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Alzheimer's disease (AD) is a progressive, degenerative brain disorder that impairs memory and thinking skills, leading to significant economic and humanistic burdens. It is associated with various neuropsychiatric symptoms (NPS) such as anxiety, agitation, depression, aggression, apathy, and psychosis. NPSs are common in patients with AD, affecting up to 97% of individuals diagnosed with AD. The severity of NPS is linked to disease progression and cognitive decline. NPS in Alzheimer's disease leads to increased morbidity, mortality, caregiver burden, earlier nursing home placement, and higher healthcare costs. Despite their significant impact, clinical research on NPS in AD is limited. In clinical settings, accurately distinguishing and diagnosing NPS related to AD remains a challenge. Additionally, conventional treatments for NPS in AD are often ineffective, highlighting the need for new therapies that target these specific symptoms. Understanding these comorbidities can aid in early diagnosis and better management of AD. In this review, we provide a summary of the various neurological and psychiatric symptoms (NPS) associated with AD and new candidates under development for the treatment of NPS based on their therapeutic targets and mechanisms. On top of the conventional NPS studied so far, this review adds recent advancements in the understanding of social functional impairment in AD. This review also provides information that can contribute to the advancement of studies and translational research in this field by emphasizing therapeutic targets and mechanisms of action focused on AD-related NPS rather than conventional mechanisms targeted in AD drug development. Above all, considering the relative lack of research in this new field despite the importance of clinical, medical, and translational research, it may increase interest in NPS in AD, its pathophysiological mechanisms, and potential therapeutic candidates such as molecules with antioxidant potential.

The blood-brain barrier (BBB) breakdown has been suggested as an early marker for Alzheimer's disease (AD); yet the relationship between BBB breakdown and AD-specific biomarkers based on the amyloid/tau/neurodegeneration framework is not clear. This study investigated the relationship between BBB permeability, AD-specific biomarkers, and cognition in patients with cognitive impairment. In this prospective study, we enrolled 62 participants with mild cognitive impairment or dementia between January 2019 and October 2020. All participants were assessed through cognitive tests, amyloid positron emission tomography (PET), dynamic contrast-enhanced magnetic resonance imaging (MRI) for BBB permeability (K trans ), cerebrospinal fluid studies for Aβ42/40 ratio, phosphorylated-tau Thr181 protein (p-tau), total tau protein (t-tau), and structural MRI for neurodegeneration. In amyloid PET (+) group, higher cortical K trans was associated with lower Aβ40 (r = -0.529 p =  0.003), higher Aβ42/40 ratio (r = 0.533, p =  0.003), lower p-tau (r = -0.452, p =  0.014) and lower hippocampal volume (r = -0.438, p =  0.017). In contrast, cortical K trans was positively related to t-tau level. (r = 0.489, p =  0.004) in amyloid PET (-) group. Our results suggest that BBB permeability is related to AD-specific biomarkers, but the relationship can vary by the presence of Aβ plaque accumulation., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Preclinical studies in transgenic models of Alzheimer's disease (AD) suggest that DHP1401 has neuroprotective and memory-enhancing effects., Objective: To evaluate the efficacy and safety of DHP1401 in AD patients treated with donepezilMethods:Methods: In a double-blind study, patients with mild-to-moderate AD were randomized (1:1:1) to receive a twice daily total dose of 500 mg or 1000 mg DHP1401 or placebo for 24 weeks. Tolerability and safety were monitored at baseline and weeks 12 and 24., Results: total of 180 patients were randomized to Active 1 (500 mg: n = 62), Active 2 (1000 mg: n = 53), and control groups (n = 65) in 16 sites in Korea. There was no significant difference in the Alzheimer's Disease Assessment Scale (ADAS-cog) score, the primary efficacy endpoint, from baseline. However, in the subgroup with mild AD patients (MMSE, 20-26) who received the high dose of DHP1401 and the group that received donepezil 5 mg, the ADAS-cog scores improved. MMSE and K-TMT-e type B were significant in both active groups at week 24. The most frequently observed symptom was dizziness (2.78%), and the most commonly observed reactions were related to metabolism and nutrition disorders (5.00%). No remarkable adverse events were observed for 24 weeks., Conclusion: Although the effectiveness of DHP1401 was not proved to be superior as the primary efficacy endpoint, the secondary endpoints, MMSE and K-TMT-e type B, showed significant beneficial effects. Also, the subgroups showed that ADAS-cog scores significantly were improved. DHP1401 could be proven beneficial for the AD treatment by further clinical trials.

Backgound: Central obesity in midlife is a risk factor of cognitive decline and dementia, and also one of the factors that make cognitive functions deteriorate rapidly., Objective: The objective of this study is to investigate the relationship between truncal body composition (fat and muscle) and cognitive impairment in patients with dementia., Methods: A total of 81 female over 60 years of age with probable Alzheimer's disease were recruited between November 2014 and September 2015. The Mini-Mental State Examination, Global Deterioration Scale, and Clinical Dementia Rating Scale were used to assess the cognitive functions. Both truncal fat and muscle mass were measured using body dual-energy X-ray absorptiometry and used as a percentage of body weight (TMM% and TFM%). Correlations between truncal composition and cognitive status were assessed by simple correlation analysis, which was followed by partial correlation analysis with age and educational years., Results: TFM% was not related to cognitive impairment. In contrast, TMM% had a significantly negative correlation with all three cognitive assessment scores. After further adjusting for age, educational years, and vascular factors, there was still a relationship between TMM% and cognitive functions., Conclusions: Unlike truncal fat mass that showed no relevance with cognitive functions, the truncal muscle mass was negatively correlated with cognitive status. The truncal muscle mass is thought to affect cognitive status in dementia patients somehow.

