Risk of Dementia and Structural Brain Changes Following Nonneurological Infections During 9-Year Follow-Up.

OBJECTIVES: Given the strong association between systemic inflammation and cognitive decline, we aimed to determine whether nonneurologic infections are associated with accelerated cognitive decline and structural changes in the brain using pre- and post-infection neuropsychologic assessments and repeated brain MR images. DESIGN: Additional analysis of the prospective observational Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort study. SETTING: Single-center study at the Radboud university medical center, Nijmegen, The Netherlands, between January 2006 and September 2015. PATIENTS: Five-hundred three participants (50-85 yr old) with cerebral small vessel disease were included and followed for 9 years. MEASUREMENTS AND MAIN RESULTS: Participants underwent repeated cognitive measurements and brain MRI. Infectious events were collected. Sepsis episodes were analyzed, and additionally, patients were stratified in three groups: having had a severe infectious episode (e.g., sepsis or hospitalization for infection), a mild, or no infectious episode. Development of dementia, trajectories of cognition, and structural brain changes on MRI in the subsequent follow-up periods were compared between the groups. Complete infectious data were available from 331 patients (mean age 64 ± 8 yr, 57% males). Twenty-nine participants (9%) suffered from a sepsis episode, 69 (21%) from a severe, 201 (61%) from a mild, and 61 (18%) had no infectious episode during follow-up. After correction for age, baseline cognition, and brain volume, each sepsis episode remained associated with an 82% increased risk to develop dementia within the follow-up period (hazard ratio, 1.82; 95% CI, 1.07-3.10; p = 0.027). Infections had no effect on the trajectory of structural changes to the brain after correction for baseline differences. CONCLUSIONS: In this 9-year observational follow-up study, sepsis episodes were associated with subsequent development of dementia. Nonneurologic infections had no effect on the trajectory of structural cerebral changes.

Elevated expression of urokinase plasminogen activator in rodent models and patients with cerebral amyloid angiopathy.

AIMS: The aim of this work is to study the association of urokinase plasminogen activator (uPA) with development and progression of cerebral amyloid angiopathy (CAA). MATERIALS AND METHODS: We studied the expression of uPA mRNA by quantitative polymerase chain reaction (qPCR) and co-localisation of uPA with amyloid-ß (Aß) using immunohistochemistry in the cerebral vasculature of rTg-DI rats compared with wild-type (WT) rats and in a sporadic CAA (sCAA) patient and control subject using immunohistochemistry. Cerebrospinal fluid (CSF) uPA levels were measured in rTg-DI and WT rats and in two separate cohorts of sCAA and Dutch-type hereditary CAA (D-CAA) patients and controls, using enzyme-linked immunosorbent assays (ELISA). RESULTS: The presence of uPA was clearly detected in the cerebral vasculature of rTg-DI rats and an sCAA patient but not in WT rats or a non-CAA human control. uPA expression was highly co-localised with microvascular Aß deposits. In rTg-DI rats, uPA mRNA expression was highly elevated at 3 months of age (coinciding with the emergence of microvascular Aß deposition) and sustained up to 12 months of age (with severe microvascular CAA deposition) compared with WT rats. CSF uPA levels were elevated in rTg-DI rats compared with WT rats (p = 0.03), and in sCAA patients compared with controls (after adjustment for age of subjects, p = 0.05 and p = 0.03). No differences in CSF uPA levels were found between asymptomatic and symptomatic D-CAA patients and their respective controls (after age-adjustment, p = 0.09 and p = 0.44). Increased cerebrovascular expression of uPA in CAA correlates with increased quantities of CSF uPA in rTg-DI rats and human CAA patients, suggesting that uPA could serve as a biomarker for CAA.

Human in vivo neuroimaging to detect reprogramming of the cerebral immune response following repeated systemic inflammation.

Despite increasing evidence that immune training within the brain may affect the clinical course of neuropsychiatric diseases, data on cerebral immune tolerance are scarce. This study in healthy volunteers examined the trajectory of the immune response systemically and within the brain following repeated lipopolysaccharide (LPS) challenges. Five young males underwent experimental human endotoxemia (intravenous administration of 2 ng/kg LPS) twice with a 7-day interval. The systemic immune response was assessed by measuring plasma cytokine levels. Four positron emission tomography (PET) examinations, using the translocator protein (TSPO) ligand 18F-DPA-714, were performed in each participant, to assess brain immune cell activation prior to and 5 hours after both LPS challenges. The first LPS challenge caused a profound systemic inflammatory response and resulted in a 53% [95%CI 36-71%] increase in global cerebral 18F-DPA-714 binding (p < 0.0001). Six days after the first challenge, 18F-DPA-714 binding had returned to baseline levels (p = 0.399). While the second LPS challenge resulted in a less pronounced systemic inflammatory response (i.e. 77 ± 14% decrease in IL-6 compared to the first challenge), cerebral inflammation was not attenuated, but decreased below baseline, illustrated by a diffuse reduction of cerebral 18F-DPA-714 binding (-38% [95%CI -47 to -28%], p < 0.0001). Our findings constitute evidence for in vivo immunological reprogramming in the brain following a second inflammatory insult in healthy volunteers, which could represent a neuroprotective mechanism. These results pave the way for further studies on immunotolerance in the brain in patients with systemic inflammation-induced cerebral dysfunction.

