Real-World Epidemiology, Treatment Patterns, and Disease Burden of Chronic Hepatitis B and HDV Co-Infection in South Korea.

INTRODUCTION: Long-term complications of chronic hepatitis B (CHB) viral infection, such as cirrhosis, hepatocellular carcinoma (HCC), and liver failure, cause a large disease burden. This study aimed to describe the epidemiology, clinical outcomes, and treatment patterns of CHB infection and co-infection with hepatitis D virus (HDV) in South Korea. METHODS: The retrospective, observational study used existing data from the Health Insurance Review and Assessment Service (HIRA) database. Confirmed cases of (CHB) and HBV/HDV co-infection were identified between 2013 and 2019. Hepatitis C virus co-infections and acute HBV infections were excluded. Incident cases diagnosed between 2015 and 2018 with no prior disease history up to 2 years were included. Patient characteristics, clinical outcomes, economic burden, and healthcare-resource utilization were described. RESULTS: The estimated 7-year prevalence of CHB and HBV/HDV co-infection were 0.9% and 0.0024%, respectively. The prevalence was higher among 45-54 years old (CHB: 1.6%, HBV/HDV: 0.0049%) and males (1.1%, 0.0035%). The 5-year cumulative incidences of compensated cirrhosis, decompensated cirrhosis, HCC, and liver transplantation were 13.3%, 7.1%, 8.4%, and 0.7%, respectively. Hyperlipidemia (40.6%), hypertension (23.5%), and peptic ulcer (23.7%) were the more prevalent comorbidities. Among CHB patients, 48.1% received ≥ 1 prescribed anti-HBV drug including interferon or nucleos(t)ide analogues and 64.4% had ≥ 1 hospitalization compared to 80.4% and 79.4% HBV/HDV patients. Estimated total healthcare costs for CHB and HBV/HDV were US$786 million and $62 million, respectively. CONCLUSIONS: These findings provide insights to the epidemiology, clinical burden, treatment patterns, and healthcare costs of CHB and HBV/HDV co-infection in South Korea.

Comparison of automated quantification of amyloid deposition between PMOD and Heuron.

Several programs are widely used for clinical and research purposes to automatically quantify the degree of amyloid deposition in the brain using positron emission tomography (PET) images. Given that very few studies have investigated the use of Heuron, a PET image quantification software approved for clinical use, this study aimed to compare amyloid deposition values quantified from 18F-flutemetamol PET images using PMOD and Heuron. Amyloid PET data obtained from 408 patients were analysed using each quantitative program; moreover, the standardized uptake value ratios (SUVRs) of target areas were obtained by dividing the standardized uptake value (SUV) of the target region by the SUV of cerebellar grey matter as a reference. Compared with PMOD, Heuron yielded significantly higher SUVRs for all target areas (paired sample t-test, p < 0.001), except for the PC/PCC (p = 0.986). However, the Bland-Altman plot analysis indicated that the two quantitative methods may be used interchangeably. Moreover, receiver operating characteristic curve analysis revealed no significant between-method difference in the performance of the SUVRs in evaluating the visual positivity of amyloid deposits (p = 0.948). In conclusion, Heuron and PMOD have comparable performance in quantifying the degree of amyloid deposits in PET images.

Diagnostic performance of a high-spatial-resolution voxelwise analysis of neuromelanin-sensitive imaging in early-stage idiopathic Parkinson's disease.

