Impaired Brain Research Articles

The Inflammasome Adaptor Protein ASC in Plasma as a Biomarker of Early Cognitive Changes.

Dementia is a group of symptoms including memory loss, language difficulties, and other types of cognitive and functional impairments that affects 57 million people worldwide, with the incidence expected to double by 2040. Therefore, there is an unmet need to develop reliable biomarkers to diagnose early brain impairments so that emerging interventions can be applied before brain degeneration. Here, we performed biomarker analyses for apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid-β 42/40 (Aβ42/40) ratio in the plasma of older adults. Participants had blood drawn at baseline and underwent two annual clinical and cognitive evaluations. The groups tested either cognitively normal on both evaluations (NN), cognitively normal year 1 but cognitively impaired year 2 (NI), or cognitively impaired on both evaluations (II). ASC was elevated in the plasma of the NI group compared to the NN and II groups. Additionally, Aβ42 was increased in the plasma in the NI and II groups compared to the NN group. Importantly, the area under the curve (AUC) for ASC in participants older than 70 years old in NN vs. NI groups was 0.81, indicating that ASC is a promising plasma biomarker for early detection of cognitive decline.

Comparison of patients with chronic and episodic migraine with healthy individuals by brain volume and cognitive functions

Objectives: Migraine is a complex neurological disease. In addition to headache, individuals with migraine may develop structural changes inside the brain and cognitive impairment. There is increased evidence associated with impairments in brain volume and cognitive functions in patients with migraine. The present study aimed to investigate the impairment in memory function in individuals with migraine using brain magnetic resonance imaging, volume measurement, and neuropsychological tests. Methods: The study included 20 patients with episodic migraine, 20 patients with chronic migraine, and 20 healthy controls. Subcortical volumes of all participants were measured by FreeSurfer, an automatic segmentation method. The Wechsler Memory Scale-Revised Form (WMS-R), Stroop test, Raven’s Standard Progressive Matrices, Verbal Fluency Test, and Lines Orientation Test were applied in all the study participants. Results: Putamen volume decreased as migraine duration increased, and subcortical gray matter, left cerebellar cortex, and bilateral thalamus volumes were lower in the chronic and episodic group compared to the control group, bilateral putamen and right cerebellar cortex volumes were lower in patients with chronic migraine compared to patients in episodic migraine and control groups. Upon neuropsychological examination, delayed memory was affected as the duration of migraine increased, and there was impairment in patients with chronic migraine upon fluency tests and mental control tests. Conclusions: Changes in subcortical volume and cognitive effects in patients with migraine raise questions about whether migraine qualifies as a benign disease. Structural changes and cognitive impairment may contribute to migraine-associated disability, and therefore, these causalities should be investigated by future studies. Silent infarcts, white matter damage, and cortical spreading depression, which occur in migraine cases, may be associated with subcortical volume changes and thus, cognitive effects. In the context, studies with larger samples to achieve a better understanding are needed.

T2*-Relaxometry MRI to Assess Third Trimester Placental and Fetal Brain Oxygenation and Placental Characteristics in Healthy Fetuses and Fetuses With Congenital Heart Disease.

