Different Inflammatory Signatures in Alzheimer’s Disease and Frontotemporal Dementia Cerebrospinal Fluid

Abstract

Background: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases. Objective: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD. Methods: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for age, gender, collection unit, and multiple testing. Results: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95%confidence interval [CI] 1.14–1.53, q = 0.018; MCI/AD: FC = 1.53, 95%CI 1.20–1.94, q = 0.045; and FTD: FC = 1.42, 95%CI 1.10–1.83, q = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q < 0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q < 0.05). Conclusion: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders.

Biomarkers of Inflammation Increase with Tau and Neurodegeneration but not with Amyloid-β in a Heterogenous Clinical Cohort

“…At the level of individual markers, multiple studies have shown that MMP-10 levels are increased in AD and frontotemporal dementia (FTD) CSF compared to healthy controls [ 9, 30, 31 ]. Matrix metallo-proteinases (MMPs) are important enzymes for the function of the blood-brain barrier, with both detrimental and beneficial effects for the host, depending on the MMP studied.…”

“…Elevated levels of MMP-10 have also been reported in other forms of dementia. For example, Boström et al show increased CSF MMP-10 in patients with FTD, when compared to healthy controls [ 9 ]. Santaella et al showed that elevated levels of CSF MMP-10 correlate with disease progression in patients diagnosed with Parkinson’s disease [ 35 ].…”

“…Inflammatory mediators exacerbate the production of A␤, the propagation of tau pathology and neuronal loss [7]. Several recent studies have identified increased CSF levels of a wide range of inflammatory markers including in patients with AD in well controlled research cohorts [8][9][10].…”

Relationship between Cerebrospinal Fluid Matrix Metalloproteinases Levels and Brain Amyloid Deposition in Mild Cognitive Impairment

“…In this study, several MMPs, namely, MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, and MMP-13, were below the limit of detection in CSF. A number of studies have reported variable findings regarding the CSF levels of MMPs and TIMPs in patients with AD, such as increased or decreased levels of MMP-3 [8,32,41,42], increased or undetectable levels of MMP-9 and MMP-10 [42,54], increased or decreased levels of TIMP-1 [32,42], and increased levels of TIMP-2 [55] compared to controls. These confounding findings may be due to differences in subject selection and the measurement methods used to determine MMP and TIMP.…”

Pathophysiological Underpinnings of Extra-Motor Neurodegeneration in Amyotrophic Lateral Sclerosis: New Insights From Biomarker Studies

“…For instance, increased CSF and serum levels of some monocyte-derived cytokines linked with the inflammatory response such as TNF-α, IL-1β, IL-17, and TGF-β reveal a microglial and white blood cell participation in the ALS-FTD pathologic continuum ( 113 , 182 , 183 ). In addition, increased CSF levels compared to controls of Matrix Metalloproteinase-10 and decreased CSF levels of some chemokines and growth factors (such as IL-8, IL-12B, TGF-α among others) have been recently reported in a multicentric study ( 184 ). Other surrogate markers of acute-phase systemic inflammation have been reported in ALS, including lipopolysaccharide-binding protein, C reactive protein, and soluble CD14 ( 181 , 185 ).…”