Case-control study on the interplay between immunoparalysis and delirium after cardiac surgery.

BACKGROUND: Delirium occurs frequently following cardiothoracic surgery, and infectious disease is an important risk factor for delirium. Surgery and cardiopulmonary bypass induce suppression of the immune response known as immunoparalysis. We aimed to investigate whether delirious patients had more pronounced immunoparalysis following cardiothoracic surgery than patients without delirium, to explain this delirium-infection association. METHODS: A prospective matched case-control study was performed in two university hospitals. Cytokine production (tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8 and IL-10) of ex vivo lipopolysaccharide (LPS)-stimulated whole blood was analyzed in on-pump cardiothoracic surgery patients preoperatively, and at 5 timepoints up to 3 days after cardiothoracic surgery. Delirium was assessed by trained staff using two validated delirium scales and chart review. RESULTS: A total of 89 patients were screened of whom 14 delirious and 52 non-delirious patients were included. Ex vivo-stimulated production of TNF-α, IL-6, IL-8, and IL-10 was severely suppressed following cardiothoracic surgery compared to pre-surgery. Postoperative release of cytokines in non-delirious patients was attenuated by 84% [IQR: 13-93] for TNF-α, 95% [IQR: 78-98] for IL-6, and 69% [IQR: 55-81] for IL-10. The attenuation in ex vivo-stimulated production of these cytokines was not significantly different in patients with delirium compared to non-delirious patients (p > 0.10 for all cytokines). CONCLUSIONS: The post-operative attenuation of ex vivo-stimulated production of pro- and anti-inflammatory cytokines was comparable between patients that developed delirium and those who remained delirium-free after on-pump cardiothoracic surgery. This finding suggests that immunoparalysis is not more common in cardiothoracic surgery patients with delirium compared to those without.

Neuroinflammation in cognitive decline post-cardiac surgery (the FOCUS study): an observational study protocol.

INTRODUCTION: Postoperative cognitive dysfunction occurs frequently after coronary artery bypass grafting (CABG). The underlying mechanisms remain poorly understood, but neuroinflammation might play a pivotal role. We hypothesise that systemic inflammation induced by the surgical trauma could activate the innate immune (glial) cells of the brain. This could lead to an exaggerated neuroinflammatory cascade, resulting in neuronal dysfunction and loss of neuronal cells. Therefore, the aims of this study are to assess neuroinflammation in vivo presurgery and postsurgery in patients undergoing major cardiac surgery and investigate whether there is a relationship of neuroinflammation to cognitive outcomes, changes to brain structure and function, and systemic inflammation. METHODS AND ANALYSIS: The FOCUS study is a prospective, single-centre observational study, including 30 patients undergoing elective on-pump CABG. Translocator protein (TSPO) positron emission tomography neuroimaging will be performed preoperatively and postoperatively using the second generation tracer 18F-DPA-714 to assess the neuroinflammatory response. In addition, a comprehensive cerebral MRI will be performed presurgery and postsurgery, in order to discover newly developed brain and vascular wall lesions. Up to 6 months postoperatively, serial extensive neurocognitive assessments will be performed and blood will be obtained to quantify systemic inflammatory responses and peripheral immune cell activation. ETHICS AND DISSEMINATION: Patients do not benefit directly from engaging in the study, but imaging neuroinflammation is considered safe and no side effects are expected. The study protocol obtained ethical approval by the Medical Research Ethics Committee region Arnhem-Nijmegen. This work will be published in peer-reviewed international medical journals and presented at medical conferences. TRIAL REGISTRATION NUMBER: NCT04520802.

Precision Immunotherapy for Sepsis.

Decades of sepsis research into a specific immune system-targeting adjunctive therapy have not resulted in the discovery of an effective compound. Apart from antibiotics, source control, resuscitation and organ support, not a single adjunctive treatment is used in current clinical practice. The inability to determine the prevailing immunological phenotype of patients and the related large heterogeneity of study populations are regarded by many as the most important factors behind the disappointing results of past clinical trials. While the therapeutic focus has long been on immunosuppressive strategies, increased appreciation of the importance of sepsis-induced immunoparalysis in causing morbidity and mortality in sepsis patients has resulted in a paradigm shift in the sepsis research field towards strategies aimed at enhancing the immune response. However, similar to immunosuppressive therapies, precision medicine is imperative for future trials with immunostimulatory compounds to succeed. As such, identifying those patients with a severely suppressed or hyperactive immune system who will most likely benefit from either immunostimulatory or immunosuppressive therapy, and accurate monitoring of both the immune and treatment response is crucial. This review provides an overview of the challenges lying ahead on the path towards precision immunotherapy for patients suffering from sepsis.