Ischemic stroke is a prevalent clinical condition that poses a significant global challenge. Developing innovative strategies to address this issue is crucial. Annexin A1 (ANXA1), a key member of the annexin superfamily, performs various functions, such as inhibiting inflammatory factor release, promoting phagocytosis, and blocking leukocyte migration. Evidence indicates that ANXA1 plays a pivotal role in the pathogenesis of ischemic stroke. The present article reviews involvement of ANXA1 in anti‑atherosclerosis, inflammatory processes, blood‑brain barrier protection, platelet aggregation and anti‑apoptotic mechanisms. The potential applications of ANXA1 in treating ischemic stroke are also explored.

Cardiovascular risk factors (CRFs) like hypertension, high cholesterol, and diabetes mellitus are increasingly linked to cognitive decline and dementia, especially in cerebral small vessel disease (cSVD). White matter hyperintensities (WMH) are closely associated with cognitive impairment, but the mechanisms behind their development remain unclear. Blood-brain barrier (BBB) dysfunction may be a key factor, particularly in cSVD.

This study explores the relationship between CRFs, BBB integrity, and WMH burden.

The study included 155 participants from the Biomarkers and Cognition Study, Singapore (BIOCIS). CRFs were assessed through blood tests for glucose and lipid profiles, and blood pressure measurements. WMH volumes were quantified using MRI.

BBB integrity was evaluated using a Transendothelial Electrical Resistance (TEER) assay with human brain microvascular endothelial cells (hBMEC) exposed to participant plasma.

Plasma from individuals with a higher WMH burden was associated with increased BBB disruption in hBMEC. Higher systolic and diastolic blood pressure, as well as body mass index, were correlated with greater BBB disruption. Regression analyses revealed that elevated blood glucose and lipid levels were linked to increased BBB disruption. Both periventricular and subcortical WMH burdens were associated with increased BBB disruption.

This study highlights a relationship between CRFs, BBB disruption, and WMH burden, suggesting that CRFs may impair BBB integrity and contribute to WMH and cognitive decline in cSVD.

Diabetic cognitive impairment (DCI) is a central nervous system complication induced by peripheral metabolic dysfunction of diabetes mellitus. Cumulative studies have shown that neuro-immune crosstalk is involved in the pathological progression of DCI. However, current studies mostly focus on the interaction between innate immunity cells and neurons, while ignoring the role of adaptive immunity cells in DCI. Notably, recent studies have revealed adaptive immune cells are involved in cognitive development and the progression of neurodegenerative diseases. Equally important, accumulated past studies have also shown that diabetic patients experience imbalanced peripheral adaptive immune homeostasis and disrupted transmission of adaptive immune cells to the central system. Therefore, this review first updated the cognitive mechanism of adaptive immune regulation, and then summarized the contribution of adaptive immunity to DCI from the aspects of peripheral adaptive immune homeostasis, transmission pathways, and brain tissue infiltration. Furthermore, we also summarized the potential of anti-diabetic drugs to regulate adaptive immunity, and looked forward to the potential value of regulatory adaptive immunity in the prevention and treatment of DCI, to provide a new strategy for the prevention and treatment of DCI.

The blood-brain barrier (BBB) is formed by microvascular endothelial cells which are ensembled with pericytes, astrocytes, microglia and neurons in the neurovascular unit (NVU) that is crucial for neuronal function. Given that the NVU and the BBB are highly dynamic and regulated structures, their integrity is continuously challenged by intrinsic and extrinsic factors. Herein, factors from peripheral organs such as gonadal and adrenal hormones may influence vascular function also in CNS endothelial cells in a sex- and age-dependent manner. The communication between the periphery and the CNS likely takes place in specific areas of the brain among which the circumventricular organs have a central position due to their neurosensory or neurosecretory function, owing to physiologically leaky blood vessels. In acute and chronic pathological conditions like liver, kidney, pulmonary disease, toxins and metabolites are generated that reach the brain via the circulation and may directly or indirectly affect BBB functionality via the activation of the immunes system. For example, chronic kidney disease (CKD) currently affects more than 840 million people worldwide and is likely to increase along with western world comorbidities of the cardio-vascular system in continuously ageing societies. Toxins leading to the uremic syndrome, may further lead to neurological complications such as cognitive impairment and uremic encephalopathy. Here we summarize the effects of hormones, toxins and inflammatory reactions on the brain vasculature, highlighting the urgent demand for mechanistically exploring the communication between the periphery and the CNS, focusing on the BBB as a last line of defense for brain protection.

