Biomarker Of Neuroinflammation Research Articles

Translocator protein (18kDa) positron emission tomography imaging as a biomarker of neuroinflammation in epilepsy.

Increasing evidence indicate that neuroinflammation triggered by glial cells plays a significant role in epileptogenesis. To this effect, the overexpression of translocator protein 18kDa (TSPO) in activated microglia and astrocytes has been identified as an inflammatory biomarker in epilepsy. It is now possible to quantify neuroinflammation using non-invasive positron emission tomography (PET) imaging of TSPO. With the advancement of radiotracers, TSPO PET has become an innovative tool in elucidating the "neuroinflammatory machinery" of drug-resistant epilepsy. Furthermore, TSPO PET has demonstrated potential in detecting MRI-negative epileptogenic zones (EZ) and provided an innovative perspective in epileptic medical treatment. This manuscript presents a comprehensive exploration of the neuroinflammatory mechanisms of epilepsy, alongside a thorough review of TSPO PET studies conducted in clinical and preclinical settings. The primary objective is to deepen our understanding of epilepsy progression and to establish TSPO PET as an effective monitoring tool for treatment efficacy.

Is Methylglyoxal a Potential Biomarker for the Warburg Effect Induced by the Lipopolysaccharide Neuroinflammation Model?

Methylglyoxal (MG) is considered a classical biomarker of diabetes mellitus and its comorbidities. However, a role for this compound in exacerbated immune responses, such as septicemia, is being increasingly observed and requires clarification, particularly in the context of neuroinflammatory responses. Herein, we used two different approaches (in vivo and acute hippocampal slice models) to investigate MG as a biomarker of neuroinflammation and the neuroimmunometabolic shift to glycolysis in lipopolysaccharide (LPS) inflammation models. Our data reinforce the hypothesis that LPS-induced neuroinflammation stimulates the cerebral innate immune response by increasing IL-1β, a classical pro-inflammatory cytokine, and the astrocyte reactive response, via elevating S100B secretion and GFAP levels. Acute neuroinflammation promotes an early neuroimmunometabolic shift to glycolysis by elevating glucose uptake, lactate release, PFK1, and PK activities. We observed high serum and cerebral MG levels, in association with a reduction in glyoxalase 1 detoxification activity, and a close correlation between serum and hippocampus MG levels with the systemic and neuroinflammatory responses to LPS. Findings strongly suggest a role for MG in immune responses.

Evaluation of the Effect of Loratadine versus Diosmin/Hesperidin Combination on Vinca Alkaloids-Induced Neuropathy: A Randomized Controlled Clinical Trial.

Neurological injury is a crucial problem that interferes with the therapeutic use of vinca alkaloids as well as the quality of patient life. This study was conducted to assess the impact of using loratadine or diosmin/hesperidin on neuropathy induced by vinca alkaloids. Patients were randomized into one of three groups as follows: group 1 was the control group, group 2 received 450 mg diosmin and 50 mg hesperidin combination orally twice daily, and group 3 received loratadine 10 mg orally once daily. Subjective scores (numeric pain rating scale, douleur neuropathique 4, and functional assessment of cancer therapy/gynecologic oncology group-neurotoxicity (FACT/GOG-Ntx) scores), neuroinflammation biomarkers, adverse drug effects, quality of life, and response to chemotherapy were compared among the three groups. Both diosmin/hesperidin and loratadine improved the results of the neurotoxicity subscale in the FACT/GOG-Ntx score (p < 0.001, p < 0.01 respectively) and ameliorated the upsurge in neuroinflammation serum biomarkers. They also reduced the incidence and timing of paresthesia (p = 0.001 and p < 0.001, respectively) and dysuria occurrence (p = 0.042). Both loratadine and diosmin/hesperidin attenuated the intensity of acute neuropathy triggered by vinca alkaloids. Furthermore, they did not increase the frequency of adverse effects or interfere with the treatment response.

Serum YKL-40 as a Predictive Biomarker of Cerebral Amyloid Angiopathy-Related Intracerebral Hemorrhage Recurrence.

