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      Prediction of cognitive impairment via deep learning trained with multi-center neuropsychological test data

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          Abstract

          Background

          Neuropsychological tests (NPTs) are important tools for informing diagnoses of cognitive impairment (CI). However, interpreting NPTs requires specialists and is thus time-consuming. To streamline the application of NPTs in clinical settings, we developed and evaluated the accuracy of a machine learning algorithm using multi-center NPT data.

          Methods

          Multi-center data were obtained from 14,926 formal neuropsychological assessments (Seoul Neuropsychological Screening Battery), which were classified into normal cognition (NC), mild cognitive impairment (MCI) and Alzheimer’s disease dementia (ADD). We trained a machine learning model with artificial neural network algorithm using TensorFlow ( https://www.tensorflow.org) to distinguish cognitive state with the 46-variable data and measured prediction accuracies from 10 randomly selected datasets. The features of the NPT were listed in order of their contribution to the outcome using Recursive Feature Elimination.

          Results

          The ten times mean accuracies of identifying CI (MCI and ADD) achieved by 96.66 ± 0.52% of the balanced dataset and 97.23 ± 0.32% of the clinic-based dataset, and the accuracies for predicting cognitive states (NC, MCI or ADD) were 95.49 ± 0.53 and 96.34 ± 1.03%. The sensitivity to the detection CI and MCI in the balanced dataset were 96.0 and 96.0%, and the specificity were 96.8 and 97.4%, respectively. The ‘time orientation’ and ‘3-word recall’ score of MMSE were highly ranked features in predicting CI and cognitive state. The twelve features reduced from 46 variable of NPTs with age and education had contributed to more than 90% accuracy in predicting cognitive impairment.

          Conclusions

          The machine learning algorithm for NPTs has suggested potential use as a reference in differentiating cognitive impairment in the clinical setting.

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          Most cited references27

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          Machine learning framework for early MRI-based Alzheimer's conversion prediction in MCI subjects.

          Mild cognitive impairment (MCI) is a transitional stage between age-related cognitive decline and Alzheimer's disease (AD). For the effective treatment of AD, it would be important to identify MCI patients at high risk for conversion to AD. In this study, we present a novel magnetic resonance imaging (MRI)-based method for predicting the MCI-to-AD conversion from one to three years before the clinical diagnosis. First, we developed a novel MRI biomarker of MCI-to-AD conversion using semi-supervised learning and then integrated it with age and cognitive measures about the subjects using a supervised learning algorithm resulting in what we call the aggregate biomarker. The novel characteristics of the methods for learning the biomarkers are as follows: 1) We used a semi-supervised learning method (low density separation) for the construction of MRI biomarker as opposed to more typical supervised methods; 2) We performed a feature selection on MRI data from AD subjects and normal controls without using data from MCI subjects via regularized logistic regression; 3) We removed the aging effects from the MRI data before the classifier training to prevent possible confounding between AD and age related atrophies; and 4) We constructed the aggregate biomarker by first learning a separate MRI biomarker and then combining it with age and cognitive measures about the MCI subjects at the baseline by applying a random forest classifier. We experimentally demonstrated the added value of these novel characteristics in predicting the MCI-to-AD conversion on data obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. With the ADNI data, the MRI biomarker achieved a 10-fold cross-validated area under the receiver operating characteristic curve (AUC) of 0.7661 in discriminating progressive MCI patients (pMCI) from stable MCI patients (sMCI). Our aggregate biomarker based on MRI data together with baseline cognitive measurements and age achieved a 10-fold cross-validated AUC score of 0.9020 in discriminating pMCI from sMCI. The results presented in this study demonstrate the potential of the suggested approach for early AD diagnosis and an important role of MRI in the MCI-to-AD conversion prediction. However, it is evident based on our results that combining MRI data with cognitive test results improved the accuracy of the MCI-to-AD conversion prediction.
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            Clinical and empirical applications of the Rey-Osterrieth Complex Figure Test.

            The Rey-Osterrieth Complex Figure Test (ROCF), which was developed by Rey in 1941 and standardized by Osterrieth in 1944, is a widely used neuropsychological test for the evaluation of visuospatial constructional ability and visual memory. Recently, the ROCF has been a useful tool for measuring executive function that is mediated by the prefrontal lobe. The ROCF consists of three test conditions: Copy, Immediate Recall and Delayed Recall. At the first step, subjects are given the ROCF stimulus card, and then asked to draw the same figure. Subsequently, they are instructed to draw what they remembered. Then, after a delay of 30 min, they are required to draw the same figure once again. The anticipated results vary according to the scoring system used, but commonly include scores related to location, accuracy and organization. Each condition of the ROCF takes 10 min to complete and the overall time of completion is about 30 min.
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              Consensus report of the Working Group on: "Molecular and Biochemical Markers of Alzheimer's Disease". The Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the National Institute on Aging Working Group.

