Deep learning model for individualized trajectory prediction of clinical outcomes in mild cognitive impairment.

Objectives: Accurately predicting when patients with mild cognitive impairment (MCI) will progress to dementia is a formidable challenge. This work aims to develop a predictive deep learning model to accurately predict future cognitive decline and magnetic resonance imaging (MRI) marker changes over time at the individual level for patients with MCI. Methods: We recruited 657 amnestic patients with MCI from the Samsung Medical Center who underwent cognitive tests, brain MRI scans, and amyloid-ß (Aß) positron emission tomography (PET) scans. We devised a novel deep learning architecture by leveraging an attention mechanism in a recurrent neural network. We trained a predictive model by inputting age, gender, education, apolipoprotein E genotype, neuropsychological test scores, and brain MRI and amyloid PET features. Cognitive outcomes and MRI features of an MCI subject were predicted using the proposed network. Results: The proposed predictive model demonstrated good prediction performance (AUC = 0.814 ± 0.035) in five-fold cross-validation, along with reliable prediction in cognitive decline and MRI markers over time. Faster cognitive decline and brain atrophy in larger regions were forecasted in patients with Aß (+) than with Aß (-). Conclusion: The proposed method provides effective and accurate means for predicting the progression of individuals within a specific period. This model could assist clinicians in identifying subjects at a higher risk of rapid cognitive decline by predicting future cognitive decline and MRI marker changes over time for patients with MCI. Future studies should validate and refine the proposed predictive model further to improve clinical decision-making.

Identification of amnestic mild cognitive impairment by structural and functional MRI using a machine-learning approach.

OBJECTIVE: The importance of early treatment for mild cognitive impairment (MCI) has been extensively shown. However, classifying patients presenting with memory complaints in clinical practice as having MCI vs normal results is difficult. Herein, we assessed the feasibility of applying a machine learning approach based on structural volumes and functional connectomic profiles to classify the cognitive levels of cognitively unimpaired (CU) and amnestic MCI (aMCI) groups. We further applied the same method to distinguish aMCI patients with a single memory impairment from those with multiple memory impairments. METHODS: Fifty patients with aMCI were enrolled and classified as having either verbal or visual-aMCI (verbal or visual memory impairment), or both aMCI (verbal and visual memory impairments) based on memory test results. In addition, 26 CU patients were enrolled in the control group. All patients underwent structural T1-weighted magnetic resonance imaging (MRI) and resting-state functional MRI. We obtained structural volumes and functional connectomic profiles from structural and functional MRI, respectively, using graph theory. A support vector machine (SVM) algorithm was employed, and k-fold cross-validation was performed to discriminate between groups. RESULTS: The SVM classifier based on structural volumes revealed an accuracy of 88.9% at classifying the cognitive levels of patients with CU and aMCI. However, when the structural volumes and functional connectomic profiles were combined, the accuracy increased to 92.9%. In the classification of verbal or visual-aMCI (n = 22) versus both aMCI (n = 28), the SVM classifier based on structural volumes revealed a low accuracy of 36.7%. However, when the structural volumes and functional connectomic profiles were combined, the accuracy increased to 53.1%. CONCLUSION: Structural volumes and functional connectomic profiles obtained using a machine learning approach can be used to classify cognitive levels to distinguish between aMCI and CU patients. In addition, combining the functional connectomic profiles with structural volumes results in a better classification performance than the use of structural volumes alone for identifying both "aMCI versus CU" and "verbal- or visual-aMCI versus both aMCI" patients.

Polyether-based waterborne synergists: effect of polymer topologies on pigment dispersion.