BACKGROUND: Quantitative assessments of neuromelanin (NM) of the substantia nigra pars compacta (SNpc) in neuromelanin-sensitive MRI (NM-MRI) to determine its abnormality have been conducted by measuring either the volume or contrast ratio (CR) of the SNpc. A recent study determined the regions in the SNpc that are significantly different between early-stage idiopathic Parkinson's disease (IPD) patients and healthy controls (HCs) using a high spatial-resolution NM-MRI template, which enables a template-based voxelwise analysis to overcome the susceptibility of CR measurement to inter-rater discrepancy. We aimed to assess the diagnostic performance, which has not been reported, of the CRs between early-stage IPD patients and HCs using a NM-MRI template. METHODS: We retrospectively enrolled early-stage IPD patients (n = 50) and HCs (n = 50) who underwent 0.8-mm isovoxel NM-MRI and dopamine-transporter PET as the standard of reference. A template-based voxelwise analysis revealed two regions in nigrosomes 1 and 2 (N1 and N2, respectively), with significant differences in each substantia nigra (SNpc) between IPD and HCs. The mean CR values of N1, N2, volume-weighted mean of N1 and N2 (N1 + N2), and whole SNpc on each side were compared between IPD and HC using the independent t-test or the Mann-Whitney U test. The diagnostic performance was compared in each region using receiver operating characteristic curves. RESULTS: The mean CR values in the right N1 (0.149459 vs. 0.194505), left N1 (0.133328 vs. 0.169160), right N2 (0.230245 vs. 0.278181), left N2 (0.235784 vs. 0.314169), right N1 + N2 (0.155322 vs. 0.278143), left N1 + N2 (0.140991 vs. 0.276755), right whole SNpc (0.131397 vs. 0.141422), and left whole SNpc (0.127099 vs. 0.137873) significantly differed between IPD patients and HCs (all p < 0.001). The areas under the curve of the left N1 + N2, right N1 + N2, left N1, right N1, left N2, right N2, left whole SNpc, and right whole SNpc were 0.994 (sensitivity, 98.0%; specificity, 94.0%), 0.985, 0.804, 0.802, 0.777, 0.766, 0.632, and 0.606, respectively. CONCLUSION: Our NM-MRI template-based CR measurements revealed significant differences between early-stage IPD patients and HCs. The CR values of the left N1 + N2 demonstrated the highest diagnostic performance.

Targeted Literature Review of the Burden of Respiratory Syncytial Infection among High-Risk and Elderly Patients in Asia Pacific Region.

INTRODUCTION: The burden of respiratory syncytial virus (RSV), which causes acute respiratory illness, is well recognized among the pediatric population but also imposes a significant risk to the elderly (age ≥ 60) and those with underlying comorbidities. The study aimed to review the most recent data on epidemiology and burden (clinical and economic) of RSV in the elderly/high-risk populations in China, Japan, South Korea, Taiwan, and Australia. METHODS: A targeted review was conducted of English, Japanese, Korean, and Chinese language articles published from 1 January 2010 to 7 October 2020 relevant for the purpose. RESULTS: A total of 881 studies were identified, and 41 were included. The median proportion of elderly patients with RSV in all adult patients with acute respiratory infection (ARI) or community acquired pneumonia was 79.78% (71.43-88.12%) in Japan, 48.00% (3.64-80.00%) in China, 41.67% (33.33-50.00%) in Taiwan, 38.61% in Australia, and 28.57% (22.76-33.33%) in South Korea. RSV was associated with a high clinical burden on those patients with comorbidities such as asthma and chronic obstructive pulmonary disease. In China, inpatients with ARI showed a significantly higher rate of RSV-related hospitalization than outpatients (13.22% versus 4.08%, p < 0.01). The median length of hospital stay among elderly patients with RSV was longest in Japan (30 days) and shortest in China (7 days). Mortality data varied by region with some studies reporting rates as high as 12.00% (9/75) in hospitalized elderly patients. Finally, data on the economic burden was only available for South Korea, with the median cost of a medical admission for an elderly patient with RSV being US dollar (USD) 2933. CONCLUSION: RSV infection is a major source of disease burden among elderly patients, especially in regions with aging populations. It also complicates the management of those with underlying diseases. Appropriate prevention strategies are required to reduce the burden among the adult, especially the elderly, population. Data gaps regarding economic burden of RSV infection in the Asia Pacific region indicates the need for further research to increase our understanding on the burden of this disease in this region.

