Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00441
Jun Sun , Yongguo Zhang
Amyotrophic lateral sclerosis is a neurodegenerative disorder. Despite extensive studies, it remains challenging to treat ALS. Recent ALS studies have shown dysbiosis (e.g., loss of microbial diversity and beneficial function in the gut microbiota) is correlated with intestinal inflammation and change of intestinal integrity in ALS. The novel concepts and the roles of microbiome and microbial metabolites through the gut-microbiome-neuron axis in ALS pathogenesis have been slowly recognized by the neurology research field. Here, we will discuss the recent progress of microbiome, including bacteria, fungi, and viruses, in the ALS research. We will discuss our understanding of microbial metabolites in ALS. Micronutrition refers to the intake of essential vitamins, minerals, and other micronutrients. We will summarize the literation related to micronutrition and ALS. Furthermore, we will consider the mutual interactions of microbiome and micronutrition in the ALS progression and treatment. We further propose that the mechanistic and translational studies that shift from suspension of disbelief to cogent ingenuity, and from bench study to bed-side application, should allow new strategies of diagnosis and treatment for ALS.
肌萎缩侧索硬化症是一种神经退行性疾病。尽管进行了大量研究，但 ALS 的治疗仍面临挑战。最近的 ALS 研究表明，菌群失调（如肠道微生物群中微生物多样性和有益功能的丧失）与 ALS 的肠道炎症和肠道完整性的改变相关。微生物组和微生物代谢物通过肠道-微生物组-神经元轴在 ALS 发病机制中的新概念和作用已慢慢被神经病学研究领域所认识。在此，我们将讨论微生物组（包括细菌、真菌和病毒）在 ALS 研究中的最新进展。我们将讨论我们对ALS中微生物代谢物的理解。微营养是指必需维生素、矿物质和其他微量营养素的摄入量。我们将总结与微营养和渐冻症有关的文献。此外，我们还将考虑微生物组和微营养在 ALS 的发展和治疗中的相互影响。我们还将进一步提出，机理研究和转化研究应从 "不相信 "转变为 "有说服力的独创性"，从 "实验室研究 "转变为 "床旁应用"，从而为 ALS 的诊断和治疗提供新的策略。
{"title":"Microbiome and micronutrient in ALS: From novel mechanisms to new treatments","authors":"Jun Sun , Yongguo Zhang","doi":"10.1016/j.neurot.2024.e00441","DOIUrl":"10.1016/j.neurot.2024.e00441","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis is a neurodegenerative disorder. Despite extensive studies, it remains challenging to treat ALS. Recent ALS studies have shown dysbiosis (e.g., loss of microbial diversity and beneficial function in the gut microbiota) is correlated with intestinal inflammation and change of intestinal integrity in ALS. The novel concepts and the roles of microbiome and microbial metabolites through the gut-microbiome-neuron axis in ALS pathogenesis have been slowly recognized by the neurology research field. Here, we will discuss the recent progress of microbiome, including bacteria, fungi, and viruses, in the ALS research. We will discuss our understanding of microbial metabolites in ALS. Micronutrition refers to the intake of essential vitamins, minerals, and other micronutrients. We will summarize the literation related to micronutrition and ALS. Furthermore, we will consider the mutual interactions of microbiome and micronutrition in the ALS progression and treatment. We further propose that the mechanistic and translational studies that shift from suspension of disbelief to cogent ingenuity, and from bench study to bed-side application, should allow new strategies of diagnosis and treatment for ALS.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00441"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mexiletine is the first choice drug in the treatment of non-dystrophic myotonias. However, 30% of patients experience little benefit from mexiletine due to poor tolerability, contraindications and limited efficacy likely based on pharmacogenetic profile. Safinamide inhibits neuronal voltage-gated sodium and calcium channels and shows anticonvulsant activity, in addition to a reversible monoamine oxidase-B inhibition. We evaluated the preclinical effects of safinamide in an animal model of Myotonia Congenita, the ADR (arrested development of righting response) mouse. In vitro studies were performed using the two intracellular microelectrodes technique in current clamp mode. We analyzed sarcolemma excitability in skeletal muscle fibers isolated from male and female ADR (adr/adr) and from Wild-Type (wt/wt) mice, before and after the application of safinamide and the reference compound mexiletine. In ADR mice, the maximum number of action potentials (N-spikes) elicited by a fixed current is higher with respect to that of WT mice. Myotonic muscles show an involuntary firing of action potential called after-discharges. A more potent activity of safinamide compared to mexiletine has been demonstrated in reducing N-spikes and the after-discharges in myotonic muscle fibers. The time of righting reflex (TRR) before and after administration of safinamide and mexiletine was evaluated in vivo in ADR mice. Safinamide was able to reduce the TRR in ADR mice to a greater extent than mexiletine. In conclusion, safinamide counteracted the abnormal muscle hyperexcitability in myotonic mice both in vitro and in vivo suggesting it as an effective drug to be indicated in Myotonia Congenita.
