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Background: Angelman syndrome (AS) is a rare neurodevelopmental genetic disorder caused by the loss of function of the ubiquitin ligase E3A (UBE3A) gene, affecting approximately 1:15,000 live births. We have recently shown that mitochondrial function in AS is altered during mid to late embryonic brain development leading to increased oxidative stress and enhanced apoptosis of neural precursor cells. However, the overall alterations of metabolic processes are still unknown. Hence, as a follow-up, we aim to investigate the metabolic profiles of wild-type (WT) and AS littermates and to identify which metabolic processes are aberrant in the brain of AS model mice during embryonic development., Methods: We collected brain tissue samples from mice embryos at E16.5 and performed metabolomic analyses using proton nuclear magnetic resonance ( 1 H-NMR) spectroscopy. Multivariate and Univariate analyses were performed to determine the significantly altered metabolites in AS mice. Pathways associated with the altered metabolites were identified using metabolite set enrichment analysis., Results: Our analysis showed that overall, the metabolomic fingerprint of AS embryonic brains differed from those of their WT littermates. Moreover, we revealed a significant elevation of distinct metabolites, such as acetate, lactate, and succinate in the AS samples compared to the WT samples. The elevated metabolites were significantly associated with the pyruvate metabolism and glycolytic pathways., Limitations: Only 14 metabolites were successfully identified and investigated in the present study. The effect of unidentified metabolites and their unresolved peaks was not determined. Additionally, we conducted the metabolomic study on whole brain tissue samples. Employing high-resolution NMR studies on different brain regions could further expand our knowledge regarding metabolic alterations in the AS brain. Furthermore, increasing the sample size could reveal the involvement of more significantly altered metabolites in the pathophysiology of the AS brain., Conclusions: Ube3a loss of function alters bioenergy-related metabolism in the AS brain during embryonic development. Furthermore, these neurochemical changes could be linked to the mitochondrial reactive oxygen species and oxidative stress that occurs during the AS embryonic development., (© 2024. The Author(s).)

Treatment of brain-related diseases is one of the most strenuous challenges in drug delivery research due to numerous hurdles, including poor blood-brain barrier penetration, lack of specificity, and severe systemic toxicities. Our research primarily focuses on the delivery of natural therapeutic compound, α-asarone, for the treatment of brain-related diseases. However, α-asarone has poor aqueous solubility, bioavailability, and stability, all of which are critical issues that need to be addressed. This study aims at formulating a lipid nanoparticulate system of α-asarone (A-LNPs) that could be used as a brain drug delivery system. The physicochemical, solid-state properties, stability, and in vitro and in vivo studies of the A-LNPs were characterized. The release of α-asarone from the A-LNPs was prolonged and sustained. After intravenous administration of A-LNPs or free α-asarone, significantly higher levels of α-asarone from the A-LNPs were detected in murine plasma and brain parenchyma fractions, confirming the ability of A-LNPs to not only maintain a therapeutic concentration of α-asarone in the plasma, but also transport α-asarone across the blood-brain barrier. These findings confirm that lipid nanoparticulate systems enable penetration of natural therapeutic compound α-asarone through the blood-brain barrier and may be a candidate for the treatment of brain-related diseases.