Correlation Between Neuromelanin-Sensitive MRI and 18F-FP-CIT PET in Early-Stage Parkinson's Disease: Utility of a Voxel-Wise Analysis by Using High-Spatial-Resolution MRI.

BACKGROUND AND PURPOSE: The correlation between dopamine transporter (DAT) imaging and neuromelanin-sensitive magnetic resonance imaging (NM-MRI) in early-stage Parkinson's disease (PD) has not yet been established. This study aimed to determine the correlation between NM-MRI and DAT positron-emission tomography (PET) in patients with early-stage PD. METHODS: Fifty drug-naïve patients with early-stage PD who underwent both 0.8-mm isovoxel NM-MRI and DAT PET were enrolled retrospectively. Using four regions of interest (nigrosome 1 and nigrosome 2 [N1 and N2] regions) from a previous study, the contrast ratios (CRs) of 12 regions were measured: N1, N2, flipped N1, flipped N2, combined N1 and N2, and whole substantia nigra pars compacta [SNpc] (all on both sides). The clinically more affected side was separately assessed. The standardized uptake value ratios (SUVRs) were measured in the striatum using DAT PET. A partial correlation analysis was performed between the SUVR and CR measurements. RESULTS: CR of the flipped left N1 region was significantly correlated with SUVR of the right posterior putamen (p=0.047), and CR values of the left N1 region, left N2 region, flipped right N1 region, and combined left N1 and N2 regions were significantly correlated with SUVR of the left posterior putamen (p=0.011, 0.038, 0.020, and 0.010, respectively). SUVR of the left anterior putamen was significantly correlated with CR of the left N2 region (p=0.027). On the clinically more affected side, the CR values of the N1 region, combined N1 and N2 regions, and the whole SNpc were significantly correlated with SUVR of the posterior putamen (p=0.001, 0.024, and 0.021, respectively). There were significant correlations between the SUVR of the anterior putamen and the CR values of the N1 region, combined N1 and N2 regions, and whole SNpc (p=0.027, 0.001, and 0.036, respectively). CONCLUSIONS: This study found that there were significant correlations between CR values in the SNpc on NM-MRI and striatal SUVR values on DAT PET on both sides in early-stage PD.

White Matter Lesions Predominantly Located in Deep White Matter Represent Embolic Etiology Rather Than Small Vessel Disease.

Background and Purpose: We investigated the correlation between the deep distribution of white matter hyperintensity (WMH) (dWMH: WMH in deep and corticomedullary areas, with minimal periventricular WMH) and a positive agitated saline contrast echocardiography result. Methods: We retrospectively recruited participants with comprehensive dementia evaluations, an agitated saline study, and brain imaging. The participants were classified into two groups according to WMH-distributions: dWMH and dpWMH (mainly periventricular WMH with or without deep WMH.) We hypothesized that dWMH is more likely associated with embolism, whereas dpWMH is associated with small-vessel diseases. We compared the clinical characteristics, WMH-distributions, and positive rate of agitated saline studies between the two groups. Results: Among 90 participants, 27 and 12 met the dWMH and dpWMH criteria, respectively. The dWMH-group was younger (62.2±7.5 vs. 78.9±7.3, p<0.001) and had a lower prevalence of hypertension (29.6% vs. 75%, p=0.008), diabetes mellitus (3.7% vs. 25%, p=0.043), and hyperlipidemia (33.3% vs. 83.3%, p=0.043) than the dpWMH-group. Regarding deep white matter lesions, the number of small lesions (<3 mm) was higher in the dWMH-group(10.9±9.7) than in the dpWMH-group (3.1±6.4) (p=0.008), and WMH was predominantly distributed in the border-zones and corticomedullary areas. Most importantly, the positive agitated saline study rate was higher in the dWMH-group than in the dpWMH-group (81.5% vs. 33.3%, p=0.003). Conclusions: The dWMH-group with younger participants had fewer cardiovascular risk factors, showed more border-zone-distributions, and had a higher agitated saline test positivity rate than the dpWMH-group, indicating that corticomedullary or deep WMH-distribution with minimal periventricular WMH suggests embolic etiologies.

