Immune markers are associated with cognitive performance in a multiethnic cohort: The Northern Manhattan Study

Elkind, Mitchell S.V.; Moon, Michelle; Rundek, Tatjana; Wright, Clinton B.; Cheung, Ken; Sacco, Ralph L.; Hornig, Mady

doi:10.1016/j.bbi.2021.07.011

Cited by 7 publications

(9 citation statements)

References 55 publications

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“…Multiple lines of observational evidence have implicated inflammation in the pathogenesis of atherosclerosis, all causes of stroke, and cognitive function. 4,10 Though no randomized controlled trial has been yet completed in stroke, colchicine, which has anti-inflammatory properties by inhibiting β-tubulin polymerization, has been shown to reduce recurrent vascular events among those with myocardial infarction. 46 In a meta-analysis of trials designed for the study of coronary artery disease, colchicine-treated participants had half the risk of stroke as control arms.…”

Section: Discussionmentioning

confidence: 99%

“…9 The assay included immune biomarkers related to activation of Th1 ([T helper cell type 1], proinflammatory), Th2 ([T helper cell type 2], counterregulatory autoimmunity promoting), Th17 ([T helper cell type 17], innate mucosal antipathogen defenses, including in gut), T regulatory, B (antibody producing), and natural killer cells, and, more generally, markers of innate and adaptive immunity, chemokines, growth factors (including those vital to vascular remodeling), neurotrophic factors, cell adhesion markers, and adipokines. 10 We coded, randomized, and assayed plasma samples in duplicate. Flow-and fluorescence-based Luminex 200 detection platform (Luminex Corporation, Austin, TX) determined the median fluorescence intensities of each analyte-specific immunoassay bead set.…”

Section: Immunoassay Assessmentmentioning

confidence: 99%

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Immune Markers Are Associated With Asymptomatic Intracranial Large Artery Stenosis and Future Vascular Events in NOMAS

Yang,

Liu,

Khasiyev

et al. 2023

Stroke

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Background: Inflammation contributes to atherosclerosis but is incompletely characterized in intracranial large artery stenosis (ICAS). We hypothesized that immune markers would be associated with ICAS and modify the risk ICAS confers on future vascular events. Methods: This study included a subsample of stroke-free participants in the prospective NOMAS (Northern Manhattan Study), who had blood samples analyzed with a 60-plex immunoassay (collected from 1993 to 2001) and ICAS assessment with time-of-flight magnetic resonance angiography (obtained from 2003 to 2008). We dichotomized ICAS as either ≥50% stenosis or not (including no ICAS). We ascertained post–magnetic resonance imaging vascular events. We used least absolute shrinkage and selection operator procedures to select immune markers independently associated with ICAS. Then, we grouped selected immune markers into a derived composite Z score. Using proportional odds regression, we quantified the association of the composite immune marker Z score, ICAS, and risk of vascular events. Results: Among 1211 participants (mean age, 71±9 years; 59% women; 65% Hispanic participants), 8% had ≥50% ICAS. Using least absolute shrinkage and selection operator regression, we identified CXCL9 (C-X-C motif chemokine ligand 9), HGF (hepatocyte growth factor), resistin, SCF (stem cell factor), and VEGF-A(vascular endothelial growth factor A) to have the strongest positive relationships with ≥50% ICAS in fully adjusted models. Selected markers were used to derive a composite immune marker Z score. Over an average follow-up of 12 years, we found that each unit increase in immune marker Z scores was associated with an 8% (95% CI, 1.05–1.11), 11% (95% CI, 1.06–1.16), and 5% (95% CI, 1.01–1.09) increased hazard of death, vascular death, and any vascular event, respectively, in adjusted models. We did not find a significant interaction between immune marker Z scores and ICAS in their relationship with any longitudinal outcome. Conclusions: Among a diverse stroke-free population, selected serum immune markers were associated with ICAS and future vascular events. Further study is needed to better understand their role in the pathogenesis of ICAS and as a potential therapeutic target in stroke prevention.

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Section: Discussionmentioning

confidence: 99%

Section: Immunoassay Assessmentmentioning

confidence: 99%

Immune Markers Are Associated With Asymptomatic Intracranial Large Artery Stenosis and Future Vascular Events in NOMAS

Yang,

Liu,

Khasiyev

et al. 2023

Stroke

Self Cite

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“…While CXCL9 is the most strongly dependent on interferon gamma for expression, TNF-α can induce CXCL9 mRNA expression in endothelial cells ( Murphy, 2003 ). Increased expression of CXCL9 in the serum and CSF has been associated with cognitive decline and is increased in AD brain ( Galimberti et al, 2003 ; Elkind et al, 2021 ). CSF levels of TNF-α, CXCL9, and IL-6 are also elevated in other neuroinflammatory diseases such as multiple sclerosis ( Lepennetier et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Early therapeutic effects of an Angiopoietin-1 mimetic peptide in middle-aged rats with vascular dementia

Gao

Findeis

Culmone

et al. 2023

Front. Aging Neurosci.

