{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:24:01Z","timestamp":1787318641500,"version":"build-2736575974"},"reference-count":37,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ross University Veterinary School of Medicine seed grant"},{"name":"Florida Atlantic University LEARN program"},{"name":"Florida Atlantic University undergraduate OURI research program"},{"name":"National Institute on Aging (National Institutes of Health Grant","award":["U19AG024904"],"award-info":[{"award-number":["U19AG024904"]}]},{"DOI":"10.13039\/100000070","name":"National Institute of Biomedical Imaging and Bioengineering","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000070","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000070","name":"National Institute of Biomedical Imaging and Bioengineering","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000070","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"crossref"}]},{"name":"AbbVie, Alzheimer\u2019s Association"},{"name":"Alzheimer\u2019s Drug Discovery Foundation"},{"name":"Araclon Biotech"},{"DOI":"10.13039\/100007742","name":"BioClinica, Inc.","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007742","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100005614","name":"Biogen","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100005614","id-type":"DOI","asserted-by":"crossref"}]},{"name":"BristolMyers Squibb Company"},{"name":"CereSpir, Inc."},{"name":"Cogstate"},{"name":"Eisai Inc."},{"name":"Elan Pharmaceuticals, Inc."},{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100004312","id-type":"DOI","asserted-by":"crossref"}]},{"name":"EuroImmun"},{"DOI":"10.13039\/100007013","name":"F. Hoffmann-La Roche Ltd.","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007013","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004328","name":"Genentech, Inc.","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100004328","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Fujirebio"},{"DOI":"10.13039\/100006775","name":"GE Healthcare","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100006775","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100015725","name":"IXICO Ltd.","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100015725","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Janssen Alzheimer Immunotherapy Research & Development, LLC."},{"name":"Johnson & Johnson Pharmaceutical Research & Development LLC."},{"name":"Lumosity"},{"name":"Lundbeck"},{"DOI":"10.13039\/100004334","name":"Merck & Co., Inc.","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100004334","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Meso Scale Diagnostics, LLC."},{"name":"NeuroRx Research"},{"name":"Neurotrack Technologies"},{"DOI":"10.13039\/100008272","name":"Novartis Pharmaceuticals Corporation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008272","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004319","name":"Pfizer Inc.","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Piramal Imaging"},{"DOI":"10.13039\/501100011725","name":"Servier","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100011725","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Takeda Pharmaceutical Company"},{"name":"Transition Therapeutics"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>18F-Florbetapir PET imaging is widely used to assess amyloid-\u03b2 (A\u03b2) burden in the brain, particularly in the context of Alzheimer\u2019s disease (AD). Conventional assessments typically rely on selected individual slices, which may limit spatial accuracy and are prone to image blurring. In the present study, we introduce novel techniques to enhance the spatial resolution and clarity of A\u03b2 signal visualization in individuals pretreated with 18F-florbetapir. PET scans were retrospectively obtained from the Imaging and Data Archive for twelve individuals, including six cognitively unimpaired subjects and six diagnosed with AD. Each dataset consisted of 346 raw images, comprising 90 axial, 128 coronal, and 128 sagittal slices. Images were reconstructed into a single 3D volume using the 3D Slicer platform. Crucially, we applied artificial intelligence or AI-driven signal enhancement techniques to suppress background noise and amplify A\u03b2 signals. This AI-enhanced processing improved image clarity and enabled visualization of subtle and spatially organized signal patterns. To verify anatomical location, A\u03b2 PET signals were registered with MRI. This integrated workflow allowed us to visualize A\u03b2 signals across regions of interest, including the brain parenchyma, skull, and cervical tissues. Our analytical approaches revealed that A\u03b2 signals are highly concentrated and confined within non-CNS fluid compartments, forming canal-like networks that extend from the brain parenchyma toward the skull base, particularly the occipital clivus, and connect to the cervical lymph nodes. Additional A\u03b2 signals were observed along the internal carotid plexus. These findings suggest that, when reconstruction in 3D and enhanced with AI, 18F-florbetapir PET imaging may not only reflect A\u03b2 plaque burden in the brain but also visualize soluble A\u03b2 species concentrated within anatomical clearance pathways leading to the peripheral lymphatic system. This approach offers a new dimension to PET signal interpretation and highlights the potential of AI-enhanced 3D in advancing neuroimaging analysis.