Brain最新文献

{"title":"Biallelic PTPMT1 variants disrupt cardiolipin metabolism and lead to a neurodevelopmental syndrome.","authors":"Micol Falabella, Chiara Pizzamiglio, Luis Carlos Tabara, Benjamin Munro, Mohamed S Abdel-Hamid, Ece Sonmezler, William L Macken, Shanti Lu, Lisa Tilokani, Padraig J Flannery, Nina Patel, Simon A S Pope, Simon J R Heales, Dania B H Hammadi, Charlotte L Alston, Robert W Taylor, Hanns Lochmuller, Cathy E Woodward, Robyn Labrum, Jana Vandrovcova, Henry Houlden, Efstathia Chronopoulou, Germaine Pierre, Reza Maroofian, Michael G Hanna, Jan-Willem Taanman, Semra Hiz, Yavuz Oktay, Maha S Zaki, Rita Horvath, Julien Prudent, Robert D S Pitceathly","doi":"10.1093/brain/awae268","DOIUrl":"10.1093/brain/awae268","url":null,"abstract":"<p><p>Primary mitochondrial diseases (PMDs) are among the most common inherited neurological disorders. They are caused by pathogenic variants in mitochondrial or nuclear DNA that disrupt mitochondrial structure and/or function, leading to impaired oxidative phosphorylation (OXPHOS). One emerging subcategory of PMDs involves defective phospholipid metabolism. Cardiolipin, the signature phospholipid of mitochondria, resides primarily in the inner mitochondrial membrane, where it is biosynthesized and remodelled via multiple enzymes and is fundamental to several aspects of mitochondrial biology. Genes that contribute to cardiolipin biosynthesis have recently been linked with PMD. However, the pathophysiological mechanisms that underpin human cardiolipin-related PMDs are not fully characterized. Here, we report six individuals, from three independent families, harbouring biallelic variants in PTPMT1, a mitochondrial tyrosine phosphatase required for de novo cardiolipin biosynthesis. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome comprising developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy and white matter changes. Using patient-derived fibroblasts and skeletal muscle tissue, combined with cellular rescue experiments, we characterized the molecular defects associated with mutant PTPMT1 and confirmed the downstream pathogenic effects that loss of PTPMT1 has on mitochondrial structure and function. To further characterize the functional role of PTPMT1 in cardiolipin homeostasis, we created a ptpmt1 knockout zebrafish. This model had abnormalities in body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency. Together, these data indicate that loss of PTPMT1 function is associated with a new autosomal recessive PMD caused by impaired cardiolipin metabolism, highlighting the contribution of aberrant cardiolipin metabolism towards human disease and emphasizing the importance of normal cardiolipin homeostasis during neurodevelopment.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"647-662"},"PeriodicalIF":10.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive head-to-head comparison of key plasma phosphorylated tau 217 biomarker tests.","authors":"Noëlle Warmenhoven, Gemma Salvadó, Shorena Janelidze, Niklas Mattsson-Carlgren, Divya Bali, Anna Orduña Dolado, Hartmuth Kolb, Gallen Triana-Baltzer, Nicolas R Barthélemy, Suzanne E Schindler, Andrew J Aschenbrenner, Cyrus A Raji, Tammie L S Benzinger, John C Morris, Laura Ibanez, Jigyasha Timsina, Carlos Cruchaga, Randall J Bateman, Nicholas Ashton, Burak Arslan, Henrik Zetterberg, Kaj Blennow, Alexa Pichet Binette, Oskar Hansson","doi":"10.1093/brain/awae346","DOIUrl":"10.1093/brain/awae346","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Plasma phosphorylated-tau 217 (p-tau217) is currently the most promising biomarker for reliable detection of Alzheimer's disease pathology. Various p-tau217 assays have been developed, but their relative performance is unclear. We compared key plasma p-tau217 tests using cross-sectional and longitudinal measures of amyloid-β (Aβ)-PET, tau-PET and cognition as outcomes and benchmarked them against CSF biomarker tests. Samples from 998 individuals [mean (range) age 68.5 (20.0-92.5) years, 53% female] from the Swedish BioFINDER-2 cohort, including both cognitively unimpaired and cognitively impaired individuals, were analysed. Plasma p-tau217 was measured with mass spectrometry assays [the ratio between phosphorylated and non-phosphorylated (%p-tau217WashU) and p-tau217WashU] and with immunoassays (p-tau217Lilly, p-tau217Janssen