Pub Date : 2026-01-01Epub Date: 2026-01-17DOI: 10.1016/j.neurot.2026.e00832
Rui Wang , Miaomiao Liu , Quanyuan Liu , Yifei You , Xu Li , Yan Chen , Yuwei Liu , Jing Wang , Man Wang , Xianzhi Wang , Zhijie Yin , Jiande DZ. Chen , Xianglin Li , Hongcai Wang
Home-based transcutaneous auricular vagus nerve stimulation (taVNS) holds therapeutic potential for neurological disorders, yet its application in Parkinson's disease (PD) remains underexplored. In this single-blinded, placebo-controlled randomized clinical trial, PD patients received either home-based taVNS with specific stimulation parameters or sham stimulation for three weeks. TaVNS significantly improved motor symptoms, reflected as reduced MDS-UPDRS Ⅲ scores, and alleviated non-motor symptoms including quality of life and sleep disturbances compared with sham stimulation. Neuroimaging revealed that taVNS decreased glutamate levels in the striatum and thalamus, increased Regional Homogeneity values in the rolandic operculum, and enhanced fractional anisotropy in the left hippocampal cingulum and right inferior longitudinal fasciculus. Serum acetylcholine levels were elevated following taVNS and correlated with motor improvement. No serious adverse events occurred. These findings suggest that taVNS with specific parameters effectively alleviates motor and non-motor symptoms in PD, possibly through modulation of brain networks and vagal activity.
{"title":"Home-based transcutaneous auricular vagus nerve stimulation (taVNS) improves motor and non-motor symptoms by improving autonomic and brain functions in patients with Parkinson's disease: A randomized clinical trial","authors":"Rui Wang , Miaomiao Liu , Quanyuan Liu , Yifei You , Xu Li , Yan Chen , Yuwei Liu , Jing Wang , Man Wang , Xianzhi Wang , Zhijie Yin , Jiande DZ. Chen , Xianglin Li , Hongcai Wang","doi":"10.1016/j.neurot.2026.e00832","DOIUrl":"10.1016/j.neurot.2026.e00832","url":null,"abstract":"<div><div>Home-based transcutaneous auricular vagus nerve stimulation (taVNS) holds therapeutic potential for neurological disorders, yet its application in Parkinson's disease (PD) remains underexplored. In this single-blinded, placebo-controlled randomized clinical trial, PD patients received either home-based taVNS with specific stimulation parameters or sham stimulation for three weeks. TaVNS significantly improved motor symptoms, reflected as reduced MDS-UPDRS Ⅲ scores, and alleviated non-motor symptoms including quality of life and sleep disturbances compared with sham stimulation. Neuroimaging revealed that taVNS decreased glutamate levels in the striatum and thalamus, increased Regional Homogeneity values in the rolandic operculum, and enhanced fractional anisotropy in the left hippocampal cingulum and right inferior longitudinal fasciculus. Serum acetylcholine levels were elevated following taVNS and correlated with motor improvement. No serious adverse events occurred. These findings suggest that taVNS with specific parameters effectively alleviates motor and non-motor symptoms in PD, possibly through modulation of brain networks and vagal activity.</div></div><div><h3>Trial registration</h3><div>Chinese Clinical Trial Registry: ChiCTR230007082.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 1","pages":"Article e00832"},"PeriodicalIF":6.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2026-02-17DOI: 10.1016/j.neurot.2026.e00854
Andrew A. Pieper, Francis S. Lee
{"title":"Advances in neuropsychiatry: From objective diagnostics to mechanism-based therapeutics","authors":"Andrew A. Pieper, Francis S. Lee","doi":"10.1016/j.neurot.2026.e00854","DOIUrl":"10.1016/j.neurot.2026.e00854","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 1","pages":"Article e00854"},"PeriodicalIF":6.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146213825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2026-02-24DOI: 10.1016/j.neurot.2026.e00862
Xiaoyu Yu , Shulei Gao , Yunguang Chen , Long Ye , Bin Wang , Lvyang Xu , Ao Sun , Chenrui Liang , Sihan Lu , Xiaolu Li , Zhenyu Fan , Yu Wang
Although the pathophysiological underpinnings of major depressive disorder (MDD) are increasingly recognized to involve microglia-mediated neuroinflammation, the underlying molecular processes are still not fully understood. To identify key molecular regulators associated with neuroinflammatory processes, we conducted transcriptomic analysis on hippocampus tissue from chronic unpredictable stress (CUS) mouse models, as well as in vitro microglial inflammation models. Here, we identified lipocalin-2 (LCN2) as a crucial mediator of these neuroinflammatory processes. The expression of LCN2 was significantly upregulated in both MDD patients and CUS mice, and its expression level was positively correlated with the severity of depressive symptoms. In vitro experiments demonstrated that LCN2 knockdown effectively suppresses pro-inflammatory activation of primary microglia. Furthermore, in vivo studies revealed that inhibition of LCN2 expression via gene silencing or neutralizing antibodies markedly alleviates depressive-like behaviors in CUS mice. Mechanistic investigations indicated that knockdown of LCN2 inhibits mitochondrial dynamics imbalance of microglia and then inhibits its proinflammatory activation, thereby reducing neuroinflammation. This study not only identifies a promising therapeutic target for anti-neuroinflammatory interventions in depression but also provides systematic evidence that LCN2-induced mitochondrial dysfunction plays a pivotal role in the pathogenesis and progression of MDD.
