Ko Woon Kim

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.

Social Event Memory Test (SEMT): A Video-based Memory Test for Predicting Amyloid Positivity for Alzheimer’s Disease

Recent improvements in neuroimaging and molecular markers of Alzheimer’s disease (AD) have aided diagnosis in the early stage of the disease, which greatly increases the chance for successful prevention and treatment. However, the expanding resources for AD diagnosis are unlikely to benefit all elderly due to economic burden. Here, we aimed to develop an inexpensive and sensitive method to detect early-stage AD. A scenario for real-world social event memory test (SEMT) was created and filmed in 360° video. Participants watched the 7-min video through head-mounted display (HMD) and then answered questionnaire about the video. We categorized the SEMT score into recall, recognition, and place-matching scores and compared them to scores on the Mini-Mental State Examination and Seoul Verbal Learning Test. Using the SEMT scores, we built a logistic regression model that discriminated between amyloid positivity and negativity of the participants, with a cross-validation AUC. Furthermore, a classifier was created using support vector machine, which produced 93.8–95.1% sensitivity in classifying individuals into four groups of normal, mild cognitive impairment with or without amyloid, and AD elderly. The high correlation between the SEMT score and amyloid positivity in individuals who experienced virtual social gathering through an HMD opens a new possibility for early diagnosis of AD.

COGNITIVE TRAJECTORIES IN PATIENTS WITH NON-AMNESTIC MILD COGNITIVE IMPAIRMENT: A LONGITUDINAL STUDY

is to examine patterns of apathy and agitation in a residential center, and their relation with general patterns of behavioral and psychological symptoms of dementia (BPSD) and with cognition. Methods: Residents of a nursing home-care facility in L ancara, Lugo(Spain) participated. Groups were created according to Clinical Dementia Rating (CDR) scores. From the total population of 195 residents assessed, 39 participants with CDR-2 (25 women, mean age1⁄483,S.D.1⁄48.10), 55 with CDR-3 (40 women, mean age1⁄4 85.84,S.D.1⁄47.31) and 80 with CRD-4 (63 women, mean age1⁄4 85.76,S.D.1⁄45.52) where selected. Apathy was assessed with the Apathy in Dementia–Nursery Home scale (APADEM-NH), and agitation was assessed with the Spanish version of the Cohen-Mansfield Agitation Inventory (CMAI), within a comprehensive assessment that also included the Neuro-Psychiatric Inventory (NPI), Cornell Scale for Depression in Dementia (CSDD), Spanish versions of the Mini-Mental State Examination (MMSE) and Severe MSSE (SMMSE). The psychopharmacological treatment was also recorded. Bivariate correlations and group comparisons were conducted using non-parametric tests. Results: Group differences were found according to the CDR groups for APADEM-NH (c1⁄469.13; df1⁄42;p<0.000) and CMAI scores (c1⁄423.61; df1⁄42;p<0.000), with higher levels of apathy and agitation in CDR-3. APADEM level obtained high negative correlations with MMSE (r1⁄4-0.80) and SMMSE (r1⁄4-0.79) scores, but did not reach significance in its correlations with NPI, CSDD and CMAI. CMAI obtained significant but low correlations with MMSE (r1⁄4-0.21) and SMMSE (r1⁄4-0.25), and high correlations with NPI (r1⁄40.58) and CSDD (r1⁄40.79) total scores. Significantly higher APADEM-NH and CMAI scores were associated with the intake of antipsychotics (Z1⁄4-2.28; df1⁄41; p<0.05 and Z1⁄4-1.85; df1⁄41; p<0.000, respectively) and sedatives (Z1⁄42.96; df1⁄41; p<0.05 and Z1⁄4-2.39; df1⁄41; p<0.05, respectively), and significantly higher APADEM-NH scores with the intake of cognitive enhancers (Z1⁄4-2.09; df1⁄41; p<0.05). Conclusions: Different patterns of apathy and agitation can be observed in a sample of dementia patients living in a nursing home. Further analyses are needed in order to classify the patients according to the BPSD observed and their use of drugs, and to explore implications for care.

CLINICAL EFFECT OF SMALL-VESSEL DISEASE AND WHITE MATTER NETWORK ON DEPRESSION IN PATIENTS WITH COGNITIVE IMPAIRMENT

grey matter density at every voxel. The images were false discovery rate corrected at 0.01. We further carried out an analysis of variance to compare the synergistic model with the independent and additive models. Results: We found that the synergism between, rather than the independent or additive effects of, amyloid-b and tau pathologies in the precuneus, posterior cingulate, inferior parietal, lateral temporal andmedial prefrontal corticeswas associatedwithworse clinical status in the predementia phase ofAD (Fig.1). In addition, an analysis of variance strongly supported that the model with the interaction term best described the cognitive status, as compared to models testing only amyloid-b, only tau, and amyloid-b plus tau with a P<0.0001 in all three cases. Conclusions:These findings expand upon previous studies using cerebrospinal fluid by suggesting that amyloid-b and tau synergistically, rather than independently or additively, determine disease progression in the predementia phase of AD. Interestingly, the regions where such a synergismdeterminedworse clinical statuswere confined to the functional hubs of the brain’s default model network, which are postulated to be fundamental to the large-scale brain organization. [1] Pascoal.TA.et.al.Synergistic interaction between amyloid and tau predicts the progression to dementia. Alzheimer’s&dementia.2016. [2] Pascoal.TA.et.al.Amyloid-beta and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer’s disease. Mol.Psychiatry 2016.

