Emerging Role of Immunity in Cerebral Small Vessel Disease

Fu, Ying; Yan, Yaping

doi:10.3389/fimmu.2018.00067

Cited by 66 publications

(51 citation statements)

References 141 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Intracerebral hemorrhage is also associated with high levels of IFN-γ [69,70]. Blood-brain barrier alterations and chronic inflammation are classical pathological features of cerebral small vessel disease, characterized by multiple strokes, blood-brain barrier dysfunction, and chronic inflammation at the neurovascular unit [71]. In line with these observations, db/db [72] and APP/PS1xdb/db mice [17,31] show widespread spontaneous bleeding.…”

Section: Discussionmentioning

confidence: 77%

See 1 more Smart Citation

Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer’s mouse model

Sankar

Infante-Garcia

Weinstock

et al. 2020

J Neuroinflammation

View full text Add to dashboard Cite

Background: Diabetes is a risk factor for developing Alzheimer's disease (AD); however, the mechanism by which diabetes can promote AD pathology remains unknown. Diabetes results in diverse molecular changes in the brain, including dysregulation of glucose metabolism and loss of cerebrovascular homeostasis. Although these changes have been associated with increased Aβ pathology and increased expression of glial activation markers in APPswe/ PS1dE9 (APP/PS1) mice, there has been limited characterization, to date, of the neuroinflammatory changes associated with diabetic conditions. Methods: To more fully elucidate neuroinflammatory changes associated with diabetes that may drive AD pathology, we combined the APP/PS1 mouse model with either high-fat diet (HFD, a model of pre-diabetes), the genetic db/db model of type 2 diabetes, or the streptozotocin (STZ) model of type 1 diabetes. We then used a multiplexed immunoassay to quantify cortical changes in cytokine proteins. Results: Our analysis revealed that pathology associated with either db/db, HFD, or STZ models yielded upregulation of a broad profile of cytokines, including chemokines (e.g., MIP-1α, MIP-1β, and MCP-1) and proinflammatory cytokines, including IL-1α, IFN-γ, and IL-3. Moreover, multivariate partial least squares regression analysis showed that combined diabetic-APP/PS1 models yielded cooperatively enhanced expression of the cytokine profile associated with each diabetic model alone. Finally, in APP/PS1xdb/db mice, we found that circulating levels of Aβ1-40, Aβ1-42, glucose, and insulin all correlated with cytokine expression in the brain, suggesting a strong relationship between peripheral changes and brain pathology. Conclusions: Altogether, our multiplexed analysis of cytokines shows that Alzheimer's and diabetic pathologies cooperate to enhance profiles of cytokines reported to be involved in both diseases. Moreover, since many of the identified cytokines promote neuronal injury, Aβ and tau pathology, and breakdown of the blood-brain barrier, our data suggest that neuroinflammation may mediate the effects of diabetes on AD pathogenesis. Therefore, strategies targeting neuroinflammatory signaling, as well as metabolic control, may provide a promising strategy for intervening in the development of diabetes-associated AD.

show abstract

Section: Discussionmentioning

confidence: 77%

“…In line with these observations, db/db [72] and APP/PS1xdb/db mice [17,31] show widespread spontaneous bleeding. In this context, IFN-γ may lead to diffuse neuron and oligodendrocyte damage [71].…”

Section: Discussionmentioning

confidence: 99%

Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer’s mouse model

Sankar

Infante-Garcia

Weinstock

et al. 2020

J Neuroinflammation

View full text Add to dashboard Cite

show abstract

“…Cerebral small vessel disease (cSVD) is a leading contributor to vascular cognitive impairment and is estimated to cause 1/5 th of strokes in older adults [1]. cSVD has been associated with global cognitive decline, decreased executive function and reduced processing speeds [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