and p-tau217ALZpath). CSF biomarkers included p-tau217Lilly, the US Food and Drug Administration-approved p-tau181/Aβ42Elecsys, and p-tau181Elecsys. All plasma p-tau217 tests exhibited a high ability to detect abnormal Aβ-PET [area under the curve (AUC) range: 0.91-0.96] and tau-PET (AUC range: 0.94-0.97). Plasma %p-tau217WashU had the highest performance, with significantly higher AUCs than all the immunoassays (Pdiff &lt; 0.007). For detecting Aβ-PET status, %p-tau217WashU had an accuracy of 0.93 (immunoassays: 0.83-0.88), sensitivity of 0.91 (immunoassays: 0.84-0.87) and a specificity of 0.94 (immunoassays: 0.85-0.89). Among immunoassays, p-tau217Lilly and plasma p-tau217ALZpath had higher AUCs than plasma p-tau217Janssen for Aβ-PET status (Pdiff &lt; 0.006), and p-tau217Lilly outperformed plasma p-tau217ALZpath for tau-PET status (Pdiff = 0.025). Plasma %p-tau217WashU exhibited stronger associations with all PET load outcomes compared with immunoassays; baseline Aβ-PET load (R2: 0.72; immunoassays: 0.47-0.58; Pdiff &lt; 0.001), baseline tau-PET load (R2: 0.51; immunoassays: 0.38-0.45; Pdiff &lt; 0.001), longitudinal Aβ-PET load (R2: 0.53; immunoassays: 0.31-0.38; Pdiff &lt; 0.001) and longitudinal tau-PET load (R2: 0.50; immunoassays: 0.35-0.43; Pdiff &lt; 0.014). Among immunoassays, plasma p-tau217Lilly was more associated with Aβ-PET load than plasma p-tau217Janssen (Pdiff &lt; 0.020) and with tau-PET load than both plasma p-tau217Janssen and plasma p-tau217ALZpath (all Pdiff &lt; 0.010). Plasma %p-tau217 also correlated more strongly with baseline cognition (Mini-Mental State Examination) than all immunoassays (R2: %p-tau217WashU: 0.33; immunoassays: 0.27-0.30; Pdiff &lt; 0.024). The main results were replicated in an external cohort from Washington University in St Louis (n = 219). Finally, p-tau217NULISA showed similar performance to other immunoassays in subsets of both cohorts. In summary, both mass spectrometry- and immunoassay-based p-tau217 tests generally perform well in identifying Aβ-PET, tau-PET and cognitive abnormalities, but %p-tau217WashU performed significantly better than all the examined immunoassays. Plasma %p-tau217 ma","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"416-431"},"PeriodicalIF":10.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BOK-engaged mitophagy alleviates neuropathology in Alzheimer's disease.","authors":"Yang Yang, Hui Chen, Shuwen Huang, Hao Chen, Alexei Verkhratsky, Jianqin Niu, Yibo Qu, Chenju Yi","doi":"10.1093/brain/awae241","DOIUrl":"10.1093/brain/awae241","url":null,"abstract":"<p><p>Mitochondrial malfunction associated with impaired mitochondrial quality control and self-renewal machinery, known as mitophagy, is an under-appreciated mechanism precipitating synaptic loss and cognitive impairments in Alzheimer's disease. Promoting mitophagy has been shown to improve cognitive function in Alzheimer's disease animals. However, the regulatory mechanism was unclear, which formed the aim of this study. Here, we found that a neuron-specific loss of Bcl-2 family member BOK in patients with Alzheimer's disease and APPswe/PS1dE9 (APP/PS1) mice is closely associated with mitochondrial damage and mitophagy defects. We further revealed that BOK is the key to the Parkin-mediated mitophagy through competitive binding to the MCL1/Parkin complex, resulting in Parkin release and translocation to damaged mitochondria to initiate mitophagy. Furthermore, overexpressing bok in hippocampal neurons of APP/PS1 mice alleviated mitophagy and mitochondrial malfunction, resulting in improved cognitive function. Conversely, the knockdown of bok worsened the aforementioned Alzheimer's disease-related changes. Our findings uncover a novel mechanism of BOK signalling through regulating Parkin-mediated mitophagy to mitigate amyloid pathology, mitochondrial and synaptic malfunctions, and cognitive decline in Alzheimer's disease, thus representing a promising therapeutic target.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"432-447"},"PeriodicalIF":10.