Journal of Cerebral Blood Flow and Metabolism最新文献

{"title":"Extracellular vesicles lay the ground for neuronal plasticity by restoring mitochondrial function, cell metabolism and immune balance.","authors":"Dirk M Hermann, Chen Wang, Ayan Mohamud Yusuf, Josephine Herz, Thorsten R Doeppner, Bernd Giebel","doi":"10.1177/0271678X251325039","DOIUrl":"10.1177/0271678X251325039","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) convey complex signals between cells that can be used to promote neuronal plasticity and neurological recovery in brain disease models. These EV signals are multimodal and context-dependent, making them unique therapeutic principles. This review analyzes how EVs released from various cell sources control neuronal metabolic function, neuronal survival and plasticity. Preferential sites of EV communication in the brain are interfaces between pre- and postsynaptic neurons at synapses, between astrocytes and neurons at plasma membranes or tripartite synapses, between oligodendrocytes and neurons at axons, between microglial cells/macrophages and neurons, and between cerebral microvascular cells and neurons. At each of these interfaces, EVs support mitochondrial function and cell metabolism under physiological conditions and orchestrate neuronal survival and plasticity in response to brain injury. In the injured brain, the promotion of neuronal survival and plasticity by EVs is tightly linked with EV actions on mitochondrial function, cell metabolism, oxidative stress and immune responses. Via the stabilization of cell metabolism and immune balance, neuronal plasticity responses are activated and functional neurological recovery is induced. As such, EV lay the ground for neuronal plasticity.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"185-206"},"PeriodicalIF":4.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sickle cell mice exhibit elevated plasma bilirubin and altered intracranial cerebral blood velocities that are exacerbated by hypoxia-reoxygenation.","authors":"Francisco J Nunez, Ashraf M Mohieldin, Amy Y Pan, Sean P Palecek, Rahima Zennadi, Ramani Ramchandran, Kevin R Rarick, Surya M Nauli","doi":"10.1177/0271678X251338961","DOIUrl":"10.1177/0271678X251338961","url":null,"abstract":"<p><p>Sickle cell disease (SCD) is a genetic disorder characterized by sickle red blood cells (RBCs). Sickle RBCs cause cerebral vasculopathies including vaso-occlusive events, leading to ischemia-reperfusion injury and hypoxic tissue environment. To date, the physiological blood flow velocities in cerebral vessels of preclinical SCD models has not been evaluated under hypoxic-reoxygenation. In our study, we used transcranial ultrasound techniques to measure abnormal blood flow velocities in the internal carotid (ICA) and middle cerebral arteries (MCA) of transgenic sickle cell mice (SS) challenged with hypoxia-reoxygenation. Our study showed that SS mice that underwent hypoxic stress exhibited lower relative mean velocities in the MCA compared to wildtype mice (AA) (0.67 ± 0.18 vs. 0.95 ± 0.15; <i>p</i> < 0.05). Comparison of the Lindegaard ratio between normoxia and hypoxia in SS mice suggested that the MCA underwent vasodilation (0.67 ± 0.18 vs. 0.95 ± 0.15; <i>p</i> <i><</i> 0.05). Bilirubin, a potential biomarker for cerebral vasculopathies in SCD, was higher in SS than AA mice (0.56<math><mo> </mo><mo>±</mo><mo> </mo></math>0.28 vs. 0.05<math><mo> </mo><mo>±</mo><mo> </mo></math>0.07 mg/dL; <i>p</i> <i><</i> 0.05). Correlation analyses revealed a significant association between bilirubin levels and blood velocities of MCA (r = -0.9377, <i>p</i> = 0.0002) and ICA (r = 0.8203, <i>p</i> = 0.0068), especially in hypoxic conditions of SS mice. We propose that the reactivity of cerebral vessels in SS mice is correlated with the elevated plasma bilirubin level.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"2329-2341"},"PeriodicalIF":4.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12635036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimal cerebral perfusion pressure in aneurysmal subarachnoid hemorrhage and its relation to perfusion deficits on CT-perfusion.","authors":"Vesna Malinova, Beate Kranawetter, Sheri Tuzi, Onnen Moerer, Veit Rohde, Dorothee Mielke","doi":"10.1177/0271678X241237879","DOIUrl":"10.1177/0271678X241237879","url":null,"abstract":"<p><p>Preservation of optimal cerebral perfusion is a crucial part of the acute management after aneurysmal subarachnoid hemorrhage (aSAH). A few studies indicated possible benefits of maintaining a cerebral perfusion pressure (CPP) near the calculated optimal CPP (CPPopt), representing an individually optimal condition at which cerebral autoregulation functions at its best. This retrospective observational monocenter study was conducted to investigate, whether \"suboptimal\" perfusion with actual