Neuroinflammation is a major cause of secondary brain injury in intracerebral hemorrhage (ICH). To date, the prognostic value of YKL-40 (chitinase-3-like-1 protein), a biomarker of neuroinflammation, in cerebral amyloid angiopathy-related intracerebral hemorrhage (CAA-ICH) remains undiscovered. To evaluate the relationships between serum YKL-40 and CAA-ICH recurrence. Clinical and imaging information of 68 first-onset probable CAA-ICH cases and 95 controls were collected at baseline. Serum YKL-40 was measured by Luminex assay. Cox proportional hazards model was used to analyze the associations between YKL-40 level and CAA-ICH recurrence. Serum YKL-40 level was significantly higher in CAA-ICH cases than healthy controls (median [interquartile range, IQR], 46.1 [19.8, 93.4] versus 24.4 [13.9, 59.0] ng/mL, p = 0.004). Higher level of YKL-40 predicted increased risk of CAA-ICH recurrence adjusted for age, ICH volume and enlarged perivascular space score (ePVS) (above versus below 115.5 ng/ml, adjusted hazard ratios 4.721, 95% confidence intervals 1.829-12.189, p = 0.001) within a median follow-up period of 2.4 years. Adding YKL-40 to a model of only MRI imaging markers including ICH volume and ePVS score improved the discriminatory power (concordance index from 0.707 to 0.772, p = 0.001) and the reclassification power (net reclassification improvement 28.4%; integrated discrimination index 11.0%). Serum YKL-40 level might be a candidate prognostic biomarker for CAA-ICH recurrence.

Association of Biomarkers of Neuronal Injury and Inflammation With Insomnia Trajectories After Traumatic Brain Injury: A TRACK-TBI Study.

Insomnia affects about one-third of patients with traumatic brain injury and is associated with worsened outcomes after injury. We hypothesized that higher levels of plasma neuroinflammation biomarkers at the time of TBI would be associated with worse 12-month insomnia trajectories. Participants were prospectively enrolled from 18 level-1 trauma centers participating in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury study from February 26, 2014, to August 8, 2018. Plasma glial fibrillary acidic protein (GFAP), high-sensitivity C-reactive protein (hsCRP), S100b, neuron-specific enolase (NSE), and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) were collected on days 1 (D1) and 14 (D14) after TBI. The insomnia severity index was collected at 2 weeks, 3, 6, and 12 months postinjury. Participants were classified into insomnia trajectory classes based on a latent class model. We assessed the association of biomarkers with insomnia trajectories, controlling for medical and psychological comorbidities and demographics. Two thousand twenty-two individuals with TBI were studied. Elevations in D1 hsCRP were associated with persistent insomnia (severe, odds ratio [OR] = 1.33 [1.11, 1.59], p = 0.002; mild, OR = 1.10 [1.02, 1.19], p = 0.011). Similarly, D14 hsCRP elevations were associated with persistent insomnia (severe, OR = 1.27 [1.02, 1.59], p = 0.03). Of interest, D1 GFAP was lower in persistent severe insomnia (median [Q1, Q3]: 154 [19, 445] pg/mL) compared with resolving mild (491 [154, 1,423], p < 0.001) and persistent mild (344 [79, 1,287], p < 0.001). D14 GFAP was similarly lower in persistent (11.8 [6.4, 19.4], p = 0.001) and resolving (13.9 [10.3, 20.7], p = 0.011) severe insomnia compared with resolving mild (20.6 [12.4, 39.6]. Accordingly, increases in D1 GFAP were associated with reduced likelihood of having persistent severe (OR = 0.76 [95% CI 0.63-0.92], p = 0.004) and persistent mild (OR = 0.88 [0.81, 0.96], p = 0.003) compared with mild resolving insomnia. No differences were found with other biomarkers. Elevated plasma hsCRP and, surprisingly, lower GFAP were associated with adverse insomnia trajectories after TBI. Results support future prospective studies to examine their utility in guiding insomnia care after TBI. Further work is needed to explore potential mechanistic connections between GFAP levels and the adverse insomnia trajectories.

