Alterations In Central Nervous System Research Articles

Cross-Sectional Brain-Predicted Age Differences in Community-Dwelling Middle-Aged and Older Adults with High Impact Knee Pain.

Knee OA-related pain varies in impact across individuals and may relate to central nervous system alterations like accelerated brain aging processes. We previously reported that older adults with chronic musculoskeletal pain had a significantly greater brain-predicted age, compared to pain-free controls, indicating an "older" appearing brain. Yet this association is not well understood. This cross-sectional study examines brain-predicted age differences associated with chronic knee osteoarthritis pain, in a larger, more demographically diverse sample with consideration for pain's impact. Participants (mean age = 57.8 ± 8.0 years) with/without knee OA-related pain were classified according to pain's impact on daily function (ie, impact): low-impact (n=111), and high-impact (n=60) pain, and pain-free controls (n=31). Participants completed demographic, pain, and psychosocial assessments, and T1-weighted magnetic resonance imaging. Brain-predicted age difference (brain-PAD) was compared across groups using analysis of covariance. Partial correlations examined associations of brain-PAD with pain and psychosocial variables. Individuals with high-impact chronic knee pain had significantly "older" brains for their age compared to individuals with low-impact knee pain (p < 0.05). Brain-PAD was also significantly associated with clinical pain, negative affect, passive coping, and pain catastrophizing (p's<0.05). Our findings suggest that high impact chronic knee pain is associated with an older appearing brain on MRI. Future studies are needed to determine the impact of pain-related interference and pain management on somatosensory processing and brain aging biomarkers for high-risk populations and effective intervention strategies.

Determining the neural sites of motor impairment in athletes with patellar tendinopathy

Introduction: Motor impairments are well documented in patellar tendinopathy, however the mechanisms underlying these impairments are poorly understood. Existing investigations for central nervous system alterations have focused on measures of net corticospinal excitability, or the activity of specific synaptic sites, in isolation. This study aimed to utilise a segmental approach, to enable greater understanding for cortical and spinal contributions to net corticospinal excitability in patellar tendinopathy.

Differences in the choroid plexus volume and microstructure are associated with body adiposity.

The choroid plexus (CP) is a cerebral structure located in the ventricles that functions in producing most of the brain’s cerebrospinal fluid (CSF) and transporting proteins and immune cells. Alterations in CP structure and function has been implicated in several pathologies including aging, multiple sclerosis, Alzheimer’s disease, and stroke. However, identification of changes in the CP remains poorly characterized in obesity, one of the main risk factors of neurodegeneration, including in the absence of frank central nervous system alterations. Our goal here was to characterize the association between obesity, measured by the body mass index (BMI) or waist circumference (WC) metrics, and CP microstructure and volume, assessed using advanced magnetic resonance imaging (MRI) methodology. This cross-sectional study was performed in the clinical unit of the National Institute on Aging and included a participant population of 123 cognitively unimpaired individuals spanning the age range of 22 – 94 years. Automated segmentation methods from FreeSurfer were used to identify the CP structure. Our analysis included volumetric measurements, quantitative relaxometry measures (T 1 and T 2), and the diffusion tensor imaging (DTI) measure of mean diffusivity (MD). Strong positive associations were observed between WC and all MRI metrics, as well as CP volume. When comparing groups based on the established cutoff point by the National Institutes of Health for WC, a modest difference in MD and a significant difference in T 1 values were observed between obese and lean individuals. We also found differences in T1 and MD between obese and overweight individuals as defined using the BMI cutoff. We conjecture that these observations in CP volume and microstructure are due to obesity-induced inflammation, diet, or, very likely, dysregulations in leptin binding and transport. These findings demonstrate that obesity is strongly associated with a decline in CP microstructural integrity. We expect that this work will lay the foundation for further investigations on obesity-induced alterations in CP structure and function.

Processing speed impairment in chronic inflammatory demyelinating polyneuropathy patients: a cross-sectional study.