{"title":"Down-regulation of lipocalin-2 alleviates depressive-like behaviors in mice through modulation of microglial activation","authors":"Xiaoyu Yu , Shulei Gao , Yunguang Chen , Long Ye , Bin Wang , Lvyang Xu , Ao Sun , Chenrui Liang , Sihan Lu , Xiaolu Li , Zhenyu Fan , Yu Wang","doi":"10.1016/j.neurot.2026.e00862","DOIUrl":"10.1016/j.neurot.2026.e00862","url":null,"abstract":"<div><div>Although the pathophysiological underpinnings of major depressive disorder (MDD) are increasingly recognized to involve microglia-mediated neuroinflammation, the underlying molecular processes are still not fully understood. To identify key molecular regulators associated with neuroinflammatory processes, we conducted transcriptomic analysis on hippocampus tissue from chronic unpredictable stress (CUS) mouse models, as well as <em>in vitro</em> microglial inflammation models. Here, we identified lipocalin-2 (LCN2) as a crucial mediator of these neuroinflammatory processes. The expression of LCN2 was significantly upregulated in both MDD patients and CUS mice, and its expression level was positively correlated with the severity of depressive symptoms. <em>In vitro</em> experiments demonstrated that LCN2 knockdown effectively suppresses pro-inflammatory activation of primary microglia. Furthermore, <em>in vivo</em> studies revealed that inhibition of LCN2 expression via gene silencing or neutralizing antibodies markedly alleviates depressive-like behaviors in CUS mice. Mechanistic investigations indicated that knockdown of LCN2 inhibits mitochondrial dynamics imbalance of microglia and then inhibits its proinflammatory activation, thereby reducing neuroinflammation. This study not only identifies a promising therapeutic target for anti-neuroinflammatory interventions in depression but also provides systematic evidence that LCN2-induced mitochondrial dysfunction plays a pivotal role in the pathogenesis and progression of MDD.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 1","pages":"Article e00862"},"PeriodicalIF":6.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147308570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-11-29DOI: 10.1016/j.neurot.2025.e00809
Ulf Dettmer
{"title":"α-Synuclein antibody therapy: The case for being aggregate-specific","authors":"Ulf Dettmer","doi":"10.1016/j.neurot.2025.e00809","DOIUrl":"10.1016/j.neurot.2025.e00809","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 1","pages":"Article e00809"},"PeriodicalIF":6.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-12-13DOI: 10.1016/j.neurot.2025.e00816
Fabiana Filogamo, Fabrizio Maria Liguori , Giovanna La Rana, Roberto Russo, Claudia Cristiano
Several studies show that neurosteroids currently play a significant role in autism spectrum disorders (ASD). However, the pathway of neurosteroid synthesis involved in ASD remains unclear. This study aimed to investigate the crosstalk between autism and neurosteroids, focusing on the mechanism of allopregnanolone production. We used the BTBR T+ tf/J (BTBR) mouse, a well-established animal model of ASD that exhibits typical autism-like behaviors along with neuroinflammation. In the hippocampus of BTBR mice, we observed a marked overexpression of pregnenolone and a related reduction in allopregnanolone levels. This neurosteroid imbalance also appears to be associated with an inflammatory pattern and the manifestation of repetitive and asocial behaviors. The combination of low doses of ultramicronized palmitoylethanolamide (PEA-um) and docosahexaenoic acid (DHA) restores allopregnanolone production modulating neurosteroidogenesis. In association with neurosteroid modulation, this restoration reduces repetitive behaviors and improves social interactions in BTBR mice, also modulating the inflammatory profile with a significant reduction in proinflammatory cytokines and brain-derived neurotrophic factor (BDNF) levels in the hippocampus. These effects demonstrate an important role of the peroxisome proliferator-activated receptor alpha (PPAR-α), whose expression is particularly reduced in BTBR mice. In addition, the pivotal involvement of PPAR-α was further supported by administering a specific antagonist that abolished the advantageous effects of PEA-um + DHA. Overall, our findings demonstrate the potential synergistic effect of the low-dose combination of PEA-um and DHA, confirming their therapeutic effect in ASD and the involvement of neurosteroids in their mechanism of action.