Biomarkers of neuroinflammation in the diagnosis of traumatic brain injury and neurodegenerative diseases: a literature review

Biomarkers of neuroinflammation in the diagnosis of traumatic brain injury and neurodegenerative diseases: a literature review

Brain temperature and free water increases after mild COVID-19 infection

The pathophysiology underlying the post-acute sequelae of COVID-19 remains understudied and poorly understood, particularly in healthy adults with a history of mild infection. Chronic neuroinflammation may underlie these enduring symptoms, but studying neuroinflammatory phenomena in vivo is challenging, especially without a comparable pre-COVID-19 dataset. In this study, we present a unique dataset of 10 otherwise healthy individuals scanned before and after experiencing mild COVID-19. Two emerging MR-based methods were used to map pre- to post-COVID-19 brain temperature and free water changes. Post-COVID-19 brain temperature and free water increases, which are indirect biomarkers of neuroinflammation, were found in structures functionally associated with olfactory, cognitive, and memory processing. The largest pre- to post-COVID brain temperature increase was observed in the left olfactory tubercle (p = 0.007, 95% CI [0.48, 3.01]), with a mean increase of 1.75 °C. Notably, the olfactory tubercle is also the region of the primary olfactory cortex where participants with chronic olfactory dysfunction showed the most pronounced increases as compared to those without lingering olfactory dysfunction (adjusted pFDR = 0.0189, 95% CI [1.42, 5.27]). These preliminary insights suggest a potential link between neuroinflammation and chronic cognitive and olfactory dysfunction following mild COVID-19, although further investigations are needed to improve our understanding of what underlies these phenomena.

Longer sleep duration and neuroinflammation in at-risk elderly with a parental history of Alzheimer's disease.

Although short sleep could promote neurodegeneration, long sleep may be a marker of ongoing neurodegeneration, potentially as a result of neuroinflammation. The objective was to evaluate sleep patterns with age of expected Alzheimer's disease (AD) onset and neuroinflammation. We tested 203 dementia-free participants (68.5 ± 5.4 years old, 78M). The PREVENT-AD cohort includes older persons with a parental history of AD whose age was nearing their expected AD onset. We estimated expected years to AD onset by subtracting the participants' age from their parent's at AD dementia onset. We extracted actigraphy sleep variables of interest (times of sleep onset and morning awakening, time in bed, sleep efficiency, and sleep duration) and general profiles (sleep fragmentation, phase delay, and hypersomnia). Cerebrospinal fluid (CSF) inflammatory biomarkers were assessed with OLINK multiplex technology. Proximity to, or exceeding, expected age of onset was associated with a sleep profile suggestive of hypersomnia (longer sleep and later morning awakening time). This hypersomnia sleep profile was associated with higher CSF neuroinflammatory biomarkers (IL-6, MCP-1, and global score). Interaction analyses revealed that some of these sleep-neuroinflammation associations were present mostly in those closer/exceeding the age of expected AD onset, APOE4 carriers, and those with better memory performance. Proximity to, or exceeding, parental AD dementia onset was associated with a longer sleep pattern, which was related to elevated proinflammatory CSF biomarkers. We speculate that longer sleep may serve a compensatory purpose potentially triggered by neuroinflammation as individuals are approaching AD onset. Further studies should investigate whether neuroinflammatory-triggered long sleep duration could mitigate cognitive deficits.

Host single nucleotide polymorphisms and biomarkers of neuronal damage and inflammation in people living with HIV

ObjectivesBlood-brain barrier impairment is frequent in people living with human immunodeficiency virus (PLWHIV), affecting the penetration of target cells and antiretrovirals into the central nervous system, through transporters (e.g. ABCB1), leading to neuroinflammation. This study aimed to identify variants of genes encoding transporters able to predict neuroinflammation biomarker levels. MethodsCerebrospinal fluid (CSF) and plasma samples were obtained from PLWHIV. The CSF biomarkers were quantified by commercial assays. Genetic variants were evaluated through real-time polymerase chain reaction (PCR). ResultsA total of 107 PLWHIV (163 samples) were included in the study: 79% were male, median age was 48.5 years, CD4% was 25%, and HIV-associated neurocognitive disorder (HAND) was observed in 17.8%. The ABCB1 2677G>T genetic variant showed a different allelic distribution according to the clinical group (P = 0.026). In linear regression analyses, HIV-related central nervous system disorders, ABCG2 1194+928CC genotype, log viral load, CSF-to-serum albumin ratio, β-1,42 levels, and CSF proteins were retained in the final model as factors independently associated with CSF neopterin levels; CSF proteins and integrase inhibitor use were associated with CSF tau level in the multivariate model. Phospho-tau regression analysis reported the ABCB1 2677GT/TT genotype and CSF proteins as predictors in the final model; sex, protease inhibitors, neopterin, and ABCB1 2677 GT/ TT genotype were predictors in the multivariate regression for β-1,42. ConclusionsFor the first time, pharmacogenetic and clinical features were found to be predictors of neuro-inflammation biomarkers.