Congenital heart disease (CHD) has been linked to impaired placental and fetal brain development. Assessing the placenta and fetal brain in parallel may help further our understanding of the relationship between development of these organs. 1) Placental and fetal brain oxygenation are correlated, 2) oxygenation in these organs is reduced in CHD compared to healthy controls, and 3) placental structure is altered in CHD. Retrospective case-control. Fifty-one human fetuses with CHD (32 male; median [IQR] gestational age [GA] = 32.0 [30.9-32.9] weeks) and 30 from uncomplicated pregnancies with normal birth outcomes (18 male; median [IQR] GA = 34.5 [31.9-36.7] weeks). 1.5 T single-shot multi-echo-gradient-echo echo-planar imaging. Masking was performed using an automated nnUnet model. Mean brain and placental T2* and quantitative measures of placental texture, volume, and morphology were calculated. Spearman's correlation coefficient for determining the association between brain and placental T2*, and between brain and placental characteristics with GA. P-values for comparing brain T2*, placenta T2*, and placental characteristics between groups derived from ANOVA. Significance level P < 0.05. There was a significant positive association between placental and fetal brain T2* (⍴ = 0.46). Placental and fetal brain T2* showed a significant negative correlation with GA (placental T2* ⍴ = -0.65; fetal brain T2* ⍴ = -0.32). Both placental and fetal brain T2* values were significantly reduced in CHD, after adjusting for GA (placental T2*: control = 97 [±24] msec, CHD = 83 [±23] msec; brain T2*: control = 218 [±26] msec, CHD = 202 [±25] msec). Placental texture and morphology were also significantly altered in CHD (Texture: control = 0.84 [0.83-0.87], CHD = 0.80 [0.78-0.84]; Morphology: control = 9.9 [±2.2], CHD = 10.8 [±2.0]). For all fetuses, there was a significant positive association between placental T2* and placental texture (⍴ = 0.46). Placental and fetal brain T2* values are associated in healthy fetuses and those with CHD. Placental and fetal brain oxygenation are reduced in CHD. Placental appearance is significantly altered in CHD and shows associations with placental oxygenation, suggesting altered placental development and function may be related. 3 TECHNICAL EFFICACY: Stage 3.

Cholesterol Metabolism in Neurodegenerative Diseases.

Significance: Cholesterol plays a crucial role in the brain, where it is highly concentrated and tightly regulated to support normal brain functions. It serves as a vital component of cell membranes, ensuring their integrity, and acts as a key regulator of various brain processes. Dysregulation of cholesterol metabolism in the brain has been linked to impaired brain function and the onset of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease. Recent Advances: A significant advancement has been the identification of astrocyte-derived apoliprotein E as a key regulator of de novo cholesterol biosynthesis in neurons, providing insights into how extracellular signals influence neuronal cholesterol levels. In addition, the development of antibody-based therapies, particularly for AD, presents promising opportunities for therapeutic interventions. Critical Issues: Despite significant research, the association between cholesterol and neurodegenerative diseases remains inconclusive. It is crucial to distinguish between plasma cholesterol and brain cholesterol, as these pools are relatively independent. This differentiation should be considered when evaluating statin-based treatment approaches. Furthermore, assessing not only the total cholesterol content in the brain but also its distribution among different types of brain cells is essential. Future Direction: Establishing a causal link between changes in brain/plasma cholesterol levels and the onset of brain dysfunction/neurodegenerative diseases remains a key objective. In addition, conducting cell-specific analyses of cholesterol homeostasis in various types of brain cells under pathological conditions will enhance our understanding of cholesterol metabolism in neurodegenerative diseases. Manipulating cholesterol levels to restore homeostasis may represent a novel approach for alleviating neurological symptoms.

Convergent functional change of frontoparietal network in obsessive-compulsive disorder: a voxel-based meta-analysis.

Obsessive-compulsive disorder (OCD) is a chronic psychiatric illness with complex clinical manifestations. Cognitive dysfunction may underlie OC symptoms. The frontoparietal network (FPN) is a key region involved in cognitive control. However, the findings of impaired FPN regions have been inconsistent. We employed meta-analysis to identify the fMRI-specific abnormalities of the FPN in OCD. PubMed, Web of Science, Scopus, and EBSCOhost were searched to screen resting-state functional magnetic resonance imaging (rs-fMRI) studies exploring dysfunction in the FPN of OCD patients using three indicators: the amplitude of low-frequency fluctuation/fractional amplitude of low-frequency fluctuation (ALFF/fALFF), regional homogeneity (ReHo) and functional connectivity (FC). We compared all patients with OCD and control group in a primary analysis, and divided the studies by medication in secondary meta-analyses with the activation likelihood estimation (ALE) algorithm. A total of 31 eligible studies with 1359 OCD patients (756 men) and 1360 healthy controls (733 men) were included in the primary meta-analysis. We concluded specific changes in brain regions of FPN, mainly in the left dorsolateral prefrontal cortex (DLPFC, BA9), left inferior frontal gyrus (IFG, BA47), left superior temporal gyrus (STG, BA38), right posterior cingulate cortex (PCC, BA29), right inferior parietal lobule (IPL, BA40) and bilateral caudate. Additionally, altered connectivity within- and between-FPN were observed in the bilateral DLPFC, right cingulate gyrus and right thalamus. The secondary analyses showed improved convergence relative to the primary analysis. OCD patients showed dysfunction FPN, including impaired local important nodal brain regions and hypoconnectivity within the FPN (mainly in the bilateral DLPFC), during the resting state. Moreover, FPN appears to interact with the salience network (SN) and default mode network (DMN) through pivotal brain regions. Consistent with the hypothesis of fronto-striatal circuit dysfunction, especially in the dorsal cognitive circuit, these findings provide strong evidence for integrating two pathophysiological models of OCD.

