Ji Soo Shin

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.

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.

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.

Cortical Thinning in Subcortical Vascular Dementia with Negative 11C-PiB PET

To determine the existence of cortical thinning in subcortical vascular dementia (SVaD) with a negative 11C-Pittsburgh compound B (PiB) positron emission tomography scan and to compare the topography of cortical thinning between PiB-negative SVaD and Alzheimers disease (AD), we enrolled 24 patients with PiB(-) SVaD, 81 clinically probable AD individuals, and 72 normal cognitive controls. Compared with controls, cortical thinning in PiB(-) SVaD was most profound in the perisylvian area, medial prefrontal area, and posterior cingulate gyri, while the precuneus and medial temporal lobes were relatively spared. When the cortical thickness of AD and PiB(-) SVaD were directly compared, PiB(-) SVaD demonstrated significant cortical thinning in the bilateral inferior frontal, superior temporal gyri, and right medial frontal and orbitofrontal lobes, while AD showed significant cortical thinning in the right medial temporal region. SVaD without amyloid burden may lead to substantial cortical atrophy. Moreover, characteristic topography of cortical thinning in PiB(-) SVaD suggests different mechanisms of cortical thinning in PiB(-) SVaD and AD.

Distinctive Resting State Network Disruptions Among Alzheimer’s Disease, Subcortical Vascular Dementia, and Mixed Dementia Patients

BACKGROUND Recent advances in resting-state functional MRI have revealed altered functional networks in Alzheimers disease (AD), especially those of the default mode network (DMN) and central executive network (CEN). However, few studies have evaluated whether small vessel disease (SVD) or combined amyloid and SVD burdens affect the DMN or CEN. OBJECTIVE The aim of this study was to evaluate whether SVD or combined amyloid and SVD burdens affect the DMN or CEN. METHODS In this cross-sectional study, we investigated the resting-state functional connectivity within DMN and CEN in 37 Pittsburgh compound-B (PiB)(+) AD, 37 PiB(-) subcortical vascular dementia (SVaD), 13 mixed dementia patients, and 65 normal controls. RESULTS When the resting-state DMN of PiB(+) AD and PiB(-) SVaD patients were compared, the PiB(+) AD patients displayed lower functional connectivity in the inferior parietal lobule while the PiB(-) SVaD patients displayed lower functional connectivity in the medial frontal and superior frontal gyri. Compared to the PiB(-) SVaD or PiB(+) AD, the mixed dementia patients displayed lower functional connectivity within the DMN in the posterior cingulate gyrus. When the resting-state CEN connectivity of PiB(+) AD and PiB(-) SVaD patients were compared, the PiB(-) SVaD patients displayed lower functional connectivity in the anterior insular region. Compared to the PiB(-) SVaD or PiB(+) AD, the mixed dementia patients displayed lower functional connectivity within the CEN in the inferior frontal gyrus. CONCLUSIONS Our findings suggest that in PiB(+) AD and PiB(-) SVaD, there is divergent disruptions in resting-state DMN and CEN. Furthermore, patients with combined amyloid and SVD burdens exhibited more disrupted resting-state DMN and CEN than patients with only amyloid or SVD burden.

Dual Therapy with Cidofovir and Mirtazapine for Progressive Multifocal Leukoencephalopathy in a Sarcoidosis Patient

Background: Progressive multifocal leukoencephalopathy (PML) is a demyelinating central nervous system disease caused by JC virus (JCV) reactivation in immunocompromised patients. The disease course of PML is often progressive, fatal and at present, there are few reports on successful treatment outcomes. Case Report: A 45-year-old man with systemic sarcoidosis presented with rapidly progressive dementia and right hemiparesis. The patient was diagnosed with PML as confirmed via brain biopsy and JCV PCR. With a combination treatment of cidofovir and mirtazapine, there was significant improvement of neurological symptoms without measurable functional deficit. Conclusion: This case suggests that dual therapy with cidofovir and mirtazapine might be an effective treatment option in PML patients with sarcoidosis.

Cerebellar atrophy in patients with subcortical-type vascular cognitive impairment.

Recent studies suggest that the role of the cerebellum extends into cognitive regulation and that subcortical vascular dementia (SVaD) can result in cerebellar atrophy. However, there has been no evaluation of the cerebellar volume in the preclinical stage of SVaD. We aimed to compare cerebellar volume among patients with amnestic mild cognitive impairment (aMCI) and subcortical vascular mild cognitive impairment (svMCI) and evaluate which factors could have contributed to the cerebellar volume. Participants were composed of 355 patients with aMCI, svMCI, Alzheimers disease (AD), and SVaD. Cerebellar volumes were measured using automated methods. A direct comparison of the cerebellar volume in SVaD and AD groups showed that the SVaD group had a statistically smaller cerebellar volume than the AD group. Additionally, the svMCI group had a smaller cerebellar volume than the aMCI group, with the number of lacunes (especially in the supratentorial regions) being associated with cerebellar volume. Cerebellar volumes were associated with some neuropsychological tests, digit span backward and ideomotor apraxia. These findings suggest that cerebellar atrophy may be useful in differentiating subtypes of dementia and the cerebellum plays a potential role in cognition.

Excessive TV watching in patients with frontotemporal dementia

The “environmental dependency syndrome” refers to a loss of personal autonomy such that a person’s environment almost entirely controls their actions. The goal of this study is to learn if patients with frontotemporal degeneration (FTD) exhibit prolonged TV watching, a behavior which may be a symptom of environmental dependency. We recruited 40 patients with FTD and 48 patients with Alzheimer’s disease (AD), and asked these participants’ caregivers about TV watching behaviors including total viewing time and channel/show preference, along with other behaviors indicative of environmental dependency. Compared to AD patients, FTD patients watched TV for a longer time. In addition, the patients who watched more TV showed more signs of environmental dependency. Increased TV watching may be a sign of environmental dependency, however further research is needed to explore other hypotheses.