There is a lack of evidence of cognitive involvement in chronic inflammatory demyelinating polyneuropathy (CIDP) and, the reports about the involvement of the brain and central nervous system (CNS) are few and controversial. The Five Digit Test (FDT) evaluates processing speed (PS) and executive functions orally. To evaluate the performance on the FDT of CIDP patients with and without CNS (brain/cerebellum) alterations observed on brain Magnetic Resonance Imaging (MRI) scans. The Hospital Anxiety and Depression Scale (HADS, to assess neuropsychiatry symptoms), the Rasch-built Overall Disability Scale (R-ODS; to assess disability), and the FDT (to assess cognition) were applied to 14 CIDP patients and 24 age-matched healthy control subjects. The patients were submitted to routine brain MRI and, according to the results, they were divided into two groups: those with abnormalities on the MRI (CIDPabnl) and those with normal parameters on the MRI (CIDPnl). The FDT data of five CIDPnl patients and nine CIDPabnl subjects were analyzed. Comparisons between the groups were performed for each task of the FDT. We found statistical differences for both groups of CIDP patients in terms of PS, for the patients spent more time performing the PS tasks than the controls. The PS measures were negatively associated with disability scores (reading: r = -0.47; p = 0.003; counting: r = -0.53; p = 0.001). Our data suggested the presence of PS impairment in CIDP patients. Disability was associated with slow PS.

Applicability of a semiautomated volumetric approach (5D CNS+™) for detailed antenatal reconstruction of abnormal fetal CNS anatomy

BackgroundThe aim of this study was to evaluate the accuracy and reliability of a semiautomated volumetric approach (5D CNS+™) when examining fetuses with an apparent abnormal anatomy of the central nervous system (CNS).MethodsStored 3D volumes extracted from a cohort of > 1.400 consecutive 2nd and 3rd trimester pregnancies (range 15–36 gestational weeks) were analyzed using the semiautomatic software tool 5D CNS+™, enabling detailed reconstruction of nine diagnostic planes of the fetal brain. All 3D data sets were examined and judged for plane accuracy, the need for manual adjustment, and fetal CNS anomalies affecting successful plane reconstruction.ResultsBased on our data of 91 fetuses with structural cerebral anomalies, we were able to reveal details of a wide range of CNS anomalies with application of the 5D CNS+™ technique. The corresponding anatomical features and consecutive changes of neighboring structures could be clearly demonstrated. Thus, a profound assessment of the entire altered CNS anatomy could be achieved in nearly all cases. The comparison with matched controls showed a significant difference in volume acquisition (p < 0.001) and in need for manual adjustment (p < 0.001) but not in the drop-out rates (p = 0.677) of both groups.Conclusion5D CNS+™ is applicable in the majority of cases with brain lesions and constitutes a reliable tool even if the integrity of the fetal CNS is compromised by structural anomalies. Using volume data that were acquired in identical cutting sections needed for conventional biometry allows for detailed anatomic surveys grossly independent of the examiner’s experience.

Molecular Genetic Profile of 300 Japanese Patients with Diffuse Gliomas Using a Glioma-tailored Gene Panel.

Rapid technological advances in molecular biology, including next-generation sequencing, have identified key genetic alterations in central nervous system (CNS) tumors. Accordingly, the fifth edition of the World Health Organization (WHO) CNS tumor classification was published in 2021. We analyzed 303 patients with diffuse glioma using an amplicon-based glioma-tailored gene panel for detecting 1p/19q codeletion and driver gene mutations such as IDH1/2, TERTp, EGFR, and CDKN2A/B on a single platform. Within glioblastomas (GBMs), the most commonly mutated genes were TERTp, TP53, PTEN, NF1, and PDGFRA, which was the most frequently mutated tyrosine kinase receptor in GBM, followed by EGFR. The genes that most commonly showed evidence of loss were PTEN, CDKN2A/B, and RB1, whereas the genes that most commonly showed evidence of gain/amplification were EGFR, PDGFRA, and CDK4. In 22 grade III oligodendroglial tumors, 3 (14%) patients had CDKN2A/B homozygous deletion, and 4 (18%) patients had ARID1A mutation. In grade III oligodendroglial tumors, an ARID1A mutation was associated with worse progression-free survival. Reclassification based on the WHO 2021 classification resulted in 62.5% of grade II/III isocitrate dehydrogenase (IDH)-wildtype astrocytomas being classified as IDH-wildtype GBM and 37.5% as not elsewhere classified. In summary, our glioma-tailored gene panel was applicable for molecular diagnosis in the WHO 2021 classification. In addition, we successfully reclassified the 303 diffuse glioma cases based on the WHO 2021 classification and clarified the genetic profile of diffuse gliomas in the Japanese population.

