Yeshin Kim

Comparison of cortical thickness in patients with early-stage versus late-stage amnestic mild cognitive impairment.

Disappointing outcomes from clinical trials involving amyloid‐modifying therapies for Alzheimers disease (AD) have prompted more focus on the concept of early‐stage (E) amnestic mild cognitive impairment (E‐aMCI). However, limited evidence suggests that E‐aMCI may represent aMCI at a very early stage of AD. Furthermore, the nature of the progression of E‐aMCI to late‐stage aMCI (L‐aMCI) remains unclear. Therefore, the aim of the present study was to characterize patterns of cortical thinning in both E‐aMCI and L‐aMCI patients.

Prognostic value of amyloid PET scan in normal pressure hydrocephalus

Amyloid positron emission tomography ([18F] florbetaben (FBB) PET) can be used to determine concomitant Alzheimer’s disease (AD) in idiopathic normal pressure hydrocephalus (iNPH) patients. FBB PET scans and the tap test were performed in 31 patients with clinically suspected iNPH, and amyloid positive (iNPH/FBB+) and negative (iNPH/FBB−) groups were compared with respect to clinical characteristics. We evaluated prognostic value of FBB PET scans by analyzing the response to the tap test using a linear mixed model. We also performed a multivariable regression analysis to investigate whether amyloid PET positivity can predict the positive tap test response independent of other AD biomarkers. The results showed that the iNPH/FBB+ group (7/31, 22.6%) had a higher percentage of APOE4 carriers, lower Aβ42, higher CSF t-tau, and p-tau/Aβ42 ratio than the iNPH/FBB− group (24/31, 77.4%), while the two groups did not differ in imaging characteristics. The iNPH/FBB− group had a higher percentage of tap responders and showed a greater improvement in gait scores after the tap test than the iNPH/FBB+ group (group-tap test effect interaction, pxa0=xa00.035). A multivariable logistic regression analysis showed that amyloid positivity on PET scans (OR 0.03, pxa0=xa00.029) and CSF p-tau (OR 0.87, pxa0=xa00.044) were independently associated with the positive tap test response. Among 21 tap responders in the iNPH/FBB− group, 14 patients received shunt surgery and 12/14 (85.7%) patients showed symptom improvement. Our findings suggest that amyloid PET scans can help determine which iNPH patients will benefit from shunt surgery by discriminating concomitant AD.

Assessment of Extent and Role of Tau in Subcortical Vascular Cognitive Impairment Using 18F-AV1451 Positron Emission Tomography Imaging

Importance Amyloid-&bgr; (A&bgr;), tau, and cerebral small vessel disease (CSVD), which occasionally coexist, are the most common causes of cognitive impairments in older people. However, whether tau is observed in patients with subcortical vascular cognitive impairment (SVCI), as well as its associations with A&bgr; and CSVD, are not yet established. More importantly, the role of tau underlying cognitive impairments in SVCI is unknown. Objective To investigate the extent and the role of tau in patients with SVCI using 18F-AV1451, which is a new ligand to detect neurofibrillary tangles in vivo. Design, Setting, and Participants This cross-sectional study recruited 64 patients with SVCI from June 2015 to December 2016 at Samsung Medical Center, Seoul, Korea. The patients had significant ischemia on brain magnetic resonance imaging, defined as periventricular white matter hyperintensity at least 10 mm and deep white matter hyperintensity at least 25 mm. We excluded 3 patients with SVCI owing to segmentation error during AV1451 positron emission tomography analysis. Main Outcomes and Measures We calculated CSVD scores based on the volumes of white matter hyperintensities, numbers of lacunes, and microbleeds using magnetic resonance imaging data. The presence of A&bgr; was assessed using fluorine 18–labeled (18F) florbetaben positron emission tomography. Tau was measured using 18F-AV1451 positron emission tomography. We determined the spreading order of tau by sorting the regional frequencies of cortical involvement. We evaluated the complex associations between A&bgr;, CSVD, AV1451 uptake, and cognition in patients with SVCI. Results Of the 61 patients with SVCI, 44 (72.1%) were women and the mean (SD) age was 78.7 (6.3) years. Patients with SVCI, especially patients with A&bgr;-negative SVCI, showed higher AV1451 uptake in the inferior temporal areas compared with normal control individuals. In patients with SVCI, A&bgr; positivity and CSVD score were each independently associated with increased AV1451 uptake in the medial temporal and inferior temporal regions, respectively. Involvement frequency of AV1451 uptake in the fusiform gyrus, inferior temporal, and precuneus regions were higher than that in the parahippocampal region. In patients with SVCI, higher AV1451 uptake in the inferior temporal and medial temporal regions correlated with worse language and general cognitive function. In patients with SVCI, A&bgr; positivity and CSVD score each correlated with worse general cognitive function, which was completely mediated by AV1451 uptake in the entorhinal cortex and inferior temporal gyrus, respectively. Conclusions and Relevance Our findings suggest that in SVCI, both A&bgr; and CSVD were independently associated with increased tau accumulation. Furthermore, tau burden played a pivotal role because it was the final common pathway for the cognitive impairment in patients with SVCI.

