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Objective The aim of this study is to assess the effectiveness of continuous regional arterial infusion (CRAI) of protease inhibitors in patients with severe acute pancreatitis (SAP) including acute necrotizing pancreatitis. Methods This retrospective study was conducted among 44 institutions in Japan from 2009 to 2013. Patients 18 years or older diagnosed with SAP according to the criteria of the Japanese Ministry of Health, Labour and Welfare study group (2008) were consecutively enrolled. We evaluated the association between CRAI of protease inhibitors and mortality, incidence of infection, and the need for surgical intervention using multivariable logistic regression analysis. Results Of 1159 patients admitted, 1097 patients with all required data were included for analysis. Three hundred and seventy-four (34.1%) patients underwent CRAI of protease inhibitors and 723 (65.9%) did not. In multivariable analysis, CRAI of protease inhibitors was not associated with a reduction in mortality, infection rate, or need for surgical intervention (odds ratio [OR] 0.79, 95% confidence interval [CI] 0.47-1.32, P = 0.36; OR 0.97, 95% CI 0.61-1.54, P = 0.89; OR 0.76, 95% CI 0.50-1.15, P = 0.19; respectively). Conclusions Continuous regional arterial infusion of protease inhibitors was not efficacious in the treatment of patients with SAP.

Background Studies have shown significant associations of chronic kidney disease (CKD) and diabetes mellitus (DM) with cardiovascular disease (CVD) mortality. The impact on the general population is an important public health issue. However, the population attributable fraction (PAF) of CVD because of CKD and/or DM in a general population is uncertain. Methods We followed 7229 participants (age: ≥30 years) with no history of CVD in a Japanese community. We divided participants into four categories according to CKD and/or DM and calculated hazard ratios (HRs) of CVD mortality for each category using a Cox proportional hazards model adjusted for age, dyslipidemia, smoking and alcohol consumption. In addition, PAFs of CVD were estimated among populations with CKD and/or DM. Results During 20-year follow-up, 488 participants died. HRs for CVD were 1.63 [95% confidence interval (CI): 1.16-2.30] with DM only, 1.42 (95% CI: 1.08-1.86) with CKD only and 2.37 (95% CI: 1.40-4.01) with CKD + DM. In men, the corresponding HRs for CVD were 1.88 (95% CI: 1.19-2.97), 1.71 (95% CI: 1.15-2.56) and 3.26 (95% CI: 1.69-6.30), respectively; the corresponding PAFs of CVD were 4.1%, 5.1% and 2.9%, respectively. PAFs for CVD among women were lower than those in men, 1.6% for DM only, 2.0% for CKD only and 0.7% for CKD + DM. Conclusions PAFs of CVD mortality due to CKD and/or DM were not so high in past 20 years; however, they might increase in the future because of recent increase in prevalence of these in Japanese population.

Coronary computed tomography angiography is widely used to evaluate the graft patency, but information on the progression of native-vessel disease remains limited. We sought to evaluate the impact of bypass grafting on native-vessel progression after coronary artery bypass grafting. We evaluated new native-vessel occlusion defined as occlusion length ≥15 mm as a surrogate marker of native-vessel progression. We evaluated 911 patients with 2,271 nonoccluded vessels who underwent coronary artery bypass grafting and received follow-up coronary computed tomography angiography. Over a mean follow-up period of 4.7 years, the new occlusion rates were 9.2% for left anterior descending artery (LAD), and 13.9% for non-LAD, respectively. For non-LAD, new occlusion rate of vessels with bypass grafts was higher compared to those without bypass graft regardless of baseline native-vessel stenosis (intermediate stenosis: 8.6% vs 1.7%, p <0.001; severe stenosis: 20.5% vs 9.9%, p = 0.003). Furthermore, new occlusion rate of vessels with venous graft was the highest, followed by vessels with arterial graft and vessels without bypass graft, regardless of baseline stenosis (intermediate stenosis: 11.1% vs 5.2% vs 1.7%, p <0.001; severe stenosis: 23.7% vs 15.9% vs 9.9%, p <0.001). By multivariate analysis, bypass grafting was associated with new native-vessel occlusion for non-LAD (odds ratio 3.04, 95% confidence interval 1.79 to 5.14; p <0.001). Bypass graft was associated with new native-vessel disease progression regardless of baseline stenosis. In conclusion, the decision to bypass or leave a native vessel with intermediate stenosis should cautiously be considered.

