{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T04:20:13Z","timestamp":1787804413152,"version":"build-2784847793"},"reference-count":49,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006477","name":"National Taiwan University","doi-asserted-by":"publisher","award":["NTU-CC-111L892303"],"award-info":[{"award-number":["NTU-CC-111L892303"]}],"id":[{"id":"10.13039\/501100006477","id-type":"DOI","asserted-by":"publisher"}]},{"award":["NTU-CC-111L892303"],"award-info":[{"award-number":["NTU-CC-111L892303"]}],"id":[{"id":"https:\/\/ror.org\/05bqach95","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Science and Technology Council","award":["NSTC 112-2635-B-002-005"],"award-info":[{"award-number":["NSTC 112-2635-B-002-005"]}]},{"name":"National Science and Technology Council","award":["NSTC 114-2313-B-002-050"],"award-info":[{"award-number":["NSTC 114-2313-B-002-050"]}]},{"award":["NSTC 112-2635-B-002-005"],"award-info":[{"award-number":["NSTC 112-2635-B-002-005"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NSTC 114-2313-B-002-050"],"award-info":[{"award-number":["NSTC 114-2313-B-002-050"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Animals"],"abstract":"<jats:p>The serum neurofilament light chain (NfL) is a promising circulating biomarker for canine cognitive dysfunction syndrome (CCDS). This cross-sectional study evaluated serum NfL (sNfL) as a surrogate for cerebrospinal fluid NfL (cNfL) and assessed the effects of physiological factors on its clinical utility. Biofluid NfL was analyzed using the single-molecule array (Simoa) across 126 clinical samples, comprising 44 cNfL and 25 paired cNfL\/sNfL samples in geriatric dogs (&gt;8 years) and 16 paired samples from a younger cohort (\u22648 years). A moderate monotonic correlation was observed between cNfL and sNfL in geriatric dogs, but this association was not maintained in the younger cohort after adjusting for body weight. In the geriatric cohort, raw sNfL levels differentiated cerebral atrophy from controls but not from other intracranial pathologies. Notably, the ability of cNfL to discriminate structural, atrophic, and mixed brain pathologies from controls significantly improved after adjustment for confounding effects of age and body weight. A similar optimization strategy may be applicable to sNfL. Systematically controlling for these physiological covariates in larger cohorts could potentially further improve the diagnostic precision of blood-based NfL screening in primary veterinary practice.<\/jats:p>","DOI":"10.3390\/ani16172659","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T08:00:48Z","timestamp":1787644848000},"page":"2659","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Investigation of Serum Neurofilament Light Chain as a Surrogate for Cerebrospinal Fluid Neurofilament Light Chain in Canine Cognitive Dysfunction Syndrome"],"prefix":"10.3390","volume":"16","author":[{"given":"Chih-Ching","family":"Wu","sequence":"first","affiliation":[{"name":"National Taiwan University Veterinary Hospital, College of Bioresources and Agriculture, National Taiwan University, Taipei 106328, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0098-0278","authenticated-orcid":false,"given":"Wei-Hsiang","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Comparative Pathobiology, School of Veterinary Medicine, National Taiwan University, Taipei 106319, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5123-7062","authenticated-orcid":false,"given":"Ya-Pei","family":"Chang","sequence":"additional","affiliation":[{"name":"National Taiwan University Veterinary Hospital, College of Bioresources and Agriculture, National Taiwan University, Taipei 106328, Taiwan"},{"name":"Institute of Veterinary Clinical Sciences, School of Veterinary Medicine, National Taiwan University, Taipei 106328, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/0169-328X(91)90088-F","article-title":"Conservation of the Sequence of the Alzheimer\u2019s Disease Amyloid Peptide in Dog, Polar Bear and Five Other Mammals by Cross-Species Polymerase Chain Reaction Analysis","volume":"10","author":"Johnstone","year":"1991","journal-title":"Mol. Brain Res."},{"key":"ref_2","doi-asserted-by":"crossref","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. N. Am. Small Anim. Pract."