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Neurodegenerative diseases pose a significant health burden globally, with limited treatment options available. Among the various cell types involved in the pathogenesis of these disorders, microglia, the resident immune cells of the central nervous system, play a pivotal role. Dysregulated microglial activation contributes to neuroinflammation and neuronal damage, making them an attractive target for therapeutic intervention. Adeno-associated virus (AAV) vectors have emerged as powerful tools for delivering therapeutic genes to specific cell types in the central nervous system with remarkable precision and safety. In the current review, we discuss the strategies employed to achieve selective transduction of microglia, including the use of cell-specific promoters, engineered capsids, and microRNA (miRNA) strategies. Additionally, we address the challenges and future directions in the development of AAV-based therapies targeting microglia. Overall, AAV-mediated targeting of microglia holds promise as a novel therapeutic approach for neurodegenerative diseases, offering the potential to modify disease progression and improve patient outcomes.

Autism Spectrum Disorders (ASD) comprise a range of early age-onset neurodevelopment disorders with genetic heterogeneity. Most ASD related genes are involved in synaptic function, which is regulated by mature brain-derived neurotrophic factor (mBDNF) and its precursor proBDNF in a diametrically opposite manner: proBDNF inhibits while mBDNF potentiates synapses. Here we generated a knock-in mouse line (BDNF met/leu ) in which the conversion of proBDNF to mBDNF is attenuated. Biochemical experiments revealed residual mBDNF but excessive proBDNF in the brain. Similar to other ASD mouse models, the BDNF met/leu mice showed reduced dendritic arborization, altered spines, and impaired synaptic transmission and plasticity in the hippocampus. They also exhibited ASD-like phenotypes, including stereotypical behaviors and deficits in social interaction. Moreover, the plasma proBDNF/mBDNF ratio was significantly increased in ASD patients compared to normal children in a case-control study. Thus, deficits in proBDNF to mBDNF conversion in the brain may contribute to ASD-like behaviors, and plasma proBDNF/mBDNF ratio may be a potential biomarker for ASD.

Methylmalonic acidemia (MMAemia) is an inborn error of organic acid metabolism characterized by the accumulation of toxic metabolites—including methylmalonic acid (MMA), 2-methylcitric acid (2-MCA), propionic acid (PA), homocysteine (Hcy), ammonia, and lactate—due to defects in methylmalonyl-CoA mutase or impaired cobalamin metabolism. These metabolites exert profound effects on the central nervous system, contributing to neurological injury through tightly interconnected mechanisms, including mitochondrial dysfunction, neuroinflammation, and excitotoxicity. This review synthesizes current evidence on how these metabolites trigger neurological dysfunction, integrating findings from clinical studies, animal models, and cellular systems. We also highlight the increasingly recognized role of aberrant post-translational modifications (e.g., methylmalonylation, propionylation, lactylation) in disrupting metabolic network architecture and reprogramming cellular metabolism. Despite advances in supportive therapies, intracerebral metabolite accumulation remains a therapeutic challenge. We discuss emerging strategies targeting mitochondrial protection, redox homeostasis, and inflammation—including enzyme replacement, gene therapy, antioxidant regimens, and exosome-based delivery. A deeper mechanistic understanding of metabolite-driven neurotoxicity is critical to the development of targeted interventions that can improve neurological outcomes in MMAemia.

Ferroptosis is an iron-dependent form of cell death that is characterized by early lipid peroxidation and different from other forms of regulated cell death in terms of its genetic components, specific morphological features, and biochemical mechanisms. Different initiation pathways of ferroptosis have been reported, including inhibition of system X , inactivation of glutathione-dependent peroxidase 4, and reduced glutathione levels, all of which ultimately promote the production of reactive oxygen species, particularly through enhanced lipid peroxidation. Although ferroptosis was first described in cancer cells, emerging evidence now links mechanisms of ferroptosis to many different diseases, including cerebral ischemia and brain hemorrhage. For example, neonatal brain injury is an important cause of developmental impairment and of permanent neurological deficits, and several types of cell death, including iron-dependent pathways, have been detected in the process of neonatal brain damage. Iron chelators and erythropoietin have both shown neuroprotective effects against neonatal brain injury. Here, we have summarized the potential relation between ferroptosis and neonatal brain injury, and according therapeutic intervention strategies.