Correlations between Gray Matter and White Matter Degeneration in Pure Alzheimer’s Disease, Pure Subcortical Vascular Dementia, and Mixed Dementia

Alzheimer’s disease dementia (ADD) and subcortical vascular dementia (SVaD) both show cortical thinning and white matter (WM) microstructural changes. We evaluated different patterns of correlation between gray matter (GM) and WM microstructural changes in pure ADD, pure SVaD, and mixed dementia. We enrolled 40 Pittsburgh compound B (PiB) positive ADD patients without WM hyperintensities (pure ADD), 32 PiB negative SVaD patients (pure SVaD), 23 PiB positive SVaD patients (mixed dementia), and 56 normal controls. WM microstructural integrity was quantified using fractional anisotropy (FA), axial diffusivity (DA), and radial diffusivity (DR) values. We used sparse canonical correlation analysis to show correlated regions of cortical thinning and WM microstructural changes. In pure ADD patients, lower FA in the frontoparietal area correlated with cortical thinning in the left inferior parietal lobule and bilateral paracentral lobules. In pure SVaD patients, lower FA and higher DR across extensive WM regions correlated with cortical thinning in bilateral fronto-temporo-parietal regions. In mixed dementia patients, DR and DA changes across extensive WM regions correlated with cortical thinning in the bilateral fronto-temporo-parietal regions. Our findings showed that the relationships between GM and WM degeneration are distinct in pure ADD, pure SVaD, and mixed dementia, suggesting that different pathomechanisms underlie their correlations.

Higher C‐peptide levels are associated with regional cortical thinning in 1093 cognitively normal subjects

Recent studies have demonstrated an association between increased insulin secretion and cognitive impairment. However, there is no previous study that directly evaluates the association between increased insulin secretion and cortical thickness to our knowledge. Therefore, our aim was to evaluate the effect of hyperinsulinemia, as measured by C‐peptide level, on cortical thickness in a large sample of cognitively normal individuals.

Distinctive Clinical Effects of Haemorrhagic Markers in Cerebral Amyloid Angiopathy

Restricted lobar cerebral microbleeds (CMBs) and cortical superficial siderosis (CSS) are the characteristic markers of cerebral amyloid angiopathy (CAA). However, their effects on clinical features has not been evaluated well. The purpose of this study is to investigate the clinical implication of these markers in clinical-radiologically diagnosed CAA. A total of 372 patients with possible or probable CAA who met the modified Boston criteria were recruited in a memory clinic setting. Cortical thickness was measured using surface based methods. Presence of restricted multiple lobar CMBs were independently associated with cortical thinning across the entire cortical regions while presence of CSS was independently associated with cortical thinning primarily in the bilateral frontal region. Presence of restricted multiple lobar CMBs was associated with impairment in all cognitive domains such as attention, language, visuospatial, memory and frontal executive functions while presence of CSS was associated with attention and frontal dysfunction. The relationships of restricted multiple lobar CMBs or CSS with cognitive impairment were partially mediated by thinning in the corresponding cortical regions. Our findings suggested that restricted multiple lobar CMBs and CSS affect distinctive clinical features, providing new insights into potential mechanisms in CAA.

Amyloid involvement in subcortical regions predicts cognitive decline

PurposeWe estimated whether amyloid involvement in subcortical regions may predict cognitive impairment, and established an amyloid staging scheme based on degree of subcortical amyloid involvement.MethodsData from 240 cognitively normal older individuals, 393 participants with mild cognitive impairment, and 126 participants with Alzheimer disease were acquired at Alzheimer’s Disease Neuroimaging Initiative sites. To assess subcortical involvement, we analyzed amyloid deposition in amygdala, putamen, and caudate nucleus. We staged participants into a 3-stage model based on cortical and subcortical amyloid involvement: 382 with no cortical or subcortical involvement as stage 0, 165 with cortical but no subcortical involvement as stage 1, and 203 with both cortical and subcortical involvement as stage 2.ResultsAmyloid accumulation was first observed in cortical regions and spread down to the putamen, caudate nucleus, and amygdala. In longitudinal analysis, changes in MMSE, ADAS-cog 13, FDG PET SUVR, and hippocampal volumes were steepest in stage 2 followed by stage 1 then stage 0 (p value <0.001). Stage 2 showed steeper changes in MMSE score (β [SE]u2009=u2009−0.02 [0.004], pu2009<u20090.001), ADAS-cog 13 (0.05 [0.01], pu2009<u20090.001), FDG PET SUVR (−0.0008 [0.0003], pu2009=u20090.004), and hippocampal volumes (−4.46 [0.65], pu2009<u20090.001) compared to stage 1.ConclusionsWe demonstrated a downward spreading pattern of amyloid, suggesting that amyloid accumulates first in neocortex followed by subcortical structures. Furthermore, our new finding suggested that an amyloid staging scheme based on subcortical involvement might reveal how differential regional accumulation of amyloid affects cognitive decline through functional and structural changes of the brain.