Air pollution has become one of the most serious issues for human health and has been shown to be particularly concerning for neural and cognitive health. Recent studies suggest that fine particulate matter of less than 2.5 (PM2.5), common in air pollution, can reach the brain, potentially resulting in the development and acceleration of various neurological disorders including Alzheimer's disease, Parkinson's disease, and other forms of dementia, but the underlying pathological mechanisms are not clear. Astaxanthin is a red-colored phytonutrient carotenoid that has been known for anti-inflammatory and neuroprotective effects. In this study, we demonstrated that exposure to PM2.5 increases the neuroinflammation, the expression of proinflammatory M1, and disease-associated microglia (DAM) signature markers in microglial cells, and that treatment with astaxanthin can prevent the neurotoxic effects of this exposure through anti-inflammatory properties. Diesel particulate matter (Sigma-Aldrich) was used as a fine particulate matter 2.5 in the present study. Cultured rat glial cells and BV-2 microglial cells were treated with various concentrations of PM2.5, and then the expression of various inflammatory mediators and signaling pathways were measured using qRT-PCR and Western blot. Astaxanthin was then added and assayed as above to evaluate its effects on microglial changes, inflammation, and toxicity induced by PM2.5. PM2.5 increased the production of nitric oxide and reactive oxygen species and upregulated the transcription of various proinflammatory markers including Interleukin-1β (IL-1β), Interleukin-6 (IL-6), Tumor necrosis factor α (TNFα), inducible nitric oxide synthase (iNOS), triggering receptor expressed on myeloid cells 2 (TREM2), Toll-like receptor 2/4 (TLR2/4), and cyclooxygenase-2 (COX-2) in BV-2 microglial cells. However, the mRNA expression of IL-10 and arginase-1 decreased following PM2.5 treatment. PM2.5 treatment increased c-Jun N-terminal kinases (JNK) phosphorylation and decreased Akt phosphorylation. Astaxanthin attenuated these PM2.5-induced responses, reducing transcription of the proinflammatory markers iNOS and heme oxygenase-1 (HO-1), which prevented neuronal cell death. Our results indicate that PM2.5 exposure reformulates microglia via proinflammatory M1 and DAM phenotype, leading to neurotoxicity, and the fact that astaxanthin treatment can prevent neurotoxicity by inhibiting transition to the proinflammatory M1 and DAM phenotypes. These results demonstrate that PM2.5 exposure can induce brain damage through the change of proinflammatory M1 and DAM signatures in the microglial cells, as well as the fact that astaxanthin can have a potential beneficial effect on PM2.5 exposure of the brain.

Background: Neuropsychological tests (NPTs) are important tools for informing diagnoses of cognitive impairment (CI). However, interpreting NPTs requires specialists and is thus time-consuming. To streamline the application of NPTs in clinical settings, we developed and evaluated the accuracy of a machine learning algorithm using multi-center NPT data., Methods: Multi-center data were obtained from 14,926 formal neuropsychological assessments (Seoul Neuropsychological Screening Battery), which were classified into normal cognition (NC), mild cognitive impairment (MCI) and Alzheimer's disease dementia (ADD). We trained a machine learning model with artificial neural network algorithm using TensorFlow (https://www.tensorflow.org) to distinguish cognitive state with the 46-variable data and measured prediction accuracies from 10 randomly selected datasets. The features of the NPT were listed in order of their contribution to the outcome using Recursive Feature Elimination., Results: The ten times mean accuracies of identifying CI (MCI and ADD) achieved by 96.66 ± 0.52% of the balanced dataset and 97.23 ± 0.32% of the clinic-based dataset, and the accuracies for predicting cognitive states (NC, MCI or ADD) were 95.49 ± 0.53 and 96.34 ± 1.03%. The sensitivity to the detection CI and MCI in the balanced dataset were 96.0 and 96.0%, and the specificity were 96.8 and 97.4%, respectively. The 'time orientation' and '3-word recall' score of MMSE were highly ranked features in predicting CI and cognitive state. The twelve features reduced from 46 variable of NPTs with age and education had contributed to more than 90% accuracy in predicting cognitive impairment., Conclusions: The machine learning algorithm for NPTs has suggested potential use as a reference in differentiating cognitive impairment in the clinical setting.

Purpose: To assess the prevalence and characteristics of motor cortex hypointensity on 3-T susceptibility-weighted imaging (SWI) in patients with cognitive impairment and examine its clinical significance., Methods: The institutional review board approved this retrospective study and waived the requirement for informed consent. A total of 127 patients with a clinical diagnosis of probable Alzheimer's disease (AD) (n = 32) or mild cognitive impairment (MCI) (n = 95) and 127 age- and sex-matched control subjects underwent 3-T brain magnetic resonance imaging. SWI was analyzed for both subjective visual scoring and the quantitative estimation of phase shift in the posterior bank of the motor cortex. A multivariate logistic regression analysis was performed to identify clinical and imaging variables associated with motor cortex hypointensity on SWI., Results: Motor cortex hypointensity on SWI was observed in 94/127 cognitively impaired patients (74.0%) and 72/127 control subjects (56.7%) (p = 0.004). Age was the only variable that was significantly associated with motor cortex hypointensity in patients with cognitive impairment (odds ratio, 1.15; 95% confidence interval, 1.065-1.242; p < 0.001). The quantitative analysis confirmed a significant increase in phase shifting in the posterior bank of the motor cortex in patients with positive motor cortex hypointensity on SWI (p < 0.001)., Conclusion: Motor cortex hypointensity on SWI was more frequently found in patients with cognitive impairment than in age-matched controls and was positively associated with age. Thus, it may be a potential imaging marker of iron accumulation in patients with MCI or AD.

