Brain communications最新文献

{"title":"Polygenic scores contribution to Parkinson's disease comorbidities.","authors":"Carlos F Hernández, Camilo Villaman, Cristian Tejos, Gabriela M Repetto, Costin Leu, Dennis Lal, Ignacio F Mata, Andrés D Klein, Eduardo Pérez-Palma","doi":"10.1093/braincomms/fcaf325","DOIUrl":"10.1093/braincomms/fcaf325","url":null,"abstract":"<p><p>Comorbidities are common in Parkinson's disease and significantly impact the disease progression and management. While polygenic scores have been widely used to assess genetic risk for complex diseases, their role in comorbidity presentation in Parkinson's disease remains unclear. This study investigates whether genetic predisposition to comorbidities, as measured by polygenic scores, differs between individuals with Parkinson's disease and the general population and explores how genetic risk influences disease onset and sex-related differences. We analysed data from 4144 individuals with Parkinson's disease and 370 480 individuals from the general population in the UK Biobank, focusing on four comorbidities with high-quality genome-wide association study data: Type 2 diabetes, major depressive disorder, migraine headaches and epilepsy. We first compared polygenic score distributions between individuals with Parkinson's disease and the general population. While our findings indicate that comorbidities and polygenic risk scores do not significantly differ between individuals with Parkinson's disease and the general population, we show an association with disease onset and sex-specific differences. Individuals with earlier disease onset (50-70 years old) had higher genetic risk for major depressive disorder (odds ratio: 2.19, <i>P</i>-value: 1.27 × 10⁻¹⁵) and epilepsy (odds ratio: 1.58, <i>P</i>-value: 0.00845). Additionally, a female participant with Parkinson's disease exhibited higher genetic risk scores for major depressive disorder (odds ratio: 1.5, <i>P</i>-value: 0.0119) and migraine headaches (odds ratio: 2.1, <i>P</i>-value: 0.0155), while a male participant displayed higher genetic risk scores for Type 2 diabetes (odds ratio: 2.7, <i>P</i>-value: 2.11 × 10⁻¹⁷). Comorbidity-polygenic score did not differ between people with versus without Parkinson's disease, yet within Parkinson's disease, a higher genetic burden for specific comorbidities was linked to earlier onset and sex-specific presentation, implicating common variants as modifiers of clinical heterogeneity rather than the primary disease risk. These results enhance our understanding of the genetic influences shaping the broader clinical presentation of Parkinson's disease and highlight the need for further research into the interplay between genetic risk factors, comorbidities and disease heterogeneity.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 5","pages":"fcaf325"},"PeriodicalIF":4.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145115225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutant huntingtin exon 1 protein detected in mouse brain with neoepitope antibody: effects of CAG repeat expansion, MutS Homolog 3 silencing and aggregation.","authors":"Ellen Sapp, Adel Boudi, Andrew Iwanowicz, Jillian Belgrad, Rachael Miller, Riannon Robertson, Daniel O'Reilly, Ken Yamada, Yunping Deng, Marion Joni, Xueyi Li, Kimberly Kegel-Gleason, Anastasia Khvorova, Anton Reiner, Neil Aronin, Marian DiFiglia","doi":"10.1093/braincomms/fcaf314","DOIUrl":"10.1093/braincomms/fcaf314","url":null,"abstract":"<p><p><i>HTT1a</i> was identified in human and mouse Huntington's disease brain as the pathogenic exon 1 mRNA generated from aberrant splicing between exon 1 and 2 of <i>HTT</i> that contributes to aggregate formation and neuronal dysfunction. Detection of the huntingtin exon 1 protein (HTT1a) has been accomplished with Meso Scale Discovery, Homogeneous Time Resolved Fluorescence and immunoprecipitation assays in Huntington's disease knock-in mice, but direct detection in homogenates by gel electrophoresis and western blot assay has been lacking. Subcellular fractions prepared from mouse and human Huntington's disease brain were separated by gel electrophoresis and probed by western blot with neoepitope monoclonal antibodies 1B12 and 11G2 directed to the C-terminal eight residues of HTT1a. In caudate putamen of an allelic series of 6-month-old Huntington's disease knock-in mice (Q50, Q80, Q111, Q140 and Q175), HTT1a migration was inversely correlated with CAG repeat length and appeared as a sodium dodecyl sulphate soluble high molecular mass smear in Q111, Q140 and Q175 mice but