Developmental Comparison of Ceramide in Wild-Type and Cln3Δex7/8 Mouse Brains and Sera

CLN3 disease is a neurodevelopmental disease leading to early visual failure, motor decline, and death. CLN3 pathogenesis has been linked to dysregulation of ceramide, a key intracellular messenger impacting various biological functions. Ceramide is upregulated in brains of CLN3 patients and activates apoptosis. Ceramide levels over the lifespan of WT and Cln3Δex7/8 mice were measured using the DGK assay. Ceramide subspecies were determined by LC-MS. Ceramide synthesis enzymes and pre- and post-synaptic mRNA expression was measured in Cln3Δex7/8 and normal mouse brains. Neuronal cell death was established by PARP cleavage and Caspases 3/6/9 and cytochrome C mRNA expression in Cln3Δex7/8 and normal mouse brains. In WT mouse, a ceramide peak was noted at 3 weeks of age. The absence of this peak in Cln3Δex7/8 mice might be related to early disease pathogenesis. Increase of ceramide in Cln3Δex7/8 mouse brain at 24 weeks of age precedes neuronal apoptosis. The correlation between serum and brain ceramide in WT mice, and dysregulation of ceramide in serum and brain of Cln3Δex7/8 mice, and the significant increase in ceramide in Cln3Δex7/8 mouse brains and sera argue for use of easily accessible serum ceramide levels to track response to novel therapies in human CLN3 disease

Large-Scale Phenotyping of an Accurate Genetic Mouse Model of JNCL Identifies Novel Early Pathology Outside the Central Nervous System

Cln3Δex7/8 mice harbor the most common genetic defect causing juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive disease involving seizures, visual, motor and cognitive decline, and premature death. Here, to more thoroughly investigate the manifestations of the common JNCL mutation, we performed a broad phenotyping study of Cln3Δex7/8 mice. Homozygous Cln3Δex7/8 mice, congenic on a C57BL/6N background, displayed subtle deficits in sensory and motor tasks at 10–14 weeks of age. Homozygous Cln3Δex7/8 mice also displayed electroretinographic changes reflecting cone function deficits past 5 months of age and a progressive decline of retinal post-receptoral function. Metabolic analysis revealed increases in rectal body temperature and minimum oxygen consumption in 12–13 week old homozygous Cln3Δex7/8mice, which were also seen to a lesser extent in heterozygous Cln3Δex7/8 mice. Heart weight was slightly increased at 20 weeks of age, but no significant differences were observed in cardiac function in young adults. In a comprehensive blood analysis at 15–16 weeks of age, serum ferritin concentrations, mean corpuscular volume of red blood cells (MCV), and reticulocyte counts were reproducibly increased in homozygous Cln3Δex7/8 mice, and male homozygotes had a relative T-cell deficiency, suggesting alterations in hematopoiesis. Finally, consistent with findings in JNCL patients, vacuolated peripheral blood lymphocytes were observed in homozygous Cln3Δex7/8 neonates, and to a greater extent in older animals. Early onset, severe vacuolation in clear cells of the epididymis of male homozygous Cln3Δex7/8 mice was also observed. These data highlight additional organ systems in which to study CLN3 function, and early phenotypes have been established in homozygous Cln3Δex7/8 mice that merit further study for JNCL biomarker development

Effets d'un élevage en milieu physiquement et socialement enrichi sur certains marqueurs cognitifs et neurochimiques du rat agé