{"title":"Low-dose combination of ultramicronized palmitoylethanolamide and docosahexaenoic acid on neurosteroid and neuroinflammatory dysregulation in autism spectrum disorders","authors":"Fabiana Filogamo, Fabrizio Maria Liguori , Giovanna La Rana, Roberto Russo, Claudia Cristiano","doi":"10.1016/j.neurot.2025.e00816","DOIUrl":"10.1016/j.neurot.2025.e00816","url":null,"abstract":"<div><div>Several studies show that neurosteroids currently play a significant role in autism spectrum disorders (ASD). However, the pathway of neurosteroid synthesis involved in ASD remains unclear. This study aimed to investigate the crosstalk between autism and neurosteroids, focusing on the mechanism of allopregnanolone production. We used the BTBR T+ tf/J (BTBR) mouse, a well-established animal model of ASD that exhibits typical autism-like behaviors along with neuroinflammation. In the hippocampus of BTBR mice, we observed a marked overexpression of pregnenolone and a related reduction in allopregnanolone levels. This neurosteroid imbalance also appears to be associated with an inflammatory pattern and the manifestation of repetitive and asocial behaviors. The combination of low doses of ultramicronized palmitoylethanolamide (PEA-um) and docosahexaenoic acid (DHA) restores allopregnanolone production modulating neurosteroidogenesis. In association with neurosteroid modulation, this restoration reduces repetitive behaviors and improves social interactions in BTBR mice, also modulating the inflammatory profile with a significant reduction in proinflammatory cytokines and brain-derived neurotrophic factor (BDNF) levels in the hippocampus. These effects demonstrate an important role of the peroxisome proliferator-activated receptor alpha (PPAR-α), whose expression is particularly reduced in BTBR mice. In addition, the pivotal involvement of PPAR-α was further supported by administering a specific antagonist that abolished the advantageous effects of PEA-um + DHA. Overall, our findings demonstrate the potential synergistic effect of the low-dose combination of PEA-um and DHA, confirming their therapeutic effect in ASD and the involvement of neurosteroids in their mechanism of action.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 1","pages":"Article e00816"},"PeriodicalIF":6.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-12-29DOI: 10.1016/j.neurot.2025.e00827
Ying Li , Yi Xie , Rui Liu , Hao Huang , Ziyue Wang , Xuantong Liu , Zhiyuan Yu , Minghuan Wang , Wei Wang , Xiang Luo
Spinal cord injury (SCI) triggers reactive astrogliosis, leading to the formation of an astrocyte scar around the lesion. Regulatory T cells (Tregs), a subset of immune cells, infiltrate the peri-lesional area through the compromised blood-spinal cord barrier. However, the regulatory role of Tregs in post-SCI astrogliosis and its underlying mechanisms remain unclear. Here, we demonstrated that Tregs attenuate astrogliosis and promote neurological recovery after SCI. Treg-depleted mice exhibited exacerbated astrocyte activation, increased chondroitin sulfate proteoglycan (CSPG) deposition, and impaired axonal remodeling post-SCI. Through transcriptomic profiling, we identified vimentin (Vim) as a key gene in astrocytes upregulated by Treg depletion following SCI. In vitro Treg co-culture attenuated oxygen-glucose deprivation/reoxygenation (OGD/R)-induced astrocyte activation, CSPG secretion, and vimentin high expression. Virus-mediated vimentin knockdown recapitulated Treg-mediated suppression of in vitro astrocyte activation and in vivo astrogliosis, and further ameliorated Treg depletion-induced pathological outcomes. In vitro pharmacological studies in astrocytes reveal that vimentin expression is modulated by exogenous IL-10 signaling and downstream STAT3/PKC phosphorylation. These findings demonstrate that Tregs attenuate post-SCI astrogliosis via the IL-10/STAT3/PKC/vimentin signaling axis, thereby facilitating axonal remodeling and promoting neurological recovery. Our study provides novel insights into the Treg-mediated neuroimmune repair mechanisms and establishes promising therapeutic targets for SCI treatment.
