Geon Ha Kim

The Role of Oxidative Stress in Neurodegenerative Diseases.

Oxidative stress is induced by an imbalanced redox states, involving either excessive generation of reactive oxygen species (ROS) or dysfunction of the antioxidant system. The brain is one of organs especially vulnerable to the effects of ROS because of its high oxygen demand and its abundance of peroxidation-susceptible lipid cells. Previous studies have demonstrated that oxidative stress plays a central role in a common pathophysiology of neurodegenerative diseases such as Alzheimers disease and Parkinsons disease. Antioxidant therapy has been suggested for the prevention and treatment of neurodegenerative diseases, although the results with regard to their efficacy of treating neurodegenerative disease have been inconsistent. In this review, we will discuss the role of oxidative stress in the pathophysiology of neurodegenerative diseases and in vivo measurement of an index of damage by oxidative stress. Moreover, the present knowledge on antioxidant in the treatment of neurodegenerative diseases and future directions will be outlined.

Identification of pure subcortical vascular dementia using 11C-Pittsburgh compound B

Background: Subcortical vascular dementia (SVaD) is considered the most common type of vascular dementia and often follows a slowly progressive course, simulating Alzheimer disease (AD). Whether the progressive cognitive decline is associated with pure SVaD or concomitant AD remains unknown. The purpose of this study was to determine what proportion of patients with SVaD lack abnormal amyloid imaging, and to examine differences in the clinical or MRI features between subjects with SVaD with cortical amyloid deposition and those without. Methods: We measured brain amyloid deposition using 11C-Pittsburgh compound B (PiB) PET in 45 patients (men: women = 19:26; mean age 74.2 ± 7.6 years) with SVaD. They all met DSM-IV criteria for vascular dementia and had severe white matter high signal intensities without territorial infarction or macrohemorrhage on MRI. Results: Thirty-one (68.9%) of 45 patients with SVaD were negative for cortical PiB binding. There was significant difference between 11C-PiB-positive and 11C-PiB-negative groups in terms of age (79.5 vs 71.9 years), Mini-Mental State Examination score (18.6 vs 22.6), the number of lacunes (3.9 vs 9.0), and the visual rating scale of hippocampal atrophy (3.1 vs 2.3). The neuropsychological assessments revealed that patients with 11C-PiB-negative SVaD performed better on the delayed recall of both the verbal and visual memory test than did those with 11C-PiB-positive scan. Conclusion: SVaD without abnormal amyloid imaging was more common than expected. Patients with SVaD with and without abnormal amyloid imaging differed in clinical and MRI features, although there was considerable overlap.

Pathogenesis of cerebral microbleeds: In vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment

Cerebral microbleeds (CMBs) are a neuroimaging marker of small vessel disease (SVD) with relevance for understanding disease mechanisms in cerebrovascular disease, cognitive impairment, and normal aging. It is hypothesized that lobar CMBs are due to cerebral amyloid angiopathy (CAA) and deep CMBs are due to subcortical ischemic SVD. We tested this hypothesis using structural magnetic resonance imaging (MRI) markers of subcortical SVD and in vivo imaging of amyloid in patients with cognitive impairment.

Anatomical heterogeneity of Alzheimer disease Based on cortical thickness on MRIs

Objective: Because the signs associated with dementia due to Alzheimer disease (AD) can be heterogeneous, the goal of this study was to use 3-dimensional MRI to examine the various patterns of cortical atrophy that can be associated with dementia of AD type, and to investigate whether AD dementia can be categorized into anatomical subtypes. Methods: High-resolution T1-weighted volumetric MRIs were taken of 152 patients in their earlier stages of AD dementia. The images were processed to measure cortical thickness, and hierarchical agglomerative cluster analysis was performed using Wards clustering linkage. The identified clusters of patients were compared with an age- and sex-matched control group using a general linear model. Results: There were several distinct patterns of cortical atrophy and the number of patterns varied according to the level of cluster analyses. At the 3-cluster level, patients were divided into (1) bilateral medial temporal–dominant atrophy subtype (n = 52, ∼34.2%), (2) parietal-dominant subtype (n = 28, ∼18.4%) in which the bilateral parietal lobes, the precuneus, along with bilateral dorsolateral frontal lobes, were atrophic, and (3) diffuse atrophy subtype (n = 72, ∼47.4%) in which nearly all association cortices revealed atrophy. These 3 subtypes also differed in their demographic and clinical features. Conclusions: This cluster analysis of cortical thickness of the entire brain showed that AD dementia in the earlier stages can be categorized into various anatomical subtypes, with distinct clinical features.