{"title":"Preclinical study of the antimyotonic efficacy of safinamide in the myotonic mouse model","authors":"Ileana Canfora , Concetta Altamura , Jean-Francois Desaphy , Brigida Boccanegra , Silvia Vailati , Carla Caccia , Elsa Melloni , Gloria Padoani , Annamaria De Luca , Sabata Pierno","doi":"10.1016/j.neurot.2024.e00455","DOIUrl":"10.1016/j.neurot.2024.e00455","url":null,"abstract":"<div><div>Mexiletine is the first choice drug in the treatment of non-dystrophic myotonias. However, 30% of patients experience little benefit from mexiletine due to poor tolerability, contraindications and limited efficacy likely based on pharmacogenetic profile. Safinamide inhibits neuronal voltage-gated sodium and calcium channels and shows anticonvulsant activity, in addition to a reversible monoamine oxidase-B inhibition. We evaluated the preclinical effects of safinamide in an animal model of Myotonia Congenita, the ADR (arrested development of righting response) mouse. In vitro studies were performed using the two intracellular microelectrodes technique in current clamp mode. We analyzed sarcolemma excitability in skeletal muscle fibers isolated from male and female ADR (adr/adr) and from Wild-Type (wt/wt) mice, before and after the application of safinamide and the reference compound mexiletine. In ADR mice, the maximum number of action potentials (N-spikes) elicited by a fixed current is higher with respect to that of WT mice. Myotonic muscles show an involuntary firing of action potential called after-discharges. A more potent activity of safinamide compared to mexiletine has been demonstrated in reducing N-spikes and the after-discharges in myotonic muscle fibers. The time of righting reflex (TRR) before and after administration of safinamide and mexiletine was evaluated in vivo in ADR mice. Safinamide was able to reduce the TRR in ADR mice to a greater extent than mexiletine. In conclusion, safinamide counteracted the abnormal muscle hyperexcitability in myotonic mice both in vitro and in vivo suggesting it as an effective drug to be indicated in Myotonia Congenita.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00455"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00460
Karin Prillinger , Gabriel Amador de Lara , Manfred Klöbl , Rupert Lanzenberger , Paul L. Plener , Luise Poustka , Lilian Konicar , Stefan T. Radev
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.
{"title":"Multisession tDCS combined with intrastimulation training improves emotion recognition in adolescents with autism spectrum disorder","authors":"Karin Prillinger , Gabriel Amador de Lara , Manfred Klöbl , Rupert Lanzenberger , Paul L. Plener , Luise Poustka , Lilian Konicar , Stefan T. Radev","doi":"10.1016/j.neurot.2024.e00460","DOIUrl":"10.1016/j.neurot.2024.e00460","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00460"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00467
Luis E. Salazar Leon , Linda H. Kim , Roy V. Sillitoe
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—Ptf1aCre;Vglut2fx/fx and Pdx1Cre;Vglut2fx/fx—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 Ptf1aCre;Vglut2fx/fx 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.
{"title":"Cerebellar deep brain stimulation as a dual-function therapeutic for restoring movement and sleep in dystonic mice","authors":"Luis E. Salazar Leon , Linda H. Kim , Roy V. Sillitoe","doi":"10.1016/j.neurot.2024.e00467","DOIUrl":"10.1016/j.neurot.2024.e00467","url":null,"abstract":"<div><div>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—<em>Ptf1a</em><sup><em>Cre</em></sup><em>;Vglut2</em><sup><em>fx/fx</em></sup> and <em>Pdx1</em><sup><em>Cre</em></sup><em>;Vglut2</em><sup><em>fx/fx</em></sup>—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 <em>Ptf1a</em><sup><em>Cre</em></sup><em>;Vglut2</em><sup><em>fx/fx</em></sup> 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 <em>in vivo</em> therapeutic strategy.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00467"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00457
Laura Moles , Ane Otaegui-Chivite , Miriam Gorostidi-Aicua , Leire Romarate , Idoia Mendiburu , Hirune Crespillo-Velasco , Amaya Álvarez de Arcaya , Eva Ferreira , Maialen Arruti , Tamara Castillo-Triviño , David Otaegui
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.
