Central Nervous System Impairment Research Articles

Intracerebroventricular Enzyme Replacement Therapy in Patients with Neuropathic Form of Mucopolysaccharidosis Type II: to Help Practicing Physician

Mucopolysaccharidosis type II (Hunter syndrome, MPS II) is a rare hereditary disease from the group of hereditary metabolic diseases. There are neuropathic and non-neuropathic forms of this disease. The neuropathic form is most common and leads to severe cognitive impairment and progressive damage of central nervous system. Nowadays, early diagnosis and timely initiation of pathogenetic therapy in patients with orphan diseases is the crucial problem of modern pediatrics. Intracerebroventricular administration of idursulfase beta is one of the promising treatment options in patients with neuropathic form of MPS II as it prevents severe complications development. The study of new pathogenetic therapy methods for rare hereditary diseases will help doctors of pediatric specialties to route patient correctly in timely manner to receive all the necessary treatment.

Long Noncoding RNA NR_030777 Alleviates Cobalt Nanoparticles-Induced Neurodegenerative Damage by Promoting Autophagosome-Lysosome Fusion.

Potential exposure to cobalt nanoparticles (CoNPs) occurs in various fields, including hard alloy industrial production, the increasing use of new energy lithium-ion batteries, and millions of patients with metal-on-metal joint prostheses. Evidence from human, animal, and in vitro experiments suggests a close relationship between CoNPs and neurotoxicity. However, a systematic assessment of central nervous system (CNS) impairment due to CoNPs exposure and the underlying molecular mechanisms is lacking. In this study, we found that CoNPs induced neurodegenerative damage both in vivo and in vitro, including cognitive impairment, β-amyloid deposition and Tau hyperphosphorylation. CoNPs promoted the formation of autophagosomes and impeding autophagosomal-lysosomal fusion in vivo and in vitro, leading to toxic protein accumulation. Moreover, CoNPs exposure reduced the level of transcription factor EB (TFEB) and the abundance of lysosome, causing a blockage in autophagosomal-lysosomal fusion. Interestingly, overexpression of long noncoding RNA NR_030777 mitigated CoNPs-induced neurodegenerative damage in both in vivo and in vitro models. Fluorescence in situ hybridization assay revealed that NR_030777 directly binds and stabilizes TFEB mRNA, alleviating the blockage of autophagosomal-lysosomal fusion and ultimately restoring neurodegeneration induced by CoNPs in vivo and in vitro. In summary, our study demonstrates that autophagic dysfunction is the main toxic mechanism of neurodegeneration upon CoNPs exposure and NR_030777 plays a crucial role in CoNPs-induced autophagic dysfunction. Additionally, the proposed adverse outcome pathway contributes to a better understanding of CNS toxicity assessment of CoNPs.

Targeting Neurological Aspects of Mucopolysaccharidosis Type II: Enzyme Replacement Therapy and Beyond.

Mucopolysaccharidosis type II (MPS II) is a rare, pediatric, neurometabolic disorder due to the lack of activity of the lysosomal hydrolase iduronate 2-sulfatase (IDS), normally degrading heparansulfate and dermatansulfate within cell lysosomes. The deficit of activity is caused by mutations affecting the IDS gene, leading to the pathological accumulation of both glycosaminoglycans in the lysosomal compartment and in the extracellular matrix of most body districts. Although a continuum of clinical phenotypes is described, two main forms are commonly recognized-attenuated and severe-the latter being characterized by an earlier and faster clinical progression and by a progressive impairment of central nervous system (CNS) functions. However, attenuated forms havealso been recently described as presenting some neurological involvement, although less deep, such as deficits of attention and hearing loss. The main treatment for the disease is represented by enzyme replacement therapy (ERT), applied in several countries since 2006, which, albeit showing partial efficacy on some peripheral organs, exhibited a very poor efficacy on bones and heart, and a total inefficacy on CNS impairment, due to the inability of the recombinant enzyme to cross the blood-brain barrier (BBB). Together with ERT, whose design enhancements, performed in the last few years, allowed a possible brain penetration of the drug through the BBB, other therapeutic approaches aimed at targeting CNS involvement in MPS II were proposed and evaluated in the last decades, such as intrathecal ERT, intracerebroventricular ERT, ex vivo gene therapy, or adeno-associated viral vector (AAV) gene therapy. The aim of this review is to summarize the main clinical aspects of MPS II in addition to current therapeutic options, with particular emphasis on the neurological ones and on the main CNS-targeted therapeutic approaches explored through the years.