CPP deviating from CPPopt correlates with perfusion deficits detected by CT-perfusion (CTP). A consecutive cohort of aSAH-patients was reviewed and patients with available parameters for CPPopt-calculation, who simultaneously received CTP, were analyzed. By plotting the pressure reactivity index (PRx) versus CPP, CPP correlating the lowest PRx value was identified as CPPopt. Perfusion deficits on CTP were documented. In 86 out of 324 patients, the inclusion criteria were met. Perfusion deficits were detected in 47% (40/86) of patients. In 43% of patients, CPP was lower than CPPopt, which correlated with detected perfusion deficits (r = 0.23, p = 0.03). Perfusion deficits were found in 62% of patients with CPP<CPPopt compared to 34% in patients without deviation or CPP>CPPopt (OR 3, p = 0.01). These findings support the hypothesis, that a deviation of CPP from CPPopt is an indicator of suboptimal cerebral perfusion.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"2256-2263"},"PeriodicalIF":4.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11572175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140859259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FTO promotes post-stroke neuroprotection by m⁶A demethylation of c-Jun.","authors":"Anil K Chokkalla, Suresh L Mehta, Soomin Jeong, Hui-Lung Sun, Qing Dai, Raghu Vemuganti","doi":"10.1177/0271678X251340808","DOIUrl":"10.1177/0271678X251340808","url":null,"abstract":"<p><p><i>N</i>⁶-methyladenosine (m⁶A) is a critical epitranscriptomic regulator of neuronal function. Cerebral ischemia induces m⁶A hypermethylation due to decreased expression of m⁶A demethylase fat mass and obesity-associated (FTO) protein. Previously, we showed that cerebral overexpression of FTO with an adeno-associated virus (AAV) 9 protects the post-stroke brain. We presently evaluated the mechanistic basis for FTO-dependent m⁶A demethylation in post-ischemic neuroprotection using the mice transient middle cerebral artery occlusion model of experimental stroke. Based on the bioinformatic predictions and m⁶A abundance, pro-apoptotic transcription factor Jun proto-oncogene (c-Jun) with 19 m⁶A sites was chosen as an exemplary target. FTO overexpression normalized the post-stroke m⁶A hypermethylation of c-Jun without altering its transcript levels. FTO-dependent m⁶A demethylation suppressed translation of c-Jun. Consequently, several c-Jun target genes are transcriptionally repressed, and the post-ischemic neuronal apoptosis is decelerated, as seen by decreased cleaved caspase-3 levels and TUNEL⁺ neurons in the FTO AAV9 treated group compared to the control AAV9 treated group. Moreover, replenishing c-Jun precluded the FTO-mediated post-stroke neuroprotection and functional recovery. Collectively, this study demonstrated that the FTO/m⁶A/c-Jun axis ameliorates post-stroke neuronal apoptosis and brain damage, leading to better functional outcomes.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1877-1890"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amplitude fluctuations of cerebrovascular oscillations and CSF movement desynchronize during NREM3 sleep.","authors":"Vidhya V Nair, Brianna R Kish, Hideyuki Oshima, Adam M Wright, Qiuting Wen, A J Schwichtenberg, Yunjie Tong","doi":"10.1177/0271678X251337637","DOIUrl":"10.1177/0271678X251337637","url":null,"abstract":"<p><p>Fluctuations in cerebral blood volume (CBV) are a dominant mechanism aiding cerebrospinal fluid (CSF) movement in the brain during wakefulness and non-rapid eye movement (NREM) sleep. However, it is unclear if the amplitudes of CBV oscillations also change in proportion to the changes in amplitude of CSF movement across specific NREM sleep states. It is also not known if the coupling strength between them varies between NREM sleep states. To investigate these relationships, we measured cerebral hemodynamics and craniad CSF movement at the fourth ventricle simultaneously during wakefulness and NREM sleep states using concurrent Electroencephalography and functional Magnetic Resonance Imaging. We found that the amplitude fluctuations of cerebral hemodynamics and CSF oscillations desynchronize from one another only during deep NREM3 state, despite the strong mechanical coupling between CBV changes and CSF movement, which was consistent across all states. This suggests the existence of a different mechanism, linked to the cortical interstitial volume/resistance change, that regulates the NREM3 CSF inflow into the brain.