Pub Date : 2025-12-01DOI: 10.1016/j.bbih.2025.101149
Polina Stepanova , Merja H. Voutilainen , Ove Eriksson , Dan Lindholm
Modelling of human neurological diseases uses a plethora of ever-more sophisticated methods and approaches. For Huntington's disease (HD), which affects specific neuronal types and circuits in the brain, this has meant the use of both neurotoxic compounds and various animal models of different complexity, ranging from rodents to non-primate ones. Genetic models are classified based on the use of specific constructs including gene including gene fragments, full-length, knock-out and knock-in models. In this review, we will discuss the available animal models for HD, highlighting their pros and cons in studying the neuropathology, behavioural alterations, and biological mechanisms that prevail in HD and during the disease progression. We also highlight present knowledge gaps and difficulties to fully recapitulate the human disease. At the end we will further elaborate on current outstanding questions in HD research that warrant further studies using both animal models and patient data. This may help to guide future research and increase the translational relevance of the models to solve key questions and pave the way for better treatment options and design of drugs to alleviate the course of HD.
{"title":"Animal models of Huntington's disease. Pros and cons","authors":"Polina Stepanova , Merja H. Voutilainen , Ove Eriksson , Dan Lindholm","doi":"10.1016/j.bbih.2025.101149","DOIUrl":"10.1016/j.bbih.2025.101149","url":null,"abstract":"<div><div>Modelling of human neurological diseases uses a plethora of ever-more sophisticated methods and approaches. For Huntington's disease (HD), which affects specific neuronal types and circuits in the brain, this has meant the use of both neurotoxic compounds and various animal models of different complexity, ranging from rodents to non-primate ones. Genetic models are classified based on the use of specific constructs including gene including gene fragments, full-length, knock-out and knock-in models. In this review, we will discuss the available animal models for HD, highlighting their pros and cons in studying the neuropathology, behavioural alterations, and biological mechanisms that prevail in HD and during the disease progression. We also highlight present knowledge gaps and difficulties to fully recapitulate the human disease. At the end we will further elaborate on current outstanding questions in HD research that warrant further studies using both animal models and patient data. This may help to guide future research and increase the translational relevance of the models to solve key questions and pave the way for better treatment options and design of drugs to alleviate the course of HD.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101149"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145684289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.bbih.2025.101150
Xiujuan wang , Mu Liu , Liuzhao Cao , Hao Huang , Juan Yang , Haiqing Zhang , chengyu pan , Zucai Xu
This review systematically summarizes the key pathological mechanisms and therapeutic potential of the gut microbiota–neuroinflammation axis in comorbid depression in epilepsy. Approximately 30–50 % of epilepsy patients suffer from depression, which leads to poor treatment adherence and significantly increases the risk of mortality and suicide. Studies have shown that dysbiosis of the gut microbiota and central nervous system inflammation interact through multiple pathways—including microbial metabolites, immune modulation, and the vagus nerve—to form a “gut–brain–emotion” regulatory network. Epilepsy patients often exhibit reduced diversity and abnormal composition of gut microbiota, most notably dysregulation of Firmicutes, which promotes systemic inflammation and activation of local central nervous system inflammation. Neuroinflammation, by affecting neurotransmitter metabolism, blood-brain barrier function, and neuroplasticity, exacerbates abnormal neuronal discharges and depressive symptoms, thereby creating a vicious cycle. Intervention strategies targeting this axis have shown promising prospects, including supplementation with probiotics or prebiotics, modulation of microbial metabolites, anti-inflammatory therapies, and dietary regulation, all of which can significantly improve both the frequency of epileptic seizures and emotional states. Multi-omics analysis and precise subtyping are advancing the development of individualized treatment plans, bridging the gaps among neuroscience, immunology, and microbiology. Although challenges remain in standardized sampling, causal mechanism validation, and long-term follow-up studies, the gut microbiota–neuroinflammation axis has emerged as a new frontier in the precise prevention and treatment of comorbid depression in epilepsy, providing a tangible theoretical foundation and practical strategies for improving patient outcomes.