Positron emission tomography imaging of the P2X7 receptor with a novel tracer, [18F]GSK1482160, in a transgenic mouse model of Alzheimer's disease and healthy non‐human primates

AbstractThis study aimed to evaluate [18F]GSK1482160 Positron emission tomography imaging for targeting P2X7R, a biomarker for neuroinflammation. Studies of acute neuroinflammation in rodents and transgenic mice with Alzheimer's disease (AD), as well as wild‐type (WT) controls, were conducted via PET‐CT‐MRI scans after tail vein injection of [18F]GSK1482160. Imaging was quantified based on the time‐activity curve, the standardized uptake value ratio, and the binding kinetics distribution volume ratio (DVR) to assess the expression of P2X7R. Tissues were collected post‐PET for immunofluorescence staining. Correlation analysis was performed between DVR and Morris water maze test results. Finally, dynamic Positron Emission Tomography‐Magnetic Resonance Imaging (PET‐MRI) scans were performed in healthy non‐human primates (NHPs). Our study demonstrated that AD mice had a significantly higher DVR than WT mice in the hippocampus (0.92 ± 0.06 vs. 0.79 ± 0.02, p &lt; 0.05), cortex (1.09 ± 0.03 vs. 0.88 ± 0.04, p &lt; 0.05), and striatum (1.02 ± 0.10 vs. 0.83 ± 0.1, p &lt; 0.05). Immunofluorescence staining showed increased expression of P2X7R in the AD, along with its colocalization with activated microglia and astrocytes. Correlation analysis indicated that brain regions with higher binding of [18F]GSK1482160 (i.e., the cortex, striatum, and hippocampus) were more vulnerable to cognitive impairment. PET‐MRI scans of healthy NHPs demonstrated the feasibility of brain penetration and P2X7R target engagement for the translation of [18F]GSK1482160 in human studies.

Increased levels of circulating soluble CD226 in multiple sclerosis

Background: The glycoprotein CD226 plays a key role in regulating immune cell function. Soluble CD226 (sCD226) is increased in sera of patients with several chronic inflammatory diseases but its levels in neuroinflammatory diseases such as multiple sclerosis (MS) are unknown. Objective: To investigate the presence and functional implications of sCD226 in persons with multiple sclerosis (pwMS) and other neurological diseases. Methods: The mechanisms of sCD226 production were first investigated by analyzing CD226 surface expression levels and supernatants of CD3/CD226-coactivated T cells. The role of sCD226 on dendritic cell maturation was evaluated. The concentration of sCD226 in the sera from healthy donors (HD), pwMS, neuromyelitis optica (NMO), and Alzheimer’s disease (AD) was measured. Results: CD3/CD226-costimulation induced CD226 shedding. Addition of sCD226 to dendritic cells during their maturation led to an increased production of the pro-inflammatory cytokine interleukin (IL)-23. We observed a significant increase in sCD226 in sera from pwMS and NMO compared to HD and AD. In MS, levels were increased in both relapsing–remitting multiple sclerosis (RRMS) and secondary-progressive multiple sclerosis (SPMS) compared to clinically isolated syndrome (CIS). Conclusion: Our data suggest that T-cell activation leads to release of sCD226 that could promote inflammation and raises the possibility of using sCD226 as a biomarker for neuroinflammation.

Neuroinflammation and acquired traumatic CNS injury: a mini review.