DIAGONAL EARLOBE CREASE, CEREBRAL SMALL VESSEL DISEASE, AND BETA-AMYLOIDOSIS IN COGNITIVELY IMPAIRED PATIENTS

and the covariance parameters between the baseline CSF Ab42, TAU and PTAU volume change over time indicated that OSA participants experienced a faster decrease in CSF Ab42 and increases in TAU and PTAU volumes over time (p < .0001 for all) in both the CN and MCI groups. Conclusions: OSA possibly accelerates longitudinal changes in brain amyloid deposition, and CSF biomarkers burden, both in elderly cognitive normal and MCI individuals. Further research examining mechanisms underlying these observed effects are needed.

18 F-AV1451 PET IMAGING IN SUBCORTICAL VASCULAR COGNITIVE IMPAIRMENT

TAOK inhibitor. The resulting alterations in Tau phosphorylation and neuron morphology were examined using immunofluorescence and immunoblotting. Changes in TAOK catalytic activity associated with neurodegeneration were assessed by immunohistochemical staining of human AD (Braak II-VI) brains and transgenic hTau and rTg4510 mouse brain sections. Results: A novel TAOK inhibitor reduces Tau phosphorylation in primary rat cortical neurons and cells transfected with human Tau. Two novel PHF-Tau associated residues (Thr 123 and Thr 427) were identified and shown to be phosphorylated by TAOKs. Both Tau residues appear to be phosphorylated specifically by TAOKs and were identified to be phosphorylated in brain sections from AD patients (Braak II-VI) and tauopathy mouse models. Conclusions: The results demonstrate that Tau is a key substrate for TAOKs and that the phosphorylation of Tau by TAOKs can be reduced by a novel small molecule inhibitor. Catalytically active TAOKs and phosphorylated Tau (p-Thr123 and p-Thr427) occur in NFTs in early (Braak II) and late (Braak V-VI) AD brain sections and also in brain sections from Tau transgenic mouse models. These results are consistent with functional roles for TAOKs in the development of Tau pathology in neurodegenerative disease.

TRAJECTORIES OF PHYSIOLOGICAL BRAIN AGING AND RELATED FACTORS IN PEOPLE AGED 20 TO OVER 80

O2-11-01 TRAJECTORIES OF PHYSIOLOGICAL BRAIN AGING AND RELATED FACTORS IN PEOPLE AGED 20 TO OVER 80 Jin San Lee, Seonwoo Kim, Heejin Yoo, Young Kyoung Jang, Hee Jin Kim, Ko Woon Kim, Yeshin Kim, Hyemin Jang, Kristine Yaffe, Key-Chung Park, Duk L. Na, Sang Won Seo, Kyung Hee University Hospital, Seoul, Republic of South Korea; Samsung Medical Center, Seoul, Republic of South Korea; University of California San Francisco, San Francisco, CA, USA; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of South Korea. Contact e-mail: xpist@naver.com

SYNERGISTIC EFFECT OF TAU, AMYLOID, AND VASCULAR BURDEN ON COGNITIVE DECLINE IN PATIENTS WITH SUBCORTICAL VASCULAR COGNITIVE IMPAIRMENTS