{"title":"Gut microbiota–neuroinflammation axis: A new mechanism and therapeutic target for comorbid depression in epilepsy","authors":"Xiujuan wang , Mu Liu , Liuzhao Cao , Hao Huang , Juan Yang , Haiqing Zhang , chengyu pan , Zucai Xu","doi":"10.1016/j.bbih.2025.101150","DOIUrl":"10.1016/j.bbih.2025.101150","url":null,"abstract":"<div><div>This review systematically summarizes the key pathological mechanisms and therapeutic potential of the gut microbiota–neuroinflammation axis in comorbid depression in epilepsy. Approximately 30–50 % of epilepsy patients suffer from depression, which leads to poor treatment adherence and significantly increases the risk of mortality and suicide. Studies have shown that dysbiosis of the gut microbiota and central nervous system inflammation interact through multiple pathways—including microbial metabolites, immune modulation, and the vagus nerve—to form a “gut–brain–emotion” regulatory network. Epilepsy patients often exhibit reduced diversity and abnormal composition of gut microbiota, most notably dysregulation of Firmicutes, which promotes systemic inflammation and activation of local central nervous system inflammation. Neuroinflammation, by affecting neurotransmitter metabolism, blood-brain barrier function, and neuroplasticity, exacerbates abnormal neuronal discharges and depressive symptoms, thereby creating a vicious cycle. Intervention strategies targeting this axis have shown promising prospects, including supplementation with probiotics or prebiotics, modulation of microbial metabolites, anti-inflammatory therapies, and dietary regulation, all of which can significantly improve both the frequency of epileptic seizures and emotional states. Multi-omics analysis and precise subtyping are advancing the development of individualized treatment plans, bridging the gaps among neuroscience, immunology, and microbiology. Although challenges remain in standardized sampling, causal mechanism validation, and long-term follow-up studies, the gut microbiota–neuroinflammation axis has emerged as a new frontier in the precise prevention and treatment of comorbid depression in epilepsy, providing a tangible theoretical foundation and practical strategies for improving patient outcomes.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101150"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.bbih.2025.101151
Yu-Wei Lin , Daw-Yang Hwang , Yi-Yung Hung
Introduction
Major depressive disorder (MDD) is a debilitating disease possibly linked to immune defense mechanisms. TNIP1, a key anti-inflammatory regulator in NF-κB and TLR pathways, is implicated in MDD, but its transcriptional regulation and role in treatment response are unclear.
Methods
We analyzed mRNA expression of TNIP1 and 13 transcription factors in monocytes from pre- and post-treatment (4–6 weeks) MDD patients and healthy controls. Peripheral blood mononuclear cells were isolated, tagged by CD14, and mRNA was extracted and analyzed. Participants were recruited at Kaohsiung Chang Gung Memorial Hospital (2014–2025). ANCOVA, paired t-tests, and multiple linear regression adjusted for age, gender, BMI, and smoking were used to compare groups and predict treatment outcomes.
Results
This study encompassed 62 MDD patients and 52 healthy controls. Pre-treatment HAMD-17 averaged 23.90 ± 4.60, and post-treatment HAMD-17 averaged 8.43 ± 4.24. MDD patients showed higher PPAR-γ (p < 0.001), FOS (p = 0.023), and lower JUN (p = 0.029) expression than controls. Post-treatment, TNIP1 expression increased (p = 0.031). Lower pre-treatment PPAR-γ predicted greater symptom improvement (p = 0.016).
Conclusion
This study highlights the differential expression of PPAR-γ, FOS, and JUN in MDD patients, underscoring their potential roles in immune regulation. The association between lower pre-treatment PPAR-γ expression and improved treatment outcomes suggests its utility as a biomarker for predicting therapeutic response.