Control of polymer topologies is essential to determine their unique physical properties and potential applications. The polymer topologies can have a critical effect on pigment dispersion owing to their unique architectures; however, studies using polymer topologies on pigment dispersion in aqueous systems are scarce. Thus, this study proposes various topologies of polyether-based waterborne synergists, such as linear, hyperbranched, and branched cyclic structures. Specifically, we applied branched types of polyglycidols (PGs) as a synergist to provide polymer topology-dependent dispersibility for the surface-modification of Red 170 particles through adsorption and steric hindrance. The topology-controlled PG synergists (PGSs) were successfully prepared by post-polymerization modification with phthalimide and benzoyl groups. Particularly, the branched types of PGSs, branched cyclic PGS (bc-PGS), and hyperbranched PGS (hb-PGS) exhibited improved dispersibility through adsorption on top of the pigment, interaction between dispersant (BYK 190) and pigment, and steric effect. Surprisingly, hb-PGS conferred the Red 170 pigment particles with superior storage stability than that of bc-PGS despite their similar structural features. This study suggests the widespread potential application of PGSs as waterborne synergists for various dispersion applications.

Brain networks and epilepsy development in patients with Alzheimer disease.

INTRODUCTION: This study aimed to investigate the association between brain networks and epilepsy development in patients with Alzheimer disease (AD). METHODS: We enrolled patients newly diagnosed with AD at our hospital who underwent three-dimensional T1-weighted magnetic resonance imaging at the time of AD diagnosis and included healthy controls. We obtained the cortical, subcortical, and thalamic nuclei structural volumes using FreeSurfer and applied graph theory to obtain the global brain network and intrinsic thalamic network based on the structural volumes using BRAPH. RESULTS: We enrolled 25 and 56 patients with AD with and without epilepsy development, respectively. We also included 45 healthy controls. The global brain network differed between the patients with AD and healthy controls. The local efficiency (2.026 vs. 3.185, p = .048) and mean clustering coefficient (0.449 vs. 1.321, p = .024) were lower, whereas the characteristic path length (0.449 vs. 1.321, p = .048) was higher in patients with AD than in healthy controls. Both global and intrinsic thalamic networks were significantly different between AD patients with and without epilepsy development. In the global brain network, local efficiency (1.340 vs. 2.401, p = .045), mean clustering coefficient (0.314 vs. 0.491, p = .045), average degree (27.442 vs. 41.173, p = .045), and assortative coefficient (-0.041 vs. -0.011, p = .045) were lower, whereas the characteristic path length (2.930 vs. 2.118, p = .045) was higher in patients with AD with epilepsy development than in those without. In the intrinsic thalamic network, the mean clustering coefficient (0.646 vs. 0.460, p = .048) was higher, whereas the characteristic path length (1.645 vs. 2.232, p = .048) was lower in patients with AD with epilepsy development than in those without. CONCLUSION: We found that the global brain network differs between patients with AD and healthy controls. In addition, we demonstrated significant associations between brain networks (both global brain and intrinsic thalamic networks) and epilepsy development in patients with AD.

Research Note: Interactions among the MDA5, MAVS, and STING signaling pathways in chicken cells.

Innate immunity, as an organism's first line of defense, plays a crucial role in rapidly responding to and protecting the body against invading pathogens. As a cytosolic RNA sensor for viral infections, including infections caused by influenza virus, the innate immune system in chickens has 2 major pathogen-recognition receptors (PRRs): Toll-like receptor 3 (TLR3) and melanoma differentiation-associated protein 5 (MDA5). The signaling pathways activated by PRRs are complex, systemic processes that underlie the response to foreign molecules. In this study, we investigated the interactions among MDA5, mitochondrial antiviral signaling protein (MAVS), and stimulator of interferon genes (STING) signaling in chicken cells. To exclude the effects of TLR3, we transfected the clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9 (CRISPR-Cas9) expression vector and TLR3-targeted gRNA plasmid into chicken DF-1 cells. We selected TLR3-knockout (KO) cell line and sequentially, we established 2 double-KO cell lines: TLR3-MAVS KO and TLR3-STING KO. After treatment with polyinosinic:polycytidylic acid (poly(I:C)), type I interferon (IFN), IFN-stimulated gene, and antiviral gene (IFN regulatory factor 7, IFNß, Mx1, and protein kinase R1) expression was not completely activated in TLR3-MAVS KO cells, whereas it was consistently upregulated in wild-type and TLR3-STING KO DF-1 cells. These results suggest that STING is not an intermediator between MDA5 and MAVS; moreover, it does not directly interact with MDA5 during innate immune activation in chicken DF-1 cells.

