Seung Joo Kim

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.

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.

Author Correction: Distinctive Clinical Effects of Haemorrhagic Markers in Cerebral Amyloid Angiopathy

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

CLINICAL EFFECTS OF FRONTAL BEHAVIOR IMPAIRMENT IN NON-DEMENTED INDIVIDUALS: CORTICAL THINNING AND COGNITIVE DECLINE

psychiatric disorders with similar clinical presentations. Methods: We conducted a multi-center naturalistic follow-up study. We included subjects aged 45-75 years presenting with a frontal lobe syndrome, consisting of apathy, disinhibition, and/or compulsive behavior. All participants underwent extensive neuropsychiatric phenotyping, MRI of the brain, [18F]FDG-PET, and CSF biomarker analysis. Genetic analysis was performed when appropriate and in the majority of patients C9orf72 status was investigated. Results:We included 137 subjects. After 2 years of follow-up, data were available of 105 patients. The diagnostic distribution was bvFTD (34 (32%); 30 probable, 4 definite); psychiatric disorders (43 (41%)), and other neurological disorders (28 (27%)). All subjects with a diagnosis of possible bvFTD at baseline (n1⁄45) received a psychiatric diagnosis at follow-up. Depression was the most prevalent psychiatric disorder. Contributing clinical features were stereotyped behavior and disinhibition in favor of bvFTD; and a history of psychiatric disorder, male gender, depressed mood and nervousness in favor of a psychiatric disorder. The Ekman Faces Test successfully discriminated bvFTD from both other groups. MRI had a sensitivity of 70% and specificity of 93% for bvFTD. [18F]FDG-PET, which was performed when MRI was normal or inconclusive, had a sensitivity of 90%, but a specificity of only 68% for bvFTD. The relatively high rate of false-positive bvFTD diagnoses at baseline was partly attributable to false-positive [18F]FDG-PET scans. Combined CSF neurofilament light chain, YKL40, and P-tau/tau ratio had a high diagnostic accuracy to discriminate bvFTD from psychiatric disorders (AUC 0.94). Genetic mutation carriers more often had atypical additional investigations.Conclusions:Our study shows that an abnormal [18F] FDG-PET should be interpreted with caution in the differential diagnosis of the late-onset frontal lobe syndrome, whereas additional CSF biomarkers might be helpful in case of doubt during the diagnostic process. Our findings stress the need for an adapted diagnostic paradigm for bvFTD.

THE BRAIN DONATION PROGRAM IN SOUTH KOREA

pathology, several amyloid plaques were found within the neocortex (fig.2), basal ganglia and entorhinal cortex (Thal stage 3, Montine A2). Diffuse tau pathology was present at the entorhinal cortex (fig.3), and to a lesser degree, at the temporal and parietal cortices (Braak stage II, Montine B2 and C3). a-synuclein immunoreactivity was detected in Substantia Nigra (fig.4) and amygdala (Beach stage III). Conclusions:Our data confirm that neuropathological lesions are part of “normal” aging. They often do not cause a disease when a compensation is triggered. In this subject, the preservation of cognitive abilities may be correlated to his cognitively and socially active life, preventing the clinical manifestation of the disease.

A NOMOGRAM FOR PREDICTING AMYLOID PET POSITIVITY IN AMNESTIC MILD COGNITIVE IMPAIRMENT

load (participants with positive versus negative brain amyloid load) will be determined. Results:Hyperspectral retinal imaging will be completed for the remaining n1⁄440 participants, aged 60 years and above. Data will be analysed via image processing and preliminary findings presented at the conference. Conclusions:Successful validation of hyperspectral retinal imaging will serve as an early, non-invasive and economical diagnostic tool for preclinical AD.