Background:There is increasing evidence that cerebrovascular disease (CVD) plays a role in Alzheimer’s disease (AD) pathogenesis. Neuroimaging studies typically measure CVD markers and neurodegeneration and then treat them as separate factors. Clinical manifestations of AD likely result from a combination of CVD and neurodegeneration, which varies across individuals. We created a single MRI-based phenotype score that captures the relative contribution AD-related CVD and neurodegeneration.Methods:In a community-based study of aging and dementia, MRI scans were acquired on 1,333 participants (mean age1⁄477.3+6.4,62% women), in two independent samples (n1⁄4768 and n1⁄4564) and analyzed for two cerebrovascular markers (white matter hyperintensity[WMH] volume, presence of infarct) and two neurodegeneration markers (hippocampal volume, cortical thickness). We used linear regression to examine the relative independent relationship of each with age-adjusted memory scores in the first sample. We computed the phenotype score by taking the linear combination of the four MRI markers weighted by their relative contribution to memory, and tested the extent to which this score related to memory in the second sample and to diagnosis in a combined analysis. We further validated the phenotype among 42 participants who came to autopsy. Results:Based on b weights from the linear regression, the phenotype was derived with the following equation: CVD-AD phenotype1⁄4-0.067*WMH volume-0.031*infarct presence+0.00018*hippocampus volume+0.76*cortical thickness. This CVD-AD score was strongly related to memory in the first, second, and combined samples (all ps<0.001). Those with AD(n1⁄442) had lower scores than those with MCI(n1⁄4200), who had lower scores than controls (n1⁄4766;F1⁄446.78,p<0.001). The phenotype was strongly related to pathology measures of neurofibrillary tangles(r1⁄4-0.435,p1⁄40.004), neuropil threads(r1⁄4-0.381,p1⁄40.001), neuronal loss(r1⁄40.361,p1⁄40.023), atrophy(r1⁄4-0.367,p1⁄40.017), and small vessel cerebrovascular disease(r1⁄40.308,p1⁄40.042). Conclusions:We derived a single phenotype that reflects the combination of AD-related CVD and neurodegeneration weighted by their relative importance to memory. We validated the score in an independent sample, and by showing its relationship with diagnostic category and neuropathology. In addition to its utility as an outcome or predictor, our findings suggest that both CVD and neurodegeneration are core features of AD and that the expression of the disease clinically in an individual may be due to the unique combination of the two features.

PREVALENCE OF AMYLOID-PET POSITIVITY ACCORDING TO AGE AND APOE GENOTYPE IN PATIENTS WITH SUBCORTICAL VASCULAR COGNITIVE IMPAIRMENT

Background:Amnestic mild cognitive impairment (aMCI) refers to transitional state between normal aging and Alzheimer’s disease dementia. Previous studies suggested that there is a hierarchical order in aMCI. Especially, pathological studies revealed that aMCI had a variety of neurofibrillary Braak stages ranging 0 to VI. Recently, positron emission tomography (PET) tracers such as F-THK5351 ligand has been developed to detect tau deposition in-vivo. However, not much is known about the extent of in-vivo tau accumulation and its impact on cognition in aMCI patients. Therefore, we aimed to measure in-vivo Braak stage using FTHK5351 PET imaging. In addition, we evaluated the association between tau burden and cognition. Methods: We recruited 56 aMCI patients from Samsung Medical Center and Asan Medical Center. The presence of amyloid-ß was assessed by F-florbetaben PET. Paired helical filament tau was measured by F-THK5351 PET. Using conditional inference tree method, we classified each patient into in-vivo Braak stages based on mean THK5351 SUVR in the regions of anatomical Braak stages. Results: Of 56 aMCI patients, 6 (10.7%) were classified to in-vivo Braak stage 0, 6 (10.7%) to Braak stage I/II, 24 (42.9%) to Braak stage III/IV, and 20 (35.7%) to Braak stage V/VI. Among 31 amyloid positive aMCI patients, majority of patients were in Braak stage V/VI (45.2%), followed by Braak stage III/IV (38.7%), Braak stage I/II (10.7%) and Braak stage 0 (10.7%). However, among 25 amyloid negative aMCI patients, majority of patients were in Braak stage III/IV (48.0%), followed by Braak stage V/VI (24.0%), Braak stage I (16.0%), and Braak stage 0 (12.0%). THK5351 SUVR in limbic (Braak III/IV ROI) or isocortical (Braak V/VI ROI) area each correlated with visuospatial dysfunction; and THK5351 SUVR in entorhinal (Braak I/II ROI), limbic or isocortical area each correlated with visual memory impairment. Conclusions: We suggest that both amyloid positive and negative aMCI patients have various in-vivo Braak stages and that amyloid positive patients tend to be in higher Braak stages. Tau burden in limbic or isocortical areas was related to visuospatial and visual memory function.

PROTECTIVE EFFECTS OF EDUCATION ON THK-5351 UPTAKES IN MILD COGNITIVE IMPAIRMENT WITH SUSPECTED NON-ALZHEIMER PATHOLOGY

A-NLeft rostal middle frontal .730 .040 Left parahippocampal -.726 .042 Left temporal pole .892 .003 Left transverse temporal .784 .021 Left entorhinal -.783 .022 Right temporal pole .735 .038 Left caudal anterior cingulate .934 .001 Left posterior cingulate .848 .008 Left rostal anterior cingulate .712 .048 A-N+ Left pars orbitalis -.537 .039 Left pars triangularis -.630 .012 Left isthmus cingulate -.430 .036 Left banks of superior temporal sulcus -.523 .046 Right transverse temporal -.520 .047 Left precuneus -.538 .038 Left supramarginal -.546 .035 Left inferiorparietal -.554 .032 Right supramarginal -.527 .044 Left cuneus -.540 .038 Left isthmus cingulate -.577 .024 Poster Presentations: Monday, July 17, 2017 P798