Innate immunity protein interferon induced transmembrane protein 3 (IFITM3) is a transmembrane protein that has a wide array of functions, including in viral infections, Alzheimer's Disease (AD), and cancer. As an interferon stimulated gene (ISG), IFITM3's expression is upregulated by type-I, II, and III interferons. Moreover, the antiviral activity of IFITM3 is modulated by post-translational modifications. IFITM3 functions in innate immunity to disrupt viral fusion and entry to the plasma membrane as well as prevent viral escape from endosomes. As a γ-secretase modulatory protein, IFITM3 distinctly modulates the processing of amyloid precursor protein (APP) to generate amyloid beta peptides (Aβ) and Notch1 cleavages. Increased IFITM3 expression, which can result from aging, cytokine activation, inflammation, and infection, can lead to an upregulation of γ-secretase for Aβ production that causes a risk of AD. Therefore, the prevention of IFITM3 upregulation has potential in the development of novel therapies for the treatment of AD.

Dynamin-1 (DNM1) is crucial for synaptic activity, neurotransmission, and associative memory, positioning it as a potential biomarker of cancer-related cognitive impairment (CRCI), a neurological consequence of cancer treatment characterized by memory loss, poor concentration, and impaired executive function. Through a stepwise approach, this study investigated the role of DNM1 in CRCI pathogenesis, incorporating both human data and animal models. The human study recruited newly diagnosed, chemotherapy-naïve adolescent and young adult cancer and non-cancer controls to complete a cognitive instrument (FACT-Cog) and blood draws for up to three time points. Following that, a syngeneic young-adult WT (C57BL/6) female mouse model of breast cancer chemobrain was developed to study DNM1 expression in the hippocampus. Samples from eighty-six participants with 30 adolescent and young adult (AYA) cancer and 56 non-cancer participants were analyzed. DNM1 levels were 32 ​% lower (P ​= ​0.041) among cancer participants compared to non-cancer prior to treatment. After receiving cytotoxic treatment, cognitively impaired cancer patients were found to have 46 ​% lower DNM1 levels than those without impairment (P ​= ​0.049). In murine breast cancer-bearing mice receiving chemotherapy, we found a greater than 40 ​% decline (P ​< ​0.0001) in DNM1 immunoreactivity in the hippocampal CA1 and CA3 subregions concurrent with a deterioration in spatial recognition memory (P ​< ​0.02), compared to control mice without exposure to cancer and chemotherapy. Consistently observed in both human and animal studies, the downregulation of DNM1 is linked with the onset of CRCI. DNM1 might be a biomarker and therapeutic target for CRCI.

Little is known about the mechanisms that generate epileptic spasms following perinatal brain injury. Recent studies have implicated reduced levels of Insulin-like Growth Factor 1 (IGF-1) in these patients' brains. Other studies have reported low levels of the inhibitory neurotransmitter, GABA. In the TTX brain injury model of epileptic spasms, we undertook experiments to evaluate the impact of IGF-1 deficiencies on neocortical interneurons and their role in spasms. Quantitative immunohistochemical analyses revealed that neocortical interneurons that express glutamic acid decarboxylase, parvalbumin, or synaptotagmin 2 co-express IGF-1. In epileptic rats, expression of these three interneuron markers were reduced in the neocortex. IGF-1 expression was also reduced, but surprisingly this loss was confined to interneurons. Interneuron connectivity was reduced in tandem with IGF-1 deficiencies. Similar changes were observed in surgically resected neocortex from infantile epileptic spasms syndrome (IESS) patients. To evaluate the impact of IGF-1 deficiencies on interneuron development, IGF-1R levels were reduced in the neocortex of neonatal conditional IGF-1R knock out mice by viral injections. Four weeks later, this experimental maneuver resulted in similar reductions in interneuron connectivity. Treatment with the IGF-1 derived tripeptide, (1-3)IGF-1, abolished epileptic spasms in most animals, rescued interneuron connectivity, and restored neocortical levels of IGF-1. Our results implicate interneuron IGF-1 deficiencies, possibly impaired autocrine IGF-1 signaling and a resultant interneuron dysmaturation in epileptic spasm generation. By restoring IGF-1 levels, (1-3)IGF-1 likely suppresses spasms by rescuing interneuron connectivity. Results point to (1-3)IGF-1 and its analogues as potential novel disease-modifying therapies for this neurodevelopmental disorder.

