Yong S. Shim

Clinical Characteristics of a Nationwide Hospital-based Registry of Mild-to-Moderate Alzheimer's Disease Patients in Korea: A CREDOS (Clinical Research Center for Dementia of South Korea) Study

With rapid population aging, the socioeconomic burden caused by dementia care is snowballing. Although a few community-based studies of Alzheimers 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.

Difference of the hippocampal and white matter microalterations in MCI patients according to the severity of subcortical vascular changes: neuropsychological correlates of diffusion tensor imaging.

OBJECTIVES Most imaging studies of mild cognitive impairment (MCI) have focused on gray matter alterations, although many MCI patients demonstrate subcortical vascular changes. We investigated the changes of the hippocampal area and various white matter areas in MCI patients with using diffusion tensor imaging (DTI), according to the severity of subcortical vascular changes, and we then correlated the DTI findings with the neuropsychological results. PATIENTS AND METHODS Among the 40 MCI patients, the 21 non-vascular MCI (nvMCI) and 19 vascular MCI (vMCI) patients were subdivided according to Erkinjunttis imaging criteria. The mean diffusivity (MD) and fractional anisotropy (FA) were compared in the bilateral temporal, frontal, parietal and occipital white matter regions, as well as in the bilateral hippocampi, centrum semiovale, and the midline genu and splenum of the corpus callosum among the nvMCI and vMCI patients and the 17 controls. The neuropsychological findings were also compared between the subgroups. RESULTS All the MCI patients showed decreased FA and increased MD in all the regions except the occipital areas. In the parietal regions and centrum semiovale, the vMCI patients had a greater FA decrease than the nvMCI patients and controls. In the hippocampi, the FA was lowest in the nvMCI patients. The memory function in the nvMCI patients was more impaired than that in the vMCI patients. The vMCI patients showed impairment of the visuospatial and frontal executive functions. CONCLUSION We were able to correlate the microstructural alterations with the neuropsychological findings in the MCI subgroups.

Impact of white matter changes on activities of daily living in mild to moderate dementia.

The association between white matter changes and activities of daily living (ADL) in a large, well-defined cohort of patients with mild-to-moderate dementia (either Alzheimer’s disease or subcortical vascular dementia) were investigated. A total of 289 patients were divided into three groups (140 mild, 99 moderate, and 50 severe) depending on the degree of white matter changes as indicated on brain magnetic resonance image scans. Further, we analyzed the three groups’ performances on basic and instrumental ADL. The degree of white matter changes was associated with greater age, hypertension, previous history of stroke, higher Hachinski Ischemic Score, worse global cognitive and functional status, and an increased impairment of basic ADL and instrumental ADL. The increased impairment with regard to the severe group’s performance on both the basic and instrumental ADL remained significant after adjustment for age and hypertension. Tasks involving physical activities were most significant. This was the first study investigating the association between white matter changes and ADL in a large, well-defined dementia cohort. The present study suggests that severe white matter changes may be associated with higher impairment on both basic and instrumental ADL.

Tolerability and efficacy of memantine add-on therapy to rivastigmine transdermal patches in mild to moderate Alzheimer's disease: a multicenter, randomized, open-label, parallel-group study

Abstract Objective: To compare the tolerability and efficacy of combination therapy of memantine plus rivastigmine patch with rivastigmine patch monotherapy in patients with mild to moderate Alzheimers disease (AD). Research design and methods: In this multicenter, randomized, open-label study, patients entered an 8-week run-in period (a 5 cm2 rivastigmine patch for 4 weeks, then a 10 cm2 patch for 4 weeks) followed by 16 weeks of memantine plus rivastigmine patch or rivastigmine patch monotherapy. The primary outcome measure was the retention rate at the end of the trial. Clinical trial registration: clinicaltrials.gov. NCT01025466. Results: Overall, 88 and 84 patients received rivastigmine patch with and without memantine, respectively, and of these, 77 (87.5%) and 70 (83.3%) patients completed the study. The difference in retention rate was not significant (95% confidence interval: −6.3–14.7%). The incidence of adverse events (AEs) (53.4 vs. 50.6%) and discontinuation due to AEs (6.8 vs. 4.8%) were not different between patients with and without memantine. The most frequent AEs were skin irritation in patients with and without memantine (42.0 vs. 34.9%, p = 0.71), but discontinuation due to skin irritation was rare (4.5 vs. 2.4%, p = 0.74). The incidence of gastrointestinal AEs was very low in patients with and without memantine (nausea, 2.3 vs. 1.2%; vomiting, 1.1 vs. 1.2%). The Korean Version of the Cohen Mansfield Agitation Inventory scores favored rivastigmine patch monotherapy at the end of treatment (p = 0.01). Changes in other efficacy measures were similar between the groups. Conclusion: There were no significant differences in tolerability and safety between the treatment groups. The combination therapy of memantine plus rivastigmine patch did not show an advantage over rivastigmine patch monotherapy on efficacy analyses. The sample size for comparing tolerability may have been too small to detect a difference of efficacy between the two groups.

