Cerebrospinal Fluid and Blood CX3CL1 as a Potential Biomarker in Early Diagnosis and Prognosis of Dementia

Kulczyńska-Przybik, Agnieszka; Słowik, Agnieszka; Mroczko, Piotr; Borawski, Bartłomiej; Groblewska, Magdalena; Borawska, Renata; Mroczko, Barbara

doi:10.2174/1567205017666201109095657

Cited by 18 publications

(17 citation statements)

References 51 publications

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“…1 Mean normalised protein expression values for the chemokines in controls and each of PPA groups in CSF. Significant differences with p values are shown on the graphs CCL3, and CX3CL1 in this group parallel previous studies in those with a typical AD clinical presentation [13][14][15][16][17][18]. CCL2 (MCP-1) is expressed by neurons, astrocytes, and microglia and has previously been shown to be raised in the CSF of people with typical AD including those with mild cognitive impairment (MCI) [13,14,19].…”

Section: Discussionsupporting

confidence: 85%

Differential chemokine alteration in the variants of primary progressive aphasia—a role for neuroinflammation

Sogorb‐Esteve

Swift

Woollacott

et al. 2021

J Neuroinflammation

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Background The primary progressive aphasias (PPA) represent a group of usually sporadic neurodegenerative disorders with three main variants: the nonfluent or agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA). They are usually associated with a specific underlying pathology: nfvPPA with a primary tauopathy, svPPA with a TDP-43 proteinopathy, and lvPPA with underlying Alzheimer’s disease (AD). Little is known about their cause or pathophysiology, but prior studies in both AD and svPPA have suggested a role for neuroinflammation. In this study, we set out to investigate the role of chemokines across the PPA spectrum, with a primary focus on central changes in cerebrospinal fluid (CSF) Methods Thirty-six participants with sporadic PPA (11 svPPA, 13 nfvPPA, and 12 lvPPA) as well as 19 healthy controls were recruited to the study and donated CSF and plasma samples. All patients with lvPPA had a tau/Aβ42 biomarker profile consistent with AD, whilst this was normal in the other PPA groups and controls. We assessed twenty chemokines in CSF and plasma using Proximity Extension Assay technology: CCL2 (MCP-1), CCL3 (MIP-1a), CCL4 (MIP-1β), CCL7 (MCP-3), CCL8 (MCP-2), CCL11 (eotaxin), CCL13 (MCP-4), CCL19, CCL20, CCL23, CCL25, CCL28, CX3CL1 (fractalkine), CXCL1, CXCL5, CXCL6, CXCL8 (IL-8), CXCL9, CXCL10, and CXCL11. Results In CSF, CCL19 and CXCL6 were decreased in both svPPA and nfvPPA compared with controls whilst CXCL5 was decreased in the nfvPPA group with a borderline significant decrease in the svPPA group. In contrast, CCL2, CCL3 and CX3CL1 were increased in lvPPA compared with controls and nfvPPA (and greater than svPPA for CX3CL1). CXCL1 was also increased in lvPPA compared with nfvPPA but not the other groups. CX3CL1 was significantly correlated with CSF total tau concentrations in the controls and each of the PPA groups. Fewer significant differences were seen between groups in plasma, although in general, results were in the opposite direction to CSF, i.e. decreased in lvPPA compared with controls (CCL3 and CCL19), and increased in svPPA (CCL8) and nfvPPA (CCL13). Conclusion Differential alteration of chemokines across the PPA variants is seen in both CSF and plasma. Importantly, these results suggest a role for neuroinflammation in these poorly understood sporadic disorders, and therefore also a potential future therapeutic target.

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Section: Discussionsupporting

confidence: 85%

Differential chemokine alteration in the variants of primary progressive aphasia—a role for neuroinflammation

Sogorb‐Esteve

Swift

Woollacott

et al. 2021

J Neuroinflammation

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“…In keeping with lvPPA being associated with underlying AD pathology, the ndings of increased CCL2, CCL3 and CX3CL1 in this group parallel previous studies in those with a typical AD clinical presentation (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). CCL2 (MCP-1) is expressed by neurons, astrocytes and microglia, and has previously been shown to be raised in the CSF of people with typical AD including those with mild cognitive impairment (MCI) (14)(15)(16).…”

Section: Discussionsupporting

confidence: 85%

“…Importantly, from an AD perspective, CX3CL1 has also been shown to be upregulated in the hippocampus during memory-associated synaptic plasticity (23). Several studies have demonstrated signi cantly higher CSF concentrations of CX3CL1 in people with MCI and AD (20), with concentration being shown to differentiate MCI from controls with high sensitivity and speci city (24). Our study also showed a strong correlation with t-tau in lvPPA as well as in the controls and other groups, suggesting an association with increased neuronal damage particularly in the AD brain.…”

Section: Discussionmentioning

confidence: 99%

Differential Chemokine Alteration in the Variants of Primary Progressive Aphasia – A Role for Neuroinflammation