Spatially resolved multiomics on the neuronal effects induced by spaceflight in mice

Impairment of the central nervous system (CNS) poses a significant health risk for astronauts during long-duration space missions. In this study, we employed an innovative approach by integrating single-cell multiomics (transcriptomics and chromatin accessibility) with spatial transcriptomics to elucidate the impact of spaceflight on the mouse brain in female mice. Our comparative analysis between ground control and spaceflight-exposed animals revealed significant alterations in essential brain processes including neurogenesis, synaptogenesis and synaptic transmission, particularly affecting the cortex, hippocampus, striatum and neuroendocrine structures. Additionally, we observed astrocyte activation and signs of immune dysfunction. At the pathway level, some spaceflight-induced changes in the brain exhibit similarities with neurodegenerative disorders, marked by oxidative stress and protein misfolding. Our integrated spatial multiomics approach serves as a stepping stone towards understanding spaceflight-induced CNS impairments at the level of individual brain regions and cell types, and provides a basis for comparison in future spaceflight studies. For broader scientific impact, all datasets from this study are available through an interactive data portal, as well as the National Aeronautics and Space Administration (NASA) Open Science Data Repository (OSDR).

Extracellular vesicles produced by HIV-1 Nef-expressing cells induce myelin impairment and oligodendrocyte damage in the mouse central nervous system

HIV-associated neurocognitive disorders (HAND) are a spectrum of cognitive impairments that continue to affect approximately half of all HIV-positive individuals despite effective viral suppression through antiretroviral therapy (ART). White matter pathologies have persisted in the ART era, and the degree of white matter damage correlates with the degree of neurocognitive impairment in patients with HAND. The HIV protein Nef has been implicated in HAND pathogenesis, but its effect on white matter damage has not been well characterized. Here, utilizing in vivo, ex vivo, and in vitro methods, we demonstrate that Nef-containing extracellular vesicles (Nef EVs) disrupt myelin sheaths and inflict damage upon oligodendrocytes within the murine central nervous system. Intracranial injection of Nef EVs leads to reduced myelin basic protein (MBP) staining and a decreased number of CC1 + oligodendrocytes in the corpus callosum. Moreover, cerebellar slice cultures treated with Nef EVs exhibit diminished MBP expression and increased presence of unmyelinated axons. Primary mixed brain cultures and enriched oligodendrocyte precursor cell cultures exposed to Nef EVs display a decreased number of O4 + cells, indicative of oligodendrocyte impairment. These findings underscore the potential contribution of Nef EV-mediated damage to oligodendrocytes and myelin maintenance in the pathogenesis of HAND.