Background: Although underweight young women are targets for interventions to prevent low bone mineral density (BMD), the relationship between change in body mass index (BMI) from youth to older age and BMD has not been widely investigated in community dwellers. Methods: In 749 healthy Japanese women aged 40-74 years, BMD was measured by quantitative ultrasound and anthropometric measurements, and BMI was calculated from body weight and height. The BMI of participants at age 20 years was estimated by self-reported body weight and their present height. They were classified into four groups according to the presence of underweight (BMI <18.5 kg/m2) at 20 and/or at present. Logistic regression models were used to estimate multivariate-adjusted odds ratios (ORs) of the presence of underweight at 20 and/or at present for osteopenia (BMD T score <-1 standard deviations) compared with participants with BMI ≥18.5 kg/m2 both at 20 and at present. Results: The participants who were underweight both at 20 and at present had a higher OR for osteopenia compared with those with BMI ≥18.5 kg/m2 at 20 and at present (OR 3.94; 95% confidence interval [CI], 1.97-7.89). Those underweight only at present also had significantly increased OR of developing osteopenia (OR 2.95; 95% CI, 1.67-5.24). The OR of those underweight only at 20 was 0.87 (95% CI, 0.51-1.48). Conclusions: Current underweight was associated with increased risk for osteopenia among Japanese women, especially in those who were underweight both at 20 and at present. To prevent low BMD in the future, maintaining appropriate body weight might be effective for young underweight women.

Aims: There is no community-based cohort study to examine the effect of very high level of highdensity lipoprotein cholesterol (HDL-C) on coronary heart disease (CHD) and other cause-specific mortality. Therefore, we investigated the relationship between HDL-C including very high level and cause-specific mortality in a 20-year cohort study of the representative sample of Japanese. Methods: We followed 7,019 individuals from the Japanese general population (2,946 men and 4,073 women). We defined HDL-C levels as follow: low (HDL-C

Aim: To investigate the relationship between serum uric acid levels and cardiovascular disease in Asians. Methods: We examined the above relationship using the data of Evidence for Cardiovascular Prevention from Observational Cohorts in Japan (EPOCH-JAPAN Study). The data of 36,313 subjects (15,628 men and 20,685 women aged 35 –89 years without histories of stroke, coronary heart disease, or cancer at baseline) were used for the analyses. Sex-specific hazard ratios (HRs) of mortality from cardiovascular disease were estimated according to the quintiles of serum uric acid using Cox hazard models stratified by cohorts. Results: During 441,771 person-years of follow-up, we documented 1,288 cardiovascular deaths. A J-or U-shaped relationship between serum uric acid level and cardiovascular disease mortality was observed. Compared with the lowest quintile of serum uric acid levels, the highest quintile was associated with an increased cardiovascular disease mortality in men [HR: 1.28; 95% confidence interval (CI): 1.01– 1.63] and women (HR: 1.51; 95% CI: 1.14–1.99). However, there was no significant association with mortality from stroke, coronary heart disease or heart failure in both men and women. Conclusion: This large pooled analysis in Japan suggested a J-or U-shaped relationship between serum uric acid levels and cardiovascular mortality. The highest quintile of serum uric acid levels was associated with increased cardiovascular disease mortality in both Japanese men and women.

Low levels of serum high-density lipoprotein cholesterol (HDL-C) have been shown to be associated with increased risk of coronary heart disease (CHD). However, because this is usually observed in the context of other lipid abnormalities, it is not known whether isolated low serum HDL-C levels are an independent risk factor for CHD. We performed a large pooled analysis in Japan using data from nine cohorts with 41,206 participants aged 40–89 years who were free of cardiovascular disease at baseline. We divided participants into three groups: isolated low HDL-C, non-isolated low HDL-C, and normal HDL-C. Cohort-stratified Cox proportional hazards models were used to estimate multivariate-adjusted hazard ratios (HRs) for death due to CHD, ischemic stroke, and intracranial cerebral hemorrhage; during a 12.9-year follow-up, we observed 355, 286, and 138 deaths, respectively, in these groups. Non-isolated low HDL-C was significantly associated with increased risk of CHD compared with normal HDL-C (HR 1.37, 95 % confidence interval (CI) 1.04–1.80); however, isolated low HDL-C was not. Although isolated low HDL-C was significantly associated with decreased risk of CHD (HR 0.51, 95 % CI 0.29–0.89) in women, it was significantly associated with increased risk of intracranial cerebral hemorrhage in all participants (HR 1.62, 95 % CI 1.04–2.53) and in men (HR 2.00, 95 % CI 1.04–3.83). In conclusion, isolated low HDL-C levels are not associated with increased risk of CHD in Japan. CHD risk may, therefore, be more strongly affected by serum total cholesterol levels in this population.

