Cerebral Changes Research Articles

Variability of day-to-day pulsatility index change in children with cerebral malaria

IntroductionCerebral malaria (CM) is a devastating disease and better understanding of etiologies of the resulting neurologic injury is needed. The purpose of this study is to describe the day-to-day (DTD) pulsatility index (PI) change measured by transcranial Doppler ultrasound (TCD), a novel measure of cerebral and vascular changes, in children with CM.MethodsA retrospective analysis of 122 children in sub-Saharan Africa with CM and 3 or more sequential TCD measurements was performed. Variability of DTD PI change was calculated as a measure of changes in vasculature overtime. Neurologic outcome was determined by the Pediatric Cerebral Performance Category (PCPC) score, a measure of neurologic function.ResultsOf the 122 participants, 77.9% had a good neurologic outcome (no neurologic sequelae), and 22.1% had a poor outcome (neurologic sequelae or died). Patients who had a poor neurologic outcome had higher levels of variability of DTD PI change in the right middle cerebral artery (MCA) (0.14 ± 0.21) and left MCA (0.17 ± 0.41) compared to those who had a good neurologic outcome (0.1 ± 0.1 and 0.11 ± 0.19, respectively). A higher variability of both left and right MCA DTD PI change was also associated with higher brain volume assessed through neuroimaging.DiscussionVariability of DTD PI change may provide early prognostic information regarding PCPC outcomes and brain volume changes seen in CM patients. Expanded research on pathophysiologic contributors to variability of DTD PI changes in children with CM is warranted.

The cerebral and cognitive changes after intermittent theta burst stimulation (iTBS) treatment for depression: study protocol for a randomized double-blind sham-controlled trial.

The therapeutic use of intermittent theta burst stimulation (iTBS) delivered to the left dorsolateral prefrontal cortex (LDLPFC) is a relatively new but promising treatment option for depression. There is a need for more knowledge on the mechanisms involved in its antidepressant effects. This is a single-centre, prospective, randomized, double-blind, placebo-controlled trial with two arms, iTBS and sham iTBS. Adult outpatients with unipolar major depressive disorder of at least moderate severity will undergo cognitive assessment with an N-back task (0-back and 2-back), functional and structural magnetic resonance imaging and assessment of depression severity before and after brain stimulation. Neuronavigated iTBS or sham stimulation will be targeted at the LDPFC once a day for 10 consecutive workdays. ITBS will be delivered with the parameters 120% of resting motor threshold, triplet 50Hz bursts repeated at 5Hz; 2s on and 8s off, 600 pulses per session with a total duration of 3min 9s. The severity of depression will be measured with the Montogomery Aasberg Depression Rating Scale and the Beck Depression Inventory - second edition. In the iTBS group relative to sham, we expect significant antidepressant effects and improved N-back performance, associated with increased integrity in white matter tracts functionally connected with the LDLPFC and emotion regulation areas within the rostral anterior cingulate cortices, alongside potential increases in cortical thickness in these regions. On functional imaging, we expect to observe increased brain activity in the LDPFC during the performance of the N-back condition with higher cognitive load (2-back) in the iTBS group relative to sham. iTBS is a promising, time-efficient, and considered a safe treatment option for depression according to existing evidence. This trial aims to assess the neurocognitive impact of a 2-week, once-daily iTBS compared to sham iTBS, targeting the LDLPFC in depressed adult outpatients. The study investigates the relationships between changes in cerebral measures and cognitive performance on an N-back task in relation to the antidepressant effect following iTBS. This trial delves into the neurocognitive mechanisms of iTBS in depression, potentially offering novel scientific insights into its treatment effects and mechanisms of action. ClinicalTrials.gov NCT06534684. Retrospectively registered on August 1st 2024.

Magnetic resonance diffusion tensor imaging for detecting the cerebral microstructure changes in patients with CSVD -induced mild cognitive impairment.