Towards efficient motor imagery interventions after lower-limb amputation

BackgroundThe therapeutic benefits of motor imagery (MI) are now well-established in different populations of persons suffering from central nervous system impairments. However, research on similar efficacy of MI interventions after amputation remains scarce, and experimental studies were primarily designed to explore the effects of MI after upper-limb amputations.ObjectivesThe present comparative study therefore aimed to assess the effects of MI on locomotion recovery following unilateral lower-limb amputation.MethodsNineteen participants were assigned either to a MI group (n = 9) or a control group (n = 10). In addition to the course of physical therapy, they respectively performed 10 min per day of locomotor MI training or neutral cognitive exercises, five days per week. Participants’ locomotion functions were assessed through two functional tasks: 10 m walking and the Timed Up and Go Test. Force of the amputated limb and functional level score reflecting the required assistance for walking were also measured. Evaluations were scheduled at the arrival at the rehabilitation center (right after amputation), after prosthesis fitting (three weeks later), and at the end of the rehabilitation program. A retention test was also programed after 6 weeks.ResultsWhile there was no additional effect of MI on pain management, data revealed an early positive impact of MI for the 10 m walking task during the pre-prosthetic phase, and greater performance during the Timed Up and Go Test during the prosthetic phase. Also, a lower proportion of participants still needed a walking aid after MI training. Finally, the force of the amputated limb was greater at the end of rehabilitation for the MI group.ConclusionTaken together, these data support the integration of MI within the course of physical therapy in persons suffering from lower-limb amputations.

Biomarkers for prediction of CAR T therapy outcomes: current and future perspectives.

Chimeric antigen receptor (CAR) T cell therapy holds enormous potential for the treatment of hematologic malignancies. Despite its benefits, it is still used as a second line of therapy, mainly because of its severe side effects and patient unresponsiveness. Numerous researchers worldwide have attempted to identify effective predictive biomarkers for early prediction of treatment outcomes and adverse effects in CAR T cell therapy, albeit so far only with limited success. This review provides a comprehensive overview of the current state of predictive biomarkers. Although existing predictive metrics correlate to some extent with treatment outcomes, they fail to encapsulate the complexity of the immune system dynamics. The aim of this review is to identify six major groups of predictive biomarkers and propose their use in developing improved and efficient prediction models. These groups include changes in mitochondrial dynamics, endothelial activation, central nervous system impairment, immune system markers, extracellular vesicles, and the inhibitory tumor microenvironment. A comprehensive understanding of the multiple factors that influence therapeutic efficacy has the potential to significantly improve the course of CAR T cell therapy and patient care, thereby making this advanced immunotherapy more appealing and the course of therapy more convenient and favorable for patients.

Mechanistic Insights and Potential Therapeutic Implications of NRF2 in Diabetic Encephalopathy.

Diabetic encephalopathy (DE) is a complication of diabetes, especially type 2 diabetes (T2D), characterized by damage in the central nervous system and cognitive impairment, which has gained global attention. Despite the extensive research aimed at enhancing our understanding of DE, the underlying mechanism of occurrence and development of DE has not been established. Mounting evidence has demonstrated a close correlation between DE and various factors, such as Alzheimer's disease-like pathological changes, insulin resistance, inflammation, and oxidative stress. Of interest, nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor with antioxidant properties that is crucial in maintaining redox homeostasis and regulating inflammatory responses. The activation and regulatory mechanisms of NRF2 are a relatively complex process. NRF2 is involved in the regulation of multiple metabolic pathways and confers neuroprotective functions. Multiple studies have provided evidence demonstrating the significant involvement of NRF2 as a critical transcription factor in the progression of DE. Additionally, various molecules capable of activating NRF2 expression have shown potential in ameliorating DE. Therefore, it is intriguing to consider NRF2 as a potential target for the treatment of DE. In this review, we aim to shed light on the role and the possible underlying mechanism of NRF2 in DE. Furthermore, we provide an overview of the current research landscape and address the challenges associated with using NRF2 activators as potential treatment options for DE.

Infrequent patterns in cerebrospinal fluid isofocusing test: Clinical significance and contribution of IgG index and Reiber diagram to their interpretation