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The systemic complexity of a monogenic disease: the molecular network of spinal muscular atrophy.","authors":"Ines Tapken, Theresa Schweitzer, Martina Paganin, Tobias Schüning, Nora T Detering, Gaurav Sharma, Moritz Niesert, Afshin Saffari, Daniela Kuhn, Amy Glynn, Federica Cieri, Pamela Santonicola, Claire Cannet, Florian Gerstner, Kiterie M E Faller, Yu-Ting Huang, Rashmi Kothary, Thomas H Gillingwater, Elia Di Schiavi, Christian M Simon, Niko Hensel, Andreas Ziegler, Gabriella Viero, Andreas Pich, Peter Claus","doi":"10.1093/brain/awae272","DOIUrl":"10.1093/brain/awae272","url":null,"abstract":"<p><p>Monogenic diseases are well-suited paradigms for the causal analysis of disease-driving molecular patterns. Spinal muscular atrophy (SMA) is one such monogenic model, caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. Although several functions of the SMN protein have been studied, single functions and pathways alone do not allow the identification of crucial disease-driving molecules. Here, we analysed the systemic characteristics of SMA, using proteomics, phosphoproteomics, translatomics and interactomics, from two mouse models with different disease severities and genetics. This systems approach revealed subnetworks and proteins characterizing commonalities and differences of both models. To link the identified molecular networks with the disease-causing SMN protein, we combined SMN-interactome data with both proteomes, creating a comprehensive representation of SMA. By this approach, disease hubs and bottlenecks between SMN and downstream pathways could be identified. Linking a disease-causing molecule with widespread molecular dysregulations via multiomics is a concept for analyses of monogenic diseases.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"580-596"},"PeriodicalIF":10.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Amyloid-β-activated microglia can induce compound proteinopathies.","authors":"","doi":"10.1093/brain/awae284","DOIUrl":"10.1093/brain/awae284","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"e13"},"PeriodicalIF":10.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Presynaptic hyperexcitability reversed by positive allosteric modulation of a GABABR epilepsy variant.","authors":"Marielle Minere, Martin Mortensen, Valentina Dorovykh, Gary Warnes, Dean Nizetic, Trevor G Smart, Saad B Hannan","doi":"10.1093/brain/awae232","DOIUrl":"10.1093/brain/awae232","url":null,"abstract":"<p><p>GABABRs are key membrane proteins that continually adapt the excitability of the nervous system. These G-protein coupled receptors are activated by the brain's premier inhibitory neurotransmitter GABA. They are obligate heterodimers composed of GABA-binding GABABR1 and G-protein-coupling GABABR2 subunits. Recently, three variants (G693W, S695I, I705N) have been identified in the gene (GABBR2) encoding for GABABR2. Individuals that harbour any of these variants exhibit severe developmental epileptic encephalopathy and intellectual disability, but the underlying pathogenesis that is triggered in neurons remains unresolved. Using a range of confocal imaging, flow cytometry, structural modelling, biochemistry, live cell Ca2+ imaging of presynaptic terminals, whole-cell electrophysiology of human embryonic kidney (HEK)-293 T cells and neurons and two-electrode voltage clamping of Xenopus oocytes, we have probed the biophysical and molecular trafficking and functional profiles of G693W, S695I and I705N variants. We report that all three point mutations impair neuronal cell surface expression of GABABRs, reducing signalling efficacy. However, a negative effect evident for one variant perturbed neurotransmission by elevating presynaptic Ca2+ signalling. This is reversed by enhancing GABABR signalling via positive allosteric modulation. Our results highlight the importance of studying neuronal receptors expressed in nervous system tissue and provide new mechanistic insights into how GABABR variants can initiate neurodevelopmental disease whilst highlighting the translational suitability and therapeutic potential of allosteric modulation for correcting these deficits.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"533-548"},"PeriodicalIF":10.