Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor protein predominantly expressed in microglia within the central nervous system (CNS). TREM2 regulates multiple microglial functions, including lipid metabolism, immune reaction, inflammation, and microglial phagocytosis. Recent studies have found that TREM2 is highly expressed in activated microglia after ischemic stroke. However, the role of TREM2 in the pathologic response after stroke remains unclear. Herein, TREM2-deficient microglia exhibit an impaired phagocytosis rate and cholesteryl ester (CE) accumulation, leading to lipid droplet formation and upregulation of Perilipin-2 (PLIN2) expression after hypoxia. Knockdown of TREM2 results in increased lipid synthesis (PLIN2, SOAT1) and decreased cholesterol clearance and lipid hydrolysis (LIPA, ApoE, ABCA1, NECH1, and NPC2), further impacting microglial phenotypes. In these lipid droplet-rich microglia, the TGF-β1/Smad2/3 signaling pathway is downregulated, driving microglia towards a pro-inflammatory phenotype. Meanwhile, in a neuron-microglia co-culture system under hypoxic conditions, we found that microglia lost their protective effect against neuronal injury and apoptosis when TREM2 was knocked down. Under in vivo conditions, TREM2 knockdown mice express lower TGF-β1 expression levels and a lower number of anti-inflammatory M2 phenotype microglia, resulting in increased cerebral infarct size, exacerbated neuronal apoptosis, and aggravated neuronal impairment. Our work suggests that TREM2 attenuates stroke-induced neuroinflammation by modulating the TGF-β1/Smad2/3 signaling pathway. TREM2 may play a direct role in the regulation of inflammation and also exert an influence on the post-ischemic inflammation and the stroke pathology progression via regulation of lipid metabolism processes. Thus, underscoring the therapeutic potential of TREM2 agonists in ischemic stroke and making TREM2 an attractive new clinical target for the treatment of ischemic stroke and other inflammation-related diseases.

Hypoxia triggers reactive microglial inflammation and lipid droplet (LD) accumulation under stroke conditions, although the mutual interactions between these two processes are insufficiently understood. Hence, the involvement of transforming growth factor (TGF)-β1 in inflammation and LD accumulation in cultured microglia exposed to hypoxia were analyzed herein. Primary microglia were exposed to oxygen-glucose deprivation (OGD) injury and lipopolysaccharide (LPS) stimulation. For analyzing the role of TGF-β1 patterns under such conditions, a TGF-β1 siRNA and an exogenous recombinant TGF-β1 protein were employed. Further studies applied Triacsin C, an inhibitor of LD formation, in order to directly assess the impact of LD formation on the modulation of inflammation. To assess mutual microglia-to-neuron interactions, a co-culture model of these cells was established. Upon OGD exposure, microglial TGF-β1 levels were significantly increased, whereas LPS stimulation yielded decreased levels. Elevating TGF-β1 expression proved highly effective in suppressing inflammation and reducing LD accumulation in microglia exposed to LPS. Conversely, inhibition of TGF-β1 led to the promotion of microglial cell inflammation and an increase in LD accumulation in microglia exposed to OGD. Employing the LD formation inhibitor Triacsin C, in turn, polarized microglia towards an anti-inflammatory phenotype. Such modulation of both microglial TGF-β1 and LD levels significantly affected the resistance of co-cultured neurons. This study provides novel insights by demonstrating that TGF-β1 plays a protective role against microglia-mediated neuroinflammation through the suppression of LD accumulation. These findings offer a fresh perspective on stroke treatment, suggesting the potential of targeting this pathway for therapeutic interventions.

Following cardiac surgery, postoperative cognitive decline (POCD) is a common complication that can impair the quality of life and increase mortality. The aim of this study was to investigate whether early postoperative cognitive training can decrease POCD after cardiac surgery. The study was a multi-centred, two-arm, randomized (1:1 ratio), controlled trial involving older patients undergoing elective heart valve surgery with extracorporeal circulation. Recruitment took place at the Department of Cardiac Surgery of the Kerckhoff-Clinic in Bad Nauheim (Germany) and the University-Hospital in Giessen (Germany). The patients were randomized to either a paper-and-pencil-based cognitive training group or a standard rehabilitation care control group. The cognitive training started 1 week after surgery and lasted about 3 weeks until discharge from rehabilitation. To detect POCD, neuropsychological functions were assessed prior to surgery, upon discharge from rehabilitation (primary outcome), and 3 months after discharge (secondary outcome). Data were primarily analysed in a per-protocol fashion. The frequency of POCD at discharge from rehabilitation (training group, n = 37; control group, n = 44) was 50% in the control group and 19% in the training group (χ²[1] = 8.45, P = 0.004; odds ratio = 4.29, 95% confidence interval [1.56–11.80]). Three months after the cognitive training (training group, n = 33; control group, n = 34), POCD frequency was 29% in the control group and 6% in the training group (χ²[1] = 6.21, P = 0.013; odds ratio = 6.46, 95% confidence interval [1.29–32.28]). Since our cognitive training showed beneficial effects, it could be a promising method to prevent POCD.