Aging plays a pivotal role in the pathogenesis of cerebral small vessel disease (CSVD), contributing to the onset and progression of vascular cognitive impairment and dementia (VCID). In older adults, CSVD often leads to significant pathological outcomes, including blood-brain barrier (BBB) disruption, which in turn triggers neuroinflammation and white matter damage. This damage is frequently observed as white matter hyperintensities (WMHs) in neuroimaging studies. There is mounting evidence that older adults with atherosclerotic vascular diseases, such as peripheral artery disease, ischemic heart disease, and carotid artery stenosis, face a heightened risk of developing CSVD and VCID. This review explores the complex relationship between peripheral atherosclerosis, the pathogenesis of CSVD, and BBB disruption. It explores the continuum of vascular aging, emphasizing the shared pathomechanisms that underlie atherosclerosis in large arteries and BBB disruption in the cerebral microcirculation, exacerbating both CSVD and VCID. By reviewing current evidence, this paper discusses the impact of endothelial dysfunction, cellular senescence, inflammation, and oxidative stress on vascular and neurovascular health. This review aims to enhance understanding of these complex interactions and advocate for integrated approaches to manage vascular health, thereby mitigating the risk and progression of CSVD and VCID.

Glioblastoma (GBM) is one of the common malignant tumors of the central nervous system (CNS), characterized by rapid proliferation, heterogeneity, aggressiveness, proneness to recurrence after surgery, and poor prognosis. There is increasing evidence that tumorigenesis is inextricably linked to immune escape, and immunotherapy is undoubtedly an important complement to clinical treatment options for GBM, and will be a focus and hot topic in GBM treatment research. The purpose of this study was to visualize and analyze the scientific results and research trends of immunotherapy for GBM.

Publications concerning immunotherapy for GBM were retrieved from the Web of Science Core Collection (WOScc) database. Bibliometric and visual analysis was performed mainly using CiteSpace and R software, and the Online Analysis Platform of Literature Metrology (https://bibliometric.com/app) for countries/regions, authors, journals, references and keywords related to publications in the field.

Among totally 3491 publications retrieved in this field, 1613 publications were finally obtained according to the screening criteria, including 1007 articles (62.43%) and 606 reviews (37.57%). The number of publications increased year by year, with an average growth rate (AGR) of 17.41%. Such a number was the largest in the USA (717, 44.45%), followed by China (283, 17.55%), and the USA showed the strongest international collaboration. Among the research institutions, Duke Univ (94, 5.83%) was the largest publisher in the field, followed by Harvard Med Sch (70, 4.34%). In addition, the most prolific authors in this field were OHN H SAMPSON (51) and MICHAEL LIM (43), and the degree of collaboration (DC) between authors was 98.26%. Among the co-cited authors, STUPP R (805) was the most cited author, followed by REARDON DA (448). The journal with the most published publications was FRONTIERS IN IMMUNOLOGY (75), and the most cited journal in terms of co-citation was CLIN CANCER RES (1322), followed by CANCER RES (1230). The high-frequency keyword included glioblastoma (672) and immunotherapy (377). Cluster analysis was performed on the basis of keyword co-occurrence analysis, yielding 17 clusters, based on which the current research status and future trends in the field of immunotherapy for GBM were identified.

Immunotherapy is currently a novel treatment strategy for GBM that has attracted much attention. In the future, it is necessary to strengthen cooperation and exchanges between countries and institutions towards relevant research to promote the development of this field. Immunotherapy is expected to be an important part of the future treatment strategy for GBM, and it has already become a hot spot of current research and will be the key focus of future research.