Cerebrospinal fluid (CSF) isoelectrofocusing (IEF) is considered as the gold standard for detecting an intrathecal synthesis of IgG, which is a hallmark of multiple sclerosis (MS). This corresponds to the presence of CSF-restricted IgG oligoclonal bands (OCB) (typically type 2 pattern). Moreover, this technique can also detect a systemic immune reaction with passive transfer of IgG (type 3 and 4 patterns) for which the clinical relevance is less understood. The aim of our study was to determine the frequency and disease associations of IEF type 3 and 4 patterns and to investigate the potential usefulness of including quantitative data (IgG index and Reiber Diagram) in interpreting such IEF profiles.Among 544 patients who underwent CSF IEF (Hydragel CSF isofocusing kit, Sebia®, France) in our Laboratory during a six-year-period, those who presented type 3 or 4 patterns were selected. Clinical data and results of other immunological tests were analyzed for 27 patients followed in the Neurological Department.Frequencies of type 3 and type 4 patterns were relatively low (2.3 % and 3.4 % respectively). Among patients with type 3 pattern included in our study (n = 10), 5 were diagnosed with MS. For the 5 other patients, the diagnosis was a clinically isolated syndrome (CIS) (2 cases), a probable auto-immune encephalitis (2 cases) and a possible genetic neurodegenerative disease (1 case). MS patients had an IgG index >0.7 and fell into area 4 of Reiber diagram while non-MS patients had an IgG index <0.7 and fell into area 1, except the last case. Regarding type 4 pattern (n = 17), the diagnoses were as follows: MS (3), CIS (4), Neuromyelitis optica spectrum disorders with positive anti-AQP4 antibodies (3) and anti-NMDAR autoimmune encephalitis (1). The remaining cases had central nervous system impairment related to vascular, metabolic or tumoral etiologies (3) or peripheral nervous system impairment (3). In this group (type 4 pattern), IgG index was <0.7 in 15/17 cases. Interpretation using Reiber diagram showed an abnormal blood-brain barrier for 8/17 patients.Type 3 and 4 IEF patterns are infrequently observed in routine neurology practice. It is important for the diagnostic laboratory professional as well as for the neurologist to understand their clinical relevance. Our findings highlight the contribution of quantitative evaluation of CSF (IgG index, Reiber diagram) for the interpretation of such situations. Despite the small size of our study population, our results emphasize the importance of reporting the exact type of IEF pattern and not only the positivity or not of OCB.

Molecular Investigation and Preliminary Validation of Candidate Genes Associated with Neurological Damage in Heat Stroke.

Heat stroke (HS) is a severe medical condition characterized by a systemic inflammatory response that may precipitate multi-organ dysfunction, with a particular predilection for inducing profound central nervous system impairments. We aim to employ bioinformatics techniques for the retrieval and analysis of genes associated with heat stroke-induced neurological damage. We performed a comprehensive analysis of the GSE64778 dataset from the Sequence Read Archive, resulting in the identification of 1178 significantly differentially expressed genes (DEGs). We retrieved 2914 genes associated with heat stroke from the GeneCards database and 2377 genes associated with heat stroke from the Comparative Toxicogenomics Database (CTD). The intersection of the top 300 DEGs in the GSE64778 dataset intersected with the search results of GeneCards and CTD, yielding 25 final candidates for DEGs associated with heat stroke. Gene Ontology functional annotation results indicated that the target genes were mainly involved in apoptosis, stress response, and negative regulation of cellular processes and function in processes such as protein dimerization and protein binding. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed a predominant enrichment of candidate target genes within the PI3K-AKT signaling pathway. Subsequent protein-protein interaction network analysis highlighted HSP90aa1 as a central gene, indicating its pivotal role by possessing the highest number of edges among the genes enriched in the PI3K-AKT signaling pathway. Quantitative reverse transcription-polymerase chain reaction analysis performed on blood samples from patients validated the expression of Hsp90aa1 in individuals exhibiting early neurological damage in HS, consistent with the findings from the mRNA bioinformatics analysis. Additionally, the bioinformatics analysis of the upstream microRNAs (miRNAs) regulating HSP90aa1 and the target miRNAs associated with candidate long non-coding RNAs (lncRNAs) identified three lncRNAs, eight miRNAs, and one mRNA in the regulatory network. The DIANA Tools database and algorithms were employed for pathway enrichment and correlation analysis, revealing a significant association between LOC102547734 and MIR-206-3p, with the latter being identified as a target binding site Moreover, the analysis unveiled a correlation between MIR-206-3p and HSP90aa1, implicating the latter as a potential target binding site within the regulatory network.