Acquired traumatic central nervous system (CNS) injuries, including traumatic brain injury (TBI) and spinal cord injury (SCI), are devastating conditions with limited treatment options. Neuroinflammation plays a pivotal role in secondary damage, making it a prime target for therapeutic intervention. Emerging therapeutic strategies are designed to modulate the inflammatory response, ultimately promoting neuroprotection and neuroregeneration. The use of anti-inflammatory agents has yielded limited support in improving outcomes in patients, creating a critical need to re-envision novel approaches to both quell deleterious inflammatory processes and upend the progressive cycle of neurotoxic inflammation. This demands a comprehensive exploration of individual, age, and sex differences, including the use of advanced imaging techniques, multi-omic profiling, and the expansion of translational studies from rodents to humans. Moreover, a holistic approach that combines pharmacological intervention with multidisciplinary neurorehabilitation is crucial and must include both acute and long-term care for the physical, cognitive, and emotional aspects of recovery. Ongoing research into neuroinflammatory biomarkers could revolutionize our ability to predict, diagnose, and monitor the inflammatory response in real time, allowing for timely adjustments in treatment regimens and facilitating a more precise evaluation of therapeutic efficacy. The management of neuroinflammation in acquired traumatic CNS injuries necessitates a paradigm shift in our approach that includes combining multiple therapeutic modalities and fostering a more comprehensive understanding of the intricate neuroinflammatory processes at play.

Inflammatory Biomarkers, Cognitive Functioning, and Brain Imaging Abnormalities in Bipolar Disorder: A Systematic Review.

Recent studies have pointed to neuroinflammation and neurotrophic factors as crucial mediators in the pathophysiology origins of mood disorders. The aim of this review is to assess the potential association between cognitive impairment, brain imaging abnormalities, and inflammatory biomarkers in patients affected by bipolar disorder (BD). Following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, we systematically searched PubMed, Google Scholar, Scopus, and Web of Science databases, with no year restriction, up until August 2023, for human studies that examined the relationship between inflammatory markers and cognitive impairment in BD patients. Studies based on neuroimaging, such as MRI, DTI, and fMRI, were also included, along with those examining the moderating role of specific inflammatory markers in the alteration of the brain. 59 human clinical studies satisfied the criteria for consideration. Most of the studies reviewed concur that inflammatory state, measured by peripheral blood levels of CRP and cytokines, constitutes an important contributor to cognitive impairment observed in patients with BD. Robust evidence indicates an association between cognitive impairment and CRP, IL-1RA, IL-6, and TNF-α with its receptors, whereas there is no convincing evidence for the involvement of other neuroinflammatory biomarkers. Neuroimaging studies suggest that brain structural/functional abnormalities seen in BD could also be linked to a neuroinflammatory condition. Current data provide evidence of a link between cognitive impairments observed in BD patients and mechanisms of neuroinflammation. Emerging evidence indicates that systemic inflammation might also play an important role in the deterioration of brain structures critical to cognitive functions in patients with BD. The convergence of findings across these studies strengthens our understanding of the complex neurobiological underpinnings of these disorders. Identification of BD specific inflammatory markers may be of assistance for future early therapeutic interventions.

Association of soluble TREM2 with Alzheimer's disease and mild cognitive impairment: a systematic review and meta-analysis.

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is a potential neuroinflammatory biomarker linked to the pathogenesis of Alzheimer's disease (AD) and mild cognitive impairment (MCI). Previous studies have produced inconsistent results regarding sTREM2 levels in various clinical stages of AD. This study aims to establish the correlation between sTREM2 levels and AD progression through a meta-analysis of sTREM2 levels in cerebrospinal fluid (CSF) and blood. Comprehensive searches were conducted in PubMed, Embase, Web of Science, and the Cochrane Library to identify observational studies reporting CSF and blood sTREM2 levels in AD patients, MCI patients, and healthy controls. A random effects meta-analysis was used to calculate the standardized mean difference (SMD) and 95% confidence intervals (CIs). Thirty-six observational studies involving 3,016 AD patients, 3,533 MCI patients, and 4,510 healthy controls were included. CSF sTREM2 levels were significantly higher in both the AD [SMD = 0.28, 95% CI (0.15, 0.41)] and MCI groups [SMD = 0.30, 95% CI (0.13, 0.47)] compared to the healthy control group. However, no significant differences in expression were detected between the AD and MCI groups [SMD = 0.09, 95% CI (-0.09, 0.26)]. Furthermore, increased plasma sTREM2 levels were associated with a higher risk of AD [SMD = 0.42, 95% CI (0.01, 0.83)]. CSF sTREM2 levels are positively associated with an increased risk of AD and MCI. Plasma sTREM2 levels were notably higher in the AD group than in the control group and may serve as a promising biomarker for diagnosing AD. However, sTREM2 levels are not effective for distinguishing between different disease stages of AD. Further investigations are needed to explore the longitudinal changes in sTREM2 levels, particularly plasma sTREM2 levels, during AD progression. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024514593.