Cerebral small vessel disease (CSVD)-induced mild cognitive impairment (MCI) has been linked to cognitive decline. Brain atrophy is considered the most common change in MCI patients, which can be measured by diffusion tensor imaging (DTI). The study aimed to explore the relationship between DTI parameters and cognitive function in CSVD patients with MCI. This retrospective analysis involved 185 patients with CSVD, comprising 87 cases with MCI and 98 cases without MCI (NMCI). Analyses of demographic and clinical characteristics were conducted. DTI-measured fractional anisotropy (FA) and mean diffusivity (MD) in the hippocampus and entorhinal cortex regions were examined. The diagnostic values were determined using receiver-operative-curve (ROC) analysis, with the Youden Index identifying optimum sensitivity and specificity. Correlations between Montreal cognitive assessment (MoCA) scores and FA or MD in MCI patients were further assessed. No significant differences were observed in demographic and clinical characteristics between MCI and NMCI groups (all p>0.05), except for diabetes prevalence (p=0.011). Notably, the ROC analysis highlighted the diagnostic potential of FA, showing the maximum area under the curve values (Hippocampus-Left: 0.76; Hippocampus-Right: 0.66; Entorhinal cortex-Left: 0.62; Entorhinal cortex-Right: 0.64). MD exhibited a significant negative correlation with MoCA scores (Hippocampus-Left: r=-0.58, p<0.001; Hippocampus-Right: r=-0.41, p<0.001; Entorhinal cortex-Left: r=-0.49, p<0.001; Entorhinal cortex-Right: r=-0.27, p<0.001), while FA showed a significant positive correlation (Hippocampus-Left: r=0.51, p<0.001; Hippocampus-Right: r=0.31, p=0.004; Entorhinal cortex-Left: r=0.35, p<0.001; Entorhinal cortex-Right: r=0.38, p<0.001). The study demonstrates the diagnostic value of DTI parameters in CSVD patients with MCI, emphasizing the associations between microstructural brain changes and cognitive function.

Effect of Controlled Expiratory Pressures on Cerebrovascular Changes During Valsalva Maneuver

This study aimed to investigate the effects of Valsalva maneuver (VM) with the controlled expiratory pressures on vascular stiffness of common carotid artery (CCA) and cerebral hemodynamic changes using diagnostic ultrasonography. Twenty-seven healthy participants (mean and standard deviation of age = 22.78 ± 1.89) performed 30 and 40 mmHg VM. The right CCA stiffness index and pulse wave velocity (PWV) were measured before (PRE) and after (POST) VM. The peak systolic velocity (PSV), resistance index (RI), and heart rate (HR) were measured before (PRE) and after (POST1 and POST2 during the first and the second 15 s, respectively) VM. Near-infrared spectroscopy (NIRS) was utilized to measure regional oxygen saturation (rSO2) and oxyhemoglobin (HbO) on the left and right prefrontal cortex. Stiffness index decreased by 1.76 (p &lt; 0.001) from PRE to POST only after 30 mmHg VM. PWV decreased by 0.69 m/s (p &lt; 0.001, 30 mmHg) and 0.34 m/s (p = 0.022, 40 mmHg) in POST. Conversely, PSV increased by 5.36 cm/s (p = 0.031, 30 mmHg) and 4.77 cm/s (p = 0.04, 40 mmHg) in POST2. Increase in RI (p = 0.017) and decrease in HR (p = 0.003) occurred only after the 40 mmHg VM. Right HbO decreased after 30 mmHg VM (p = 0.023) from PRE to POST1, and right rSO2 increased after 40 mmHg VM (p = 0.036) from VM (during) to POST1. Both 30 and 40 mmHg VM showed a significant improvement in PWV and an increase in PSV. However, at 30 mmHg VM, a significant decrease in HbO was observed after VM owing to increased cerebral oxygen exchange, and at 40 mmHg VM, an rSO2 increase was observed after VM owing to high vascular pressure. Additionally, the increased pressure and rSO2 at 40 mmHg may have been caused by increased RI. The results indicated that the 30 mmHg VM was more effective on CCA stiffness than the 40 mmHg VM.

Effects of different endovascular treatments on cerebral perfusion changes and stroke recurrence in patients with intracranial atherosclerosis.