},{"key":"ref_3","doi-asserted-by":"crossref","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":"ref_4","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1007\/s004010050714","article-title":"Deposition of Amyloid \u03b2 Protein (A\u03b2) Subtypes [A\u03b240 and A\u03b242(43)] in Canine Senile Plaques and Cerebral Amyloid Angiopathy","volume":"94","author":"Nakamura","year":"1997","journal-title":"Acta Neuropathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.brainres.2005.11.021","article-title":"Cognitive Disturbances in Old Dogs Suffering from the Canine Counterpart of Alzheimer\u2019s Disease","volume":"1069","author":"Rofina","year":"2006","journal-title":"Brain Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e70212","DOI":"10.1002\/trc2.70212","article-title":"From Companionship to Science: The Importance of Dogs in Advancing Translational Research on Alzheimer\u2019s Disease\u2014A Scoping Review","volume":"12","author":"Ribeiro","year":"2026","journal-title":"Alzheimer\u2019s Dement. Transl. Res. Clin. Interv."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"498","DOI":"10.2460\/javma.25.10.0668","article-title":"The Canine Cognitive Dysfunction Syndrome Working Group Guidelines for Diagnosis and Monitoring of Canine Cognitive Dysfunction Syndrome","volume":"264","author":"Olby","year":"2026","journal-title":"J. Am. Vet. Med. Assoc."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"MacQuiddy, B., Moreno, J.A., Kusick, B., and McGrath, S. (2022). Assessment of Risk Factors in Dogs with Presumptive Advanced Canine Cognitive Dysfunction. Front. Vet. Sci., 9.","DOI":"10.3389\/fvets.2022.958488"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1111\/vru.12528","article-title":"Evaluation of Interthalamic Adhesion Size as an Indicator of Brain Atrophy in Dogs with and without Cognitive Dysfunction","volume":"58","author":"Noh","year":"2017","journal-title":"Vet. Radiol. Ultrasound"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1016\/j.exger.2011.02.013","article-title":"Plasma \u03b2-Amyloid Peptides in Canine Aging and Cognitive Dysfunction as a Model of Alzheimer\u2019s Disease","volume":"46","author":"Rosado","year":"2011","journal-title":"Exp. Gerontol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1111\/jvim.13633","article-title":"Cognitive Function, Progression of Age-Related Behavioral Changes, Biomarkers, and Survival in Dogs More Than 8 Years Old","volume":"29","author":"Toft","year":"2015","journal-title":"J. Vet. Intern. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Phochantachinda, S., Chantong, B., Reamtong, O., and Chatchaisak, D. (2021). Change in the Plasma Proteome Associated with Canine Cognitive Dysfunction Syndrome (CCDS) in Thailand. BMC Vet. Res., 17.","DOI":"10.1186\/s12917-021-02744-w"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Yoon, J.-W., Nam, C.-S., Lee, K.-S., Dan, T.-J., Jeon, H.-J., Kang, M.-A., and Park, H.-M. (2025). Evaluation of Blood-Based Diagnostic Biomarkers for Canine Cognitive Dysfunction Syndrome. Animals, 15.","DOI":"10.3390\/ani15131974"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Alsulami, A., Boland, S.W., McGrath, S., MacLean, E.L., Latimer, C.S., Darvas, M., and Moreno, J.A. (2025). Plasma and Cerebrospinal Fluid Biomarkers in Aged Dogs with Cognitive Decline. BMC Vet. Res., 21.","DOI":"10.1186\/s12917-025-05027-w"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.yasa.2022.07.002","article-title":"Peripheral Concentration of Amyloid-\u03b2, TAU Protein, and Neurofilament Light Chain as Markers of Cognitive Dysfunction Syndrome in Senior Dogs: A Meta-Analysis","volume":"3","author":"Piotti","year":"2022","journal-title":"Adv. Small Anim. Care"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Vikartovska, Z., Farbakova, J., Smolek, T., Hanes, J., Zilka, N., Hornakova, L., Humenik, F., Maloveska, M., Hudakova, N., and Cizkova, D. (2021). Novel Diagnostic Tools for Identifying Cognitive Impairment in Dogs: Behavior, Biomarkers, and Pathology. Front. Vet. Sci., 7.","DOI":"10.3389\/fvets.2020.551895"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.3233\/JAD-215562","article-title":"Use of Cognitive Testing, Questionnaires, and Plasma Biomarkers to Quantify Cognitive Impairment in an Aging Pet Dog Population","volume":"87","author":"Fefer","year":"2022","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3143","DOI":"10.1007\/s12035-020-01951-0","article-title":"Plasma Neurofilament Light Chain as a Translational Biomarker of Aging and Neurodegeneration in Dogs","volume":"57","author":"Panek","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"135593","DOI":"10.1016\/j.neulet.2020.135593","article-title":"Neurofilament Light Plasma Concentration Positively Associates with Age and Negatively Associates with Weight and Height in the Dog","volume":"744","author":"Perino","year":"2021","journal-title":"Neurosci. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3472","DOI":"10.1073\/pnas.84.10.3472","article-title":"Neurofilament Gene Expression: A Major Determinant of Axonal Caliber","volume":"84","author":"Hoffman","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"25729","DOI":"10.18632\/aging.203790","article-title":"Factors Influencing Serum Neurofilament Light Chain Levels in Normal Aging","volume":"13","author":"Koini","year":"2021","journal-title":"Aging"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1038\/s41467-020-14612-6","article-title":"Serum Neurofilament Light Levels in Normal Aging and Their Association with Morphologic Brain Changes","volume":"11","author":"Khalil","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1136\/jnnp-2018-320106","article-title":"Neurofilament Light Chain as a Biomarker in Neurological Disorders","volume":"90","author":"Gaetani","year":"2019","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e000143","DOI":"10.1136\/bmjno-2021-000143","article-title":"Correlation between CSF and Blood Neurofilament Light Chain Protein: A Systematic Review and Meta-Analysis","volume":"3","author":"Alagaratnam","year":"2021","journal-title":"BMJ Neurol. Open"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.neurobiolaging.2020.07.018","article-title":"Blood and Cerebrospinal Fluid Neurofilament Light Differentially Detect Neurodegeneration in Early Alzheimer\u2019s Disease","volume":"95","author":"Andersson","year":"2020","journal-title":"Neurobiol. Aging"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9982","DOI":"10.1038\/s41467-024-52937-8","article-title":"Comparative Neurofilament Light Chain Trajectories in CSF and Plasma in Autosomal Dominant Alzheimer\u2019s Disease","volume":"15","author":"Hofmann","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1111\/jvim.16184","article-title":"Neurofilament Light Chain as a Biomarker of Meningoencephalitis of Unknown Etiology in Dogs","volume":"35","author":"Yun","year":"2021","journal-title":"J. Vet. Intern. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"24129","DOI":"10.1038\/s41598-024-73812-y","article-title":"On the Utility of Cerebrospinal Fluid Biomarkers in Canine Neurological Disorders","volume":"14","author":"Smolek","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2196","DOI":"10.1111\/jvim.17110","article-title":"Use of Neurofilament Light Chain to Identify Structural Brain Diseases in Dogs","volume":"38","author":"Sung","year":"2024","journal-title":"J. Vet. Intern. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2437","DOI":"10.1002\/acn3.50942","article-title":"Neurofilament Light Is a Treatment-responsive Biomarker in CLN2 Disease","volume":"6","author":"Ru","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Lambertsen, K.L., Soares, C.B., Gaist, D., and Nielsen, H.H. (2020). Neurofilaments: The C-Reactive Protein of Neurology. Brain Sci., 10.","DOI":"10.3390\/brainsci10010056"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41582-024-00955-x","article-title":"Neurofilaments as Biomarkers in Neurological Disorders\u2014Towards Clinical Application","volume":"20","author":"Khalil","year":"2024","journal-title":"Nat. Rev. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e200045","DOI":"10.1212\/NXI.0000000000200045","article-title":"Effect of Estimated Blood Volume and Body Mass Index on GFAP and NfL Levels in the Serum and CSF of Patients with Multiple Sclerosis","volume":"10","author":"Yalachkov","year":"2023","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"ajvr.23.12.0292","DOI":"10.2460\/ajvr.23.12.0292","article-title":"Neurofilament Light Chain Concentration Does Not Correlate with Disease Status in Labrador Retrievers Affected with Idiopathic Laryngeal Paralysis","volume":"85","author":"Perino","year":"2024","journal-title":"Am. J. Vet. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"109","DOI":"10.12779\/dnd.2023.22.3.109","article-title":"Comparing Neurofilament Light Chain Levels in Serum and Plasma","volume":"22","author":"Kwon","year":"2023","journal-title":"Dement. Neurocognitive Disord."