Brainstem Research Articles

Comparative study of virus and lymphocyte distribution with clinical data suggests early high dose immunosuppression as potential key factor for the therapy of patients with BoDV-1 infection

ABSTRACT Borna disease virus 1 (BoDV-1) was just recently shown to cause predominantly fatal encephalitis in humans. Despite its rarity, bornavirus encephalitis (BVE) can be considered a model disease for encephalitic infections caused by neurotropic viruses and understanding its pathomechanism is of utmost relevance. Aim of this study was to compare the extent and distribution pattern of cerebral inflammation with the clinical course of disease, and individual therapeutic procedures. For this, autoptic brain material from seven patients with fatal BVE was included in this study. Tissue was stained immunohistochemically for pan-lymphocytic marker CD45, the nucleoprotein of BoDV-1, as well as glial marker GFAP and microglial marker Iba1. Sections were digitalized and counted for CD45-positive and BoDV-1-positive cells. For GFAP and Iba1, a semiquantitative score was determined. Furthermore, detailed information about the individual clinical course and therapy were retrieved and summarized in a standardized way. Analysis of the distribution of lymphocytes shows interindividual patterns. In contrast, when looking at the BoDV-1-positive glial cells and neurons, a massive viral involvement in the brain stem was noticeable. Three of the seven patients received early high-dose steroids, which led to a significantly lower lymphocytic infiltration of the central nervous tissue and a longer survival compared to the patients who were treated with steroids later in the course of disease. This study highlights the potential importance of early high-dose immunosuppressive therapy in BVE. Our findings hint at a promising treatment option which should be corroborated in future observational or prospective therapy studies. ABBREVIATIONS: BoDV-1: Borna disease virus 1; BVE: bornavirus encephalitis; Cb: cerebellum; CNS: central nervous system; FL: frontal lobe; GFAP: glial fibrillary acid protein; Hc: hippocampus; Iba1: ionized calcium-binding adapter molecule 1; Iba1act: general activation of microglial cells; Iba1nod: formation of microglial nodules; IL: insula; Me: mesencephalon; Mo: medulla oblongata; OL: occipital lobe; pASS: per average of 10 screenshots; patearly: patients treated with early high dose steroid shot; patlate: patients treated with late or none high dose steroid shot; Po: pons; So: stria olfactoria; Str: striatum

Brain death diagnostics: use of ancillary tests

AbstractWith the determination of the definitive, irreversible loss of the overall function of the cerebrum, cerebellum and brain stem (irreversible loss of brain function, IHA, "brain death"), the death of the human being is determined from a scientific-medical point of view. The determination of IHA, with cardiovascular function being maintained by intensive care, requires special diagnostics ("brain death diagnostics"). This is carried out in the intensive care unit either to assess the medical prognosis, or as a prerequisite for post-mortem organ donation. In Germany, in accordance with the Transplantation Act, the procedural rules for determining IHA are laid down in corresponding guidelines of the German Medical Association (RL-BÄK), the 5th update of which has been in force since September 2022. Here, the indications, the requirements and the technical procedures of ancillary tests (electroencephalography, early auditory and somatosensory evoked potentials, Doppler and duplex sonography, computed tomography angiography, radionuclide perfusion scintigraphy, digital subtraction angiography) according to the German guidelines are outlined.

Basilar Artery, Anterior Inferior Cerebellar Artery, Superior Cerebellar Artery

The basilar artery(BA)is formed by the fusion of two longitudinal arteries, and incomplete development may lead to BA fenestration. The BA provides many short perforating arteries and long lateral pontine arteries to the brain stem. The anterior inferior cerebellar artery(AICA)usually branches from the proximal third of the BA and primarily perfuses the ventral, inferior and lateral aspect of the cerebellum and inner ear organ. However, there are many variations to the AICA that depend on the degree of posterior inferior cerebellar artery development. The superior cerebellar artery(SCA)branches into not only to the rostral, ventral aspect of the cerebellar hemisphere, but also to the deeper cerebellar nucleus and brain stem. Duplications within this vessel are frequently identified, but it is not missing.

Injectable Hydrogel Loaded with CDs and FTY720 Combined with Neural Stem Cells for the Treatment of Spinal Cord Injury.