Chemotherapy-induced peripheral neuropathy (CIPN) and its related pain are common challenges for patients receiving oxaliplatin chemotherapy. Oxaliplatin accumulation in dorsal root ganglion (DRGs) is known to impair gene transcription by epigenetic dysregulation. We hypothesized that sodium butyrate, a pro-resolution short-chain fatty acid, inhibited histone acetylation in DRGs and abolished K channel dysregulation-induced neuronal hyperexcitability after oxaliplatin treatment. Mechanical allodynia and cold hyperalgesia of mice receiving an accumulation of 15 ​mg/kg oxaliplatin, with or without intraperitoneal sodium butyrate supplementation, were assessed using von Frey test and acetone evaporation test. Differential expressions of histone deacetylases (HDACs) and pain-related K channels were quantified with rt-qPCR and protein assays. Immunofluorescence assays of histone acetylation at H3K9/14 were performed in primary DRG cultures treated with sodium butyrate. Current clamp recording of action potentials and persistent outward current of Twik-related-spinal cord K (TRESK) channel were recorded in DRG neurons with small diameters extract. Accompanied by mechanical allodynia and cold hyperalgesia, HDAC1 was upregulated in mice receiving oxaliplatin treatment. Sodium butyrate enhanced global histone acetylation at H3K9/14 in DRG neurons. In vivo sodium butyrate supplementation restored oxaliplatin-induced Kcnj9 and Kcnk18 expression and pain-related behaviors in mice for at least 14 days. Oxaliplatin-induced increase in action potentials frequencies and decrease in magnitudes of KCNK18-related current were reversed in mice receiving sodium butyrate supplementation. This study suggests that sodium butyrate was a useful agent to relieve oxaliplatin-mediated neuropathic pain.

Parkinson's Disease (PD) is a progressive neurodegenerative disorder with substantial impact on patients' quality of life. Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced PD, but patient responses vary, necessitating predictive models for personalized care. Recent advancements in medical imaging and machine learning offer opportunities to enhance predictive accuracy, particularly through deep learning and multi-instance learning (MIL) techniques. This retrospective study included 127 PD patients undergoing STN-DBS. Medical records and imaging data were collected, and patients were categorized based on treatment outcomes. Advanced segmentation models were trained for automated region of interest (ROI) delineation. A novel 2.5D deep learning approach incorporating multi-slice representation was developed to extract detailed ROI features. Multi-instance learning fusion techniques integrated predictions across multiple slices, combining radiomics and deep learning features to enhance model performance. Various machine learning algorithms were evaluated, and model robustness was assessed using cross-validation and hyperparameter optimization. The MIL model achieved an area under the curve (AUC) of 0.846 for predicting STN-DBS outcomes, surpassing the radiomics model's AUC of 0.825. Integration of MIL and radiomics features in the DLRad model further improved discriminative ability to an AUC of 0.871. Calibration tests showed good model reliability, and decision curve analysis demonstrated clinical utility, affirming the model's predictive advantage. This study demonstrates the efficacy of integrating MIL, radiomics, and deep learning techniques to predict STN-DBS outcomes in PD patients. The multimodal fusion approach enhances predictive accuracy, supporting personalized treatment planning and advancing patient care.

Traumatic brain injury (TBI) is a major cause of morbidity and mortality, not least in the elderly. The incidence of aged TBI patients has increased dramatically during the last decades. High age is a highly negative prognostic factor in TBI, and pharmacological treatment options are lacking. We used the controlled cortical impact (CCI) TBI model in 23-month-old male and female mice and analyzed the effect of post-injury treatment with 7,8 dihydroxyflavone (7,8-DHF), a brain-derived neurotrophic factor (BDNF)-mimetic compound, on white matter pathology. Following CCI or sham injury, mice received subcutaneous 7,8-DHF injections (5 ​mg/kg) 30 ​min post-injury and were sacrificed on 2, 7 or 14 days post-injury (dpi) for histological and immunofluorescence analyses. Histological assessment with Luxol Fast Blue (LFB)/Cresyl Violet stain showed that administration of 7,8-DHF resulted in preserved white matter tissue at 2 and 7 dpi with no difference in cortical tissue loss at all investigated time points. Treatment with 7,8-DHF led to reduced axonal swellings at 2 and 7 dpi, as visualized by SMI-31 (Neurofilament Heavy Chain) immunofluorescence, and reduced number of TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labelling)/CC1-positive mature oligodendrocytes at 2 dpi in the perilesional white matter. Post-injury proliferation of Platelet-derived Growth Factor Receptor (PDGFRα)-positive oligodendodrocyte progenitor cells was not altered by 7,8-DHF. Our results suggest that 7,8-DHF can attenuate white matter pathology by mitigating axonal injury and oligodendrocyte death in the aged mouse brain following TBI. These data argue that further exploration of 7,8-DHF towards clinical use is warranted.