Classification and prediction of cognitive trajectories of cognitively unimpaired individuals.

Objectives: Efforts to prevent Alzheimer's disease (AD) would benefit from identifying cognitively unimpaired (CU) individuals who are liable to progress to cognitive impairment. Therefore, we aimed to develop a model to predict cognitive decline among CU individuals in two independent cohorts. Methods: A total of 407 CU individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 285 CU individuals from the Samsung Medical Center (SMC) were recruited in this study. We assessed cognitive outcomes by using neuropsychological composite scores in the ADNI and SMC cohorts. We performed latent growth mixture modeling and developed the predictive model. Results: Growth mixture modeling identified 13.8 and 13.0% of CU individuals in the ADNI and SMC cohorts, respectively, as the "declining group." In the ADNI cohort, multivariable logistic regression modeling showed that increased amyloid-ß (Aß) uptake (ß [SE]: 4.852 [0.862], p < 0.001), low baseline cognitive composite scores (ß [SE]: -0.274 [0.070], p < 0.001), and reduced hippocampal volume (ß [SE]: -0.952 [0.302], p = 0.002) were predictive of cognitive decline. In the SMC cohort, increased Aß uptake (ß [SE]: 2.007 [0.549], p < 0.001) and low baseline cognitive composite scores (ß [SE]: -4.464 [0.758], p < 0.001) predicted cognitive decline. Finally, predictive models of cognitive decline showed good to excellent discrimination and calibration capabilities (C-statistic = 0.85 for the ADNI model and 0.94 for the SMC model). Conclusion: Our study provides novel insights into the cognitive trajectories of CU individuals. Furthermore, the predictive model can facilitate the classification of CU individuals in future primary prevention trials.

Production of chickens with green fluorescent protein-knockin in the Z chromosome and detection of green fluorescent protein-positive chicks in the embryonic stage.

OBJECTIVE: The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) system, which is the most efficient and reliable tool for precisely targeted modification of the genome of living cells, has generated considerable excitement for industrial applications as well as scientific research. In this study, we developed a gene-editing and detection system for chick embryo sexing during the embryonic stage. METHODS: By combining the CRISPR/Cas9 technical platform and germ cell-mediated germline transmission, we not only generated Z chromosome-targeted knockin chickens but also developed a detection system for fluorescence-positive male chicks in the embryonic stage. RESULTS: We targeted a green fluorescent protein (GFP) transgene into a specific locus on the Z chromosome of chicken primordial germ cells (PGCs), resulting in the production of ZGFP-knockin chickens. By mating ZGFP-knockin females (ZGFP/W) with wild males (Z/Z) and using a GFP detection system, we could identify chick sex, as the GFP transgene was expressed on the Z chromosome only in male offspring (ZGFP/Z) even before hatching. CONCLUSION: Our results demonstrate that the CRISPR/Cas9 technical platform with chicken PGCs facilitates the production of specific genome-edited chickens for basic research as well as practical applications.

Transferability of Alzheimer Disease Polygenic Risk Score Across Populations and Its Association With Alzheimer Disease-Related Phenotypes.