Introduction: Many factors are known to affect the rate of cognitive decline; however, studies on clinical outcomes are rare. Muscle profile and their relationship to dementia trajectories have not been extensively investigated. We investigated factors that affect the rate of clinical decline and the usefulness of muscle profiles for predicting the clinical outcomes of patients with Alzheimer's dementia (AD)., Objective: Sixty-nine subjects with probable AD were included and several factors that are known to affect the rate of cognitive decline were evaluated., Methods: Over a period of 3 years, each subject received an annual evaluation that included a clinical interview and an assessment of their cognitive status as measured by a clinical dementia rating-sum of boxes (CDR-SOB) score. Linear mixed-effects models were used to test for associations between each factor and the -CDR-SOB score over time. These analyses were repeated in a multivariate linear mixed-effects model after adjusting the covariates., Results: Age, diabetes mellitus, and baseline dementia severity were identified as potential covariates that influence clinical progression. However, a subject's muscle profile was not found to predict dementia progression., Conclusions: We expect that early screening and intervention, as well as new drugs with mechanisms of action similar to those of antidiabetic medications, will help patients with dementia maintain their clinical status., (© 2019 S. Karger AG, Basel.)

Background/aims: Alzheimer's disease (AD) is the most common cause of dementia worldwide. Interestingly, muscle mass (MM) and muscle strength (MS) are related to AD. In addition to the muscle profile, brain atrophy is also a prominent feature of AD. There is substantial evidence showing an association between muscle profile and dementia, but the role of the muscle profile and cerebral cortical atrophy within this association is less well understood. The objective of this study was to determine if there is any association between muscle profile and brain regional volume in AD. A secondary objective was to determine whether this relationship continues as the clinical stage of AD progresses., Methods: We recruited 28 patients with probable AD without weakness. We assessed the patients' basic demographic characteristics, Mini-Mental State Examination score, and brain magnetic resonance images. MM was measured using body dual-energy X-ray absorptiometry. MS was assessed in Nm/kg with an isokinetic knee extensor using an isokinetic device at an angular velocity of 60°/s. An automatic analysis program was used for brain regional volumetric measurements. Dementia was divided into two stages: mild and moderate., Results: MS was related to left hippocampal volume ratio. After adjusting for age and cognitive status, the relationship remained. MS did not demonstrate any relationship to any brain regional volume ratio in the mild stage; however, in the moderate stage, it was positively related to both the right and the left hippocampal volume ratio., Conclusions: Our findings imply a shared underlying pathology relating MS and brain volume and suggest cognitive functional declines through the muscle-brain axis. Further longitudinal studies are needed to find possible and related causes of reduced MS and cortical atrophy in patients with dementia., (© 2019 S. Karger AG, Basel.)

Introduction: Neurodegenerative disease is one of the main contributing factors affecting muscle atrophy. However, this intriguing brain-muscle axis has been explained by the unsubstantial mechanisms. Although there have been several studies that have evaluated the muscle profile and its relation to cognition in patients with dementia, there is still lack of data using standardized methods and only few published studies on Korean populations. The objective of this study is to evaluate the relationship of muscle mass and strength to cognition in patients with Alzheimer's disease dementia (AD)., Methods: We recruited 91 patients with probable AD without weakness. We assessed patients' basic demographic characteristics, vascular risk, body mass index, and global cognitive assessment scores. Muscle mass was measured using body dual-energy X-ray absorptiometry. Muscle strength was assessed by isokinetic knee extensor using an isokinetic device at an angular velocity of 60°/s in nm/kg., Results: The muscle mass and strength were not related to each other in both male and female groups. Only muscle strength, but not muscle mass, was negatively related to cognition. After adjusting for covariates, the relationship between muscle strength and cognition still remained in the male group, however, was attenuated in the female group., Conclusions: In patients with AD dementia, abundant muscle mass did not mean strong power. The simple lower-extremity muscle strength assessment is more effective in predicting cognition than a muscle mass measure in male patients.

Objective: The purpose of this study was to compare the diagnostic efficacies of an automated volumetric assessment tool and visual assessment in the evaluation of medial temporal lobar atrophy in mild-to-moderate Alzheimer disease (AD)., Materials and Methods: This retrospective study included 30 patients with mild-to-moderate AD and 25 age-matched healthy control subjects undergoing MRI with a 3D fast spoiled gradient recalled-echo sequence at 3 T. The images were processed with fully automated volumetric analysis software. To assess medial temporal lobe (MTL) atrophy, two MTL indexes, which took into account the volumes of the hippocampus and the inferior lateral ventricle, were calculated with the automated volumetric assessment software. In addition, two neuroradiologists assessed MTL atrophy visually using the Scheltens scale. ROC curve analysis was used to compare the diagnostic performances of the two methods. The weighted kappa statistic was used to assess the intrarater and interrater reliability of visual inspection., Results: The automated volumetric assessment tool had moderate sensitivity (63.3%) and high specificity (100%) in differentiating patients with mild-to-moderate AD from control subjects. Visual inspection showed sensitivity of 63.3% and specificity of 92.0%. The diagnostic performance was not significantly different between the two methods (p = 0.536-0.906). Intraobserver reliability for visual inspection was 0.858 and 0.902 for the two reviewers, and interobserver reliability was 0.692-0.780., Conclusion: Both the automated volumetric assessment tool and visual inspection can be used to evaluate MTL atrophy and differentiate patients with AD from healthy individuals with good diagnostic accuracy. Thus, the automated tool can be a useful and efficient adjunct in clinical practice for evaluating MTL atrophy in the diagnosis of AD.