Cognitive decline covers a broad spectrum of disorders, not only resulting from brain diseases but also from systemic diseases, which seriously influence the quality of life and life expectancy of patients. As a highly selective anatomical and functional interface between the brain and systemic circulation, the blood-brain barrier (BBB) plays a pivotal role in maintaining brain homeostasis and normal function. The pathogenesis underlying cognitive decline may vary, nevertheless, accumulating evidences support the role of BBB disruption as the most prevalent contributing factor. This may mainly be attributed to inflammation, metabolic dysfunction, cell senescence, oxidative/nitrosative stress and excitotoxicity. However, direct evidence showing that BBB disruption causes cognitive decline is scarce, and interestingly, manipulation of the BBB opening alone may exert beneficial or detrimental neurological effects. A broad overview of the present literature shows a close relationship between BBB disruption and cognitive decline, the risk factors of BBB disruption, as well as the cellular and molecular mechanisms underlying BBB disruption. Additionally, we discussed the possible causes leading to cognitive decline by BBB disruption and potential therapeutic strategies to prevent BBB disruption or enhance BBB repair. This review aims to foster more investigations on early diagnosis, effective therapeutics, and rapid restoration against BBB disruption, which would yield better cognitive outcomes in patients with dysregulated BBB function, although their causative relationship has not yet been completely established.

Neurological diseases with a neurodegenerative component have been associated with alterations in the cerebrovasculature. At the anatomical level, these are centred around changes in cerebral blood flow and vessel organisation. At the molecular level, there is extensive expression of cellular adhesion molecules and increased release of pro-inflammatory mediators. Together, these has been found to negatively impact blood-brain barrier integrity. Systemic inflammation has been found to accelerate and exacerbate endothelial dysfunction, neuroinflammation and degeneration. Here, we review the role of cerebrovasculature dysfunction in neurodegenerative disease and discuss the potential contribution of intermittent pro-inflammatory systemic disease in causing endothelial pathology, highlighting a possible mechanism that may allow broad-spectrum therapeutic targeting in the future.

Inflammatory bowel diseases (IBDs) disrupt the intestinal epithelium, leading to severe chronic inflammation. Current therapies cause adverse effects and are expensive, invasive, and ineffective for most patients. Annexin A1 (AnxA1) is a pivotal endogenous anti-inflammatory and tissue repair protein in IBD. Nanostructured compounds loading AnxA1 or its active N-terminal mimetic peptides improve IBD symptomatology.

To further explore their potential as a therapeutic candidate, the AnxA1 N-terminal mimetic peptide Ac2-26 was incorporated into SBA-15 ordered mesoporous silica and covered with EL30D-55 to deliver it by oral treatment into the inflamed gut.

The systems SBA-Ac2-26 developed measurements revealed self-assembled rod-shaped particles, likely on the external surface of SBA-15, and 88% of peptide incorporation. SBA-15 carried the peptide Ac2-26 into cultured Raw 264.7 macrophages and Caco-2 epithelial cells. Moreover, oral administration of Eudragit-SBA-15-Ac2-26 (200 μg; once a day; for 4 days) reduced colitis clinical symptoms, inflammation, and improved epithelium recovery in mice under dextran-sodium sulfate-induced colitis.

The absorption of SBA-15 in gut epithelial cells is typically low; however, the permeable inflamed barrier can enable microparticles to cross, being phagocyted by macrophages. These findings suggest that Ac2-26 is successfully delivered and binds to its receptors in both epithelial and immune cells, aligning with the clinical results.

Our findings demonstrate a simple and cost-effective approach to delivering Ac2-26 orally into the inflamed gut, highlighting its potential as non-invasive IBD therapy.

Neurological conditions such as Alzheimer's disease and stroke represent a substantial health burden to the world's ageing population. Cerebrovascular dysfunction is a key contributor to these conditions, affecting an individual's risk profile, age of onset, and severity of neurological disease. Recent data shows that early-life events, such as maternal health during pregnancy, birth weight and exposure to environmental toxins can 'prime' the vascular system for later changes. With age, blood vessels can become less flexible and more prone to damage. This can lead to reduced blood flow to the brain, which is associated with cognitive decline and an increased risk of stroke and other cerebrovascular diseases. These in turn increase the risk of vascular dementia and Alzheimer's disease.

We aim to explore how early life factors influence cerebrovascular health, ageing and disease.

We have reviewed recently published literature from epidemiological studies, clinical cases and basic research which explore mechanisms that contribute to cerebrovascular and blood-brain barrier dysfunction, with a particularly focus on those that assess contribution of early-life events or vascular priming to subsequent injury.