Importance: Polygenic risk scores (PRSs), which aggregate the genetic effects of single-nucleotide variants identified in genome-wide association studies (GWASs), can help distinguish individuals at a high genetic risk for Alzheimer disease (AD). However, genetic studies have predominantly focused on populations of European ancestry. Objective: To evaluate the transferability of a PRS for AD in the Korean population using summary statistics from a prior GWAS of European populations. Design, Setting, and Participants: This cohort study developed a PRS based on the summary statistics of a large-scale GWAS of a European population (the International Genomics of Alzheimer Project; 21 982 AD cases and 41 944 controls). This PRS was tested for an association with AD dementia and its related phenotypes in 1634 Korean individuals, who were recruited from 2013 to 2019. The association of a PRS based on a GWAS of a Japanese population (the National Center for Geriatrics and Gerontology; 3962 AD cases and 4074 controls) and a transancestry meta-analysis of European and Japanese GWASs was also evaluated. Data were analyzed from December 2020 to June 2021. Main Outcomes and Measures: Risk of AD dementia, amnestic mild cognitive impairment (aMCI), earlier symptom onset, and amyloid ß deposition (Aß). Results: A total of 1634 Korean patients (969 women [59.3%]), including 716 individuals (43.6%) with AD dementia, 222 (13.6%) with aMCI, and 699 (42.8%) cognitively unimpaired controls, were analyzed in this study. The mean (SD) age of the participants was 71.6 (9.0) years. Higher PRS was associated with a higher risk of AD dementia independent of APOE ɛ4 status in the Korean population (OR, 1.95; 95% CI, 1.40-2.72; P < .001). Furthermore, PRS was associated with aMCI, earlier symptom onset, and Aß deposition independent of APOE ɛ4 status. The PRS based on a transancestry meta-analysis of data sets comprising 2 distinct ancestries showed a slightly improved accuracy. Conclusions and Relevance: In this cohort study, a PRS derived from a European GWAS identified individuals at a high risk for AD dementia in the Korean population. These findings emphasize the transancestry transferability and clinical value of PRSs and suggest the importance of enriching diversity in genetic studies of AD.

Interaction between Alzheimer's Disease and Cerebral Small Vessel Disease: A Review Focused on Neuroimaging Markers.

Alzheimer's disease (AD) is characterized by the presence of ß-amyloid (Aß) and tau, and subcortical vascular cognitive impairment (SVCI) is characterized by cerebral small vessel disease (CSVD). They are the most common causes of cognitive impairment in the elderly population. Concurrent CSVD burden is more commonly observed in AD-type dementia than in other neurodegenerative diseases. Recent developments in Aß and tau positron emission tomography (PET) have enabled the investigation of the relationship between AD biomarkers and CSVD in vivo. In this review, we focus on the interaction between AD and CSVD markers and the clinical effects of these two markers based on molecular imaging studies. First, we cover the frequency of AD imaging markers, including Aß and tau, in patients with SVCI. Second, we discuss the relationship between AD and CSVD markers and the potential distinct pathobiology of AD markers in SVCI compared to AD-type dementia. Next, we discuss the clinical effects of AD and CSVD markers in SVCI, and hemorrhagic markers in cerebral amyloid angiopathy. Finally, this review provides both the current challenges and future perspectives for SVCI.

Effect of education on functional network edge efficiency in Alzheimer's disease.

We investigated the effect of education on the edge efficiency in resting state functional networks (RSFNs) in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease dementia (ADD). We collected the data of 57 early aMCI, 141 late aMCI, 173 mild ADD, and 39 moderate-to-severe ADD patients. We used years of education as a proxy for cognitive reserve. We measured edge efficiency for each edge in RSFNs, and performed simple slope analyses to discover their associations with education level among the four groups. In the late aMCI, a sub-network that had hub nodes in the right middle frontal gyrus and the right posterior cingulate gyrus, showed a positive association between RSFN edge efficiency and education (threshold = 2.5, p = 0.0478). There was no negative effect of education on the RSFN edge efficiency. In the early aMCI, mild ADD, and moderate-to-severe ADD, there were no sub-networks showing positive or negative correlation between education and RSFN edge efficiency. There was a positive effect of higher education on RSFN edge efficiency in the late aMCI, but not in the early aMCI or ADD. This indicates that in late aMCI, those who have higher education level have greater ability to resist collapsed functional network.

Existence and Significance of Internal Border Zone Infarcts with Accessory Lesions Located in the Anteromedial Temporal Lobe.