weakly in Q80 and not in wild-type mice or Q50 indicating a CAG repeat size threshold for detecting HTT1a. HTT1a immunoreactivity diminished if 1B12 and 11G2 antibodies were preincubated with an eight amino acid peptide containing the C-terminus of HTT1a but not with an unrelated peptide sequence. Migration of HTT1a and its high molecular mass smear changed with age in caudate putamen of Q111, Q175 and YAC128 mice. Reducing levels of MutS Homolog 3 (MSH3) protein >84% in Q111 mice caudate putamen with small interfering RNA to <i>MSH3</i>, a modifier of CAG repeat expansion, significantly reduced levels of the high molecular mass smear suggesting that the effects of curbing CAG repeat expansion on HTT1a were quantifiable. A prominent 56-60 kDa doublet detected by 1B12 and 11G2 antibodies in lysates from human Huntington's disease brain was not blocked by preincubation with C-terminal HTT1a blocking peptide and also appeared in brains of Parkinson's disease patients. 1B12 and 11G2 antibodies did not immunoprecipitate huntingtin (HTT) proteins from either Huntington's disease mouse or human brain lysates using conditions that pulled down full-length HTT with anti-HTT antibody 2B7. Altogether, these data show that 11G2 and 1B12 antibodies can be used in western blot assays to track and quantify immunoreactive HTT1a levels, solubility and subcellular localization in Huntington's disease mouse brain.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 5","pages":"fcaf314"},"PeriodicalIF":4.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12416564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bridging speech and sight: white matter anatomy in ticker-tape synaesthesia.","authors":"Romain Delsanti, Fabien Hauw, Romain Lahbari, Florence Bouhali, Laurent Cohen","doi":"10.1093/braincomms/fcaf316","DOIUrl":"10.1093/braincomms/fcaf316","url":null,"abstract":"<p><p>Ticker-tape synaesthesia is an informative yet little studied developmental condition in which persons see automatically and vividly in their mind's eye the written form of the spoken words they are hearing. Ticker-tapers show an over-activation and a functional over-connectivity of core regions of the left-hemispheric reading system: the posterior superior temporal and supramarginal gyri (pSTG/SMG), where speech is processed and interfaced with vision, and the Visual Word Form Area (VWFA), which supports orthographic representations in the occipitotemporal cortex. We predicted that synesthetes should show increased anatomical connectivity between these regions. We scanned 17 synesthetes and 17 matched controls with diffusion-weighted MRI, and used probabilistic tractography to compare the density of streamlines between groups. We found that ticker-tapers had a higher streamline density in the white matter underlying the SMG, and connecting the SMG and the mid and posterior STG. We propose that those increased white matter connections at the temporoparietal junction and towards the VWFA boost the top-down influence of phonology on orthography, giving rise to the ticker-tape phenomenology. More generally, while atypical anatomical connectivity may be detrimental to the acquisition of culture-dependent abilities, as in dyslexia, it may also underlie a gain of function, as illustrated by ticker-tape synaesthesia.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 5","pages":"fcaf316"},"PeriodicalIF":4.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145042333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sleep deprivation affects memory function, depression and anxiety-like behaviours in rats and mice: a systematic review and meta-analysis.","authors":"Xiaofan Zhang, Cheng-Wei Liu, Xin Sheng, Yifan Jiang, Sheng Zhang, XiaoYan Mo, Yuan Yang, Fengfei Ding","doi":"10.1093/braincomms/fcaf309","DOIUrl":"10.1093/braincomms/fcaf309","url":null,"abstract":"<p><p>Sleep deprivation paradigms have been employed in rat and mouse models to elucidate the function of sleep. The effects of sleep deprivation on memory function, as well as changes in depression- and anxiety-like behaviours, have been extensively investigated; however, the findings have often been inconsistent. In the present study, we conducted a comprehensive literature review of researches utilizing sleep deprivation paradigms in both rats and mice. A total of 164 original studies were analysed to extract results from behavioural tests concerning memory function and depression- and anxiety-like behaviours in wild-type rats or mice before and after sleep deprivation. The meta-analysis revealed