This study compared the predictive value of three diagnostic criteria for bronchopulmonary dysplasia (BPD) in relation to death or neurodevelopmental impairment (NDI) at a corrected age of 24 months in preterm infants born before 32 weeks’ gestation. In this retrospective cohort study conducted at a single center, 508 preterm infants with a median gestational age of 30.0 weeks were admitted between January 2019 and December 2021. BPD was diagnosed using the 2001 NICHD, 2018 NICHD, and 2019 Jensen definitions. Multivariate logistic regression and receiver operating characteristic (ROC) curve analysis were used to assess the predictive value of each definition. Of the infants, 52 (10.2%) experienced death or NDI. Severe BPD defined by the 2018 NICHD and 2019 Jensen criteria, and the presence of periventricular leukomalacia (PVL), were significant risk factors for adverse outcomes. Both the 2018 NICHD and 2019 Jensen definitions demonstrated superior predictive value compared to the 2001 NICHD definition. Combining these criteria with PVL further improved prediction efficiency. These findings suggest that newer BPD definitions, especially when combined with neuroimaging indicators, enhance prognostic accuracy for long-term neurodevelopmental outcomes in preterm infants.

Autism spectrum disorder (ASD) is a neurological and developmental condition that begins in infancy or earlier and lasts through the individual's lifetime. The aetiology and mechanisms of ASD are not yet fully understood, and current treatment comprises mainly education and rehabilitation, without significant improvement in the core symptoms. Recent studies suggest that microbiota change in children with ASD after the ingestion of probiotics may improve the balance of microbiota and thus ASD symptoms. The objectives of this study are to evaluate the efficacy of probiotics on the symptoms of children with ASD and the possible mechanisms involved. This is a prospective controlled trial. A total of 160 children with ASD will be stratified and allocated to placebo and probiotics groups randomised according to the severity of their ASD symptoms. The probiotics group will be given probiotics supplements orally twice a day for 3 months and the control group will be given a placebo at the same amount, in addition to the baseline therapy of education and rehabilitation. All the children will be evaluated systematically by using different scales, questionnaires before, during, and after 3 months' treatment, as well as 3 months after discontinuation. The potential impact of probiotics on immunity and inflammation, metabolism, and metagenome will also be investigated. Our previous study showed that the abundance of intestinal flora was greatly different in children with ASD, and that Bifidobacterium was associated with the severity of ASD. In the present study, we will investigate the impact of probiotics supplementation on the symptoms of Children with ASD, with the purpose of evaluating the possible therapeutic effects of additives on ASD and of providing a reference for clinical treatment. The results will help to disclose as yet unknown relationship between probiotics and ASD. This study has been registered with Chinese Clinical Trial Registry (ChiCTR-2000037941).

The results from epidemiologic studies linking blood folate concentrations, folic acid supplementation, or dietary folate to the risk of preterm birth are inconsistent. In this study, we aimed to summarize the available evidence on these associations. A systematic search of the PubMed/MEDLINE, Google Scholar, Web of Science, and Cochrane Library databases up to October 20, 2018 was performed and reference lists of retrieved articles were screened. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for the highest vs. the lowest levels of folate concentrations, folic acid supplementation, and dietary folate were calculated using random-effects models. Subgroup analyses and univariate meta-regression were performed to explore the sources of heterogeneity. Ten studies (six prospective cohort studies and four case-control studies) were included on folate concentrations, 13 cohort studies were included about folic acid supplementation, and 4 cohort studies were included regarding dietary folate intake. Higher maternal folate levels were associated with a 28% reduction in the risk of preterm birth (OR 0.72, 95% CI 0.56-0.93). Higher folic acid supplementation was associated with 10% lower risk of preterm birth (OR 0.90, 95% CI 0.85-0.95). In addition, a significant negative association was observed between dietary folate intake and the risk of preterm birth (OR 0.68, 95% CI 0.55-0.84), but no significant relation was seen between dietary folate and the risk of spontaneous preterm birth (OR 0.89, 95% CI 0.57-1.41). In the subgroup analysis, higher maternal folate levels in the third trimester were associated with a lower risk of preterm birth (OR 0.58, 95% CI 0.36-0.94). To initiate taking folic acid supplementation early before conception was adversely associated with preterm birth risk (OR 0.89, 95% CI 0.83-0.95). In conclusion, higher maternal folate levels and folic acid supplementation were significantly associated with a lower risk of preterm birth. The limited data currently available suggest that dietary folate is associated with a significantly decreased risk of preterm birth.

