Systemic Inflammation in Non-Demented Elderly Human Subjects: Brain Microstructure and Cognition

Arfanakis, Konstantinos; Fleischman, Debra; Grisot, Giorgia; Barth, Christopher M.; Varentsova, Anna; Morris, Martha Clare; Barnes, Lisa L.; Bennett, David A.

doi:10.1371/journal.pone.0073107

Cited by 59 publications

(49 citation statements)

References 65 publications

(82 reference statements)

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“…A systemic inflammatory response has been reported in both aging[30, 31] and AD[32–35], although the utility of plasma inflammation as an indicator of CNS immune dysregulation has been more controversial and remarkably understudied. One of the two primary goals of our study was to assess the association between CSF and plasma inflammation to clarify how well plasma inflammation reflects CNS inflammation.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal Fluid and Plasma Levels of Inflammation Differentially Relate to CNS Markers of Alzheimer’s Disease Pathology and Neuronal Damage

Bettcher

Johnson

Fitch

et al. 2018

JAD

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Inflammatory markers have been shown to predict neurocognitive outcomes in aging adults; however, the degree to which peripheral markers mirror the central nervous system remains unknown. We investigated the association between plasma and CSF markers of inflammation, and explored whether these markers independently predict CSF indicators of Alzheimer’s disease (AD) pathology or neuronal damage. Plasma and CSF samples were analyzed for inflammatory markers in a cohort of asymptomatic older adults (n=173). CSF samples were analyzed for markers of AD pathology (Aβ42, phosphorylated tau [p-tau], sAPP-β) or neuronal damage (total tau; neurofilament light chain [NFL])(n=147). Separate linear models for each analyte were conducted with CSF and plasma levels entered simultaneously as predictors and markers of AD pathology or neuronal damage as outcome measures. Strong associations were noted between CSF and plasma MIP-1β levels, and modest associations were observed for remaining analytes. With respect to AD pathology, higher levels of plasma and CSF IL-8, CSF MIP-1β, and CSF IP-10 were associated with higher levels of p-tau. Higher levels of CSF IL-8 were associated with higher levels of CSF Aβ1-42. Higher CSF sAPP-beta levels were associated with higher plasma markers only (IL-8; MCP-1). In terms of neuronal injury, higher levels of plasma and CSF IL-8, CSF IP-10, and CSF MIP-1β were associated with higher levels of CSF total tau. Exploratory analyses indicated that CSF Aβ42 modifies the relationship between plasma inflammatory levels and CSF tau levels. Results suggest that both plasma and CSF inflammatory markers independently relay integral information about AD pathology and neuronal damage.

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Section: Discussionmentioning

confidence: 99%

Cerebrospinal Fluid and Plasma Levels of Inflammation Differentially Relate to CNS Markers of Alzheimer’s Disease Pathology and Neuronal Damage

Bettcher

Johnson

Fitch

et al. 2018

JAD

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“…However, only a few studies explored the relationship between peripheral inflammatory biomarkers in relation to brain measures among older adults without dementia, and the results remain inconclusive(31). Only three studies (32-34) investigated white matter microstructure and showed that systemic inflammation was associated with reduced fractional anisotropy (FA), an indicator of white matter integrity. CRP or IL6 was associated with reduced total brain volume (TBV)(35), total gray matter volume (TGMV)(36-38), total white matter volume (TWMV)(37), and hippocampal volume(36, 37, 39).…”

Section: Introductionmentioning

confidence: 99%

“…In one study of elderly adults, higher IL-6 was associated with accelerated annual rates of cortical thinning in the inferior temporal poles bilaterally(43), while another study found no cross-sectional associations of IL6 or CRP with CT in adults aged 30–54 years(37). Thus, inconsistency remains regarding the relationship between peripheral inflammatory biomarkers and brain volume; some brain measures such as microstructural white matter integrity(32-34), CT (37, 43), as well as regional brain volumes(37) were rarely examined. The role of ACT in brain structure is largely unknown despite its involvement in the Aβ-related pathogenesis in AD (44, 45).…”

Section: Introductionmentioning

confidence: 99%

Circulating inflammatory biomarkers in relation to brain structural measurements in a non-demented elderly population

