{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T19:57:15Z","timestamp":1789588635073,"version":"build-2803163510"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Office of the Senior Vice President for Research and Biotechnology at Western University of Health Sciences, Pomona, CA"},{"name":"True One Medicine Initiative"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Canine Cognitive Dysfunction (CCD) is an increasingly prevalent naturally occurring neurodegenerative condition in senescent dogs that share neuropathological and clinical features with human Alzheimer\u2019s disease (AD). Metabolic profiling allows for identification of new candidates for AD biomarkers, diagnostics, and therapeutics. Despite its translational potential, plasma metabolomic profiling of dogs with CDD has not been previously characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This case\u2013control study analyzed plasma samples from ten client-owned geriatric dogs, including five with severe CCD and five age-matched, clinically healthy controls. Untargeted plasma metabolomics was performed using ultra-performance liquid chromatography\u2013mass spectrometry (UPLC\u2013MS). Multivariate and univariate statistical analyses identified significant metabolic differences between the groups. Metabolites were considered significant based on a variable importance in projection (VIP) score &amp;gt; 1.5, fold change (FC)\u202f&amp;gt;\u202f2.0, and adjusted\n                      <jats:italic>p<\/jats:italic>\n                      -value &amp;lt;0.05.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Fifteen metabolites across seven chemical classes were significantly altered in CCD dogs compared to controls, including glycerophospholipids, steroid derivatives, indoles, and mitochondrial-related compounds. Notably, elevated lysophosphatidic acid (LPA 20:2\/0:0) and reduced ubiquinone-2 levels suggest dysregulation in neuroinflammatory and oxidative stress pathways. Cholesterol exhibited the highest FC and VIP scores, further reinforcing its role in AD pathogenesis. Hierarchical clustering and pathway enrichment analyses supported distinct metabolic signatures in CCD that mirror those observed in human AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This is the first untargeted plasma metabolomic profiling of dogs with CCD, revealing systemic metabolic disturbances that align with AD pathophysiology. Data was collected from senescent community-dwelling companion dogs, which enhances the study\u2019s ecological and translational relevance. It supports the utility of CCD as an AD model and highlight candidate plasma biomarkers that warrant further investigation. Future longitudinal studies integrating metabolomics with neuroimaging, histopathology, and behavioral assessments are required to validate these findings and contribute to AD biomarker discovery and therapeutic development.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnins.2026.1681817","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T14:19:46Z","timestamp":1773757186000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Untargeted plasma metabolomics in canine cognitive dysfunction: the naturally occurring Alzheimer\u2019s disease analog in dogs"],"prefix":"10.3389","volume":"20","author":[{"given":"Tonatiuh","family":"Melgarejo","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine, Western University of Health Sciences","place":["Pomona, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scarlett","family":"Harrison","sequence":"additional","affiliation":[{"name":"Modern Animal Hospital","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Chang","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine & Biomedical Sciences, Colorado State University","place":["Fort Collins, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Munoz","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Western University of Health Sciences","place":["Pomona, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Kim","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine, Ross University","place":["Basseterre, Saint Kitts and Nevis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youna","family":"Choi","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Western University of Health Sciences","place":["Pomona, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce G.","family":"Riveroll-Gonzalez","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Western University of Health Sciences","place":["Pomona, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Natterson-Horowitz","sequence":"additional","affiliation":[{"name":"Department of Global Health and Social Medicine, Harvard Medical School","place":["Boston, MA, United States"]},{"name":"Department of Human Evolutionary Biology, Harvard University","place":["Cambridge, MA, United States"]},{"name":"David Geffen School of Medicine, University of California, Los Angeles","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Linde","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Western