenesis and disease stage. Recent development in neuroimaging has provided a way to reveal the complex dynamics of amyloid and tau in the brain in vivo, and studies of blood biomarkers are taking another leap forward in diagnosis and treatment of AD. In the field of basic and translational research, the development of animal models and a deeper understanding of the role of neuroinflammation are taking a step closer to clarifying the pathogenesis of AD. Development of big data and the Internet of Things is also incorporating dementia care and research into other aspects. Large-scale genetic research has identified genetic abnormalities that can provide a foundation for precision medicine along with the aforementioned digital technologies. Through the first international conference of the Korean Dementia Association, experts from all over the world gathered to exchange opinions with association members on these topics. The Academic Committee of the Korean Dementia Association briefly summarizes the contents of the lectures to convey the depth of the conference and discussions. This will be an important milestone in understanding the latest trends in AD's pathogenesis, diagnostic and therapeutic research and in establishing a future direction.

We evaluate the longitudinal outcomes of amnestic mild cognitive impairment (aMCI) according to the modality of memory impairment involved. We recruited 788 aMCI patients and followed them up. aMCI patients were categorized into three groups according to the modality of memory impairment: Visual-aMCI, only visual memory impaired; Verbal-aMCI, only verbal memory impaired; and Both-aMCI, both visual and verbal memory impaired. Each aMCI group was further categorized according to the presence or absence of recognition failure. Risk of progression to dementia was compared with pooled logistic regression analyses while controlling for age, gender, education, and interval from baseline. Of the sample, 219 (27.8%) aMCI patients progressed to dementia. Compared to the Visual-aMCI group, Verbal-aMCI (OR = 1.98, 95% CI = 1.19-3.28, p = 0.009) and Both-aMCI (OR = 3.05, 95% CI = 1.97-4.71, p < 0.001) groups exhibited higher risks of progression to dementia. Memory recognition failure was associated with increased risk of progression to dementia only in the Visual-aMCI group, but not in the Verbal-aMCI and Both-aMCI groups. The Visual-aMCI without recognition failure group were subcategorized into aMCI with depression, small vessel disease, or accelerated aging, and these subgroups showed a variety of progression rates. Our findings underlined the importance of heterogeneous longitudinal outcomes of aMCI, especially Visual-aMCI, for designing and interpreting future treatment trials in aMCI.

Background:Subjective memory impairment (SMI) refers to conditions in which people complain of memory problems despite intact cognition. The primary purpose of the present study was to examine the roles of self-focused attention and depressive symptomatology in subjective memory complaints.Methods:One hundred and eight patients who visited a memory disorder clinic with complaints of memory decline, but who were found on subsequent neuropsychological assessment to have normal cognitive function, were recruited to participate in the study. The severity of subjective memory complaints was measured with the modified Multifactorial Memory Questionnaire. In addition, neuropsychological functions, self-focused attention, and depressive symptomatology were also assessed.Results:The results showed that the severity of SMI was not significantly correlated with any of the neuropsychological test scores except for the complex figure copy. The severity of SMI, however, was significantly correlated with self-focused attention and depressive symptomatology. Hierarchical regression analysis revealed that self-focused attention and depressive symptomatology significantly contributed to the severity of subjective memory complaints over and above the neuropsychological test performance. The interaction effects between self-focused attention/depressive symptomatology and objective memory performance on the severity of SMI were not significant.Conclusions:In conclusion, self-focused attention and depressive symptomatology appear to play important roles in the severity of SMI, even though it is not clear how these factors interact with objective memory performance. Clinical implications as well as limitations of the present study were discussed.

Background and purpose Disappointing outcomes from clinical trials involving amyloid-modifying therapies for Alzheimer's disease (AD) have prompted more focus on the concept of early-stage (E) amnestic mild cognitive impairment (E-aMCI). However, limited evidence suggests that E-aMCI may represent aMCI at a very early stage of AD. Furthermore, the nature of the progression of E-aMCI to late-stage aMCI (L-aMCI) remains unclear. Therefore, the aim of the present study was to characterize patterns of cortical thinning in both E-aMCI and L-aMCI patients. Methods Cortical thicknesses were measured in 190 patients with aMCI and 147 subjects with normal cognition. In accordance with memory test scores involving delayed recall items, aMCI patients were divided into two subgroups, containing 73 E-aMCI subjects with milder memory impairment [scores between −1.5 standard deviation (SD) and −1.0 SD compared with age- and education-matched norms] and 117 L-aMCI subjects with more severe memory impairment (scores lower than −1.5 SD). Results Compared with controls, the E-aMCI group exhibited cortical thinning in the left medial temporal and insular regions, whereas the L-aMCI group showed cortical thinning in widespread regions, including the bilateral dorsolateral prefrontal, anterior and medial temporal, and temporo-parietal association cortices, and the precuneus. When the two aMCI groups were directly compared, the L-aMCI group showed greater cortical thinning in the right superior prefrontal, medial temporal, posterior cingulate and lateral parietal cortices. Conclusion Our findings suggest that E-aMCI might represent an early symptomatic stage of AD. Furthermore, L-aMCI might resemble AD more closely than E-aMCI, in terms of the topography of cortical thinning.