{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T02:40:09Z","timestamp":1790476809604,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T00:00:00Z","timestamp":1663027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institute of Health","doi-asserted-by":"publisher","award":["1UG3TR002978-01"],"award-info":[{"award-number":["1UG3TR002978-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institute of Health","doi-asserted-by":"publisher","award":["4UH3TR002978-03"],"award-info":[{"award-number":["4UH3TR002978-03"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institute of Health","doi-asserted-by":"publisher","award":["1U18TR003778-01"],"award-info":[{"award-number":["1U18TR003778-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biosensors"],"abstract":"<jats:p>Early diagnosis of Alzheimer\u2019s Disease (AD) is critical for disease prevention and cure. However, currently, techniques with the required high sensitivity and specificity are lacking. Recently, with the advances and increased accessibility of data analysis tools, such as machine learning, research efforts have increasingly focused on using these computational methods to solve this challenge. Here, we demonstrate a convolutional neural network (CNN)-based AD diagnosis approach using the surface-enhanced Raman spectroscopy (SERS) fingerprints of human cerebrospinal fluid (CSF). SERS and CNN were combined for biomarker detection to analyze disease-associated biochemical changes in the CSF. We achieved very high reproducibility in double-blind experiments for testing the feasibility of our system on human samples. We achieved an overall accuracy of 92% (100% for normal individuals and 88.9% for AD individuals) based on the clinical diagnosis. Further, we observed an excellent correlation coefficient between our test score and the Clinical Dementia Rating (CDR) score. Our findings offer a substantial indication of the feasibility of detecting AD biomarkers using the innovative combination of SERS and machine learning. We are hoping that this will serve as an incentive for future research in the field.<\/jats:p>","DOI":"10.3390\/bios12090753","type":"journal-article","created":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T21:06:52Z","timestamp":1663103212000},"page":"753","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["The Feasibility of Early Alzheimer\u2019s Disease Diagnosis Using a Neural Network Hybrid Platform"],"prefix":"10.3390","volume":"12","author":[{"given":"Xinke","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Materials Science and Engineering, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siddharth","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7375-5215","authenticated-orcid":false,"given":"Shan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6977-5056","authenticated-orcid":false,"given":"Eric","family":"Hayden","sequence":"additional","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Teplow","sequence":"additional","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Hong","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering, University of California, Los Angeles, CA 90095, USA"},{"name":"Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1001\/archneur.1976.00500040001001","article-title":"The Prevalence and Malignancy of Alzheimer Disease: A Major Killer","volume":"33","author":"Katzman","year":"1976","journal-title":"Arch. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1001\/jama.1997.03550160069041","article-title":"van Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease: A Meta-Analysis","volume":"278","author":"Farrer","year":"1997","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1152\/physrev.2001.81.2.741","article-title":"Alzheimer\u2019s Disease: Genes, Proteins, and Therapy","volume":"81","author":"Selkoe","year":"2001","journal-title":"Physiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1126\/science.1074069","article-title":"Alzheimer\u2019s Disease Is a Synaptic Failure","volume":"298","author":"Selkoe","year":"2002","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"(2022). 2022 Alzheimer\u2019s Disease Facts and Figures. Alzheimer\u2019s Dement., 18, 700\u2013789.","DOI":"10.1002\/alz.12638"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/S1474-4422(03)00502-7","article-title":"Treatment of Alzheimer\u2019s Disease: Current Status and New Perspectives","volume":"2","author":"Scarpini","year":"2003","journal-title":"Lancet Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"S34","DOI":"10.1212\/WNL.64.12_suppl_3.S34","article-title":"Diagnosis and Treatment of Alzheimer\u2019s Disease","volume":"64","author":"Desai","year":"2005","journal-title":"Neurology"},{"key":"ref_8","first-page":"S339","article-title":"The Growing Burden of Alzheimer\u2019s Disease","volume":"17","author":"Lopez","year":"2011","journal-title":"Am. J. Manag. Care"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1515\/cclm-2021-0549","article-title":"Establishing Pre-Analytical Requirements and Maximizing Peptide Recovery in the Analytical Phase for Mass Spectrometric Quantification of Amyloid-\u03b2 Peptides 1-42 and 1-40 in CSF","volume":"60","author":"Forgrave","year":"2022","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_10","first-page":"e12168","article-title":"Effects of Pre-Analytical Procedures on Blood Biomarkers for Alzheimer\u2019s Pathophysiology, Glial Activation, and Neurodegeneration. Alzheimer\u2019s Dement. Diagnosis, Assess","volume":"13","author":"Ashton","year":"2021","journal-title":"Dis. Monit."