{"title":"PPARγ as a predictive biomarker for antidepressant response in major depressive disorder: Insights from TNIP1 transcriptional regulation","authors":"Yu-Wei Lin , Daw-Yang Hwang , Yi-Yung Hung","doi":"10.1016/j.bbih.2025.101151","DOIUrl":"10.1016/j.bbih.2025.101151","url":null,"abstract":"<div><h3>Introduction</h3><div>Major depressive disorder (MDD) is a debilitating disease possibly linked to immune defense mechanisms. TNIP1, a key anti-inflammatory regulator in NF-κB and TLR pathways, is implicated in MDD, but its transcriptional regulation and role in treatment response are unclear.</div></div><div><h3>Methods</h3><div>We analyzed mRNA expression of TNIP1 and 13 transcription factors in monocytes from pre- and post-treatment (4–6 weeks) MDD patients and healthy controls. Peripheral blood mononuclear cells were isolated, tagged by CD14, and mRNA was extracted and analyzed. Participants were recruited at Kaohsiung Chang Gung Memorial Hospital (2014–2025). ANCOVA, paired t-tests, and multiple linear regression adjusted for age, gender, BMI, and smoking were used to compare groups and predict treatment outcomes.</div></div><div><h3>Results</h3><div>This study encompassed 62 MDD patients and 52 healthy controls. Pre-treatment HAMD-17 averaged 23.90 ± 4.60, and post-treatment HAMD-17 averaged 8.43 ± 4.24. MDD patients showed higher PPAR-γ (<em>p</em> < 0.001), FOS (<em>p</em> = 0.023), and lower JUN (<em>p</em> = 0.029) expression than controls. Post-treatment, TNIP1 expression increased (<em>p</em> = 0.031). Lower pre-treatment PPAR-γ predicted greater symptom improvement (<em>p</em> = 0.016).</div></div><div><h3>Conclusion</h3><div>This study highlights the differential expression of PPAR-γ, FOS, and JUN in MDD patients, underscoring their potential roles in immune regulation. The association between lower pre-treatment PPAR-γ expression and improved treatment outcomes suggests its utility as a biomarker for predicting therapeutic response.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"51 ","pages":"Article 101151"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145712145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.bbih.2025.101140
Courtney N. Dye , Dominic V. Franceschelli , Caitlin Goodpaster , Lynde M. Wangler , Amanda Ringland , Jonathan P. Godbout , Kathryn M. Lenz , Benedetta Leuner
Postpartum depression (PPD) affects 20 % of new mothers. Little is known about what contributes to this prevalence, though one of the strongest risk factors for developing PPD is stress during pregnancy. Pregnancy and the postpartum period are accompanied by dramatic changes in the endocrine, nervous, and immune systems, which may confer heightened vulnerability to maternal mental illness. Microglia, the brain's main immune cells, are important for displaying maternal behaviors. Environmental insults to microglia, such as stress, lead to hormonal dysregulation and aberrant synaptic pruning, both of which have been implicated in the pathophysiology of mood disorders like depression. Given these links, we hypothesized that stress during pregnancy would lead to dysregulated neuroimmune and endocrine profiles and produce synaptic changes in the maternal brain. We used a 2-week variable stress model in pregnancy and assessed neuroimmune changes in the nucleus accumbens (NAc), a brain region that regulates functions impaired in PDD including mood and maternal caregiving. Peripheral hormones and cytokines were also measured. While peripheral cytokine levels were not affected by stress exposure, gestational stress induced central immune changes in the NAc of maternal rats. This included increased microglia immunolabeling and changes in pro- and anti-inflammatory transcripts measured by a Nanostring nCounter panel. Astrocytes also increased in the NAc following gestational stress exposure. Peripheral estradiol and progesterone concentrations were reduced in late pregnancy of stressed mothers, and at the transcript level, hormone receptor and synthesis molecules were altered in the NAc. Gestational stress also altered transcripts associated with synapses and synaptic plasticity during late pregnancy and the postpartum period. There was no impact of stress on engulfment of pre- and postsynaptic proteins by microglia. However, microglia engulfed more of the postsynaptic marker, PSD95, in late pregnancy relative to postpartum, indicating a potential role for microglia in remodeling synapses in the NAc. Overall, these studies provide novel evidence that gestational stress impacts endocrine, synaptic and neuroimmune factors in the maternal NAc, suggesting possible mechanisms by which stress during pregnancy contributes to peripartum mood disorders.