Objective: Physical activity is known to be preventive against various non-communicable diseases. We investigated the relationship between daily physical activity level and plasma metabolites using a targeted metabolomics approach in a population-based study. Methods: A total of 1,193 participants (male, aged 35 to 74 years) with fasting blood samples were selected from the baseline survey of a cohort study. Information on daily total physical activity, classified into four levels by quartile of metabolic equivalent scores, and sedentary behavior, defined as hours of sitting per day, was collected through a self-administered questionnaire. Plasma metabolite concentrations were quantified by capillary electrophoresis mass spectrometry method. We performed linear regression analysis models with multivariable adjustment and corrected p-values for multiple testing in the original population (n = 808). The robustness of the results was confirmed by replication analysis in a separate population (n = 385) created by random allocation. Results: Higher levels of total physical activity were associated with various metabolite concentrations, including lower concentrations of amino acids and their derivatives, and higher concentrations of pipecolate (FDR p <0.05 in original population). The findings persisted after adjustment for age, body mass index, smoking, alcohol intake, and energy intake. Isoleucine, leucine, valine, 4-methyl-2-oxoisopentanoate, 2-oxoisopentanoate, alanine, and proline concentrations were lower with a shorter sitting time. Conclusions: Physical activity is related to various plasma metabolites, including known biomarkers for future insulin resistance or type 2 diabetes. These metabolites might potentially play a key role in the protective effects of higher physical activity and/or less sedentary behavior on non-communicable diseases.

Background: The utility of casual serum triglyceride (TG) as a predictor of type 2 diabetes mellitus (DM) is unclear, especially during the most productive years. Methods: Participants were 3271 workers (913 men and 2358 women, age 20–57) without DM at baseline. They underwent consecutive annual medical check-ups for 8 years. The association between newly diagnosed DM and casual serum TG level was determined by classifying the participants into 4 groups according to casual serum TG level at baseline: below 50 mg/dL (group A), 50–100 mg/dL (group B), 100–150 mg/dL (group C), and ≥150 mg/dL (group D). The effects of casual serum TG level in combination with sex, obesity, or serum glucose level on newly diagnosed DM were also evaluated. Results: A total of 222 newly diagnosed type 2 DM cases with a mean age of 50 years old were observed during the follow-up period, i.e., 10/406 in group A, 66/1534 in group B, 58/712 in group C, and 88/619 in group D. Compared with group A, the odds ratio (ORs) for newly diagnosed DM (after adjusting for DM-associated factors) was found to increase with casual serum TG level: 1.38 (group B), 1.79 (group C), and 2.36 (group D). Moreover, the OR for newly diagnosed DM was higher in participants with high casual serum TG levels who were also male (OR 2.46), obese (OR 4.18), or had a high serum glucose level (OR 6.96) than in the reference group. Conclusions: Serum TG level ≥150 mg/dL when fasting or nonfasting is a significant predictor of type 2 diabetes in middle-aged Japanese workers.