A Comprehensive Review on Hepatic Encephalopathy: Pathophysiology, Symptoms, Epidemiology, Classification, Diagnosis and Treatment

The condition known as hepatic encephalopathy (HE) is a state of impaired brain function that can be reversed and is experienced by patients who are suffering from severe liver diseases. Neurotoxins, decreased neurotransmission as a result of metabolic anomalies in liver failure, changes in brain energy metabolism, systemic inflammatory response, and alterations of the blood brain barrier are the primary hypotheses that are still being explored in relation to the precise pathophysiology of hepatic encephalopathy (HE). There is a wide spectrum of severity regarding the neurological and mental symptoms that can be brought on by HE. For the purpose of diagnosing limited HE, abnormal psychometric tests are utilised. Alterations in personality, altered states of consciousness, gradual spatial and temporal disorientation, lethargy, stupor, and coma are some of the characteristics of HE that are clinically noticeable. For the purpose of diagnosis, specific testing is not required outside of clinical studies. HE is classified according to the underlying disease, the severity of symptoms, the length of time it has been present, and whether or not there are triggers that cause it to occur. Hepatic encephalopathy refers to a collection of neuropsychiatric illnesses that can be treated and are characterised by the presence of symptoms in individuals who have liver disease or who have undergone portosystemic shunting. Entephalopathy, a disabling result of cirrhosis, affects thirty-five percent to forty-five percent of cirrhotic patients. Before recently, the treatment choices for HE that were available in hospitals were depending on anecdotal evidence, the availability of medication, and the norms of the relevant institutions. An increasing number of randomised controlled trials (RCTs) are providing further confirmation of the central significance of the basic HE therapy techniques (lactulose, branched-chain amino acids, and rifaximin), as well as the rising body of evidence showing the large beneficial advantages associated with these strategies. The liver transplantation and embolisation of large PSSs are two treatments that have proven to be effective for a select group of patients who have been carefully selected. Not only does it have a significant influence on the day-to-day lives of patients and carers, but it is also associated with increased rates of sickness and death and consumes a significant amount of resources in the healthcare system. In this article, we examine the history of hepatic encephalopathy, as well as the current understanding of the condition and the potential treatments for it.

Midline structures and cortical development in late-onset fetal growth restriction according to Doppler status: prospective study.