An IL-18-centered inflammatory network as a biomarker for cerebral white matter injury

et al. 2020

View full text Add to dashboard Cite

Chronic systemic sterile inflammation is implicated in the pathogenesis of cerebrovascular disease and white matter injury. Non-invasive blood markers for risk stratification and dissection of inflammatory molecular substrates in vivo are lacking. We sought to identify whether an interconnected network of inflammatory biomarkers centered on IL-18 and all previously associated with white matter lesions could detect overt and antecedent white matter changes in two populations at risk for cerebral small vessel disease. In a cohort of 167 older adults (mean age: 76, SD 7.1, 83 females) that completed a cognitive battery, physical examination, and blood draw in parallel with MR imaging including DTI, we measured cerebral white matter hyperintensities (WMH) and free water (FW). Concurrently, serum levels of a biologic network of inflammation molecules including MPO, GDF-15, RAGE, ST2, IL-18, and MCP-1 were measured. The ability of a log-transformed population mean-adjusted inflammatory composite score (ICS) to associate with MR variables was demonstrated in an age and total intracranial volume adjusted model. In this cohort, ICS was significantly associated with WMH (β = 0.222, p = 0.013), FW (β = 0.3, p = 0.01), and with the number of vascular risk factor diagnoses (r = 0.36, p<0.001). In a second cohort of 131 subjects presenting for the evaluation of acute neurologic deficits concerning for stroke, we used serum levels of 11 inflammatory biomarkers in an unbiased principal component analysis which identified a single factor significantly associated with WMH. This single factor was strongly correlated with the six component ICS identified in the first cohort and was associated with WMH in a generalized linear regression model adjusted for age and gender (p = 0.027) but not acute stroke. A network of inflammatory molecules driven by IL-18

show abstract

“…2 Recurrent minor strokes, blood-brain barrier (BBB) impairment, inflammatory responses and leukocyte infiltration are classical pathological features of CSVD. 3 The inflammatory reaction is triggered both at the onset of ischemic and hemorrhagic stroke (attack phase) 4 and chronic stages (remitting phase) of "silent CSVD". 5 Sleep and the circadian system exert a strong regulatory influence on immune functions.…”

Section: Introductionmentioning

confidence: 99%

<p>Chronic Insomnia Is Associated with Higher Circulating Interleukin-8 in Patients with Atherosclerotic Cerebral Small Vessel Disease</p>

Wang

Chen

Men

et al. 2020

NSS

View full text Add to dashboard Cite

Objective: Chronic inflammatory responses and leukocyte infiltration are classical pathological features of cerebral small vessel disease (CSVD). To date, limited evidence of a relationship between chronic insomnia and inflammatory responses in patients with CSVD has been uncovered. The purpose of the present study was to investigate the potential relationship between chronic insomnia and pro-inflammatory cytokine levels in patients with atherosclerotic CSVD (A-CSVD). Methods: In total, 76 A-CSVD patients with or without chronic insomnia (CI) confirmed using magnetic resonance (MR) were prospectively recruited. Overnight polysomnography (PSG) was performed and serum levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-17A, IL-8, and IL-12 assessed. Cytokine levels were compared between CSVD+CI (study group) and CSVD without CI (control group) patients, and the correlations between PSG parameters and cytokine levels were explored in all patients via multiple linear regression analyses. Results: The serum IL-8 level of the study group (12.3±4.4 pg/mL) was significantly higher than that of the control group (7.5±2.2 pg/mL; P<0.05). PSG measurements showed that patients in the study group had significantly higher sleep onset latency (SOL), arousal index (ArI) and wake after sleep onset (WASO) as well as lower total sleep time (TST), sleep efficiency (SE) and stage 3 NREM sleep (N-3) ratio, compared with the control group (P<0.05). Multiple linear regression analyses led to the identification of ArI (β=0.026, P<0.05) and TST (β=−0.054, P<0.05) as significant positive and negative predictors of the IL-8 level, respectively. Conclusion: Chronic insomnia, in particular, sleep fragmentation and short sleep duration, may be involved in promotion of serum IL-8 expression in patients with atherosclerotic CSVD.

show abstract

Emerging Role of Immunity in Cerebral Small Vessel Disease

Cited by 66 publications

References 141 publications

Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer’s mouse model

Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer’s mouse model

An IL-18-centered inflammatory network as a biomarker for cerebral white matter injury

<p>Chronic Insomnia Is Associated with Higher Circulating Interleukin-8 in Patients with Atherosclerotic Cerebral Small Vessel Disease</p>

Contact Info

Product

Resources

About