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Introduction: Subjective cognitive decline (SCD) is a self-reported cognitive decline without objective cognitive impairment. The relationship between audiometric hearing loss (HL) and cognitive function has not been reported in SCD. The purpose of this study was to investigate whether HL affects cognition-related indexes in SCD individuals. Methods: This is a cross-sectional study that used the baseline data of a multicenter cohort study that monitors clinical progression from SCD to dementia. Individuals aged ≥60 years who reported cognitive decline but had no objective cognitive impairment on comprehensive neuropsychological tests were recruited. Participants were grouped into the normal-hearing (NH) and bilateral HL groups. The demographics, clinical characteristics, dementia biomarkers, global cognition, questionnaire scores, neuropsychological test scores, and segmental brain volumes from MRI were compared between the groups. Results: Of a total of 120 participants, one hundred and two had NH (n = 57) or bilateral HL (n = 45). There were no group differences in the demographic and clinical data except the age. The biomarkers, global cognition, and questionnaire scores were not different between the groups. The HL group performed worse (the z-score of −0.06) in the Stroop Color Word Test than the NH group (0.27) (p = 0.025). Brain volumetric analysis revealed that the HL group had reduced gray matter volumes in four brain subregions: left temporal pole, left caudal middle frontal gyrus, left hippocampus, and right isthmus of the cingulate gyrus. Conclusion: In SCD, HL exerted an adverse effect on cognitive function, primarily frontal executive function tested in the Stroop task. HL was also related to gray matter volume reductions in brain subregions, although causality needs further investigation. This study may provide evidence for a potential link between hearing and cognition in SCD, an emerging clinical entity.

Introduction: Subjective cognitive decline (SCD) can be considered as the preclinical manifestation of Alzheimer’s disease (AD). The National Institute on Aging and the Alzheimer’s Association criteria for preclinical AD proposed that subtle cognitive changes appear along with AD biomarkers in the late stage of preclinical AD. The objective of this study was to explore whether subtle cognitive impairment (SCI) in individuals with SCD is associated with brain amyloid-β (Aβ) status and SCD severity. Methods: One hundred twenty individuals with SCD (mean age: 70.87 ± 6.10 years) were included in this study. SCI was defined as performance ≤ −1.0 SD on at least two neuropsychological tests. Participants underwent an amyloid positron emission tomography, which was assessed visually and quantitatively using standardized uptake value ratio (SUVR). The severity of SCD was assessed using two self-reported questionnaires: the SCD questionnaire based on the SCD-plus features and the Korean-Everyday Cognition (K-ECog) scale. Results: SCD individuals with SCI (n = 25) had more Aβ positivity than the SCD only group (n = 95) (44% vs. 15.79%; p = 0.002). In addition, the SCI group had a higher global SUVR than the SCD only group (p = 0.048). For self-reported questionnaires, there were no differences in SCD questionnaire total scores and K-ECog global and cognitive domain-specific scores between two groups. Conclusions: In SCD individuals, SCI was associated with higher Aβ positivity, but not with the severity of self-reported cognitive decline, compared to the SCD only group. These results suggest that the recognition of objectively defined subtle cognitive deficits may contribute to the early identification of AD in SCD.

Background: Subjective cognitive decline (SCD) is a self-perceived cognitive worsening without objective cognitive impairment. Due to its heterogeneity and potential risk of Alzheimer’s disease (AD), baseline biomarkers to predict progression are clinically important. In the present study, cognitive trajectories during a 24-month period were compared between amyloid-positive SCD (A+SCD) and amyloid-negative SCD (A−SCD) subjects, and biomarkers associated with memory decline were investigated. Methods: Data from a prospective cohort study in Korea between 2016 and 2019 were analyzed. SCD subjects ≥50 years of age were eligible. All participants underwent neuropsychological tests, brain magnetic resonance imaging, and florbetaben positron emission tomography scans. Amyloid burden and regional volumes were measured. Cognitive changes corrected for age were compared between A+SCD and A−SCD groups. Biomarkers associated with memory decline were assessed. Results: Forty-seven SCD subjects (69.9 ± 6.7 years, mini-mental state examination (MMSE) score 27.5) were enrolled, and 31 completed at least 1 annual follow-up (mean follow-up: 24.7 months). Baseline characteristics except age, hippocampal atrophy, and white matter hyperintensities were similar between A+SCDs (n = 12, 25.6%) and A−SCDs (n = 35). A+SCD subjects showed greater decline in the verbal memory function compared with the A−SCD subjects after adjustment for age. MMSE scores decreased more in the A+SCD (1.1 in the A+SCD; 0.55 in the A−SCD), although it was not statistically significant. Amyloid burden and baseline memory score were associated with memory decline. Conclusions: Within SCD, A+SCD subjects showed faster memory decline compared with the A−SCD subjects and amyloid burden might be associated with future memory decline in SCD.