Sandwich spatial saturation for neuromelanin-sensitive MRI: Development and multi-center trial.

Neuromelanin (NM)-sensitive MRI using a magnetization transfer (MT)-prepared T1-weighted sequence has been suggested as a tool to visualize NM contents in the brain. In this study, a new NM-sensitive imaging method, sandwichNM, is proposed by utilizing the incidental MT effects of spatial saturation RF pulses in order to generate consistent high-quality NM images using product sequences. The spatial saturation pulses are located both superior and inferior to the imaging volume, increasing MT weighting while avoiding asymmetric MT effects. When the parameters of the spatial saturation were optimized, sandwichNM reported a higher NM contrast ratio than those of conventional NM-sensitive imaging methods with matched parameters for comparability with sandwichNM (SandwichNM: 23.6 ± 5.4%; MT-prepared TSE: 20.6 ± 7.4%; MT-prepared GRE: 17.4 ± 6.0%). In a multi-vendor experiment, the sandwichNM images displayed higher means and lower standard deviations of the NM contrast ratio across subjects in all three vendors (SandwichNM vs. MT-prepared GRE; Vendor A: 28.4 ± 1.5% vs. 24.4 ± 2.8%; Vendor B: 27.2 ± 1.0% vs. 13.3 ± 1.3%; Vendor C: 27.3 ± 0.7% vs. 20.1 ± 0.9%). For each subject, the standard deviations of the NM contrast ratio across the vendors were substantially lower in SandwichNM (SandwichNM vs. MT-prepared GRE; subject 1: 1.5% vs. 8.1%, subject 2: 1.1 % vs. 5.1%, subject 3: 0.9% vs. 4.0%, subject 4: 1.1% vs. 5.3%), demonstrating consistent contrasts across the vendors. The proposed method utilizes product sequences, requiring no alteration of a sequence and, therefore, may have a wide practical utility in exploring the NM imaging.

The fasciola cinereum subregion of the hippocampus is important for the acquisition of visual contextual memory.

The fasciola cinereum (FC) is a subregion of the hippocampus that has received relatively little attention compared with other hippocampal subregions with respect to anatomical characteristics and functional significance. Here, we show that the FC exhibits clear anatomical borders with the distalmost region of the CA1. Principal neurons in the FC resemble the granule cells in the dentate gyrus (DG). However, adult neurogenesis was not found unlike in the DG. The FC receives inputs mostly from the lateral entorhinal cortex and perirhinal cortex while projecting exclusively to the crest of the DG within the hippocampus. Neurotoxic lesions in the FC using colchicine impaired the acquisition, but not retrieval, of visual contextual memory in rats. FC lesions also impaired place recognition and object-in-place memory. As the rat performed the contextual memory task on the T-maze, place cells in the FC exhibited robust place fields and were indiscriminable from those in CA1 with respect to the basic firing properties. However, place cells in the FC fired only transiently in their place fields on the maze compared with those in CA1. Our findings suggest that the episodic firing patterns of the place cells in the FC may play critical roles in learning a novel contextual environment by facilitating temoporally structured contextual pattern separation in the DG of the hippocampus.

Intracerebroventricular injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer's disease dementia: a phase I clinical trial.