High occupational attainment has been known as a marker of cognitive reserve. Previous studies in the general population have shown that high occupational attainment is associated with reduced risk of Alzheimer's disease (AD). However, few studies have assessed the effect of occupational attainment on the clinical course of mild cognitive impairment (MCI). In this study, we evaluated whether individuals with high occupational attainment show more frequent progression from MCI to AD. Participants (n = 961) with MCI were recruited from a nationwide, hospital-based multi-center cohort, and were followed for up to 60 months (median: 17.64, interquartile range [12.36, 29.28]). We used Cox regression for competing risks to analyze the effect of occupational attainment on development of AD, treating dementia other than AD as a competing risk. Among the 961 individuals with MCI, a total of 280 (29.1%) converted to dementia during the follow-up period. The risk of progression to AD was higher in the individuals with high occupational attainment after controlling for potential confounders (hazard ratio = 1.83, 95% confidence interval = 1.25-2.69, p = 0.002). High occupational attainment in individuals with MCI is an independent risk factor for higher progression rate of MCI to AD. This result suggests that the protective effect of high occupational attainment against cognitive decline disappears in the MCI stage, and that careful assessment of occupational history can yield important clinical information for prognosis in individuals with MCI.

The Lewy body composite risk score (LBCRS) is a useful clinical screening tool to help determine whether the dementia is related to Lewy body pathology. The purpose of this study is to verify reliability, validity, and diagnostic usefulness of Korean version of LBCRS (K-LBCRS). CDR-sum of boxes, Mini-Mental State Examination, and standardized scales related to cognition, mood, behavior, and motor function were administered to a total of 107 subjects, including 30 dementia with Lewy bodies (DLB), 54 Alzheimer's disease (AD), and 23 cognitively normal elderly people and their collateral informants. Internal consistency of the K-LBCRS was good with Cronbach's alpha of 0.85, and concurrent validity was also satisfactory, with K-LBCRS correlating highly with CDR-SB and other scales. The test-retest reliability was very high with a Pearson correlation coefficient of 0.97. The mean scores of K-LBCRS were significantly different among three groups, with DLB (6.2±2.4), AD (1.4±1.3), and controls (0.3±0.6). We identified a cut-off score of 3 as best to differentiate between DLB and AD, having AUC of 0.97 (95% CI 0.94-1.00), sensitivity 97%, specificity 83%, positive predictive value 76%, negative predictive value 98%, which is the same score suggested in the original study. This study shows K-LBCRS as a new useful screening tool for Korean DLB patients in clinical settings.