Vascular and Vasogenic Manifestations of Systemic ANCA-Associated Vasculitis with Renal Involvement in Non-Contrast Brain MRI in Patients with Acute Disease Onset.

Background. Data concerning central nervous system (CNS) alterations in ANCA-associated vasculitis with renal involvement (AAVR) are sparse. The study aimed to assess vascular and vasogenic brain alterations in patients with acute onset of AAVR and the applicability of non-contrast magnetic resonance imaging (MRI) techniques in this diagnosis. Methods. Thirty-eight patients with acute onset of AAVR were included in the study. BVAS/WG, c-ANCA, p-ANCA, renal function and perfusion, neurological assessment, and brain MRI were performed. Results. Cerebral vascular alternating narrowing and dilatation (VAND) was detected in 42.1% of patients, and the black-blood was significantly more diagnostic than the TOF technique (p < 0.001). VAND occurrence was independently associated with the concentration of p-ANCA. The vasogenic white matter lesions (VWML) were found in 94.4% of patients, and in their detection, SWAN was significantly better than the FLAIR technique (p = 0.002). The number of VWML correlated with age and cranial nerve damage. Hemosiderin deposits were found in 21.6% of patients and were associated with a gait impairment and paresthesia. Conclusions. Vascular and vasogenic alterations in the CNS are frequent in patients with acute onset of systemic ANCA-associated vasculitis with renal involvement. Non-contrast MRI is useful in the diagnosis of brain vasculitis.

OROFACIAL FEATURES IN GOLDENHAR SYNDROME

Goldenhar syndrome (GS) or hemifacial microsomia (OMIM #164210) is a rare genetic disorder related to gene 14q32, which involves defects in the 1st and 2nd branchial arches reflecting in craniofacial, cardiac, vertebral, and central nervous system alterations. The objective of this work was to demonstrate orofacial characteristics in Goldenhar syndrome. A 7-year-old male patient with GS was referred for dental treatment. Medical history revealed bronchitis and asthma, recurrent pneumonia, and epilepsy, along with motor and sensory impairment and surgeries for ear concha reconstruction and testicle repositioning. On physical evaluation, facial asymmetry, auricular, ocular, and maxillomandibular alterations were observed. Intraoral examination revealed mixed dentition with delayed eruption, caries lesions, poor oral hygiene, and occlusal alteration. Panoramic x-ray was requested. Dental management consisted in caries removal and oral hygiene instructions. Dentists should be aware of oral features of GS for proper dental management.

Seed-induced Aβ deposits in the corpus callosum disrupt white matter integrity in a mouse model of Alzheimer's disease.

Neuropathologically, Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-beta peptide (Aβ) and subsequent formation of the so-called Aβ plaques. Along with neuronal loss, previous studies report white matter anomalies and corpus callosum (CC) atrophy in AD patients. Notably, perturbations in the white matter can be observed years before expected disease onset, suggesting that early stages of disease progression play a role in AD-associated loss of myelin integrity. Through seed-induced deposition of Aβ, we are able to examine alterations of central nervous system (CNS) integrity during the initial stages of plaque formation. In this study, we investigate the impact of Aβ seeding in the CC utilizing various imaging techniques as well as quantitative gene expression analysis and demonstrate that Aβ deposits result in an imbalance of glial cells in the CC. We found increased amounts of phagocytic microglia and reactive astrocytes, while oligodendrocyte progenitor cell (OPC) numbers were reduced. Moreover, white matter aberrations adjacent to the Aβ seeding were observed together with an overall decline in callosal myelination. This data indicate that the initial stages of plaque formation induce oligodendrocyte dysfunction, which might ultimately lead to myelin loss.

Myelin toxicity of chlorhexidine in zebrafish larvae.