{"title":"Regulatory T cells attenuate astrogliosis via IL-10/STAT3/PKC/vimentin signaling and promote neurological recovery after spinal cord injury","authors":"Ying Li , Yi Xie , Rui Liu , Hao Huang , Ziyue Wang , Xuantong Liu , Zhiyuan Yu , Minghuan Wang , Wei Wang , Xiang Luo","doi":"10.1016/j.neurot.2025.e00827","DOIUrl":"10.1016/j.neurot.2025.e00827","url":null,"abstract":"<div><div>Spinal cord injury (SCI) triggers reactive astrogliosis, leading to the formation of an astrocyte scar around the lesion. Regulatory T cells (Tregs), a subset of immune cells, infiltrate the peri-lesional area through the compromised blood-spinal cord barrier. However, the regulatory role of Tregs in post-SCI astrogliosis and its underlying mechanisms remain unclear. Here, we demonstrated that Tregs attenuate astrogliosis and promote neurological recovery after SCI. Treg-depleted mice exhibited exacerbated astrocyte activation, increased chondroitin sulfate proteoglycan (CSPG) deposition, and impaired axonal remodeling post-SCI. Through transcriptomic profiling, we identified vimentin (<em>Vim</em>) as a key gene in astrocytes upregulated by Treg depletion following SCI. In vitro Treg co-culture attenuated oxygen-glucose deprivation/reoxygenation (OGD/R)-induced astrocyte activation, CSPG secretion, and vimentin high expression. Virus-mediated vimentin knockdown recapitulated Treg-mediated suppression of in vitro astrocyte activation and in vivo astrogliosis, and further ameliorated Treg depletion-induced pathological outcomes. In vitro pharmacological studies in astrocytes reveal that vimentin expression is modulated by exogenous IL-10 signaling and downstream STAT3/PKC phosphorylation. These findings demonstrate that Tregs attenuate post-SCI astrogliosis via the IL-10/STAT3/PKC/vimentin signaling axis, thereby facilitating axonal remodeling and promoting neurological recovery. Our study provides novel insights into the Treg-mediated neuroimmune repair mechanisms and establishes promising therapeutic targets for SCI treatment.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 1","pages":"Article e00827"},"PeriodicalIF":6.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145864257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2026-01-29DOI: 10.1016/j.neurot.2026.e00838
Jae Hyun Han , Ye Rim Kim , Yoojeong Lee , Youngmin Park , Dohyoung Kim , Guiyoung Bong , Hee Jeong Yoo
Trigeminal nerve stimulation (TNS) is a minimal-risk, noninvasive neuromodulation method with growing evidence of efficacy across psychiatric conditions. However, its safety and potential effects in autism spectrum disorder (ASD) remain underexplored. This exploratory pilot study aimed primarily to evaluate the safety and tolerability, and secondarily to explore changes in ASD-related symptoms - including impairments in social communication and reciprocity, attention, executive functioning, emotional regulation, sleep, and sensory processing - in children with ASD, and to examine associated changes using quantitative electroencephalography (qEEG). This double-blind, sham-controlled, randomized exploratory pilot trial enrolled 29 children aged 7–12 years with ASD. The participants were randomized to receive 28 nightly sessions of active or sham TNS over 4 weeks. At baseline and week 4, we assessed safety, clinical outcomes and Clinical Global Impression scales, in addition to analyzing qEEG band power. No serious adverse events were observed, and TNS was well tolerated. Exploratory analyses showed nominal between-group differences (unadjusted) favoring the TNS group in maladaptive behavior (Vineland-II: 1.38 vs 0.08; p = .017) and social reciprocity (Social Responsiveness Scale-2: 12.07 vs −1.43; p = .025). Exploratory qEEG analyses revealed decreased gamma/high-frequency and increased alpha power in the left frontal and parietal regions, changes that significantly correlated with improvements in social (r = −0.917; p = .001) and overall (r = −0.680; p = .030) functioning. TNS was safe and showed preliminary evidence of potential benefits in improving behavioral and social functioning in children with ASD. Larger trials are required to confirm these findings. Clinical trial registration information: http://clinicaltrials.gov/; NCT06233279.