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1980-1992"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repeatability and reliability of cerebrovascular reactivity in young adults using multi-echo, multi-contrast MRI.","authors":"Elizabeth G Keeling, Maurizio Bergamino, Lauren R Ott, Molly M McElvogue, Ashley M Stokes","doi":"10.1177/0271678X251345292","DOIUrl":"10.1177/0271678X251345292","url":null,"abstract":"<p><p>Cerebrovascular reactivity (CVR) shows promise as a biomarker of vascular integrity and may benefit from a repeatable, reliable, and microvasculature-sensitive acquisition. A combined spin- and gradient-echo (SAGE) functional MRI (fMRI) acquisition may improve repeatability and reliability compared to single spin- (SE) and gradient-echo (GRE) fMRI and provide a microvascular-weighted analysis. The most repeatable and reliable MRI acquisition CVR maps were compared across three CVR paradigms: a breath-hold task, a breath modulation task, and a resting state acquisition. SAGE-fMRI data was acquired in fifteen young adults at two timepoints. Mean gray matter (GM) within-subject coefficient of variation (wCV) and intraclass correlation coefficient (ICC) were compared within the quantitative and weighted SAGE-fMRI CVR maps and single GRE- and SE-fMRI CVR. Total and microvascular MRI inputs with lowest wCV and highest ICC were used to compare three CVR paradigms. Total and microvascular weighted SAGE-fMRI CVR had the lowest wCV and highest ICC across paradigms. The breath-hold paradigm produced significantly higher GM CVR estimates. SAGE repeatably and reliably measures CVR and offers a simultaneous, complementary analysis on total and microvascular scales. The breath-hold paradigm showed significantly higher CVR estimates, but less compliance-dependent protocols may be ideal for applications in patient populations.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"2030-2046"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12106380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Environmental enrichment promotes functional recovery from stroke via enhancing neuroplasticity through the action of β-HB.","authors":"Zhuang-Yin Qu, Chang-Jing Zhang, Ya-Lan Hou, Hui-Lin Li, Long Lin, Ai Teng, Chang-Run Shi, Wen-Shuo Lu, Xiao-Wei Zhang, Fei Li, Lei Chang, Yu-Hui Lin","doi":"10.1177/0271678X251328179","DOIUrl":"10.1177/0271678X251328179","url":null,"abstract":"<p><p>Stroke is a leading cause of adult disability worldwide, unfortunately, no drugs are clinically available to promote functional recovery after stroke. Although animal environmental enrichment is a recognized paradigm for promoting stroke repair, elusive mechanisms hinder its clinical translation. Here, we show that β-hydroxybutyrate (β-HB) level in the peri-infarct cortex is upregulated after environmental enrichment (EE) exposure. Importantly, exogenous supplementation of β-HB promotes functional recovery to a similar extent as EE exposure. Moreover, the beneficial effects of EE on stroke recovery, including functional recovery, neuroplasticity-related proteins upregulation, and structural and functional plasticity enhancement, are abolished by β-HB transporter inhibitor, AR-C155858. Intriguingly, supplementation with (R)-3-hydroxybutyl (R)-β-HB, a ketone ester (KE), substantially increases β-HB level and lessens motor functional impairments. Together, our findings indicate that β-HB is a critical substrate for EE-mediated stroke recovery and supplementation with β-HB monoester drinks may serve as a novel strategy to translate EE from bench to bedside.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1918-1931"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring differences in circulating metabolites of females and males with Alzheimer's disease.","authors":"Sara Serafini, Antonella Angiolillo, Gabriella Ferretti, Giulia Viviani, Carmela Matrone, Alfonso Di Costanzo","doi":"10.1177/0271678X251340513","DOIUrl":"10.1177/0271678X251340513","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to cognitive and functional decline and primarily affects the elderly population. Metabolic alterations, particularly in the amino acid and fatty acid pathways, are increasingly being recognized in AD. However, the role of sex in these metabolic changes remains insufficiently understood, despite evidence suggesting that AD may manifest more strongly in females. This study investigated sex-specific metabolic patterns in AD by analyzing routine and non-routine hematological tests, including amino acids and fatty acid profiles. The results showed that certain metabolites such as citrulline and alanine were frequently altered in patients with AD. Notably, docosahexaenoic acid, dihomo-gamma-linolenic acid, and gamma-linolenic acid levels were exclusively elevated in female patients. Additionally, females exhibited significantly lower Aβ42 and higher gamma-linolenic acid levels than males, with the trend becoming more pronounced during the early stages of the disease. Despite these differences, most metabolic markers did not show significant sex-based variation. These findings suggest that while some sex-specific metabolic differences exist in AD, a larger cohort is needed to confirm these patterns and fully understand the influence of sex on AD-related metabolic changes.