Current and emerging biomarkers of cognitive dysfunction in aging dogs: A systematic review

Canine cognitive dysfunction syndrome (CCDS) is a progressive condition affecting aging dogs, characterized by behavioral and cognitive decline. While biomarkers are routinely used in human medicine to assess cognitive impairment, their role in veterinary neurology remains to be fully defined. This systematic review evaluated current evidence on biomarkers for staging CCDS, focusing on cerebrospinal fluid (CSF), blood, neuroimaging, and postmortem findings, and their correlation with clinical severity. A systematic search of Scopus and PubMed was conducted through March 2025 using predefined terms related to CCDS and biomarkers, identifying 337 articles, of which 37 met the inclusion criteria following PRISMA guidelines. Investigated biomarkers included beta-amyloid (Aβ42), tau protein, and neurofilament light chain (NfL) in CSF or blood; oxidative and nitrosative stress markers; MRI and PET imaging; and histopathological changes. Aβ42 results were mixed across studies, while NfL was consistently elevated in dogs with mild cognitive impairment, suggesting its potential diagnostic value. Tau protein showed low and inconsistent detectability. Structural MRI findings, such as interthalamic adhesion thinning and cortical atrophy, supported evidence of brain aging but lacked disease specificity. 18F-flutemetamol PET imaging shows promise for in vivo amyloid detection, though studies in CCDS are limited. Pathological findings highlight glial activation, neuronal loss, and synaptic dysfunction. Overall, current evidence indicates that several biomarkers may support the diagnosis and staging of CCDS; however, further research is needed to validate their clinical utility and guide future diagnostic approaches to validate their clinical utility.