University of Health Sciences","place":["Pomona, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"742408","DOI":"10.3389\/fnagi.2022.742408","article-title":"Alzheimer\u2019s disease: an update and insights into pathophysiology","volume":"14","author":"Abubakar","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/s0278-5846(00)00101-9","article-title":"The canine as a model of human cognitive aging: recent developments","volume":"24","author":"Adams","year":"2000","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1186\/s13195-024-01542-4","article-title":"Association of oxidative stress and inflammatory metabolites with Alzheimer\u2019s disease cerebrospinal fluid biomarkers in mild cognitive impairment","volume":"16","author":"Ahmad","year":"2024","journal-title":"Alzheimer's Res. Ther."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1186\/s12917-025-05027-w","article-title":"Plasma and cerebrospinal fluid biomarkers in aged dogs with cognitive decline","volume":"21","author":"Alsulami","year":"2025","journal-title":"BMC Vet. Res."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1002\/alz.12683","article-title":"The role of mitochondrial dysfunction in Alzheimer\u2019s disease pathogenesis","volume":"19","author":"Ashleigh","year":"2023","journal-title":"Alzheimers Dement."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1188839","DOI":"10.3389\/fnins.2023.1188839","article-title":"Neuroprotective effects of coenzyme Q10 on neurological diseases: a review article","volume":"17","author":"Bagheri","year":"2023","journal-title":"Front. Neurosci."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"298","DOI":"10.2174\/156720512800107546","article-title":"Dogs with cognitive dysfunction syndrome: a natural model of Alzheimer\u2019s disease","volume":"9","author":"Bosch","year":"2012","journal-title":"Curr. Alzheimer Res."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/1750-1326-2-2","article-title":"Increased isoprostane and prostaglandin are prominent in neurons in Alzheimer disease","volume":"2","author":"Casadesus","year":"2007","journal-title":"Mol. Neurodegener."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1585","DOI":"10.3390\/antiox13121585","article-title":"Neuroprotective potential of indole-based compounds: a biochemical study on antioxidant properties and amyloid disaggregation in Neuroblastoma cells","volume":"13","author":"Ciaglia","year":"2024","journal-title":"Antioxidants (Basel)"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"2183","DOI":"10.1007\/s12035-020-02232-6","article-title":"Cholesterol metabolism in neurodegenerative diseases: molecular mechanisms and therapeutic targets","volume":"58","author":"Dai","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1039\/c7md00569e","article-title":"Design, synthesis and evaluation of indole derivatives as multifunctional agents against Alzheimer\u2019s disease","volume":"9","author":"Denya","year":"2018","journal-title":"Medchemcomm"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/j.cvsm.2019.01.013","article-title":"Canine cognitive dysfunction: pathophysiology, diagnosis, and treatment","volume":"49","author":"Dewey","year":"2019","journal-title":"Vet. Clin. North Am. Small Anim. Pract."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"211","DOI":"10.3233\/JAD-2011-110209","article-title":"Coenzyme Q10 decreases amyloid pathology and improves behavior in a transgenic mouse model of Alzheimer\u2019s disease","volume":"27","author":"Dumont","year":"2011","journal-title":"J. Alzheimer's Dis"},{"key":"ref14","first-page":"2643","article-title":"Traditional uses, chemical constituents and pharmacological effects of Boschniakia rossica: a systematic review","volume-title":"Trop. J. Pharm. Res.","author":"Fan","year":"2019"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"690372","DOI":"10.3389\/fnagi.2021.690372","article-title":"Cholesterol and Alzheimer\u2019s disease; from risk genes to pathological effects","volume":"13","author":"Feringa","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"191","DOI":"10.3390\/antiox13020191","article-title":"CoQ10 and mitochondrial dysfunction in Alzheimer\u2019s disease","volume":"13","author":"Fi\u0161ar","year":"2024","journal-title":"Antioxidants (Basel)"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"e90633","DOI":"10.7554\/eLife.90633","article-title":"Lost in translation: inconvenient truths on the utility of mouse models in Alzheimer\u2019s disease research","volume":"13","author":"Granzotto","year":"2024","journal-title":"eLife"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"58","DOI":"10.3389\/fnmol.2020.00058","article-title":"Lysophospholipids and their G-coupled protein signaling in Alzheimer\u2019s disease: from physiological performance to pathological impairment","volume":"13","author":"Hao","year":"2020","journal-title":"Front. Mol. Neurosci."