Acute pain is a transient sensation that typically serves as part of the body's defense mechanism. However, in certain patients, acute pain can evolve into chronic pain, which persists for months or even longer. Neuroplasticity refers to the capacity for variation and adaptive alterations in the morphology and functionality of neurons and synapses, and it plays a significant role in the transmission and modulation of pain. In this paper, we explore the molecular mechanisms and signaling pathways underlying neuroplasticity during the transition of pain. We also examine the effects of neurotransmitters, inflammatory mediators, and central sensitization on neuroplasticity, as well as the potential of neuroplasticity as a therapeutic strategy for preventing chronic pain. The aims of this article is to clarify the role of neuroplasticity in the transformation from acute pain to chronic pain, with the hope of providing a novel theoretical basis for unraveling the pathogenesis of chronic pain and offering more effective strategies and approaches for its diagnosis and treatment.

Dystonia arises with cerebellar dysfunction, which plays a key role in the emergence of multiple pathophysiological deficits that range from abnormal movements and postures to disrupted sleep. Current therapeutic interventions typically do not simultaneously address both the motor and non-motor symptoms of dystonia, underscoring the necessity for a multi-functional therapeutic strategy. Deep brain stimulation (DBS) is effectively used to reduce motor symptoms in dystonia, with existing parallel evidence arguing for its potential to correct sleep disturbances. However, the simultaneous efficacy of DBS for improving sleep and motor dysfunction, specifically by targeting the cerebellum, remains underexplored. Here, we test the effect of cerebellar DBS in two genetic mouse models with dystonia that exhibit sleep defects-Ptf1a;Vglut2 and Pdx1;Vglut2-which have overlapping cerebellar circuit miswiring defects but differing severity in motor phenotypes. By targeting DBS to the fiber tracts located between the cerebellar fastigial and the interposed nuclei (FN ​+ ​INT-DBS), we modulated sleep dysfunction by enhancing sleep quality and timing. This DBS paradigm improved wakefulness and rapid eye movement sleep in both mutants. Additionally, the latency to reach REM sleep, a deficit observed in human dystonia patients, was reduced in both models. Cerebellar DBS also induced alterations in the electrocorticogram (ECoG) patterns that define sleep states. As expected, DBS reduced the severe dystonic twisting motor symptoms that are observed in the Ptf1a;Vglut2 mice. These findings highlight the potential for using cerebellar DBS to simultaneously improve sleep and reduce motor dysfunction in dystonia and uncover its potential as a dual-effect in vivo therapeutic strategy.

Mirodenafil is a phosphodiesterase 5 (PDE5) inhibitor with high specificity for its target and good blood-brain barrier permeability. The drug, which is currently used for treatment of erectile dysfunction, reduces Aβ and pTau levels and improves cognitive function in mouse models of Alzheimer's disease. In the present study, we investigated the effect of mirodenafil in the transient and permanent middle cerebral artery occlusion (tMCAO and pMCAO) models of stroke in rats. Starting 24 ​h after cerebral artery occlusion, mirodenafil was administered subcutaneously at doses of 0.5, 1, and 2 ​mg/kg per day for 9 days in the tMCAO model and for 28 days in the pMCAO model. Mirodenafil significantly increased sensorimotor and cognitive recovery of tMCAO and pMCAO rats compared to saline control rats, and significantly decreased the amount of degenerative cells and cleaved caspase-3 and cleaved PARP immunoreactive cells. Effects were seen in a dose-dependent manner up to 1 ​mg/kg mirodenafil. The benefits of mirodenafil treatment increased with longer treatment duration, and the largest improvements over control were typically observed on the last assessment day. There was no effect of mirodenafil on infarct volume in both tMCAO and pMCAO rats. In an experiment to determine the treatment window for mirodenafil effects, a protective effect was observed when treatment was delayed 72 ​h after MCAO, although the most improvement was observed with shorter treatment windows. Using pMCAO and tMCAO rat models of stroke, we determined that mirodenafil improves the recovery of sensorimotor and cognitive functions after MCAO and protects cortical cells from apoptosis and degeneration. Greater benefit was observed with longer duration of treatment, and improvement was seen even when treatment was delayed.