NATURAL HISTORY OF SUBCORTICAL VASCULAR COGNITIVE IMPAIRMENT: AN 8.5-YEAR LONGITUDINAL STUDY

disease and poorer cognition), 2-1, and 2-2 (associated with greater risk for myocardial infarction and mortality). An additional polymorphism in the promoter of the Hp2 allele, restricted to AA descent, yields a fourth genotype, Hp 2-1m. AA have higher prevalence of Hp 1-1 (w33%) compared to Whites (w14%), but the role of the Hp genotype in cognition in AA individuals is unknown. Methods:We used publicly available data and specimens from The Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) study to investigate the association of Hp genotypes with cognitive performance and decline in 466 AA T2D participants. We hypothesized that the Hp 1-1 genotype is associated with greater cognitive impairment and faster cognitive decline compared to other genotypes. Associations were examined with ANCOVA and linear regression adjusting for sociodemographic and T2D-related characteristics. Results:Genotype prevalence was Hp 1-1:29.4%, Hp 2-1:36.1%, Hp 2-1m:10.9%, and Hp 2-2:23.6%. In the overall ANCOVA, the groups differed in their MMSE (p1⁄40.006; Figure). At baseline Hp 2-1m had the highest MMSE score (mean1⁄427.2; SE1⁄40.36, and Hp 1-1 had the poorest MMSE score (mean1⁄425.7; SE1⁄40.23). The MMSE declined in the Hp1-1(adjusted mean decline -0.42 over 40 months), 2-1 (-0.21) and 2-2 (-0.65) genotype carriers whereas the Hp2-1m carriers improved (0.14). The change model adjusted for the same set of covariates, in addition to baseline MMSE. The 40-month decline was significant for Hp 2-2 (p1⁄40.004) and Hp 1-1 (p1⁄40.045). However, the overall comparison across the four groups did not reach statistical significance (p1⁄40.202). Conclusions: The Hp 1-1 genotype, which is 2-fold more prevalent in AA than in Whites, is associated with poorer cognitive function in T2D AA participants in the ACCORD MIND study. Future studies of Hp genotype using more sensitive tests of cognitive function are warranted.

ALZHEIMER’S DEMENTIA CONVERSION IN AMNESTIC MCI ACCORDING TO NEUROPSYCHOLOGICAL PROFILE

annualized change in SUVR were compared between DLB and CN using generalized additive models accounting for matching. Associations between annualized global measures of clinical progression and b-amyloid accumulation were assessed in DLB. Results: The trajectories of longitudinal b-amyloid accumulation were similar between DLB and CN (p1⁄40.425 for difference in trajectory shape; p1⁄40.22 for difference in vertical shift; Figure 1). Rates of b-amyloid accumulation increased up to 1.8 baseline SUVR and then decreased. Increasing changes in clinical dementia rating -sum of boxes were independently associated with higher baseline SUVR (p1⁄40.023) and a greater change in SUVR (p1⁄40.025) until reaching 1.8 baseline SUVR; no relationship was present for >1.8 baseline SUVR (Figure 2). Conclusions: In DLB, b-amyloid accumulation accelerates and is associated with clinical decline up to 1.8 baseline SUVR. At >1.8 baseline SUVR, the accumulation decelerates and dissociates from the clinical progression. Acceleration–deceleration denotes a sigmoid-shaped functional form which is the same in unimpaired, clinical AD dementia, and as we have shown in DLB. Baseline PiB SUVR should be considered in designing clinical trials targeting b-amyloid pathology in DLB.

AMYLOID DEPOSITION IN THE SUBCORTICAL REGION PREDICTS COGNITIVE DECLINE

IC-P-050 AMYLOID DEPOSITION IN THE SUBCORTICAL REGION PREDICTS COGNITIVE DECLINE Soo Hyun Cho, Jeong-Hyeon Shin, Hyemin Jang, Seongbeom Park, Hee Jin Kim, Yeshin Kim, Si Eun Kim, Seung Joo Kim, Hanna Cho, Jin San Lee, Samuel N. Lockhart, Duk L. Na, Joon-Kyung Seong, Sang Won Seo, Samsung Medical Center, Seoul, South Korea; Korea University, Seoul, South Korea; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Yonsei University College of Medicine, Seoul, South Korea; Kyung Hee University Hospital, Seoul, South Korea; Wake Forest School of Medicine, Winston-Salem, NC, USA. Contact e-mail: k906141h@ hanmail.net