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"State-dependent effects of responsive neurostimulation depend on seizure localization.","authors":"Sharon Chiang, Ankit N Khambhati, Thomas K Tcheng, Audra Plenys Loftman, Nicholas R Hasulak, Emily A Mirro, Martha J Morrell, Vikram R Rao","doi":"10.1093/brain/awae240","DOIUrl":"10.1093/brain/awae240","url":null,"abstract":"<p><p>Brain-responsive neurostimulation (RNS) is firmly ensconced among treatment options for drug-resistant focal epilepsy, but over a quarter of patients treated with the RNS® System do not experience meaningful seizure reduction. Initial titration of RNS therapy is typically similar for all patients, raising the possibility that treatment response might be enhanced by consideration of patient-specific variables. Indeed, small, single-centre studies have yielded preliminary evidence that RNS System effectiveness depends on the brain state during which stimulation is applied. The generalizability of these findings remains unclear, however, and it is unknown whether state-dependent effects of responsive neurostimulation are also stratified by location of the seizure onset zone where stimulation is delivered. We aimed to determine whether state-dependent effects of the RNS System are evident in the large, diverse, multi-centre cohort of RNS System clinical trial participants and to test whether these effects differ between mesiotemporal and neocortical epilepsies. Eighty-one of 256 patients treated with the RNS System across 31 centres during clinical trials met the criteria for inclusion in this retrospective study. Risk states were defined in relation to phases of daily and multi-day cycles of interictal epileptiform activity that are thought to determine seizure likelihood. We found that the probabilities of risk state transitions depended on the stimulation parameter being changed, the starting seizure risk state and the stimulated brain region. Changes in two commonly adjusted stimulation parameters, charge density and stimulation frequency, produced opposite effects on risk state transitions depending on seizure localization. Greater variance in acute risk state transitions was explained by state-dependent responsive neurostimulation for bipolar stimulation in neocortical epilepsies and for monopolar stimulation in mesiotemporal epilepsies. Variability in the effectiveness of RNS System therapy across individuals may relate, at least partly, to the fact that current treatment paradigms do not account fully for fluctuations in brain states or locations of simulation sites. State-dependence of electrical brain stimulation may inform the development of next-generation closed-loop devices that can detect changes in brain state and deliver adaptive, localization-specific patterns of stimulation to maximize therapeutic effects.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"521-532"},"PeriodicalIF":10.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Why inflammatory reductionism is a threat to psychiatry (and the rest of medicine).","authors":"Thomas A Pollak","doi":"10.1093/brain/awae381","DOIUrl":"10.1093/brain/awae381","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"349-351"},"PeriodicalIF":10.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blood inflammation relates to neuroinflammation and survival in frontotemporal lobar degeneration.","authors":"Maura Malpetti, Peter Swann, Kamen A Tsvetanov, Leonidas Chouliaras, Alexandra Strauss, Tanatswa Chikaura, Alexander G Murley, Nicholas J Ashton, Peter Barker, Peter Simon Jones, Tim D Fryer, Young T Hong, Thomas E Cope, George Savulich, Duncan Street, William Richard Bevan-Jones, Timothy Rittman, Kaj Blennow, Henrik Zetterberg, Franklin I Aigbirhio, John T O'Brien, James B Rowe","doi":"10.1093/brain/awae269","DOIUrl":"10.1093/brain/awae269","url":null,"abstract":"<p><p>Neuroinflammation is an important pathogenic mechanism in many neurodegenerative diseases, including those caused by frontotemporal lobar degeneration. Post-mortem and in vivo imaging studies have shown brain inflammation early in these conditions, proportional to symptom severity and rate of progression. However, evidence for corresponding blood markers of inflammation and their relationships to central inflammation and clinical outcome are limited. There is a pressing need for such scalable, accessible and mechanistically relevant blood markers because these will reduce the time, risk and costs of experimental medicine trials. We therefore assessed inflammatory patterns of serum cytokines from 214 patients with clinical syndromes associated with frontotemporal lobar degeneration in comparison to healthy