Background: Donepezil 23 mg is considered for Alzheimer’s disease (AD) to optimize cognitive benefits; however, increased adverse events (AEs) can negatively influence drug adherence. We investigated whether body weight (BW) differs based on the presence of AEs, and which baseline factors were relevant to the safety of high-dose donepezil. Methods: This study was a post hoc analysis of a multicenter randomized trial between 2014 and 2016. We included patients with moderate to severe AD treated with 10 mg/day of donepezil, and the daily dose was escalated to 23 mg with/without dose titration. Dose titration indicates 15 mg/day of donepezil before escalation or 10 mg and 23 mg/day on alternate days before escalation during the first 4 weeks. The patients were divided into 2 groups based on occurrence of AEs of special interest (AESIs) to compare baseline characteristics. We also assessed relationships between BW and AESIs. Results: Among the 160 participants in the safety population, the baseline BWs differed between the AESI (+) (n = 67) and AESI (−) (n = 93) groups. Baseline BW was inversely correlated with the occurrence of AESIs (p = 0.020), and this relationship was prominent in the no-dose titration group (p = 0.009) but absent in the dose-titration groups (p > 0.05). Conclusions: BW is the most important factor that correlated with cholinergic AEs. Hence, stepwise dose titration should be considered, particularly in patients with low BW, to minimize the inverse relationship between BW and the occurrence of AEs (“Clinicaltrials.gov” No. NCT02550665 registered on September 15, 2015).

We investigated the amyloid and vascular burden in Pittsburgh compound B (PiB)-negative subcortical vascular mild cognitive impairment (svMCI) and PiB-negative subcortical ischemic vascular dementia (SIVD) to elucidate the potential roles of amyloid deposition and small vessel disease (SVD). Thirty-eight svMCI patients and 42 SIVD patients were enrolled. The regional PiB uptake values and SVD markers were obtained and compared between groups. Additionally, correlations among amyloid burden, SVD, and cognition were made. Patients with PiB-negative SIVD showed more amyloid deposition than those with PiB-negative svMCI, particularly in the cuneus, lingual gyrus, supramarginal, and angular gyri. Despite subthreshold levels for amyloid deposition, our findings showed a marked regional difference in amyloid uptake between svMCI and SIVD, particularly in posteriorly located brain areas. However, lacune, a proxy for vascular burden, showed a broader association with cognition and had more impacts on developing dementia than amyloid burden. The topographical pattern of amyloid deposition and its impact on clinical status in pure subcortical vascular cognitive impairment were different from those in Alzheimer's disease.

BACKGROUND & OBJECTIVE Depression frequently combines with dementia, including early-onset Alzheimer's disease (EOAD). We investigated differences in prevalence and characteristics of depressive symptoms according to dementia severity in EOAD patients. METHODS The 15-item Korean version of the Geriatric Depression Scale (GDS-15) was administered to 412 EOAD patients. Factor analysis was used to assess GDS-15 factor structure. We subdivided participants into three groups by disease severity, then compared the frequencies and scores of individual GDS-15 items and performed logistic regression analysis to assess associations between depressive symptoms and EOAD stage. RESULTS Factor analysis yielded three factor categories: 1) "hopelessness and ominousness" (symptoms no. 6, 8, 12, 14, 15); 2) "unhappiness and dissatisfaction" (no. 1, 3, 5, 7, 11); and 3) "monotony and lack of energy" (no. 2, 4, 9, 10, 13). Factor 2 depressive symptoms (no. 1, 5, 11) were less common in moderate EOAD. The risk of Factor 1 symptoms: no. 12 (OR, 2.04; 95% CI, 1.19-3.50; p = 0.010) and 14 (OR, 1.84; 95% CI, 1.07-3.16; p = 0.028) was higher in mild than very mild EOAD. The risk of Factor 2 symptoms: no. 9 (OR, 2.69; 95% CI, 1.08-6.71; p = 0.033) and 13 (OR, 2.12; 95% CI, 1.02-4.40; p = 0.043) was higher in moderate than mild EOAD. CONCLUSION We confirmed that depressive symptoms differ according to EOAD severity. When assessing depressive symptoms related to dementia progression, we recommend focusing on "hopelessness and ominousness" in very mild EOAD and "unhappiness and dissatisfaction" in mild EOAD.