Objects: We designed this study to extensively compare the neuropsychological profiles of Alzheimer's disease (AD) and mixed dementia (MD) in a large multicenter cohort of patients. Specifically, we performed subgroup analyses to examine group differences associated with dementia severity., Methods: A total of 1021 AD patients and 577 MD patients were included from the Clinical Research Center for Dementia of South Korea (CREDOS) Study. All patients underwent comprehensive neuropsychological and functional ratings, as well as complete physical and neurological examinations. To avoid floor confounds, only patients with Clinical Dementia Rating (CDR) scores of 0.5-2.0 were included., Results: Overall, MD patients showed worse performance in frontal/executive function than those with AD. Stratification by dementia severity revealed a significant difference in global cognitive function scores between AD and MD patients only in the low severity groups (CDR 0.5). Also, MD patients showed worse performance in frontal/executive function domains in the CDR 0.5 groups whereas they had better performance in the memory domain in the CDR 1 groups than did AD patients. Additionally, AD patients showed better performance than MD patients with respect to activities of daily living at CDR levels 0.5 and 1. All differences had disappeared at the CDR 2 level of global dementia severity., Conclusion: This study suggests that there are significant differences in neuropsychological profiles between AD and MD patients, with the pattern of this difference varying distinctively according to dementia severity., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Although previous studies have suggested that neuronal nitric oxide synthase (nNOS)-derived NO has neuroprotective effects on the development of Alzheimer's disease (AD), the underlying molecular mechanisms are not fully elucidated. Here, we investigated whether and how disruption of nNOS dimerization contributes to the development of AD. No differences in synaptic number or expression of synaptic markers, including synaptophysin and postsynaptic density 95, were found in the cortex of 5 × FAD mice, which possess 5 familial AD mutations, at 6 months of age compared with control littermates. nNOS dimerization was disrupted in the 5 × FAD cortex, accompanied by an increase in reactive oxygen species (ROS) production. The subcellular distribution of cyclin-dependent kinase 5 (CDK5) shifted more diffusely toward a cytosolic compartment, but there was no change in total expression. Furthermore, the levels of p25, a CDK5 activator, increased significantly and it colocalized with nNOS in the 5 × FAD cortex. In silico analysis revealed that a new nNOS-specific GSP (glycine-serine-proline) motif was well-conserved across species at nNOS-Ser(293), which is located ahead of the N-terminal hook. This motif was not present in the closely related isoform, endothelial NOS. Motif scan analysis also predicted that CDK5 can phosphorylate nNOS-Ser(293) with a high likelihood. An in vitro phosphorylation assay clearly showed that CDK5/p25 does indeed phosphorylate nNOS-Ser(293). Finally, nNOS-S293D mutant, a phosphomimetic form of nNOS-Ser(293), and nNOS-S293A mutant, a neutral form of nNOS-Ser(293), significantly decreased nNOS dimerization and NO production. Taken together, our results demonstrate that nNOS dimers are disrupted in the 5 × FAD cortex, and nNOS-Ser(293), a potential site of CDK5 phosphorylation, may be involved in the decrease in nNOS dimerization and NO production, and the development of AD., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: Extrapyramidal signs (EPS), commonly observed in Alzheimer disease (AD), predict cognitive impairment and functional decline. This study investigated the association between EPS and five cognitive subdomains in a large number of participants with AD., Design: Cross-sectional analyses of the nationwide Clinical Research of Dementia of South Korea (CREDOS) study, 2005-2012., Setting: Multicenter clinical settings., Participants: 1,737 participants with AD drawn from the CREDOS study., Measurements: The EPS group was defined by the presence of at least one EPS based on neurologic examination. We assessed five cognitive subdomains: attention, language, visuospatial function, memory, and frontal/executive function using the Seoul Neuropsychological Screening Battery-Dementia version. The associations of EPS with each cognitive subdomain were analyzed with a multiple linear regression model after controlling for confounding factors: sex, age, years of education, severity of dementia (Clinical Dementia Rating Sum of Boxes), and white matter hyperintensities., Results: 164 AD participants (9.4%) had EPS. AD participants with EPS showed lower performance compared with those without EPS in two cognitive subdomains: attention and visuospatial function. The language, memory, and frontal/executive subdomains did not differ between the EPS-positive and the EPS-negative groups. In addition, we found a significant moderating relationship between EPS and deep white matter hyperintensities on visuospatial function score., Conclusions: EPS in AD are associated with severe cognitive impairment in attention and visuospatial function. Careful screening for EPS in patients with AD may assist in prediction of cognitive profile., (Copyright © 2016 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Emerging evidence suggests that the excessive accumulation of iron in subcortical and deep gray matter has been related to dementia. However, the presence and pattern of iron accumulation in vascular dementia (VaD) and Alzheimer's disease (AD) are rarely investigated., Objective: To examine and compare the pattern and presence of brain iron accumulation of VaD and AD using quantitative susceptibility mapping (QSM)., Materials and Methods: Twelve patients with VaD, 27 patients with AD, and 18 control subjects were recruited in this institutional review-board approved study. Susceptibility maps were reconstructed from a three-dimensional multiecho spoiled gradient-echo sequence. Four regions of interest were drawn manually on QSM images, namely the globus pallidus, putamen, caudate nucleus, and pulvinar nucleus of the thalamus. Comparisons of patient demographics, and iron concentrations among the VaD, AD, and control subjects were assessed using analysis of variance and post-hoc analyses. The relationships of age and cognitive state with susceptibility values were assessed using partial correlation analysis., Results: In VaD and AD, overall susceptibility values were higher than those of control subjects. A significant difference in susceptibility values was found in the putamen and caudate nucleus (p <  0.001 and p = 0.002, respectively). However, susceptibility values did not differ between VaD and AD. Age and cognitive deficit severity were not related to susceptibility values in the VaD and AD groups., Conclusion: Increased iron deposition in the putamen and caudate nucleus in VaD and AD patients was not associated with age or the severity of cognitive deficits. Further evaluations are needed to determine the temporal changes in iron load and their diagnostic role in dementia pathology.

The insular cortex is associated with neuropsychiatric symptoms, changes in cardiovascular and autonomic control, and mortality in Alzheimer's dementia. However, the insular cortex does not provide information on the contribution of the other cortices to cognitive decline. We hypothesized that the factors that affect to atrophy in insular cortex are different from other cortical regions. A total of 42 patients with probable Alzheimer's dementia were included in the analyses. The manual drawing of regions of interest was used to detect insular cortex located in the deep gray matter and to avoid coatrophy. Covariates, which could affect to the atrophy of the cerebral cortex, were selected based on previous studies. Any of the demographic factors, vascular risk factors, and the severity scales of dementia was not associated with any insular volume ratio. We suggest that the pathomechanisms of atrophy in insular cortex are different from those of other cortex regions in Alzheimer's disease., (© The Author(s) 2015.)

Background & Objective: Early-onset Alzheimer's disease (EOAD, onset age < 65 years) may differ from late-onset Alzheimer's disease (LOAD) in terms of cognitive profiles and neuropsychiatric symptoms. There have been few studies for Korean EOAD patients using well-structured databases. Previous studies focusing on cognitive profiles between the two groups had a variety of demographic data and comparability. The purpose of this study was to identify the unique profiles of cognitive functions and neuropsychiatric symptoms in Korean EOAD patients that differentiate from LOAD., Methods: Through propensity score matching, a total of 435 patients with EOAD and a total of 435 patients with LOAD were included in this nationwide, multicenter, hospital-based study. Each patient underwent comprehensive neurological examination, interview for caregiver, neuropsychological tests, and brain magnetic resonance imaging., Results: Neuropsychological test results showed worse performances on frontal/executive functions, visuospatial function, and visual memory in EOAD patients as compared to LOAD patients. In terms of neuropsychiatric symptoms, apathy was more common in EOAD patients, while delusions were more prevalent in LOAD patients. The differences in neuropsychiatric symptoms between the two groups were most pronounced in patients with the APOE ε4 allele, suggesting that neuropsychiatric symptoms in AD may be influenced by the APOE genotype., Conclusion: Our results suggested that EOAD may be an important phenotype, fronto-parietal dysfunction, in the spectrum of AD, and this finding can provide for early diagnosis of EOAD patients.