Recent experimental and clinical data demonstrate a significant dysregulation of the gut microbiome in individuals with Parkinson's disease (PD). With an immense influence on all aspects of physiology, this dysregulation has potential to directly or indirectly contribute to disease pathology. Experimental models have bridged these associations toward defined contributions, identifying various microbiome-dependent impacts to PD pathology. These studies have laid the foundation for human translation, examining whether certain members of the microbiome and/or whole restoration of the gut microbiome community can provide therapeutic benefit for people living with PD. Here, we review recent and ongoing clinically-focused studies that use microbiome-targeted therapies to limit the severity and progression of PD. Fecal microbiome transplants, prebiotic interventions, and probiotic supplementation are each emerging as viable methodologies to augment the gut microbiome and potentially limit PD symptoms. While still early, the data in the field to date support continued cross-talk between experimental systems and human studies to identify key microbial factors that contribute to PD pathologies.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons. While there has been significant progress in defining the genetic contributions to ALS, greater than 90 ​% of cases are sporadic, which suggests an environmental component. The gut microbiota is altered in ALS and is an ecological factor that contributes to disease by modulating immunologic, metabolic, and neuronal signaling. Depleting the microbiome worsens disease in the SOD1 ALS animal model, while it ameliorates disease in the C9orf72 model of ALS, indicating critical subtype-specific interactions. Furthermore, administering beneficial microbiota or microbial metabolites can slow disease progression in animal models. This review discusses the current state of microbiome research in ALS, including interactions with different ALS subtypes, evidence in animal models and human studies, key immunologic and metabolomic mediators, and a path toward microbiome-based therapies for ALS.

Multiple sclerosis (MS) is a chronic immune-mediated and heterogeneous disease characterized by demyelination, axonal damage, and physical and cognitive impairment. Recent studies have highlighted alterations in the microbiota of people with MS (pwMS). However, the intricate nature of the disease and the wide range of treatments available make it challenging to identify specific microbial populations or functions associated with MS symptoms and disease progression. This study aimed to characterize the microbiota of pwMS treated with the oral drug teriflunomide (TF) and compare it with that of pwMS treated with beta interferons (IFNβ), pwMS treated with no previous disease modifying therapies (naïve), and healthy controls. Our findings demonstrate significant alterations in both the composition and function of the gut microbiota in pwMS that are further influenced by disease-modifying therapies. Specifically, oral treatment with TF had a notable impact on the gut microbiota of pwMS. Importantly, the dysregulated microbial environment within the gut was associated with symptoms commonly experienced by pwMS, including fatigue, anxiety, and depression.

The angioedema risk may vary among stroke patients receiving different thrombolytic agents. This study aimed to investigate the angioedema risk associated with different thrombolytic agents and to identify associated risk factors. We conducted a large-scale retrospective pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS) database. Stroke patients receiving thrombolytic therapy (i.e., alteplase or tenecteplase) were identified, and the associations with angioedema were explored using disproportionality analysis and time-to-onset analysis. Additionally, we used adapted Bradford Hill criteria to confirm these associations. Risk factors for angioedema were explored using stepwise logistic regression. A total of 17,776 stroke patients were included, with 2973 receiving alteplase and 278 receiving tenecteplase. Disproportionality analysis revealed that angioedema might be associated with alteplase (adjusted ROR [aROR] 5.13 [95 ​% CI, 4.55-5.79]) or tenecteplase (aROR 2.72 [95 ​% CI, 1.98-3.67]). The adapted Bradford Hill criteria suggested a probable causal relationship between alteplase and angioedema, whereas there was insufficient evidence of a probable causal relationship with tenecteplase. Multivariate analysis revealed that ACE-inhibitors use (aROR 9.73 [95 ​% CI, 7.29-12.98]), female sex (aROR 1.38 [95 ​% CI, 1.13-1.67]) and hypertension (aROR 2.11 [95 ​% CI, 1.52-2.92]) were significant risk factors for angioedema among alteplase-treated stroke patients. Our study suggested that alteplase is associated with a greater risk of angioedema among stroke patients, but there is insufficient evidence to support an association between tenecteplase and angioedema. Clinicians should be vigilant for this potentially life-threatening complication, particularly in patients with identified risk factors. It is also prudent to consider tenecteplase as an alternative, if available.