Spinal cord injury (SCI) is an incurable and disabling event that is accompanied by complex inflammation-related pathological processes, such as the production of excessive reactive oxygen species (ROS) by infiltrating inflammatory immune cells and their release into the extracellular microenvironment, resulting in extensive apoptosis of endogenous neural stem cells. In this study, we noticed the neuroregeneration-promoting effect as well as the ability of the innovative treatment method of FTY720-CDs@GelMA paired with NSCs to increase motor function recovery in a rat spinal cord injury model. Carbon dots (CDs) and fingolimod (FTY720) were added to a hydrogel created by chemical cross-linking GelMA (FTY720-CDs@GelMA). The basic properties of FTY720-CDs@GelMA hydrogels were investigated using TEM, SEM, XPS, and FTIR. The swelling and degradation rates of FTY720-CDs@GelMA hydrogels were measured, and each group's ability to scavenge reactive oxygen species was investigated. The in vitro biocompatibility of FTY720-CDs@GelMA hydrogels was assessed using neural stem cells. The regeneration of the spinal cord and recovery of motor function in rats were studied following co-treatment of spinal cord injury using FTY720-CDs@GelMA hydrogel in combination with NSCs, utilising rats with spinal cord injuries as a model. Histological and immunofluorescence labelling were used to determine the regeneration of axons and neurons. The recovery of motor function in rats was assessed using the BBB score. The hydrogel boosted neurogenesis and axonal regeneration by eliminating excess ROS and restoring the regenerative environment. The hydrogel efficiently contained brain stem cells and demonstrated strong neuroprotective effects in vivo by lowering endogenous ROS generation and mitigating ROS-mediated oxidative stress. In a follow-up investigation, we discovered that FTY720-CDs@GelMA hydrogel could dramatically boost NSC proliferation while also promoting neuronal regeneration and synaptic formation, hence lowering cavity area. Our findings suggest that the innovative treatment of FTY720-CDs@GelMA paired with NSCs can effectively improve functional recovery in SCI patients, making it a promising therapeutic alternative for SCI.

Dysfunction of M channels in the insular cortex is involved in pathogenesis of primary hypertension

Heightened sympathetic nerve activity is critically involved in the pathogenesis of primary hypertension. However, the sources driving increased sympathetic vasomotor tone remain unclear. The posterior insular cortex (PIC) is a brain region involved in regulating blood pressure and sympathetic tone. Neurons in the PIC project to the rostral ventrolateral medulla (RVLM), a key brain stem region in regulating sympathetic nerve activity and blood pressure. The non-inactivating voltage-dependent K+ channels, M channels (Kv7/KCNQ channel family) encoded by KCNQ2/3 genes, play a unique role in stabilizing the neuronal membrane potential and regulating neuronal excitability. Here, we determined if the M channel activity of neurons in the PIC is altered in a primary hypertension. Compared with Wistar-Kyoto (WKY) rats, the mRNA and protein expression levels of Kv7.2/Kv7.3 in the PIC tissue were significantly reduced in spontaneously hypertensive rats (SHRs). Microinjection of M channel blocker 10, 10-bis (4-pyridinylmethyl)-9(10H)-anthracnose (XE-991) into the PIC increased arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) in anesthetized WKY rats, while induced minimal changes of ABP and RSNA in SHRs. M currents recorded from PIC neurons in brain slices labeled by retrograde tracer, Fluospheres, injected into the RVLM were significantly smaller in SHRs than in WKY rats. Furthermore, bath application of specific M channel blocker XE-991 increased the firing rate of PIC-RVLM output neurons in WKY rats while caused a minimal increase in firing rate of PIC-RVLM output neurons in SHRs. In addition, M currents recorded from PIC-RVLM output neurons in SHRs were significantly smaller than those recorded from WKY rats. These data suggest that M channel activity is diminished in PIC-RVLM output neurons in SHRs, and the diminished Kv7 channel activity contributes to elevated sympathetic outflow in primary hypertension. This novel information provides new a mechanistic insight into the pathogenesis of neurogenic hypertension. Supported by grants from National Institutes of Health (HL139523, HL142133, and HL159157 to DPL). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Location matters: altered interhemispheric homotopic connectivity in post-stroke dyskinesia.