that sleep deprivation consistently impaired memory function, irrespective of the paradigms, durations and species involved [<i>P</i> = 0.000, SMD (standardized mean difference) 95% CI (confidence intervals at 95%): -0.73 (-0.89, -0.57) for sleep deprivation; <i>P</i> = 0.000, SMD (95% CI): -0.75 (-0.93, -0.57) for rapid eye movement sleep deprivation]. Similar, albeit less pronounced, effects were observed on depression-like behaviours [<i>P</i> = 0.000, SMD (95% CI): -0.41 (-0.52, -0.29) for sleep deprivation; <i>P</i> = 0.000, SMD (95% CI): -0.60 (-0.79, -0.42) for rapid eye movement sleep deprivation]. The impact of sleep deprivation on anxiety-like behaviours was more variable. When considering both mice and rats, sleep deprivation generally exhibited anxiogenic effects [<i>P</i> = 0.049, SMD (95% CI): -0.19 (-0.39, -0.00) for sleep deprivation; <i>P</i> = 0.705, SMD (95% CI): 0.04 (-0.18, 0.27) for rapid eye movement sleep deprivation]. However, subgroup analyses indicated that rodent species and sleep durations demonstrated distinct responses to sleep deprivation. This study provides critical insights for selecting optimal paradigms, durations, species and behavioural tests in experimental designs.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 5","pages":"fcaf309"},"PeriodicalIF":4.5,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cortical morphology changes in default mode network regions as predictors of cognitive decline in relation to amyloid and tau deposits.","authors":"Arianna Menardi, Ceren Saglam, Beatrice La Rocca, Diego Cecchin, Annalena Venneri, Annachiara Cagnin, Antonino Vallesi","doi":"10.1093/braincomms/fcaf320","DOIUrl":"10.1093/braincomms/fcaf320","url":null,"abstract":"<p><p>Alzheimer's disease can be classified based on amyloid, tau and neurodegeneration status. The Default Mode Network is notably vulnerable to these processes, making early structural alterations in this network of particular interest for identifying prodromal biomarkers. In this longitudinal cross-sectional study, we analysed data from 279 participants in the Alzheimer's Disease Neuroimaging Initiative (mean age = 73.7 ± 9 years, 53.2% males). Structural measures-sulcal depth, gyrification and cortical thickness-were extracted for all Default Mode Network regions. Their ability to predict memory performance (encoding, retrieval and recall) was tested at baseline and 2-year follow-up by means of multiple linear regression models, which were all corrected for the risk of multiple comparisons. Covariates included Mini Mental State Examination scores, amyloid status and regional tau burden, to examine interactions with structural changes. Our results showed distinct Default Mode Network alteration patterns based on tau burden and amyloid status, highlighting patterns of morphological features with different susceptibility to proteinopathy. In individuals with concordant (both positive or both negative) amyloid and tau status, preserved structural integrity and complexity were linked to better cognitive performance and appeared protective against decline. However, mainly negative associations were instead observed in individuals with discordant amyloid or tau status (i.e. positive for only either amyloid or tau accumulation). We discuss these findings as a possible reflection of a mismatch between abnormal protein accumulation and structural damage in these populations. The multimodal nature of this study helps clarifying the heterogeneous findings reported in existing literature regarding structural integrity and cognitive outcomes in Alzheimer's disease.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 5","pages":"fcaf320"},"PeriodicalIF":4.5,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12418381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145042347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping the brain's fatigue network: a transdiagnostic systematic review and meta-analysis on functional correlates of mental fatigue.","authors":"Andy Schumann, Monica Di Giuliano, Steffen Schulz, Feliberto de la Cruz, Teresa Kreuder, Georg Seifert, Karl-Jürgen Bär","doi":"10.1093/braincomms/fcaf315","DOIUrl":"10.1093/braincomms/fcaf315","url":null,"abstract":"<p><p>Mental fatigue is a significant psychopathological symptom that has recently gained attention, particularly in chronic fatigue syndrome/myalgic encephalomyelitis and Post-COVID-19 condition. However, fatigue is a clinically relevant symptom across a wide range of mental and neurological disorders. To identify a transdiagnostic functional