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      Comparative analyses of plasma amyloid-β levels in heterogeneous and monomerized states by interdigitated microelectrode sensor system

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          Abstract

          We compared levels of Aβ by self-standard in plasma using an interdigitated microelectrode sensor to detect Alzheimer disease.

          Abstract

          Detection of amyloid-β (Aβ) aggregates contributes to the diagnosis of Alzheimer disease (AD). Plasma Aβ is deemed a less invasive and more accessible hallmark of AD, as Aβ can penetrate blood-brain barriers. However, correlations between biofluidic Aβ concentrations and AD progression has been tenuous. Here, we introduce a diagnostic technique that compares the heterogeneous and the monomerized states of Aβ in plasma. We used a small molecule, EPPS [4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid], to dissociate aggregated Aβ into monomers to enhance quantification accuracy. Subsequently, Aβ levels of EPPS-treated plasma were compared to those of untreated samples to minimize inter- and intraindividual variations. The interdigitated microelectrode sensor system was used to measure plasma Aβ levels on a scale of 0.1 pg/ml. The implementation of this self-standard blood test resulted in substantial distinctions between patients with AD and individuals with normal cognition (NC), with selectivity and sensitivity over 90%.

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          Frequent amyloid deposition without significant cognitive impairment among the elderly.

          To characterize the prevalence of amyloid deposition in a clinically unimpaired elderly population, as assessed by Pittsburgh Compound B (PiB) positron emission tomography (PET) imaging, and its relationship to cognitive function, measured with a battery of neuropsychological tests. Subjects underwent cognitive testing and PiB PET imaging (15 mCi for 90 minutes with an ECAT HR+ scanner). Logan graphical analysis was applied to estimate regional PiB retention distribution volume, normalized to a cerebellar reference region volume, to yield distribution volume ratios (DVRs). University medical center. From a community-based sample of volunteers, 43 participants aged 65 to 88 years who did not meet diagnostic criteria for Alzheimer disease or mild cognitive impairment were included. Regional PiB retention and cognitive test performance. Of 43 clinically unimpaired elderly persons imaged, 9 (21%) showed evidence of early amyloid deposition in at least 1 brain area using an objectively determined DVR cutoff. Demographic characteristics did not differ significantly between amyloid-positive and amyloid-negative participants, and neurocognitive performance was not significantly worse among amyloid-positive compared with amyloid-negative participants. Amyloid deposition can be identified among cognitively normal elderly persons during life, and the prevalence of asymptomatic amyloid deposition may be similar to that of symptomatic amyloid deposition. In this group of participants without clinically significant impairment, amyloid deposition was not associated with worse cognitive function, suggesting that an elderly person with a significant amyloid burden can remain cognitively normal. However, this finding is based on relatively small numbers and needs to be replicated in larger cohorts. Longitudinal follow-up of these subjects will be required to support the potential of PiB imaging to identify preclinical Alzheimer disease, or, alternatively, to show that amyloid deposition is not sufficient to cause Alzheimer disease within some specified period.
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            Beta-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer's disease.

            Beta-amyloid (Abeta) deposition is pathognomic for Alzheimer's disease (AD), but may occur in normal elderly people without apparent cognitive effect. Episodic memory impairment is an early and prominent sign of AD, but its relationship with Abeta burden in non-demented persons and in AD patients is unclear. We examined this relationship using 11C-PIB-PET as a quantitative marker of Abeta burden in vivo in healthy ageing (HA), mild cognitive impairment (MCI) and AD. Thirty-one AD, 33 MCI and 32 HA participants completed neuropsychological assessment and a 11C-PIB-PET brain scan. Multiple linear regression analyses were conducted relating episodic memory performance and other cognitive functions to Abeta burden. Ninety-seven percent of AD, 61% of MCI and 22% of HA cases had increased cortical PIB binding, indicating the presence of Abeta plaques. There was a strong relationship between impaired episodic memory performance and PIB binding, both in MCI and HA. This relationship was weaker in AD and less robust for non-memory cognitive domains. Abeta deposition in the asymptomatic elderly is associated with episodic memory impairment. This finding, together with the strong relationship between PIB binding and the severity of memory impairment in MCI, suggests that individuals with increased cortical PIB binding are on the path to Alzheimer's disease. The data also suggests that early intervention trials for AD targeted to non-demented individuals with cerebral Abeta deposition are warranted.
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              Seoul Neuropsychological Screening Battery-Dementia Version (SNSB-D): A Useful Tool for Assessing and Monitoring Cognitive Impairments in Dementia Patients