CSF 14–3-3 zeta(ζ) isoform is associated with tau pathology and cognitive decline in Alzheimer's disease

14–3-3 is a family of conserved proteins that consist of seven isoforms which are highly expressed in the brain, and 14–3-3 zeta(ζ) is one of the isoforms encoded by the YWHAZ gene. Previous studies demonstrated that 14–3-3ζ is deposited in the neurofibrillary tangles of Alzheimer's disease (AD) brains, and that 14–3-3ζ interacts with tau from the purified neurofibrillary tangles of AD brain extract. The present study examined the cerebrospinal fluid (CSF) 14–3-3ζ levels of 719 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively normal (CN) participants, patients with mild cognitive impairment (MCI) and patients with AD dementia, and aimed to identify whether CSF 14–3-3ζ is associated with tau pathology. CSF 14–3-3ζ levels were increased in AD, and particularly elevated among tau pathology positive individuals. CSF 14–3-3ζ levels were associated with CSF phosphorylated tau 181 (p-tau) (r = 0.741, P < 0.001) and plasma p-tau (r = 0.293, P < 0.001), which are fluid biomarkers of tau pathology, and could predict tau pathology positive status with high accuracy (area under the receiver operating characteristic curve [AUC], 0.891). CSF 14–3-3ζ levels were also correlated to synaptic biomarker CSF GAP-43 (r = 0.609, P < 0.001) and neuroinflammatory biomarker CSF sTREM-2 (r = 0.507, P < 0.001). High CSF 14–3-3ζ levels at baseline were associated with progressive decline of cognitive function and neuroimaging findings during follow up. In conclusion, this study suggests that CSF 14–3-3ζ is a potential biomarker of AD that may be useful in clinical practice.

Lipid-polymer hybrid nanoparticles loaded with N-acetylcysteine for the modulation of neuroinflammatory biomarkers in human iPSC-derived PSEN2 (N141I) astrocytes as a model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive impairment associated with the accumulation of beta-amyloid protein (Aβ). Aβ activates glial cells in the brain, increasing the secretion of proinflammatory cytokines, which leads to neuroinflammation and neuronal death. Currently, there are no effective treatments that cure or stop its progression; therefore, AD is considered a global health priority. The main limitations are the low drug bioavailability and impermeability of the blood-brain barrier (BBB). Fortunately, nanomedicine has emerged as a promising field for the development of new nanosystems for the controlled and targeted delivery of drugs to the brain. Therefore, in this work, lipid-polymer hybrid nanoparticles (LPHNPs) conjugated with transferrin (Tf) to facilitate crossing the BBB and loaded with N-acetylcysteine (NAC) for its anti-inflammatory effect were synthesized, and their physicochemical characterization was carried out. Subsequently, an in vitro model involving human astrocytes derived from induced pluripotent stem cells (iPSC) from an AD-diagnosed patient was developed, which was brought to a reactive state by stimulation with lipopolysaccharides (LPSs). The cell culture was treated with either Tf-conjugated LPHNPs loaded with NAC (NAC-Tf-LPHNPs) at 0.25 mg mL-1, or free NAC at 5 mM. The results showed that NAC-Tf-LPHNPs favorably modulated the expression of proinflammatory genes such as interleukin-1β (IL-1β), amyloid precursor protein (APP) and glial fibrillary acidic protein (GFAP). In addition, they reduced the secretion of the proinflammatory cytokines interleukin 6 (IL-6), IL-1β and interferon-gamma (INF-γ). Results for both cases were compared to the group of cells that did not receive any treatment. In contrast, free NAC only had this effect on the expression of IL-1β and the secretion of the cytokines IL-6 and INF-γ. These results indicate the potential of NAC-Tf-LPHNPs for AD treatment.