Introduction: Postoperative delirium (POD) and postoperative cognitive decline (POCD) can be observed after cardiosurgical interventions. Taken together, these postoperative neurocognitive disorders (PNCDs) contribute to increased morbidity and mortality. Preoperative risk factors of PNCD, such as decreased neuropsychometric performance or decreased cognitive daily activities, can be interpreted as reduced cognitive reserve. This study aims to build up cognitive reserves to protect against the development of PNCD through preoperative, home-based, cognitive training.Methods: The planned research project is a monocentric, two-arm randomized controlled intervention study involving 100 patients undergoing elective cardiac surgery with extracorporeal circulation. Patients will be assigned to a training group or control group. The intervention involves a standardized, paper-and-pencil-based cognitive training that will be performed by the patients at home for ~40 min per day over a preoperative period of 2–3 weeks. The control group will receive neither cognitive training nor a placebo intervention. A detailed assessment of psychological functions will be performed ~2–3 weeks before the start of training, at the end of the training, during hospitalization, at discharge from the acute clinic, and 3 months after surgery. The primary objective of this study is to investigate the interventional effect of preoperative cognitive training on the incidence of POD during the stay in the acute clinic, the incidence of POCD at the time of discharge from the acute clinic, and 3 months after surgery. Secondary objectives are to determine the training effect on objective cognitive functions before the surgery and subjective cognitive functions, as well as health-related quality of life 3 months after surgery.Discussion: Should it become evident that the use of our cognitive training can both reduce the incidence of POCD and POD and improve health-related quality of life, this intervention may be integrated into a standardized prehabilitation program.

Background: The occurrence of postoperative cognitive deficits, especially after heart surgery, has been demonstrated in several studies. These deficits can clearly be noticed by the patients and by their close relatives in daily life. Furthermore, postoperative cognitive deficits can decrease quality of life in social functioning and earning capacity. The aim of this study is to investigate whether early postoperative cognitive training can reduce subjective and objective postoperative cognitive deficits.Methods: The proposed study is a multicenter, two-arm, randomized controlled trial involving 144 elderly patients undergoing elective heart-valve surgery with extracorporeal circulation. Patients will be assigned to either a training group or a control group. The intervention involves paper-and-pencil-based cognitive training, which is conducted for 36 min over a period of 18 days. The training starts about 1 week after surgery and is carried out during the hospitalized rehabilitation phase. The control group will not receive cognitive training or a placebo intervention. A detailed assessment of psychological functions and health-related quality of life prior to surgery at discharge from rehabilitation and 3 and 12 months after discharge will be performed. The primary outcome of this trial is the training effect on objective cognitive functions at discharge from rehabilitation. Secondary outcomes are the training effect on objective and subjective cognitive functions (3 and 12 months after discharge), depression, health-related quality of life, and the impact of perioperative cerebral ischemia on the training effect. Perioperative cerebral ischemia will be measured with postoperative magnetic resonance imaging including diffusion-weighted sequences.Discussion: Should it be shown that our cognitive training can improve postoperative cognitive deficits and quality of life, one possibility could be to integrate this intervention into early rehabilitation. Furthermore, we hope that the investigation of perioperative ischemia by diffusion-weighted magnetic resonance imaging will improve our understanding of neurobiological factors influencing the course of postoperative cognitive plasticity.Trial registration: German Clinical Trials Register (DRKS),DRKS00015512. Retrospectively registered on 21 September 2018.

Background: Heart surgery is a risk factor for objectively and subjectively assessable postoperative cognitive decline (POCD), which is relevant for everyday life. The aim of this study was to investigate whether early postoperative cognitive training has an impact on health‐related quality of life and cognitive failures in daily living after cardiac surgery.Methods: The study was a two‐arm, randomized, controlled, outcome‐blinded trial involving older patients undergoing elective heart valve surgery with extracorporeal circulation (ECC). Recruitment took place at the Departments of Cardiac Surgery of the Kerckhoff Clinic in Bad Nauheim (Germany) and the University Hospital in Giessen (Germany). The patients were randomized (1:1 ratio) to either a paper‐and‐pencil–based cognitive training group or a control group. We applied the Short Form Health Survey (SF‐36) and the Cognitive Failures Questionnaire (CFQ) prior to surgery and 3 months after the cognitive training. Data were analyzed in a per‐protocol fashion.Results: Three months after discharge from rehabilitation, the training group (n = 31) showed improvement in health‐related quality of life compared to the control group (n = 29), especially in role limitations due to emotional problems (U = −2.649, p = .008, η² = 0.121), energy and fatigue (F[2.55] = 5.72, p = .020, η² = 0.062), social functioning (U = −2.137, p = .033, η² = 0.076), the average of all SF‐36 factors (U = −2.374, p = .018, η² = 0.094), health change from the past year to the present time (U = −2.378, p = .017, η² = 0.094), and the mental component summary (U = −2.470, p = .013, η² = 0.102).Conclusion: As our cognitive training has shown beneficial effects, this intervention could be a promising method to enhance health‐related quality of life after cardiac surgery.