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e000958","DOI":"10.1136\/bmjmed-2024-000958","article-title":"Blood Level of Neurofilament Light Chain as a Biomarker for Neurological Disorders","volume":"4","author":"Turner","year":"2025","journal-title":"BMJ Med."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Le Brech, S., Amat, M., Temple, D., and Manteca, X. (2022). Evaluation of Two Practical Tools to Assess Cognitive Impairment in Aged Dogs. Animals, 12.","DOI":"10.3390\/ani12243538"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0891-0618(96)00117-2","article-title":"Distribution of Neurofilament Protein and Calcium-Binding Proteins Parvalbumin, Calbindin, and Calretinin in the Canine Hippocampus","volume":"11","author":"Hof","year":"1996","journal-title":"J. Chem. Neuroanat."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.nbd.2017.04.007","article-title":"NF-L in Cerebrospinal Fluid and Serum Is a Biomarker of Neuronal Damage in an Inducible Mouse Model of Neurodegeneration","volume":"104","author":"Brureau","year":"2017","journal-title":"Neurobiol. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/S0140-6736(02)07948-5","article-title":"Uses and Abuses of Screening Tests","volume":"359","author":"Grimes","year":"2002","journal-title":"Lancet"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Yuan, A., and Nixon, R.A. (2021). Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies. Front. Neurosci., 15.","DOI":"10.3389\/fnins.2021.689938"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/acn3.50972","article-title":"Confounding Effect of Blood Volume and Body Mass Index on Blood Neurofilament Light Chain Levels","volume":"7","author":"Manouchehrinia","year":"2020","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"20350","DOI":"10.1038\/s41598-020-76990-7","article-title":"Renal Function Is Associated with Blood Neurofilament Light Chain Level in Older Adults","volume":"10","author":"Akamine","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1515\/cclm-2022-0904","article-title":"Pre-Analytical Long-Term Stability of Neopterin and Neurofilament Light in Stored Cerebrospinal Fluid Samples","volume":"61","author":"Rosadas","year":"2023","journal-title":"Clin. Chem. Lab. Med. CCLM"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"120637","DOI":"10.1016\/j.cca.2025.120637","article-title":"Neurofilament Light Chain\u2014Matrix Comparison and Long-Term Stability in Frozen Serum","volume":"579","author":"Tybirk","year":"2026","journal-title":"Clin. Chim. Acta"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1515\/cclm-2022-0007","article-title":"Pre-Analytical Stability of Serum Biomarkers for Neurological Disease: Neurofilament-Light, Glial Fibrillary Acidic Protein and Contactin-1","volume":"60","author":"Verberk","year":"2022","journal-title":"Clin. Chem. Lab. Med. CCLM"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Chang, Y.-M., Hadox, E., Szladovits, B., and Garden, O.A. (2016). Serum Biochemical Phenotypes in the Domestic Dog. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0149650"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Lawrence, J., Chang, Y.-M.R., Szladovits, B., Davison, L.J., and Garden, O.A. (2013). Breed-Specific Hematological Phenotypes in the Dog: A Natural Resource for the Genetic Dissection of Hematological Parameters in a Mammalian Species. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0081288"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1002\/acn3.51676","article-title":"Age- and Disease-Specific Reference Values for Neurofilament Light Presented in an Online Interactive Support Interface","volume":"9","author":"Vermunt","year":"2022","journal-title":"Ann. Clin. Transl. Neurol."}],"container-title":["Animals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2615\/16\/17\/2659\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T04:14:42Z","timestamp":1787804082000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2615\/16\/17\/2659"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,25]]},"references-count":49,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ani16172659"],"URL":"https:\/\/doi.org\/10.3390\/ani16172659","relation":{},"ISSN":["2076-2615"],"issn-type":[{"value":"2076-2615","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,25]]}}}