Byoung Seok Ye

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.

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.

Clinical effect of white matter network disruption related to amyloid and small vessel disease

Background: We tested our hypothesis that the white matter network might mediate the effect of amyloid and small vessel disease (SVD) on cortical thickness and/or cognition. Methods: We prospectively recruited 232 patients with cognitive impairment. Amyloid was assessed using Pittsburgh compound B–PET. SVD was quantified as white matter hyperintensity volume and lacune number. The regional white matter network connectivity was measured as regional nodal efficiency by applying graph theoretical analysis to diffusion tensor imaging data. We measured cortical thickness and performed neuropsychological tests. Results: SVD burden was associated with decreased nodal efficiency in the bilateral frontal, lateral temporal, lateral parietal, and occipital regions. Path analyses showed that the frontal nodal efficiency mediated the effect of SVD on the frontal atrophy and frontal-executive dysfunction. The temporoparietal nodal efficiency mediated the effect of SVD on the temporoparietal atrophy and memory dysfunction. However, Pittsburgh compound B retention ratio affected cortical atrophy and cognitive impairment without being mediated by nodal efficiency. Conclusions: We suggest that a disrupted white matter network mediates the effect of SVD, but not amyloid, on specific patterns of cortical atrophy and/or cognitive impairment. Therefore, our findings provide insight to better understand how amyloid and SVD burden can give rise to brain atrophy or cognitive impairment in specific patterns.

Effects of education on the progression of early- versus late-stage mild cognitive impairment.

BACKGROUND Highly educated participants with normal cognition show lower incidence of Alzheimers disease (AD) than poorly educated participants, whereas longitudinal studies involving AD have reported that higher education is associated with more rapid cognitive decline. We aimed to evaluate whether highly educated amnestic mild cognitive impairment (aMCI) participants show more rapid cognitive decline than those with lower levels of education. METHODS A total of 249 aMCI patients enrolled from 31 memory clinics using the standard assessment and diagnostic processes were followed with neuropsychological evaluation (duration 17.2 ± 8.8 months). According to baseline performances on memory tests, participants were divided into early-stage aMCI (-1.5 to -1.0 standard deviation (SD)) and late-stage aMCI (below -1.5 SD) groups. Risk of AD conversion and changes in neuropsychological performances according to the level of education were evaluated. RESULTS Sixty-two patients converted to AD over a mean follow-up of 1.43 years. The risk of AD conversion was higher in late-stage aMCI than early-stage aMCI. Cox proportional hazard models showed that aMCI participants, and late-stage aMCI participants in particular, with higher levels of education had a higher risk of AD conversion than those with lower levels of education. Late-stage aMCI participants with higher education showed faster cognitive decline in language, memory, and Clinical Dementia Rating Sum of Boxes (CDR-SOB) scores. On the contrary, early-stage aMCI participants with higher education showed slower cognitive decline in MMSE and CDR-SOB scores. CONCLUSIONS Our findings suggest that the protective effects of education against cognitive decline remain in early-stage aMCI and disappear in late-stage aMCI.

Long‐term efficacy and tolerability of topiramate as add‐on therapy in refractory partial epilepsy: An observational study

Purpose:  To evaluate the long‐term efficacy and tolerability of topiramate (TPM) as add‐on therapy in patients with refractory partial epilepsy.

Amyloid deposition in early onset versus late onset Alzheimer's disease.

BACKGROUND Patients with early-onset Alzheimers disease (EOAD) may differ from those with late-onset Alzheimers disease (LOAD) in cognitive impairment profiles and clinical course. Postmortem studies also reported that EOAD has a greater pathologic burden than LOAD. We examined the effects of age at onset on the burden and distribution of amyloid plaques in patients with AD, using a statistical parametric mapping (SPM) and regions of interest (ROIs) analyses of the Pittsburgh compound B (PiB)-PET. METHODS We initially recruited 72 patients with AD who had completed the [11C] PiB-PET scan, but four patients were excluded due to familial AD or incomplete MRI data. Of the 68 patients, 61 were classified as PiB-positive (PiB+) and seven as PiB-negative (PiB-) using the measured global PiB uptake ratio values. Of the 61 patients with PiB+ AD, in order to maximize the effect of onset age, we excluded 20 patients in their 60 s. Thus among the remaining 41 patients, the amyloid deposition of only 17 patients with EOAD (age onset <60 years) and 24 patients with LOAD (onset age ≥70 years) were compared. RESULTS There were no significant differences in the global mean PiB index between EOAD and LOAD patients, whereas SPM and ROIs analyses showed that those with EOAD retained higher levels of PiB in the bilateral basal ganglia, bilateral thalamus, left superior temporal cortex, and left cuneus compared to those with LOAD. CONCLUSION Our findings demonstrated that EOAD patients differed from those with LOAD in the topography of amyloid deposition, which may partly account for the findings from previous studies that extrapyramidal symptoms and frontal dysfunction are more common in EOAD than in LOAD patients.

Amyloid burden, cerebrovascular disease, brain atrophy, and cognition in cognitively impaired patients

We investigated the independent effects of Alzheimers disease (AD) and cerebrovascular disease (CVD) pathologies on brain structural changes and cognition.

Shape Changes of the Basal Ganglia and Thalamus in Alzheimer's Disease: A Three-Year Longitudinal Study

BACKGROUND A large number of Alzheimers disease (AD) studies have focused on medial temporal and cortical atrophy, while changes in the basal ganglia or thalamus have received less attention. OBJECTIVE The aim of this study was to investigate the existence of progressive topographical shape changes in the basal ganglia (caudate nucleus, putamen, and globus pallidus) and thalamus concurrent with AD disease progression over three years. This study also examined whether declines in volumes of the basal ganglia or thalamus might be responsible for cognitive decline in patients with AD. METHODS Thirty-six patients with early stage AD and 14 normal control subjects were prospectively recruited for this study. All subjects were assessed with neuropsychological tests and MRI at baseline and Years 1 and 3. A longitudinal shape analysis of the basal ganglia and thalamus was performed by employing a boundary surface-based shape analysis method. RESULTS AD patients exhibited specific regional atrophy in the right caudate nucleus and the bilateral putamen at baseline, and as the disease progressed, regional atrophic changes in the left caudate nucleus were found to conform to a distinct topography after controlling the total brain volume. Volumetric decline of the caudate nucleus and putamen correlated with cognitive decline in frontal function after controlling for age, gender, education, follow-up years, and total brain volume changes. CONCLUSION Our findings suggest that shape changes of the basal ganglia occurred regardless of whole brain atrophy as AD progressed and were also responsible for cognitive decline that was observed from the frontal function tests.

Cortical thickness and hippocampal shape in pure vascular mild cognitive impairment and dementia of subcortical type

The progression pattern of brain structural changes in patients with isolated cerebrovascular disease (CVD) remains unclear. To investigate the role of isolated CVD in cognitive impairment patients, patterns of cortical thinning and hippocampal atrophy in pure subcortical vascular mild cognitive impairment (svMCI) and pure subcortical vascular dementia (SVaD) patients were characterized.