Diagonal Earlobe Crease is a Visible Sign for Cerebral Small Vessel Disease and Amyloid-β

We investigated the frequency and clinical significance of diagonal earlobe crease (DELC) in cognitively impaired patients using imaging biomarkers, such as white matter hyperintensities (WMH) on MRI and amyloid-β (Aβ) PET. A total of 471 cognitively impaired patients and 243 cognitively normal (CN) individuals were included in this study. Compared with CN individuals, cognitively impaired patients had a greater frequency of DELC (OR 1.6, 95% CI 1.1–2.2, Pu2009=u20090.007). This relationship was more prominent in patients with dementia (OR 1.8, 95% CI 1.2–2.7, Pu2009=u20090.002) and subcortical vascular cognitive impairment (OR 2.4, 95% CI 1.6–3.6, Pu2009<u20090.001). Compared with Aβ-negative cognitively impaired patients with minimal WMH, Aβ-positive patients with moderate to severe WMH were significantly more likely to exhibit DELC (OR 7.3, 95% CI 3.4–16.0, Pu2009<u20090.001). We suggest that DELC can serve as a useful supportive sign, not only for the presence of cognitive impairment, but also for cerebral small vessel disease (CSVD) and Aβ-positivity. The relationship between DELC and Aβ-positivity might be explained by the causative role of CSVD in Aβ accumulation.

Pathologically Confirmed Cerebral Amyloid Angiopathy with No Radiological Sign in a Patient with Early Onset Alzheimer's Disease

Cerebral amyloid angiopathy (CAA) is associated with perivascular disruption, which is caused by progressive amyloid-beta (Aβ) deposition in vessels. Previous autopsy studies have shown that the prevalence of CAA in Alzheimers disease (AD) is 70% to 90%. CAA is principally characterized by restricted lobar microbleeds (MBs), which can be detected by gradient-echo T2* (GRE) and susceptibility-weighted imaging (SWI). We herein report on a 62-year-old man who presented with 8 years of memory impairment. The apolipoprotein E (APOE) genotype was ε4/ε4, and a brain GRE performed 28 months before death revealed mild atrophy and no MBs. At autopsy, the patient scored “A3, B3, C3” according to the National Institute on Aging-Alzheimers Association guidelines; the patient thus exhibited a high level of AD neuropathological changes. Furthermore, immunohistochemical staining for Aβ showed antibody accumulation and severe cerebral amyloid angiopathic changes in numerous vessels with amyloid deposits. Our case suggests that radiological CAA markers, such as cerebral microbleed (CMB) or cerebral superficial siderosis, may not suffice to detect amyloid angiopathy in cerebral vessels. CAA should therefore be considered as a combined pathology in APOE ε4 homozygotes with AD, even if such patients do not exhibit CMB on MRI.

Machine Learning-based Individual Assessment of Cortical Atrophy Pattern in Alzheimer's Disease Spectrum: Development of the Classifier and Longitudinal Evaluation

To develop a new method for measuring Alzheimer’s disease (AD)-specific similarity of cortical atrophy patterns at the individual-level, we employed an individual-level machine learning algorithm. A total of 869 cognitively normal (CN) individuals and 473 patients with probable AD dementia who underwent high-resolution 3T brain MRI were included. We propose a machine learning-based method for measuring the similarity of an individual subject’s cortical atrophy pattern with that of a representative AD patient cohort. In addition, we validated this similarity measure in two longitudinal cohorts consisting of 79 patients with amnestic-mild cognitive impairment (aMCI) and 27 patients with probable AD dementia. Surface-based morphometry classifier for discriminating AD from CN showed sensitivity and specificity values of 87.1% and 93.3%, respectively. In the longitudinal validation study, aMCI-converts had higher atrophy similarity at both baseline (pu2009<u20090.001) and first year visits (pu2009<u20090.001) relative to non-converters. Similarly, AD patients with faster decline had higher atrophy similarity than slower decliners at baseline (pu2009=u20090.042), first year (pu2009=u20090.028), and third year visits (pu2009=u20090.027). The AD-specific atrophy similarity measure is a novel approach for the prediction of dementia risk and for the evaluation of AD trajectories on an individual subject level.