Background: Perilesional gliosis is an important substrate for seizures in patients harboring a calcified neurocysticercosis (NCC) lesion and magnetic resonance imaging (MRI) is useful for evaluating gliosis., Aims: The purpose of this study was to evaluate the usefulness of double-inversion recovery (DIR) sequence for identifying perilesional gliosis., Settings and Design: Hospital-based cross-sectional study., Methods and Materials: Forty-five patients with seizures were included in this study and a total of 88 calcified lesions identified on susceptibility weighted imaging (SWI) were evaluated on 3D-fluid attenuating inversion recovery (FLAIR), 3D-DIR, and 3D-postcontrast T1-weighted imaging on a 3T MRI for the presence of perilesional signal changes/enhancement. Perilesional signal was rated on a semiquantitative scale from grade 0 to 2 by independent raters., Statistical Analysis Used: Friedman, Wilcoxon signed rank, and Kappa tests were used., Results: 3D-DIR sequence performed better than both 3D-FLAIR and postcontrast 3D-T1W sequences as more number of lesions showed perilesional signal change on DIR sequence. DIR sequence showed perilesional signal abnormality in 24 lesions in which 3D-FLAIR was normal, whereas in another 18 lesions, it demonstrated perilesional signal changes better than 3D-FLAIR. In only three lesions, FLAIR was found to be superior to DIR sequence, whereas postcontrast T1W images showed rim enhancement in five cases where no perilesional signal change was seen on FLAIR/DIR sequences., Conclusions: Combining 3D-DIR with 3D-FLAIR, and postcontrast 3D-T1W sequences is beneficial for evaluation of calcified NCC lesions and 3D-DIR sequence is better than other two sequences for perilesional signal abnormalities., Competing Interests: None

Delayed brain development in perinatally HIV-infected children may affect the functional brain activity and subsequently cognitive function. The current study evaluated the functional brain activity in HIV-infected children by quantifying the amplitude of low frequency fluctuations (ALFF) and functional connectivity (FC). Additionally, correlation of ALFF and FC with cognitive measures was performed. Twenty-six HIV-infected children and 20 control children underwent neuropsychological (NP) assessment and resting-state functional magnetic resonance imaging (rs-fMRI). ALFF and FC maps were generated and group differences were analyzed using two-sample t-test. Furthermore, ALFF and FC showing significant group differences were correlated with NP scores using Pearson's correlation. Significantly lower ALFF in the left middle temporal gyrus, precentral and post central gyrus was observed in HIV-infected children compared to controls. FC was significantly reduced in the right inferior parietal, vermis, middle temporal and left postcentral regions, and significantly increased in the right precuneus, superior parietal and left middle frontal regions in HIV-infected children as compared to control. HIV-infected children showed significantly lower NP scores in various domains including closure, exclusion, memory, verbal meaning, quantity and hidden figure than controls. These waning cognitive functions were significantly associated with changes in ALFF and FC in HIV-infected children. The findings suggest that abnormal ALFF and FC may responsible for cognitive deficits in HIV-infected children. ALFF and FC in association with cognitive evaluation may provide a clinical biomarker to evaluate functional brain activity and to plan neurocognitive intervention in HIV-infected children undergoing standard treatment., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Pediatric HIV patients often suffer with neurodevelopmental delay and subsequently cognitive impairment. While tissue injury in cortical and subcortical regions in the brain of adult HIV patients has been well reported there is sparse knowledge about these changes in perinatally HIV infected pediatric patients. We analyzed cortical thickness, subcortical volume, structural connectivity, and neurocognitive functions in pediatric HIV patients and compared with those of pediatric healthy controls. With informed consent, 34 perinatally infected pediatric HIV patients and 32 age and gender matched pediatric healthy controls underwent neurocognitive assessment and brain magnetic resonance imaging (MRI) on a 3 T clinical scanner. Altered cortical thickness, subcortical volumes, and abnormal neuropsychological test scores were observed in pediatric HIV patients. The structural network connectivity analysis depicted lower connection strengths, lower clustering coefficients, and higher path length in pediatric HIV patients than healthy controls. The network betweenness and network hubs in cortico-limbic regions were distorted in pediatric HIV patients. The findings suggest that altered cortical and subcortical structures and regional brain connectivity in pediatric HIV patients may contribute to deficits in their neurocognitive functions. Further, longitudinal studies are required for better understanding of the effect of HIV pathogenesis on brain structural changes throughout the brain development process under standard ART treatment.