BACKGROUNDS: Alzheimer's disease is the most common cause of dementia, and currently, there is no disease-modifying treatment. Favorable functional outcomes and reduction of amyloid levels were observed following transplantation of mesenchymal stem cells (MSCs) in animal studies. OBJECTIVES: We conducted a phase I clinical trial in nine patients with mild-to-moderate Alzheimer's disease dementia to evaluate the safety and dose-limiting toxicity of three repeated intracerebroventricular injections of human umbilical cord blood-derived MSCs (hUCB-MSCs). METHODS: We recruited nine mild-to-moderate Alzheimer's disease dementia patients from Samsung Medical Center, Seoul, Republic of Korea. Four weeks prior to MSC administration, the Ommaya reservoir was implanted into the right lateral ventricle of the patients. Three patients received a low dose (1.0 × 107 cells/2 mL), and six patients received a high dose (3.0 × 107 cells/2 mL) of hUCB-MSCs. Three repeated injections of MSCs were performed (4-week intervals) in all nine patients. These patients were followed up to 12 weeks after the first hUCB-MSC injection and an additional 36 months in the extended observation study. RESULTS: After hUCB-MSC injection, the most common adverse event was fever (n = 9) followed by headache (n = 7), nausea (n = 5), and vomiting (n = 4), which all subsided within 36 h. There were three serious adverse events in two participants that were considered to have arisen from the investigational product. Fever in a low dose participant and nausea with vomiting in another low dose participant each required extended hospitalization by a day. There were no dose-limiting toxicities. Five participants completed the 36-month extended observation study, and no further serious adverse events were observed. CONCLUSIONS: Three repeated administrations of hUCB-MSCs into the lateral ventricle via an Ommaya reservoir were feasible, relatively and sufficiently safe, and well-tolerated. Currently, we are undergoing an extended follow-up study for those who participated in a phase IIa trial where upon completion, we hope to gain a deeper understanding of the clinical efficacy of MSC AD therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02054208. Registered on 4 February 2014. ClinicalTrials.gov NCT03172117. Registered on 1 June 2017.

Prediction of tau accumulation in prodromal Alzheimer's disease using an ensemble machine learning approach.

We developed machine learning (ML) algorithms to predict abnormal tau accumulation among patients with prodromal AD. We recruited 64 patients with prodromal AD using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Supervised ML approaches based on the random forest (RF) and a gradient boosting machine (GBM) were used. The GBM resulted in an AUC of 0.61 (95% confidence interval [CI] 0.579-0.647) with clinical data (age, sex, years of education) and a higher AUC of 0.817 (95% CI 0.804-0.830) with clinical and neuropsychological data. The highest AUC was 0.86 (95% CI 0.839-0.885) achieved with additional information such as cortical thickness in clinical data and neuropsychological results. Through the analysis of the impact order of the variables in each ML classifier, cortical thickness of the parietal lobe and occipital lobe and neuropsychological tests of memory domain were found to be more important features for each classifier. Our ML algorithms predicting tau burden may provide important information for the recruitment of participants in potential clinical trials of tau targeting therapies.

Goal-directed interaction of stimulus and task demand in the parahippocampal region.

The hippocampus and parahippocampal region are essential for representing episodic memories involving various spatial locations and objects, and for using those memories for future adaptive behavior. The "dual-stream model" was initially formulated based on anatomical characteristics of the medial temporal lobe, dividing the parahippocampal region into two streams that separately process and relay spatial and nonspatial information to the hippocampus. Despite its significance, the dual-stream model in its original form cannot explain recent experimental results, and many researchers have recognized the need for a modification of the model. Here, we argue that dividing the parahippocampal region into spatial and nonspatial streams a priori may be too simplistic, particularly in light of ambiguous situations in which a sensory cue alone (e.g., visual scene) may not allow such a definitive categorization. Upon reviewing evidence, including our own, that reveals the importance of goal-directed behavioral responses in determining the relative involvement of the parahippocampal processing streams, we propose the Goal-directed Interaction of Stimulus and Task-demand (GIST) model. In the GIST model, input stimuli such as visual scenes and objects are first processed by both the postrhinal and perirhinal cortices-the postrhinal cortex more heavily involved with visual scenes and perirhinal cortex with objects-with relatively little dependence on behavioral task demand. However, once perceptual ambiguities are resolved and the scenes and objects are identified and recognized, the information is then processed through the medial or lateral entorhinal cortex, depending on whether it is used to fulfill navigational or non-navigational goals, respectively. As complex sensory stimuli are utilized for both navigational and non-navigational purposes in an intermixed fashion in naturalistic settings, the hippocampus may be required to then put together these experiences into a coherent map to allow flexible cognitive operations for adaptive behavior to occur.