Motor impairment is the most prevalent consequence following a stroke. Interhemispheric homotopic connectivity, which varies regionally and hierarchically along the axis of the somatomotor-association cortex, plays a critical role in sustaining normal motor functions. However, the impact of strokes occurring in various locations on homotopic connectivity is not fully understood. This study aimed to explore how motor deficits resulting from acute strokes in different locations influence homotopic connectivity. Eighty-four acute ischemic stroke patients with dyskinesia were recruited and divided into four demographically-matched subgroups based on stroke locations: Group 1 (G1; frontoparietal, n = 15), Group 2 (G2; radiation coronal, n = 16), Group 3 (G3; basal ganglia, n = 30), and Group 4 (G4; brain stem, n = 23). An additional 37 demographically-matched healthy controls were also recruited in the study. Multimodal MRI data, motor function assessments, and cognitive tests were gathered for analysis. Interhemispheric homotopic functional and structural connectivity were measured using resting-state functional MRI and diffusion tensor imaging, respectively. These measurements were then correlated with motor function scores to investigate the relationships. Voxel-mirrored homotopic connectivity (VMHC) analysis showed that strokes in the frontoparietal and basal ganglia regions led to diminished homotopic connectivity in the somatosensory/motor cortex. In contrast, strokes in the radiation coronal and brainstem regions affected subcortical motor circuits. Structural homotopic connectivity analysis using diffusion tensor imaging showed that frontoparietal and basal ganglia strokes predominantly affected association fibers, while radiation coronal and brainstem strokes caused widespread disruption in the integrity of both cortical-cortical and cortical-subcortical white matter fibers. Correlation analyses demonstrated significant associations between the Fugl-Meyer Assessment (FMA), Modified Barthel Index (MBI), and National Institutes of Health Stroke Scale (NIHSS) scores with the VMHC in the inferior temporal gyrus for G1 (G1; r = 0.838, p < 0.001; r = 0.793, p < 0.001; and r = -0.834, p < 0.001, respectively). No statistically significant associations were observed in Groups 2, 3, and 4. Our results suggest that motor deficits following strokes in various regions involve distinct pathways from cortical to subcortical areas. Alterations in lesion topography and regional functional homotopy provide new insights into the understanding of neural underpinnings of post-stroke dyskinesia.

Reduction in Constitutively Activated Auditory Brainstem Microglia in Aging and Alzheimer's Disease.

Alzheimer's disease (AD) pathology is considered to begin in the brainstem, and cerebral microglia are known to play a critical role in AD pathogenesis, yet little is known about brainstem microglia in AD. Translocator protein (TSPO) PET, sensitive to activated microglia, shows high signal in dorsal brainstem in humans, but the precise location and clinical correlates of this signal are unknown. To define age and AD associations of brainstem TSPO PET signal in humans. We applied new probabilistic maps of brainstem nuclei to quantify PET-measured TSPO expression over the whole brain including brainstem in 71 subjects (43 controls scanned using 11C-PK11195; 20 controls and 8 AD subjects scanned using 11C-PBR28). We focused on inferior colliculi (IC) because of visually-obvious high signal in this region, and potential relevance to auditory dysfunction in AD. We also assessed bilateral cortex. TSPO expression was normally high in IC and other brainstem regions. IC TSPO was decreased with aging (p = 0.001) and in AD subjects versus controls (p = 0.004). In cortex, TSPO expression was increased with aging (p = 0.030) and AD (p = 0.033). Decreased IC TSPO expression with aging and AD-an opposite pattern than in cortex-highlights underappreciated regional heterogeneity in microglia phenotype, and implicates IC in a biological explanation for strong links between hearing loss and AD. Unlike in cerebrum, where TSPO expression is considered pathological, activated microglia in IC and other brainstem nuclei may play a beneficial, homeostatic role. Additional study of brainstem microglia in aging and AD is needed.

An integrative miRNA-mRNA expression analysis identifies miRNA signatures associated with SOD1 and TARDBP patient-derived motor neurons.

MicroRNAs (miRNAs) are a subset of small non-coding single-stranded RNA molecules involved in the regulation of post-transcriptional gene expression of a variety of transcript targets. Therefore altered miRNA expression may result in the dysregulation of key genes and biological pathways that has been reported with the onset and progression of neurodegenerative diseases, such as Amyotrophic lateral sclerosis (ALS). ALS is marked by a progressive degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Although the pathomechanism underlying molecular interactions of ALS remains poorly understood, alterations in RNA metabolism, including dysregulation of miRNA expression in familial as well as sporadic forms are still scarcely studied. In this study, we performed combined transcriptomic data and miRNA profiling in MN samples of the same samples of iPSC-derived MNs from SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls. We report a global upregulation of mature miRNAs, and suggest that differentially expressed (DE) miRNAs have a significant impact on mRNA-level in SOD1-, but not in TARDBP-linked ALS. Furthermore, in SOD1-ALS we identified dysregulated miRNAs such as miR-124-3p, miR-19b-3p and miR-218 and their potential targets previously implicated in important functional process and pathogenic pathways underlying ALS. These miRNAs may play key roles in the neuronal development and cell survival related functions in SOD1-ALS. Altogether, we provide evidence of miRNA regulated genes expression mainly in SOD1 rather than TDP43-ALS.