Alzheimer's disease (AD) is the leading cause of dementia, and the most prevalent neurodegenerative disease in the elderly. The prevalence of AD is predicted to rise as life expectancy grows across populations. The exact cause of this devastating disease is still unknown; however, it is an aging-related multi-factorial disorder, and growing evidence supports the contribution of modifiable environmental factors to unmodifiable factors such as gene and ageing itself. The recent advancement of methodologies and techniques for early diagnosis of AD facilitates the investigation of strategies to reduce the risk for AD progression in the earliest stages of the disease. Pharmacological attempts at curing, halting or modifying it have, by and large, been unsuccessful, and no breakthrough is seen in the near future. However, a lot of elements that seem to contribute to the disease such as risk factors have been identified, mainly from epidemiological and basic research studies. Many of these are amenable to lifestyle modification. Therefore, prevention in the preclinical stage is likely the most effective way to decrease the incidence of this age-associated dreadful neurodegenerative condition, and its associated burden for individuals and society. We provide an overview of modifiable risk factors for AD along with the supporting evidence.

Introduction: The purpose of this study is to determine whether vascular risk factors are associated with severity of neuropsychiatric symptoms (NPS) in patients of Alzheimer's dementia., Methods: We reviewed medical records of 162 patients with Alzheimer's dementia. The NPS were assessed using the Neuropsychiatric Inventory (NPI). Hypertension and cardiovascular events were detected through detailed history taking. Diabetes mellitus and hyperlipidemia were uncovered through laboratory test. The asymptomatic stroke and white matter hyperintensities (WMH) were defined by magnetic resonance imaging. Partial correlation analysis was used., Results: Hypertension was correlated with the severity of apathy (r = 0.231, p = 0.015). The asymptomatic stroke was related to the severity of depression (r = 0.255, p = 0.007). The remaining vascular factors were not significant., Conclusion: Presence of hypertension and asymptomatic stroke are related with the severity of apathy and depression in Alzheimer's dementia.

Our study aimed to compare cognitive status and declines in AD with/without small vessel disease (SVD) and SIVD at baseline and 1-year follow-up. Patients with Alzheimer's disease without small vessel disease (AD(-)SVD) (n=148), Alzheimer's disease with small vessel disease (AD(+)SVD) (n=94) and SIVD (n=60) were recruited from database of multiple centers in Korea. Basic demographics and detailed neuropsychological results were compared. AD, regardless of SVD, showed worse memory and better executive function than SIVD at baseline. Mini-Mental State Examination scores and visual memory function declined more in AD than those in SIVD whereas Barthel Activities of Daily Living (B-ADL) scores declined more in SIVD. AD showed different patterns of cognitive impairment compared with SIVD. After 1 year, AD showed more rapid cognitive decline in some domains. Further investigations with longer follow-up duration may be needed to confirm the cumulative effects of SVD in AD and different patterns of decline between AD and SIVD., (Copyright © 2013. Published by Elsevier Ireland Ltd.)

Anticipatory dementia is related to anxiety, which is a clinical predictor of early conversion to Alzheimer's disease. The Fear of Alzheimer's Disease Scale (FADS) is a reliable and valid instrument to address anticipatory dementia. The aim of the present investigation was to develop the Korean version of the Fear of Alzheimer's Disease Scale (K-FADS) and to verify its reliability and validity. We developed the K-FADS to consist of 30 items with total scores ranging from 0 to 120, as in the original FADS. One hundred eight healthy volunteer participants, drawn from 3 different university hospitals, were evaluated. The K-FADS revealed good reliability (Cronbach α=0.96) and good validity as compared to the Korean version of the State-Trait Anxiety Inventory Form (r=0.242, P=0.013). Test-retest reliability was excellent, as the intra-class correlation coefficient comparing the retest to test was 0.98 (95% confidence interval, 0.96-0.99). Our results show that the K-FADS is a suitable and valuable scale to assess anticipatory dementia in elderly Koreans.

Background: Alzheimer's disease (AD) is a devastating illness that results in progressive cognitive decline and neuropsychiatric symptoms. The neuropsychiatric symptoms are associated with a rapid decline in cognition and activities of daily living and increased mortality, however the neuroanatomical localisation involved in the development of neuropsychiatric symptoms remains poorly understood. The aim of this study was to identify the association with the regional volume of the insular cortex and each neuropsychiatric symptom in patients with AD., Methods: Subjects diagnosed with AD (n = 40) were evaluated. Magnetic resonance images were obtained and the insular cortex was subdivided into four subregions through the central sulcus of the insula and bilaterally: right anterior insular cortex, right posterior insular cortex, left anterior insular cortex and left posterior insular cortex. The neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory. A partial correlation analysis was performed., Results: A significant negative correlation existed between apathy, the irritability subscale score and the volume ratio of the bilateral anterior insular cortex and right posterior insular cortex (r = -0.457, -0.433 and -0.572, respectively, p = 0.032, 0.044 and 0.005, respectively)., Conclusion: The findings suggest that the regional atrophy of the insular cortex is associated with neuropsychiatric symptoms in AD patients., (© 2014 S. Karger AG, Basel.)

Background: Extrapyramidal signs (EPSs) are commonly observed in patients with Alzheimer disease (AD). We report here the base rate of EPS in a large cohort of patients with AD who were not receiving neuroleptic drugs, and the associations of EPS with functional outcomes and depressive symptoms., Methods: In a consortium involving 56 clinics, we recruited 2614 patients with AD. We estimated basic activities of daily living (ADL) and instrumental ADL by the Barthel index and the Seoul-Instrumental Activities of Daily Living (S-IADL) scales, respectively. Depressive symptoms were assessed using the 15-item Geriatric Depression Scale (GDS-15). The EPS group was defined by the presence of at least 1 EPS based on a focused neurologic examination., Results: The prevalence of EPS-positive patients was 12%. These had lower Korean version of the Mini-Mental State Examination (K-MMSE) scores than the EPS-negative cases (P < .001). After controlling for demographic, medical, radiological, genetic, and cognitive (K-MMSE) factors, the proportion of patients with impaired ADL was significantly higher in the EPS group than in the non-EPS group (P < .001, odds ratio = 1.90, 95% confidence interval, 1.45-2.48, and logistic regression). The S-IADL scores were significantly higher in the EPS group than this in the non-EPS group (P < .001, regression coefficient = 3.19, and median regression). The GDS-15 scores were higher in the EPS group (P = .04, regression coefficient = 0.89, and median regression)., Conclusion: The presence of EPS in patients with AD who were not receiving neuroleptic drugs was associated with more impaired basic and instrumental ADL functioning and with greater depression symptoms.