In patients with refractory intracranial atherosclerotic disease (ICAD), percutaneous transluminal balloon angioplasty (PTBA) is less complex but typically results in higher postprocedural residual stenosis than percutaneous transluminal angioplasty with stenting (PTAS). This study included patients with symptomatic ICAD with 70-99% stenosis treated with either PTBA or PTAS. All patients underwent preprocedural and postprocedural CT perfusion, which was processed by automated RAPID software. The rate of cerebral perfusion change was defined as the ratio of the volume of perfusion change to the preprocedural perfusion volume. Perioperative complications within a 30-day follow-up period were documented. Baseline characteristics, degree of stenosis before and after procedures, perioperative complications, and the rates of cerebral perfusion change were compared between groups. Patients were followed up for stroke recurrence within 1 year postprocedure, with survival analysis used to examine the relationship between procedure type and recurrence. Between March and December 2021, 107 patients were enrolled: 30 (28.0%) were treated with PTBA and 77 (72.0%) with percutaneous transluminal angioplasty with stenting (PTAS). The PTBA group showed higher postprocedural residual stenosis than the PTAS group (P<0.004). The cerebral perfusion change rates were not significantly different between the groups (P=0.891). Three (3.9%) complications occurred in the PTAS group and none in the PTBA group during the 30-day follow-up. Stroke recurrence did not significantly differ between the procedures (P=0.960). Immediate cerebral perfusion changes and the rate of stroke recurrences have no significant difference between the two groups.

Sleep quality and the integrity of ascending reticular activating system – A multimodal MRI study

Sleep is crucial for maintaining brain homeostasis and individuals with insufficient sleep are prone to more pronounced brain atrophy as compared to sufficiently sleeping peers. Moreover, sleep quality deteriorates with ageing and ageing is also associated with cerebral structural and functional changes, pointing to their mutual bidirectional interrelationship. This study aimed at determining whether sleep quality and age, separately, affect brain integrity and subsequently, whether sleep significantly modulates the effect of age on brain structural and functional integrity. 113 healthy volunteers underwent a multi-modal MRI imaging to extract information about the microstructure and function of major nodes of the ascending reticular activating system. Sleep quality was assessed by self-administered Pittsburgh's sleep quality index (PSQI) questionnaire. Subject were divided into good (global PSQI score <5) and poor (global PSQI score ≥5) sleep quality group. Whereas only borderline correlations were found between sleep quality and MRI metrics, age exhibited widespread correlations with both functional and microstructural MRI metrics. The latter effect was significantly modulated by sleep quality in ascending reticular activating system, hypothalamus, thalamus and also hippocampus in MRI metrics associated with iron load, cellularity and connectivity, mainly in the subgroup with poor sleep quality. Ergo, our results indicate sleep quality as a substantial contributor to both microstructural and functional brain changes in ageing and call for further research in this emerging topic.

Phase-contrast MRI analysis of cerebral blood and CSF flow dynamic interactions

BackgroundFollowing the Monro-Kellie doctrine, the Cerebral Blood Volume Changes (CB_VC) should be mirrored by the Cerebrospinal Fluid Volume Changes (CSF_VC) at the spinal canal. Cervical level is often chosen to estimate CB_VC during the cardiac cycle. However, due to the heterogeneity in the anatomy of extracranial internal jugular veins and their high compliance, we hypothesize that the intracranial level could be a better choice to investigate blood and cerebrospinal fluid (CSF) interactions. This study aims to determine which level, intracranial or extracranial, is more suitable for measuring arterial and venous flows to study cerebral blood and CSF dynamics interactions.MethodsThe spinal CSF and cerebral blood flow measured at intracranial and extracranial levels were quantified using cine phase-contrast magnetic resonance imaging (PC-MRI) in 38 healthy young adults. Subsequently, CSF_VC and CB_VC were calculated, and by linear regression analysis (R2 and slope), the relationship between CB_VC at both levels and the spinal CSF_VC was compared. The differences between extracranial and intracranial measurements were assessed using either a paired Student’s t-test or Wilcoxon’s test, depending on the normality of the data distribution.ResultsThe CB_VC amplitude was significantly higher at the extracranial level (0.89 ± 0.28 ml/CC) compared to the intracranial level (0.73 ± 0.19 ml/CC; p < 0.001). CSF oscillations through the spinal canal do not completely balance blood volume changes. The R2 and the slope values obtained from the linear regression analysis between CSF and blood flows were significantly higher in magnitude for the intracranial CB_VC (R2: 0.82 ± 0.16; slope: − 0.74 ± 0.19) compared to the extracranial CB_VC (R2: 0.47 ± 0.37; slope: -0.36 ± 0.33; p < 0.001). Interestingly, extracranial CB_VC showed a greater variability compared to intracranial CB_VC.ConclusionOur results confirmed that CSF does not completely and instantaneously balance cerebral blood expansion during the cardiac cycle. Nevertheless, the resting volume is very small compared to the total intracranial volume. To our knowledge, this study is the first to demonstrate these findings using cerebral blood flow measured intracranially below the Circle of Willis. Additionally, our findings show that cerebral arterial and venous flow dynamic measurements during the cardiac cycle obtained by PC-MRI at the intracranial plane strongly correlate with CSF oscillations measured in the spinal canal. Therefore, the intracranial vascular plane is more relevant for analyzing cerebral blood and CSF interactions during the cardiac cycle compared to measurements taken at the cervical vascular level.