Quantitative brain stem assessment in discriminating neurodegenerative disorders from normal pressure hydrocephalus.

Differentiating idiopathic normal pressure hydrocephalus (iNPH) from neurodegenerative disorders such as progressive supranuclear palsy (PSP), Multiple System Atrophy-parkinsonian type (MSA-P), and vascular dementia (VaD) is challenging due to overlapping clinical and neuroimaging findings. This study assesses if quantitative brain stem and cerebellum metrics can aid in this differentiation. We retrospectively compared the sagittal midbrain area, midbrain to pons ratio, MR parkinsonism index (MRPI), and cerebellar atrophy in 30 PSP patients, 31 iNPH patients, 27 MSA-P patients, 32 VaD patients, and 25 healthy controls. Statistical analyses determined group differences, sensitivity, specificity, and the area under the receiver operating characteristic curves. There was an overlap in midbrain morphology between PSP and iNPH, as assessed with MRPI, midbrain to pons ratio, and midbrain area. A cutoff value of MRPI>13 exhibited 84% specificity in distinguishing PSP from iNPH and 100% in discriminating PSP from all other conditions. A cutoff value of midbrain to pons ratio at <0.15 yielded 95% specificity for differentiating PSP from iNPH and 100% from all other conditions. A cutoff value of midbrain area at <87mm2 exhibited 97% specificity for differentiating PSP from iNPH and 100% from all other conditions. All measures showed low sensitivity. Cerebellar atrophy did not differ significantly among groups. Our study questions MRPI's diagnostic performance in distinguishing PSP from iNPH. Simpler indices such as midbrain to pons ratio and midbrain area showed similar or better accuracy. However, all these indices displayed low sensitivity despite significant differences among PSP, MSA-P, and VaD.

Impact of ischemic stroke topography on early clinical outcome of basilar artery occlusion: a retrospective study.

Basilar artery occlusion (BAO) may be etiologically attributed to embolism or in situ thrombosis due to basilar stenosis (BS). Patients with BAO due to BS (BAOS) are known to have worse outcomes than patients with embolic occlusions (BAOE). BAOS occurs more proximally in the basilar artery (BA) than BAOE. We hypothesize that differing brain stem infarct patterns contribute to outcome differences between these stroke etiologies. This retrospective study includes 199 consecutive patients with BAO who received endovascular treatment at a single center. Final infarction in brain parenchyma dependent on the posterior circulation was graded semiquantitatively on magnetic resonance imaging (MRI). Associations to underlying stenosis and angiographic and clinical outcome variables were tested. The primary endpoint was early good clinical outcome (EGCO, mRS score ≤ 3 at discharge). Infarct extension of the medulla oblongata (OR = 0.25; 95% CI = 0.07-0.86; p = 0.03), the inferior pons (OR = 0.328; 95% CI = 0.17-0.63; p = 0.001), the superior pons (OR = 0.57; 95% CI = 0.33-0.99; p = 0.046), and the occipital lobes (OR = 0.46; 95% CI = 0.26-0.80; p = 0.006) negatively predicted EGCO. Infarct extension for other posterior-circulation-dependent brain regions was not independently associated with unfavorable early outcomes. Patients with BAOS had more proximal occlusions and greater infarct volumes in the inferior brain stem. Successful reperfusion (mTICI 2b-3) occurred more often in patients with BAOE than in BAOS (BAOE: 131 (96.3%); BAOS: 47 (83.9%), p = 0.005). Unfavorable early outcomes in patients with BAOS may be explained by a higher likelihood of inferior brain stem infarcts and lower rates of reperfusion success. Basilar artery occlusion due to underlying stenosis is associated with a poorer prognosis than that caused by embolism; these results suggest that aggressive endovascular therapy, usually involving the placement of a permanent stent, may be warranted in these patients. Inferior brain stem and occipital infarcts are prognostically unfavorable in basilar artery occlusion. Basilar artery occlusion due to stenosis occurs more proximally and is associated with worse outcomes. Differentiating etiologies of basilar artery occlusion may influence how aggressively treated the occlusion is.