{"title":"Microbiota modulation by teriflunomide therapy in people with multiple sclerosis: An observational case-control study","authors":"Laura Moles , Ane Otaegui-Chivite , Miriam Gorostidi-Aicua , Leire Romarate , Idoia Mendiburu , Hirune Crespillo-Velasco , Amaya Álvarez de Arcaya , Eva Ferreira , Maialen Arruti , Tamara Castillo-Triviño , David Otaegui","doi":"10.1016/j.neurot.2024.e00457","DOIUrl":"10.1016/j.neurot.2024.e00457","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00457"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00470
Jea Woo Kang , Vaibhav Vemuganti , Jessamine F. Kuehn , Tyler K. Ulland , Federico E. Rey , Barbara B. Bendlin
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.
{"title":"Gut microbial metabolism in Alzheimer's disease and related dementias","authors":"Jea Woo Kang , Vaibhav Vemuganti , Jessamine F. Kuehn , Tyler K. Ulland , Federico E. Rey , Barbara B. Bendlin","doi":"10.1016/j.neurot.2024.e00470","DOIUrl":"10.1016/j.neurot.2024.e00470","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00470"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00476
Andrea R. Merchak , MacKenzie L. Bolen , Malú Gámez Tansey , Kelly B. Menees
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.
{"title":"Thinking outside the brain: Gut microbiome influence on innate immunity within neurodegenerative disease","authors":"Andrea R. Merchak , MacKenzie L. Bolen , Malú Gámez Tansey , Kelly B. Menees","doi":"10.1016/j.neurot.2024.e00476","DOIUrl":"10.1016/j.neurot.2024.e00476","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00476"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00452
Leo J.Y. Kim , Bornali Kundu , Paolo Moretti , Andres M. Lozano , Shervin Rahimpour
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by choreic movements, behavioral changes, and cognitive impairment. The pathogenesis of this process is a consequence of mutant protein toxicity in striatal and cortical neurons. Thus far, neurosurgical management of HD has largely been limited to symptomatic relief of motor symptoms using ablative and stimulation techniques. These interventions, however, do not modify the progressive course of the disease. More recently, disease-modifying experimental therapeutic strategies have emerged targeting intrastriatal infusion of neurotrophic factors, cell transplantation, HTT gene silencing, and delivery of intrabodies. Herein we review therapies requiring neurosurgical intervention, including those targeting symptom management and more recent disease-modifying agents, with a focus on safety, efficacy, and surgical considerations.
{"title":"Advancements in surgical treatments for Huntington disease: From pallidotomy to experimental therapies","authors":"Leo J.Y. Kim , Bornali Kundu , Paolo Moretti , Andres M. Lozano , Shervin Rahimpour","doi":"10.1016/j.neurot.2024.e00452","DOIUrl":"10.1016/j.neurot.2024.e00452","url":null,"abstract":"<div><div>Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by choreic movements, behavioral changes, and cognitive impairment. The pathogenesis of this process is a consequence of mutant protein toxicity in striatal and cortical neurons. Thus far, neurosurgical management of HD has largely been limited to symptomatic relief of motor symptoms using ablative and stimulation techniques. These interventions, however, do not modify the progressive course of the disease. More recently, disease-modifying experimental therapeutic strategies have emerged targeting intrastriatal infusion of neurotrophic factors, cell transplantation, <em>HTT</em> gene silencing, and delivery of intrabodies. Herein we review therapies requiring neurosurgical intervention, including those targeting symptom management and more recent disease-modifying agents, with a focus on safety, efficacy, and surgical considerations.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00452"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00456
Alyssa F. Balleste , Jacqueline C. Alvarez , Fabiola Placeres-Uray , Patrizzia Mastromatteo-Alberga , Maria Dominguez Torres , Carlos A. Dallera , W. Dalton Dietrich , Tom J. Parry , Todd A. Verdoorn , Clare B. Billing Jr. , Benjamin Buller , Coleen M. Atkins
Neuroactive steroids reduce mortality, decrease edema, and improve functional outcomes in preclinical and clinical traumatic brain injury (TBI) studies. In this study, we tested the efficacy of two related novel neuroactive steroids, NTS-104 and NTS-105, in a rat model of TBI. NTS-104 is a water-soluble prodrug of NTS-105, a partial progesterone receptor agonist. To investigate the effects of NTS-104 on TBI recovery, adult male Sprague Dawley rats received moderate parasagittal fluid-percussion injury or sham surgery and were treated with vehicle or NTS-104 (10 mg/kg, intramuscularly) at 4, 10, 24, and 48 h post-TBI. The therapeutic time window was also assessed using the neuroactive steroid NTS-105 (3 mg/kg, intramuscularly). Edema in the parietal cortex and hippocampus, measured at 3 days post-injury (DPI), was reduced by NTS-104 and NTS-105. NTS-105 was effective in reducing edema when given at 4, 10, or 24 h post-injury. Sensorimotor deficits in the cylinder test at 3 DPI were ameliorated by NTS-104 and NTS-105 treatment. Cognitive recovery, assessed with cue and contextual fear conditioning and retention of the water maze task assessed subacutely 1–3 weeks post-injury, also improved with NTS-104 treatment. Cortical and hippocampal atrophy at 22 DPI did not improve, indicating that NTS-104/NTS-105 may promote post-TBI cognitive recovery by controlling edema and other processes. These results demonstrate that NTS-104/NTS-105 is a promising therapeutic approach to improve motor and cognitive recovery after moderate TBI.