Vorburger

Scarmeas

et al. 2017

Brain, Behavior, and Immunity

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Objective The aim of this investigation was to determine whether circulating inflammatory biomarkers c-reactive protein (CRP), interleukin-6 (IL6), and alpha 1-antichymotrypsin (ACT) were related to structural brain measures assessed by magnetic resonance imaging (MRI). Methods High-resolution structural MRI was collected on 680 non-demented elderly (mean age 80.1 years) participants of a community-based, multiethnic cohort. Approximately three quarters of these participants also had peripheral inflammatory biomarkers (CRP, IL6, and ACT) measured using ELISA. Structural measures including brain volumes and cortical thickness (with both global and regional measures) were derived from MRI scans, and repeated MRI measures were obtained after 4.5 years. Mean fractional anisotropy was used as the indicator of white matter integrity assessed with diffusion tensor imaging. We examined the association of inflammatory biomarkers with brain volume, cortical thickness, and white matter integrity using regression models adjusted for age, gender, ethnicity, education, APOE genotype, intracranial volume. Results A doubling in CRP (b= -2.48, p=0.002) was associated with a smaller total gray matter volume, equivalent to approximately 1.5 years of aging. A doubling in IL6 was associated with smaller total brain volume (b= -14.96, p<0.0001), equivalent to approximately 9 years of aging. Higher IL6 was also associated with smaller gray matter (b=-6.52, p=0.002) and white matter volumes (b=-7.47, p=0.004). The volumes of most cortical regions including frontal, occipital, parietal, temporal, as well as subcortical regions including pallidum and thalamus were associated with IL6. In a model additionally adjusted for depression, vascular factors, BMI, and smoking status, the association between IL6 and brain volumes remained, and a doubling in ACT was marginally associated with 0.054 (p=0.004) millimeter thinner mean cortical thickness, equivalent to that of approximately 2.7 years of aging. None of the biomarkers was associated with mean fractional anisotropy or longitudinal change of brain volumes and thickness. Conclusions Among older adults, increased circulating inflammatory biomarkers were associated with smaller brain volume and cortical thickness but not the white matter tract integrity. Our preliminary findings suggest that peripheral inflammatory processes may be involved in the brain atrophy in the elderly.

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“…Recently, a connection between systemic inflammatory biomarkers, brain microstructure and visuospatial ability has also been found [12].…”

Section: Introductionmentioning

confidence: 99%

Increased Inflammatory Response in Cytomegalovirus Seropositive Patients with Alzheimer’s Disease

et al. 2014

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Alzheimer’s disease (AD) has been associated with increased local inflammation in the affected brain regions, and in some studies also with elevated levels of proinflammatory cytokines in peripheral blood. Cytomegalovirus (CMV) is known to promote a more effector-oriented phenotype in the T-cell compartment, increasing with age. The aim of this study was to investigate the inflammatory response of peripheral blood mononuclear cells (PBMCs) from AD patients and non-demented (ND) controls. Using a multiplex Luminex xMAP assay targeting GM-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IP-10 and TNF-α, cytokine profiles from PBMCs were analysed after stimulation with anti-CD3/CD28 beads, CMV pp65 peptide mix or amyloid β (Aβ) protofibrils, respectively. CMV seropositive AD subjects presented with higher IFN-γ levels after anti-CD3/CD28 and CMV pp65 but not after Aβ stimulation, compared to CMV seropositive ND controls. When analysing IFN-γ response to anti-CD3/CD28 stimulation on a subgroup level, CMV seropositive AD subjects presented with higher levels compared to both CMV seronegative AD and CMV seropositive ND subjects. Taken together, our data from patients with clinically manifest AD suggest a possible role of CMV as an inflammatory promoter in AD immunology. Further studies of AD patients at earlier stages of disease, could provide better insight into the pathophysiology.

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Systemic Inflammation in Non-Demented Elderly Human Subjects: Brain Microstructure and Cognition

Cited by 59 publications

References 65 publications

Cerebrospinal Fluid and Plasma Levels of Inflammation Differentially Relate to CNS Markers of Alzheimer’s Disease Pathology and Neuronal Damage

Cerebrospinal Fluid and Plasma Levels of Inflammation Differentially Relate to CNS Markers of Alzheimer’s Disease Pathology and Neuronal Damage

Circulating inflammatory biomarkers in relation to brain structural measurements in a non-demented elderly population

Increased Inflammatory Response in Cytomegalovirus Seropositive Patients with Alzheimer’s Disease

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