A lumped parameter modelling study of cerebral autoregulation in normal pressure hydrocephalus suggests the brain chooses to be ischemic

Normal pressure hydrocephalus (NPH) is associated with a reduction in cerebral blood flow and an ischemic metabolic state. Ischemia should exhaust the available autoregulation in an attempt to correct the metabolic imbalance. There is evidence of some retained autoregulation reserve in NPH. The aim of this study is to model the cerebral autoregulation in NPH to discover a solution to this apparent paradox. A lumped parameter model was developed utilizing the known limits of autoregulation in man. The model was tested by predicting the cerebral blood volume changes which would be brought about by changes in resistance. NPH and the post shunt state were then modeled using the known constraints provided from the literature. The model successfully predicted the cerebral blood volume changes brought about by altering the cerebral perfusion pressure to the limit of autoregulation. The model suggests that NPH is associated with a balanced increase in resistance within the arterial and venous outflow segments. The arterial resistance decreased after modelling shunt insertion. The model suggests that the cerebral blood flow is actively limited in NPH by arteriolar constriction. This may occur to minimize the rise in ICP by reducing the apparent CSF formation rate.

Age-related cerebral changes during different n-back tasks: a functional near-infrared spectroscopy study.

The n-back task is a widely used paradigm to assess working memory and is commonly applied in research on age-related cognitive decline. However, studies utilizing functional near-infrared spectroscopy (fNIRS) to explore this area are limited. This study aims to investigate age-related differences in brain activation during the n-back task using fNIRS. fNIRS data were collected from 18 elderly and 19 young participants while performing different n-back tasks. Brain activation patterns and peripheral performance were compared between the two groups. Significant differences in brain activation patterns were observed between elderly and young participants. Under the 3-back condition, the older group exhibited reduced activation in brain regions adjacent to prefrontal cognitive areas compared to the younger group. Additionally, the older group's performance plateaued at the 2-back level, along with a decline in prefrontal activation. These findings may suggest potential markers for cognitive decline, providing a new target for future screening.

Predicting cerebral edema in patients with spontaneous intracerebral hemorrhage using machine learning.

The early prediction of cerebral edema changes in patients with spontaneous intracerebral hemorrhage (SICH) may facilitate earlier interventions and result in improved outcomes. This study aimed to develop and validate machine learning models to predict cerebral edema changes within 72 h, using readily available clinical parameters, and to identify relevant influencing factors. An observational study was conducted between April 2021 and October 2023 at the Quzhou Affiliated Hospital of Wenzhou Medical University. After preprocessing the data, the study population was randomly divided into training and internal validation cohorts in a 7:3 ratio (training: N = 150; validation: N = 65). The most relevant variables were selected using Support Vector Machine Recursive Feature Elimination (SVM-RFE) and Least Absolute Shrinkage and Selection Operator (LASSO) algorithms. The predictive performance of random forest (RF), GDBT, linear regression (LR), and XGBoost models was evaluated using the area under the receiver operating characteristic curve (AUROC), precision-recall curve (AUPRC), accuracy, F1-score, precision, recall, sensitivity, and specificity. Feature importance was calculated, and the SHapley Additive exPlanations (SHAP) and Local Interpretable Model-Agnostic Explanations (LIME) methods were employed to explain the top-performing model. A total of 84 (39.1%) patients developed cerebral edema changes. In the validation cohort, GDBT outperformed LR and RF, achieving an AUC of 0.654 (95% CI: 0.611-0.699) compared to LR of 0.578 (95% CI, 0.535-0.623, DeLong: p = 0.197) and RF of 0.624 (95% CI, 0.588-0.687, DeLong: p = 0.236). XGBoost also demonstrated similar performance with an AUC of 0.660 (95% CI, 0.611-0.711, DeLong: p = 0.963). However, in the training set, GDBT still outperformed XGBoost, with an AUC of 0.603 ± 0.100 compared to XGBoost of 0.575 ± 0.096. SHAP analysis revealed that serum sodium, HDL, subarachnoid hemorrhage volume, sex, and left basal ganglia hemorrhage volume were the top five most important features for predicting cerebral edema changes in the GDBT model. The GDBT model demonstrated the best performance in predicting 72-h changes in cerebral edema. It has the potential to assist clinicians in identifying high-risk patients and guiding clinical decision-making.