{"title":"Improvement in edema and cognitive recovery after moderate traumatic brain injury with the neurosteroid prodrug NTS-104","authors":"Alyssa F. Balleste , Jacqueline C. Alvarez , Fabiola Placeres-Uray , Patrizzia Mastromatteo-Alberga , Maria Dominguez Torres , Carlos A. Dallera , W. Dalton Dietrich , Tom J. Parry , Todd A. Verdoorn , Clare B. Billing Jr. , Benjamin Buller , Coleen M. Atkins","doi":"10.1016/j.neurot.2024.e00456","DOIUrl":"10.1016/j.neurot.2024.e00456","url":null,"abstract":"<div><div>Neuroactive steroids reduce mortality, decrease edema, and improve functional outcomes in preclinical and clinical traumatic brain injury (TBI) studies. In this study, we tested the efficacy of two related novel neuroactive steroids, NTS-104 and NTS-105, in a rat model of TBI. NTS-104 is a water-soluble prodrug of NTS-105, a partial progesterone receptor agonist. To investigate the effects of NTS-104 on TBI recovery, adult male Sprague Dawley rats received moderate parasagittal fluid-percussion injury or sham surgery and were treated with vehicle or NTS-104 (10 mg/kg, intramuscularly) at 4, 10, 24, and 48 h post-TBI. The therapeutic time window was also assessed using the neuroactive steroid NTS-105 (3 mg/kg, intramuscularly). Edema in the parietal cortex and hippocampus, measured at 3 days post-injury (DPI), was reduced by NTS-104 and NTS-105. NTS-105 was effective in reducing edema when given at 4, 10, or 24 h post-injury. Sensorimotor deficits in the cylinder test at 3 DPI were ameliorated by NTS-104 and NTS-105 treatment. Cognitive recovery, assessed with cue and contextual fear conditioning and retention of the water maze task assessed subacutely 1–3 weeks post-injury, also improved with NTS-104 treatment. Cortical and hippocampal atrophy at 22 DPI did not improve, indicating that NTS-104/NTS-105 may promote post-TBI cognitive recovery by controlling edema and other processes. These results demonstrate that NTS-104/NTS-105 is a promising therapeutic approach to improve motor and cognitive recovery after moderate TBI.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00456"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00426
Piyali Saha, Sangram S. Sisodia
Alzheimer's disease (AD) presents distinct pathophysiological features influenced by biological sex, with women disproportionately affected due to sex-specific genetic, hormonal, and epigenetic factors. This review delves into three critical areas of sex differences in AD: First, we explore how genetic predisposition and hormonal changes, particularly those involving sex-specific modifications, influence susceptibility and progression of the disease. Second, we examine the neuroimmune dynamics in AD, emphasizing variations in microglial activity between sexes during crucial developmental stages and the effects of hormonal interventions on disease outcomes. Crucially, this review highlights the significant role of gut microbiome perturbations in shaping AD pathophysiology in a sex-specific manner, suggesting that these alterations can further influence microglial activity and overall disease trajectory. Third, we provide a viewpoint that advocates for personalized therapeutic strategies that integrate the understanding of hormonal fluctuations and microbiome dynamics into treatment plans in order to optimize patient outcomes.
阿尔茨海默病（AD）受生理性别的影响而呈现出不同的病理生理学特征，由于特定性别的遗传、荷尔蒙和表观遗传因素，女性受到的影响更大。本综述将深入探讨 AD 性别差异的三个关键领域：首先，我们探讨遗传易感性和激素变化，尤其是涉及性别特异性修饰的变化，如何影响疾病的易感性和进展。其次，我们研究了 AD 的神经免疫动态，强调了在关键发育阶段两性之间微胶质细胞活动的差异，以及激素干预对疾病结果的影响。最重要的是，这篇综述强调了肠道微生物组的扰动在以性别特异性的方式塑造 AD 病理生理学方面的重要作用，表明这些改变会进一步影响微胶质细胞的活性和整个疾病的发展轨迹。第三，我们提出了一种观点，主张采用个性化治疗策略，将对激素波动和微生物组动态的了解融入治疗计划中，以优化患者的预后。
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