              (2015)
              The ideal biomarker for Alzheimer's disease (AD) should detect a fundamental feature of neuropathology and be validated in neuropathologically-confirmed cases; it should have a sensitivity >80% for detecting AD and a specificity of >80% for distinguishing other dementias; it should be reliable, reproducible, non-invasive, simple to perform, and inexpensive. Recommended steps to establish a biomarker include confirmation by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. Our review of current candidate markers indicates that for suspected early-onset familial AD, it is appropriate to search for mutations in the presenilin 1, presenilin 2, and amyloid precursor protein genes. Individuals with these mutations typically have increased levels of the amyloid Abeta42 peptide in plasma and decreased levels of APPs in cerebrospinal fluid. In late-onset and sporadic AD, these measures are not useful, but detecting an apolipoprotein E e4 allele can add confidence to the clinical diagnosis. Among the other proposed molecular and biochemical markers for sporadic AD, cerebrospinal fluid assays showing low levels of Abeta42 and high levels of tau come closest to fulfilling criteria for a useful biomarker.
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                Author and article information

                Contributors
                minju0321@naver.com
                neuroksy@snu.ac.kr
                dukna@naver.com
                byeckim@gmail.com
                neuroman@catholic.ac.kr
                eunjookim@pusan.ac.kr
                neuna102@gmail.com
                neurohan5403@gmail.com
                jhlee@amc.seoul.kr
                jh7521@naver.com
                khpark@gachon.ac.kr
                neuropark@dau.ac.kr
                alzdoc@kuh.ac.kr
                sykim@amc.seoul.kr
                trumind@eulji.ac.kr
                boradori3@hanmail.net
                sangwonseo@empas.com
                symoon.bv@gmail.com
                astro76@naver.com
                ysshim@catholic.ac.kr
                mjbaek1208@hanmail.net
                jjeong@ewha.ac.kr
                seonghye@inha.ac.kr
                82-2-6299-1485 , neudoc@cau.ac.kr
                Journal
                BMC Med Inform Decis Mak
                BMC Med Inform Decis Mak
                BMC Medical Informatics and Decision Making
                BioMed Central (London )
                1472-6947
                21 November 2019
                21 November 2019
                2019
                : 19
                : 231
                Affiliations
                [1 ]ISNI 0000 0004 0470 5905, GRID grid.31501.36, Department of Neurology, , Seoul National University College of Medicine & Seoul National University Bundang Hospital, ; Seoul, South Korea
                [2 ]Department of Neurology, Veterans Health Service Medical Center, Seoul, South Korea
                [3 ]ISNI 0000 0001 2181 989X, GRID grid.264381.a, Department of Neurology, Samsung Medical Center, , Sungkyunkwan University School of Medicine, ; Seoul, South Korea
                [4 ]ISNI 0000 0001 0356 9399, GRID grid.14005.30, Department of Neurology, , Chonnam National University Medical School, ; Gwangju, South Korea
                [5 ]ISNI 0000 0004 0470 4224, GRID grid.411947.e, Department of Neurology, College of Medicine, , The Catholic University of Korea, ; Seoul, South Korea
                [6 ]Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Busan, South Korea
                [7 ]ISNI 0000 0004 0608 4962, GRID grid.476893.7, The Brain Fitness Center, , Bobath Memorial Hospital, ; Seongnam, South Korea
                [8 ]ISNI 0000 0004 0475 0976, GRID grid.416355.0, Department of Neurology, , Myongji Hospital, Hanyang University College of Medicine, ; Goyang, South Korea
                [9 ]ISNI 0000 0001 0842 2126, GRID grid.413967.e, Department of Neurology, , University of Ulsan College of Medicine, Asan Medical Center, ; Seoul, South Korea
                [10 ]ISNI 0000 0004 0647 2391, GRID grid.416665.6, Department of Neurology, Dementia Center, , Ilsan Hospital, National Health Insurance Service, ; Goyang, South Korea
                [11 ]GRID grid.411652.5, Department of Neurology, , College of Medicine, Gachon University Gil Hospital, ; Incheon, South Korea
                [12 ]ISNI 0000 0001 2218 7142, GRID grid.255166.3, Department of Neurology, , Dong-A University College of Medicine and Institute of Convergence Bio-Health, ; Busan, South Korea
                [13 ]ISNI 0000 0004 0371 843X, GRID grid.411120.7, Department of Neurology, , Konkuk University Medical Center, ; Seoul, South Korea
                [14 ]ISNI 0000 0001 0842 2126, GRID grid.413967.e, Department of Psychiatry, , University of Ulsan College of Medicine, Asan Medical Center, ; Seoul, South Korea
                [15 ]ISNI 0000 0004 1798 4296, GRID grid.255588.7, Department of Neurology, , Eulji University College of Medicine, ; Daejeon, South Korea
                [16 ]Department of Neurology, Konyang University Hospital, College of Medicine, Konyang University, Daejeon, South Korea
                [17 ]ISNI 0000 0004 0532 3933, GRID grid.251916.8, Department of Neurology, , Ajou University School of Medicine, ; Suwon, South Korea
                [18 ]ISNI 0000 0004 0470 4224, GRID grid.411947.e, Department of Neurology, , Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, ; Seoul, South Korea
                [19 ]ISNI 0000 0001 2171 7754, GRID grid.255649.9, Department of Neurology, , Ewha Womans University School of Medicine, ; Seoul, South Korea
                [20 ]ISNI 0000 0001 2364 8385, GRID grid.202119.9, Department of Neurology, , Inha University School of Medicine, ; Incheon, South Korea
                [21 ]ISNI 0000 0001 0789 9563, GRID grid.254224.7, Department of Neurology, College of Medicine, , Chung-Ang University, ; Seoul, South Korea
                Author information
                http://orcid.org/0000-0002-2742-1759
                Article
                974
                10.1186/s12911-019-0974-x
                6873409
                31752864
                dafdb928-dc05-423e-8085-7b1027685db9
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 18 April 2019
                : 8 November 2019
                Funding
                Funded by: Minister of Education of the Republic of Korea and the National Research foundation of Korea
                Award ID: NRF-2017S1A6A3A01078538
                Award Recipient :
                Funded by: Korea Ministry of Health & Welfare, and from the Original Technology Research Program for Brain Science through the National Research Foundation of Korea funded by the Korean Government
                Award ID: 2014M3C7A1064752
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                Bioinformatics & Computational biology
                machine learning,neuropsychological test,dementia,mild cognitive impairment,alzheimer’s disease

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