Ce travail a déterminé si un élevage en milieu enrichi (EE) durant la vie entière est capable d atténuer les déficits attentionels et mnésiques émergeant avec l âge chez le rat. Nos résultats montrent que l EE prévient certains déficits attentionnels. En ce qui concerne la mémoire spatiale, l EE a un effet bénéfique sur l acquisition et sur la rétention à court terme à tous les âges, et sur la rétention à long terme chez les rats jeunes et moyennement- âgés. Nos résultats montrent également une dissociation entre les effets de l EE sur l attention (observé uniquement chez les âgés) et ceux produits sur la mémoire (observés à tous les âges). Le fait que l EE a des effets bénéfiques sur les performances de mémoire à tous les âges, mais ne prévienne de la dégradation des performances attentionnelles qu à un âge avancé, s explique par le fait que l EE stimule la neuroplasticité, un phénomène moins crucial pour l attention soutenue que pour la formation et la persistance de la mémoire.The present study aimed at determining if lifelong environmental enrichment EE was able to attenuate the attention and memory deficits that emerged with aging. Our results show for the first time that a lifelong exposure to EE may prevent attention deficits which appear with advanced aging. EE enhances also spatial memory performances as it has beneficial effect on acquisition and on short-term retention at all ages, and a robust effect on long-term retention but only in young and middle-aged rats. They also indicate a dissociation between the effect of EE on attention (which was only seen in aged rats) and memory (which was seen at all ages). The fact that EE produced positive effects on memory at all ages, but affected attention only in aged rats can be related to the fact that EE stimulates neuroplasticity, a phenomenon which is probably less crucial for sustained visual attention performance than for memory formation.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Orexins/Hypocretins: Gatekeepers of Social Interaction and Motivation

Ever since the discovery of the brain’s orexin/hypocretin system, most research was directed toward unveiling its contribution to the normal functioning of individuals. The investigation of reward-seeking behaviors then gained a lot of attention once the distribution of orexinergic neurons was revealed. Here, we discuss findings on the involvement of orexins in social interaction, a natural reward type. While some studies have succeeded in defining the relationship between orexin and social interaction, the controversy regarding its nature (direct or inverse relation) raises questions about what aspects have been overlooked until now. Upon examining the literature, we identified a research gap concerning conditions influencing the impact of orexins on social behavior expression. In this review, we introduce a number of factors (e.g., stress, orexin’s source) that must be considered while studying the role of orexins in social interaction. Furthermore, we refer to published research to investigate the stage at which orexins affect social interaction and we highlight the nucleus accumbens (NAc) shell’s role in social interaction and other rewarding behaviors. Finally, the underlying orexin molecular pathway influencing social motivation in particular illnesses is proposed. We conclude that orexin’s impact on social interaction is multifactorial and depends on specific conditions available at a time

Association between vitamin D deficiency and multiple sclerosis- MRI significance: A scoping review

Background/Objective: Multiple Sclerosis is a common demyelinating disease of the central nervous system. Several studies suggested a link between vitamin D deficiency and multiple sclerosis disease activity, which can be evaluated by magnetic resonance imaging. Thereby, the main objective of the following scoping review is to summarize the magnetic resonance imaging findings assessing the probable effects of vitamin D on MS disease activity. Methodology: PRISMA checklist for systematic reviews and meta-analyses was employed to structure this review. Literature was searched for observational and clinical studies tackling the given matter using several search engines including PubMed, CORE, and Embase. Data was extracted in a systematic manner, and the articles meeting the inclusion criteria were quality-assessed by Jadad scale for randomized clinical trials (RCTs) and Newcastle-Ottawa scale for observational studies. Results: A total of 35 articles were included. Twenty-one (60%) studies noted a statistically significant association between vitamin D and Multiple Sclerosis MRI-detected disease activity. MRI-detected features involved lower contrast-enhancing T1 lesions, lower hyperintense T2 lesions, and a decrease in lesions volume. On the other hand, 40% (14 articles) of the articles did not detect any significant effect of vitamin D on Multiple Sclerosis disease activity. Due to the heterogeneity of the studies involved, meta-analysis was not employed in the given review. Discussion/conclusion: There was an abundance in the number of research studies investigating the relationship between vitamin D and Multiple Sclerosis while highlighting the significant role of MRI in assessing the activity of the disease. Numerous studies found that higher serum vitamin D levels are associated with decreased new active cortical and subcortical lesions and lower lesions volume. These findings highlight the importance of imaging modalities in the various aspects of neurological diseases and encourage further research to focus on the preventive effects of vitamin D on MS patients

Thyroxine (T4) Transfer from Blood to Cerebrospinal Fluid in Sheep Isolated Perfused Choroid Plexus: Role of Multidrug Resistance-Associated Proteins and Organic Anion Transporting Polypeptides

