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Purpose The purpose of this study was to investigate whether routine insertion of peripherally inserted central catheter (PICC) at admission to a hospice-palliative care (HPC) unit is acceptable in terms of safety and efficacy and whether it results in superior patient satisfaction compared to usual intravenous (IV) access.Materials and Methods Terminally ill cancer patients were randomly assigned to two arms: routine PICC access and usual IV access arm. The primary endpoint was IV maintenance success rate, defined as the rate of functional IV maintenance until the intended time (discharge, transfer, or death).Results A total of 66 terminally ill cancer patients were enrolled and randomized to study arms. Among them, 57 patients (routine PICC, 29; usual IV, 28) were analyzed. In the routine PICC arm, mean time to PICC was 0.84 days (range, 0 to 3 days), 27 patients maintained PICC with function until the intended time. In the usual IV arm, 11 patients maintained peripheral IV access until the intended time, and 15 patients underwent PICC insertion. The IV maintenance success rate in the routine PICC arm (27/29, 93.1%) was similar to that in the usual IV arm (26/28, 92.8%, p=0.958). Patient satisfaction at day 5 was better in the routine PICC arm (97%, ‘a little comfort’ or ‘much comfort’) compared with the usual IV arm (21%) (p

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.

A quantitative analysis of brain volume can assist in diagnosis of Alzheimer’s disease (AD) ususally accompannied by brain atrophy. With an automated analysis program Quick Brain Volumetry (QBraVo) developed for volumetric measurements, we measured regional volumes and ratios to evaluate their performance in discriminating AD dementia (ADD) and mild cognitive impairment (MCI) patients from normal controls (NC). Validation of QBraVo was based on intra-rater and inter-rater reliability with a manual measurement. The regional volumes and ratios to total intracranial volume (TIV) and to total brain volume (TBV) or total cerebrospinal fluid volume (TCV) were compared among subjects. The regional volume to total cerebellar volume ratio named Standardized Atrophy Volume Ratio (SAVR) was calculated to compare brain atrophy. Diagnostic performances to distinguish among NC, MCI, and ADD were compared between MMSE, SAVR, and the predictive model. In total, 56 NCs, 44 MCI, and 45 ADD patients were enrolled. The average run time of QBraVo was 5 minutes 36 seconds. Intra-rater reliability was 0.999. Inter-rater reliability were high for TBV, TCV, and TIV (R = 0.97, 0.89 and 0.93, respectively). The medial temporal SAVR showed the highest performance for discriminating ADD from NC (AUC = 0.808, diagnostic accuracy = 80.2%). The predictive model using both MMSE and medial temporal SAVR improved the diagnostic performance for MCI in NC (AUC = 0.844, diagnostic accuracy = 79%). Our results demonstrated QBraVo as a fast and accurate method to measure brain volume. The regional volume calculated as SAVR could help to diagnose ADD and MCI and increase diagnostic accuracy for MCI.

Background and purpose Subjective cognitive decline (SCD) may be the first stage corresponding to subtle cognitive changes in patients with Alzheimer's disease (AD) spectrum disorders. We evaluated the differences in cortical thinning patterns among patients with SCD who progressed to mild cognitive impairment or dementia (pSCD), those who remained stable (sSCD), and healthy normal controls (NCs). Methods We retrospectively recruited SCD subjects (14 pSCD and 21 sSCD cases) and 29 NCs. Structural 3-dimensional-T1-weighted magnetic resonance imaging was performed using a single 1.5 Tesla scanner. Freesurfer software was used to map cortical thickness for group comparisons. Results Compared with NC group, the sSCD group showed diffuse cortical atrophy associated with bilateral fronto-parieto-temporal area. The pSCD group showed further characteristic cortical atrophy in AD-vulnerable regions including the inferior parieto-temporal and middle temporal areas. Cortical thinning in the bilateral medial frontal areas was observed in patients with sSCD and involved the right inferior temporal and left precentral areas in those with pSCD. Conclusions Our study showed that SCD subjects exhibit different cortical thinning patterns depending on their prognosis.