Introduction: To explore the neuroanatomical correlates of primary writing tremor (PWT) and the role of cerebellum, using advanced structural neuroimaging. Till date, there are no studies exploring the gray and white matter changes using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) in PWT., Methods: Ten male patients with PWT were evaluated clinically and with magnetic resonance imaging. VBM and DTI images of patients were compared with that of 10 healthy male subjects. Spatially unbiased infra-tentorial template (SUIT) analysis was done to investigate the alterations of cerebellar gray matter. Region-of-interest analysis was performed on regions observed to be significantly different on DTI analysis., Results: The mean duration of illness and mean age of the patients were 3.5 ± 1.9 and 51.7 ± 8.6 years, respectively. On VBM analysis, the cluster of gray matter atrophy was found in bilateral cerebellar areas of culmen and left declive, right superior and medial frontal gyrus, bilateral middle frontal gyrus, bilateral anterior cingulate gyrus, and bilateral parahippocampal gyrus. DTI showed significantly reduced fractional anisotrophy of the anterior thalamic radiation, cingulum, and inferior fronto-occipital fasciculus in PWT patients compared to controls. The axial diffusivity, mean diffusivity, and radial diffusivity maps did not reveal any significant differences. On SUIT analysis, significant atrophy was found in right uvula and semilunar lobule in patients with PWT compared to controls., Conclusions: Our study found that patients with PWT had predominant gray matter atrophy in parts of cerebellum and frontal lobe along with white matter changes of the cingulum and frontal lobe connections.

Introduction: The resting state functional MRI (rsfMRI) approach is useful to explore the brain's functional organization in health and disease conditions. In this study, using rsfMRI the alteration in brain due to vitamin B12 deficiency and reversibility of these alterations following therapy was studied., Methods: Thirteen patients with clinical and biochemical evidence of vitamin B12 deficiency were recruited in this study. Fifteen age and sex matched healthy controls were also included. Patients and controls were clinically evaluated using neuropsychological test (NPT). The analysis was carried out using regional homogeneity (ReHo) and low frequency oscillations (LFO) of BOLD signals in resting state. Six patients were also evaluated with rsfMRI and NPT after 6 weeks replacement therapy., Results: ReHo values in patients with vitamin B12 deficiency were significantly lower than controls in the entire cerebrum and the brain networks associated with cognition control, i.e., default mode, cingulo-opercular and fronto-parietal network. There was no significant difference using LFO and it did not show significant correlations with NPT scores. ReHo showed significant correlation with NPT scores. All the 6 patients showed increase in ReHo after replacement therapy., Conclusion: We conclude that brain networks associated with cognition control are altered in patients with vitamin B12 deficiency, which partially recover following six weeks of replacement therapy. This is the first study to evaluate the rsfMRI in the light of clinical neuropsychological evaluation in patients. rsfMRI may be used as functional biomarker to assess therapeutic response in vitamin B12 deficiency patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Neuroleptic malignant syndrome (NMS) is a life-threatening neurologic emergency associated with the use of mainly typical antipsychotic drugs. It is characterized by fever, altered mental status, generalized rigidity, autonomic instability, myoclonus, raised creatine phosphokinase, rhabdomyolysis, and leukocytosis. Neuroimaging (brain computed tomography/magnetic resonance imaging [MRI]) is usually normal in most of the cases of NMS. Magnetic resonance imaging findings have not been well elucidated in NMS as yet. Very few cases have been reported worldwide. We herein, report a case of a 42-year-old patient of NMS, who presented to us with reversible changes in MRI brain. This case report highlights the possible MRI changes in NMS and their plausible mechanism.

