TL;DR
This is the first demonstration that these three plasma biomarkers are useful not only for detecting CWD, but also for identifying it at early antemortem stages of disease, to enable earlier detection and assist with disease management.
Canine Cognitive Dysfunction (CCD) is a naturally occurring neurodegenerative syndrome in aging dogs that shares clinical and neuropathological parallels with Alzheimer’s disease (AD). As the demand for objective diagnostic tools grows, identifying reliable biofluid biomarkers is essential for clinical staging and therapeutic monitoring. This review synthesizes evidence on cerebrospinal fluid (CSF) and blood-based biomarkers (BBM) of CCD, focusing on amyloid-β (Aβ), neurofilament light chain (NfL), tau, and glial fibrillary acidic protein (GFAP). Evidence shows that Aβ42 and Aβ42/Aβ40 ratios exhibit stage-dependent, non-linear alterations resembling early compensatory phases in human AD. In contrast, tau pathology in CCD consists mainly of pre-tangle synaptic hyperphosphorylation rather than abundant neurofibrillary tangles, limiting its current diagnostic utility. GFAP, a marker of astroglial activation, shows inconsistent associations with cognitive decline and remains exploratory. Conversely, NfL has emerged as the most robust biomarker; CSF and plasma NfL levels consistently increase with age, correlate with cognitive impairment, and reflect central axonal pathology, making it the leading candidate for staging and monitoring disease progression. Overall, the CCD biomarker landscape supports a multimodal approach integrating Aβ dysregulation, axonal injury, and glial activation. Advancing this field requires harmonized diagnostic criteria, standardized sampling, and longitudinal studies. Such efforts will strengthen the translational value of CCD as a model for human dementia, accelerating discovery and therapeutic development across species.
Chronic Wasting Disease (CWD) is a transmissible spongiform encephalopathy (TSE) of cervids (elk, deer, moose, and reindeer) that is increasing in prevalence and expanding to new geographical areas. TSEs, commonly referred to as prion diseases, are fatal neurodegenerative diseases that occur in a variety of mammals, including humans, and typically exhibit species-specific characteristics. This study reports the sequencing of the prion protein gene (PRNP) in retropharyngeal lymph node samples from 358 Montana mule deer (Odocoileus hemionus) and the identification of 36 PRNP genetic variants, many of which have not been reported previously. Further investigations tracked spatiotemporal characteristics of variants to hunting districts, year of harvest, and CWD status. PRNP polymorphisms V12F, D20G, R40Q, and S225F were examined with EmCAST computational predictions to determine the relationship between sequence and structural variations providing further insights into mechanisms affecting CWD outcomes. EmCAST predictions suggest the novel variant V12F phenotype is attributable to functional changes such as altered protein–protein interactions that might be linked to the CWD positive status of the samples. Notably, the analysis of S225F by EmCAST predicted that S225F is a neutral variation for folded PrP and incompatible with fibril PrP, suggesting a potential structural mechanism for reduced fibril PrP formation, which is consistent with the previously proposed protective role of this variant. The CWD-positive samples harboring PRNP variants were examined with the prion RT-QuIC assay, including the novel variant V12F, which resulted in prion seeding activity.
This is the first systematic comparative study of age-related changes in neurodegeneration biomarkers in two closely related nonhuman primates using comparable age ranges and sample sizes, and the same multiplex assay.
Abstract Neuroinflammation is increasingly recognized as a key pathological process in neurodegenerative disease and can be monitored using biofluid biomarkers. Objective biomarkers may aid diagnosis, prognosis and progression. We conducted a scoping review of neuroinflammation biomarkers across major neurodegenerative diseases covering the past 23 years, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington’s disease, Lewy body dementia, multiple system atrophy and progressive supranuclear palsy. PubMed and Web of Science were systematically searched for observational studies from 2003 to 2025 reporting neuroinflammation biomarkers in adult human subjects. Included markers encompassed blood, cerebrospinal fluid, saliva and urine, providing possible complementary information. Original studies on non-neuroinflammatory mechanisms, cellular or post-mortem biomarkers, animal models, genetics and comparisons between diseases were excluded. Two reviewers independently screened articles; biomarkers reported in ≥3 independent cohorts per disease were analysed. A total of 388 studies were included, predominantly in Alzheimer’s disease/mild cognitive impairment (n = 214) and Parkinson’s disease (n = 92). Eight biomarkers were most frequently reported: IL-6, TNF-α, IL-1β, CRP/hs-CRP, IL-10, MCP-1, YKL-40 and neutrophil-to-lymphocyte ratio (NLR), measured in blood or cerebrospinal fluid (CSF) as indicators of inflammatory processes associated with neurodegeneration. Across biomarkers, the strength and scope of evidence varied. Most studies demonstrated higher biomarker levels in disease, with more advanced stages, greater clinical severity and faster progression. NLR showed the most consistent pattern across staging, severity and progression, but is currently under-represented across diseases. CSF YKL-40 generally increased with disease presence and advancement; IL-6 showed consistent increases in advanced stages and with severity, although significant results were limited; MCP-1, CRP and TNF-α were mostly linked to severity and progression; IL-1β and IL-10 remained largely inconsistent. Other markers, including GFAP, showed associations in Alzheimer’s disease but remain underexplored in other neurodegenerative diseases. Variability across studies, including differences in biofluid source, assay sensitivity, population characteristics and statistical approaches, limits interpretability and comparability. Although neuroinflammation is elevated in neurodegenerative diseases and generally intensifies as these diseases progress, potentially contributing to downstream pathology, the precise timing, role and predictive value of these biomarkers remain uncertain. A subset of markers, including NLR, YKL-40 and GFAP, shows relatively consistent associations and may warrant further investigation across diseases. In clinical practice, neuroinflammation biomarkers could serve as complementary tools to capture inflammatory processes related to disease heterogeneity and progression. Future longitudinal studies tracking pre-symptomatic and early-stage individuals, with standardized approaches, are needed to define temporal dynamics and explore their utility for monitoring disease progression and therapeutic response.
This study demonstrates relevance of the PSEN1 pigs to study AD and suggests necessary refinements to study AD pathogenesis using the PSEN1 pigs.
The dual and stage‐dependent roles of microglia and astrocytes are explored, discussion of blood–brain barrier dysfunction and peripheral immune infiltration as underappreciated pathogenic contributors are expanded, and emerging evidence linking neuroinflammation specifically to tau pathology is integrated.