{"title":"Gestational stress disrupts the neuroimmune environment in the nucleus accumbens of maternal rats","authors":"Courtney N. Dye , Dominic V. Franceschelli , Caitlin Goodpaster , Lynde M. Wangler , Amanda Ringland , Jonathan P. Godbout , Kathryn M. Lenz , Benedetta Leuner","doi":"10.1016/j.bbih.2025.101140","DOIUrl":"10.1016/j.bbih.2025.101140","url":null,"abstract":"<div><div>Postpartum depression (PPD) affects 20 % of new mothers. Little is known about what contributes to this prevalence, though one of the strongest risk factors for developing PPD is stress during pregnancy. Pregnancy and the postpartum period are accompanied by dramatic changes in the endocrine, nervous, and immune systems, which may confer heightened vulnerability to maternal mental illness. Microglia, the brain's main immune cells, are important for displaying maternal behaviors. Environmental insults to microglia, such as stress, lead to hormonal dysregulation and aberrant synaptic pruning, both of which have been implicated in the pathophysiology of mood disorders like depression. Given these links, we hypothesized that stress during pregnancy would lead to dysregulated neuroimmune and endocrine profiles and produce synaptic changes in the maternal brain. We used a 2-week variable stress model in pregnancy and assessed neuroimmune changes in the nucleus accumbens (NAc), a brain region that regulates functions impaired in PDD including mood and maternal caregiving. Peripheral hormones and cytokines were also measured. While peripheral cytokine levels were not affected by stress exposure, gestational stress induced central immune changes in the NAc of maternal rats. This included increased microglia immunolabeling and changes in pro- and anti-inflammatory transcripts measured by a Nanostring nCounter panel. Astrocytes also increased in the NAc following gestational stress exposure. Peripheral estradiol and progesterone concentrations were reduced in late pregnancy of stressed mothers, and at the transcript level, hormone receptor and synthesis molecules were altered in the NAc. Gestational stress also altered transcripts associated with synapses and synaptic plasticity during late pregnancy and the postpartum period. There was no impact of stress on engulfment of pre- and postsynaptic proteins by microglia. However, microglia engulfed more of the postsynaptic marker, PSD95, in late pregnancy relative to postpartum, indicating a potential role for microglia in remodeling synapses in the NAc. Overall, these studies provide novel evidence that gestational stress impacts endocrine, synaptic and neuroimmune factors in the maternal NAc, suggesting possible mechanisms by which stress during pregnancy contributes to peripartum mood disorders.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101140"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145684161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.bbih.2025.101157
Ashley J. Douthitt , Aaron Bennett , Alexandra Koustova , Asim Abdelfattah , Darijana Horvat , Cédric G. Geoffroy
Spinal cord injury induces extensive neurological impairment and drives systemic and tissue-level inflammatory responses that accelerate secondary systemic damage. Emerging evidence suggests that gut microbiota-derived metabolites can influence post-injury inflammation, presenting a potential therapeutic approach. This study examines whether the tryptophan-derived metabolites indole and indole-3-propionic acid modulate inflammatory responses and improve outcomes following spinal cord injury. Female C57BL/6J mice received a severe thoracic-8 contusion-compression injury and were administered indole or indole-3-proprionic acid daily via oral gavage for the duration of the observation period. In an acute cohort, 7 days post-injury, neither treatment altered plasma inflammatory profiles relative to injury controls. However, both metabolites significantly reduced CD68+ macrophage presence within the injured spinal cord. In a chronic cohort, 42 days post-injury, metabolite treatment mitigated injury-induced body composition changes, improved locomotor recovery and reduced inflammatory pathologies within the liver and spinal cord. These findings identify gut-derived metabolites as a promising therapeutic strategy targeting the gut-spinal cord axis to attenuate systemic injury mechanisms and support recovery.