controls, including their correlation with brain regional microglial activation and disease progression. Serum assays used the MesoScale Discovery V-Plex-Human Cytokine 36 plex panel plus five additional cytokine assays. A subgroup of patients underwent 11C-PK11195 mitochondrial translocator protein PET imaging, as an index of microglial activation. A principal component analysis was used to reduce the dimensionality of cytokine data, excluding cytokines that were undetectable in >50% of participants. Frequentist and Bayesian analyses were performed on the principal components to compare each patient cohort with controls and test for associations with central inflammation, neurodegeneration-related plasma markers and survival. The first component identified by the principal component analysis (explaining 21.5% variance) was strongly loaded by pro-inflammatory cytokines, including TNF-α, TNF-R1, M-CSF, IL-17A, IL-12, IP-10 and IL-6. Individual scores of the component showed significant differences between each patient cohort and controls. The degree to which a patient expressed this peripheral inflammatory profile at baseline was correlated negatively with survival (higher inflammation, shorter survival), even when correcting for baseline clinical severity. Higher pro-inflammatory profile scores were associated with higher microglial activation in frontal and brainstem regions, as quantified with 11C-PK11195 mitochondrial translocator protein PET. A permutation-based canonical correlation analysis confirmed the association between the same cytokine-derived pattern and central inflammation across brain regions in a fully data-based manner. This data-driven approach identified a pro-inflammatory profile across the frontotemporal lobar degeneration clinical spectrum, which is associated with central neuroinflammation and worse clinical outcome. Blood-based markers of inflammation could increase the scalability and access to neuroinflammatory assessment of people with dementia, to facilitate clinical trials and experimental medicine studies.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"493-505"},"PeriodicalIF":10.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic inflammatory markers in ageing, Alzheimer's disease and other dementias.","authors":"Huimin Cai, Tan Zhao, Yana Pang, Xiaofeng Fu, Ziye Ren, Shuiyue Quan, Longfei Jia","doi":"10.1093/brain/awae230","DOIUrl":"10.1093/brain/awae230","url":null,"abstract":"<p><p>Systemic inflammation with alterations in inflammatory markers is involved in ageing and Alzheimer's disease. However, few studies have investigated the longitudinal trajectories of systemic inflammatory markers during ageing and Alzheimer's disease, and specific markers contributing to Alzheimer's disease remain undetermined. In this study, a longitudinal cohort (cohort 1: n = 290; controls, 136; preclinical Alzheimer's disease, 154) and a cross-sectional cohort (cohort 2: n = 351; controls, 62; Alzheimer's disease, 63; vascular dementia, 58; Parkinson's disease dementia, 56; behavioural variant frontotemporal dementia, 57; dementia with Lewy bodies, 55) were included. Plasma levels of inflammatory markers were measured every 2 years during a 10-year follow-up in the longitudinal cohort and once in the cross-sectional cohort. The study demonstrated that the inflammatory markers significantly altered during both ageing and the development of Alzheimer's disease. However, only complement C3, interleukin-1β and interleukin-6 exhibited significant changes in participants with preclinical Alzheimer's disease, and their longitudinal changes were significantly associated with the development of Alzheimer's disease compared to controls over the 10-year follow-up. In the cross-sectional cohort, complement C3 demonstrated specificity to Alzheimer's disease, while interleukin-1β and interleukin-6 were also altered in other dementias. The study provides a new perspective on the involvement of inflammatory markers in the ageing process and the development of Alzheimer's disease, implying that regulating inflammation may have a pivotal role in promoting successful ageing and in the prevention and treatment of Alzheimer's disease.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"480-492"},"PeriodicalIF":10.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}