The pathogenesis and therapeutic strategies of heat stroke-induced myocardial injury.

Heat stroke (HS) is a febrile illness characterized by an elevation in the core body temperature to over 40°C, accompanied by central nervous system impairment and subsequent multi-organ dysfunction syndrome. In recent years, the mortality rate from HS has been increasing as ambient temperatures continue to rise each year. The cardiovascular system plays an important role in the pathogenesis process of HS, as it functions as one of the key system for thermoregulation and its stability is associated with the severity of HS. Systemic inflammatory response and endothelial cell damage constitute pivotal attributes of HS, other factors such as ferroptosis, disturbances in myocardial metabolism and heat shock protein dysregulation are also involved in the damage to myocardial tissue in HS. In this review, a comprehensively detailed description of the pathogenesis of HS-induced myocardial injury is provided. The current treatment strategies and the promising therapeutic targets for HS are also discussed.

Microglia in Neurodegenerative Diseases.

Neurodegenerative diseases are manifested by a progressive death of neural cells, resulting in the deterioration of central nervous system (CNS) functions, ultimately leading to specific behavioural and cognitivesymptoms associated with affected brain regions. Several neurodegenerative disorders are caused by genetic variants or mutations, although the majority of cases are sporadic and linked to various environmental risk factors, with yet an unknown aetiology. Neuroglial changes are fundamental and often lead to the pathophysiology of neurodegenerative diseases. In particular, microglial cells, which are essential for maintaining CNS health, become compromised in their physiological functions with the exposure to environmental risk factors, genetic variants or mutations, as well as disease pathology. In this chapter, we cover the contribution of neuroglia, especially microglia, to several neurodegenerative diseases, including Nasu-Hakola disease, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, infectious disease-associated neurodegeneration, and metal-precipitated neurodegeneration. Future research perspectives for the field pertaining to the therapeutic targeting of microglia across these disease conditions are also discussed.

Severe CNS involvement in a subset of long-term treated children with infantile-onset Pompe disease

IntroductionThe standard of care for patients with infantile-onset Pompe disease (IOPD) is enzyme replacement therapy (ERT), which does not cross the blood brain barrier. While neuromuscular manifestations of IOPD are well-described, central nervous system (CNS) manifestations of this disorder are far less characterized. Here we describe severe CNS-related neurological manifestations including seizures and encephalopathy in six individuals with IOPD. MethodWe identified six children with IOPD who developed CNS manifestations such as seizures and/or encephalopathy. We studied their brain magnetic resonance imaging scans (MRIs) and graded the severity of white matter hyperintensities (WMHI) using the Fazekas scale scoring system as previously published. Longitudinal cognitive measures were available from 4/6 children. ResultsAll six IOPD patients (4 males/2 females) had been treated with ERT for 12–15 years. Seizures and/or encephalopathy were noted at a median age at onset of 11.9 years (range 9–15 years). All were noted to have extensive WMHI in the brain MRIs and very high Fazekas scores which preceded the onset of neurological symptoms. Longitudinal IQ scores from four of these children suggested developmental plateauing. DiscussionAmong a subset of IOPD patients on long-term ERT, CNS manifestations including hyperreflexia, encephalopathy and seizures may become prominent, and there is likely an association between these symptoms and significant WMHI on MRI. Further study is needed to identify risk factors for CNS deterioration among children with IOPD and develop interventions to prevent neurological decline.