Fetuses with late-onset growth restriction (FGR) have a higher risk of suboptimal neurocognitive performance after birth. Previous studies have reported that impaired brain and cortical development can start in utero. The primary aim of this study was to report midline structure growth and cortical development in fetuses with late-onset FGR according to its severity; the secondary aim was to elucidate whether the severity of FGR, as defined by the presence of abnormal Doppler findings, plays a role in affecting brain growth and maturation. This was a prospective observational study that included fetuses with late-onset FGR (defined according to the Delphi FGR criteria) undergoing neurosonography between 32 and 34 weeks' gestation. Midline structure (corpus callosum (CC) and cerebellar vermis (CV)) length and cortical development, including the depth of the Sylvian (SF), parieto-occipital (POF) and calcarine (CF) fissures, were compared between late-onset FGR, small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA) fetuses. Subgroup analysis according to the severity of FGR (normal vs abnormal fetal Doppler) was also performed. Univariate analysis was used to analyze the data. A total of 52 late-onset FGR fetuses with normal Doppler findings, 60 late-onset FGR fetuses with abnormal Doppler findings, 64 SGA fetuses and 100 AGA fetuses were included in the analysis. When comparing AGA controls with SGA fetuses, late-onset FGR fetuses with normal Doppler findings and late-onset FGR fetuses with abnormal Doppler findings, there was a progressive and significant reduction in the absolute values of the following parameters: CC length (median (interquartile range (IQR)), 43.5 (28.9-56.1) mm vs 41.9 (27.8-51.8) mm vs 38.5 (29.1-50.5) mm vs 31.7 (23.8-40.2) mm; K = 26.68; P < 0.0001), SF depth (median (IQR), 14.5 (10.7-16.8) mm vs 12.7 (9.8-15.1) mm vs 11.9 (9.1-13.4) mm vs 8.3 (6.7-10.3) mm; K = 75.82; P < 0.0001), POF depth (median (IQR), 8.6 (6.3-11.1) mm vs 8.1 (5.6-10.4) mm vs 7.8 (6.1-9.3) mm vs 6.6 (4.2-8.0) mm; K = 45.06; P < 0.0001) and CF depth (median (IQR), 9.3 (6.7-11.5) mm vs 8.2 (5.7-10.7) mm vs 7.7 (5.2-9.4) mm vs 6.3 (4.5-7.2) mm; K = 46.14; P < 0.0001). Absolute CV length was significantly higher in AGA fetuses compared with all other groups, although the same progressive pattern was not noted (median (IQR), 24.9 (17.6-29.2) mm vs 21.6 (15.2-26.1) mm vs 19.1 (13.8-25.9) mm vs 21.0 (13.5-25.8) mm; K = 16.72; P = 0.0008). When the neurosonographic variables were corrected for fetal head circumference, a significant difference in the CC length and SF, POF and CF depths, but not CV length, was observed only in late-onset FGR fetuses with abnormal Doppler findings when compared with AGA and SGA fetuses. Fetuses with late-onset FGR had shorter CC length and delayed cortical development when compared with AGA fetuses. After controlling for fetal head circumference, these differences remained significant only in late-onset FGR fetuses with abnormal Doppler. These findings support the existence of a link between brain development and impaired placental function. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Modeling the impact of neuromorphological alterations in Down syndrome on fast neural oscillations.

Cognitive disorders, including Down syndrome (DS), present significant morphological alterations in neuron architectural complexity. However, the relationship between neuromorphological alterations and impaired brain function is not fully understood. To address this gap, we propose a novel computational model that accounts for the observed cell deformations in DS. The model consists of a cross-sectional layer of the mouse motor cortex, composed of 3000 neurons. The network connectivity is obtained by accounting explicitly for two single-neuron morphological parameters: the mean dendritic tree radius and the spine density in excitatory pyramidal cells. We obtained these values by fitting reconstructed neuron data corresponding to three mouse models: wild-type (WT), transgenic (TgDyrk1A), and trisomic (Ts65Dn). Our findings reveal a dynamic interplay between pyramidal and fast-spiking interneurons leading to the emergence of gamma activity (∼40 Hz). In the DS models this gamma activity is diminished, corroborating experimental observations and validating our computational methodology. We further explore the impact of disrupted excitation-inhibition balance by mimicking the reduction recurrent inhibition present in DS. In this case, gamma power exhibits variable responses as a function of the external input to the network. Finally, we perform a numerical exploration of the morphological parameter space, unveiling the direct influence of each structural parameter on gamma frequency and power. Our research demonstrates a clear link between changes in morphology and the disruption of gamma oscillations in DS. This work underscores the potential of computational modeling to elucidate the relationship between neuron architecture and brain function, and ultimately improve our understanding of cognitive disorders.

Atypical intrinsic neural timescale in the left angular gyrus in Alzheimer's disease.