Background High-dose donepezil is currently prescribed for patients with Alzheimer’s disease (AD) who showed poor or waning response to a lower dose at the risk of increasing cholinergic side effects. However, the adverse events (AEs) depending on the method of dose escalation have not been clarified yet. This study aimed to find out whether dose titration before escalating to donepezil 23 mg is preferred. We investigated safety and tolerability of donepezil 23 mg during the first 12 weeks of dose escalation in patients with moderate to severe AD. Methods This study was a 12-week, multicenter, randomized, open-label prospective trial. We included patients with moderate to severe AD who were treated with a stable dose of donepezil 10 mg/day. Patients were randomized into 3 groups according to the dose escalation method: 15 mg of donepezil for 4 weeks before escalating to 23 mg (group 1), 10 mg and 23 mg on alternate days for 4 weeks prior to escalation (group 2), and direct escalation to 23 mg (group 3). Safety analyses included incidence, severity, timing of AEs, relationship to the study drug, and premature study discontinuation due to AEs between the groups. Results Among 175 enrolled, 110 patients completed the study. Baseline characteristics were similar among the groups. Using safety population (N = 160), cholinergic gastrointestinal symptoms including anorexia and nausea were the most common AEs and titration groups showed significantly fewer cases of nausea as compared with those in no-titration group. Conclusions In this study, dose titration before escalating to donepezil 23 mg/day showed better safety in terms of cholinergic AEs. We suggest that dose titration during the first 4 weeks can be recommended for patients with moderate to severe AD. Trial registration Clinicaltrials.gov, NCT02550665. Retrospectively registered on 15 Sep 2015. Electronic supplementary material The online version of this article (10.1186/s13195-019-0492-1) contains supplementary material, which is available to authorized users.

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).

Background and purpose Semantic memory remains more stable than episodic memory across the lifespan, which makes it potentially useful as a marker for distinguishing pathological aging from normal senescence. To obtain a better understanding of the transitional stage evolving into Alzheimer's dementia (AD), we focused on the amnestic mild cognitive impairment (aMCI) stage stratified based on β-amyloid (Aβ) pathology. Methods We analyzed the raw data from Korean version of the Boston Naming Test (K-BNT) and the Controlled Oral Word Association Test (COWAT). For K-BNT, the frequencies of six error types and accuracy rates were evaluated. For a qualitative assessment of the COWAT, we computed the number of switching, number of clusters, and mean cluster size. Results The data from 217 participants were analyzed (53 normal controls, 66 with Aβ- aMCI, 56 with Aβ+ aMCI, and 42 disease controls). There were fewer semantically related errors and more semantically unrelated errors on the K-BNT in Aβ+ aMCI than in Aβ- aMCI, without a gross difference in the z score. We also found that Aβ+ aMCI showed a more prominent deficit in the number of clusters in the semantic fluency task [especially for animal names (living items)] than Aβ- aMCI. Conclusions In spite of similar clinical manifestations, Aβ+ aMCI was more similar to AD than Aβ- aMCI in terms of semantic memory disruption. Semantic memory may serve as an early indicator of brain Aβ pathology. Therefore, semantic memory dysfunction deserves more consideration in clinical practice. Longitudinal research with the follow-up data is needed.

This study aimed to detect different patterns of cerebral hypoperfusion in DLB according to clinical staging. Thirty-three patients with DLB were recruited by clinical dementia rating (CDR) stage. Compared with control, cerebral hypoperfusion was mainly observed in the lingual gyrus, the cuneus, the occipital gyrus in CDR 0.5 group; the fusiform gyrus, the middle temporal gyrus, and the posterior cingulate in CDR 1; and the lingual gyrus, the cuneus, the hippocampus, the fusiform gyrus, and the inferior frontal gyrus in CDR 2. Our findings suggest that cerebral hypoperfusion spreads to the frontal cortex and temporal lobes as disease progresses.