Cost-effectiveness of a national immunization program with the 13-valent pneumococcal conjugate vaccine compared with the 10-valent pneumococcal conjugate vaccine in South Korea.

INTRODUCTION: Globally, pneumococcal disease represents a significant burden. South Korea implemented the 7-valent pneumococcal conjugate vaccine (PCV7) in 2003, replaced with the 10-valent (PCV10) and 13-valent (PCV13) vaccine in 2010. In 2014, both vaccines were introduced in the national immunization program (NIP) for infants with 3 primary doses and one booster dose We performed a cost-effectiveness evaluation to elucidate which vaccine may be expected to provide greater impact if included in a NIP. METHODOLOGY: Using an established model, we estimated the impact of introducing either PCV13 or PCV10 into the South Korean NIP in 2015. Vaccine impact was based on historic observed impact of PCV13 from 2010 to 2015 in Korea given high uptake of PCV13, and PCV10 impact was estimated based on experiences in countries using PCV10. Incidence and costs for all ages and including invasive pneumococcal disease, pneumonia, and acute otitis media were derived from the literature and Health Insurance Review and Assessment database. RESULTS: In the base-case, over 5-years PCV13 was estimated to avert 550,000 more cases of pneumococcal disease compared to PCV10, driven by broader serotype coverage and less replacement due to serotypes 3 and 19A. This translated to a cost-savings of $47.4 million USD despite PCV13's higher cost. Sensitivity analysis found incremental cost-effectiveness ratios (ICERs) ranged from cost-saving to $7,300 USD per quality-adjusted life year (QALY). CONCLUSION: A NIP using PCV13 was estimated to have a more substantial public health impact and be cost-saving compared to a program with PCV10 due to broader serotype coverage.

The Impact of Amyloid-ß or Tau on Cognitive Change in the Presence of Severe Cerebrovascular Disease.

BACKGROUND: As Alzheimer's disease (AD) and cerebral small vessel disease (CSVD) commonly coexist, the interaction between two has been of the considerable interest. OBJECTIVE: We determined whether the association of Aß and tau with cognitive decline differs by the presence of significant CSVD. METHODS: We included 60 subcortical vascular cognitive impairment (SVCI) from Samsung Medical Center and 82 Alzheimer's disease-related cognitive impairment (ADCI) from ADNI, who underwent Aß (florbetaben or florbetapir) and tau (flortaucipir, FTP) PET imaging. They were retrospectively assessed for 5.0±3.9 and 5.6±1.9 years with Clinical Dementia Rating-sum of boxes (CDR-SB)/Mini-Mental State Examination (MMSE). Mixed effects models were used to investigate the interaction between Aß/tau and group on CDR-SB/MMSE changes. RESULTS: The frequency of Aß positivity (45% versus 54.9%, p = 0.556) and mean global FTP SUVR (1.17±0.21 versus 1.16±0.17, p = 0.702) were not different between the two groups. We found a significant interaction effect of Aß positivity and SVCI group on CDR-SB increase/MMSE decrease (p = 0.013/p < 0.001), and a significant interaction effect of global FTP uptake and SVCI group on CDR-SB increase/MMSE decrease (p < 0.001 and p = 0.030). Finally, the interaction effects of regional tau and group were prominent in the Braak III/IV (p = 0.001) and V/VI (p = 0.003) not in Braak I/II region (p = 0.398). CONCLUSION: The association between Aß/tau and cognitive decline is stronger in SVCI than in ADCI. Therefore, our findings suggested that Aß positivity or tau burden (particularly in the Braak III/IV or V/VI regions) and CSVD might synergistically affect cognitive decline.