<\/jats:p>","DOI":"10.3390\/cells14221754","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T10:35:31Z","timestamp":1762770931000},"page":"1754","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Three-Dimensional PET Imaging Reveals Canal-like Networks for Amyloid Beta Clearance to the Peripheral Lymphatic System"],"prefix":"10.3390","volume":"14","author":[{"given":"Giselle","family":"Shim","sequence":"first","affiliation":[{"name":"Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolf","family":"Hall","sequence":"additional","affiliation":[{"name":"Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim M.","family":"Shokry","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine, Ross University, Basseterre P.O. Box 334, Saint Kitts and Nevis"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"To","sequence":"additional","affiliation":[{"name":"Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lillian","family":"Cruz","sequence":"additional","affiliation":[{"name":"Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary C.","family":"Adam","sequence":"additional","affiliation":[{"name":"Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard","family":"Prentice","sequence":"additional","affiliation":[{"name":"Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jang-Yen","family":"Wu","sequence":"additional","affiliation":[{"name":"Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2147-3646","authenticated-orcid":false,"given":"Hongbo","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Civil, Environmental and Geomatics Engineering, Florida Atlantic University, Boca Raton, FL 33431, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3814-9367","authenticated-orcid":false,"given":"Rui","family":"Tao","sequence":"additional","affiliation":[{"name":"Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"NIA-AA Research Framework: Toward a biological definition of Alzheimer\u2019s disease","volume":"14","author":"Jack","year":"2018","journal-title":"Alzheimers Dement."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1007\/s00259-020-05174-2","article-title":"Visual assessment of [(18)F]flutemetamol PET images can detect early amyloid pathology and grade its extent","volume":"48","author":"Collij","year":"2021","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1186\/s13195-024-01494-9","article-title":"Amyloid-PET imaging predicts functional decline in clinically normal individuals","volume":"16","author":"Quenon","year":"2024","journal-title":"Alzheimers Res. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"14745","DOI":"10.1073\/pnas.0905127106","article-title":"Structure-neurotoxicity relationships of amyloid beta-protein oligomers","volume":"106","author":"Ono","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"19590","DOI":"10.1074\/jbc.M115.691840","article-title":"Amyloid-beta(1\u201342) Aggregation Initiates Its Cellular Uptake and Cytotoxicity","volume":"291","author":"Jin","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1111\/jnc.13887","article-title":"Pittsburgh Compound-B (PiB) binds amyloid beta-protein protofibrils","volume":"140","author":"Yamin","year":"2017","journal-title":"J. Neurochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1212\/WNL.58.12.1791","article-title":"Phases of A beta-deposition in the human brain and its relevance for the development of AD","volume":"58","author":"Thal","year":"2002","journal-title":"Neurology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.2967\/jnumed.109.065284","article-title":"Preclinical properties of 18F-AV-45: A PET agent for Abeta plaques in the brain","volume":"50","author":"Choi","year":"2009","journal-title":"J. Nucl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1097\/WAD.0b013e31821300bc","article-title":"Correlation of amyloid PET ligand florbetapir F 18 binding with Abeta aggregation and neuritic plaque deposition in postmortem brain tissue","volume":"26","author":"Choi","year":"2012","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"ref_10","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_11","doi-asserted-by":"crossref","first-page":"S567","DOI":"10.3233\/JAD-179941","article-title":"The Amyloid-beta Oligomer Hypothesis: Beginning of the Third Decade","volume":"64","author":"Cline","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"110179","DOI":"10.1016\/j.abb.2024.110179","article-title":"Critical aggregation concentration and reversibility of amyloid-beta (1\u201340) oligomers","volume":"761","author":"Illodo","year":"2024","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/S0167-4838(99)00228-9","article-title":"Temperature-dependent beta-sheet formation in beta-amyloid Abeta(1\u201340) peptide in water: Uncoupling beta-structure folding from aggregation","volume":"1476","author":"Gursky","year":"2000","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1021\/acsmedchemlett.1c00062","article-title":"A New Highly Deuterated [(18)F]AV-45, [(18)F]D15FSP, for Imaging beta-Amyloid Plaques in the Brain","volume":"12","author":"Xiao","year":"2021","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_15","unstructured":"Mai, J.K., Assheuer, J., and Paxinos, G. (2016). Atlas of the Human Brain, Academic Press. [4th ed.]."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s13024-019-0312-x","article-title":"Dural lymphatics regulate clearance of extracellular tau from the CNS","volume":"14","author":"Patel","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e70136","DOI":"10.1002\/alz.70136","article-title":"Tauopathy after long-term cervical lymphadenectomy","volume":"21","author":"Wu","year":"2025","journal-title":"Alzheimers Dement."