Sexually dimorphic murine brain uptake of the 18 kDa translocator protein PET radiotracer [18F]LW223.

The 18 kDa translocator protein is a well-known biomarker of neuroinflammation, but also plays a role in homeostasis. PET with 18 kDa translocator protein radiotracers [11C]PBR28 in humans and [18F]GE180 in mice has demonstrated sex-dependent uptake patterns in the healthy brain, suggesting sex-dependent 18 kDa translocator protein expression, although humans and mice had differing results. This study aimed to assess whether the 18 kDa translocator protein PET radiotracer [18F]LW223 exhibited sexually dimorphic uptake in healthy murine brain and peripheral organs. Male and female C57Bl6/J mice (13.6 ± 5.4 weeks, 26.8 ± 5.4 g, mean ± SD) underwent 2 h PET scanning post-administration of [18F]LW223 (6.7 ± 3.6 MBq). Volume of interest and parametric analyses were performed using standard uptake values (90-120 min). Statistical differences were assessed by unpaired t-test or two-way ANOVA with Šidak's test (alpha = 0.05). The uptake of [18F]LW223 was significantly higher across multiple regions of the male mouse brain, with the most pronounced difference detected in hypothalamus (P < 0.0001). Males also exhibited significantly higher [18F]LW223 uptake in the heart when compared to females (P = 0.0107). Data support previous findings on sexually dimorphic 18 kDa translocator protein radiotracer uptake patterns in mice and highlight the need to conduct sex-controlled comparisons in 18 kDa translocator protein PET imaging studies.

Possible role of gut derived metabolites in communication between systemic inflammation and CNS in delirium development.

AbstractBackgroundDementia and delirium are strongly correlated. Patients with dementia are more prone to develop delirium, while delirium can lead to accelerated cognitive decline. Biomarkers present in the CSF have been considered to belong to the pathophysiological pathways between systemic inflammation, neuroinflammation, gut microbiota and consequently, contribute to the etiology of both the cognition impairments, ie. delirium and dementia. Despite multiple studies on inflammatory biomarkers in CSF, the link with systemic inflammation has still not been deciphered. Multiple studies have indicated that inflammatory pathways in patients with cognitive decline are mediated by gut microbiota.MethodIn this narrative review we screened PubMed for studies, where neuroinflammatory biomarkers detected in CSF were investigated in relation to delirium. We will explain the link to microbiome by comparing these delirium studies to microbiome studies in dementia. These studies were published in English till January 2023.ResultWe found that in patients with Alzheimer’s disease (AD) and delirium altered levels of at least 70 different neuroinflammatory biomarkers in CSF were found. Also altered microbiome has been identified in AD and its correlation with the CNS inflammation was shown. Interestingly, in case of AD, a recent study demonstrated that a microbial‐derived metabolite, trimethylamine N‐oxide (TMAO), reaches the CNS and that its elevated levels are present in AD patients.In case of delirium, we found two studies indicating contribution of disbalanced gut microbiota in acute CNS inflammation in human. It has been shown that preoperative status of gut microbiota can allow prediction of postoperative delirium in patients with gastric cancer. Interestingly, there was already one case described where fecal microbiota transplantation ameliorated patient’s infection and delirium. No studies on microbiome‐derived metabolites, which could constitute a possible link with the acute inflammation of CNS in delirium, have been found.ConclusionThere is irrefutable evidence that altered levels of neuroinflammatory biomarkers in CSF are associated with pathology of both AD and delirium. Implication of the microbiome, and microbial‐derived metabolite TMAO in inflammatory processes and in pathophysiology of AD has already been found. This has encouraged us to investigate the role of TMAO in the acute CNS inflammatory condition, i.e. delirium.