三叉神经刺激（TNS）是一种风险最小、无创的神经调节方法，越来越多的证据表明它对精神疾病有效。然而，其安全性和对自闭症谱系障碍（ASD）的潜在影响仍未得到充分研究。本探索性试点研究的主要目的是评估ASD的安全性和耐受性，其次是探索ASD儿童的ASD相关症状的变化，包括社会沟通和互惠、注意力、执行功能、情绪调节、睡眠和感觉处理方面的障碍，并使用定量脑电图（qEEG）检查相关变化。这项双盲、假对照、随机探索性试点试验招募了29名7-12岁的自闭症儿童。在4周的时间里，参与者被随机分配接受28个每晚的主动或假TNS治疗。在基线和第4周，除了分析qEEG频带功率外，我们还评估了安全性、临床结果和临床总体印象量表。未观察到严重不良事件，TNS耐受性良好。探索性分析显示，TNS组在适应不良行为（Vineland-II: 1.38 vs 0.08; p = 0.017）和社会互惠（社会反应量表-2:12.07 vs -1.43; p = 0.025）方面的组间差异（未经调整）有利于TNS组。探索性qEEG分析显示，左额叶和顶叶区域的伽马/高频下降和阿尔法功率增加，这些变化与社交功能（r = -0.917; p = .001）和整体功能（r = -0.680; p = .030）的改善显著相关。TNS是安全的，初步证据表明，TNS在改善ASD儿童的行为和社会功能方面有潜在的益处。需要更大规模的试验来证实这些发现。临床试验注册信息：http://clinicaltrials.gov/；NCT06233279。
{"title":"Double-blind, sham-controlled, pilot study of trigeminal nerve stimulation for autism spectrum disorder","authors":"Jae Hyun Han , Ye Rim Kim , Yoojeong Lee , Youngmin Park , Dohyoung Kim , Guiyoung Bong , Hee Jeong Yoo","doi":"10.1016/j.neurot.2026.e00838","DOIUrl":"10.1016/j.neurot.2026.e00838","url":null,"abstract":"<div><div>Trigeminal nerve stimulation (TNS) is a minimal-risk, noninvasive neuromodulation method with growing evidence of efficacy across psychiatric conditions. However, its safety and potential effects in autism spectrum disorder (ASD) remain underexplored. This exploratory pilot study aimed primarily to evaluate the safety and tolerability, and secondarily to explore changes in ASD-related symptoms - including impairments in social communication and reciprocity, attention, executive functioning, emotional regulation, sleep, and sensory processing - in children with ASD, and to examine associated changes using quantitative electroencephalography (qEEG). This double-blind, sham-controlled, randomized exploratory pilot trial enrolled 29 children aged 7–12 years with ASD. The participants were randomized to receive 28 nightly sessions of active or sham TNS over 4 weeks. At baseline and week 4, we assessed safety, clinical outcomes and Clinical Global Impression scales, in addition to analyzing qEEG band power. No serious adverse events were observed, and TNS was well tolerated. Exploratory analyses showed nominal between-group differences (unadjusted) favoring the TNS group in maladaptive behavior (Vineland-II: 1.38 vs 0.08; <em>p</em> = .017) and social reciprocity (Social Responsiveness Scale-2: 12.07 vs −1.43; <em>p</em> = .025). Exploratory qEEG analyses revealed decreased gamma/high-frequency and increased alpha power in the left frontal and parietal regions, changes that significantly correlated with improvements in social (<em>r</em> = −0.917; <em>p</em> = .001) and overall (<em>r</em> = −0.680; <em>p</em> = .030) functioning. TNS was safe and showed preliminary evidence of potential benefits in improving behavioral and social functioning in children with ASD. Larger trials are required to confirm these findings. Clinical trial registration information: <span><span>http://clinicaltrials.gov/</span><svg><path></path></svg></span>; NCT06233279.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 1","pages":"Article e00838"},"PeriodicalIF":6.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146093492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-11-19DOI: 10.1016/j.neurot.2025.e00792
Jessica P. Hayes , Velda X. Han , Brooke A. Keating , Hiroya Nishida , Erica Tsang , Xianzhong Lau , Ruwani Dissanayake , Nader Aryamanesh , Wendy Gold , Melanie Wong , Carolyn Ellaway , Brian S. Gloss , Shekeeb S. Mohammad , Markus J. Hofer , Peter Valtchev , Shrujna Patel , Russell C. Dale