Effects of Medial Temporal Atrophy and White Matter Hyperintensities on the Cognitive Functions in Patients with Alzheimer’s Disease

Aims: We conducted this study to investigate the independent association of medial temporal atrophy (MTA) and white matter hyperintensities (WMH) with cognitive impairments of Alzheimer’s disease (AD) patients and the interaction between MTA and WMH. Methods: From 13 centers, a total of 216 AD patients were consecutively recruited and their MTA and WMH were visually rated. We evaluated the association of MTA and WMH with the various cognitive domains, and the interaction between MTA and WMH. Results: MTA independently correlated with scores of the Mini-Mental State Examination (MMSE), Clinical Dementia Rating scale (CDR), delayed recalls of the Seoul Verbal Learning Test (SVLT), the Boston Naming Test (BNT), and Word Fluency. WMH independently correlated with MMSE, CDR, Digit Span, and Stroop word reading, but not with delayed recall. There were interactions of WMH and MTA on CDR (p = 0.004), SVLT (p = 0.023), BNT (p = 0.002) and the semantic Word Fluency (p = 0.007). Conclusion: MTA and WMH independently affected cognitive deficits in AD patients, with somewhat different patterns where MTA was associated mostly with memory and language, while WMH were associated with attention and frontal executive functions. This study also showed interactions between MTA and WMH on some cognitive deficits and dementia severity, suggesting that they synergistically contribute to cognitive impairment in AD.

Microstructural changes in the hippocampus and posterior cingulate in mild cognitive impairment and Alzheimer’s disease: a diffusion tensor imaging study

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.

Comparison of regional cerebral blood flow in two subsets of subcortical ischemic vascular dementia: statistical parametric mapping analysis of SPECT.

BACKGROUND The brain imaging criteria for subcortical ischemic vascular dementia (SIVD), as proposed by Erkinjuntti, incorporated two clinical entities, the lacunar state and Binswangers disease. However it has not been proven whether these two subtypes of SIVD have common pathophysiological features. This study investigated the changes of regional cerebral blood flow (CBF) in the two subsets of SIVD to establish whether these two subtypes could be incorporated into the same group for the purpose of conducting clinical trials. METHODS Twelve SIVD patients with predominant white matter lesions, 13 patients with predominant lacunar infarctions and 17 controls were evaluated. Single photon emission computed tomography (SPECT) was performed to measure the regional CBF, and statistical parametric mapping (SPM) was applied to the analysis of the SPECT data. RESULTS The normalized CBF (nCBF) in the bilateral thalami, the anterior cingulate gyri, the superior temporal gyri, the caudate heads and the left parahippocampal gyrus was significantly decreased in the SIVD patients compared to the controls. This pattern of nCBF reduction was same in both the two subtypes of SIVD patients. CONCLUSION Our study suggests that the two subsets of SIVD may have a common nCBF abnormality, and Erkinjunttis criteria offer a solution for researchers to identify the more homogeneous group of vascular dementia patients.

Different Associations of Periventricular and Deep White Matter Lesions with Cognition, Neuropsychiatric Symptoms, and Daily Activities in Dementia

We investigated the associations of periventricular white matter hyperintensities (PWMHs) and deep white matter hyperintensities (DWMHs) with cognition, activities of daily living (ADLs), and neuropsychiatric symptoms in dementia. This was a hospital-based MRI300 study. We recruited patients newly diagnosed with mild-to-moderate dementia caused either by Alzheimer’s disease or subcortical ischemic vascular dementia from 13 dementia clinics at university or general hospitals in South Korea. We enrolled 289 patients aged over 50 from August 2007 to March 2008. We compared cognition, ADLs, and neuropsychiatric symptoms among 3 groups according to the severities of PWMHs and DWMHs, respectively, by adjusting for age, vascular risk factors, and level of other WMHs. A higher severity of PWMHs was related to lower cognitive function and severer neuropsychiatric symptoms, whereas basic ADLs were associated with DWMH. Both PWMHs and DWMHs exhibited different associations with cognition, neuropsychiatric symptoms, and daily activities.

A serial study of regional cerebral blood flow deficits in patients with left anterior thalamic infarction : Anatomical and neuropsychological correlates

Thalamic damage is associated with a variety of neuropsychological dysfunctions, as well as strategic infarct dementia. However, only a limited number of reports in the medical literature have discussed the correlation between the clinical findings and the specific functional changes observed on images. We investigated the neuropsychological correlation of the regional cerebral blood flow (rCBF) deficits in four patients with left anterior thalamic infarction within two days after their stroke. All of the patients showed anterograde amnesia on the verbal memory test. Some dysexecutive features were present such as decreased word fluency and an impaired performance on the Stroop test. A decreased rCBF was observed in the left supramarginal gyrus, the superior temporal gyrus, the middle and inferior frontal gyri, and the medial dorsal and anterior nuclei of the left thalamus. The changes of rCBF may have been due to remote suppression by the interruption of the thalamo-cortical circuit that connects the anterior thalamic nucleus and various cortical areas. These initial findings remained unchanged even on the follow-up studies.

Effect of literacy and education on the visuoconstructional ability of non-demented elderly individuals.

Learning to read and to write influences not only verbal skills but also global cognitive performance. Our study aimed to compare the visuoconstructional abilities of elderly illiterates with those of elderly literates. A total of 125 healthy subjects over 65 years old were recruited. Korean version of Mini-Mental State Examination (K-MMSE) and the Alzheimers Disease Assessment Scale-cognitive subscale (ADAS-cog) constructional praxis examination were used. We divided subjects into three groups (educated literate n = 53, uneducated literate n = 36 and uneducated illiterate n = 36). Interlocking pentagons drawing, a part of the K-MMSE, was scored using the 6-point hierarchical scale. The uneducated-illiterate group obtained significantly lower scores than did the other two groups. Scores on the ADAS-cog constructional praxis test were highest in the educated-literate group and those in the uneducated-illiterate group obtained the lowest scores. We demonstrated that illiteracy influences not only language performance but also visuoconstructional functioning.