Background and aims The European Society of Cardiology developed prediction models (SCORE) for low- and high-risk populations in the European countries. However, whether or not these models are valid in different ethnicities is unknown. We aimed to evaluate the performance of the low-risk SCORE model in the general Japanese population. Methods Healthy middle-aged Japanese participating in the NIPPON DATA80 cohort had been observed. The predicted 10-year cardiovascular death risk was calculated using the low-risk SCORE model for the overall population as well as for each gender individually. The model performance of the low-risk SCORE model was evaluated with the Harrel's c-statistics for discrimination and the Grønnesby and Borgan goodness-of-fit test for calibration. Results A total of 4842 participants aged 40–64 years old and 47,606 person-years were evaluated in our study. 203 (4.19%) died within the ten-years of follow-up and 44 (0.91%) CV deaths were observed. The low-risk SCORE model in the overall population had reasonable discrimination (c statistics 0.72, 95% CI 0.71–0.73) but poor calibration (R2, 0.67, Chi-square value 6.15, p = 0.01). Discrimination was reasonable in both men (c statistics 0.71, 95% CI 0.69–0.73) and women (c statistics 0.71, 95% CI 0.70–0.73). However, calibration was poor in men (R2, 0.22, Chi-square value 0.749, p = 0.38) compared to women (R2, 0.96, Chi-square value 1.39, p = 0.24). Conclusions Although the low-risk SCORE model performs reasonably well in women, the SCORE models generally overestimated the risk of cardiovascular death risk in the Japanese general population.

Background: The mortality and morbidity associated with acute kidney injury (AKI) remains high, despite advances in interventions. A multifunctional heparin-binding growth factor, midkine (MK), is involved in the pathogenesis of ischemic kidney injury. However, the clinical relevance of MK has not yet been elucidated. The present study investigated whether urinary MK can serve as a novel biomarker of AKI. Methods: We initially compared the predictive value of MK with other urinary biomarkers, including N-acetyl-β-d-glucosaminidase (NAG), interleukin (IL)-18, and neutrophil gelatinase-associated lipocalin (NGAL), for the detection and differential diagnosis of established AKI (549 patients). Subsequently, the reliability of MK for the early detection of AKI was prospectively evaluated in 40 patients undergoing elective abdominal aortic aneurysm surgery. Urine samples were obtained at baseline, the period of aortic cross-clamping and declamping, the end of the surgery, and on post-operative day 1. Results: The areas under the receiver operating characteristic curves for the diagnosis of AKI in various kidney diseases were 0.88, 0.70, 0.72, and 0.84 for MK, NAG, IL-18, and NGAL, respectively. When the optimal cutoff value of urinary MK was set at 11.5 pg/mL, the sensitivity and specificity were 0.87 and 0.85, respectively. In the second study, urinary MK peaked at the period of aortic declamping, about 1 h after cross-clamping in patients with AKI. Interestingly, the rise of MK in AKI patients was very precipitous compared with other biomarker candidates. Conclusion: Urinary MK was prominent in its ability to detect AKI and may allow the start of preemptive medication.

STUDY DESIGN.: A prospective multicenter >10-year cohort study of outpatients with rheumatoid arthritis (RA). OBJECTIVE.: To identify predictive risk factors of cervical spine instabilities which may induce compression myelopathy in RA patients. SUMMARY OF BACKGROUND DATA.: Many reports described the natural course of cervical spine involvement in RA. However, only a few studies conducted comprehensive evaluation of its prognostic factors. METHODS.: Cervical spine instability was radiographically defined as atlantoaxial subluxation (AAS) with the atlantodental interval (ADI) >3?mm, vertical subluxation (VS) with the Ranawat value 10 years. The Cox proportional hazards regression analysis was performed to determine predictors for the development of “severe” instabilities. To exclude biases from the low follow-up rate, similar assessments were performed in 223 patients followed for >5 years from baseline. RESULTS.: The incidence of cervical spine instabilities and “severe” instabilities significantly increased during >10 years in both 143 and 223 cohorts (all P10-year analysis of two different settings.Level of Evidence: 3

Aims: Although previous reports suggest that an elevated endogenous erythropoietin (EPO) level is associated with worse clinical outcomes in chronic heart failure (HF) patients, the prognostic implication of EPO in patients with acute decompensated HF (ADHF) and underlying mechanisms of the high EPO level in severe HF patients who have a poor prognosis remain unclear. Methods and results: We examined 539 consecutive ADHF patients with EPO measurement on admission from our registry. During a median follow-up period of 329 days, a higher EPO level on admission was independently associated with worse clinical outcomes [hazard ratio (HR) 1.25, 95% confidence interval (CI) 1.06–1.48, P = 0.008], and haemoglobin level was the strongest determinant of EPO level (P <0.001), whereas estimated glomerular filtration rate (eGFR) was not significant in multivariate regression analysis. In the anaemic subgroup of 318 patients, a higher EPO level than expected on the basis of their haemoglobin level was related to increased adverse events (HR 1.63, 95% CI 1.05–2.49, P = 0.028). Moreover, estimated plasma volume excess rate was positively associated with EPO level (P = 0.003), and anaemic patients with a higher than expected EPO level tended to have a higher estimated plasma volume excess rate and plasma lactate level, and lower systemic oxygen saturation level with the preservation of the reticulocyte production index than those with a lower than expected EPO level. Conclusion: A high EPO level predicts long-term worse clinical outcomes in ADHF patients, independent of anaemia and impaired renal function. Anaemia and hypoxia due to severe congestion may synergistically contribute to a high EPO level in high-risk HF patients.