Alzheimer's disease is characterized by cognitive impairment and progressive brain atrophy. Recent human neuroimaging studies reported atypical anatomical and functional changes in some regions in the default mode network in patients with Alzheimer's disease, but which brain area of the default mode network is the key region whose atrophy disturbs the entire network activity and consequently contributes to the symptoms of the disease remains unidentified. Here, in this case-control study, we aimed to identify crucial neural regions that mediated the phenotype of Alzheimer's disease, and as such, we examined the intrinsic neural timescales-a functional metric to evaluate the capacity to integrate diverse neural information-and grey matter volume of the regions in the default mode network using resting-state functional MRI images and structural MRI data obtained from individuals with Alzheimer's disease and cognitively typical people. After confirming the atypically short neural timescale of the entire default mode network in Alzheimer's disease and its link with the symptoms of the disease, we found that the shortened neural timescale of the default mode network was associated with the aberrantly short neural timescale of the left angular gyrus. Moreover, we revealed that the shortened neural timescale of the angular gyrus was correlated with the atypically reduced grey matter volume of this parietal region. Furthermore, we identified an association between the neural structure, brain function and symptoms and proposed a model in which the reduced grey matter volume of the left angular gyrus shortened the intrinsic neural time of the region, which then destabilized the entire neural timescale of the default mode network and resultantly contributed to cognitive decline in Alzheimer's disease. These findings highlight the key role of the left angular gyrus in the anatomical and functional aetiology of Alzheimer's disease.

Transdisciplinary method for exploration and visualization of neuroimaging papers and databases: Application to PTSD

A major improvement in MRI techniques has led to an exponential increase in data acquisition and, consequently, in the number of published articles reporting brain impairments and cognitive deficits underlying a disorder. Meta-analysis offers a means of synthesizing the available literature, testing existing models in the light of scientific advances, and revealing unexpected information. However, article selection, author specialization and top-down hypotheses can mask some results and introduce bias into interpretations. LinkRdata is a platform for automated, data-driven, meta-analytical methods suitable for processing large numbers of MRI articles, that can reduce selection and interpretation biases, thereby allowing scientists to review neurocognitive correlates of disorders in relation to their own corpus of articles. To validate our method, we applied it to fMRI studies of post-traumatic stress disorder. Results confirmed LinkRdata's power to uncover findings hidden by the top-down hypothesis approach.

The ketamine metabolite (2R,6R)-hydroxynorketamine rescues hippocampal mRNA translation, synaptic plasticity and memory in mouse models of Alzheimer's disease.

Impaired brain protein synthesis, synaptic plasticity, and memory are major hallmarks of Alzheimer's disease (AD). The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) has been shown to modulate protein synthesis, but its effects on memory in AD models remain elusive. We investigated the effects of HNK on hippocampal protein synthesis, long-term potentiation (LTP), and memory in AD mouse models. HNK activated extracellular signal-regulated kinase 1/2 (ERK1/2), mechanistic target of rapamycin (mTOR), and p70S6 kinase 1 (S6K1)/ribosomal protein S6 signaling pathways. Treatment with HNK rescued hippocampal LTP and memory deficits in amyloid-β oligomers (AβO)-infused mice in an ERK1/2-dependent manner. Treatment with HNK further corrected aberrant transcription, LTP and memory in aged APP/PS1 mice. Our findings demonstrate that HNK induces signaling and transcriptional responses that correct synaptic and memory deficits in AD mice. These results raise the prospect that HNK could serve as a therapeutic approach in AD. The ketamine metabolite HNK activates hippocampal ERK/mTOR/S6 signaling pathways. HNK corrects hippocampal synaptic and memory defects in two mouse models of AD. Rescue of synaptic and memory impairments by HNK depends on ERK signaling. HNK corrects aberrant transcriptional signatures in APP/PS1 mice.

Associations of serum uric acid variability with neuroimaging metrics and cognitive decline: a population-based cohort study

BackgroundThe relationship between variation in serum uric acid (SUA) levels and brain health is largely unknown. This study aimed to examine the associations of long-term variability in SUA levels with neuroimaging metrics and cognitive function.MethodsThis study recruited 1111 participants aged 25–83 years from a multicenter, community-based cohort study. The SUA concentrations were measured every two years from 2006 to 2018. We measured the intraindividual SUA variability, including the direction and magnitude of change by calculating the slope value. The associations of SUA variability with neuroimaging markers (brain macrostructural volume, microstructural integrity, white matter hyperintensity, and the presence of cerebral small vessel disease) and cognitive function were examined using generalized linear models. Mediation analyses were performed to assess whether neuroimaging markers mediate the relationship between SUA variation and cognitive function.ResultsCompared with the stable group, subjects with increased or decreased SUA levels were all featured by smaller brain white matter volume (beta = − 0.25, 95% confidence interval [CI] − 0.39 to − 0.11 and beta = − 0.15, 95% CI − 0.29 to − 0.02). Participants with progressively increased SUA exhibited widespread disrupted microstructural integrity, featured by lower global fractional anisotropy (beta = − 0.24, 95% CI − 0.38 to − 0.10), higher mean diffusivity (beta = 0.16, 95% CI 0.04 to 0.28) and radial diffusivity (beta = 0.19, 95% CI 0.06 to 0.31). Elevated SUA was also associated with cognitive decline (beta = − 0.18, 95% CI − 0.32 to − 0.04). White matter atrophy and impaired brain microstructural integrity mediated the impact of SUA increase on cognitive decline.ConclusionsIt is the magnitude of SUA variation rather than the direction that plays a critical negative role in brain health, especially for participants with hyperuricemia. Smaller brain white matter volume and impaired microstructural integrity mediate the relationship between increased SUA level and cognitive function decline. Long-term stability of SUA level is recommended for maintaining brain health and preventing cognitive decline.