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"2004-2015"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12084220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic treatment with adenosine A1 receptor antagonist promotes neurogenesis and improves outcome after cerebral ischemia.","authors":"Maria Ardaya, Monica Benito-Muñoz, Esther Rubio-López, Maider Garbizu, Laura Aguado, Naroa Mocha-Muñoz, Leyre Iglesias, Unai Alduntzin, Carlos Matute, Federico N Soria, Vanessa Gómez-Vallejo, Aitzol García-Etxarri, Jordi Llop, Fabio Cavaliere, Abraham Martín","doi":"10.1177/0271678X251345294","DOIUrl":"10.1177/0271678X251345294","url":null,"abstract":"<p><p>Adenosine A1 receptors (A1ARs) are promising targets for stroke treatment, potentially due to their relatively unexplored effects on proliferation and differentiation of newborn neurons. In this study, we investigated the impact of chronic treatment with the A1ARs antagonist DPCPX on neurogenesis following MCAO in rodents, using PET with [¹⁸F]FLT in rats and immunohistochemistry in mice. In addition, we assessed the therapeutic properties of DPCPX on stroke recovery with a comprehensive battery of neurological and behavioral tests. The outcome shows that blocking A1ARs signaling with DPCPX improved immunohistochemical results in 8 to 28 days after MCAO in mice. PET imaging with [¹⁸F]FLT revealed an increase in cellular proliferation following DPCPX treatment in the subventricular zone at day 8 post-ischemia in rats, a result further supported by IHC in SVZ of ischemic animals. Furthermore, DPCPX enhanced the production and integration of newborn neurons while reducing astrocytic differentiation in the ischemic areas. Finally, behavioral tests showed that chronic treatment with DPCPX ameliorated motor and memory deficits after brain ischemia. All taken in consideration, our results provide novel and compelling evidence of the therapeutic potential of the A1AR antagonist DPCPX for ischemic stroke recovery.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"2016-2029"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144135917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel approach for modeling <i>in vivo</i> enzyme turnover in the presence of a suicide inhibitor drug: A proof-of-concept brain PET study on MAG lipase.","authors":"Tommaso Volpi, Daniel Holden, Jean-Dominique Gallezot, Nabeel Nabulsi, Keunpoong Lim, David Labaree, Hong Gao, Michael Kapinos, Edmund J Keliher, Kari R Fonseca, Patrick Trapa, Andrea Varrone, Christer Halldin, Kevin P Maresca, Yiyun Huang, Richard E Carson","doi":"10.1177/0271678X251329254","DOIUrl":"10.1177/0271678X251329254","url":null,"abstract":"<p><p>PET imaging allows the study of enzyme concentration and activity <i>in vivo</i>. The enzyme natural turnover <math><mi>α</mi></math>, relevant for drug development, can be estimated if a suicide inhibitor drug is used. The main aim of this study was to develop a model for estimating <math><mi>α</mi></math> by accounting for the presence of residual inhibitor. We analyzed nonhuman primate PET data with monoacyglycerol lipase (MAGL) tracer [¹¹C]PF-06809247, and suicide inhibitor PF-06818883 (0.03-1.27 mg/kg, active compound PF-06807893). As [¹¹C]PF-06809247 is an irreversible tracer, we used simulations to evaluate the impact of flow limitation on identifiability of kinetic parameters. Based on this, MAGL activity estimates were obtained from three outcome parameters: <i>K</i>_i, <i>k</i>₃, <math><msub><mrow><mover><mrow><mi>K</mi></mrow><mo>˜</mo></mover></mrow><mrow><mn>3</mn></mrow></msub></math> (=<math><mfrac><mrow><msub><mrow><mi>K</mi></mrow><mrow><mn>1</mn></mrow></msub><msub><mrow><mi>K</mi></mrow><mrow><mi>i</mi></mrow></msub></mrow><mrow><msub><mrow><mi>K</mi></mrow><mrow><mn>1</mn></mrow></msub><msub><mrow><mo>-</mo><mi>K</mi></mrow><mrow><mi>i</mi></mrow></msub></mrow></mfrac></math>). A new model, which links enzyme activity to the inhibitor drug's plasma concentration, was used to estimate <math><mi>α</mi></math>. Using a conservative statistical cut-off, MAGL turnover half-lives were estimated (<i>K</i>_i: 3.9 h; <i>k</i>₃: 4.6 h; <math><msub><mrow><mover><mrow><mi>K</mi></mrow><mo>˜</mo></mover></mrow><mrow><mn>3</mn></mrow></msub></math>: 6.1 h) - with faster turnover for <i>K</i>_i (flow-limited). Serial PET experiments and measuring the drug's plasma concentration allowed to estimate <math><mi>α</mi></math> correcting for residual suicide inhibition. This approach can be extended to other PET enzyme targets, improving our understanding of enzyme pathological alterations and suicide inhibitor-based therapies.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1947-1960"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}