Age‐ and Sex‐ dependent changes in Translocator Protein 18 kDa (TSPO) expression, cellular sources, and association with amyloid‐β plaques in the 5XFAD murine model of Alzheimer’s Disease

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder that affects cognition, memory, and social abilities with devastating effects on individuals and families. The hallmark AD pathology is the formation of amyloid‐β‐(Aβ)‐plaques and Tau neurofibrillary tangles leading to neurodegeneration. Neuroinflammation, and microglia activation, also play an important role in the initiation and progression of AD, a process that begins earlier than cognitive decline. TSPO is a well‐validated and widely used biomarker of neuroinflammation that is expressed in glial cells, and it is markedly increased in the brain of AD subjects and in AD animal models. Previous studies have not assessed a detailed trajectory of TSPO in the progression of AD. In the present study, we determined the age‐and sex‐dependent increase in brain TSPO levels, cellular sources, and association with Aβ‐plaques in parallel with behavior.MethodBehavioral performance was measured using the Barnes Maze (cognition) in male and female wild‐type (WT) and 5XFAD mice at 3 months (3M), and 7 months (7M). To evaluate pathological endpoints, we measured Aβ‐load (number, size, and % area covered), TSPO quantitative autoradiography using the TSPO‐specific radioligand [3H]‐DPA‐713, and quadruple‐label immunofluorescent confocal imaging to determine the cellular sources of the TSPO response and its association with Aβ‐plaques.ResultAt 3M, we observed no significant differences in behavioral performance between WT and 5XFAD in either sex. At 7M, 5XFAD males showed no cognitive dysfunction, however, there was a significant cognitive impairment in 5XFAD females. We found an increase of Aβ‐plaques in an age‐and sex‐dependent manner. TSPO autoradiography showed a significant increase in TSPO levels in 5XFAD mice in both sexes and ages with a higher increase in females. Furthermore, we show that TSPO expression is colocalized with plaque‐associated microglia and not astrocytes.ConclusionThese results indicate that brain TSPO is an early biomarker of neuroinflammation and TSPO levels increase at the same time that Aβ‐aggregation and much earlier than cognitive decline. Furthermore, the increase in TSPO levels was associated with microglia surrounding or embedded with Aβ‐plaques suggesting a role in plaque formation.

Temporal evaluation of imaging and biofluid biomarkers, spatial neuropathology and glial function in the TgF344‐AD rat model

AbstractBackgroundThe development and characterization of Alzheimer’s disease (AD) animal models is particularly important for the investigation of pathophysiological mechanisms and drug development. The TgF344‐AD rat is a model harboring human APP/PS1 mutations with comprehensive presentation, including age‐dependent development of amyloid‐β (Aβ) plaques, neuronal loss and tau deposits, but not yet fully characterized. In light of this, we evaluated imaging and biofluid biomarkers, spatial neuropathology and glial function in these animals across multiple key ages.MethodsTgF344‐AD rats and wild‐type littermates were longitudinally evaluated at 3, 6, 9, 12 and 16‐18 months of age. Rats underwent [18F]FDG‐microPET scans and CSF samplings. CSF glial and immune markers (GFAP, S100B, TREM2, IL‐6, TNF‐α, IL‐10) were measured by multiplex immunoassay. A cross‐sectional cohort was used to measure cortical glutamate uptake (ex‐vivo slices) and follow the spatial distribution of Aβ plaques (6E10 antibody) at the same time points.ResultsAt 3, 6, 12 and 16‐18mo, no changes in [18F]FDG metabolism were observed. At 9mo, we identified a significant cortical hypermetabolism in the TgF344‐AD rats. CSF GFAP levels were elevated at 6 and 9 months of age, while CSF S100B was decreased at 9mo. The CSF inflammatory markers IL‐6, TNF‐α and IL‐10 were elevated at 16‐18mo. Additionally, the glutamate uptake was increased in the cortex at 9mo and 12mo, and in the hippocampus at 12mo. TREM2 was not altered in any of the ages evaluated. The (Aβ) plaques deposition starts at 6mo in the posterior temporal cortices and hippocampus and spreads slowly to frontal brain regions, reaching a plateau around 16mo.ConclusionThis work shows that the TgF344‐AD rat model recapitulates the early and transient glucose hypermetabolism seen in AD patients. Our results also indicate an associated early astrocyte response in these animals, with changes in relevant astrocyte biomarkers and function (glutamate uptake). Due to the critical role of astrocytes in brain glucose handling, these findings suggest that astrocyte reactivity could be driving glucose hypermetabolism. In contrast, the neuroinflammatory biomarkers changes identified suggest a strong neuroinflammatory response only at later stages in this rat model, however, further investigations are necessary to better elucidate these findings.