BACKGROUND/OBJECTIVE There is insufficient evidence to guide decisions concerning how long anti-dementia drug (ADD) regimens should be maintained in severe Alzheimer's disease (AD). We investigated whether patients with extremely severe AD who were already receiving donepezil or memantine benefited from continuing treatment. METHODS In this randomized and rater-blinded trial, 65 AD patients with a Mini-Mental State Examination score from 0 to 5 and a score of 6c or worse on Functional Assessment Staging were randomly assigned to an ADD-continuation group (N = 30) or an ADD-discontinuation group (N = 35). The current use of donepezil or memantine was maintained for 12 weeks in the ADD-continuation group and was discontinued after baseline in the ADD-discontinuation group. Efficacy measures were obtained at baseline and 12 weeks. The primary efficacy variable was the change from baseline to the end of the study in Baylor Profound Mental State Examination (BPMSE) scores. RESULTS The change in the BPMSE from baseline to the end of the study in the ADD-continuation group (a 0.4-point improvement) was not equivalent to that in the ADD-discontinuation group (a 0.5-point decline), as determined by two one-sided tests of equivalence. Study withdrawals due to adverse events (11.4% versus 6.7%) were more frequent in the ADD-discontinuation group than in the ADD-continuation group. CONCLUSION Continued treatment with donepezil or memantine seems unequal and might be superior to withdrawal of the drugs in terms of the effects on global cognition in patients with extremely severe AD. Current Controlled Trials number: KCT0000874 (CRIS).

Background/Aims: The aims of this study were to determine baseline factors related to the progression of subjective memory impairment (SMI) in elderly subjects and to develop a new modeling scale to predict progression. Methods: Elderly subjects with SMI were recruited from the nationwide Clinical Research Centers for Dementia of South Korea (CREDOS) multicenter cohort and divided into two groups: (1) progressed to mild cognitive impairment or Alzheimer's disease or (2) stable without progression. Baseline clinical characteristics were compared between the groups, and the most relevant predictors of progression were assessed. A new modeling scale combining the predictors was developed. Results: In total, 129 subjects with SMI were analyzed. The follow-up duration was 0.5-4.7 years, and the median time to event was 3.64 years. The progressing group (n = 29) differed from the stable group (n = 100) in terms of baseline age, apolipoprotein E4 (APOE4) status, and some cognitive domains. Older age, a lower Mini-Mental State Examination recall score, APOE4 carrier, and a lower verbal delayed recall score were the most relevant predictors of progression, and a new modeling scale with these 4 predictors provided a better explanation of progression. Conclusion: SMI subjects with a higher risk of progression can be identified using a new modeling scale and might need further evaluations and more frequent follow-up.

Background: We investigated differences in the prevalence of anosognosia and neuropsychiatric symptoms (NPSs) characteristics according to disease severity in patients with early-onset Alzheimer disease (EOAD). Methods: We recruited 616 patients with EOAD. We subdivided participants into 2 groups based on the presence or absence of anosognosia and then again by Clinical Dementia Rating (CDR) scale. We compared the differences in the Neuropsychiatric Inventory (NPI) scores according to anosognosia and disease severity. Results: The percentage of patients with anosognosia in each CDR group steadily increased as the CDR rating increased (CDR 0.5 8.6% vs CDR 1 13.6% vs CDR 2 26.2%). The NPI total score was significantly higher in patients with anosognosia in the CDR 0.5 and 1 groups; by contrast, it had no association in the CDR 2 group. Frontal lobe functions were associated with anosognosia only in the CDR 0.5 and 1 groups. After stratification by CDR, in the CDR 0.5 group, the prevalence of agitation ( P = .040) and appetite ( P = .013) was significantly higher in patients with anosognosia. In the CDR 1 group, patients with anosognosia had a significantly higher prevalence of delusions ( P = .032), hallucinations ( P = .048), and sleep disturbances ( P = .047). In the CDR 2 group, we found no statistical difference in the frequency of symptoms between patients with and without anosognosia. Conclusion: These results confirm that the prevalence of anosognosia as well as the individual NPS and cognitive functions associated with it differ according to EOAD severity.