{"title":"Leveraging microbiota-metabolites to reduce inflammation and promote functional recovery following spinal cord injury in female mice","authors":"Ashley J. Douthitt , Aaron Bennett , Alexandra Koustova , Asim Abdelfattah , Darijana Horvat , Cédric G. Geoffroy","doi":"10.1016/j.bbih.2025.101157","DOIUrl":"10.1016/j.bbih.2025.101157","url":null,"abstract":"<div><div>Spinal cord injury induces extensive neurological impairment and drives systemic and tissue-level inflammatory responses that accelerate secondary systemic damage. Emerging evidence suggests that gut microbiota-derived metabolites can influence post-injury inflammation, presenting a potential therapeutic approach. This study examines whether the tryptophan-derived metabolites indole and indole-3-propionic acid modulate inflammatory responses and improve outcomes following spinal cord injury. Female C57BL/6J mice received a severe thoracic-8 contusion-compression injury and were administered indole or indole-3-proprionic acid daily via oral gavage for the duration of the observation period. In an acute cohort, 7 days post-injury, neither treatment altered plasma inflammatory profiles relative to injury controls. However, both metabolites significantly reduced CD68<sup>+</sup> macrophage presence within the injured spinal cord. In a chronic cohort, 42 days post-injury, metabolite treatment mitigated injury-induced body composition changes, improved locomotor recovery and reduced inflammatory pathologies within the liver and spinal cord. These findings identify gut-derived metabolites as a promising therapeutic strategy targeting the gut-spinal cord axis to attenuate systemic injury mechanisms and support recovery.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101157"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145684290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.bbih.2025.101155
Floriana De Cillis , Veronica Begni , Ilari D'Aprile , Giulia Petrillo , Marco Andrea Riva , Annamaria Cattaneo
Bipolar disorder (BD) is increasingly associated with immune system dysregulation encompassing both peripheral and central components. Peripheral low-grade inflammation, marked by elevated proinflammatory cytokines and impaired anti-inflammatory responses, contributes to systemic immune imbalance in BD. This peripheral inflammatory state may compromise blood–brain barrier (BBB) integrity, facilitating the entry of peripheral immune mediators into the central nervous system (CNS) and triggering neuroinflammatory cascades. Within the CNS, neuroinflammation is orchestrated primarily by microglial and astrocytic activation, which disrupts neuronal homeostasis and synaptic function. Additionally, oxidative stress acts as a crucial mediator, exacerbating neuronal damage. Based on current findings, this review synthesises evidence linking both central and peripheral inflammation to the pathophysiology of BD, offering a perspective on its underlying biology. A comprehensive understanding of the dynamic interplay between peripheral inflammation and central neuroimmune responses is essential for identifying novel therapeutic targets and developing interventions that effectively address both systemic and CNS components of BD pathophysiology.
{"title":"Immune dysregulation and neuroinflammation in bipolar disorder: Pathophysiological insights and therapeutic perspectives","authors":"Floriana De Cillis , Veronica Begni , Ilari D'Aprile , Giulia Petrillo , Marco Andrea Riva , Annamaria Cattaneo","doi":"10.1016/j.bbih.2025.101155","DOIUrl":"10.1016/j.bbih.2025.101155","url":null,"abstract":"<div><div>Bipolar disorder (BD) is increasingly associated with immune system dysregulation encompassing both peripheral and central components. Peripheral low-grade inflammation, marked by elevated proinflammatory cytokines and impaired anti-inflammatory responses, contributes to systemic immune imbalance in BD. This peripheral inflammatory state may compromise blood–brain barrier (BBB) integrity, facilitating the entry of peripheral immune mediators into the central nervous system (CNS) and triggering neuroinflammatory cascades. Within the CNS, neuroinflammation is orchestrated primarily by microglial and astrocytic activation, which disrupts neuronal homeostasis and synaptic function. Additionally, oxidative stress acts as a crucial mediator, exacerbating neuronal damage. Based on current findings, this review synthesises evidence linking both central and peripheral inflammation to the pathophysiology of BD, offering a perspective on its underlying biology. A comprehensive understanding of the dynamic interplay between peripheral inflammation and central neuroimmune responses is essential for identifying novel therapeutic targets and developing interventions that effectively address both systemic and CNS components of BD pathophysiology.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"52 ","pages":"Article 101155"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145898084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.bbih.2025.101141
Riccardo Bortoletto , Marco Garzitto , Marta Basaldella , Claudia Scipioni , Orietta Sepulcri , Martina Fabris , Francesco Curcio , Matteo Balestrieri , Marco Colizzi
Clinical high-risk (CHR) for psychosis state still lacks effective and safe treatments. Recent evidence supports the anti-neuroinflammatory properties of fatty acid palmitoylethanolamide (PEA) dietary supplementation across the psychosis spectrum. Sixteen subjects at CHR for psychosis with attenuated psychotic symptoms (APS) enrolled in a 12-week, open-label, nonrandomized, single-arm clinical trial of ultramicronized-PEA (um-PEA, 600 mg/day). Biobehavioral assessments were conducted at baseline, 4 weeks, and 12 weeks, particularly using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and quantifying changes in peripheral neuroimmune biomarkers. Linear mixed-effects models showed significant reductions in CAARMS total APS (Δ12-weeks = −3.8 units, −30.0 %) and Unusual Thought Content (UTC; Δ12-weeks = −2.0, −52.5 %). No treatment-emergent side effects were reported. In exploratory analyses including neuroimmune biomarkers as covariates and potential moderators, lower baseline Interleukin (IL)-1β was associated with greater improvement in UTC, while time-varying IL-10/IL-6 ratio, Interferon (IFN)-γ, and IL-6 were linked to changes in CAARMS total APS and UTC.