Biological Pathways Associated with Vitamins in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is characterized by early-appearing social communication deficits, with genetic and environmental factors potentially playing a role in its etiology, which remains largely unknown. During pregnancy, certain deficiencies in critical nutrients are mainly associated with central nervous system impairment. The vitamin B9 (folate) is primarily related to one-carbon and methionine metabolism, participating in methyl donor generation. In addition, supplementation with folic acid (FA) is recommended by the World Health Organization (WHO) in the first three gestational months to prevent neural tube defects. Vitamin B12 is related to folate regeneration, converting it into an active form. Deficiencies in this vitamin have a negative impact on cognitive function and brain development since it is involved in myelin synthesis. Vitamin D is intimately associated with Ca2+ levels, acting in bone development and calcium-dependent signaling. This vitamin is associated with ASD at several levels since it has a relation with ASD genes and oxidative stress environment. This review carries the recent literature about the role of folate, vitamin B12, and vitamin D in ASD. In addition, we discuss the possible impact of nutrient deficiency or hypersupplementation during fetal development. On the other hand, we explore the biases of vitamin supplementation studies such as the loss of participants in retrospective studies, as well as multiple variants that are not considered in the conclusion, like dietary intake or auto-medication during pregnancy. In this regard, we aim to contribute to the discussion about the role of vitamins in ASD currency, but also in pregnancy and fetal development as well. Furthermore, stress during pregnancy can be an ASD predisposition, with cortisol as a regulator. In this view, we propose that cortisol is the bridge of susceptibility between vitamin disorders and ASD prevalence.

Two non-familial cases of Galloway-Mowat syndrome carrying the homozygous mutations of WDR73 and TP53RK

Galloway–Mowat syndrome (GAMOS) is a rare hereditary disease manifested as a combination of nephrotic syndrome and central nervous system impairment. To date, many GAMOS cases attributed to various gene mutations have been reported such as WHAMM, NUP107, WDR73, OSGEP, and TP53RK. We detected two novel homozygous mutations of WDR73 ‘’NM_032856:c.G287A:p.R96K‘’ and TP53RK ‘’NM_033550:c.A193O:p.K65Q‘’ in two female kids of the consanguineous parents from different families using whole exome sequencing. Both patients almost manifested similar neurodegenerative phenotypes, including developmental delay, microcephaly, hypotonia, and brain atrophy on magnetic resonance imaging during infancy. WDR73-positive GAMOS case manifested a late-onset minimal nephrotic syndrome at the age 4 years while TP53RK-positive case presented nephrotic syndrome at the age 1 which progressed to steroid-resistant nephrotic syndrome due to lack of remission after 4-6 weeks of initial treatment with prednisone. Despite the brain abnormalities and the onset time difference of renal abnormalities, both patients are still alive. Given the heterogeneity of the renal phenotype among GAMOS types, accurate recognition of expanding spectrum of phenotype findings and regular renal function screening are necessary for an early diagnosis and timely treatment.

Antibody Deficiency in Patients with Biallelic KARS1 Mutations.

Biallelic KARS1 mutations cause KARS-related diseases, a rare syndromic condition encompassing central and peripheral nervous system impairment, heart and liver disease, and deafness. KARS1 encodes the t-RNA synthase of lysine, an aminoacyl-tRNA synthetase, involved in different physiological mechanisms (such as angiogenesis, post-translational modifications, translation initiation, autophagy and mitochondrial function). Although patients with immune-hematological abnormalities have been individually described, results have not been collectively discussed and functional studies investigating how KARS1 mutations affect B cells have not been performed.Here, we describe one patient with severe developmental delay, sensoneurinal deafness, acute disseminated encephalomyelitis, hypogammaglobulinemia and recurrent infections. Pathogenic biallelic KARS1 variants (Phe291Val/ Pro499Leu) were associated with impaired B cell metabolism (decreased mitochondrial numbers and activity). All published cases of KARS-related diseases were identified. The corresponding authors and researchers involved in the diagnosis of inborn errors of immunity or genetic syndromes were contacted to obtain up-to-date clinical and immunological information. Seventeen patients with KARS-related diseases were identified. Recurrent/severe infections (9/17) and B cell abnormalities (either B cell lymphopenia [3/9], hypogammaglobulinemia [either IgG, IgA or IgM; 6/15] or impaired vaccine responses [4/7]) were frequently reported. Immunoglobulin replacement therapy was given in five patients. Full immunological assessment is warranted in these patients, who may require detailed investigation and specific supportive treatment.