Assessment Of Neuroradiological Features Of Wolfram Syndrome

The WOLFRAM syndrome is a rare hereditary neurodegenerative disorder described for the first time in 1938 as the coexistence of a diabetes mellitus and optic atrophy to which join frequently a diabetes insipidus and a bilateral deafness. Here we report cranial MRI findings in a 20 year old patient who presented with diabetes mellitus, decreased visual loss since 3 years with progressive loss of hearing since 6 months. We reviewed the brain MR images to determine the frequency and characteristics of common neuroradiologic findings. Imaging findings include absence of the normal high signal of the neurohypophysis, atrophy of visual pathways, the brainstem, cerebellum and cerebral cortex and abnormal signal changes in pons

Cerebral cortex changes in FD, IBS, and GERD: A Mendelian randomization study

BackgroundProspective and cross-sectional studies have reported an association between functional gastrointestinal disorders and anxiety and depression. However, the causal relationship is unclear. Therefore, we used Mendelian randomization (MR) to determine the causal effects of common gastrointestinal disorders on cortical structures. MethodsGenome-wide association study (GWAS) data for functional dyspepsia (FD), irritable bowel syndrome (IBS), and gastroesophageal reflux disease (GERD) were obtained from 329,262, 16,792, and 602,604 Europeans, respectively. GWAS cerebral cortical architecture data for cortical thickness (TH) and surface area (SA) were obtained from 51,665 MRI scans. MR was used to analyze the casual relationship between FD, IBS, GERD, and cortical structures. Inverse-variance weighted, weighted median, and MR–Egger tests were performed as assessment indicators. We also evaluated heterogeneity and pleiotropy. ResultsThe results revealed that FD significantly decreases the TH in the rostral anterior cingulate cortex (βTH = −0.022 mm; 95%CI: −0.035 mm to −0.009 mm2; PTH = 6.89 × 10−4), and IBS significantly decreases the SA of the pars triangularis (βSA = −21.91 mm2; 95%CI: −32.99 mm to −10.83 mm2; PSA = 1.06 × 10−4), precuneus (βSA = −47.53 mm2; 95%CI: −73.57 mm to-21.48 mm2; PSA = 3.48 × 10−4) and superior frontal regions (βSA = −78.70 mm2; 95%CI: −122.61 mm to −34.78 mm2; PSA = 4.4 × 10−4). At the local functional level, GERD significantly increases the SA of the inferior temporal region (βSA = −113.58 mm2, 95%CI: −113.58 mm to −39.01 mm2, PSA = 6.05 × 10−5). ConclusionsFD, IBS and GERD can affect the cerebral cortex architecture through the brain-gut axis, thus increasing the risks of mental illness and cognitive dysfunction.

A narrative review of magnetic resonance imaging findings in pediatric idiopathic intracranial hypertension.