Chlorhexidine gluconate (CHG) is a topical antiseptic solution recommended for skin preparation before central venous catheter placement and maintenance in adults and children. Although CHG is not recommended for use in children aged <2 months owing to limited safety data, it is commonly used in neonatal intensive care units worldwide. We used zebrafish model to verify the effects of early-life exposure to CHG on the developing nervous system, highlighting its impact on oligodendrocyte development and myelination. Zebrafish embryos were exposed to different concentrations of CHG from 4 h post fertilization to examine developmental toxicity. The hatching rate, mortality, and malformation of the embryos/larvae were monitored. Oligodendrocyte lineage in transgenic zebrafish embryos was used to investigate defects in oligodendrocytes and myelin. Myelin structure, locomotor behavior, and expression levels of genes involved in myelination were investigated. Exposure to CHG significantly induced oligodendrocyte defects in the central nervous system, delayed myelination, and locomotor alterations. Ultra-microstructural changes with splitting and fluid-accumulated vacuoles between the myelin sheaths were found. Embryonic exposure to CHG decreased myelination, in association with downregulated mbpa, plp1b, and scrt2 gene expression. Our results suggest that CHG has a potential for myelin toxicity in the developing brain. To date, the neurodevelopmental toxicity of chlorhexidine gluconate (CHG) exposure on the developing brains of infants remains unknown. We demonstrated that CHG exposure to zebrafish larvae resulted in significant defects in oligodendrocytes and myelin sheaths. These CHG-exposed zebrafish larvae exhibited structural changes and locomotor alterations. Given the increased CHG use in neonates, this study is the first to identify the risk of early-life CHG exposure on the developing nervous system.

ETMR-11. Transcriptional changes upon knockdown of alteredBCOR/BCORL1 transcripts in preclinical models of CNS embryonal tumors with BCOR-related alterations

BCL-6 transcriptional corepressor (BCOR) is an epigenetic regulator that silences gene expression mainly via the polycomb repressive complex 1.1 (PRC1.1). BCOR genomic alterations are found in a variety of different tumors and recently central nervous system (CNS) tumors with BCOR internal tandem duplication (ITD) were classified as a distinct molecular subgroup. We established and characterized two cell models derived from BCOR altered CNS tumor patients. One model is characterized by a frameshift mutation in the BCOR gene resulting in the expression of a truncated protein lacking the C-terminal PUFD domain required for correct assembly of the PRC1.1. Additionally, this model harbors a translocation of the BCOR homologue BCORL1. The second model has a characteristic internal tandem duplication (ITD) within the BCOR gene. To study the effects of mutated BCOR/BCORL1 on gene expression, we performed siRNA mediated knockdown of altered BCOR/BCORL1 transcripts in both models and analyzed transcriptional changes by mRNA expression array. Differentially expressed genes in BCOR/BCORL1 knockdown versus wild type conditions were enriched for signaling pathways involved in cell cycle progression, cell growth, DNA replication and cancer. This suggests that the alterations in BCOR/BCORL1 might have pro-oncogenic effects and thereby contribute to the aggressive phenotype of this disease. Especially in the BCOR ITD model knockdown of BCOR led to transcriptional downregulation of genes associated with the development of brain tumors such as FGF18, PDGFA and PDGFRA. Our results indicate that specific BCOR/BCORL1 alterations might impair its endogenous function as transcriptional repressor and deregulate the expression of multiple PRC1.1 target genes. An in depth characterization of epigenetic and transcriptional changes in BCOR/BCORL1 altered CNS tumors could lead to the identification of critical downstream effectors and ultimately reveal new therapeutic vulnerabilities.

Inhibition of Forebrain Microglia Ameliorates Non‐alcoholic Fatty Liver Disease During Obesity