Background: This study aimed to evaluate the relationship between loss of white matter cholinergic pathways, atrophy of the nucleus basalis of Meynert (NBM), and cognitive function in patients with subcortical ischemic vascular dementia (SIVD) or Alzheimer's disease (AD)., Methods: The participants included 26 SIVD, 17 probable AD with or without white-matter changes, and 20 age-matched healthy controls. Thin-section coronal T2-weighted images were acquired using 3.0 T MR. The extent of white matter hyperintensities within cholinergic pathways were assessed using the cholinergic pathways hyperintensities scale (CHIPS). NBM atrophy was assessed from the thickness of the substantia innominata (SI) at the level of the crossing of the anterior commissure. Cognitive impairment was measured using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). Correlations between CHIPSs, SI thickness, and cognitive impairment were evaluated using the Spearman ranked correlation test., Results: In AD, MMSE scores and CDR were correlated with SI thickness (ρ = 0.450, p = 0.006 and ρ = -0.520, p = 0.030, respectively) but not with CHIPS scores (ρ = -0.160, p = 0.530 and ρ = 0.270, p = 0.292, respectively). By contrast, aggravated MMSE score and CDR in SIVD had a tendency to correlate with elevated CHIPS scores (ρ = -0.344, p = 0.127 and ρ = 0.521, p = 0.021, respectively) but not with SI thickness (ρ = -0.210, p = 0.480 and ρ = 0.080, p = 0.736, respectively)., Conclusions: Loss of cholinergic pathways correlates with cognitive dysfunction in both AD and SIVD. The mechanisms appear to differ: NBM atrophy is likely to be the predominant contributor to cognitive impairments in AD, whereas, the cognitive dysfunction of SIVD was associated with compromised subcortical cholinergic fibers not with nucleus itself.

Objective: We hypothesized that prominent pulvinar hypointensity in brain MRI represents the disease process due to iron accumulation in Alzheimer disease (AD). We aimed to determine whether or not the pulvinar signal intensity (SI) on the fluid-attenuated inversion recovery (FLAIR) sequences at 3.0T MRI differs between AD patients and normal subjects, and also whether the pulvinar SI is correlated with the T2(*) map, an imaging marker for tissue iron, and a cognitive scale., Materials and Methods: Twenty one consecutive patients with AD and 21 age-matched control subjects were prospectively included in this study. The pulvinar SI was assessed on the FLAIR image. We measured the relative SI ratio of the pulvinar to the corpus callosum. The T2(*) values were calculated from the T2(*) relaxometry map. The differences between the two groups were analyzed, by using a Student t test. The correlation between the measurements was assessed by the Pearson's correlation test., Results: As compared to the normal white matter, the FLAIR signal intensity of the pulvinar nucleus was significantly more hypointense in the AD patients than in the control subjects (p < 0.01). The pulvinar T2(*) was shorter in the AD patients than in the control subjects (51.5 ± 4.95 ms vs. 56.5 ± 5.49 ms, respectively, p = 0.003). The pulvinar SI ratio was strongly correlated with the pulvinar T2(*) (r = 0.745, p < 0.001). When controlling for age, only the pulvinar-to-CC SI ratio was positively correlated with that of the Mini-Mental State Examination (MMSE) score (r = 0.303, p < 0.050). Conversely, the pulvinar T2(*) was not correlated with the MMSE score (r = 0.277, p = 0.080)., Conclusion: The FLAIR hypointensity of the pulvinar nucleus represents an abnormal iron accumulation in AD and may be used as an adjunctive finding for evaluating AD.

With rapid population aging, the socioeconomic burden caused by dementia care is snowballing. Although a few community-based studies of Alzheimer's disease (AD) have been performed in Korea, there has never been a nationwide hospital-based study thereof. We aimed to identify the demographics and clinical characteristics of mild-to-moderate AD patients from the Clinical Research Center for Dementia of Korea (CREDOS) registry. A total of 1,786 patients were consecutively included from September 2005 to June 2010. Each patient underwent comprehensive neurological examination, interview for caregivers, laboratory investigations, neuropsychological tests, and brain MRI. The mean age was 74.0 yr and the female percentage 67.0%. The mean period of education was 7.1 yr and the frequency of early-onset AD (< 65 yr old) was 18.8%. Among the vascular risk factors, hypertension (48.9%) and diabetes mellitus (22.3%) were the most frequent. The mean score of the Korean version of Mini-Mental State Examination (K-MMSE) was 19.2 and the mean sum of box scores of Clinical Dementia Rating (CDR-SB) 5.1. Based on the well-structured, nationwide, and hospital-based registry, this study provides the unique clinical characteristics of AD and emphasizes the importance of vascular factors in AD in Korea.