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1384","DOI":"10.1016\/j.bbadis.2013.03.016","article-title":"A canine model of human aging and Alzheimer\u2019s disease","volume":"1832","author":"Head","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/B978-012351830-9\/50032-9","volume-title":"Functional Neurobiology of Aging","author":"Head","year":"2001"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1128521","DOI":"10.3389\/fnagi.2023.1128521","article-title":"Activated gliosis, accumulation of amyloid \u03b2, and hyperphosphorylation of tau in aging canines with and without cognitive decline","volume":"15","author":"Hines","year":"2023","journal-title":"Front. Aging Neurosci."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"465544","DOI":"10.1016\/j.chroma.2024.465544","article-title":"Combination of mass spectrometry analysis and bioinformatic analysis for characterizing anti-inflammation active components from Boschniakia rossica and the targets","volume":"1739","author":"Hu","year":"2025","journal-title":"J. Chromatogr. A"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1212\/WNL.0000000000000240","article-title":"Contribution of Alzheimer disease to mortality in the United States","volume":"82","author":"James","year":"2014","journal-title":"Neurology"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"533","DOI":"10.3390\/antiox12020533","article-title":"Coenzyme Q10 and dementia: a systematic review","volume":"12","author":"Jim\u00e9nez-Jim\u00e9nez","year":"2023","journal-title":"Antioxidants (Basel)"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"4155","DOI":"10.1248\/cpb.35.4155","article-title":"Comparative studies on the constituents of a parasitic plant and its host. III. On the constituents of Boschniakia rossica Fedtsch. Et Flerov. (2)","volume":"35","author":"Konishi","year":"1987","journal-title":"Chem. Pharm. Bull."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"2255","DOI":"10.1007\/s00406-025-02013-z","article-title":"Plasma biomarkers of amyloid, tau & neuroinflammation in Alzheimer\u2019s disease and corticobasal syndrome","volume":"275","author":"Kurz","year":"2025","journal-title":"Eur. Arch. Psychiatry Clin. Neurosci."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1007\/s12272-024-01527-9","article-title":"Ideal animal models according to multifaceted mechanisms and peculiarities in neurological disorders: present and challenges","volume":"48","author":"Lamichhane","year":"2025","journal-title":"Arch. Pharm. Res."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"168","DOI":"10.3390\/cells14030168","article-title":"Modulating Neuroinflammation as a prospective therapeutic target in Alzheimer\u2019s disease","volume":"14","author":"Lee","year":"2025","journal-title":"Cells"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"629028","DOI":"10.1155\/2013\/629028","article-title":"Role of lipid peroxidation-derived \u03b1, \u03b2-unsaturated aldehydes in vascular dysfunction","volume":"2013","author":"Lee","year":"2013","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"769501","DOI":"10.3389\/fphar.2021.769501","article-title":"New insights into gut-Bacteria-derived indole and its derivatives in intestinal and liver diseases","volume":"12","author":"Li","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1016\/S0140-6736(24)01296-0","article-title":"Dementia prevention, intervention, and care: 2024 report of the lancet standing commission","volume":"404","author":"Livingston","year":"2024","journal-title":"Lancet"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.applanim.2015.08.034","article-title":"Assessment of severity and progression of canine cognitive dysfunction syndrome using the canine dementia scale (CADES)","volume":"171","author":"Madari","year":"2015","journal-title":"Appl. Anim. Behav. Sci."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"e70630","DOI":"10.1002\/alz.70630","article-title":"The companion dog as a translational model for Alzheimer\u2019s disease: development of a longitudinal research platform and post mortem protocols","volume":"21","author":"McGrath","year":"2025","journal-title":"Alzheimers Dement."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"604","DOI":"10.3389\/fnins.2019.00604","article-title":"Canine cognitive dysfunction and Alzheimer\u2019s disease - two facets of the same disease?","volume":"13","author":"Mihevc","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"572491","DOI":"10.1155\/2014\/572491","article-title":"Isoprostanes and neuroprostanes as biomarkers of oxidative stress in neurodegenerative diseases","volume":"2014","author":"Miller","year":"2014","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref36","volume-title":"Comparative Oncology Program","year":"2019"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"242","DOI":"10.3389\/fphys.2013.00242","article-title":"Interaction of aldehydes derived from lipid peroxidation and membrane proteins","volume":"4","author":"Pizzimenti","year":"2013","journal-title":"Front. Physiol."