Appropriate reference region selection of 18F-florbetaben and 18F-flutemetamol beta-amyloid PET expressed in Centiloid.

The Centiloid (CL) is a method for standardizing amyloid beta (Aß) quantification through different ligands and methods. To find the most appropriate reference region to reduce the variance in the Aß CL unit between 18F-florbetaben (FBB) and 18F-flutemetamol (FMM), we conducted head-to-head comparisons from 56 participants using the direct comparison of FBB-FMM CL (dcCL) method with four reference regions: cerebellar gray (CG), whole cerebellum (WC), WC with brainstem (WC + B), and pons. The FBB and FMM dcCL units were highly correlated in four reference regions: WC (R2 = 0.97), WC + B (R2 = 0.98), CG (R2 = 0.92), and pons (R2 = 0.98). WC showed the largest effect size in both FBB and FMM. Comparison of the variance of the dcCL values within the young control group showed that with FBB, WC + B had the smallest variance and with FMM, the WC had the smallest variance. Additionally, WC + B showed the smallest absolute difference between FBB and FMM, followed by the WC, pons, and CG. We found that it would be reasonable to use the WC or WC + B as the reference region when converting FBB and FMM SUVRs into dcCL, which can increase the accuracy of standardizing FBB and FMM PET results.

Association between APOE ε2 and Aß burden in patients with Alzheimer- and vascular-type cognitive impairment.

OBJECTIVE: To investigate the association between APOE genotype and ß-amyloid (Aß) burden, as measured by PET in patients with subcortical vascular cognitive impairment (SVCI) and those with Alzheimer disease-related cognitive impairment (ADCI). METHODS: This was a cross-sectional study of 310 patients with SVCI and 999 with ADCI. To evaluate the effects of APOE genotype or diagnostic group on Aß positivity, we performed multivariate logistic regression analyses. Further distinctive underlying features of latent subgroups were examined by employing a latent class cluster analysis approach. RESULTS: In comparison with ε3 homozygotes, in the ADCI group, ε2 carriers showed a lower frequency of Aß positivity (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.23-0.79), while in the SVCI group, ε2 carriers showed a higher frequency of Aß positivity (OR 2.26, 95% CI 1.02-5.01). In particular, we observed an interaction effect of ε2 carrier status and diagnostic group on Aß positivity (OR 5.12, 95% CI 1.93-13.56), in that relative to ε3 homozygotes, there were more Aß-positive ε2 carriers in the SVCI group than in the ADCI group. We also identified latent subgroups of Aß-positive APOE ε2 carriers with SVCI and Aß-positive APOE ε4 carriers with ADCI. CONCLUSIONS: Our findings suggest that APOE ε2 is distinctly associated with Aß deposition in patients with SVCI and those with ADCI. Our findings further suggest that there is a distinctive subgroup of Aß-positive APOE ε2 carriers with SVCI among patients with cognitive impairment.

Identifying a subtype of Alzheimer's disease characterised by predominant right focal cortical atrophy.

We aimed to identify an Alzheimer's disease (AD) subtype with right predominant focal atrophy. We recruited 17 amyloid PET positive logopenic variant primary progressive aphasia (lvPPA) and 226 amyloid PET positive AD patients. To identify AD with right focal atrophy (Rt-AD), we selected cortical areas that showed more atrophy in lvPPA than in AD and calculated an asymmetry index (AI) for this area in each individual. Using a receiver operating characteristic curve, we found that the optimal AI cut-off to discriminate lvPPA from AD was -3.1 (mean AI - 1.00 standard deviation) (sensitivity 88.2, specificity 89.8). We identified 32 Rt-AD patients whose AI was above mean AI + 1.00 standard deviation, 38 Lt-AD patients whose AI was lower than mean AI - 1.00 standard deviation, and 173 Symmetric-AD patients whose AI was within mean AI ± 1.00 standard deviation. We characterized clinical and cognitive profiles of Rt-AD patients by comparing with those of Lt-AD and Symmetric-AD patients. Compared to Symmetric-AD patients, Rt-AD patients had asymmetric focal atrophy in the right temporoparietal area and showed poor performance on visuospatial function testing (p = 0.009). Our findings suggested that there is an AD variant characterized by right focal atrophy and visuospatial dysfunction.