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BackgroundVascular Dementia (VaD) refers to dementia caused by cerebrovascular disease and/or reduced blood flow to the brain and is the second most common form of dementia after Alzheimer’s disease. We previously found that in middle-aged rats subjected to a multiple microinfarction (MMI) model of VaD, treatment with AV-001, a Tie2 receptor agonist, significantly improves short-term memory, long-term memory, as well as improves preference for social novelty compared to control MMI rats. In this study, we tested the early therapeutic effects of AV-001 on inflammation and glymphatic function in rats subjected to VaD.MethodsMale, middle-aged Wistar rats (10–12 m), subjected to MMI, were randomly assigned to MMI and MMI + AV-001 treatment groups. A sham group was included as reference group. MMI was induced by injecting 800 ± 200, 70–100 μm sized, cholesterol crystals into the internal carotid artery. Animals were treated with AV-001 (1 μg/Kg, i.p.) once daily starting at 24 h after MMI. At 14 days after MMI, inflammatory factor expression was evaluated in cerebrospinal fluid (CSF) and brain. Immunostaining was used to evaluate white matter integrity, perivascular space (PVS) and perivascular Aquaporin-4 (AQP4) expression in the brain. An additional set of rats were prepared to test glymphatic function. At 14 days after MMI, 50 μL of 1% Tetramethylrhodamine (3 kD) and FITC conjugated dextran (500 kD) at 1:1 ratio were injected into the CSF. Rats (4–6/group/time point) were sacrificed at 30 min, 3 h, and 6 h from the start of tracer infusion, and brain coronal sections were imaged using a Laser scanning confocal microscope to evaluate tracer intensities in the brain.ResultTreatment of MMI with AV-001 significantly improves white matter integrity in the corpus callosum at 14 days after MMI. MMI induces significant dilation of the PVS, reduces AQP4 expression and impairs glymphatic function compared to Sham rats. AV-001 treatment significantly reduces PVS, increases perivascular AQP4 expression and improves glymphatic function compared to MMI rats. MMI significantly increases, while AV-001 significantly decreases the expression of inflammatory factors (tumor necrosis factor-α (TNF-α), chemokine ligand 9) and anti-angiogenic factors (endostatin, plasminogen activator inhibitor-1, P-selectin) in CSF. MMI significantly increases, while AV-001 significantly reduces brain tissue expression of endostatin, thrombin, TNF-α, PAI-1, CXCL9, and interleukin-6 (IL-6).ConclusionAV-001 treatment of MMI significantly reduces PVS dilation and increases perivascular AQP4 expression which may contribute to improved glymphatic function compared to MMI rats. AV-001 treatment significantly reduces inflammatory factor expression in the CSF and brain which may contribute to AV-001 treatment induced improvement in white matter integrity and cognitive function.

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“…Higher levels of IL‐6 have been associated with poorer performance on cognitive testing and with cognitive decline in diverse groups of older men and women (Palta et al, 2015 ; Singh‐Manoux et al, 2014 ; Yaffe et al, 2003 ). A recent report identified CCL11 (eotaxin), CXCL9, hepatocyte growth factor (HGF), and serpine 1 associations with multiple cognitive domains and overall cognition that remain to be validated in other studies (Elkind et al, 2021 ). Despite several reports linking proinflammatory factors to cognitive decline, few have identified circulating inflammatory markers that have a protective effect on cognitive functions.…”

Section: Introductionmentioning

confidence: 99%

Peripheral inflammatory biomarkers are associated with cognitive function and dementia: Framingham Heart Study Offspring cohort

et al. 2023

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Inflammatory protein biomarkers induced by immune responses have been associated with cognitive decline and the pathogenesis of Alzheimer's disease (AD). Here, we investigate associations between a panel of inflammatory biomarkers and cognitive function and incident dementia outcomes in the well‐characterized Framingham Heart Study Offspring cohort. Participants aged ≥40 years and dementia‐free at Exam 7 who had a stored plasma sample were selected for profiling using the OLINK proteomics inflammation panel. Cross‐sectional associations of the biomarkers with cognitive domain scores (N = 708, 53% female, 22% apolipoprotein E (APOE) ε4 carriers, 15% APOE ε2 carriers, mean age 61) and incident all‐cause and AD dementia during up to 20 years of follow‐up were tested. APOE genotype‐stratified analyses were performed to explore effect modification. Higher levels of 12 and 3 proteins were associated with worse executive function and language domain factor scores, respectively. Several proteins were associated with more than one cognitive domain, including IL10, LIF‐R, TWEAK, CCL19, IL‐17C, MCP‐4, and TGF‐alpha. Stratified analyses suggested differential effects between APOE ε2 and ε4 carriers: most ε4 carrier associations were with executive function and memory domains, whereas most ε2 associations were with the visuospatial domain. Higher levels of TNFB and CDCP1 were associated with higher risks of incident all‐cause and AD dementia. Our study found that TWEAK concentration was associated both with cognitive function and risks for AD dementia. The association of these inflammatory biomarkers with cognitive function and incident dementia may contribute to the discovery of therapeutic interventions for the prevention and treatment of cognitive decline.

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Immune markers are associated with cognitive performance in a multiethnic cohort: The Northern Manhattan Study

Cited by 7 publications

References 55 publications

Immune Markers Are Associated With Asymptomatic Intracranial Large Artery Stenosis and Future Vascular Events in NOMAS

Immune Markers Are Associated With Asymptomatic Intracranial Large Artery Stenosis and Future Vascular Events in NOMAS

Early therapeutic effects of an Angiopoietin-1 mimetic peptide in middle-aged rats with vascular dementia

Peripheral inflammatory biomarkers are associated with cognitive function and dementia: Framingham Heart Study Offspring cohort

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