Non‐alcoholic fatty liver disease (NAFLD), characterized by increased hepatic triglycerides (i.e. steatosis), leads to an increased risk for type II diabetes, cardiovascular disease and obesity‐related mortality. Accumulating data points to central nervous system (CNS) alterations as a NAFLD contributor. In this context, we have recently shown that pharmacological inhibition of microglia, the resident immune cells of the brain, attenuates NAFLD during obesity. However, the brain regions involved in this microglial driven steatosis remains unknown. The forebrain subfornical organ (SFO), a circumventricular nucleus situated outside of the blood‐brain‐barrier, has recently been suggested to be critical in NAFLD. Based on this, we hypothesized that SFO microglia activation contributes to hepatic steatosis during obesity. To investigate this, we used a common murine model of diet‐induced NAFLD where male C57Bl/6J mice were fed a high fat diet (HFD, 60% kCal fat) or normal chow for 11 weeks, starting at 6 weeks of age. Immunohistochemistry for ionized calcium‐binding adapter molecule 1 (Iba1) revealed SFO microglia activation following HFD feeding (1.0±0.01 vs 1.4±0.15, relative Iba1 intensity, normal chow vs HFD, p&lt;0.05, n=7). 3‐dimensional analysis further indicated that HFD feeding was associated with a shift to an activated SFO microglia morphology, including decreased branching complexity and shorter dendrites (e.g. branch #/dendrite: 3.1±0.2 vs 2.5±0.1, normal chow vs HFD, p&lt;0.05, n=5/group, 203‐364 microglia/animal). Building upon this, we employed a chemogenetic strategy to selectively inhibit SFO microglia. HFD or normal chow male mice underwent SFO stereotaxic delivery of a designer receptors exclusively activated by designer drugs inhibitory construct targeted to microglia via the CD68 promoter (pAAV‐CD68‐hM4Gi‐mCherry). Following surgical recovery, the pharmacological ligand clozapine‐N‐oxide (CNO; 3 mg/kg i.p.) was administered once daily over 3 days to inhibit SFO microglia. Saline served as a control (n=7–11/group). Short‐term inhibition of SFO microglia did not alter body weight (43±1 vs 42±2 g, HFD saline vs CNO, p&gt;0.05) and food intake in normal chow or HFD fed mice. Similarly, indirect calorimetry evaluations revealed no change in oxygen consumption, respiratory exchange ratio, or energy expenditure in either diet group during SFO microglia inhibition (e.g. energy expenditure: 0.49±0.01 vs 0.49±0.01 kcal/hr, HFD saline vs CNO, p&gt;0.05). Regional adiposity including visceral, subcutaneous, and brown adipose mass was also not different between CNO and saline treated animals. However, histological examination (Oil Red O staining) revealed widespread hepatic lipid accumulation in HFD fed mice (0.4±0.1 vs 36.2±5.5 %stained area; normal chow saline vs HFD saline, p&lt;0.05), which was reduced by ~49% following 3‐day SFO microglia inhibition (18.4±5.4 %stained area, HFD CNO, p&lt;0.05 vs HFD saline). This decline in hepatic steatosis in response to SFO microglia inhibition was further confirmed with liver triglyceride measurements. In line with the direct association of NAFLD and type II diabetes, inhibition of SFO microglia also resulted in a reduction in fed blood glucose levels in obese mice (229±24 vs 182±9 mg/dl, HFD saline vs CNO, p=0.05). Collectively, these results indicate that SFO microglia activation is a critical contributor to hepatic steatosis during obesity.

Reproducible neuroimaging features for diagnosis of autism spectrum disorder with machine learning

Autism spectrum disorder (ASD) is the fourth most common neurodevelopmental disorder, with a prevalence of 1 in 160 children. Accurate diagnosis relies on experts, but such individuals are scarce. This has led to increasing interest in the development of machine learning (ML) models that can integrate neuroimaging features from functional and structural MRI (fMRI and sMRI) to help reveal central nervous system alterations characteristic of ASD. We optimized and compared the performance of 12 of the most popular and powerful ML models. Each was separately trained using 15 different combinations of fMRI and sMRI features and optimized with an unbiased model search. Deep learning models predicted ASD with the highest diagnostic accuracy and generalized well to other MRI datasets. Our model achieves state-of-the-art 80% area under the ROC curve (AUROC) in diagnosis on test data from the IMPAC dataset; and 86% and 79% AUROC on the external ABIDE I and ABIDE II datasets (with further improvement to 93% and 90% after supervised domain adaptation). The highest performing models identified reproducible putative biomarkers for accurate ASD diagnosis in accord with known ASD markers as well as novel cerebellar biomarkers. Such reproducibility lends credence to their tremendous potential for defining and using a set of truly generalizable ASD biomarkers that will advance scientific understanding of neuronal changes in ASD.

Systemic Response to Infection Induces Long-Term Cognitive Decline: Neuroinflammation and Oxidative Stress as Therapeutical Targets.