The impact of the temporal sequence of cranial radiotherapy and platin-based chemotherapy on hearing impairment in pediatric and adolescent CNS and head-and-neck cancer patients: A report from the PanCareLIFE consortium.

The impact of the temporal sequence by which cranial radiotherapy (CRT) and platin-based chemotherapy (PCth) are administered on sensorineural hearing loss (SNHL) in pediatric and adolescent central nervous system (CNS) and head-and-neck (HN) cancer patients has not yet been studied in detail. We examined the ototoxic effects of sequentially applied CRT and PCth. This study included children and adolescents with CNS and HN tumors who participated in the multicountry PanCareLIFE (PCL) consortium. Audiological outcomes were compared between patients who received CRT prior to PCth and those who received it afterwards. The incidence, degree and posttreatment progression of SNHL, defined as Muenster classification grade ≥MS2b, were evaluated in 141 patients. One hundred and nineteen patients were included in a time-to-onset analysis. Eighty-eight patients received CRT prior to PCth (Group 1) and 53 patients received PCth before CRT (Group 2). Over a median follow-up time of 1.6 years, 72.7% of patients in Group 1 experienced SNHL ≥ MS2b compared to 33.9% in Group 2 (P < .01). A time-to-onset analysis was performed for 74 patients from Group 1 and 45 patients from Group 2. Median time to hearing loss (HL) ≥ MS2b was 1.2 years in Group 1 and 4.4 years in Group 2 (P < .01). Thus, audiological outcomes were better for patients who received CRT after PCth than before. This finding should be further evaluated and considered within clinical practice in order to minimize hearing loss in children and adolescents with CNS and HN tumors.

Magnetic resonance spectroscopy findings of brain olfactory areas in patients with COVID‐19‐related anosmia: A preliminary comparative study

AbstractObjectives2019 novel coronavirus disease (COVID‐19) infection is commonly associated with olfactory dysfunctions, but the basic pathogenesis of these complications remains controversial. This study seeks to evaluate the value of magnetic resonance spectroscopy (MRS) in determining the molecular neurometabolite alterations within the main brain olfactory areas in patients with COVID‐19‐related anosmia.MethodsIn a cross‐sectional study, seven patients with persistent COVID‐19‐related anosmia (mean age: 29.57 years) and seven healthy volunteers (mean age: 27.28 years) underwent MRS in which N‐acetyl‐aspartate (NAA), choline (Cho), creatine (Cr), and their ratios were measured in the anterior cingulate cortex, dorsolateral prefrontal cortex, orbitofrontal cortex (OFC), insular cortex, and ventromedial prefrontal cortex. Data were analyzed using TARQUIN software (version 4.3.10), and the results were compared with an independent sample t‐test and nonparametric Mann–Whitney test based on the normality of the MRS data distribution.ResultsThe mean duration of anosmia before imaging was 8.5 months in COVID‐19‐related anosmia group. MRS analysis elucidated a significant association between MRS findings within OFC and COVID‐19‐related anosmia (Pdisease &lt; 0.01), and NAA was among the most important neurometabolites (Pinteraction = 0.006). Reduced levels of NAA (P &lt; 0.001), Cr (P &lt; 0.001) and NAA/Cho ratio (P = 0.007) within OFC characterize COVID‐19‐related anosmia.ConclusionsThis study emphasizes that MRS can be illuminating in COVID‐19‐related anosmia and indicates a possible association between central nervous system impairment and persistent COVID‐19‐related anosmia.