A mouse model of autoimmune inner ear disease without endolymphatic hydrops

Autoimmune inner ear disease (AIED) is an organ-specific disease characterized by irreversible, prolonged, and progressive hearing and equilibrium dysfunctions. The primary symptoms of AIED include asymmetric sensorineural hearing loss accompanied by vertigo, aural fullness, and tinnitus. AIED is divided into primary and secondary types. Research has been conducted using animal models of rheumatoid arthritis (RA), a cause of secondary AIED. However, current models are insufficient to accurately analyze vestibular function, and the mechanism underlying the onset of AIED has not yet been fully elucidated. Elucidation of the mechanism of AIED onset is urgently needed to develop effective treatments. In the present study, we analyzed the pathogenesis of vertigo in autoimmune diseases using a mouse model of type II collagen-induced RA. Auditory brain stem response analysis demonstrated that the RA mouse models exhibited hearing loss, which is the primary symptom of AIED. In addition, our vestibulo-oculomotor reflex analysis, which is an excellent vestibular function test, accurately captured vertigo symptoms in the RA mouse models. Moreover, our results revealed that the cause of hearing loss and vestibular dysfunction was not endolymphatic hydrops, but rather structural destruction of the organ of Corti and the lateral semicircular canal ampulla due to an autoimmune reaction against type II collagen. Overall, we were able to establish a mouse model of AIED without endolymphatic hydrops. Our findings will help elucidate the mechanisms of hearing loss and vertigo associated with AIED and facilitate the development of new therapeutic methods.

Development and validation of a risk prediction model for aspiration in patients with acute ischemic stroke

BackgroundAspiration is a frequently observed complication in individuals diagnosed with acute ischemic stroke, leading to potentially severe consequences. However, the availability of predictive tools for assessing aspiration probabilities remains limited. Hence, our study aimed to develop and validate a nomogram for accurately predicting aspiration probability in patients with acute ischemic stroke. MethodsWe analyzed 30 potential risk factors associated with aspiration in 359 adult patients diagnosed with acute ischemic stroke. Advanced statistical techniques, such as Least absolute shrinkage and selection operator (LASSO) and Multivariate Logistic regression, were employed to identify independent predictors. Subsequently, we developed a nomogram prediction model based on these predictors, which underwent internal validation through 1000 bootstrap resampling. Two additional cohorts (Cohort A n = 64; Cohort B, n = 105) were included for external validation. The discriminatory power and calibration performance of the nomogram were assessed using rigorous methods, including the Hosmer-Lemeshow test, area under the receiver operating characteristic curve (AUC), calibration curve analyses, and decision curve analyses (DCA). ResultsThe nomogram was established based on four variables: sputum suction, brain stem infarction, temporal lobe infarction, and Barthel Index score. The predictive model exhibited satisfactory discriminative ability, with an area under the receiver operating characteristic curve of 0.853 (95 % confidence interval, 0.795–0.910), which remained consistent at 0.852 (95 % confidence interval, 0.794–0.912) during the internal validation. The Hosmer-Lemeshow test (P = 0.394) and calibration curve demonstrated favorable consistency between the predicted and observed outcomes in the development cohort. The AUC was 0.872 (95 % confidence interval, 0.783–0.962) in validation cohort A and 0.877 (95 % confidence interval, 0.764–0.989) in validation cohort B, demonstrating sustained accuracy. DCA showed a good net clinical benefit of the nomogram. ConclusionsA nomogram for predicting the probability of aspiration in patients with acute ischemia has been successfully developed and validated.

Tebentafusp in the treatment of metastatic uveal melanoma - the first patient treated in the Czech Republic.