Idiopathic intracranial hypertension (IIH) is a rare neurological disorder in the pediatric population which is defined as an increase in intracranial pressure (ICP) without the presence of brain parenchymal lesions, hydrocephalus, or central nervous system infection. In this study, we have determined the magnetic resonance imaging (MRI) findings in IIH patients. A comprehensive literature search was conducted using the electronic databases including Web of Sciences, Scopus, and Pubmed to identify suitable and relevant articles using keyword search methods. The search included keywords such as "idiopathic intracranial hypertension," "pseudotumor cerebri," "MRI," and "pediatrics." The search was limited to the available publications up to January 2024. MRI plays a crucial role in diagnosing IIH by excluding secondary causes and revealing neuroimaging findings associated with elevated ICP. Despite fewer studies in children compared to adults, MRI serves as a cornerstone in identifying traditional neuroradiological markers such as empty sella turcica, posterior globe flattening, optic nerve tortuosity, optic nerve sheath distension, and transverse venous sinus stenosis. Additional subtle markers include increased Meckel's cave length, cerebellar tonsillar herniation, and slit-like ventricles, although these are less reliable. Diffusion-weighted imaging does not typically show cerebral ADC value changes indicative of cerebral edema in pediatric IIH. MRI findings provide valuable non-invasive diagnostic indicators that facilitate early detection, clinical management, and potential surgical intervention in pediatric IIH. The reliability of these MRI markers underscores their importance in clinical practice.

Cerebral small vessel injury in mice with damage to ACE2-expressing cerebral vascular endothelial cells and post COVID-19 patients.

The angiotensin-converting enzyme 2 (ACE2), which is expressed in cerebral vascular endothelial cells (CVECs), has been currently identified as a functional receptor for SARS-CoV-2. We specifically induced injury to ACE2-expressing CVECs in mice and evaluated the effects of such targeted damage through magnetic resonance imaging (MRI) and cognitive behavioral tests. In parallel, we recruited a single-center cohort of COVID-19 survivors and further assessed their brain microvascular injury based on cognition and emotional scales, cranial MRI scans, and blood proteomic measurements. Here, we show an array of pathological and behavioral alterations characteristic of cerebral small vessel disease (CSVD) in mice that targeted damage to ACE2-expressing CVECs, and COVID-19 survivors. These CSVD-like manifestations persist for at least 7 months post-recovery from COVID-19. Our findings suggest that SARS-CoV-2 may induce cerebral small vessel damage with persistent sequelae, underscoring the imperative for heightened clinical vigilance in mitigating or treating SARS-CoV-2-mediated cerebral endothelial injury throughout infection and convalescence. Cerebral small vessel disease-associated changes were observed after targeted damage to angiotensin-converting enzyme 2-expressing cerebral vascular endothelial cells. SARS-CoV-2 may induce cerebral small vessel damage with persistent sequelae. Clinical vigilance is needed in preventing SARS-CoV-2-induced cerebral endothelial damage during infection and recovery.

Tentative Causes of Brain and Neuropsychological Alterations in Women Victims of Intimate Partner Violence.

Victims of Intimate Partner Violence Against Women (IPVAW) experience neuropsychological and cerebral changes, which have been linked to several tentative causal mechanisms, including elevated cortisol levels, psychopathological disorders, traumatic brain injury (TBI), hypoxic/ischemic brain damage, and medical conditions related to IPVAW. While these mechanisms and their effects on brain function and neuropsychological health are well-documented in other clinical populations, they manifest with unique characteristics in women affected by IPVAW. Specifically, IPVAW is chronic and repeated in nature, and mechanisms are often cumulative and may interact with other comorbid conditions. Thus, in light of existing literature on neuropsychological alterations in other populations, and recognizing the distinct features in women who experience IPVAW, we propose a new theoretical model-the Neuro-IPVAW model. This framework aims to explain the complex interplay between these mechanisms and their impact on cognitive and brain health in IPVAW victims. We anticipate that this theoretical model will be valuable for enhancing our understanding of neuropsychological and brain changes related to intimate partner violence, identifying research gaps in these mechanisms, and guiding future research directions in this area.

Altered structure and functional connection of subcortical gray matter in female patients with classical trigeminal neuralgia.

The etiology of classical trigeminal neuralgia (CTN) is still unclear. A better understanding of the cerebral structural and functional changes in female patients with CTN may provide important novel insights into the pathophysiologic mechanisms of female CTN. A total 37 female CTN patients were included and referred to MRI scans, comprising with 19 left CTN and 18 right CTN patients. We analyzed the volume and shape of subcortical gray matter (GM), and the functional connectivity (FC) between the accumbens nucleus (NAc) and whole brain in right and left CTN patients respectively. We found left CTN patients had a reduced right NAc volume compared to controls, similarly, the right CTN had the decreased volume in the left NAc. Vertex-wise shapes of right NAc in left CTN patients showed significant regional shape deformation on the anterior, medial and ventroposterior aspects, in contrast, left NAc of right CTN patients showed significant regional shape deformation on the anterior and posterior aspect. Furthermore, patients with left CTN showed significantly lower FC between the right NAc and right orbitofrontal cortex than control subjects. The volume of NAc in all CTN was significantly related to the perception of present pain intensity. The CTN might be majorly caused by volume reduction in NAc. A greater understanding of the neurobiological basis of pain-related changes in NAc will provide the knowledge for the development of novel NAc based therapeutic targets for pain management or even prevention in CTN patients.