Aluminum exposure induces central nervous system impairment via activating NLRP3-medicated pyroptosis pathway

PurposeAluminum is an environmental toxicant whose long-term exposure is closely associated with nervous system impairment. This study mainly investigated neurological impairment induced by subchronic aluminum exposure via activating NLRP3-medicated pyroptosis pathway. MethodsIn vivo, Kunming mice were exposed to AlCl3 (30.3 mg/kg, 101 mg/kg and 303 mg/kg) via drinking water for 3 months, and administered with Rsv (100 mg/kg) by gavage for 1 month. Cognitive impairment was assessed by Morris water maze test, and pathological injury was detected via H&E staining. BBB integrity, pyroptosis and neuroinflammation were evaluated through western blotting and immunofluorescence methods. In vitro, BV2 microglia was treated with AlCl3 (0.5 mM, 1 mM and 2 mM) to sensitize pyroptosis pathway. The protein interaction was verified by co-immunoprecipitation, and neuronal damage was estimated via a conditioned medium co-culture system with BV2 and TH22 cells. ResultsOur results showed that AlCl3 induced mice memory disorder, BBB destruction, and pathological injury. Besides, aluminum caused glial activation, sensitized DDX3X-NLRP3 pyroptosis pathway, released cytokines IL-1β and IL-18, initiating neuroinflammation. BV2 microglia treated with AlCl3 emerged hyperactivation and pyroptotic death, and Ddx3x knockdown inhibited pyroptosis signaling pathway. DDX3X acted as a live-or-die checkpoint in stressed cells by regulating NLRP3 inflammasome and G3BP1 stress granules. Furthermore, aluminum-activated microglia had an adverse effect on co-cultured neurons and destroyed nervous system homeostasis. ConclusionAluminum exposure could induce pyroptosis and neurotoxicity. DDX3X determined live or die via selectively regulating pro-survival stress granules or pro-death NLRP3 inflammasome. Excessive activation of microglia might damage neurons and aggravate nerve injury.

Relationship between Cognitive Impairment and Depressive Symptoms with Somatosensory Functions in Diabetic and Non-Diabetic Older Adults and Its Impact on Quality of Life.

Aging is an inevitable process that impacts the peripheral and central nervous systems and is considered one of the strongest risk factors for neurodegenerative diseases. In addition, when it also presents with diabetes mellitus, the risk of neurological damage may be further increased. This current study aimed to explore the relationships between peripheral sensory system decline and cognitive functions, the symptoms of depression, and quality of life (QoL) as metrics of central nervous system impairment in institutionalized older adults. A total of 95 individuals participated in this case-control study, which included diabetics and non-diabetics. The superficial sensory pathway was assessed in terms of thermal sensation, nociception, and non-discriminative touch, and the deep sensory pathway was evaluated by assessing vibration and light touch-pressure sensations. To assess function at the intellectual level, the Mini-Mental State Examination (MMSE) and Trail Making Test (TMT) cognitive functional tests were used, while the symptoms of depression and QoL were explored by employing the Yesavage Geriatric Depression Scale and EuroQol 5D questionnaire (EQ-5D), respectively. In the overall population analyses, altered thermal sensation was significantly associated with cognitive impairment (CI; p < 0.05). In turn, bivariate analyses and a binary logistic regression showed that the symptoms of depression and QoL were significantly related to altered vibratory sensation when assessed using a medical tuning fork (p < 0.05). In the group of diabetic patients, those with CI also had significantly lower thermal sensation (p < 0.05) and non-discriminative touch sensation, although this was only a trend (p = 0.055). Diabetics with depression had a significantly worse non-discriminative touch (p < 0.05) and vibratory sensation when tested with a tuning fork (p < 0.05). In addition, poorer QoL was associated with reduced sensitivity to heat (p < 0.05), light touch pressure (p < 0.05), and vibrations when assessed either with a tuning fork (p < 0.05) or a biothesiometer (p < 0.05). In contrast, no relationships were found between sensory functions and cognitive assessments in non-diabetic patients. These findings indicate that superficial sensitivity damage was related to CI, while deep sensation alterations were related to depression and poor QoL, with diabetes apparently further strengthening these relationships.