A reduction in APS was observed in subjects at CHR for psychosis receiving PEA supplementation, possibly through immune-inflammatory modulation, warranting further research into its therapeutic potential for this condition.
{"title":"Effects of palmitoylethanolamide in clinical high-risk for psychosis: A nonrandomized open-label trial","authors":"Riccardo Bortoletto , Marco Garzitto , Marta Basaldella , Claudia Scipioni , Orietta Sepulcri , Martina Fabris , Francesco Curcio , Matteo Balestrieri , Marco Colizzi","doi":"10.1016/j.bbih.2025.101141","DOIUrl":"10.1016/j.bbih.2025.101141","url":null,"abstract":"<div><div>Clinical high-risk (CHR) for psychosis state still lacks effective and safe treatments. Recent evidence supports the anti-neuroinflammatory properties of fatty acid palmitoylethanolamide (PEA) dietary supplementation across the psychosis spectrum. Sixteen subjects at CHR for psychosis with attenuated psychotic symptoms (APS) enrolled in a 12-week, open-label, nonrandomized, single-arm clinical trial of ultramicronized-PEA (um-PEA, 600 mg/day). Biobehavioral assessments were conducted at baseline, 4 weeks, and 12 weeks, particularly using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and quantifying changes in peripheral neuroimmune biomarkers. Linear mixed-effects models showed significant reductions in CAARMS total APS (Δ<sub>12-weeks</sub> = −3.8 units, −30.0 %) and Unusual Thought Content (UTC; Δ<sub>12-weeks</sub> = −2.0, −52.5 %). No treatment-emergent side effects were reported. In exploratory analyses including neuroimmune biomarkers as covariates and potential moderators, lower baseline Interleukin (IL)-1β was associated with greater improvement in UTC, while time-varying IL-10/IL-6 ratio, Interferon (IFN)-γ, and IL-6 were linked to changes in CAARMS total APS and UTC.</div><div>A reduction in APS was observed in subjects at CHR for psychosis receiving PEA supplementation, possibly through immune-inflammatory modulation, warranting further research into its therapeutic potential for this condition.</div></div><div><h3>Trial registration</h3><div>ClinicalTrials.gov Identifier NCT06037993.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101141"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145618110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.bbih.2025.101144
David M. Howard , Lachlan Gilchrist , Petroula Proitsi , Elisabeth R. Paul , Markus Heilig , Lars Östman , Robin Kämpe , J. Paul Hamilton
Immune and metabolic factors are important in the pathophysiology of major depressive disorder (MDD) but we know little about how these factors manifest in relation to the status of depressive illness—from genetic risk for MDD, to a depressive episode, to depression in remission. Using genetic, diagnostic, biometric, and blood-bioassay data from the UK Biobank, we examined measures of pro-inflammatory signaling (C-reactive protein) and metabolic dysfunction (metabolic syndrome symptomatology) in females (N = 37,806) and males (N = 17,946) as a function of polygenic load for MDD (high versus low) interacting with depression status (never depressed, currently depressed, or depression in remission). We examined socioeconomic status (SES) as an exploratory factor in this design. Groups were matched for several confounders using a propensity-matching algorithm (females: n = 6301 per group for N = 37,806; n = 2991 per group for N = 17,946). In females we found increased inflammation and metabolic dysfunction in the higher-versus-lower PRS quartile, in those below-versus-above the median SES, and in those suffering currently from depression relative to their remitted depressed and healthy counterparts. This association remained when considering only non-psychotropic-medicated persons. Nonetheless, we also saw in both male and female samples that measures of immunological and metabolic dysfunction increased with increasing anti-depressant medication load. We discuss these findings in terms of the epidemiological significance of immune and metabolic functioning in depression and their paradoxical relation with antidepressant treatment.