network associated with fatigue, we conducted an activation likelihood estimation meta-analysis of neuroimaging studies. The primary inclusion criterion was studies involving any medical condition where patients exhibited significantly higher levels of fatigue compared to healthy controls. A systematic literature review across three major scientific databases identified 46 eligible neuroimaging studies, including a total of 2603 individuals. The meta-analysis of these studies revealed a widespread cortical-subcortical network involving frontal, limbic, basal ganglia and parietal structures. Three main clusters were highlighted: a frontal-striatal-limbic cluster, a frontal-cingulate cluster and a parietal cluster, with regions implicated in cognitive, emotional and somatosensory symptoms associated with mental fatigue. Quality analysis indicated a moderate risk of bias in the majority of the included studies. Overall, our findings provide scientific evidence for a transdiagnostic mental fatigue network in the brain, with key nodes located in the lateral frontal cortex, cingulate cortex, insula, thalamus, precuneus and caudate. These results support the theory of thalamic-striatal-cortical dysfunction, which may impair compensatory mechanisms related to mental fatigue. Additionally, abnormal activation of limbic and parietal regions may contribute to cognitive, emotional and attentional impairments linked to fatigue.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 5","pages":"fcaf315"},"PeriodicalIF":4.5,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12421237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145042465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Replication of the 2023 radiologically isolated syndrome criteria in a multi-centre cohort.","authors":"Friederike Held, Paula Uibel, Cornelius Berberich, Jonas Schaller-Nagengast, Vasil Mitrevski, Leo Hutter, Hayrettin Tumani, Joachim Havla, Christiane Gasperi, Mark Mühlau, Achim Berthele, Jan S Kirschke, Bernhard Hemmer","doi":"10.1093/braincomms/fcaf323","DOIUrl":"10.1093/braincomms/fcaf323","url":null,"abstract":"<p><p>Radiologically isolated syndrome (RIS) represents a pivotal stage for identifying individuals at high risk of transitioning into multiple sclerosis (MS). Early therapy initiation reduces the risk of conversion. The 2023-RIS criteria were proposed to identify presymptomatic individuals earlier. We aimed to replicate the diagnostic value of the 2023-RIS criteria in an independent cohort. In this retrospective cohort study, individuals diagnosed with RIS and longitudinally followed in three centres were stratified by the 2009- and 2023-RIS criteria. We conducted comparative analyses, including survival, hazard ratio and performance evaluations. Among <i>n</i> = 136 individuals, 27.2% converted to MS between 2009 and 2024 (observation time 55.4 months). We confirmed improved identification of individuals at risk using the 2023-RIS criteria (HR 4.30, <i>P</i> < 0.05; HR 4.71, <i>P</i> < 0.05) compared to 2009-RIS criteria (HR 1.32, <i>P</i> = 0.4; HR 1.43; <i>P</i> = 0.3) in 5- and 10-year intervals, respectively. 2023-RIS criteria demonstrated high sensitivity (94%) and negative predictive value (94%) but low specificity (29%). Adding CSF immunoglobulin G and M indices as an additional parameter following RIS diagnosis enhanced risk prediction specificity. We confirm the high sensitivity and predictive value of the 2023-RIS criteria for identifying individuals at risk of conversion to MS and suggest adding immunoglobulin indices to further improve specificity.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 5","pages":"fcaf323"},"PeriodicalIF":4.5,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145042487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large-scale network topography of stroke predicts functional outcome after mechanical thrombectomy.","authors":"Antonio Luigi Bisogno, Lorenzo Pini, Sofia Raccanello, Giorgia Adamo, Joseph Domenico Gabrieli, Alessandro Salvalaggio, Anna Maria Basile, Claudio Baracchini, Maurizio Corbetta","doi":"10.1093/braincomms/fcaf285","DOIUrl":"10.1093/braincomms/fcaf285","url":null,"abstract":"<p><p>Mechanical thrombectomy effectively restores blood flow in patients with acute ischaemic stroke caused by large vessel occlusion. While mechanical thrombectomy has improved functional outcomes, 35%-60% of patients still experience residual disabilities. Typically, patients are selected for mechanical thrombectomy based on degree of hypoperfusion around the core measured on