In response to pathogens or damage signs, the immune system is activated in order to eliminate the noxious stimuli. The inflammatory response to infectious diseases induces systemic events, including cytokine storm phenomenon, vascular dysfunction, and coagulopathy, that can lead to multiple-organ dysfunction. The central nervous system (CNS) is one of the major organs affected, and symptoms such as sickness behavior (depression and fever, among others), or even delirium, can be observed due to activation of endothelial and glial cells, leading to neuroinflammation. Several reports have been shown that, due to CNS alterations caused by neuroinflammation, some sequels can be developed in special cognitive decline. There is still no any treatment to avoid cognitive impairment, especially those developed due to systemic infectious diseases, but preclinical and clinical trials have pointed out controlling neuroinflammatory events to avoid the development of this sequel. In this minireview, we point to the possible mechanisms that triggers long-term cognitive decline, proposing the acute neuroinflammatory events as a potential therapeutical target to treat this sequel that has been associated to several infectious diseases, such as malaria, sepsis, and, more recently, the new SARS-Cov2 infection.

Not Only in Sensorimotor Network: Local and Distant Cerebral Inherent Activity of Chronic Ankle Instability-A Resting-State fMRI Study.

BackgroundIncreasing evidence has proved that chronic ankle instability (CAI) is highly related to the central nervous system (CNS). However, it is still unclear about the inherent cerebral activity among the CAI patients.PurposeTo investigate the differences of intrinsic functional cerebral activity between the CAI patients and healthy controls (HCs) and further explore its correlation with clinical measurement in CAI patients.Materials and MethodsA total of 25 CAI patients and 39 HCs were enrolled in this study. Resting-state functional magnetic resonance imaging (rs-fMRI) was used to detect spontaneous cerebral activity. The metrics of amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and regional homogeneity (ReHo) of the two groups were compared by two-sample t-test. The brain regions that demonstrated altered functional metrics were selected as the regions of interest (ROIs). The functional connectivity (FC) was analyzed based on the ROIs. The Spearman correlation was calculated between rs-fMRI metrics and clinical scale scores.ResultsCompared with HCs, CAI patients showed higher ALFF and ReHo values in the right postcentral gyrus, the right precentral gyrus, and the right middle frontal gyrus, while lower fALFF values in the orbital-frontal cortex (OFC, p < 0.01 after correction). Increasing FC between the right precentral gyrus and the right postcentral gyrus while decreasing FC between the right precentral gyrus and the anterior cingulum cortex (ACC), the right middle frontal gyrus and the left middle temporal gyrus, and the OFC and left inferior parietal lobule (IPL) was observed. In addition, in the CAI group, the ReHo value negatively correlated with the Cumberland Ankle Instability Tool score in the right middle frontal gyrus (r = −0.52, p = 0.007).ConclusionThe CAI patients exhibited enhanced and more coherent regional inherent neuronal activity within the sensorimotor network while lower regional inherent activity in pain/emotion modulation related region. In addition, the information exchanges were stronger within the sensorimotor network while weaker between distant interhemispheric regions. Besides, the increased inherent activity in the right middle frontal gyrus was related to clinical severity. These findings may provide insights into the pathophysiological alteration in CNS among CAI patients.

The Resting State Central Auditory Network: a Potential Marker of HIV-Related Central Nervous System Alterations.

HIV positive (HIV+) individuals with otherwise normal hearing ability show central auditory processing deficits as evidenced by worse performance in speech-in-noise perception compared with HIV negative (HIV-) controls. HIV infection and treatment are also associated with lower neurocognitive screening test scores, suggesting underlying central nervous system damage. To determine how central auditory processing deficits in HIV+ individuals relate to brain alterations in the cortex involved with auditory processing, we compared auditory network (AN) functional connectivity between HIV+ adults with or without speech-in-noise perception difficulties and age-matched HIV- controls using resting-state fMRI. Based on the speech recognition threshold of the hearing-in-noise test, twenty-seven HIV+ individuals were divided into a group with speech-in-noise perception abnormalities (HIV+SPabnl, 38.2 ± 6.8 years; 11 males and 2 females) and one without (HIV+SPnl 34.4 ± 8.8 years; 14 males). An HIV- group with normal speech-in-noise perception (HIV-, 31.3 ± 5.2 years; 9 males and 3 females) was also enrolled. All of these younger and middle-aged adults had normal peripheral hearing determined by audiometry. Participants were studied using resting-state fMRI. Independent component analysis was applied to identify the AN. Group differences in the AN were identified using statistical parametric mapping. Both HIV+ groups had increased functional connectivity (FC) in parts of the AN including the superior temporal gyrus, middle temporal gyrus, supramarginal gyrus, and Rolandic operculum compared to the HIV- group. Compared with the HIV+SPnl group, the HIV+SPabnl group showed greater FC in parts of the AN including the middle frontal and inferior frontal gyri. The classical auditory areas in the temporal lobe are affected by HIV regardless of speech perception ability. Increased temporal FC in HIV+ individuals might reflect functional compensation to achieve normal primary auditory perception. Furthermore, increased frontal FC in the HIV+SPabnl group compared with the HIV+SPnl group suggest that speech-in-noise perception difficulties in HIV-infected adults also affect areas involved in higher-level cognition, providing imaging evidence consistent with the hypothesis that HIV-related neurocognitive deficits can include central auditory processing deficits.