OBJECTIVES: To examine the existence and significance of internal border zone (IBZ) infarcts with accessory lesions in the anteromedial temporal lobe (ATL). MATERIALS AND METHODS: IBZ infarcts located at the corona radiata were selected based on diffusion-weighted imaging of 2535 consecutive patients with ischemic stroke and the presence of lesions in the ATL was identified. The Mann-Whitney U test, Student t-test, Pearson χ2 test, or Fisher exact test was used to analyze differences between the IBZ infarct groups with and without accessory lesions in the ATL. RESULTS: Thirty-six of 2535 patients (1.4%) had IBZ infarcts. The IBZ group with accessory lesions in the ATL (17 cases, 47.2%) showed a higher portion of occluded middle cerebral arteries than the IBZ group without accessory lesions in the ATL (p = 0.02). The initial National Institutes of Health Stroke Scale score (odds ratio, 2.03; 95% confidence interval, 1.04-3.99;   = 0.039) and progression after admission (odds ratio, 25.43; 95% confidence interval, 2.47-261.99; p = 0.007) were independently associated with poor prognosis in patients with IBZ infarcts. There were no differences in the progression rate and clinical outcomes, regardless of the presence of lesions in the ATL. CONCLUSIONS: Our study suggests the existence of a distinct type of IBZ infarct characterized by accessory lesions in the ATL, which is associated with different arterial features but has a similar clinical course to IBZ infarcts without accessory lesions in the ATL.

Identifying novel genetic variants for brain amyloid deposition: a genome-wide association study in the Korean population.

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 ß (Aß) 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 Aß positivity (measured by amyloid positron emission tomography). Aß 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 Aß 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 Aß positivity (p < 0.05) in the replication dataset. In a meta-analysis, two SNPs (rs7337542 and rs2903923) reached a genome-wide significant level (p < 5.0 × 10-8). Prediction performance for Aß positivity increased when rs73375428 were incorporated (area under curve = 0.75; 95% CI = 0.74-0.76) in addition to clinical factors and APOE genotype. Cis-eQTL analysis demonstrated that the rs73375428 was associated with decreased expression levels of FGL2 in the brain. CONCLUSION: The novel genetic variants associated with FGL2 decreased risk of Aß positivity in the Korean population. This finding may provide a candidate therapeutic target for AD, highlighting the importance of genetic studies in diverse populations.

Alteration of brain connectivity in neurologically asymptomatic patients with chronic kidney disease.

ABSTRACT: Our previous study demonstrated that patients with end-stage renal disease had decreased structural and functional brain connectivity, and there was a significant association between brain connectivity and cognitive function. The aim of this study was to evaluate the alterations of structural and functional connectivity using graph theoretical analysis in neurologically asymptomatic patients with relatively early-stage chronic kidney disease (CKD).We enrolled 18 neurologically asymptomatic patients with early CKD and 28 healthy controls. All the subjects underwent diffusion-tension imaging and resting functional magnetic resonance imaging. We calculated structural and functional connectivity based on diffusion-tension imaging and resting functional magnetic resonance imaging using a graph theoretical analysis. Then, we investigated differences of structural and functional connectivity between the CKD patients and the healthy controls.All the measures of structural connectivity were significantly different between the patients with CKD and healthy controls. The global efficiency, local efficiency, mean clustering coefficient, and small-worldness index were decreased, whereas the characteristic path length was increased in the patients with CKD compared with healthy controls. The structural betweenness centrality of the left calcarine and right posterior cingulum was also significantly different from that in healthy participants. However, all the measures of global functional connectivity in patients with CKD were not different from those in healthy controls. In patients with CKD, the functional betweenness centrality of the right insular cortex, right occipital pole, and right thalamus was significantly different from that in healthy participants.There are significant alterations of the global structural connectivity between the patients with CKD and the healthy subjects, whereas the global functional connectivity of the brain network is preserved. We find that the efficiency of the structural brain network is decreased in the patients with CKD.

Altered glucocorticoid metabolism in girls with central obesity.