Aims The long-term prognostic effect of non-specific 12-lead electrocardiogram findings is unknown. We aimed to evaluate the cumulative prognostic impact of axial, structural, and repolarization categorical abnormalities on cardiovascular death, independent from traditional risk scoring systems such as the Framingham risk score and the NIPPON DATA80 risk chart. Methods and Results A total of 16,816 healthy men and women from two prospective, longitudinal cohort studies were evaluated. 3,794 (22.6%) individuals died during a median follow-up of 15 years (range, 2.0-24 years). Hazard ratios for cardiovascular death, all-cause death, coronary death and stroke death were calculated for the cumulative and independent axial, structural, and repolarization categorical abnormalities adjusted for the Framingham risk score and the NIPPON DATA80 risk chart. Individuals with two or more abnormal categories had a higher risk of cardiovascular death after adjustment for Framingham risk score (men: HR 4.27, 95%CI 3.35-5.45; women: HR 4.83, 95%CI 3.76-6.22) and NIPPON DATA80 risk chart (men: HR 2.39, 95%CI 1.87-3.07; women: HR 2.04, 95%CI 1.58-2.64). Conclusion Cumulative findings of axial, structural, and repolarization abnormalities are significant predictors of long-term cardiovascular death in asymptomatic, healthy individuals independent of traditional risk stratification systems.

Background: Several studies have revealed that glucose fluctuations provoke oxidative stress that leads to endothelial cell dysfunction, progression of coronary atherosclerosis, and plaque vulnerability. However, little is known regarding their effect on neointimal growth after stenting in patients with coronary artery disease (CAD). We aimed to investigate the effects of glucose fluctuations on neointimal growth after everolimus-eluting stent (EES) implantation. Methods: This study examined 50 patients who underwent a 9-month follow-up using optical coherence tomography (OCT) after EES implantation. Glucose fluctuation was expressed as the mean amplitude of glycemic excursion (MAGE), and was determined via continuous glucose monitoring before stenting. At the OCT follow-up, we evaluated the percentage of uncovered struts and three-dimensional uniformity of neointimal distribution by calculating the mean neointimal thickness (NIT) within 360 equally-spaced radial sectors for every 1-mm cross-sectional OCT analysis, and assessed the incidence of major adverse cardiovascular events (MACE). Results: We evaluated 60 lesions in 50 patients. Linear mixed effect models were used to explore the influence of different variables on variability in NIT and the percentage of uncovered struts and to adjust for covariates. Univariate analysis showed that MAGE was most strongly correlated with the previously mentioned OCT measurements (coefficient β±standard error=0.267±0.073 and 0.016±0.003, t=3.668 and 6.092, both P<0.001, respectively). In multivariate analysis, MAGE had the strongest effect on variability in NIT (coefficient β±standard error=0.239±0.093, P=0.014) and the percentage of uncovered struts (coefficient β±standard error=0.019±0.004, P<0.001). Five lesions in four patients required target lesion revascularization (10.0%) at a mean duration of 9months after EES implantation. Compared to non-MACE cases, cases of MACE exhibited a significantly higher MAGE (99vs.68; P=0.004), maximum NIT (580vs. 330μm; P=0.002), and variability in NIT (100vs.65; P=0.007), although there was no significant difference in these groups' HbA1c levels. Conclusions: Glucose fluctuation may affect vessel healing after EES implantation in patients with CAD who are receiving lipid-lowering therapy. Therefore, glucose fluctuations may be an important target for secondary prevention after coronary stenting, which is independent of dyslipidemia control.