Changes in subcortical structures in early- versus late-onset Alzheimer's disease

Patients with early-onset Alzheimers disease (EOAD) are reported to be different from those with late-onset Alzheimers disease (LOAD) in terms of neuropsychological and neuroimaging findings. In this study, we aimed to compare the longitudinal volume changes of 6 subcortical structures (the amygdala, hippocampus, thalamus, putamen, globus pallidus, and caudate nucleus) between patients with EOAD and LOAD for 3 years. We prospectively recruited 36 patients with probable Alzheimers disease (14 EOAD, 22 LOAD) and 14 normal control subjects. We analyzed the volume of subcortical structures using an automatic surface-based method. At baseline, there were no differences in the volumes of subcortical structures between patients with EOAD and LOAD. However, over 3 years of longitudinal follow-up, patients with EOAD showed more rapid volumetric decline in the caudate, putamen, and thalamus than patients with LOAD, which is consistent with neuropsychological results. Our findings suggested that the cognitive reserve theory might be applicable to explain different decline rates of the volumes of the basal ganglia and thalamus according to onset age.

Longitudinal changes of cortical thickness in early- versus late-onset Alzheimer's disease

Early-onset Alzheimers disease (EOAD) has been shown to progress more rapidly than late-onset Alzheimers disease (LOAD). However, no studies have compared the topography of brain volume reduction over time. The purpose of this 3-year longitudinal study was to compare EOAD and LOAD in terms of their rates of decline in cognitive testing and topography of cortical thinning. We prospectively recruited 36 patients with AD (14 EOAD and 22 LOAD) and 14 normal controls. All subjects were assessed with neuropsychological tests and with magnetic resonance imaging at baseline, Year 1, and Year 3. The EOAD group showed more rapid decline than the LOAD group in attention, language, and frontal-executive tests. The EOAD group also showed more rapid cortical thinning in widespread association cortices. In contrast, the LOAD group presented more rapid cortical thinning than the EOAD group only in the left parahippocampal gyrus. Our study suggests that patients with EOAD show more rapid cortical atrophy than patients with LOAD, which accounts for faster cognitive decline on neuropsychological tests.

A new classification system for ischemia using a combination of deep and periventricular white matter hyperintensities.

The Clinical Research Center for Dementia of South Korea (CREDOS) group developed a new classification system for ischemia using a combination of deep and periventricular white matter hyperintensities (WMHs). In this study, we aimed to evaluate the validity of the CREDOS ischemia classification system. A total of 352 patients with cognitive impairments were included. Their WMH scores were rated using the CREDOS WMH visual rating scale. These patients were divided into 3 groups according to the CREDOS ischemia classification system. The volume of WMH was also automatically measured. The number of lacunes and microbleeds (MBs) were counted. The CREDOS ischemia classification system was revised with factor analysis using vascular risk factors and cerebrovascular disease (CVD) markers (WMH volume, lacunes, and MBs). External validation was performed in another group of patients with cognitive impairment using multinomial logistic regression analysis. The CREDOS WMH visual rating scale showed excellent correlation with the automatically measured volume of WMH. The factor analysis showed that the severe group was expanded to D3P1 and D3P2 in the revised CREDOS ischemia classification system. In the validation group, the presence of vascular risk factors and the severity of CVD markers could be distinguished according to the revised CREDOS ischemia classification. We validated a newly developed classification system for ischemia. This simple visual classification system was capable of providing information on vascular risk factors and CVD markers by simply rating WMH on magnetic resonance imaging.