Perinatal events have been linked to acute cerebrovascular dysfunction and long-term structural reorganisation. Systemic disease throughout the lifetime that produce inflammatory or oxidative stress may further sensitise the cerebrovasculature to disease and contribute to neurodegeneration.

By identifying these early-life determinants and understanding their mechanisms, scientists aim to develop strategies for preventing or mitigating cerebrovascular ageing-related issues.

The blood brain barrier (BBB) plays a crucial role in maintaining brain homeostasis by selectively preventing the entry of substances from the peripheral blood into the central nervous system (CNS). Comprised of endothelial cells, pericytes, and astrocytes, this highly regulated barrier encompasses the majority of the brain's vasculature. In addition to its protective function, the BBB also engages in significant crosstalk with perivascular macrophages (MΦ) and microglia, the resident MΦ of the brain. These interactions play a pivotal role in modulating the activation state of cells comprising the BBB, as well as MΦs and microglia, themselves. Alterations in systemic metabolic and inflammatory states can promote endothelial cell dysfunction, reducing the integrity of the BBB and potentially allowing peripheral blood factors to leak into the CNS compartment. This may mediate activation of perivascular MΦs, microglia, and astrocytes, and initiate further immune responses within the brain parenchyma, suggesting neuroinflammation can be triggered by signaling from the periphery, without primary injury or disease originating within the CNS. The intricate interplay between the periphery and the CNS through the BBB highlights the importance of understanding the role of microglia in mediating responses to systemic challenges. Despite recent advancements, our understanding of the interactions between microglia and the BBB is still in its early stages, leaving a significant gap in knowledge. However, emerging research is shedding light on the involvement of microglia at the BBB in various conditions, including systemic infections, diabetes, and ischemic stroke. This review aims to provide a comprehensive overview of the current research investigating the intricate relationship between microglia and the BBB in health and disease. By exploring these connections, we hope to advance our understanding of the role of brain immune responses to systemic challenges and their impact on CNS health and pathology. Uncovering these interactions may hold promise for the development of novel therapeutic strategies for neurological conditions that involve immune and vascular mechanisms.

The dysfunction of microglia in the development of diabetes is associated with various diabetic complications, while traditional insulin therapy is insufficient to rapidly restore the function of microglia. Therefore, the search for new alternative methods of treating diabetes-related dysfunction of microglia is urgently needed. Here, we evaluate the effects of transcranial photobiomodulation (tPBM) on microglial function in diabetic mice and investigate its mechanism. We find tPBM treatment effectively improves insulin therapy on microglial morphology and reactivity. We also show that tPBM stimulates brain drainage system through activation of meningeal lymphatics, which contributes to the removal of inflammatory factor, and increase of microglial purinergic receptor P2RY12. Besides, the energy expenditure and locomotor activity of diabetic mice are also improved by tPBM. Our results demonstrate that tPBM can be an efficient, non-invasive method for the treatment of microglial dysfunction caused by diabetes, and also has the potential to prevent diabetic physiological disorders.

Diabetic retinopathy (DR) is a major contributor to permanent vision loss and blindness. Changes in retinal neurons, glia, and microvasculature have been the focus of intensive study in the quest to better understand DR. However, the impact of diabetes on the rest of the visual system has received less attention. There are reports of associations of changes in the visual system with preclinical and clinical manifestations of diabetes. Simultaneous investigation of the retina and the brain may shed light on the mechanisms underlying neurodegeneration in diabetics. Additionally, investigating the links between DR and other neurodegenerative disorders of the brain including Alzheimer's and Parkinson's disease may reveal shared mechanisms for neurodegeneration and potential therapy options.