Human iPSC-derived pericyte-like cells carrying APP Swedish mutation overproduce beta-amyloid and induce cerebral amyloid angiopathy-like changes

BackgroundPatients with Alzheimer's disease (AD) frequently present with cerebral amyloid angiopathy (CAA), characterized by the accumulation of beta-amyloid (Aβ) within the cerebral blood vessels, leading to cerebrovascular dysfunction. Pericytes, which wrap around vascular capillaries, are crucial for regulating cerebral blood flow, angiogenesis, and vessel stability. Despite the known impact of vascular dysfunction on the progression of neurodegenerative diseases, the specific role of pericytes in AD pathology remains to be elucidated.MethodsTo explore this, we generated pericyte-like cells from human induced pluripotent stem cells (iPSCs) harboring the Swedish mutation in the amyloid precursor protein (APPswe) along with cells from healthy controls. We initially verified the expression of classic pericyte markers in these cells. Subsequent functional assessments, including permeability, tube formation, and contraction assays, were conducted to evaluate the functionality of both the APPswe and control cells. Additionally, bulk RNA sequencing was utilized to compare the transcriptional profiles between the two groups.ResultsOur study reveals that iPSC-derived pericyte-like cells (iPLCs) can produce Aβ peptides. Notably, cells with the APPswe mutation secreted Aβ1-42 at levels ten-fold higher than those of control cells. The APPswe iPLCs also demonstrated a reduced ability to support angiogenesis and maintain barrier integrity, exhibited a prolonged contractile response, and produced elevated levels of pro-inflammatory cytokines following inflammatory stimulation. These functional changes in APPswe iPLCs correspond with transcriptional upregulation in genes related to actin cytoskeleton and extracellular matrix organization.ConclusionsOur findings indicate that the APPswe mutation in iPLCs mimics several aspects of CAA pathology in vitro, suggesting that our iPSC-based vascular cell model could serve as an effective platform for drug discovery aimed to ameliorate vascular dysfunction in AD.

B - 41 Mild Head Injury (MHI), Unrelated Abnormal Brain Findings, Collateral Support, Video EEG and Neuropsychological Findings: a Case Study of Functional Seizure Disorder

Abstract Objective Functional seizure disorders, a form of conversion disorder with contributing biological, psychological, and social factors, pose a differential diagnostic challenge. Integrating video EEG, CT Brain Scan, collateral support and neuropsychological findings in diagnosis is discussed. Method The absence of epileptiform activity in video-EEG distinguishes functional and epileptic seizures. A case study is presented of a young adult male who sustained a MHI in a motor vehicle accident, presenting with a seizure disorder two weeks thereafter. Twenty-four-hour video EEG using photic stimulation revealed grunting sounds, head extension, clenched hands, back arching, jerking with associated paradoxical heavy breathing (shown in video clip), similar to family eyewitness descriptions. Hyperventilation was associated with generalized slowing. No epileptiform activity was noted. Unenhanced CT Brain Scan revealed global symmetrical age-incongruent cerebral involutional change. Results Neuropsychological assessment using CNS Vital Signs Test revealed variable scores, with “very low” scores on Complex Attention (raw score 17; SS = 68; 2nd Percentile); Cognitive Flexibility (raw score 28; SS =66; 1st percentile) and Processing Speed (raw score = 38; SS = 67; 1st percentile). “Above average” scores were found for Composite Memory (raw score 107; SS = 113; 81st percentile) and Verbal Memory (raw score = 59; SS = 122; 93rd percentile). Conclusions Brain involutional changes suggest pre-existing functional immaturity, instability of brain regions, or reduced neural connections may precede the diagnosis of Functional Seizure Disorders, precipitated by the MHI. In addition to video EEG, selected neuropsychological findings and collateral information provide additional support to confirm this complex disorder.