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.jim.2013.11.008","article-title":"The Impact of Pre-Analytical Variables on the Stability of Neurofilament Proteins in CSF, Determined by a Novel Validated SinglePlex Luminex Assay and ELISA","volume":"402","author":"Vennegoor","year":"2014","journal-title":"J. Immunol. Methods"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"143","DOI":"10.3389\/fneur.2015.00143","article-title":"Preanalytical Confounding Factors in the Analysis of Cerebrospinal Fluid Biomarkers for Alzheimer\u2019s Disease: The Issue of Diurnal Variation","volume":"6","author":"Cicognola","year":"2015","journal-title":"Front. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1016\/j.jalz.2018.05.008","article-title":"The Impact of Preanalytical Variables on Measuring Cerebrospinal Fluid Biomarkers for Alzheimer\u2019s Disease Diagnosis: A Review","volume":"14","author":"Hansson","year":"2018","journal-title":"Alzheimers. Dement."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.jneumeth.2013.03.011","article-title":"Pre-Analytical Factors Influencing the Stability of Cerebrospinal Fluid Proteins","volume":"215","author":"Simonsen","year":"2013","journal-title":"J. Neurosci. Methods"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/s13534-021-00201-z","article-title":"Bias-Generating Factors in Biofluid Amyloid-\u03b2 Measurements for Alzheimer\u2019s Disease Diagnosis","volume":"11","author":"Park","year":"2021","journal-title":"Biomed. Eng. Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1126\/science.1566067","article-title":"Alzheimer\u2019s Disease: The Amyloid Cascade Hypothesis","volume":"256","author":"Hardy","year":"1992","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.jalz.2011.03.005","article-title":"The Diagnosis of Dementia Due to Alzheimer\u2019s Disease: Recommendations from the National Institute on Aging-Alzheimer\u2019s Association Workgroups on Diagnostic Guidelines for Alzheimer\u2019s Disease","volume":"7","author":"McKhann","year":"2011","journal-title":"Alzheimers. Dement."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Paraskevas, G.P. (2022). The Role of Cerebrospinal Fluid Biomarkers in Dementia and Other Related Neurodegenerative Disorders. Brain Sci., 12.","DOI":"10.3390\/brainsci12050627"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1056\/NEJMoa1202753","article-title":"Clinical and Biomarker Changes in Dominantly Inherited Alzheimer\u2019s Disease","volume":"367","author":"Bateman","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/S1474-4422(16)00070-3","article-title":"CSF and Blood Biomarkers for the Diagnosis of Alzheimer\u2019s Disease: A Systematic Review and Meta-Analysis","volume":"15","author":"Olsson","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1002\/pro.3434","article-title":"Surface Enhanced Raman Spectroscopy Distinguishes Amyloid \u0392-Protein Isoforms and Conformational States","volume":"27","author":"Yu","year":"2018","journal-title":"Protein Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/s41582-022-00665-2","article-title":"Blood Phospho-Tau in Alzheimer Disease: Analysis, Interpretation, and Clinical Utility","volume":"18","author":"Karikari","year":"2022","journal-title":"Nat. Rev. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/S1474-4422(03)00530-1","article-title":"CSF Markers for Incipient Alzheimer\u2019s Disease","volume":"2","author":"Blennow","year":"2003","journal-title":"Lancet Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1002\/ana.21610","article-title":"Cerebrospinal Fluid Biomarker Signature in Alzheimer\u2019s Disease Neuroimaging Initiative Subjects","volume":"65","author":"Shaw","year":"2009","journal-title":"Ann. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/nrneurol.2010.4","article-title":"Cerebrospinal Fluid and Plasma Biomarkers in Alzheimer Disease","volume":"6","author":"Blennow","year":"2010","journal-title":"Nat. Rev. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-022-32592-7","article-title":"Earlier Alzheimer\u2019s Disease Onset Is Associated with Tau Pathology in Brain Hub Regions and Facilitated Tau Spreading","volume":"13","author":"Frontzkowski","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_27","first-page":"e12314","article-title":"Clinical Application of CSF Biomarkers for Alzheimer\u2019s Disease: From Rationale to Ratios. Alzheimer\u2019s Dement. Diagnosis, Assess","volume":"14","author":"Bouwman","year":"2022","journal-title":"Dis. Monit."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1103\/PhysRevLett.78.1667","article-title":"Single Molecule Detection Using Surface-Enhanced Raman Scattering (SERS)","volume":"78","author":"Kneipp","year":"1997","journal-title":"Phys. Rev. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1146\/annurev.anchem.1.031207.112814","article-title":"Van Surface-Enhanced Raman Spectroscopy","volume":"1","author":"Stiles","year":"2008","journal-title":"Annu. Rev. Anal. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"104678","DOI":"10.1016\/j.compbiomed.2021.104678","article-title":"Multi-Model and Multi-Slice Ensemble Learning Architecture Based on 2D Convolutional Neural Networks for Alzheimer\u2019s Disease Diagnosis","volume":"136","author":"Kang","year":"2021","journal-title":"Comput. Biol. Med."},{"key":"ref_31","first-page":"1302170","article-title":"On Improved 3D-CNN-Based Binary and Multiclass Classification of Alzheimer\u2019s Disease Using Neuroimaging Modalities and Data Augmentation Methods","volume":"2022","author":"Ullah","year":"2022","journal-title":"J. Healthc. Eng."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"012020","DOI":"10.1088\/1742-6596\/1844\/1\/012020","article-title":"Automated Classification of Alzheimer\u2019s Disease Based on MRI Image Processing Using Convolutional Neural Network (CNN) with AlexNet Architecture","volume":"1844","author":"Wijayanto","year":"2021","journal-title":"J. Phys. Conf. Ser."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Hosseini-Asl, E., Keynton, R., and El-Baz, A. (2016, January 25\u201328). Alzheimer\u2019s Disease Diagnostics by Adaptation of 3D Convolutional Network. Proceedings of the 2016 IEEE International Conference on Image Processing (ICIP), Phoenix, AZ, USA.","DOI":"10.1109\/ICIP.2016.7532332"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Sarraf, S., and Tofighi, G. (2016, January 6\u20137). Deep Learning-Based Pipeline to Recognize Alzheimer\u2019s Disease Using FMRI Data. Proceedings of the 2016 Future Technologies Conference (FTC), San Francisco, CA, USA.","DOI":"10.1109\/FTC.2016.7821697"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Farooq, A., Anwar, S., Awais, M., and Rehman, S. (2017, January 18\u201320). A Deep CNN Based Multi-Class Classification of Alzheimer\u2019s Disease Using MRI. Proceedings of the 2017 IEEE International Conference on Imaging Systems and Techniques (IST), Beijing, China.","DOI":"10.1109\/IST.2017.8261460"},{"key":"ref_36","first-page":"1","article-title":"Machine Learning Methods for Predicting Progression from Mild Cognitive Impairment to Alzheimer\u2019s Disease Dementia: A Systematic Review","volume":"13","author":"Grueso","year":"2021","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4918","DOI":"10.1002\/adma.201300635","article-title":"Ultra-Sensitive Graphene-Plasmonic Hybrid Platform for Label-Free Detection","volume":"25","author":"Wang","year":"2013","journal-title":"Adv. Mater."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4067","DOI":"10.1039\/C7AN01371J","article-title":"Deep Convolutional Neural Networks for Raman Spectrum Recognition: A Unified Solution","volume":"142","author":"Liu","year":"2017","journal-title":"Analyst"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1080\/05704928.2014.923902","article-title":"Raman Spectroscopy of Biological Tissues","volume":"50","author":"Talari","year":"2014","journal-title":"Appl. Spectrosc. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1016\/j.saa.2010.12.079","article-title":"Raman Spectra of Amino Acids and Their Aqueous Solutions. Spectrochim","volume":"78","author":"Zhu","year":"2011","journal-title":"Acta Part A Mol. Biomol. Spectrosc."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.neulet.2005.06.030","article-title":"Amino Acids and Transaminases Activity in Ventricular CSF and in Brain of Normal and Alzheimer Patients","volume":"388","author":"Fisher","year":"2005","journal-title":"Neurosci. Lett."}],"container-title":["Biosensors"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6374\/12\/9\/753\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:30:34Z","timestamp":1760142634000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6374\/12\/9\/753"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,13]]},"references-count":41,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["bios12090753"],"URL":"https:\/\/doi.org\/10.3390\/bios12090753","relation":{},"ISSN":["2079-6374"],"issn-type":[{"value":"2079-6374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,13]]}}}