Background and purpose: Poststroke cognitive impairment (PSCI) is common, but the impact of β-amyloid (Aβ) on PSCI is uncertain. The proposed study will investigate amyloid pathology in participants with PSCI and how differently their cognition progress according to the amyloid pathology. Methods: This multicenter study was designed to be prospective and observational based on a projected cohort size of 196 participants with either newly developed cognitive impairment, or rapidly aggravated CI, within 3 months after acute cerebral infarction. They will undergo 18F-flutemetamol positron emission tomography at baseline and will be categorized as either amyloid-positive (A+) or amyloid-negative (A−) by visual rating. The primary outcome measures will be based on Korean Mini-Mental State Examination changes (baseline to 12 months) between the A+ and A− groups. The secondary outcome measures will be the dementia-conversion rate and changes in the Korean version of the Montreal Cognitive Assessment (baseline to 12 months) between the A+ and A− groups. Conclusions: This study will provide a broadened perspective on the impact of Aβ on the cause and outcomes of PSCI in clinical practice. Identifying amyloid pathology in patients with PSCI will help select patients who need more focused treatments such as acetylcholinesterase inhibitors Trial registration: Clinical Research Information Service identifier: KCT0005086

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).

IntroductionRecent studies have shown that pathologically defined subtypes of Alzheimer's disease (AD) represent distinctive atrophy patterns and clinical characteristics. We investigated whether a cortical thickness–based clustering method can reflect such findings.MethodsA total of 77 AD subjects from the Alzheimer's Disease Neuroimaging Initiative 2 data set who underwent 3-T magnetic resonance imaging, [18F]-fluorodeoxyglucose-positron emission tomography (PET), [18F]-Florbetapir PET, and cerebrospinal fluid (CSF) tests were enrolled. After clustering based on cortical thickness, diverse imaging and biofluid biomarkers were compared between these groups.ResultsThree cortical thinning patterns were noted: medial temporal (MT; 19.5%), diffuse (55.8%), and parietal dominant (P; 24.7%) atrophy subtypes. The P subtype was the youngest and represented more glucose hypometabolism in the parietal and occipital cortices and marked amyloid-beta accumulation in most brain regions. The MT subtype revealed more glucose hypometabolism in the left hippocampus and bilateral frontal cortices and less performance in memory tests. CSF test results did not differ between the groups.DiscussionCortical thickness patterns can reflect pathophysiological and clinical changes in AD.

Background: Patients with mild cognitive impairment (MCI) are at an increased risk for developing dementia, especially Alzheimer disease; and pharmacological therapy for MCI is limited. As a result, nonpharmacological mediums have been considered to complement standard drug therapy. In this study, we evaluated the effects of nonpharmacological therapies, occupational therapy and music therapy, on cognitive functions and depressive mood in MCI patients. Methods: We enrolled patients with MCI from the Mapo Dementia Center and divided them into two groups, group A (n=14) who participated in a cognitive program for 12 months and group B (n=15) who did not participate in a cog- nitive program. We compared the baseline and followed-up scores of the Korean-version of Mini-Mental State Exami- nation (K-MMSE), the Seoul Neuropsychological Screening Battery (SNSB), and the short version of geriatric depres- sion scale (sGDS) between the two groups. Results: Group A showed improvements in total and language scores in the K-MMSE and digit span backward scores in the SNSB and sGDS. In contrast, group B showed a decline in the Seoul Verbal Learning Test recognition score in the SNSB. Additionally, there were significant intergroup differences in the total and language scores in K-MMSE, the digit span backward score, and the Rey Complex Figure Test-delayed recall scores and depression scores. Conclusion: Occupational therapy and music therapy may help to improve cognitive functions and depressive mood in patients with MCI.

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.

Introduction Idiopathic normal pressure hydrocephalus (INPH) is known to be a potentially treatable neurologic condition. The neurocognitive outcomes after surgery, however, have been variable. It is important to define preoperative characteristics of patients that predicts the shunting outcome. We aimed to compare baseline differences between shunt-responsive and unresponsive patients after 1 year from surgery in order to identify preoperative predictors showing favorable clinical outcomes. Methods Among 69 candidates, 31 patients with probable INPH completed the study. Patients were divided into two groups, responsive group (n = 17) and unresponsive group (n = 14), according to the clinical outcomes on INPH grading scale and modified Rankin score (MRS). Preoperative cerebrospinal (CSF) As, tau levels, MRI findings, and clinical characteristics were compared between the groups. Correlations between shunt responsiveness and preoperative characteristics were also assessed. Results After 1 year from shunt, gait problem was the most likely to improve. Shunt-responsive group showed lower CSF p-tau/As, fewer lacunes, and higher incidence of disproportionately enlarged subarachnoid space (DESH) signs on MRIs compared to those in unresponsive group. Favorable outcome was related with positive DESH sign and fewer lacunes. Conclusions Our results suggest that biomarkers representing non-INPH related pathology including Alzheimer's disease and small vessel disease might show less favorable clinical outcomes after 1 year from surgery.