Thyroxine (T4) enters the brain either directly across the blood–brain barrier (BBB) or indirectly via the choroid plexus (CP), which forms the blood–cerebrospinal fluid barrier (B-CSF-B). In this study, using isolated perfused CP of the sheep by single-circulation paired tracer and steady-state techniques, T4 transport mechanisms from blood into lateral ventricle CP has been characterized as the first step in the transfer across the B-CSF-B. After removal of sheep brain, the CPs were perfused with 125I-T4 and 14C-mannitol. Unlabeled T4 was applied during single tracer technique to assess the mode of maximum uptake (Umax) and the net uptake (Unet) on the blood side of the CP. On the other hand, in order to characterize T 125 4 protein transporters, steady-state extraction of I-T4 was measured in presence of different inhibitors such as probenecid, verapamil, BCH, or indomethacin. Increasing the concentration of unlabeled-T4 resulted in a significant reduction in Umax%, which was reflected by a complete inhibition of T4 uptake into CP. In fact, the obtained Unet% decreased as the concentration of unlabeled-T4 increased. The addition of probenecid caused a significant inhibition of T4 transport, in comparison to control, reflecting the presence of a carrier mediated process at the basolateral side of the CP and the involvement of multidrug resistance-associated proteins (MRPs: MRP1 and MRP4) and organic anion transporting polypeptides (Oatp1, Oatp2, and Oatp14). Moreover, verapamil, the P-glycoprotein (P-gp) substrate, resulted in ~34% decrease in the net extraction of T4, indicating that MDR1 contributes to T4 entry into CSF. Finally, inhibition in the net extraction of T4 caused by BCH or indomethacin suggests, respectively, a role for amino acid “Lsystem and MRP1/Oatp1 in mediating T4 transfer. The presence of a carrier-mediated transport mechanism for cellular uptake on the basolateral membrane of the CP, mainly P-gp and Oatp2, would account for the efficient T4 transport from blood to CSF. The current study highlights a carrier-mediated transport mechanism for T4 movement from blood to brain at the basolateral side of B-CSF-B/CP, as an alternative route to BBB

Evaluation of the accuracy of new modalities in the assessment and classification of lumbar lordosis: A comparison to Cobb's angle measurement

Background: Because of the association of lumbar lordosis with some clinical conditions such as low back pain, the chiropractic field has emphasized the significance of evaluating the lumbar lordotic status, by measuring Cobb's angle, regarded as the radiological gold standard, for the assessment of lumbar lordosis, on lateral radiographs. However, research has shown that this technique has some considerable drawbacks, mostly in terms of low accuracy and high variability between clinicians when compared with other radiological modalities. The main objective was to compare the diagnostic accuracy of newly established radiological measurements with one of Cobb's angle methods, for the characterization of lumbar lordosis status in a sample of Lebanese patients aged 15 and above. Material and methods: This retrospective single-center study consisted of measuring Cobb's L1-S1 and Cobb's L1-L5 angles, along with the novel established measurements which are the derivative and the normalized surface area, on 134 lateral radiographs of the lumbar spine of Lebanese patients aged fifteen years old and above, gotten from the Radiology department at Zahra'a’s Hospital in Beirut, performed by two observers using MATLAB. Inter-rater agreement was assessed by calculating the Intra-class correlation coefficients. Spearman correlation was analyzed between both Cobb's angle methods and with the derivative and normalized area respectively. 54 patients of the sample were diagnosed by two radiologists, according to their LL status. ROC curve analysis was performed to compare the diagnostic accuracy of the four techniques used. Data were analyzed with IBM SPSS Statistics 23.0 (NY, USA); P < 0.05 was considered statistically significant. Results: According to the ROC curve analysis the new methods, which are the derivative and the normalized surface area, displayed lower diagnostic accuracy (AUCderivative = 0.818 and 0.677, AUCsurface area = 0.796 and 0.828) than Cobb's L1-L5 (AUCL1-L5 = 0.924 and 0.929 values) and L1-S1 (AUCL1-S1 = 0.971 and 0.955) angles, in the characterization of hypo and hyperlordotic patients, respectively, in our Lebanese sample consisting of patients aged 15 and above, because of their lower area under the curve's values compared to the traditional Cobb's techniques. The Cobb's L1-S1 has shown to have the highest diagnostic accuracy among the four methods to characterize normal patients from hypo and hyperlordotic ones, by referring to its highest area under the curve's values. However, the sensitivity of Cobb's L1-L5 angle in characterizing hyperlordotic patients was similar to the one of the normalized surface area with a value of 100%.Conclusion: among the four modalities, the new methods didn't show a better diagnostic accuracy compared to the traditional modalities. Cobb's L1-S1 displayed the highest diagnostic accuracy despite its drawbacks. Further prospective studies are needed to validate the cut-offs obtained for Cobb's L1-S1 angle in our sample