Uveal melanoma is a rare cancer, in which metastases occur in approximately one half of cases. In metastatic disease, the prognosis is unfavorable and the median of survival does not exceed 6 months. Effective treatment options were very limited up to date. Tebentafusp is a bispecific fusion protein, which as the first drug proved efficacy in uveal melanoma. The patient was referred for suspected uveal melanoma of the left eye. She was treated for Hodgkin's disease in the past. Primarily, the tumor was treated by radiosurgery with radiotherapy of a small lesion of the vertebral body. However, later the patient had to undergo bulbus enucleation with confirmation of a large tumor category pT4b. PET/CT revealed metastases of the bones and the liver; simultaneously, haplotype A*02: 01 was confirmed. The patient underwent radiotherapy of the sternum and later, after confirmation of payment from the health insurance company, she started treatment with tebentafusp. The first three doses were administered during admission to the hospital, with a need to treat cytokine release syndrome by corticosteroids. Later, the administration was performed in an out-patient regimen, without complications, except for a transient elevation of transaminases. The first CT restaging confirmed stable disease; however, the second restaging confirmed a new osteolytic lesion in the processus of Th11. Because of progression, the treatment with tebentafusp was withdrawn after 6 months. Unfortunately, the lesion could not be treated by radiotherapy. Two months later, the patient was urgently admitted to the hospital because of right-sided hemiplegia; MRI revealed bleeding metastatic lesion in the brain stem. In this case report, we present the case of the first patient treated with this drug in the Czech Republic.

Comparison of MRI findings of hypothalamic-optic chiasmatic gliomas and craniopharyngiomas.

Differential diagnosis of hypothalamic-optic chiasmatic gliomas (HOCGs) and craniopharyngiomas on magnetic resonance imaging (MRI) can be quite challenging. To compare the MRI features of HOCGs and cranipharyngiomas. Patients diagnosed with HOCG or craniopharyngioma in histopathological evaluation between 2012 and 2022 and who underwent preoperative contrast-enhanced brain MRI were included. Various MRI features were retrospectively evaluated for each lesion: T2-weighted imaging and fluid attenuation inversion recovery hyperintensity, calcification, cystic change, T1-weighted (T1W) imaging hyperintensity of the cystic component, hemorrhage, involvement of sellar, suprasellar or other adjacent structures, lobulated appearance, presence of hydrocephalus, and contrast enhancement pattern. Apparent diffusion coefficient (ADC) values were also evaluated and compared. Among 38 patients included, 13 (34%) had HOCG and 25 (66%) had craniopharyngioma. Craniopharyngiomas had a significantly higher rate of cystic changes, calcification, and T1W imaging hyperintensity of the cystic component than HOCGs (P <0.05). Of HOCGs, 92% had chiasm involvement, 23% had optic nerve involvement, and 31% had brain stem involvement. On the other hand, chiasm involvement was observed in 8% of craniopharyngiomas, but none had optic nerve and/or brain stem involvement (P <0.05). While 62% (8/13) of HOCGs had diffuse homogeneous enhancement, 80% (20/25) of craniopharyngiomas had a diffuse heterogeneous enhancement pattern. Mean ADC values were significantly higher in craniopharyngiomas compared to HOCGs (2.1 vs. 1.6 ×10-3mm2/s, P <0.05). Although some neuroimaging findings may overlap, features such as presence of cyst and calcification, brain stem and optic pathway involvement, different enhancement patterns, and ADC values may be helpful in the differential diagnosis of HOCGs and craniopharyngiomas.

Mapping ACE2 and TMPRSS2 co-expression in human brain tissue: implications for SARS-CoV-2 neurological manifestations.

The Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily targets respiratory cells, but emerging evidence shows neurological involvement, with the virus directly affecting neurons and glia. SARS-CoV-2 entry into a target cell requires co-expression of ACE2 (Angiotensin-converting enzyme-2) and TMPRSS2 (Trans membrane serine protease-2). Relevant literature on human neurological tissue is sparse and mostly focused on the olfactory areas. This prompted our study to map brain-wide expression of these entry proteins and assess age-related changes. The normal brain tissue samples were collected from cerebral cortex, hippocampus, basal ganglia, thalamus, hypothalamus, brain stem and cerebellum; and were divided into two groups - up to 40 years (n = 10) and above 40 years (n = 10). ACE2 and TMPRSS2 gene expression analysis was done using qRT-PCR and protein co-expression was seen by immunofluorescence. The ACE2 and TMPRSS2 gene expression was observed to be highest in hypothalamus and thalamus regions, respectively. Immunoreactivity for both ACE-2 and TMPRSS2 was observed in all examined brain regions, confirming the presence of these viral entry receptors. Co-localisation was maximum in hypothalamus. Our study did not find any trend related to different age groups. The expression of both these viral entry receptors suggests that normal human brain is susceptibility to SARS-CoV-2, perhaps which could be related to the cognitive and neurological impairment that occur in patients.