BACKGROUND: Dysregulation of glucocorticoid metabolism is known to be a causative factor of obesity. However, only a few studies have evaluated the enzymatic activities involved in glucocorticoid metabolism in the pediatric population. OBJECTIVE: To examine whether circulating glucocorticoid metabolites and their ratios reflecting the activities of metabolic enzyme are associated with obesity and body composition in girls. METHODS: A total of 227 girls aged 7-13 years (131 control, 45 overweight, 51 obese) were enrolled in this study. Serum concentrations of glucocorticoids (11-deoxycortisol, cortisol, tetrahydrocortisol [THF], allo-THF, allo-dihydrocortisol [allo-DHF], and cortisone) were evaluated by gas chromatography-mass spectrometry. Enzyme activities corresponding to the ratios of cortisol and cortisone to their respective precursors and metabolites were also assessed. RESULTS: Serum levels of allo-THF were significantly higher in obese girls compared with those in overweight and control girls (P = 0.018); however, concentrations of other cortisol metabolites were not significantly different between the groups studied. According to the severity of obesity, increasing trends in the metabolic ratios reflecting the activity of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) [(cortisol + allo-DHF + allo-THF + THF)/cortisone], relative 5α/5ß-reductase [allo-THF/THF] activity, and 3α-HSD [allo-THF/allo-DHF] activity, were noted (P-for-trend <0.05). Body fat percentage and waist-to-height ratio positively correlated with the activities of 11ß-HSD1 and 3α-HSD (P < 0.05). Following covariate control, girls with central obesity demonstrated significantly higher metabolic ratios reflecting 11ß-HSD1, relative 5α/5ß-reductase, and 3α-HSD activities (P < 0.05). CONCLUSIONS: We found an altered glucocorticoid metabolism suggesting increased production of cortisol by 11ß-HSD1 and increased metabolic clearance of cortisol catalyzed by 3α-HSD in girls with central obesity.

Cognitive trajectories of patients with focal ß-amyloid deposition.

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.

Disease progression modelling from preclinical Alzheimer's disease (AD) to AD dementia.

To characterize the course of Alzheimer's disease (AD) over a longer time interval, we aimed to construct a disease course model for the entire span of the disease using two separate cohorts ranging from preclinical AD to AD dementia. We modelled the progression course of 436 patients with AD continuum and investigated the effects of apolipoprotein E ε4 (APOE ε4) and sex on disease progression. To develop a model of progression from preclinical AD to AD dementia, we estimated Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-cog 13) scores. When calculated as the median of ADAS-cog 13 scores for each cohort, the estimated time from preclinical AD to MCI due to AD was 7.8 years and preclinical AD to AD dementia was 15.2 years. ADAS-cog 13 scores deteriorated most rapidly in women APOE ε4 carriers and most slowly in men APOE ε4 non-carriers (p < 0.001). Our results suggest that disease progression modelling from preclinical AD to AD dementia may help clinicians to estimate where patients are in the disease course and provide information on variation in the disease course by sex and APOE ε4 status.

Quantitative gait and postural analyses in patients with diabetic polyneuropathy.

BACKGROUND: Although gait disturbances are relatively common symptoms in diabetic polyneuropathy (DPN), few studies have quantitatively analyzed gait and posture in DPN patients. This study aimed to analyze gait and posture quantitatively in DPN patients and to determine the association between clinical and electrophysiological parameters and gait and posture parameters. METHODS: Sixty-four DPN patients were enrolled in this study. DPN was clinically assessed using the Toronto clinical neuropathy score (TCNS). All participants underwent nerve conduction study (NCS), three-dimensional motion analysis, and static posturography. We evaluate the correlation of gait and posture parameters with electrophysiological and clinical parameters. RESULTS: Foot height, step length, and stride length among gait parameters were inversely correlated with the TCNS. Anteroposterior range during eyes-closed and mediolateral distance and range during eyes-open and eyes-closed were inversely correlated with the sensory nerve action potential amplitude in the sural nerve. Mediolateral distance during eyes-open and eyes-closed was correlated with the compound muscle action potential amplitude in the peroneal nerve. CONCLUSIONS: Gait parameters are associated with clinical parameters, and postural parameters are associated with electrophysiological parameters, particularly sensory NCS. Gait and postural analysis can be a useful tool for assessing the neurological status in DPN patients.