Background/Aims: A limited number of studies addressed MRI-based neurodegenerative changes in subjective memory impairment (SMI). We investigated changes in white matter (WM) microstructures as well as gray matter (GM) macrostructures in subjects with SMI of high and low risk for progression. Methods: A modeling scale (score range, 0-6) developed for prediction of SMI progression was used to divide SMI subjects (n = 46) into two groups: a high risk of progression (score ≥3; n = 19) and a low risk of progression (score ≤2; n = 27). Cross-sectional comparisons were performed using a region-of-interest-based diffusion tensor imaging (DTI) analysis, cortical thickness analysis, and hippocampal volumetry. Results: The high-risk group had more microstructural disruption shown by lower fractional anisotropy in the hippocampus, parahippocampal gyrus, supramarginal gyrus, and parts of frontotemporal lobes. On the other hand, GM macrostructural changes did not differ between the groups and were not associated with modeling scale scores. Conclusion: SMI subjects with a high risk of progression had more WM microstructural disruption than those with a low risk, and the changes were not explained by GM atrophy. Our findings suggest that the degree of microstructural alterations in SMI may be distinctive according to the risk factors and may precede GM atrophy.

Data collection and sharing for this project was funded by the Alzheimer''s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer''s Association; Alzheimer''s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen Idec; Bristol-Myers Squibb Company; Eisai; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICOLtd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer''s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (2013R1A1A1012925), grants of the Korea Health Technology RD grant number: 10060305), a grant from the Korea Institute of Science and Technology Institutional Open Research Program (2E24242-13-110), and grants (2015-590; 2014-0783) from the Asan Institute for Life Sciences (J.H.R.).

BACKGROUND Patients with amnestic mild cognitive impairment (aMCI) have an increased risk of dementia. However, conversion rate varies. Therefore, predicting the dementia conversion in these patients is important. OBJECTIVE We aimed to develop a nomogram to predict dementia conversion in aMCI subjects using neuropsychological profiles. METHODS A total of 338 aMCI patients from two hospital-based cohorts were used in analysis. All patients were classified into 1) verbal, visual, or both, 2) early or late, and 3) single or multiple-domain aMCI according to the modality, severity of memory dysfunction, and multiplicity of involved cognitive domains, respectively. Patients were followed up, and conversion to dementia within 3 years was defined as the primary outcome. Our patients were divided into a training data set and a validation data set. The associations of potential covariates with outcome were tested, and nomogram was constructed by logistic regression model. We also developed another model with APOE data, which included 242 patients. RESULTS In logistic regression models, both modalities compared with visual only (OR 4.44, 95% CI 1.83-10.75, p = 0.001), late compared to early (OR 2.59, 95% CI 1.17-5.72, p = 0.019), and multiple compared to single domain (OR 3.51, 95% CI 1.62-7.60, p = 0.002) aMCI were significantly associated with dementia conversion within 3 years. A nomogram incorporating these clinical variables was constructed on the training data set and validated on the validation data set. Both nomograms with and without APOE data showed good prediction performance (c-statistics ≥ 0.75). CONCLUSIONS This study showed that several neuropsychological profiles of aMCI are significantly associated with imminent dementia conversion, and a nomogram incorporating these clinical subtypes is simple and useful to help to predict disease progression.