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.

This study was to evaluate the influence on cognition and activities of daily living (ADL) by white matter hyperintensities (WMHs) based on the severity and location, as well as the interactions among WMHs, lacunes, and medial temporal atrophy (MTA). In 150 patients with amnestic mild cognitive impairment, WMHs were quantified with the use of a semiautomated volumetric method. Lacune counting and MTA assessment were performed by visual rating. The severer WMHs were, the more executive functions decreased. The influence on executive functions such as verbal fluency test and Stroop color reading test were greater in periventricular (PV) WMHs than deep WMHs, as well as bigger in anterior, middle, and posterior areas in order. The instrumental (I) ADL was strongly associated with the anterior ( P = .028) and middle area ( P = .014) of PVWMHs only. WMHs had synergistic interactions with lacunes in Controlled Oral Word Association Task-semantic (s = −1.12; R 2 = .24; P = .039), Stroop color (s = −2.07; R 2 = .15; P = .049), and IADL (s = .23; R 2 = .20; P = .009). Anterior PVWMHs demonstrated the most powerful impact on frontal executive dysfunction and poor performance of IADL. WMHs had synergistic effects with the number of lacunes on them. Therefore, it is desirable to consider WMHs and lacunes simultaneously as potential imaging biomarkers for predicting cognition and IADL in aMCI.

Background: The early stage of Alzheimer disease might show early memory impairment with normal general cognitive function. Our study aimed to investigate elderly with normal Korean version of mini-mental state examination (KMMSE) score and recall score of 0 for 1 year. We predicted that the patients would show different characteristics and would progress more rapidly compared with normal controls. Methods: This study was based on the data from complete enumeration survey of Mapo-gu Regional Center for Dementia in 2009. We divided all subjects into three groups: subjects with normal K-MMSE scores and recall score of 0 were group 1-1 (n=152), subjects with abnormal K-MMSE scores were group 1-2 (n=64) and subjects with normal K-MMSE scores and recall score of 1 to 3 were group 1-3 (n=941). We compared basic demographics and social characteristics among the three groups. After 1 year (2010), the subjects in group 1-1 (90 out of 152) underwent follow-up examinations for dementia diagnosis. They were also divided into three groups (2-1, 2-2, 2-3) according to K-MMSE and recall scores. Results: Group 1-1 showed different baseline characteristics compared with normal controls. After 1 year, 25.5% (23 out of 90) of the group 2-1 were diagnosed as mild cognitive impairment (n=16) or dementia (n=7). Conclusion: Our study suggested that subjects with normal K-MMSE scores but recall score of 0 are not entirely “normal”. Further detailed evaluation might be needed if memory impairment is suspicious although the K-MMSE scores are within normal range.

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.

Regional atrophy of gray matter (GM) in Alzheimer's disease (AD) is well known; however, the relationship between macroscopic and microscopic changes of cerebral white matter (WM) is uncertain. The aim of this study was to investigate the pattern of GM, WM atrophy, and microscopic WM changes in the same individuals with AD. All subjects (10 AD and 15 healthy controls [HC]) underwent a MRI scanning at 1.5 T, including a 3-dimensional volumetric scan and diffusion tensor imaging (DTI). We performed statistical parametric mapping (SPM) with DTI to evaluate the patterns of the microscopic WM changes, as well as voxel-based morphometry (VBM) for GM and WM volume changes between patients with AD and HC. GM atrophy was detected, mainly in posterior regions, and WM atrophy was similarly distributed, but less involved on VBM analysis. Unlike WM atrophy on VBM analysis, microscopic WM changes were shown in the medial frontal, orbitofrontal, splenium of the corpus callosum, and cingulum on DTI analysis with SPM. We demonstrated that the pattern of macroscopic WM atrophy was similar to GM atrophy, while microscopic WM changes had a different pattern and distribution. Our findings suggest that WM atrophy may preferentially reflect the secondary changes of GM atrophy, while microscopic WM changes start earlier in frontal areas before GM and WM atrophy can be detected macroscopically.