a vascular atlas. This study had two aims: (i) to evaluate the prognostic value of lesion topography onto functional outcome at 3 months post-mechanical thrombectomy, when the lesion is localized either onto a vascular atlas or large-scale, functional or structural, network atlases; and (2) to examine patterns of post-stroke structural and functional disconnection significantly related to the most common stroke functional outcome scale, i.e. the modified Rankin scale at 3 months post-event. A retrospective analysis was conducted on 70 acute stroke patients who underwent mechanical thrombectomy at the Padua University Hospital (January 2018-June 2022). Inclusion criteria involved first ever ischaemic strokes with anterior circulation large vessel occlusion. Imaging data from sub-acute structural MRI and CT scans were used to estimate indirect structural and functional disconnections. Outcome measures included the modified Rankin Scale at 3 months, with prediction analysis performed using Lasso regression across vascular, grey matter and white matter atlases. Three-month modified Rankin Scale was best predicted using Yeo's functional atlas (<i>R</i> ² = 0.382), followed by the functional white matter atlas (<i>R</i> ² = 0.338); the vascular atlas yielded the weakest prediction (<i>R</i> ² = 0.146). Lesion damage to the corticospinal tract and corona radiata was significantly associated with the modified Rankin Scale. Functional disconnection significantly correlated with disability, particularly in sensorimotor, dorsal attention (DAN) and visual networks. Structural disconnections in the corticospinal tract, corpus callosum, corona radiata, thalamic radiation and left inferior and superior longitudinal fasciculus were also associated with poor functional outcome. This study demonstrates that lesion topography embedded in a network framework provides a more robust prediction of functional outcome. These findings emphasize the importance of understanding network alterations to enhance recovery prediction and optimize treatment strategies for stroke patients. Further research should explore the integration of network-based assessments in clinical practice for evaluating revascularization treatment eligibility.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 4","pages":"fcaf285"},"PeriodicalIF":4.5,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12391757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Respiratory sensitivity is reduced in functional neurological disorder and associated with higher somatoform dissociation.","authors":"","doi":"10.1093/braincomms/fcaf300","DOIUrl":"10.1093/braincomms/fcaf300","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1093/braincomms/fcaf283.].</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 4","pages":"fcaf300"},"PeriodicalIF":4.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12378738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Noradrenergic therapies in neurodegenerative disease: from symptomatic to disease modifying therapy?","authors":"Robert Durcan, Claire O'Callaghan, James B Rowe","doi":"10.1093/braincomms/fcaf310","DOIUrl":"10.1093/braincomms/fcaf310","url":null,"abstract":"<p><p>A feature shared by many different neurodegenerative diseases is early pathology and degeneration of the pontine locus coeruleus. The human locus coeruleus contains about 50 000 neurons and is the primary source of the neurotransmitter noradrenaline. We propose the hypothesis that noradrenergic drugs can have broad, transdiagnostic benefit in slowing or preventing the progression of neurodegenerative diseases. There are direct noradrenergic anti-inflammatory effects <i>in vivo</i>, with microglia and astrocytes regulated by adrenoreceptors, and noradrenergic influences on glymphatics. Noradrenaline loss is associated with a pro-inflammatory state, promoting further neurodegeneration. Noradrenergic neuron loss is associated with worsening of both amyloid and tau deposition in animal models. There may be indirect survival benefits arising from alleviating the prognostically detrimental features of apathy and impulsivity, and noradrenergic influences on other neurotransmitters. The evidence base we set out supports the need for clinical trials of noradrenergic treatments for disease-modification.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 5","pages":"fcaf310"},"PeriodicalIF":4.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12402774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144994701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}