Pathogenic DNA variants in chromatin-related genes constitute an important minority of neurodevelopmental disorders (NDDs). Epigenetic mechanisms, including chromatin regulation driven by genetic or environmental factors, are increasingly recognised as key contributors to pathogenesis of diverse NDDs. We hypothesise that therapeutic strategies targeting chromatin dysregulation, such as histone deacetylase inhibition with butyrate, may be a potential disease modifying therapy for NDDs. We first performed peripheral blood bulk RNA sequencing (RNA-seq) to explore baseline gene regulation in children with chromatin-related NDDs (Kabuki syndrome (KMT2D, n = 4), CHARGE syndrome (CHD7, n = 2), and Rett syndrome (MECP2, n = 5), and children with NDDs but without a monogenic diagnosis (non-monogenic, n = 8), compared with sex-matched healthy controls (total n = 21). Next, to explore the effects of butyrate, single-cell RNA sequencing (scRNA-seq) was performed on 101,539 peripheral immune cells from four selected patients (one per condition) and two controls, before and after butyrate treatment. At baseline, dysregulation of ribosomal and immune pathways was seen in all four NDD cohorts (KMT2D, CHD7, MECP2, non-monogenic) compared to controls. Butyrate largely reversed these pathways, normalising ribosomal and immune pathways in patient and control cells. Butyrate induced up-regulation of ribosome, GTPase, cytoskeletal, mitochondrial pathways, and down-regulation of epigenetic and immune pathways. In conclusion, we identified a common ribosomal-immune RNA signature in chromatin-related NDDs, and a similar signature in non-monogenic NDDs. We showed that butyrate modulates epigenetic and immune gene networks in monogenic and non-monogenic NDDs, positioning butyrate as a promising therapeutic modulator across diverse NDDs.
染色质相关基因的致病性DNA变异构成了神经发育障碍（ndd）的重要少数。表观遗传机制，包括由遗传或环境因素驱动的染色质调控，越来越被认为是各种ndd发病机制的关键因素。我们假设针对染色质失调的治疗策略，如用丁酸抑制组蛋白去乙酰化酶，可能是ndd的潜在疾病修饰疗法。我们首先进行了外周血大容量RNA测序（RNA-seq），以探索与染色质相关的ndd儿童(Kabuki综合征（KMT2D, n = 4）、CHARGE综合征（CHD7, n = 2）和Rett综合征（MECP2, n = 5）以及非单基因诊断的ndd儿童（非单基因，n = 8）的基线基因调节，并与性别匹配的健康对照组（总n = 21）进行比较。接下来，为了探索丁酸盐的作用，在丁酸盐治疗前后，对来自4名患者（每种情况一个）和2名对照组的101539个外周免疫细胞进行了单细胞RNA测序（scRNA-seq）。基线时，与对照组相比，所有四个NDD队列（KMT2D、CHD7、MECP2、非单基因）的核糖体和免疫途径均出现失调。丁酸盐在很大程度上逆转了这些途径，使患者和对照细胞中的核糖体和免疫途径正常化。丁酸盐诱导核糖体、GTPase、细胞骨架、线粒体途径上调，表观遗传和免疫途径下调。总之，我们在染色质相关ndd中发现了共同的核糖体免疫RNA特征，在非单基因ndd中也发现了类似的特征。我们发现丁酸盐调节单基因和非单基因ndd的表观遗传和免疫基因网络，将丁酸盐定位为多种ndd的有前途的治疗调节剂。
{"title":"Butyrate modifies epigenetic and immune pathways in peripheral mononuclear cells from children with neurodevelopmental disorders associated with chromatin dysregulation","authors":"Jessica P. Hayes , Velda X. Han , Brooke A. Keating , Hiroya Nishida , Erica Tsang , Xianzhong Lau , Ruwani Dissanayake , Nader Aryamanesh , Wendy Gold , Melanie Wong , Carolyn Ellaway , Brian S. Gloss , Shekeeb S. Mohammad , Markus J. Hofer , Peter Valtchev , Shrujna Patel , Russell C. Dale","doi":"10.1016/j.neurot.2025.e00792","DOIUrl":"10.1016/j.neurot.2025.e00792","url":null,"abstract":"<div><div>Pathogenic DNA variants in chromatin-related genes constitute an important minority of neurodevelopmental disorders (NDDs). Epigenetic mechanisms, including chromatin regulation