{"title":"Immune and metabolic disturbance as a function of genetic risk and phase of illness in major depression","authors":"David M. Howard , Lachlan Gilchrist , Petroula Proitsi , Elisabeth R. Paul , Markus Heilig , Lars Östman , Robin Kämpe , J. Paul Hamilton","doi":"10.1016/j.bbih.2025.101144","DOIUrl":"10.1016/j.bbih.2025.101144","url":null,"abstract":"<div><div>Immune and metabolic factors are important in the pathophysiology of major depressive disorder (MDD) but we know little about how these factors manifest in relation to the status of depressive illness—from genetic risk for MDD, to a depressive episode, to depression in remission. Using genetic, diagnostic, biometric, and blood-bioassay data from the UK Biobank, we examined measures of pro-inflammatory signaling (C-reactive protein) and metabolic dysfunction (metabolic syndrome symptomatology) in females (N = 37,806) and males (N = 17,946) as a function of polygenic load for MDD (high versus low) interacting with depression status (never depressed, currently depressed, or depression in remission). We examined socioeconomic status (SES) as an exploratory factor in this design. Groups were matched for several confounders using a propensity-matching algorithm (females: n = 6301 per group for N = 37,806; n = 2991 per group for N = 17,946). In females we found increased inflammation and metabolic dysfunction in the higher-versus-lower PRS quartile, in those below-versus-above the median SES, and in those suffering currently from depression relative to their remitted depressed and healthy counterparts. This association remained when considering only non-psychotropic-medicated persons. Nonetheless, we also saw in both male and female samples that measures of immunological and metabolic dysfunction increased with increasing anti-depressant medication load. We discuss these findings in terms of the epidemiological significance of immune and metabolic functioning in depression and their paradoxical relation with antidepressant treatment.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101144"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145618113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Diverse neurological symptoms are experienced by long COVID and COVID-19 recovered individuals. However, the long-term effects of SARS-CoV-2 in the brain of both groups are underexplored. This study aimed to investigate changes in tissue microstructural and brain neurochemical levels in long COVID and recovered COVID-19 patients compared to healthy controls.
Methods
We recruited 47 participants (long COVID = 19, COVID-recovered healthy controls = 12, and healthy controls without COVID-19 infection = 16) who underwent 3T MRI scans. We acquired T1 and T2 weighted images to assess myelin signal, diffusion weighted images to assess tissue microstructure, and magnetic resonance spectroscopy data to estimate brain neurochemical levels.
Findings
Our multimodal MRI study showed altered T1w/T2w signal between long COVID vs COVID-recovered-healthy controls, long COVID vs healthy controls, and COVID-recovered-healthy controls vs healthy controls. Furthermore, T1w/T2w signal intensity was significantly correlated with physical and cognitive function. Diffusion weighted imaging also showed altered tissue microstructure in these three group comparisons. However, brain neurochemicals were only significantly different between long COVID vs COVID-recovered-healthy controls.
Interpretation
This is one of the first studies to report different myelin signal and brain neurochemical changes between long COVID, COVID-recovered-healthy controls, and healthy controls without SARS-CoV-2 infection. These brain changes provide compelling evidence for the long-term effects of SARS-CoV-2 on brain function.