This study is to observe the upregulation effect of astragaloside IV on ghrelin in diabetic cognitive impairment (DCI) rats and to investigate the pathway in prevention and treatment by reducing oxidative stress. The DCI model was induced with streptozotocin (STZ) in conjunction with a high-fat and high-sugar diet and divided into three groups: model, low-dose (40 mg/kg), and high-dose (80 mg/kg) astragaloside IV. After 30 days of gavage, the learning and memory abilities of rats, as well as their body weight and blood glucose levels, were tested using the Morris water maze and then detection of insulin resistance, SOD activity, and serum MDA levels. The whole brain of rats was sampled for hematoxylin-eosin and Nissl staining to observe pathological changes in the hippocampal CA1 region. Immunohistochemistry was used to detect ghrelin expression in the hippocampal CA1 region. A Western blot was used to determine changes in GHS-R1α/AMPK/PGC-1α/UCP2. RT-qPCR was used to determine the levels of ghrelin mRNA. Astragaloside IV reduced nerve damage, increased superoxide dismutase (SOD) activity, decreased MDA levels, and improved insulin resistance. Ghrelin levels and expression increased in serum and hippocampal tissues, and ghrelin mRNA levels increased in rat stomach tissues. According to Western blot, it increased the expression of the ghrelin receptor GHS-R1α and upregulated the mitochondrial function associated-protein AMPK-PGC-1α-UCP2. Astragaloside IV increases ghrelin expression in the brain to reduce oxidative stress and delay diabetes-induced cognitive impairment. It may be related to the promotion of ghrelin mRNA levels.

Perinatal brain injury following hypoxia-ischemia (HI) is characterized by high mortality rates and long-term disabilities. Previously, we demonstrated that depletion of Annexin A1, an essential mediator in BBB integrity, was associated with a temporal loss of blood-brain barrier (BBB) integrity after HI. Since the molecular and cellular mechanisms mediating the impact of HI are not fully scrutinized, we aimed to gain mechanistic insight into the dynamics of essential BBB structures following global HI in relation to ANXA1 expression. Global HI was induced in instrumented preterm ovine fetuses by transient umbilical cord occlusion (UCO) or sham occlusion (control). BBB structures were assessed at 1, 3, or 7 days post-UCO by immunohistochemical analyses of ANXA1, laminin, collagen type IV, and PDGFRβ for pericytes. Our study revealed that within 24 h after HI, cerebrovascular ANXA1 was depleted, which was followed by depletion of laminin and collagen type IV 3 days after HI. Seven days post-HI, increased pericyte coverage, laminin and collagen type IV expression were detected, indicating vascular remodeling. Our data demonstrate novel mechanistic insights into the loss of BBB integrity after HI, and effective strategies to restore BBB integrity should potentially be applied within 48 h after HI. ANXA1 has great therapeutic potential to target HI-driven brain injury.

Introduction: Increasing evidence indicates that neurodegenerative diseases, including Alzheimer's disease (AD), are a product of gene-by-environment interplay. The immune system is a major contributor mediating these interactions. Signaling between peripheral immune cells and those within the microvasculature and meninges of the central nervous system (CNS), at the blood-brain barrier, and in the gut likely plays an important role in AD. The cytokine tumor necrosis factor (TNF) is elevated in AD patients, regulates brain and gut barrier permeability, and is produced by central and peripheral immune cells. Our group previously reported that soluble TNF (sTNF) modulates cytokine and chemokine cascades that regulate peripheral immune cell traffic to the brain in young 5xFAD female mice, and in separate studies that a diet high in fat and sugar (HFHS) dysregulates signaling pathways that trigger sTNF-dependent immune and metabolic responses that can result in metabolic syndrome, which is a risk factor for AD. We hypothesized that sTNF is a key mediator of peripheral immune cell contributions to gene-by-environment interactions to AD-like pathology, metabolic dysfunction, and diet-induced gut dysbiosis. Methods: Female 5xFAD mice were subjected to HFHS diet for 2 months and then given XPro1595 to inhibit sTNF for the last month or saline vehicle. We quantified immune cell profiles by multi-color flow cytometry on cells isolated from brain and blood; metabolic, immune, and inflammatory mRNA and protein marker biochemical and immunhistological analyses, gut microbiome, and electrophysiology in brain slices were also performed. Results: Here, we show that selective inhibition of sTNF signaling via the biologic XPro1595 modulates the effects of an HFHS diet in 5xFAD mice on peripheral and central immune profiles including CNS-associated CD8+ T cells, the composition of gut microbiota, and long-term potentiation deficits. Discussion: Obesogenic diet induces immune and neuronal dysfunction in 5xFAD mice and sTNF inhibition mitigates its effects. A clinical trial in subjects at risk for AD due to genetic predisposition and underlying inflammation associated with peripheral inflammatory co-morbidities will be needed to investigate the extent to which these findings translate to the clinic.

