Neuroimmune proteins can differentiate between distinct neurodegenerative diseases

Background Although we have greatly increased our ability to identify the presence of neurodegenerative pathology during life, additional techniques and targets are still needed to increase diagnostic specificity. Recently, it has become evident that the neuroinflammatory response might be tailored towards distinct diseases resulting in disease specific “neuroinflammatory signatures”. Therefore, a detailed comparison of neuroinflammatory molecules present among distinct neurodegenerative diseases could provide novel information of disease specific therapeutic targets or differential biomarkers. Method To better examine potential neuroinflammatory signatures, a 71 immune‐related protein multiplex ELISA panel was utilized to analyze anterior cingulate grey matter from 127 individuals neuropathologically diagnosed with Alzheimer’s disease (AD), but chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease (AGD). A partial least square regression analysis was used for unbiased clustering and identifying proteins that were distinctly correlated with each disease correcting for age and gender. Receiver operator characteristic and binary logistic regression analyses were then used to examine the ability of each candidate protein to distinguish diseases. Validation in postmortem cerebrospinal fluid (CSF) from 15 AD and 14 CTE cases was performed to determine if candidate proteins could act as possible biomarkers. Finally, histology was performed using candidate proteins to visualize cell type expression for better understanding of potential mechanistic pathways. Result Five clusters of neuroimmune proteins were identified and compared to determine if clusters were specific to distinct disease. Each cluster was found to correlate with either CTE, AD, PSP, CBD, or AGD. When examining which proteins were the strongest driver of each cluster, it was observed the most distinctive protein for CTE was CCL21, AD was FLT3L, and PSP was IL13. Individual proteins that were specific to CBD and AGD were not observed. CCL21 was observed to be elevated in CTE CSF compared to AD, further validating the use as possible biomarkers. Conclusion Overall, these results highlight that different neuroinflammatory responses might underlie unique mechanisms in related neurodegenerative pathologies. Additionally, the use of distinct neuroinflammatory signatures could help differentiate between neuropathologi