Cognitive reserve involves decision making and is associated with left parietal and hippocampal hypertrophy in neurodegeneration

Cognitive reserve is the ability to actively cope with brain deterioration and delay cognitive decline in neurodegenerative diseases. It operates by optimizing performance through differential recruitment of brain networks or alternative cognitive strategies. We investigated cognitive reserve using Huntington’s disease (HD) as a genetic model of neurodegeneration to compare premanifest HD, manifest HD, and controls. Contrary to manifest HD, premanifest HD behave as controls despite neurodegeneration. By decomposing the cognitive processes underlying decision making, drift diffusion models revealed a response profile that differs progressively from controls to premanifest and manifest HD. Here, we show that cognitive reserve in premanifest HD is supported by an increased rate of evidence accumulation compensating for the abnormal increase in the amount of evidence needed to make a decision. This higher rate is associated with left superior parietal and hippocampal hypertrophy, and exhibits a bell shape over the course of disease progression, characteristic of compensation.

Phloroglucinol ameliorated methylglyoxal induced harmful effects in rats.

Glycation is among the underlying mechanisms attributed to ageing and associated morbidities. There is no drug available to combat this deleterious phenomenon. The present study aimed to explore phloroglucinol (PHL) for its anti-glycation potential at preclinical level. The rats were treated with methylglyoxal (MGO, 17.25 mg/kg, i.p. for 14 days) to induce glvcative stress. The treatment groups received additional administration of test drug (PHL; 0.25mg/kg, 0.5mg/kg, and 1mg/kg) or standard aminoguanidine (AG, 50 mg/kg) or saline (control, 5ml/kg). During 14 days, the weight and food intake was noted. Afterwards, the cognitive function was evaluated using Morris Water Maze (MWM) while hepatic and renal functions were assessed through liver function test (bilirubin, alkaline phosphatase, SGPT, and SGOT) and creatinine respectively, using chemical analyzer. The carboxymethyllysine (CML) levels were quantified in the blood using ELISA technique. Histopathological study was performed on the brain, liver, and kidney using H&E staining. Additionally, the qPCR was used to quantify the expression of TNF-α, RAGE and BACE-1 (brain), RAGE, TNF-α, and glyoxalase-I (liver) and RAGE, TNF-α, and VEGF (kidney), while glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as a reference housekeeping gene. The data regarding weight and food intake did not reveal significant alterations. In MWM, the MGO treatment caused significant increase in the time to reach target quadrant, while decrease in the time spent in target quadrant and number of crossings through platform position. All these effects were inhibited by both AG and PHL. The navigation maps also exhibit that the retention of spatial memory. Additionally, the MGO-induced alteration in hepatic and renal function indicators was ameliorated by both AG and PHL treatments. The plasma CML levels were found to be elevated following MGO treatment, while the concomitant administration of AG and PHL has resisted this raise. Histopathological assessment revealed no specific pathology in liver kidney and brain tissues. The qPCR data revealed enhanced expression of all genes, especially TNF-α and BACE, which were found to be reduced following both AG and PHL treatments. PHL prevented the brain, hepatic, and renal impairments caused by MGO induced glycative stress. Hence, the PHL, a clinically used anti-spasmodic drug, presents itself as a potential candidate to be repurposed as anti-glycation drug.