Sogorb‐Esteve

Swift

Woollacott

et al. 2021

Preprint

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Background The primary progressive aphasias (PPA) represent a group of usually sporadic neurodegenerative disorders with three main variants: the nonfluent or agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA). They are usually associated with a specific underlying pathology: nfvPPA with a primary tauopathy, svPPA with a TDP-43 proteinopathy, and lvPPA with underlying Alzheimer’s disease (AD). Little is known about their cause or pathophysiology but prior studies in both AD and svPPA have suggested a role for neuroinflammation. In this study we set out to investigate the role of chemokines across the PPA spectrum, with a primary focus on central changes in cerebrospinal fluid (CSF) Methods 36 participants with sporadic PPA (11 svPPA, 13 nfvPPA and 12 lvPPA) as well as 19 healthy controls were recruited to the study and donated CSF and plasma samples. All patients with lvPPA had a tau/Aβ42 biomarker profile consistent with AD, whilst this was normal in the other PPA groups and controls. We assessed twenty chemokines in CSF and plasma using Proximity Extension Assay technology: CCL2 (MCP-1), CCL3 (MIP-1a), CCL4 (MIP-1β), CCL7 (MCP-3), CCL8 (MCP-2), CCL11 (eotaxin), CCL13 (MCP-4), CCL19, CCL20, CCL23, CCL25, CCL28, CX3CL1 (fractalkine), CXCL1, CXCL5, CXCL6, CXCL8 (IL-8), CXCL9, CXCL10, and CXCL11. Results In CSF, CCL19 and CXCL6 were decreased in both svPPA and nfvPPA compared with controls whilst CXCL5, was decreased in the nfvPPA group with a borderline significant decrease in the svPPA group. In contrast, CCL2, CCL3 and CX3CL1 were increased in lvPPA compared with controls and nfvPPA (and greater than svPPA for CX3CL1). CXCL1 was also increased in lvPPA compared with nfvPPA but not the other groups. CX3CL1 was significantly correlated with CSF total tau concentrations in the controls and each of the PPA groups. Fewer significant differences were seen between groups in plasma, although in general, results were in the opposite direction to CSF i.e. decreased in lvPPA compared with controls (CCL3 and CCL19), and increased in svPPA (CCL8) and nfvPPA (CCL13). Conclusion Differential alteration of chemokines across the PPA variants is seen in both CSF and plasma. Importantly, these results suggest a role for neuroinflammation in these poorly understood sporadic disorders, and therefore also a potential future therapeutic target.

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“…Nevertheless, due to the regulatory function in inflammation, this biomarker is a promising therapeutic target. A recent Polish study reported on the predictive ability of CX3CL1 as a biomarker in the early development of mild cognitive impairment (MCI) and AD 9 . In this study, significantly higher CSF and blood levels of CX3CL1 were found in MCI and AD patients compared to cognitively healthy controls.…”

Section: Supplemental Materialsmentioning

confidence: 99%

Association of the inflammation-related proteome with dementia development at older age: results from a large, prospective, population-based cohort study

Trares

Bhardwaj

Perna

et al. 2021

Preprint

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Importance: Chronic inflammation is increasingly recognized as a central feature of several forms of dementia. Objective: To determine which biomarkers of the inflammation-related proteome are associated with all-cause dementia, Alzheimer's disease (AD), or vascular dementia (VD). Design: Analyses were performed in a case-cohort study design based on an ongoing German population-based cohort study. Setting: Serum samples of study participants were collected at baseline (2000-20002), and participants were followed up for 17 years. Information about a dementia diagnosis was collected during follow-up via collection of medical records from general practitioners. Participants: Ascertainment of potential dementia development during follow-ups was conducted for 6,284 study participants aged 50-75 years at baseline. Biomarker measurements were performed in a randomly collected sample of 1,435 participants and all incident dementia cases of the rest of the cohort (n=393). Main Outcomes and Measures: All-cause dementia, AD and VD were the primary outcomes of this analysis. Results: Biomarkers were analyzed in 504 all-cause dementia cases (mean age, 67.0 [SD, 5.1] years; 262 female [52.0%], and 242 male [48.0%]) and 1,278 controls (mean age, 61.9 [standard deviation (SD): 6.5] years; 703 female [55.0%], and 575 male [45.0%]). Among the dementia cases, 163 participants developed AD and 195 VD. After correction for multiple testing, 58 biomarkers were statistically significantly associated with all-cause dementia, 22 with AD, and 33 with VD incidence. All analyses were adjusted for potential confounders. Besides single biomarker associations, we identified four biomarker clusters based on the strongest and independently associated biomarkers CX3CL1, EN-RAGE, LAP TGF-beta-1 and VEGF-A. CX3CL1 (Odds ratio [95%-confidence interval] per 1 standard deviation increase: 1.41 [1.24-1.60]) and EN-RAGE (1.41 [1.25-1.60]) were associated with all-cause dementia incidence, EN-RAGE (1.51 [1.25-1.83]) and LAP TGF-beta-1 (1.46 [1.21-1.76]) with AD incidence, and VEGF-A (1.43 [1.20-1.70]) with VD incidence. All named associations were stronger among APOE ε4 negative subjects. Conclusion and Relevance: This study shows for the first time that the majority of inflammation-related proteins measured in serum samples (58 of 72 tested (80.6%)) are associated with all-cause dementia incidence. Future studies should not only concentrate on single biomarkers but also the complex relationships in biomarker clusters.

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Cerebrospinal Fluid and Blood CX3CL1 as a Potential Biomarker in Early Diagnosis and Prognosis of Dementia

Cited by 18 publications

References 51 publications

Differential chemokine alteration in the variants of primary progressive aphasia—a role for neuroinflammation

Differential chemokine alteration in the variants of primary progressive aphasia—a role for neuroinflammation

Differential Chemokine Alteration in the Variants of Primary Progressive Aphasia – A Role for Neuroinflammation

Association of the inflammation-related proteome with dementia development at older age: results from a large, prospective, population-based cohort study

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