Background and Purpose: Vascular pathology and Alzheimer disease (AD) pathology have been shown to coexist in the brains of dementia patients. We investigated how cognitive impairment could be exacerbated in a rat model of combined injury through the interaction of chronic cerebral hypoperfusion and amyloid beta (Aβ) toxicity., Methods: In Wistar rats, chronic cerebral hypoperfusion was modeled by permanent occlusion of bilateral common carotid arteries (BCCAo). Further, AD pathology was modeled by bilateral intracerebroventricular Aβ (Aβ toxicity) using a nonphysiological Aβ peptide (Aβ 25 to 35). The experimental animals were divided into 4 groups, including sham, single injury (Aβ toxicity or BCCAo), and combined injury (BCCAo-Aβ toxicity) groups (n=7 per group) . Cerebral blood flow and metabolism were measured using small animal positron emission tomography. A Morris water maze task, novel object location and recognition tests, and histological investigation, including neuronal cell death, apoptosis, neuroinflammation, and AD-related pathology, were performed., Results: Spatial memory impairment was synergistically exacerbated in the BCCAo-Aβ toxicity group as compared to the BCCAo or Aβ toxicity groups (P<0.05). Compared to the sham group, neuroinflammation with microglial or astroglial activation was increased both in multiple white matter lesions and the hippocampus in other experimental groups. AD-related pathology was enhanced in the BCCAo-Aβ toxicity group compared to the Aβ toxicity group., Conclusions: Our experimental results support a clinical hypothesis of the deleterious interaction between chronic cerebral hypoperfusion and Aβ toxicity. Chronic cerebral hypoperfusion-induced perturbation in the equilibrium of AD-related pathology may exacerbate cognitive impairment in a rat model of combined injury.

Objectives: Neural thread protein (NTP), a membrane-associated phosphoprotein, was selectively elevated in the urine of patients with Alzheimer disease (AD). To demonstrate the potential utility of urine NTP assays for the diagnosis of AD, we performed this study., Design: A prospective blinded multicentered study., Participants: Individuals diagnosed as having probable AD (n = 49), Parkinson's disease (PD) (n = 20), and healthy controls (n = 22) were enrolled consecutively in 4 neurology centers., Measurements: A first morning urine sample was obtained from each subject. Urine NTP measurement using competitive ELISA was tested at the central laboratory and compared with AD and PD patients and healthy controls (HC). The testing laboratory was blinded to clinical information., Results: The mean assay value in AD (n = 49, 26.8 ± 9.4 μg/mL) was significantly higher than in HC (n = 22, 18.1 ± 6.7 μg/mL) (P ≤ .001) and than in PD (n = 20, 21.0 ± 8.5 μg/mL) (P ≤ .05). Levels of 21.6 μg/mL or higher were found in 81.6% of all AD cases, in 30.0% of PD cases, and in 13.6% of HC. Urine NTP assay measurements of AD with a Clinical Dementia Rate (CDR) of 0.5 (n = 10, 24.2 ± 5.9 μg/mL, P = .063) or of 1.0 (n = 24, 30.1 ± 10.9 μg/mL, P = .000) were significantly higher than in HC. However, the AD patients with CDR of 2.0 (n = 9, 23.1 ± 7.3 μg/mL, P = .136) were not significant., Conclusion: Urine NTP could be used as a safe and promising biochemical marker of early AD., (Copyright © 2011 American Medical Directors Association. Published by Elsevier Inc. All rights reserved.)

Screening tests that briefly measure early signs of cognitive dysfunction in Alzheimer's disease (AD) are lacking. We devised a new scale focused on early detecting cognitive dysfunction: the Attention Questionnaire Scale (AQS). We prospectively studied the AQS in 268 subjects with varying degrees of cognitive dysfunction and compared it with the Mini-Mental Status Examination (MMSE), digit span test, trail making test part B, letter cancellation test, Instrumental ADL, Geriatric Depression Scale, and Clinical Dementia Rating Scale. The internal consistency was excellent with the AQS (Cronbach's α = 0.945). There were significant differences in the overall AQS scores across varying degree of cognitive dysfunction (26.80 ± 3.43 in normal elderly, 20.78 ± 4.83 in patients with mild cognitive impairment (MCI), 19.01 ± 4.49 in early AD, 16.00 ± 5.03 in mild AD, and 12.02 ± 6.28 in moderate AD), and subjects with the early stage of cognitive dysfunction could be further distinguished using the AQS than MMSE. The area under the receiver operating characteristic curve was estimated to be 0.93 (95% confidence interval 0.89-0.97) in screening for normal elderly versus patients with MCI or various stages of AD. The AQS provides greater screening ability for early stage cognitive dysfunction, used not only as a screening tool but also an appropriate simple questionnaire.

The Bayer-activities of daily living (B-ADL) is a brief and internationally applicable ADL instrument which has been validated in three European countries. The B-ADL has been developed to provide a tool for the assessment of functional deficits in performance of every day tasks as they are observed in mild to moderate stages of dementia. The B-ADL has been constructed for use in clinical trials as well as in clinical practice. From an international perspective the major application is the evaluation of treatment effects in clinical studies and the current study was to validate the Korean version of the B-ADL. The B-ADL was administered to a total of 129 subjects with varying degrees of cognitive decline. A substantial cross-sectional correlation between B-ADL and MMSE scores was found. The internal consistency of B-ADL was above 0.98. A factor analysis revealed that a one factor solution accounted for most of the total variance. The B-ADL global score significantly increased as the severity of dementia, assessed by global deterioration scale increased from stage 1 to 5. Test-retest reliabilities of B-ADL global score and each item were very high. All of these results were very similar to those from three European countries except for the proportion of 'non-applicability' in some ADL items. These findings provide evidence that the Korean version of B-ADL can be useful not only for clinical purposes but also for international multicentre studies., (Copyright 2003 John Wiley & Sons, Ltd.)