Diabetes mellitus is a heterogeneous chronic metabolic disorder characterized by the presence of hyperglycemia, commonly preceded by a prediabetic state. The excess of blood glucose can damage multiple organs, including the brain. In fact, cognitive decline and dementia are increasingly being recognized as important comorbidities of diabetes. Despite the largely consistent link between diabetes and dementia, the underlying causes of neurodegeneration in diabetic patients remain to be elucidated. A common factor for almost all neurological disorders is neuroinflammation, a complex inflammatory process in the central nervous system for the most part orchestrated by microglial cells, the main representatives of the immune system in the brain. In this context, our research question aimed to understand how diabetes affects brain and/or retinal microglia physiology. We conducted a systematic search in PubMed and Web of Science to identify research items addressing the effects of diabetes on microglial phenotypic modulation, including critical neuroinflammatory mediators and their pathways. The literature search yielded 1327 records, including 18 patents. Based on the title and abstracts, 830 papers were screened from which 250 primary research papers met the eligibility criteria (original research articles with patients or with a strict diabetes model without comorbidities, that included direct data about microglia in the brain or retina), and 17 additional research papers were included through forward and backward citations, resulting in a total of 267 primary research articles included in the scoping systematic review. We reviewed all primary publications investigating the effects of diabetes and/or its main pathophysiological traits on microglia, including in vitro studies, preclinical models of diabetes and clinical studies on diabetic patients. Although a strict classification of microglia remains elusive given their capacity to adapt to the environment and their morphological, ultrastructural and molecular dynamism, diabetes modulates microglial phenotypic states, triggering specific responses that include upregulation of activity markers (such as Iba1, CD11b, CD68, MHC-II and F4/80), morphological shift to amoeboid shape, secretion of a wide variety of cytokines and chemokines, metabolic reprogramming and generalized increase of oxidative stress. Pathways commonly activated by diabetes-related conditions include NF-κB, NLRP3 inflammasome, fractalkine/CX3CR1, MAPKs, AGEs/RAGE and Akt/mTOR. Altogether, the detailed portrait of complex interactions between diabetes and microglia physiology presented here can be regarded as an important starting point for future research focused on the microglia-metabolism interface.

Matrix metalloproteinase-2 (MMP-2) and -3 (MMP-3), and osteopontin (OPN) are associated with adipose-tissue expansion and development of metabolic disease. The purpose of the current study was to assess the circulating concentration of these markers, along with adiponectin and glucose concentrations, in response to acute exercise in individuals with overweight or obesity.

Fourteen sedentary males with overweight or obesity (29.0 ± 3.1 kg/m²) completed two separate, 3-day trials in randomised and counterbalanced order. An oral glucose tolerance test (OGTT) was performed on each day of the trial. Day two of each trial consisted of a single 30 min workload-matched bout of either high-intensity interval exercise (HIIE; alternating 100% and 50% of peak pulmonary oxygen uptake, [Formula: see text]O_2peak) or continuous moderate intensity (CME; 60% [Formula: see text]O_2peak) cycling completed 1 h prior to the OGTT. Glucose and physical activity were continuously monitored, while MMP-2, MMP-3, OPN and adiponectin were measured pre-, 0 h post-, 1 h post- and 25 h post-exercise.

Exercise transiently increased MMP-3 and decreased OPN (both p < 0.01), but not MMP-2 or adiponectin. There were no differences in the response of inflammatory markers to the different exercise formats. Exercise increased mean daily glucose concentration and area under the glucose curve during the OGTT on Day 2 and Day 3 (main effect of time; p < 0.05).

Acute cycling exercise decreased OPN, which is consistent with longer term improvements in cardiometabolic health and increased MMP-3, which is consistent with its role in tissue remodelling. Interestingly, exercise performed prior to the morning OGTT augmented the glucose concentrations in males.

ACTRN12613001086752.