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1016\/j.bbalip.2010.01.009","article-title":"The neurobiology of isoprostanes and Alzheimer\u2019s disease","volume":"1801","author":"Pratic\u00f2","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1001\/archneur.59.6.972","article-title":"Increase of brain oxidative stress in mild cognitive impairment: a possible predictor of Alzheimer disease","volume":"59","author":"Pratic\u00f2","year":"2002","journal-title":"Arch. Neurol."},{"key":"ref40","first-page":"177","volume-title":"Conn\u2019s Handbook of Models for Human Aging","author":"Sch\u00fctt","year":"2018"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1039\/d4md00630e","article-title":"Recent advancements in the therapeutic approaches for Alzheimer\u2019s disease treatment: current and future perspective","volume":"16","author":"Sharma","year":"2025","journal-title":"RSC Med. Chem."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"eS83","DOI":"10.12788\/jfp.0286","article-title":"Lifestyle intervention and Alzheimer disease","volume":"71","author":"Sherzai","year":"2022","journal-title":"J. Fam. Pract."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"1685","DOI":"10.1038\/s12276-024-01273-4","article-title":"Cholesterol imbalance and neurotransmission defects in neurodegeneration","volume":"56","author":"Shin","year":"2024","journal-title":"Exp. Mol. Med."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1007\/s00232-023-00278-w","article-title":"Role of cholesterol and its biosynthetic precursors on membrane organization and dynamics: a fluorescence approach","volume":"256","author":"Shrivastava","year":"2023","journal-title":"J. Membr. Biol."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/s43440-024-00672-8","article-title":"Acyclic sesquiterpenes nerolidol and farnesol: mechanistic insights into their neuroprotective potential","volume":"77","author":"Singh","year":"2025","journal-title":"Pharmacol. Rep."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1186\/s40478-016-0363-y","article-title":"Revisiting rodent models: Octodon degus as Alzheimer\u2019s disease model?","volume":"4","author":"Steffen","year":"2016","journal-title":"Acta Neuropathol. Commun."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"101552","DOI":"10.1016\/j.arr.2021.101552","article-title":"Association of F2-isoprostane levels with Alzheimer\u2019s disease in observational studies: a systematic review and meta-analysis","volume":"74","author":"Trares","year":"2022","journal-title":"Ageing Res. Rev."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"2379","DOI":"10.1007\/s11357-021-00422-1","article-title":"Canine cognitive dysfunction (CCD) scores correlate with amyloid beta 42 levels in dog brain tissue","volume":"43","author":"Urfer","year":"2021","journal-title":"Geroscience"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/s13024-020-00376-6","article-title":"Mitochondria dysfunction in the pathogenesis of Alzheimer\u2019s disease: recent advances","volume":"15","author":"Wang","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"4681","DOI":"10.1021\/acs.jproteome.1c00225","article-title":"Metabolomic signatures discriminate horses with clinical signs of atypical myopathy from healthy co-grazing horses","volume":"20","author":"Wouters","year":"2021","journal-title":"J. Proteome Res."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"2168","DOI":"10.14336\/AD.2024.0134","article-title":"Tryptophan metabolism in Alzheimer\u2019s disease with the involvement of microglia and astrocyte crosstalk and gut-brain Axis","volume":"15","author":"Xie","year":"2024","journal-title":"Aging Dis."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"762","DOI":"10.3390\/molecules23040762","article-title":"Response of plant secondary metabolites to environmental factors","volume":"23","author":"Yang","year":"2018","journal-title":"Molecules"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1007\/s00441-020-03198-6","article-title":"Utility of spontaneous animal models of Alzheimer\u2019s disease in preclinical efficacy studies","volume":"380","author":"Zeiss","year":"2020","journal-title":"Cell Tissue Res."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1186\/s12888-024-06375-x","article-title":"Global burden of Alzheimer\u2019s disease and other dementias attributed to metabolic risks from 1990 to 2021: results from the global burden of disease study 2021","volume":"24","author":"Zhang","year":"2024","journal-title":"BMC Psychiatry"}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2026.1681817\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T14:19:48Z","timestamp":1773757188000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2026.1681817\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,17]]},"references-count":54,"alternative-id":["10.3389\/fnins.2026.1681817"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2026.1681817","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,17]]},"article-number":"1681817"}}