driven by genetic or environmental factors, are increasingly recognised as key contributors to pathogenesis of diverse NDDs. We hypothesise that therapeutic strategies targeting chromatin dysregulation, such as histone deacetylase inhibition with butyrate, may be a potential disease modifying therapy for NDDs. We first performed peripheral blood bulk RNA sequencing (RNA-seq) to explore baseline gene regulation in children with chromatin-related NDDs (Kabuki syndrome (<em>KMT2D,</em> n = 4), CHARGE syndrome (<em>CHD7,</em> n = 2), and Rett syndrome (<em>MECP2,</em> n = 5), and children with NDDs but without a monogenic diagnosis (non-monogenic, n = 8), compared with sex-matched healthy controls (total n = 21). Next, to explore the effects of butyrate, single-cell RNA sequencing (scRNA-seq) was performed on 101,539 peripheral immune cells from four selected patients (one per condition) and two controls, before and after butyrate treatment. At baseline, dysregulation of ribosomal and immune pathways was seen in all four NDD cohorts (<em>KMT2D, CHD7, MECP2</em>, non-monogenic) compared to controls. Butyrate largely reversed these pathways, normalising ribosomal and immune pathways in patient and control cells. Butyrate induced up-regulation of ribosome, GTPase, cytoskeletal, mitochondrial pathways, and down-regulation of epigenetic and immune pathways. In conclusion, we identified a common ribosomal-immune RNA signature in chromatin-related NDDs, and a similar signature in non-monogenic NDDs. We showed that butyrate modulates epigenetic and immune gene networks in monogenic and non-monogenic NDDs, positioning butyrate as a promising therapeutic modulator across diverse NDDs.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 1","pages":"Article e00792"},"PeriodicalIF":6.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-12-24DOI: 10.1016/j.neurot.2025.e00811
Jeffrey Cummings , Shailja Sharma , G. DeAndrea , Amanda Leisgang Osse , Andrew Ortiz
Biomarkers are essential to guide decision making in Alzheimer's disease (AD) clinical trials where they have a variety of contexts of use (COUs) including diagnosis, risk, pharmacodynamic response, prognosis, prediction, monitoring, and safety. The COU of biomarkers may differ by phase of drug development with Phase 1, 2, and 3 emphasizing different types of information for decision making. A variety of biomarkers are currently serving as pharmacodynamic outcomes in clinical trials including amyloid and tau PET and fluid measures of amyloid, tau, neurodegeneration, inflammation, and synaptic plasticity. Biomarker strategies are integrated throughout drug development programs from collection and assay performance to statistical analysis and data interpretation. Data interrogation approaches using artificial intelligence and machine learning may enhance the value of biomarker observations through integration of multimodal data. Emerging biomarkers that may play a role in future AD trials include proteomics, exosome assays of co-pathology occurring in AD, EEG, ocular measures, and digital biomarkers. Biomarkers inform drug development decision-making including termination of candidate agents without sufficient biomarker effects, resourcing of promising therapies impacting the fundamental features of AD, and accelerating the development of new therapies for those with or at risk for AD.