{"title":"Altered brain tissue microstructure and neurochemical profiles in long COVID and recovered COVID-19 individuals: A multimodal MRI study","authors":"Kiran Thapaliya, Sonya Marshall-Gradisnik, Maira Inderyas, Leighton Barnden","doi":"10.1016/j.bbih.2025.101142","DOIUrl":"10.1016/j.bbih.2025.101142","url":null,"abstract":"<div><h3>Background</h3><div>Diverse neurological symptoms are experienced by long COVID and COVID-19 recovered individuals. However, the long-term effects of SARS-CoV-2 in the brain of both groups are underexplored. This study aimed to investigate changes in tissue microstructural and brain neurochemical levels in long COVID and recovered COVID-19 patients compared to healthy controls.</div></div><div><h3>Methods</h3><div>We recruited 47 participants (long COVID = 19, COVID-recovered healthy controls = 12, and healthy controls without COVID-19 infection = 16) who underwent 3T MRI scans. We acquired T1 and T2 weighted images to assess myelin signal, diffusion weighted images to assess tissue microstructure, and magnetic resonance spectroscopy data to estimate brain neurochemical levels.</div></div><div><h3>Findings</h3><div>Our multimodal MRI study showed altered T1w/T2w signal between long COVID vs COVID-recovered-healthy controls, long COVID vs healthy controls, and COVID-recovered-healthy controls vs healthy controls. Furthermore, T1w/T2w signal intensity was significantly correlated with physical and cognitive function. Diffusion weighted imaging also showed altered tissue microstructure in these three group comparisons. However, brain neurochemicals were only significantly different between long COVID vs COVID-recovered-healthy controls.</div></div><div><h3>Interpretation</h3><div>This is one of the first studies to report different myelin signal and brain neurochemical changes between long COVID, COVID-recovered-healthy controls, and healthy controls without SARS-CoV-2 infection. These brain changes provide compelling evidence for the long-term effects of SARS-CoV-2 on brain function.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101142"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145618112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.bbih.2025.101152
May A. Beydoun , Jordan Weiss , Michael F. Gerogescu , Jason Ashe , Christian A. Maino Vieytes , Tianyi Huang , Hind A. Beydoun , Nicole Noren Hooten , Indira C. Turney , Michele K. Evans , Alan B. Zonderman
Socio-environmental and health-related variables were examined in relation to longitudinal change in select neuroimaging markers through metabolomics. Data from 2255 dementia-free UK Biobank participants were utilized. Statistical analyses involved descriptives, Principal Components Analysis (PCA) for metabolomic data reduction, mixed-effects linear regression models to assess longitudinal change (i.e. empirical Bayes estimators of slope), and Additive Bayesian Networks (ABN). Age was the primary consistent contributor to brain health decline over time, with specific metabolomic markers, mainly “free cholesterol in very large high-density lipoproteins (HDL)”, potentially offering protective effects against declines in microstructural integrity, through reduction of or slower pace of increase in mean Orientation Dispersion (ODmean). Air pollution, individual and household-level SES, sex and racial minority status correlated indirectly with brain health through intracranial volumes and time interval between assessments. These insights emphasize using a multifactorial approach to understanding brain aging for predictive models of neurodegeneration.
{"title":"Socio-environmental and health-related factors and their association with longitudinal change in brain neuroimaging markers through the plasma metabolome among UK adults: An additive Bayesian network analysis","authors":"May A. Beydoun , Jordan Weiss , Michael F. Gerogescu , Jason Ashe , Christian A. Maino Vieytes , Tianyi Huang , Hind A. Beydoun , Nicole Noren Hooten , Indira C. Turney , Michele K. Evans , Alan B. Zonderman","doi":"10.1016/j.bbih.2025.101152","DOIUrl":"10.1016/j.bbih.2025.101152","url":null,"abstract":"<div><div>Socio-environmental and health-related variables were examined in relation to longitudinal change in select neuroimaging markers through metabolomics. Data from 2255 dementia-free UK Biobank participants were utilized. Statistical analyses involved descriptives, Principal Components Analysis (PCA) for metabolomic data reduction, mixed-effects linear regression models to assess longitudinal change (i.e. empirical Bayes estimators of slope), and Additive Bayesian Networks (ABN). Age was the primary consistent contributor to brain health decline over time, with specific metabolomic markers, mainly “free cholesterol in very large high-density lipoproteins (HDL)”, potentially offering protective effects against declines in microstructural integrity, through reduction of or slower pace of increase in mean Orientation Dispersion (OD<sub>mean</sub>). Air pollution, individual and household-level SES, sex and racial minority status correlated indirectly with brain health through intracranial volumes and time interval between assessments. These insights emphasize using a multifactorial approach to understanding brain aging for predictive models of neurodegeneration.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101152"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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