Correction to: A new Centiloid method for 18F-florbetaben and 18F-flutemetamol PET without conversion to PiB.

Funding information from the original version of this article was incomplete. Complete information is presented here.

Clinical significance of focal ß-amyloid deposition measured by 18F-flutemetamol PET.

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

Frontal-executive dysfunction affects dementia conversion in patients with amnestic mild cognitive impairment.

Among mild cognitive impairment (MCI) patients, those with memory impairment (amnestic MCI, aMCI) are at a high risk of dementia. However, the precise cognitive domain, beside memory, that predicts dementia conversion is unclear. Therefore, we investigated the cognitive domain that predicts dementia conversion in a longitudinal aMCI cohort. We collected data of 482 aMCI patients who underwent neuropsychological tests and magnetic resonance imaging at baseline and were followed for at least 1 year. The patients were categorized according to number (1-4) and type of impaired cognitive domains (memory, language, visuospatial, and frontal-executive function). We evaluated dementia conversion risk in each group when compared to single-domain aMCI after controlling for age, education, diabetes and dyslipidemia. Baseline cortical thickness of each group was compared to that of 410 cognitively normal controls (NCs) after controlling for age, intracranial volume, diabetes and dyslipidemia. Compared to single-domain aMCI, aMCI patients with frontal-executive dysfunction at baseline had a higher risk of dementia conversion than aMCI patients with visuospatial or language dysfunction. Compared to NCs, aMCI patients with frontal-executive dysfunction had overall cortical thinning including frontal areas. Our findings suggest that aMCI patients with frontal-executive dysfunction have poor prognosis and,thus, should be considered for intervention therapy with a higher priority among aMCI patients.

Application of an amyloid and tau classification system in subcortical vascular cognitive impairment patients.

OBJECTIVE: To apply an AT (Aß/tau) classification system to subcortical vascular cognitive impairment (SVCI) patients following recently developed biomarker-based criteria of Alzheimer's disease (AD), and to investigate its clinical significance. METHODS: We recruited 60 SVCI patients who underwent the neuropsychological tests, brain MRI, and 18F-florbetaben and 18F-AV1451 PET at baseline. As a control group, we further recruited 27 patients with AD cognitive impairment (ADCI; eight Aß PET-positive AD dementia and 19 amnestic mild cognitive impairment). ADCI and SVCI patients were classified as having normal or abnormal Aß (A-/A+) and tau (T-/T+) based on PET results. Across the three SVCI groups (A-, A+T-, and A+T+SVCI), we compared longitudinal changes in cognition, hippocampal volume (HV), and cortical thickness using linear mixed models. RESULTS: Among SVCI patients, 33 (55%), 20 (33.3%), and seven (11.7%) patients were A-, A+T-, and A+T+, respectively. The frequency of T+ was lower in A+SVCI (7/27, 25.9%) than in A+ADCI (14/20, 70.0%, p = 0.003) which suggested that cerebral small vessel disease affected cognitive impairments independently of A+. A+T-SVCI had steeper cognitive decline than A-SVCI. A+T+SVCI also showed steeper cognitive decline than A+T-SVCI. Also, A+T-SVCI had steeper decrease in HV than A-SVCI, while cortical thinning did not differ between the two groups. A+T+SVCI had greater global cortical thinning compared with A+T-SVCI, while declines in HV did not differ between the two groups. CONCLUSION: This study showed that the AT system successfully characterized SVCI patients, suggesting that the AT system may be usefully applied in a research framework for clinically diagnosed SVCI.