              The Seoul Neuropsychological Screening Battery (SNSB) is one of the standardized neuropsychological test batteries widely used in Korea. However, it may be a bit too lengthy for patients with decreased attention span; and it does not provide the score of global cognitive function (GCF), which is useful for monitoring patients longitudinally. We sought to validate a dementia version of SNSB (SNSB-D) that was shorter than the original SNSB and contained only scorable tests with a GCF score of 300. We administered SNSB-D to patients with mild cognitive impairment (MCI) (n=43) and Alzheimer's disease (AD) (n=93), and normal controls (NC) (n=77). MCI and AD groups had GCF scores significantly different from NC group, and GCF scores were able to distinguish patients with Clinical Dementia Rating of 0.5 and 1. Test-retest reliability was high, with a correlation coefficient of 0.918 for AD, 0.999 for MCI, and 0.960 for NC. The GCF score significantly correlated with the Mini-Mental State Examination (MMSE). Through ROC-curve analysis, GCF scores were found to yield more accurate diagnoses than the MMSE. The SNSB-D is a valid, reliable tool for assessing the overall cognitive function, and can be used to monitor cognitive changes in patients with dementia.
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                Author and article information

                Journal
                Sci Adv
                Sci Adv
                SciAdv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                April 2019
                17 April 2019
                : 5
                : 4
                : eaav1388
                Affiliations
                [1 ]Integrated Science and Engineering Division, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea.
                [2 ]Department of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea.
                [3 ]Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea.
                [4 ]Department of Clinical Pharmacology and Therapeutics, College of Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
                [5 ]Department of Electrical Engineering, Kwangwoon University, 20 Kwangwoon-ro, Nowon-gu, Seoul 01897, Republic of Korea.
                [6 ]Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea.
                [7 ]Department of Medical Biotechnology, Dongguk University, 30 Pildong-ro 1-gil, Jung-gu, Seoul 04620, Republic of Korea.
                [8 ]Department of Biotechnology, Yonsei University, 50 Yonsei-ro Seodaemun-gu, Seoul 03722, Republic of Korea.
                [9 ]Brain Science Institute, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
                [10 ]Department of Nuclear Medicine, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea.
                [11 ]Department of Neurology of Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea.
                [12 ]Division of RI-Convergence Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea.
                [13 ]Cantis, Sangnok-gu, Ansan-si, Gyeonggi-do 15588, Republic of Korea.
                [14 ]Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea.
                Author notes
                [* ]Corresponding author. Email: y.kim@ 123456yonsei.ac.kr (Y.K.); k.hwang@ 123456khu.ac.kr (K.S.H.)
                [†]

                These authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0001-5029-7082
                http://orcid.org/0000-0001-9003-7912
                http://orcid.org/0000-0003-3757-5652
                http://orcid.org/0000-0002-3243-0529
                http://orcid.org/0000-0002-9121-7031
                http://orcid.org/0000-0001-5839-1110
                http://orcid.org/0000-0001-6869-6671
                http://orcid.org/0000-0001-5235-7114
                http://orcid.org/0000-0002-1681-8574
                http://orcid.org/0000-0001-7344-6060
                http://orcid.org/0000-0002-1146-1916
                http://orcid.org/0000-0002-4318-495X
                http://orcid.org/0000-0003-3590-2074
                Article
                aav1388
                10.1126/sciadv.aav1388
                6469948
                31001580
                7272428c-9f9a-4843-86d2-c3db5b08e782
                Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                : 17 August 2018
                : 25 February 2019
                Funding
                Funded by: doi http://dx.doi.org/10.13039/501100002573, Yonsei University;
                Award ID: 2018-22-0022
                Funded by: doi http://dx.doi.org/10.13039/501100003693, Korea Institute of Science and Technology;
                Award ID: Open Research Program
                Funded by: doi http://dx.doi.org/10.13039/501100003693, Korea Institute of Science and Technology;
                Award ID: Bridge Program
                Funded by: doi http://dx.doi.org/10.13039/501100003710, Korea Health Industry Development Institute;
                Award ID: HI14C3319
                Funded by: doi http://dx.doi.org/10.13039/501100003725, National Research Foundation of Korea;
                Award ID: NRF-2018R1A6A1A03023718
                Funded by: doi http://dx.doi.org/10.13039/501100005006, Asan Institute for Life Sciences, Asan Medical Center;
                Award ID: 2016-0588
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