Cerebral palsy (CP), a prevalent non-progressive neurological disorder in children, lacks reliable biomarkers for early diagnosis, and its molecular mechanisms remain poorly understood. In this study, we conducted serum proteomic profiling of 346 CP patients and 190 healthy controls and developed a 10-protein multi-marker panel for application in diagnosis of CP. The panel was further validated in an independent CP cohort using an orthogonal method, enzyme-linked immunosorbent assay (ELISA). By integrating serum proteomic data with whole-exome sequencing (WES) results, we found that CP patients carrying pathogenic variants exhibited downregulation of synaptic and calcium signaling pathways at the protein level. We also explored the impact of clinical risk factors on the proteome, identifying disruptions in lipid metabolism associated with low birth weight and low gestational age. Additionally, we found a positive correlation between Immunoglobulin Heavy Variable (IGHV) families and higher Gross Motor Function Classification System (GMFCS) levels. Overall, our study provides a valuable tool for early CP diagnosis that complements standard clinical and genomic assessments, and suggests potential molecular mechanisms associated with CP pathogenesis, highlighting the interplay among genetic, environmental, and protein network factors. Cerebral palsy lacks reliable biomarkers for early and accurate diagnosis. Here, the authors show serum proteomic signatures of disease and develop a multi-biomarker diagnostic model.

Autophagy is a physiological process that occurs in normal tissues. Under external environmental pressure or internal environmental changes, cells can digest part of their contents through autophagy in order to reduce metabolic pressure or remove damaged organelles. In cancer, autophagy plays a paradoxical role, acting as a tumor suppressor—by removing damaged organelles and inhibiting inflammation or by promoting genome stability and the tumor-adaptive responses—as a pro-survival mechanism to protect cells from stress. In this article, we review the autophagy-dependent mechanisms driving childhood central nervous system tumor cell death, malignancy invasion, chemosensitivity, and radiosensitivity. Autophagy inhibitors and inducers have been developed, and encouraging results have been achieved in autophagy modulation, suggesting that these might be potential therapeutic agents for the treatment of pediatric central nervous system (CNS) tumors.

Methylmalonic acidemia (MMA) is the most common inborn organic acidemia, presenting multisystemic complications. Uric acid may have neurotoxic or neuroprotective effects due to its antioxidant or pro-inflammatory properties; however, its role in MMA brain injury remains unclear. We examined the correlation between the serum uric acid levels and brain imaging features of MMA. Data were collected from a cross-sectional study of 216 patients with MMA and 216 healthy matched controls aged 0–5 years in China. Serum uric acid levels were measured, and magnetic resonance imaging and computed tomography findings were retrieved from hospital records. Overall, 74.1% patients had brain abnormalities. Patients in the MMA group with abnormal brain imaging had higher serum uric acid levels than those in the MMA normal brain imaging and control groups. The area under the curve of serum uric acid was 0.74, 0.91, and 0.93 for MMA diagnosis with abnormal brain images, basal ganglia changes, and globus pallidus changes, respectively. Higher serum uric acid levels were independently associated with abnormal brain images. Children aged < 5 years with abnormal brain images in MMA exhibit elevated serum uric acid levels, serving as an effective auxiliary diagnostic indicator and independent risk factor for brain tissue injury.