Diffuse microglial responses and persistent EEG changes correlate with poor neurological outcome in a model of subarachnoid hemorrhage

The mechanism by which subarachnoid hemorrhage (SAH) leads to chronic neurologic deficits is unclear. One possibility is that blood activates microglia to drive inflammation that leads to synaptic loss and impaired brain function. Using the endovascular perforation model of SAH in rats, we investigated short-term effects on microglia together with long-term effects on EEG and neurologic function for up to 3 months. Within the first week, microglia were increased both at the site of injury and diffusely across the cortex (2.5-fold increase in SAH compared to controls, p = 0.012). Concomitantly, EEGs from SAH animals showed focal increases in slow wave activity and diffuse reduction in fast activity. When expressed as a fast-slow spectral ratio, there were significant interactions between group and time (p < 0.001) with less ipsilateral recovery over time. EEG changes were most pronounced during the first week and correlated with neurobehavioral impairment. In vitro, the blood product hemin was sufficient to increase microglia phagocytosis nearly six-fold (p = 0.032). Immunomodulatory treatment with fingolimod after SAH reduced microglia, improved neurological function, and increased survival. These findings, which parallel many of the EEG changes seen in patients, suggest that targeting neuroinflammation could reduce long-term neurologic dysfunction following SAH.

Preoperative cognitive function as a risk factor of postoperative delirium in cancer surgeries: A systematic review and meta-analysis.

Postoperative delirium (POD) after cancer surgeries can be a result of chemo brain, anesthesia, surgery duration, and preoperative cognitive impairment. Although older age and preoperative cognitive dysfunction were reported to increase the risk of POD in noncardiac surgery, the role of preoperative cognitive function and age in the development of POD after all types of cancer surgeries is not clear. This study aimed to determine the relationship between preoperative cognitive function and likelihood of POD after cancer surgeries. This study used three main online databases and followed PRISMA guidelines. English language original articles that examined preoperative cognitive function before solid tumor cancer surgery and assessed patients for postoperative delirium were included. We employed the random effect meta-analysis method. The overall incidence of POD ranged from 8.7% to 50.9%. The confusion assessment method was the most common tool used to assess delirium. Mini-mental state evaluation (MMSE), Mini-cog, and Montreal cognitive assessment were the most common tools to assess cognitive function. The pooled (total observation = 4676) random effects SMD was estimated at -0.84 (95% confidence interval [CI]: -1.30 to -0.31), indicating that lower MMSE scores before surgery are associated with a higher risk of POD. The pooled (total observation = 2668) random effects OR was estimated at 5.17 (95% CI: 2.51 to -10.63), indicating preoperative cognitive dysfunction can significantly predict the occurrence of POD after cancer surgeries. In conclusion, preoperative cognitive function is an independent and significant predictor of POD after solid tumor cancer surgeries.

Comprehensive examination of resting state fMRI connectomics yields new insights into brain function deficits in Gulf War illness after accounting for heterogeneity in brain impairment across the ill veteran population

An estimated 200,000 veterans (up to 32% of those deployed) of the 1991 Gulf War (GW) suffer from GW illness (GWI), an incompletely understood chronic medical condition, characterized by multiple symptoms indicative of brain function deficits in various domains. Epidemiologic and animal studies have associated GWI with exposure to neurotoxic chemicals such as nerve agents, organophosphate pesticides and pyridostigmine bromide. One factor that hampers mechanistic investigations into GWI is that there is considerable heterogeneity in brain impairments across the ill GW veteran population. This could reflect the underlying heterogeneity in both exposure to neurotoxic substances, as well as genetic predisposition or resistance to neurotoxicity. Only one of the validated case definitions, the Haley GWI criteria addresses this heterogeneity. It does so by breaking down GWI into three main syndrome variants (GWS1, GWS2, and GWS3) based on factor analysis of symptoms presented by GWI veterans. Resting state fMRI (rsfMRI) is a uniquely useful brain imaging technique in that in a 10-min fMRI scan it can probe numerous brain function domains simultaneously. In this study, we employed a connectomics approach and machine learning on rsfMRI data from a cohort of GW veterans to extract neuroimaging biomarkers specific to each of the three Haley GWI syndromes. Our results revealed a number of new insights into brain function impairment specific to each syndrome group. The findings indicate that these deficits may by and large be driven by brain mechanisms. We also found that pooling the data of all three syndromes in GWI group, as is done by commonly employed case definitions of GWI resulted in failure to detect the fMRI signatures of a lot of these brain impairments.