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

Vascular disease is associated with cognitive impairment. White matter hyperintensities (WMHs), as detected by brain magnetic resonance imaging (MRI), are associated with cognitive impairment and considered to be a marker of cerebral microvascular abnormality. Ankle-brachial pressure index (ABI) and pulse wave velocity (PWV) are noninvasive methods to assess blockage and stiffness in peripheral arteries, respectively. We investigated the associations of ABI and PWV with WMHs and cognition. We included 242 subjects representing 56 controls, 75 patients with mild cognitive impairment, and 111 patients with Alzheimer’s disease. We assessed brachial-ankle PWV (baPWV), ABI, general cognitive status with the Korean Mini-Mental State Examination (K-MMSE), and WMHs with brain MRI. The mean age of subjects correlated with values of baPWV (r=0.432, p

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.

Diffusion tensor imaging (DTI) is a sensitive MRI technique in the detection of white matter degeneration. We sought to demonstrate microstructural changes in normal controls, patients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) and to determine which DTI parameters could be a reliable tool for the early diagnosis of AD. In total, 90 participants (35 normal, 20 aMCI, 35 AD) were recruited. We included early AD patients with clinical dementia rating scores of 0.5 and 1. The fractional anisotropy and mean diffusivity values, DTI parameter, were measured with the regions of interest method in the bilateral hippocampal body and posterior cingulate. Clinical history, neurological examination, and neuropsychological assessments were conducted. The DTI parameters in the bilateral hippocampus and posterior cingulate in aMCI and AD were different from those in normal controls. No difference was found in DTI parameters of the posterior cingulate between aMCI and AD. However, hippocampal DTI parameters were different between aMCI and AD. Cognitive summary measures were significantly correlated with DTI parameters, especially FA values in the hippocampus. The DTI analysis technique demonstrated significant microstructural alterations in the hippocampus and posterior cingulate already in prodromal stage of AD. DTI parameters in the hippocampus may be a more sensitive method to determine microstructural changes in early AD states and more correlated with cognition than DTI parameters in the posterior cingulate.

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

BACKGROUND AND PURPOSE: DTI can be used to assess the degradation of WM tracts by measuring the FA and MD. Decreased FA/increased MD values in the AD hippocampus have been reported by many studies. In contrast, only a few studies reported on hydrocephalus by using the DTI technique. In elderly patients with dementia and with dilated ventricles, it is often difficult to differentiate iNPH from AD with visual measurements on MR imaging. The aim of this study was to investigate the changes of microstructural integrity of the hippocampus in iNPH by using DTI and determining whether this method could be a new diagnostic tool to differentiate iNPH from AD. MATERIALS AND METHODS: We recruited 43 participants (15 healthy controls, 15 patients with AD, and 13 patients with iNPH). The FA and MD values were measured by using the region-of-interest method in the hippocampal head, body, and tail on both sides. Clinical history, neurologic examination, and neuropsychological assessment were included. RESULTS: The FA values were the lowest in the patients with AD, the patients with iNPH, and the healthy controls in this order. The MD values were the highest in the same order. These findings were consistent in the 3 subdivisions of the bilateral hippocampal regions. Hippocampal volume was not different between patients with iNPH and AD. CONCLUSIONS: The microstructural alterations of the hippocampus were more sensitive than the volumetric changes in AD and iNPH. DTI analysis might be a useful tool for discriminating AD from iNPH.

Background Non-fluent agrammatic primary progressive aphasia (naPPA) is characterized by progressive non-fluent speech disorder and might be associated with taupathy such as corticobasal degeneration (CBD) and progressive supranuclear palsy. We report a case of overlap syndrome presented with language impairment, and diagnosed as naPPA with possible CBD. Case Report A 58-year-old woman visited a memory and dementia clinic, with a 10-month history of progressive language disturbance. She was diagnosed as naPPA and overlapping CBD, based on the clinical features and neuroimaging findings including florbetaben PET. Conclusions naPPA is pathologically caused by taupathy, and might progress to asymmetrical parkinsonism and apraxia, suggestive of CBD. Overlapping clinical features in our case represent various phenotypes of taupathy.