METHOD OF BRAIN BASED ON FLAIR MRI Dong Won Yang, Ka Won Jung, Eun Ye Lim, Jung Hee Cho, Yong Soo Shim, Bora Yoon, Yun JeongHong, Seoul St. Mary’s Hospital, Catholic University of Korea, Seoul, South Korea; 2 Bucheon St.Mary’s Hospital, Seoul, South Korea; Department of Neurology, Konyang University, Daejeon, South Korea; Hyoja Geriatric Hospital, Seoul, South Korea. Contact e-mail: neuroman@catholic.ac.kr

The clinical implications of WMHs in aMCI are inconclusive. Moreover, clinical interactions between APOE genotypes and WMHs remain unclear. This study was conducted to investigate the relationship between WMHs and cognitive functions and how this relationship interacted with APOE genotype in people with aMCI. This study included a total of 1472 patients with aMCI from the Clinical Research Center for Dementia of South Korea (CREDOS) and divided them into 3 groups according to the severity of WMHs as assessed by visual ratings of brain magnetic resonance images. The associations of WMHs with the various cognitive domains and with APOE epsilon 4 (ɛ4) status were evaluated. After multivariable adjustments, the severity of WMHs was independently associated with semantic/phonemic verbal fluency and Stroop test-color reading, while APOE ɛ4 status was associated with verbal and visual memory-immediate, delayed recall, and recognition. Moreover, there were interaction between WMHs and APOE ɛ4 status in semantic verbal fluency (animal, P=0.033; supermarket, P=0.047)/Stroop test-color reading (P=0.024). WMHs independently deleteriously affected frontal executive functions in aMCI patients, regardless of APOE ɛ4 presence. Furthermore, APOE ɛ4 possession caused a rapid decline in frontal executive functions with the increase in the WMHs severity (vs. absence), suggesting that WMHs and APOE ɛ4 genotypes synergistically contribute to frontal executive dysfunctions in aMCI.

Few studies have investigated the apolipoprotein E (APOE) e4 allele status of dementia patients with severe white matter hyperintensities (WMH). In this study, we aimed to characterize the APOE epsivlon genotypes and clinical features of dementia patients with severe WMH. Four hundred and thirty nine patients with dementia and 152 subjects with normal cognition (NC) were recruited from multiple centers in Korea, known as the Clinical Research Center for Dementia of South Korea (CREDOS), since November 2005. The WMH were rated using the scale that had been developed by the CREDOS study. Dementia patients with minimal WMH were considered to have Alzheimer's disease (AD) without WMH (AD-WMH: 325), and those with severe WMH were considered to have Subcortical Ischemic Vascular Dementia (SIVD: 50) or AD with severe WMH (AD+WMH: 64). Comparisons of APOE e4 allelic prevalence were performed using chi-square analysis. The APOE e4 allele was more prevalent in those with AD than in those with SIVD and NC (p < 0.001). It was not more prevalent in those with SIVD than in those with NC (p = 0.169). APOE e4 allele status in AD+WMH did not differ from that in AD-WMH (p = 0.625). The APOE e4 allele was more prevalent in those with AD than in those with SIVD. APOE e4 may not be associated with SIVD although it is one of the vascular risk factors.

The SCI, the MCI, and the Alzheimer's disease (AD) are on a spectrum of disease progression; therefore, identification of the earliest signs of cognitive deterioration is becoming a crucial issue. The goal of this study was to examine symptom characteristics and distinguish predictive symptoms in patients with MCI compared with SCI, using caregiver questionnaires. We assessed the Korean Dementia Screening Questionnaire (KDSQ) and Seoul Instrumental activities of Daily Living (S-IADL) of 344 subjects with SCI and 697 with MCI. Multivariate logistic regression analyses were conducted after adjusting for age, sex, and educational status. Common and rare symptoms were similar between the SCI and MCI groups. The most distinguishing features of KDSQ were 'Finds it hard to go somewhere on his/her own using public transportation' (odds ratio=OR=4.56, p

P2-111 ADAPTATED SPANISH-AMERICAN MIS VERSION. PRELIMINARY RESULTS OF ARGENTINIAN MULTICENTRIC STUDY Daniel B. Seinhart, Edith Labos, Alberto Mourino, Sofia Trojanoski, Jorge Etchepareborda, Daniel Cruz, Graciela Arguello, Diana Cristalli, Luis Camera, Hospital Italiano, Buenos Aires, Argentina; Hospital Central de San Isidro, Buenos Aires, Argentina; Centro Neurologico, Mar del Plata, Argentina; Hospital Municipal Arturo Onativia, Rafael Calzada, Argentina; Centro de Memoria, Rio Gallegos, Argentina; Hospital San Roque, Gonnet, Argentina. Contact e-mail: daniel.seinhart@ hospitalitaliano.org.ar