The incidence and pathophysiology of neurological symptoms in COVID-19

The central nervous system seems to be quite vulnerable to SARS-CoV-2, leading to a variety of alteration pathways, high incidence and variability of the neurological symptoms of COVID-19. The COVID-19 symptoms, possibly associated with alteration to the central nervous system, include hyperthermia, shortness of breath, fatigue, headache, dizziness, dysphonia, dysphagia, hyposmia and anosmia, hypogeusia and ageusia, impairment of consciousness. The impairment of olfaction and gustation are the most common symptoms of the nervous system alteration (98% and 70%, respectively), which is most likely a consequence of the alteration of the receptors. Presumably the pathogenesis of dysphonia and dysphagia may involve neurodegenerative mechanisms or may be associated with a predominantly demyelinating alteration of the caudal cranial nerves. Pathomorphological findings in the brain of the COVID-19 patients include diffuse hypoxic and focal ischemic injuries of various sizes up to ischemic infarctions (in thrombosis of large arteries); microangiopathy; vasculitis; diapedetic and confluent hemorrhages with possible progression to hemorrhagic infarctions and rarely intracerebral hematomas. Acute cerebrovascular accident worsens the course of COVID-19 and can worsen the clinical outcome, taking into account the mechanisms of the central nervous system alteration in highly contagious coronavirus infections (SARS-CoV, MERS, SARS-CoV-2), including embolism, hypoxia, neurodegeneration, systemic inflammatory response and immune-mediated alteartion to the nervous tissue. A fairly rare complication of coronavirus infection, however, acute myelitis requires attention due to the severity of neurological disorders. The literature data show high incidence and polymorphism of the symptoms of the central nervous system alteration, as well as the important role of the cerebrovascular and neurodegenerative pathogenesis of brain alteration in COVID-19, which is taken into account in examining and treating the patients with new coronavirus infection. (1 figure, bibliography: 61 refs)

La classification de l’OMS 2021 des tumeurs du système nerveux central

Rapid technical advances in molecular biology allowed for the identification of key genetic alterations in central nervous system (CNS) tumors. Our ever-expanding knowledge of brain tumor genetics and the development of new technologies, such as DNA-methylation profiling, required an update of the 2016 fourth edition of the WHO classification of CNS tumors. Updates were regularly published by the Consortium to Inform Molecular Practical Approaches to CNS Tumor Taxonomy-Not Official WHO (c-IMPACT-NOW) until the publication of the fifth edition of the WHO classification of CNS tumors in 2021. In that edition, new types and subtypes are introduced and criteria for histo-molecular diagnostic and grading are refined, especially for diffuse gliomas. The definition of a broad category “diffuse glioma, pediatric subtype” (low or high grade) is a major improvement of the classification. Moreover, the nomenclature was simplified and aligned with that of other blue books. The 2021 edition truly advances the role of molecular diagnostics in CNS tumor classification. Methyloma profiling may become a cornerstone of CNS tumor diagnostic. The new WHO classification will lead to better management of brain tumor patients.

Role of SARS-CoV-2 in causing blood-brain barrier leakage and microglial activation as a risk factor of cognitive deterioration in subjects at risk of Alzheimer's disease.