Effects of cerebrovascular disease and amyloid beta burden on cognition in subjects with subcortical vascular cognitive impairment

Cerebrovascular disease (CVD) and amyloid burden are the most frequent pathologies in subjects with cognitive impairment. However, the relationship between CVD, amyloid burden, and cognition are largely unknown. We aimed to evaluate whether CVD (lacunes, white matter hyperintensities, and microbleeds) and amyloid burden (Pittsburgh compound B [PiB] retention ratio) contribute to cognitive impairment independently or interactively. We recruited 136 patients with subcortical vascular cognitive impairment who underwent magnetic resonance imaging, PiB-positron emission tomography, and neuropsychological testing. The number of lacunes was associated with memory, frontal dysfunctions, and disease severity. The volume of white matter hyperintensities and the PiB retention ratio were associated only with memory dysfunction. There was no direct correlation between CVD markers and PiB retention ratio except that the number of lacunes was negatively correlated with the PiB retention ratio. In addition, there were no interactive effects of CVD and PiB retention ratio on cognition. Our findings suggest that CVD and amyloid burden contribute independently and not interactively to specific patterns of cognitive dysfunction in patients with subcortical vascular cognitive impairment.

Cardiovascular risk factors cause cortical thinning in cognitively impaired patients: relationships among cardiovascular risk factors, white matter hyperintensities, and cortical atrophy.

Cardiovascular risk factors are associated with cognitive impairments. However, the effects of cardiovascular risk factors on the topography of cortical thinning have not yet been studied in patients with mild cognitive impairment (MCI) or dementia. Thus, we aimed to evaluate the topography of cortical thinning related to cardiovascular risk factors and the relationships among cardiovascular risk factors, white matter hyperintensities (WMH), and cortical atrophy. Participants included 226 patients with Alzheimer disease or subcortical vascular dementia and 135 patients with amnestic MCI or subcortical vascular MCI. We automatically measured the volume of WMH and cortical thickness. Hypertension was associated with cortical thinning in the frontal and perisylvian regions, and cortical thinning related to diabetes mellitus (DM) occurred in the frontal region. In path analyses, hypertension accounted for 0.04 of the frontal thinning with the mediation of WMH and 0.16 without the mediation of WMH. In case of DM, it accounted for 0.02 of the frontal thinning with the mediation of WMH and 0.13 without the mediation of WMH. Hypertension and DM predominantly affected frontal thinning both with and without the mediation of WMH, where the effects without the mediation of WMH were greater than those with the mediation of WMH.

Cognitive deficits of pure subcortical vascular dementia vs Alzheimer disease PiB-PET–based study

Objectives: Despite many neuropsychological studies to differentiate subcortical vascular dementia (SVaD) from Alzheimer disease (AD), previous studies did not eliminate confounding effects of mixed Alzheimer and vascular pathology. We aimed to investigate neuropsychological differences between patients with Pittsburgh compound B (PiB)–negative SVaD and those with PiB-positive AD. Methods: We recruited patients who were clinically diagnosed with SVaD or AD and underwent an 11C-PiB-PET scan. All patients with SVaD fulfilled DSM-IV criteria for vascular dementia and had severe white matter hyperintensities. The diagnosis of AD was made on the basis of criteria for probable AD proposed by the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association. Results: The final patient sample consisted of 44/67 (65.7%) patients with SVaD who tested negative for PiB retention [PiB(−) SVaD] and 61/68 (89.7%) patients with AD who tested positive for PiB retention [PiB(+) AD]. Patients with PiB(−) SVaD performed better than patients with PiB(+) AD on both verbal and visual memory tests including delayed recalls of the Seoul Verbal Learning Test and Rey Complex Figure Test. Patients with PiB(−) SVaD were worse than patients with PiB(+) AD on phonemic fluency of the Controlled Oral Word Association Test and Stroop color test. Conclusions: Patients with PiB(−) SVaD were better at memory but worse at frontal function than patients with PiB(+) AD. The differences in memory/frontal functions observed between the 2 groups, however, could not differentiate all individual data due to some overlap in the cutoff threshold.