Obesity rates are increasing worldwide. Obesity leads to many complications, including predisposing individuals to the development of cognitive impairment as they age. Immune dysregulation, including inflammaging (e.g., increased circulating cytokines) and immunosenescence (declining immune system function), commonly occur in obesity and aging and may impact cognitive impairment. As such, immune system changes across the lifespan may impact the effects of obesity on neuroinflammation and associated cognitive impairment. However, the role of age in obesity-induced neuroinflammation and cognitive impairment is unclear. To further define this putative relationship, the current study examined metabolic and inflammatory profiles, along with cognitive changes using a high-fat diet (HFD) mouse model of obesity.

First, HFD promoted age-related changes in hippocampal gene expression. Given this early HFD-induced aging phenotype, we fed HFD to young adult and middle-aged mice to determine the effect of age on inflammatory responses, metabolic profile, and cognitive function. As anticipated, HFD caused a dysmetabolic phenotype in both age groups. However, older age exacerbated HFD cognitive and neuroinflammatory changes, with a bi-directional regulation of hippocampal inflammatory gene expression.

Collectively, these data indicate that HFD promotes an early aging phenotype in the brain, which is suggestive of inflammaging and immunosenescence. Furthermore, age significantly compounded the impact of HFD on cognitive outcomes and on the regulation of neuroinflammatory programs in the brain.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with disorders affecting the peripheral and the central nervous system. A high number of patients develop post-COVID-19 syndrome with the persistence of a large spectrum of symptoms, including neurological, beyond 4 weeks after infection. Several potential mechanisms in the acute phase have been hypothesized, including damage of the blood-brain-barrier (BBB). We tested weather markers of BBB damage in association with markers of brain injury and systemic inflammation may help in identifying a blood signature for disease severity and neurological complications.

Blood biomarkers of BBB disruption (MMP-9, GFAP), neuronal damage (NFL) and systemic inflammation (PPIA, IL-10, TNFα) were measured in two COVID-19 patient cohorts with high disease severity (ICUCovid; n=79) and with neurological complications (NeuroCovid; n=78), and in two control groups free from COVID-19 history, healthy subjects (n=20) and patients with amyotrophic lateral sclerosis (ALS; n=51). Samples from COVID-19 patients were collected during the first and the second wave of COVID-19 pandemic in Lombardy, Italy. Evaluations were done at acute and chronic phases of the COVID-19 infection.

Blood biomarkers of BBB disruption and neuronal damage are high in COVID-19 patients with levels similar to or higher than ALS. NeuroCovid patients display lower levels of the cytokine storm inducer PPIA but higher levels of MMP-9 than ICUCovid patients. There was evidence of different temporal dynamics in ICUCovid compared to NeuroCovid patients with PPIA and IL-10 showing the highest levels in ICUCovid patients at acute phase. On the contrary, MMP-9 was higher at acute phase in NeuroCovid patients, with a severity dependency in the long-term. We also found a clear severity dependency of NFL and GFAP levels, with deceased patients showing the highest levels.

The overall picture points to an increased risk for neurological complications in association with high levels of biomarkers of BBB disruption. Our observations may provide hints for therapeutic approaches mitigating BBB disruption to reduce the neurological damage in the acute phase and potential dysfunction in the long-term.

Dietary interventions, such as calorie restriction and ketogenic diet, have been extensively studied in ageing research, including in cognitive decline. Epidemiological studies indicate beneficial effects of certain dietary regimes on mental health, including mood disorders and dementia. However, randomised-controlled trials (the gold-standard of evidence-based medicine) on calorie restriction diets and the ketogenic diet have yet to show clinically convincing effects in neuropsychiatric disorders. This review will examine the quality of studies and evidence base for the ketogenic and calorie restriction diets in common neuropsychiatric conditions, collating findings from preclinical experiments, case reports or small clinical studies, and randomised controlled clinical trials. The major cellular mechanisms that mediate the effects of these dietary interventions on brain health include neuroinflammation, neuroprotection, and neuromodulation. We will discuss the studies that have investigated the roles of these pathways and their interactions. Popularity of the ketogenic and calorie restriction diets has grown both in the public domain and in psychiatry research, allowing for informed review of the efficacy, the limitations, and the side effects of these diets in specific patient populations. In this review we will summarise the clinical evidence for these diets in neuropsychiatry and make suggestions to improve clinical translation of future research studies.