Characterisation of ciclesonide metabolism in human placentae across gestation

IntroductionCurrent clinical management of pregnancies at risk of preterm delivery includes maternal antenatal corticosteroid (ACS) treatment. ACS activate the glucocorticoid receptor (GR) in all fetal tissues, maturing the lungs at the cost of impaired brain development, creating a need for novel treatments. The prodrug ciclesonide (CIC) activates the GR only when converted to des-CIC by specific enzymes, including acetylcholinesterase (ACHE) and carboxylesterase 1 and 2 (CES1, CES2). Importantly, the human placenta expresses ACHE and CES, and could potentially produce des-CIC, resulting in systemic fetal exposure and GR activation in all fetal tissues. We therefore investigated CES gene expression and conversion of CIC to des-CIC in human placentae collected during the second trimester (Tri2), and at preterm and term birth. MethodsDifferential expression analysis was performed in Tri2 (n = 27), preterm (n = 34), and term (n = 40) placentae using the DESeq2 R-package. Conversion of CIC to des-CIC was measured in a subset of placenta samples (Tri2 n = 7, preterm n = 26, term n = 20) using functional assays. ResultsACHE mRNA expression was higher in Tri2 male than preterm and term male placentae only, whereas CES1 mRNA expression was higher in Tri2 than preterm or term placentae of both sexes. Conversion of CIC to des-CIC did not differ between gestational ages. DiscussionConversion of CIC to des-CIC by the human placenta may preclude its use as a novel GR-agonist in threatened preterm birth. In vivo studies are required to confirm the extent to which placental activation occurs after maternal treatment.

Tackling Brain and Muscle Dysfunction in Acute Respiratory Distress Syndrome Survivors: NHLBI Workshop Report.

Acute respiratory distress syndrome (ARDS) is associated with long-term impairments in brain and muscle function that significantly impact the quality of life of those who survive the acute illness. The mechanisms underlying these impairments are not yet well understood, and evidence-based interventions to minimize the burden on patients remain unproved. The NHLBI of the NIH assembled a workshop in April 2023 to review the state of the science regarding ARDS-associated brain and muscle dysfunction, to identify gaps in current knowledge, and to determine priorities for future investigation. The workshop included presentations by scientific leaders across the translational science spectrum and was open to the public as well as the scientific community. This report describes the themes discussed at the workshop as well as recommendations to advance the field toward the goal of improving the health and well-being of ARDS survivors.

Annular Conductive Hydrogel-Mediated Wireless Electrical Stimulation for Augmenting Neurogenesis.

Electrical stimulation (ES) has a remarkable capacity to regulate neuronal differentiation and neurogenesis in the treatment of various neurological diseases. However, wired devices connected to the stimulating electrode and the mechanical mismatch between conventional rigid electrodes and soft tissues restrict their motion and cause possible infections, thereby limiting their clinical utility. An approach integrating the advantages of wireless techniques and soft hydrogels provides new insights into ES-induced nerve regeneration. Herein, a flexible and implantable wireless ES-responsive electrode based on an annular gelatin methacrylate-polyaniline (Gel/Pani) hydrogel is fabricated and used as a secondary coil to achieve wireless ES via electromagnetic induction in the presence of a primary coil. The Gel/Pani hydrogels exhibit favorable biocompatibility, biodegradability, conductivity, and compression resistance. The annular electrode of the Gel/Pani conductive hydrogel (AECH) supports neural stem cell growth, while the applied wireless ES facilitates neuronal differentiation and the formation of functional neural networks in vitro. Furthermore, AECH is implanted in vivo in rats with ischemic stroke and the results reveal that AECH-mediated wireless ES significantly ameliorates brain impairment and neurological function by activating endogenous neurogenesis. This novel flexible hydrogel system addresses wireless stimulation and implantable technical challenges, holding great potential for the treatment of neurodegenerative diseases.