{"title":"The roles of biomarkers in Alzheimer's disease clinical trials","authors":"Jeffrey Cummings , Shailja Sharma , G. DeAndrea , Amanda Leisgang Osse , Andrew Ortiz","doi":"10.1016/j.neurot.2025.e00811","DOIUrl":"10.1016/j.neurot.2025.e00811","url":null,"abstract":"<div><div>Biomarkers are essential to guide decision making in Alzheimer's disease (AD) clinical trials where they have a variety of contexts of use (COUs) including diagnosis, risk, pharmacodynamic response, prognosis, prediction, monitoring, and safety. The COU of biomarkers may differ by phase of drug development with Phase 1, 2, and 3 emphasizing different types of information for decision making. A variety of biomarkers are currently serving as pharmacodynamic outcomes in clinical trials including amyloid and tau PET and fluid measures of amyloid, tau, neurodegeneration, inflammation, and synaptic plasticity. Biomarker strategies are integrated throughout drug development programs from collection and assay performance to statistical analysis and data interpretation. Data interrogation approaches using artificial intelligence and machine learning may enhance the value of biomarker observations through integration of multimodal data. Emerging biomarkers that may play a role in future AD trials include proteomics, exosome assays of co-pathology occurring in AD, EEG, ocular measures, and digital biomarkers. Biomarkers inform drug development decision-making including termination of candidate agents without sufficient biomarker effects, resourcing of promising therapies impacting the fundamental features of AD, and accelerating the development of new therapies for those with or at risk for AD.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 1","pages":"Article e00811"},"PeriodicalIF":6.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-11-06DOI: 10.1016/j.neurot.2025.e00782
Yuxin Zheng , Meixiang Huang , R Michael Maragakis , Peter Pietri , Yu Su , Jesse Alt , Ying Wu , Colin Finney , Diane E. Peters , Xiaolei Zhu , Rana Rais , Barbara S. Slusher
Despite effective antiretroviral therapy, many people living with HIV (PLH) experience cognitive impairments, particularly in executive function and working memory. These deficits have been linked to dysregulation of brain circuits involving the neuropeptide N-acetyl-aspartyl glutamate (NAAG), which is catabolized by the enzyme glutamate carboxypeptidase II (GCPII). Inhibiting GCPII elevates brain NAAG levels and improves cognition in preclinical models. In prior magnetic resonance spectroscopy (MRS) studies, we demonstrated that higher brain NAAG levels in PLH correlate with better cognitive performance, highlighting NAAG as a potential biomarker and GCPII as a potential therapeutic target. In this study, we used EcoHIV-infected mice to model HIV-associated neurocognitive disorders and evaluated the therapeutic potential of the selective GCPII inhibitor 2-PMPA. We found that 2-PMPA treatment increased cerebrospinal fluid (CSF) NAAG levels by 800 % and reversed EcoHIV-induced deficits in social interaction, recognition memory, and fear conditioning, without affecting general locomotion or anxiety-like behavior. Furthermore, 2-PMPA restored synaptic density and preserved dendritic structure in EcoHIV-infected mice, indicating a neuroprotective effect. These findings provide strong evidence that GCPII inhibition represents a viable therapeutic strategy for HIV-associated cognitive dysfunction by elevating NAAG and protecting neural circuits critical for cognition.
{"title":"Targeting NAAG metabolism restores cognition and synaptic integrity in EcoHIV-infected mice","authors":"Yuxin Zheng , Meixiang Huang , R Michael Maragakis , Peter Pietri , Yu Su , Jesse Alt , Ying Wu , Colin Finney , Diane E. Peters , Xiaolei Zhu , Rana Rais , Barbara S. Slusher","doi":"10.1016/j.neurot.2025.e00782","DOIUrl":"10.1016/j.neurot.2025.e00782","url":null,"abstract":"<div><div>Despite effective antiretroviral therapy, many people living with HIV (PLH) experience cognitive impairments, particularly in executive function and working memory. These deficits have been linked to dysregulation of brain circuits involving the neuropeptide N-acetyl-aspartyl glutamate (NAAG), which is catabolized by the enzyme glutamate carboxypeptidase II (GCPII). Inhibiting GCPII elevates brain NAAG levels and improves cognition in preclinical models. In prior magnetic resonance spectroscopy (MRS) studies, we demonstrated that higher brain NAAG levels in PLH correlate with better cognitive performance, highlighting NAAG as a potential biomarker and GCPII as a potential therapeutic target. In this study, we used EcoHIV-infected mice to model HIV-associated neurocognitive disorders and evaluated the therapeutic potential of the selective GCPII inhibitor 2-PMPA. We found that 2-PMPA treatment increased cerebrospinal fluid (CSF) NAAG levels by 800 % and reversed EcoHIV-induced deficits in social interaction, recognition memory, and fear conditioning, without affecting general locomotion or anxiety-like behavior. Furthermore, 2-PMPA restored synaptic density and preserved dendritic structure in EcoHIV-infected mice, indicating a neuroprotective effect. These findings provide strong evidence that GCPII inhibition represents a viable therapeutic strategy for HIV-associated cognitive dysfunction by elevating NAAG and protecting neural circuits critical for cognition.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 1","pages":"Article e00782"},"PeriodicalIF":6.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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