Introduction: Vitamin B12 deficiency may cause neural tissue damage. Even in advanced stages, conventional imaging of brain usually appears normal in vitamin B12 deficient patients. The aim of this study was to assess the structural and functional changes in brain of patients with vitamin B12 deficiency before and after six weeks of vitamin B12 supplementation using diffusion tensor imaging and pseudo-continuous arterial spin labelling (PCASL)., Methods: MR imaging including DTI and PCASL and neuropsychological tests (NPT) were performed in 16 patients with vitamin B12 deficiency and 16 controls before and after 6weeks of therapy. Cerebral blood flow (CBF) derived from PCASL and DTI indices was calculated in brain of patients with vitamin B12 deficiency and controls., Results: Patient with vitamin B12 deficiency showed altered neuropsychological scores and altered CBF as well as fractional anisotropy (FA) values in various brain regions as compared with controls. Both CBF values and neuropsychological scores showed complete reversibility at 6weeks post therapy. Though FA values showed significant recovery, it failed to show complete recovery., Conclusion: Our results suggest that micro-structural recovery lags behind functional recovery in patients with vitamin B12 deficiency following therapy and CBF change may be used as an early predictor of complete recovery in patients with B12 deficiency., (Copyright © 2015. Published by Elsevier Inc.)

Heat stroke is common in tropical country like India especially during the summer season. We report an unusual case of acute vertebrobasilar territory infarcts due to heat stroke. A middle-aged man developed hyperpyrexia (42.2°C) after strenuous fieldwork in a hot summer day. Next morning, he was found in altered sensorium. The brain imaging showed acute posteromedial midbrain and cerebellar infarcts. A diagnosis of acute ischemic stroke due to heat stroke was made, and the patient was put under the intensive care unit. Two weeks later, the patient became conscious, but had slurred speech and incoordination in all the 4 limbs. Six months after rehabilitation, the patient still have scanning speech and limb ataxia. Acute ischemic stroke worsened the prognosis in our patient. Acute infarct is a very rare neurologic manifestation of heat stroke. This case report emphasizes the importance of suspecting acute infarct in heat stroke patient., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Diffusion tensor tractography (DTT) is a newer magnetic resonance imaging (MRI) technique that helps in evaluation of white matter. Presurgical planning with tractography may be valuable for evaluation of white matter tracts and their relationship with epileptogenic focus and for evaluation of cortical fibres around the epileptogenic zone., Methods: This study was carried out on 33 patients diagnosed with medically refractory epilepsy (males, 27; females, 6) with a mean age of 31.93 (range: 19-50) years. Twenty age and sex matched controls were also included. DTT evaluation was done using a 3.0 TexlaMRI scanner. Single-shot spin-echo echo-planar imaging (with 32-different diffusion gradient directions) was acquired for reconstruction of the white matter tracts. Diffusion metrics within fibre bundles that were reconstructed by a continuous fibre-track algorithm were compared between groups., Results: Patients had either partial seizures (21 patients; simple partial, complex partial or secondarily generalized seizure) or generalized seizures (12 patients; tonic clonic, tonic or myoclonic). Out of the 33 patients, 23 patients were classified into the lesional group and the rest into the non-lesional group. The lesions observed on conventional MRI included focal gliosis, hippocampal sclerosis, post-hypoxic encephalopathy, calcification and post-traumatic cavitation, in various parts of the brain. Significant differences were observed in terms of fractional anisotropy and mean diffusivity values amongst controls and patients, as well as on the lesional and non-lesional side of the brain; patients with a normal conventional imaging showed fractional anisotropy and mean diffusivity changes as well., Conclusion: We conclude that widespread diffusion abnormalities occur in the white matter tracts on the side of lesion as well as distant from the epileptic focus., (Copyright © 2013 Elsevier B.V. All rights reserved.)