BackgroundThe recent pandemic provides evidence of altered central nervous system (CNS) function in response to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). SARS‐COV‐2 invades the CNS by binding angiotensin‐converting enzyme 2 (ACE2) expressed on neurons and glia. SARS‐COV‐2 may have effects on increased permeability of endothelial cells within the blood‐brain barrier (BBB) as studies have shown that the S1 protein can transverse the BBB. This is interesting because leakage of the BBB is implicated in Alzheimer’s disease (AD) pathogenesis. We hypothesized that SARS‐CoV‐2 infection leads to innate stimulated inflammation, ultimately activating microglial cells and an influx of pro‐inflammatory cytokines and leukocytes in the meninges, contributing to increased permeability of the BBB. This BBB permeability increases AD susceptibility in subjects at risk by causing irreversible damage to the BBB and microglial cell activation.MethodWe developed a double transgenic mouse model using mice expressing human ACE2 receptor and 5xFAD mice that exhibit increased neuropathology seen in human AD allowing modeling of AD in SARS‐CoV‐2 pathogenesis. The hACE2/5xFAD double transgenic mice were intranasally inoculated with a sub‐lethal dose of SARS‐CoV‐2 to test the hypothesis that SARS‐COV‐2 potentiates AD pathology and cognitive deterioration through impairment of the BBB. Leukocyte and cytokine populations were measured by flow cytometry and single‐nuclei RNA sequencing of the meninges for characterization of microglial populations.ResultSARS‐CoV‐2 creates a cytotoxic environment in the brain immediately following infection in hACE2/5xFAD mice leading to leakage of the BBB in the meninges. Activation of microglial innate cells by SARS‐COV‐2 invasion of the CNS will cause neural deterioration having long term implications on cognitive function. The hACE2/5xFAD mouse model allows us to uncover implications for SARS‐COV‐2 on AD cognitive deterioration.ConclusionThe hACE2/5xFAD mouse allows modeling of SARS‐CoV‐2 in developing AD cases and allowed us to determine the immune environment generated in the meninges in response to SARS‐CoV‐2 infections. This mouse model provides a platform to proactively determine the effects of SARS‐CoV‐2 in developing AD cases, a methodology to be exploited for future mouse models determining the relationship of other viruses on AD pathology, and the opportunity to address phenotypes with therapeutics for preventative initiatives.

EPCO-33. CELL-TYPE PROPORTION DECONVOLUTION OF PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS FROM SINGLE NUCLEI RNA-seq UNCOVERS UNDERLYING TRANSCRIPTOMIC CHANGES FROM BULK TUMOR RNA-seq COMPARED TO NORMAL BRAIN

Abstract Identifying transcriptomic alterations in pediatric central nervous system (pCNS) tumors often relies on transcriptomic profiles from bulk tissue RNA-sequencing that can be confounded by varying cell type proportions across tumor and normal brain tissues. We utilized single nuclei RNA-sequencing (snRNA-seq) and bulk RNA-seq in 33 pCNS tumors and 3 non-diseased pediatric brain tissue samples collected from the Norris Cotton Cancer Center to identify variation in gene expression in bulk tissue attributed to overrepresentation of specific cell-type populations when determining differentially expressed genes comparing pCNS tumors to normal pediatric brain tissues. snRNA-seq of 43,515 nuclei (mean = 1,209 nuclei/sample) revealed large proportions of astrocytes (median = 0.45, range = 0.24–0.93) and oligodendrocytes (median = 0.37, range = 0.00–0.66) in pCNS tumors. Compared to normal pediatric brain, proportions of astrocytes were significantly higher (P = 9.2E-03) and neurons were significantly lower (P = 9.4E-03) in pCNS tumors. Differential expression analyses comparing bulk RNA-sequencing data from pCNS tumors to normal pediatric brain identified 902 additional differentially expressed genes (# DE genes = 1,802) when adjusting for astrocyte and neuron proportions compared with unadjusted analysis (# DE genes = 900). In cell-type proportion unadjusted analysis, top DE genes included astrocyte-specific markers, GFAP and CIITA, both of which were found to be not significantly differentially expressed in cell-type proportion adjusted analysis. Indeed, pathways enrichment analysis revealed DE genes in unadjusted models were associated with processes of the neurons and astrocytes such as interferon signaling and postsynaptic signal transmission. After adjustment for astrocyte and neuron proportions, DE genes were associated with defensins and DNA replication-related processes. Our results highlight new potential biological pathways essential in pCNS tumors and indicate the significance of the distribution of varying cell types in tissue samples when conducting studies to investigate transcriptomic alterations in bulk tissue of pCNS tumors.