OBJECTIVE:: The aim of the study was to investigate the associations of amino acids and other polar metabolites with metabolic syndrome (MetS) in postmenopausal women in a lean Asian population. METHODS:: The participants were 1,422 female residents enrolled in a cohort study from April to August 2012. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III modified for Japanese women. Associations were examined between MetS and 78 metabolites assayed in fasting plasma samples using capillary electrophoresis-mass spectrometry. Replication analysis was performed to confirm the robustness of the results in a separate population created by random allocation. RESULTS:: Analysis was performed for 877 naturally postmenopausal women, including 594 in the original population and 283 in the replication population. The average age, body mass index, and levels of high- and low-density lipoprotein cholesterol of the entire population were 64.6 years, 23.0?kg/m, 72.1?mg/dL, and 126.1?mg/dL, respectively. There was no significant difference in low-density lipoprotein cholesterol levels between women with and without MetS. Thirteen metabolites were significantly related to MetS: multiple plasma amino acids were elevated in women with MetS, including branched-chain amino acids, alanine, glutamate, and proline; and alpha-aminoadipate, which is generated by lysine degradation, was also significantly increased. CONCLUSIONS:: Our large-scale metabolomic profiling indicates that Japanese postmenopausal women with MetS have abnormal polar metabolites, suggesting altered catabolic pathways. These results may help to understand metabolic disturbance, including in persons with normal body mass index and relatively high levels of high-density lipoprotein cholesterol, and may have clinical utility based on further studies.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0

Aim: The Japan Atherosclerosis Society (JAS) Guidelines for Diagnosis and Prevention of Atherosclerotic Cardiovascular Diseases for Japanese 2012 version have set a non-high-density lipoprotein cholesterol (non-HDL-C)-management target of low-density lipoprotein cholesterol (LDL-C) + 30 mg/ dL. However, the actual difference between non-HDL-C and LDL-C is not clear. Therefore, we evaluated its joint distribution and assessed the validity of this criterion in the general Japanese population. Methods: We used baseline cross-sectional data of 4,110 participants from two studies; the KOBE Study (n=1,108) and the Tsuruoka Metabolomic Cohort Study (n= 3,002). To evaluate whether the difference between LDL-C and non-HDL-C in the general population match that of the current guidelines, we classified LDL-C levels into four groups according to the JAS Guideline and evaluated its agreement with the corresponding non-HDL-C group. Analysis was also done using six groups (the previous four groups plus the upper and lower cut-off values). Results: The mean difference (mg/dL) between the non-HDL-C and LDL-C (for the KOBE Study and Tsuruoka Metabolomic Cohort Study, respectively) was 19.6 and 24.1 (p <0.001) for men and 15.9 and 18.3 (p <0.001) for women. In both the cohort studies, the difference was lower than 30 mg/dL. It was especially small among individuals with normal triglyceride levels. Conclusions: In the general Japanese population, the difference between non-HDL-C and LDL-C was lower than the expected difference of 30 mg/dL. Changes to the criteria for non-HDL-C target levels may be considered in the future.

Although numerous studies have shown that each neuropsychological test is effective for diagnosing mild cognitive impairment (MCI) or Alzheimer’s disease (AD), studies comparing diagnostic accuracies of various neuropsychological tests are relatively rare and practical cutoff values are not available. The present study aimed to investigate the validity of neuropsychological tests and develop cutoff values for each in differentiating healthy control (HC), MCI and AD groups. A total of 84 HC, 187 with MCI and 195 with AD were evaluated by the selected seven neuropsychological tests using receiver operating characteristic (ROC) curve analysis. Logical Memory (LM) delayed recall (cutoff, 7) and Rey Auditory Verbal Learning Test (RAVLT) delayed recall (cutoff, 6) were effective for differentiating HC from MCI. To distinguish MCI and AD, Rey Osterrieth Complex Figure Test (ROCFT) 3 mindelayed recall (cutoff, 6) and LM immediate recall (cutoff, 4) were excellent. Delayed recall of verbal materials, as indexed by LM and RAVLT was sensitive for discriminating MCI from HC. Handling visual memory traces, as indexed by ROCFT and immediate verbal information by LM were sensitive for differentiating MCI and AD.