Ocular complications of HIV-related cryptococcal meningitis are reasonably common, but complete binocular blindness as the first manifestation of HIV is extremely rare. A 58-year-old man presented with binocular blindness. He experienced blurred vision for 3 days before the blindness. Mild pleocytosis was present in the cerebrospinal fluid, from which Cryptococcus neoformans was cultured. Serology revealed positivity for HIV antibody. He was treated with antifungal and antiretroviral therapy. This case indicates that HIV-related cryptococcal meningitis should be taken into consideration when determining the cause of unexpected sudden binocular blindness. J Clin Neurol 3(4):212-214, 2007

The “closing-in” phenomenon is defined as a tendency to draw objects as closely as possible or overlap the figures in severe cases.1 It was first described by Mayer-Gross.2 Since then, this phenomenon has been reported in patients with various brain lesions and in normal children.3-5 It frequently occurs in patients with Alzheimer’s disease (AD) and is considered a specific neurocognitive indicator of AD.1,6 Little is known about the mechanisms by which the closingin phenomenon occurs. However, several hypotheses have been proposed to explain the pathophysiology of the closingin phenomenon. Mayer-Gross2 described the phenomenon as an aspect of constructional apraxia that reflects “the fear of empty space”. In addition, de Ajuriaguerra et al.4 described the closAnatomical Correlates of the “Closing-In” Phenomenon

Background and Purpose The positive effects of galantamine on cognition and activities of daily living (ADL) in Alzheimer's disease (AD) are thought to be mediated via improvements in attention. The purpose of this study was to determine the effect of galantamine on attention in AD patients using a computerized attention test and to elucidate the relationship between improvements in attention and change in cognition and ADL. Methods In this multicenter, open-label, prospective study, patients with mild to moderate AD received galantamine and then submitted to computerized attention tests, the Alzheimer's Disease Assessment Scale-cognitive subscale, and instrumental ADL (IADL) at baseline, 4 weeks, and 12 weeks. The differences in reaction time on computerized tests were explored relative to the changes in cognition and IADL. Results After 12 weeks of taking the trial medication there was a significant reduction from baseline levels in the choice reaction time (baseline, 5,216±3,650 sec; 12 weeks, 4,139±2,920 sec; p

Subjective memory impairment (SMI) is now increasingly recognized as a risk factor of progression to dementia. This study investigated gray and white matter changes in the brains of SMI patients compared with normal controls and mild cognitive impairment (MCI) patients. We recruited 28 normal controls, 28 subjects with SMI, and 29 patients with MCI aged 60 or older. We analyzed gray and white matter changes using a voxel-based morphometry (VBM), hippocampal volumetry and regions of interest in diffusion tensor imaging (DTI). DTI parameters of corpus callosum and cingulum in SMI showed more white matter changes compared with those in normal controls, they were similar to those in MCI except in the hippocampus, which showed more degenerations in MCI. In VBM, SMI showed atrophy in the frontal, temporal, and parietal lobes compared with normal controls although it was not as extensive as that in MCI. Patients with SMI showed gray and white matter degenerations, the changes were distinct in white matter structures. SMI might be the first presenting symptom within the Alzheimer's disease continuum when combined with additional risk factors and neurodegenerative changes.

Background: Cultural characteristics of taking care of patients with dementia in Korea are based on the influence of Confucianism on the lifestyle of Koreans. In addition, as the family size has been getting smaller, the number of old persons who live alone has been increasing. The purpose of this study is to examine the proportion of the elderly with dementia who live alone and demographics of caregivers when such patients live with their family. Methods: From the multiple hospital-based cohort, 973 elderly patients with very mild dementia (Clinical Dementia Rating [CDR]=0.5), 1,056 patients with mild dementia (CDR=1) and 359 patients with moderate dementia (CDR=2) were recruited. We analyzed the proportion of the patients with dementia who live alone and the demographics of the caregivers if such patients live with and are taken care of by such caregivers depending upon the severity of dementia. Results: The proportion of the patients with dementia who live alone accounts for about 40% of all elderly patients with dementia. Major age groups of caregivers are of 40s and 50s. Sons, daughters, and spouses were ranked in the said order in the proportion of caregivers according to their relationship to patients. Conclusions: Up to now, family members care for about 60% of elderly patients with dementia, which may suggest that from the objective viewpoint, direct burden borne by caregivers for old patients with dementia would be considerably high. On the other hand, about 40% of dementia patients live alone, implying that the social care system is needed for them.