High fat diet exacerbates long-term metabolic, neuropathological, and behavioral derangements in an experimental mouse model of traumatic brain injury

AimsTraumatic brain injury (TBI) constitutes a serious public health concern. Although TBI targets the brain, it can exert several systemic effects which can worsen the complications observed in TBI subjects. Currently, there is no FDA-approved therapy available for its treatment. Thus, there has been an increasing need to understand other factors that could modulate TBI outcomes. Among the factors involved are diet and lifestyle. High-fat diets (HFD), rich in saturated fat, have been associated with adverse effects on brain health. Main methodsTo study this phenomenon, an experimental mouse model of open head injury, induced by the controlled cortical impact was used along with high-fat feeding to evaluate the impact of HFD on brain injury outcomes. Mice were fed HFD for a period of two months where several neurological, behavioral, and molecular outcomes were assessed to investigate the impact on chronic consequences of the injury 30 days post-TBI. Key findingsTwo months of HFD feeding, together with TBI, led to a notable metabolic, neurological, and behavioral impairment. HFD was associated with increased blood glucose and fat-to-lean ratio. Spatial learning and memory, as well as motor coordination, were all significantly impaired. Notably, HFD aggravated neuroinflammation, oxidative stress, and neurodegeneration. Also, cell proliferation post-TBI was repressed by HFD, which was accompanied by an increased lesion volume. SignificanceOur research indicated that chronic HFD feeding can worsen functional outcomes, predispose to neurodegeneration, and decrease brain recovery post-TBI. This sheds light on the clinical impact of HFD on TBI pathophysiology and rehabilitation as well.This work was funded by grants from the Science, Technology and Innovation Funding Authority to AFE (45912) and American University of Beirut Faculty of Medicine, Medical Practice Plan (AUB-FM MPP) to FK (320112). We thank the members of Dr. Ahmed El-Yazbi lab. (Nahed Mogharbil & Dr. Rana Alaaeddine) for their sincere help in conducting the cardiovascular experiments. We thank Leila Nasrallah and Yara Yehya for their help in the neurological experiments. We thank Dr. Gerry Shaw, the CEO of EnCor Biotechnology Inc. Gainesville, Fl, USA for helping us with the antibodies

Western and ketogenic diets in neurological disorders: can you tell the difference?

The prevalence of obesity tripled worldwide between 1975 and 2016, and it is projected that half of the US population will be overweight by 2030. The obesity pandemic is attributed, in part, to the increasing consumption of the high-fat, high-carbohydrate Western diet, which predisposes to the development of the metabolic syndrome and correlates with decreased cognitive performance. In contrast, the high-fat, low-carbohydrate ketogenic diet has potential therapeutic roles and has been used to manage intractable seizures since the early 1920s. The brain accounts for 25% of total body glucose metabolism and, as a result, is especially susceptible to changes in the types of nutrients consumed. Here, we discuss the principles of brain metabolism with a focus on the distinct effects of the Western and ketogenic diets on the progression of neurological diseases such as epilepsy, Parkinson's disease, Alzheimer's disease, and traumatic brain injury, highlighting the need to further explore the potential therapeutic effects of the ketogenic diet and the importance of standardizing dietary formulations to assure the reproducibility of clinical trials.Funding. This work has been funded by an American University of Beirut Faculty of Medicine grant to F.H.K. via the Medical Practice Plan (MPP), titled “Impact of metabolic stress-induced neuroinflammation on molecular and behavioral outcomes post-traumatic brain injury.” The funding agency had no role in the writing of the manuscript or the decision to submit it for publicatio