Effects of Green and Gold Kiwifruit Varieties on Antioxidant Neuroprotective Potential in Pigs as a Model for Human Adults.

Kiwifruit (KF) has shown neuroprotective potential in cell-based and rodent models by augmenting the capacity of endogenous antioxidant systems. This study aimed to determine whether KF consumption modulates the antioxidant capacity of plasma and brain tissue in growing pigs. Eighteen male pigs were divided equally into three groups: (1) bread, (2) bread + Actinidia deliciosa cv. 'Hayward' (green-fleshed), and (3) bread + A. chinensis cv. 'Hort16A' (yellow-fleshed). Following consumption of the diets for eight days, plasma and brain tissue (brain stem, corpus striatum, hippocampus, and prefrontal cortex) were collected and measured for biomarkers of antioxidant capacity, enzyme activity, and protein expression assessments. Green KF significantly increased ferric-reducing antioxidant potential (FRAP) in plasma and all brain regions compared with the bread-only diet. Gold KF increased plasma ascorbate concentration and trended towards reducing acetylcholinesterase activity in the brain compared with the bread-only diet. Pearson correlation analysis revealed a significant positive correlation between FRAP in the brain stem, prefrontal cortex, and hippocampus with the total polyphenol concentration of dietary interventions. These findings provide exploratory evidence for the benefits of KF constituents in augmenting the brain's antioxidant capacity that may support neurological homeostasis during oxidative stress.

The Impact of Enteral Nimodipine on Endothelial Cell Apoptosis in an Animal Subarachnoid Hemorrhage Model.

Enteral nimodipine is the most evidence-based and widely used drug for the treatment of delayed cerebral ischemia and is known to have various neuroprotective functions. However, the neuroprotective mechanism of nimodipine still remains unclear, and the effects of nimodipine remain ambiguous. Herein, we studied the effect of enteral nimodipine on endothelial apoptosis after subarachnoid hemorrhage (SAH). SAH was experimentally introduced in white rabbits (n = 42) that were grouped as follows: enteral nimodipine (SAH-nimodipine group, n = 14), a control that received normal saline (SAH-saline group, n = 13), and a control without hemorrhage (control group, n = 15). On the third day after SAH induction, the brain stem, including the vertebrobasilar vascular system, was extracted. The effects of enteral nimodipine were analyzed by group using histopathologic analysis, including immunohistochemical staining of apoptosis-related proteins (Bcl2 [anti-apoptotic] and Bax [pro-apoptotic]). Cytoplasmic vacuolation of smooth muscle cells was observed in two SAH hemorrhagic groups and was more prominent in the SAH-saline group. Endothelial desquamation was observed only in the SAH-saline group. For the basilar artery, expression of Bcl2 and Bax in the SAH-nimodipine group was lower than that in the SAH-saline group, but significant differences were not observed (pBcl2 = 0.311 and pBax = 0.720, respectively). In penetrated arterioles, the expression of Bax in the SAH-nimodipine group was significantly lower than that of the SAH-saline group (p < 0.001). The thickness of the tunica media in the basilar artery was thinner in the SAH-nimodipine group than in the SAH-saline group (p < 0.001). This study suggests that enteral nimodipine may have a neuroprotective function by inhibiting endothelial apoptosis in small arterioles and preventing smooth muscle cell proliferation in large arteries.

Stereotactic radiosurgery for vestibular schwannomas: evolution of the philosophy of treatment

Vestibular schwannomas are the most common tumors in the cerebellopontine angle. Stereotactic radiosurgery is included in the armamentarium of methods for treating these tumors along with surgical treatment. Given the annual incidence of more than 15 radiosurgical cases of vestibular schwannomas per 1 million population, the expected need for stereotactic radiosurgery of these tumors in Russia is more than 2000 cases annually.Stereotactic radiosurgery is located at the intersection of several clinical specialties: neuroradiology, neurosurgery and radiation therapy, each of which has made a significant contribution to the development of this treatment method. The most commonly used for this is the cobalt‑based Leksell Gamma Knife, specifically intended for the treatment of intracranial neoplasms. Treatment is also possible with modern linear accelerators and proton accelerators, which provide high accuracy and conformity of irradiation. The experience gained since the first application of this method in the treatment of vestibular schwannomas has made it possible not only to optimize the radiation doses to the tumor and adjacent critical structures (brain stem, inner ear), but also to study the features of post‑radiation micro‑ and macro‑ changes, their impact on the clinical course, to develop recommendations for radiosurgery with schwannomas of various sizes. All this contributes to high control of tumor growth and a low level of functional disorders, which, along with easy tolerability and minimal hospitalization time, determines lower cost of this treatment compared to the traditional surgical approach and significant social and economic effect.This lecture is intended for neurosurgeons and radiation therapists and focuses on the most significant factors that influenced the development, promotion and active use of stereotactic radiosurgery of vestibular schwannomas in cli nical practice.