Loss of the APP regulator RHBDL4 preserves memory in an Alzheimer's disease mouse model.

Characteristic cerebral pathological changes of Alzheimer's disease (AD) such as glucose hypometabolism or the accumulation of cleavage products of the amyloid precursor protein (APP), known as Aβ peptides, lead to sustained endoplasmic reticulum (ER) stress and neurodegeneration. To preserve ER homeostasis, cells activate their unfolded protein response (UPR). The rhomboid-like-protease 4 (RHBDL4) is an enzyme that participates in the UPR by targeting proteins for proteasomal degradation. We demonstrated previously that RHBLD4 cleaves APP in HEK293T cells, leading to decreased total APP and Aβ. More recently, we showed that RHBDL4 processes APP in mouse primary mixed cortical cultures as well. Here, we aim to examine the physiological relevance of RHBDL4 in the brain. We first found that brain samples from AD patients and an AD mouse model (APPtg) showed increased RHBDL4 mRNA and protein expression. To determine the effects of RHBDL4's absence on APP physiology in vivo, we crossed APPtg mice to a RHBDL4 knockout (R4-/-) model. RHBDL4 deficiency in APPtg mice led to increased total cerebral APP and amyloidogenic processing when compared to APPtg controls. Contrary to expectations, as assessed by cognitive tests, RHBDL4 absence rescued cognition in 5-month-old female APPtg mice. Informed by unbiased RNAseq data, we demonstrated in vitro and in vivo that RHBDL4 absence leads to greater levels of active β-catenin due to decreased proteasomal clearance. Decreased β-catenin activity is known to underlie cognitive defects in APPtg mice and AD. Our work suggests that RHBDL4's increased expression in AD, in addition to regulating APP levels, leads to aberrant degradation of β-catenin, contributing to cognitive impairment.

Abstract 55: Mouse Offspring Exposed to Preeclampsia/Eclampsia-like Symptoms Exhibit Changes in Regional Cerebral Perfusion at 2 months of age

Children born to mothers with preeclampsia, a hypertensive pregnancy disorder, or eclampsia, new-onset seizures during pregnancy, are more likely to develop learning and memory deficits and are more susceptible to neurovascular diseases compared to those born from normal pregnancies. The contributing mechanisms are unknown. The objective of this study was to determine whether mice exposed to reduced uteroplacental perfusion (RUPP), to mimic preeclampsia with or without pentylenetetrazol (PTZ) injection (to induce seizures and model eclampsia), results in regional cerebral perfusion changes at 2 months of age. On gestational day (GD) 13.5, pregnant C57BL/6 mice underwent sham or RUPP surgery followed by injection or no treatment with PTZ (40 mg/kg) on GD 18.5. At 2 months of age, cerebral perfusion was measured using Laser Speckle Imaging, and averaged to obtain mean data per sex, per litter (n = 3-6 average datapoints per group). Perfusion data were normalized to the area of each region of interest. Data were analyzed using Two-Way ANOVA. Our findings indicate a reduction in cerebral perfusion in offspring exposed indirectly to RUPP specifically of the right parietal cortex (p = 0.013), superior sagittal sinus (p = 0.003), cerebellum (p = 0.003) and whole brain (p = 0.021). We also observed an overall significant reduction in perfusion, after indirect PTZ exposure, in the right parietal cortex (p = 0.002), transverse sinus (p = 0.003), and cerebellum (p &lt; 0.001); and increase in prefrontal cortex perfusion (p = 0.001). Further observation showed an overall difference in hematocrit (p = 0.001), SPO2 (p &lt; 0.001), and cerebellum water content (p = 0.007) after indirect PTZ exposure. There was no difference in perfusion of the left parietal cortex, body weight, organ weight (except brain, where RUPP exposure led to overall increased brain weight; p = 0.030). Together, our results are consistent with the hypothesis that exposure to preeclampsia/eclampsia conditions leads to changes in offspring cerebrovascular function, with a net reduction in perfusion. Reduced cerebral perfusion is generally associated with reduced cognitive function. Whether this occurs along with changes in capillary density, or is exacerbated with age are areas of active investigation.