One-pot synthesis for gradient copolymers via concurrent tandem living radical polymerization: mild and selective transesterification of methyl acrylate through Al(acac)3 with common alcohols.

A series of gradient copolymers were synthesized by the ruthenium-catalyzed living radical polymerization (LRP) of methyl acrylate (MA) and aliphatic alcohols using aluminum acetylacetonate Al(acac)3. In this polymerization system, Al(acac)3 was successfully used not only as an additive for the Ru-catalyzed LRP but also as a catalyst for the selective transesterification of an unsaturated ester monomer in mild conditions in a process known as concurrent tandem living radical polymerization. The resulting MA-based gradient copolymers showed well-controlled molecular weight and distribution in a one-pot reaction and exhibited a well-controlled gradient sequence in their polymer chain. Control of transesterification and the metal-catalyzed living radical polymerization (Mt-LRP) rate varied depending on the concentration of the Al(acac)3 and the structure of varying alcohols, which were confirmed by 1H NMR, SEC, and DSC analysis. In particular, this research opens a new synthetic methodology for preparing acrylate-based gradient copolymers via concurrent tandem LRP not limited to the synthesis of methyl methacrylate types of gradient copolymers.

Disease progression modeling of Alzheimer's disease according to education level.

To develop a disease progression model of Alzheimer's disease (AD) that shows cognitive decline from subjective cognitive impairments (SCI) to the end stage of AD dementia (ADD) and to investigate the effect of education level on the whole disease spectrum, we enrolled 565 patients who were followed up more than three times and had a clinical dementia rating sum of boxes (CDR-SB). Three cohorts, SCI (n = 85), amnestic mild cognitive impairment (AMCI, n = 240), and ADD (n = 240), were overlapped in two consecutive cohorts (SCI and AMCI, AMCI and ADD) to construct a model of disease course, and a model with multiple single-cohorts was estimated using a mixed-effect model. To examine the effect of education level on disease progression, the disease progression model was developed with data from lower (≤ 12) and higher (> 12) education groups. Disease progression takes 274.3 months (22.9 years) to advance from 0 to 18 points using the CDR-SB. Based on our predictive equation, it takes 116.5 months to progress from SCI to AMCI and 56.2 months to progress from AMCI to ADD. The rate of CDR-SB progression was different according to education level. The lower-education group showed faster CDR-SB progression from SCI to AMCI compared to the higher-education group, and this trend disappeared from AMCI to ADD. In the present study, we developed a disease progression model of AD spectrum from SCI to the end stage of ADD. Our disease modeling provides us with more understanding of the effect of education on cognitive trajectories.

The Effects of Longitudinal White Matter Hyperintensity Change on Cognitive Decline and Cortical Thinning over Three Years.

White matter hyperintensity (WMH) has been recognised as a surrogate marker of small vessel disease and is associated with cognitive impairment. We investigated the dynamic change in WMH in patients with severe WMH at baseline, and the effects of longitudinal change of WMH volume on cognitive decline and cortical thinning. Eighty-seven patients with subcortical vascular mild cognitive impairment were prospectively recruited from a single referral centre. All of the patients were followed up with annual neuropsychological tests and 3T brain magnetic resonance imaging. The WMH volume was quantified using an automated method and the cortical thickness was measured using surface-based methods. Participants were classified into WMH progression and WMH regression groups based on the delta WMH volume between the baseline and the last follow-up. To investigate the effects of longitudinal change in WMH volume on cognitive decline and cortical thinning, a linear mixed effects model was used. Seventy patients showed WMH progression and 17 showed WMH regression over a three-year period. The WMH progression group showed more rapid cortical thinning in widespread regions compared with the WMH regression group. However, the rate of cognitive decline in language, visuospatial function, memory and executive function, and general cognitive function was not different between the two groups. The results of this study indicated that WMH volume changes are dynamic and WMH progression is associated with more rapid cortical thinning.