A Pilot Study of Simulation-Free Hippocampal-Avoidance Whole Brain Radiation Therapy Using Diagnostic MRI-Based and Online Adaptive Planning

We aimed to demonstrate the clinical feasibility and safety of simulation-free hippocampal avoidance whole brain radiation therapy (HA-WBRT) in a pilot study (National Clinical Trial 05096286). Ten HA-WBRT candidates were enrolled for treatment on a commercially available computed tomography (CT)-guided linear accelerator with online adaptive capabilities. Planning structures were contoured on patient-specific diagnostic magnetic resonance imaging (MRI), which were registered to a CT of similar head shape, obtained from an atlas-based database (AB-CT). These patient-specific diagnostic MRI and AB-CT data sets were used for preplan calculation, using NRG-CC001 constraints. At first fraction, AB-CTs were used as primary data sets and deformed to patient-specific cone beam CTs (CBCT) to give patient-matched density information. Brain, ventricle, and brain stem contours were matched through rigid translation and rotation to the corresponding anatomy on CBCT. Lens, optic nerve, and brain contours were manually edited based on CBCT visualization. Preplans were then reoptimized through online adaptation to create final, simulation-free plans, which were used if they met all objectives. Workflow tasks were timed. In addition, patients underwent CT-simulation to create immobilization devices and for prospective dosimetric comparison of simulation-free and simulation-based plans. Median time from MRI importation to completion of "preplan" was 1 weekday (range, 1-4). Median on-table workflow duration was 41 minutes (range, 34-70). NRG-CC001 constraints were achieved by 90% of the simulation-free plans. One patient's simulation-free plan failed a planning target volume coverage objective (89% instead of 90% coverage); this was deemed acceptable for first-fraction delivery, with an offline replan used for subsequent fractions. Both simulation-free and simulation CT-based plans otherwise met constraints, without clinically meaningful differences. Simulation-free HA-WBRT using online adaptive radiation therapy is feasible, safe, and results in dosimetrically comparable treatment plans to simulation CT-based workflows while providing convenience and time savings for patients.

Autoimmune GFAP Astrocytopathy—Beyond the Known Horizon, India’s First Multifaceted Institutional Experience

Background: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is an immune-mediated inflammatory disease of the central nervous system, the clinical phenotype of which includes meningoencephalitis, myelitis, optic neuritis, seizures, movement disorders, autonomic dysfunction among others, affecting people across all ages. Due to its recent discovery, there is a paucity of literature on this topic and an absolute lack of Indian case series. Purpose: This study aims to shed light on the variable presentations of anti-GFAP astrocytopathy and review the existing literature on the topic. Methods: This was a retrospective study that included all patients who tested positive in the cerebrospinal fluid(CSF) and/or serum for GFAP immunoglobulin G between February 2023 and August 2023, after obtaining ethical clearance. Relevant clinical, demographic data was collected from the electronic medical records. A descriptive analysis of data was done and the current available literature was reviewed. Results: Our case series included four patients (F:M::3:1) with a median age of 28 years at symptom onset. Two of the cases had a relapsing-remitting disease pattern, while the other two had monophasic illnesses. The clinical spectrum we encountered included ataxia, tremors, myoclonus, seizures, recurrent myelitis, brain stem syndromes, autonomic dysfunction and psychiatric manifestations. All four patients responded remarkably to steroids and two patients are on rituximab therapy. Conclusion: Autoimmune GFAP astrocytopathy encompasses an expanding clinical spectrum and should be considered in the context of myelitis, optic neuritis, ataxia, papillitis, seizures, autonomic dysfunction and movement disorders occurring in isolation or more commonly in varying combinations. Our case series, the first in India, shows a favourable clinical profile and the primary hurdle encountered in all four cases was to establish a diagnosis, further stressing the need for a predictive diagnostic algorithm.