Previous studies indicate that transcranial direct current stimulation (tDCS) is a promising emerging treatment option for autism spectrum disorder (ASD) and its efficacy could be augmented using concurrent training. However, no intrastimulation social cognition training for ASD has been developed so far. The objective of this two-armed, double-blind, randomized, sham-controlled clinical trial is to investigate the effects of tDCS combined with a newly developed intrastimulation social cognition training on adolescents with ASD. Twenty-two male adolescents with ASD were randomly assigned to receive 10 sessions of either anodal or sham tDCS at F3/right supraorbital region together with online intrastimulation training comprising basic and complex emotion recognition tasks. Using baseline magnetic resonance imaging data, individual electric field distributions were simulated, and brain activation patterns of the training tasks were analyzed. Additionally, questionnaires were administered at baseline and following the intervention. Compared to sham tDCS, anodal tDCS significantly improved dynamic emotion recognition over the course of the sessions. This task also showed the highest activations in face processing regions. Moreover, the improvement was associated with electric field density at the medial prefrontal cortex and social awareness in exploratory analyses. Both groups showed high tolerability and acceptability of tDCS, and significant improvement in overall ASD symptoms. Taken together, multisession tDCS improved dynamic emotion recognition in adolescents with ASD using a task that activates brain regions associated with the social brain network. The variability in the electric field might diminish tDCS effects and future studies should investigate individualized approaches.

The complex network of factors that contribute to neurodegeneration have hampered the discovery of effective preventative measures. While much work has focused on brain-first therapeutics, it is becoming evident that physiological changes outside of the brain are the best target for early interventions. Specifically, myeloid cells, including peripheral macrophages and microglia, are a sensitive population of cells whose activity can directly impact neuronal health. Myeloid cell activity includes cytokine production, migration, debris clearance, and phagocytosis. Environmental measures that can modulate these activities range from toxin exposure to diet. However, one of the most influential mediators of myeloid fitness is the gut microenvironment. Here, we review the current data about the role of myeloid cells in gastrointestinal disorders, Parkinson's disease, dementia, and multiple sclerosis. We then delve into the gut microbiota modulating therapies available and clinical evidence for their use in neurodegeneration. Modulating lifestyle and environmental mediators of inflammation are one of the most promising interventions for neurodegeneration and a systematic and concerted effort to examine these factors in healthy aging is the next frontier.

Peripheral neuropathies (PNs) are common diseases in elderly individuals characterized by Schwann cell (SC) dysfunction and irreversible Wallerian degeneration (WD). Although the molecular mechanisms of PN onset and progression have been widely studied, therapeutic opportunities remain limited. In this study, we investigated the pharmacological inhibition of Mammalian Ste20-like kinase 1/2 (MST1/2) by using its chemical inhibitor, XMU-MP-1 (XMU), against WD. XMU treatment suppressed the proliferation, dedifferentiation, and demyelination of SCs in models of WD in vitro, in vivo, and ex vivo. As a downstream mediator of canonical and noncanonical Hippo/MST1 pathway activation, the mature microRNA (miRNA) let-7b and its binding partners quaking homolog (QKI)/nucleolin (NCL) modulated miRNA-mediated silencing of genes involved in protein transport. Hence, direct phosphorylation of QKI and NCL by MST1 might be critical for WD onset and pathogenesis. Moreover, p38α/mitogen-activated protein kinase 14 (p38α) showed a strong affinity for XMU, and therefore, it may be an alternative XMU target for controlling WD in SCs. Taken together, our findings provide new insights into the Hippo/MST pathway function in PNs and suggest that XMU is a novel multitargeted therapeutic for elderly individuals with PNs.

Multiple studies over the last decade have established that Alzheimer's disease and related dementias (ADRD) are associated with changes in the gut microbiome. These alterations in organismal composition result in changes in the abundances of functions encoded by the microbial community, including metabolic capabilities, which likely impact host disease mechanisms. Gut microbes access dietary components and other molecules made by the host and produce metabolites that can enter circulation and cross the blood-brain barrier (BBB). In recent years, several microbial metabolites have been associated with or have been shown to influence host pathways relevant to ADRD pathology. These include short chain fatty acids, secondary bile acids, tryptophan derivatives (such as kynurenine, serotonin, tryptamine, and indoles), and trimethylamine/trimethylamine N-oxide. Notably, some of these metabolites cross the BBB and can have various effects on the brain, including modulating the release of neurotransmitters and neuronal function, inducing oxidative stress and inflammation, and impacting synaptic function. Microbial metabolites can also impact the central nervous system through immune, enteroendocrine, and enteric nervous system pathways, these perturbations in turn impact the gut barrier function and peripheral immune responses, as well as the BBB integrity, neuronal homeostasis and neurogenesis, and glial cell maturation and activation. This review examines the evidence supporting the notion that ADRD is influenced by gut microbiota and its metabolites. The potential therapeutic advantages of microbial metabolites for preventing and treating ADRD are also discussed, highlighting their potential role in developing new treatments.