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1093\/brain\/awae329","article-title":"Neurodegenerative fluid biomarkers are enriched in human cervical lymph nodes","volume":"148","author":"Provine","year":"2025","journal-title":"Brain A J. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1111\/iep.12330","article-title":"Origins of a pervasive, erroneous idea: The \u201cgreen birefringence\u201d of Congo red-stained amyloid","volume":"100","author":"Howie","year":"2019","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1016\/j.bbapap.2010.04.001","article-title":"Molecular mechanism of Thioflavin-T binding to amyloid fibrils","volume":"1804","author":"Biancalana","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13550-025-01216-8","article-title":"Autoradiographic comparison between [(11)C]PiB and [(18)F]AZD4694 in human brain tissue","volume":"15","author":"Aliaga","year":"2025","journal-title":"Ejnmmi Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1021\/acsptsci.4c00149","article-title":"Screening of [(18)F]Florbetazine for Abeta Plaques and a Head-to-Head Comparison Study with [(11)C]Pittsburgh Compound-B ([(11)C]PiB) in Human Subjects","volume":"7","author":"Li","year":"2024","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1002\/alz.12321","article-title":"Visualization of neurofibrillary tangle maturity in Alzheimer\u2019s disease: A clinicopathologic perspective for biomarker research","volume":"17","author":"Moloney","year":"2021","journal-title":"Alzheimers Dement."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s13024-019-0333-5","article-title":"The neuropathological diagnosis of Alzheimer\u2019s disease","volume":"14","author":"Dickson","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1093\/brain\/awx057","article-title":"Biochemically-defined pools of amyloid-beta in sporadic Alzheimer\u2019s disease: Correlation with amyloid PET","volume":"140","author":"Roberts","year":"2017","journal-title":"Brain A J. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"S5","DOI":"10.2967\/jnumed.124.268756","article-title":"Updated Appropriate Use Criteria for Amyloid and Tau PET: A Report from the Alzheimer\u2019s Association and Society for Nuclear Medicine and Molecular Imaging Workgroup","volume":"66","author":"Rabinovici","year":"2025","journal-title":"J. Nucl. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s13195-020-00587-5","article-title":"Comparison of amyloid PET measured in Centiloid units with neuropathological findings in Alzheimer\u2019s disease","volume":"12","author":"Amadoru","year":"2020","journal-title":"Alzheimers Res. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4411","DOI":"10.1038\/s41467-020-18115-2","article-title":"Circadian control of brain glymphatic and lymphatic fluid flow","volume":"11","author":"Hablitz","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"102774","DOI":"10.1016\/j.autneu.2021.102774","article-title":"The features of the glymphatic system","volume":"232","author":"Nycz","year":"2021","journal-title":"Auton. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1038\/s41593-018-0227-9","article-title":"CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature","volume":"21","author":"Louveau","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e20220035","DOI":"10.1084\/jem.20220035","article-title":"Conserved meningeal lymphatic drainage circuits in mice and humans","volume":"219","author":"Jacob","year":"2022","journal-title":"J. Exp. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1111\/bpa.12656","article-title":"Deep cervical lymph node ligation aggravates AD-like pathology of APP\/PS1 mice","volume":"29","author":"Wang","year":"2019","journal-title":"Brain Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Yagmurlu, K., Sokolowski, J.D., Cirak, M., Urgun, K., Soldozy, S., Mut, M., Shaffrey, M.E., Tvrdik, P., and Kalani, M.Y.S. (2020). Anatomical Features of the Deep Cervical Lymphatic System and Intrajugular Lymphatic Vessels in Humans. Brain Sci., 10.","DOI":"10.3390\/brainsci10120953"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1002\/alz.12385","article-title":"Amyloid-beta is present in human lymph nodes and greatly enriched in those of the cervical region","volume":"18","author":"Nauen","year":"2022","journal-title":"Alzheimers Dement."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.cell.2022.12.031","article-title":"Lymphatic vessels in bone support regeneration after injury","volume":"186","author":"Biswas","year":"2023","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00401-008-0457-0","article-title":"Lymphatic drainage of the brain and the pathophysiology of neurological disease","volume":"117","author":"Weller","year":"2009","journal-title":"Acta Neuropathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e14239","DOI":"10.1002\/acm2.14239","article-title":"Evaluating the Hounsfield unit assignment and dose differences between CT-based standard and deep learning-based synthetic CT images for MRI-only radiation therapy of the head and neck","volume":"25","author":"Singhrao","year":"2024","journal-title":"J. Appl. Clin. Med. Phys."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/22\/1754\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T05:22:00Z","timestamp":1762924920000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/22\/1754"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,10]]},"references-count":37,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["cells14221754"],"URL":"https:\/\/doi.org\/10.3390\/cells14221754","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,10]]}}}