To investigate the potential of RNA interference (RNAi) as antiviral agent against rabies, two small interfering RNAs (siRNAs) targeting rabies virus (RABV) nucleoprotein (N) and polymerase (L) genes were designed and evaluated. Both siRNAs knockdown or silenced the target RABV genes as evaluated in a plasmid based transient expression model. For efficient delivery, adenoviruses expressing the siRNAs were constructed and antiviral potential of the delivered siRNAs was investigated in BHK-21 cells. When cells treated with adenoviruses expressing siRNAs were challenged with RABV, there was 88.35±2.4% and 41.52±9.3% reduction in RABV multiplication in infected cells with siRNAs targeting RABV-N and L genes, respectively. Relative quantification of RABV transcripts using real-time PCR revealed knockdown of both RABV-N and L gene transcripts, however, significant reduction was observed only with adenovirus expressing siRNA against RABV-N. When mice treated intracerebrally with adenoviruses expressing siRNAs were challenged peripherally with lethal RABV by the intramuscular route in masseter muscle, there was 66.6% and 33.3% protection with adenoviruses expressing siRNAs against RABV-N and L genes, respectively. These results demonstrated that adenovirus expressing siRNA against RABV-N efficiently inhibited the RABV multiplication both, in vitro and in vivo and conferred significant protection against lethal RABV challenge. This supported the hypothesis that RNAi, based on siRNA targeting RABV-N gene can prevent RABV infection and holds the potential of RNAi as an approach to prevent rabies infection., (Copyright © 2011 Elsevier B.V. All rights reserved.)

We report noninvasive imaging of the brain of adult zebrafish (Danio rerio) using real time optical coherence tomography (OCT) capable of acquiring cross sectional 2D OCT images @ 8 frames/sec. Anatomic features such as telencephalon, tectum opticum, eminentia Granularis and cerebellum were clearly resolved in the OCT images. A 3D model of zebrafish brain was reconstructed, for the first time to our knowledge, using these 2D OCT images.

Aim: To establish normal ranges for the lateral, third, and fourth ventricular dimensions and the ventriculo-hemispheric ratio (VHR) in neonates using cranial ultrasonography., Method: Intra-cranial ventricles were assessed ultrasonographically using anterior fontanelle as acoustic window. Data were analyzed to determine correlation, coefficient of determination (R2), regression equations and plotted against gestational age (GA)., Results: Of total 1483 neonates (25-42 w GA), 372(25%) had GA < 34 weeks. GA strongly correlated with anterior horn width (AHW; 0.92), thalamo-occipital distance (TOD; 0.94), and third (0.78) and fourth (0.89) ventricular widths. The R2 values were 0.85, 0.88, 0.66 and 0.80, respectively. VHR had weak correlation (0.12, R(2)= 0.005) with GA and stayed constant (0.27-0.28) across GA. Nomograms of AHW, TOD, and third and fourth ventricular widths were constructed with respect to GA., Conclusion: Intra-cranial ventricles increase in size with GA but this increase is limited to only a few mm and is proportional to increment in brain tissue. Nomograms and regression equations of AHW, TOD and widths of third and fourth ventricles can assist in objectively assessing ventricular sizes. The almost uniform VHR can be used to screen ventricle size while suspecting hydrocephalus.

A simple method for the rapid detection of rabies virus was developed employing a single-tube reverse transcription polymerase chain reaction (RT-PCR). The method utilized a single buffer system for both RT and PCR and was performed without interruption as a single thermal cycling programme. Two primer sets within the genes coding for rabies nucleoprotein and glycoprotein were used to amplify a 533 bp and a 406 bp amplicon, respectively. The amplified products were detected with a challenge virus strain (CVS) of rabies. There was no amplified product with uninfected mouse or dog brain. The method was applied to detect rabies virus in 10 mouse inoculation test (MIT)-positive and three MIT-negative brain tissue samples. The amplified product was found only in the MIT-positive samples. The amplified product was confirmed by restriction endonuclease analysis using Hinf1. The results from RT-PCR correlated well with the results from MIT. This indicates that the single-tube RT-PCR may be a useful method for detecting rabies virus in brain tissue samples from suspected cases of rabies.

The value of step-by-step confirmation of the location of the brain biopsy probe is demonstrated, using serial CT scanning to confirm the exact source of the sample tissue. Concomitant use of CT angiography and a CT air study makes possible the biopsy of small areas and of areas near major cerebral vessels, as well as of lesions near critical areas like the optic chiasma, basal ganglia, midbrain, and other complex lesions. The pathologist on-line examination of the CT-confirmed serial samples enables the surgeon to obtain the most informative tissue for the ultimate histopathological diagnosis. Our experience with the technique is illustrated by examples of its application in some complex cases.