Distinct neuroinflammatory mechanisms in Alzheimer’s disease and Frontotemporal Lobar Degeneration
Simrika Thapa, Chloe Anastassiadis, Anna Vasilevskaya, Namita Multani, Foad Taghdiri, Cristina Salvo, Daniela Mora‐Fisher, Cassandra Jessica Anor, Brenda Maricela Varriano, Karen Misquitta, David F. Tang‐Wai, Gabor G. Kovacs, Susan Fox, Anthony E Lang, Carmela Tartaglia- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Neuroinflammation is an important pathophysiological process in neurodegenerative diseases, such as Alzheimer’s disease (AD) and Frontotemporal Lobar Degeneration (FTLD). Limited studies have revealed distinct inflammatory markers between proteinopathies. Whether AD and FTLD have distinct neuroinflammatory profiles that relate to different clinical manifestations remains unclear. We assayed a large number of inflammatory proteins to delineate neuroinflammatory signatures across different proteinopathies.
Method
Using Olink Inflammation panels, we measured 737 inflammatory proteins in CSF from 22 AD [11 early‐onset (EOAD); 11 late‐onset (LOAD)], 45 FTLD patients and 5 healthy controls (HC). Multiple linear regression analyses were performed and comparison of expression between the groups was done by ANOVA F‐tests, adjusted for age, sex and age of onset, with FDR correction for multiple comparisons. The relationship between inflammatory markers and neurofilament light chain (NfL) was examined by Pearson correlation as well as linear regression analysis incorporating the interaction effect of NfL and disease groups.
Result
Out of 442 proteins that passed quality control, five neuroinflammatory proteins (PKLR, CAT, CXCL9, MMP1, MEPE) involved in extracellular matrix regulation, neuroprotection and chemoattractant activity were significantly downregulated in AD compared to HC (q<0.05, FDR‐corrected). Comparing AD and FTLD, 40 were significantly upregulated in AD (q<0.05, FDR‐corrected). C3, a pro‐inflammatory complement protein was significantly downregulated in AD compared to FTLD. Interestingly, seven inflammatory proteins were significantly correlated with NfL in AD following FDR correction: C7 (r = 0.79, q<0.05), LGALS9 (r = 0.72, q<0.05), LYVE1 ((r = 0.72, q<0.05), ADAMTS1 (r = 0.71, q<0.05), MRC1 (r = 0.69, q<0.05), SEMA3G (r = 0.69, q<0.05), and CCN2 (r = 0.68, q<0.05). No inflammatory proteins were correlated with NfL in FTLD. Comparing EOAD and LOAD, anti‐inflammatory cytokine TGF‐β, was upregulated in EOAD compared to LOAD (q<0.05, FDR‐corrected). A significant interaction effect of NfL and AD sub‐groups (EOAD and LOAD) was found with TNFRSF13B, CCL21, IL5RA, IL7, and MZB1 (q<0.05, FDR‐corrected), where except for IL7, all proteins were positively correlated with NfL in LOAD but not in EOAD.
Conclusion
AD and FTLD patients display distinct inflammatory profiles with varying relationships between inflammatory and neurodegenerative markers. EOAD and LOAD also showed distinct inflammatory patterns. Our results underscore that proteinopathy‐specific neuroinflammatory mechanisms are involved in disease pathogenesis.