Neurotherapeutics最新文献_第2页

Mitochondria dysfunction, a potential cytoprotection target against ischemia-reperfusion injury in a mouse stroke model.

IF 5.6 2区医学

Neurotherapeutics Pub Date : 2025-02-10 DOI: 10.1016/j.neurot.2025.e00549

Elodie Ong, Paul Clottes, Christelle Leon, Hala Guedouari, Noelle Gallo-Bona, Megane Lo Grasso, Lucas Motter, Radu Bolbos, Michel Ovize, Norbert Nighogossian, Marlene Wiart, Melanie Paillard

{"title":"Mitochondria dysfunction, a potential cytoprotection target against ischemia-reperfusion injury in a mouse stroke model.","authors":"Elodie Ong, Paul Clottes, Christelle Leon, Hala Guedouari, Noelle Gallo-Bona, Megane Lo Grasso, Lucas Motter, Radu Bolbos, Michel Ovize, Norbert Nighogossian, Marlene Wiart, Melanie Paillard","doi":"10.1016/j.neurot.2025.e00549","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00549","url":null,"abstract":"More than 50 % of patients undergoing mechanical thrombectomy (MT) for ischemic stroke have a poor functional outcome despite timely and successful angiographic reperfusion, highlighting the need for adjunctive treatments to reperfusion therapy. Mitochondria are key regulators of cell fate, by controlling cell bioenergetics via oxidative phosphorylation (OXPHOS) and cell death through the mitochondrial permeability transition pore (mPTP). Whether these two main mitochondrial functions are altered by reperfusion and could represent a new cytoprotective approach remains to be elucidated in mice. Swiss male mice underwent either permanent or transient middle cerebral artery occlusion (pMCAO or tMCAO), with neuroscore evaluation and multimodal imaging. The area at risk of necrosis was evaluated by per-occlusion dynamic contrast-enhanced ultrasound. Final infarct size was assessed at day 1 by MRI. Cortical mitochondrial isolation was subsequently performed to assess mPTP sensitivity by calcium retention capacity (CRC) and OXPHOS. A cytoprotective treatment targeting mitochondria, ciclosporine A (CsA), was tested in tMCAO, to mimick the clinical situation of patients treated with MT. Reperfusion after 60 min of ischemia improves neuroscores but does not significantly reduce infarct size or mitochondrial dysfunction compared to permanent ischemia. CsA treatment at reperfusion mitigates stroke outcome, decreases final infarct size and improves mitochondrial CRC and OXPHOS. Mitochondrial dysfunctions, i.e. reduced mPTP sensitivity and decreased oxygen consumption rates, were observed in pMCAO and tMCAO regardless of the reperfusion status. CsA improved mitochondrial functions when injected at reperfusion. These suggest that both mPTP opening and OXPHOS alterations are thus early but reversible hallmarks of cerebral ischemia/reperfusion.","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00549"},"PeriodicalIF":5.6,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Carnosine supplementation improves cognitive outcomes in younger participants of the NEAT trial.

IF 5.6 2区医学

Neurotherapeutics Pub Date : 2025-02-06 DOI: 10.1016/j.neurot.2025.e00541

Timothy E O'Toole, Alok R Amraotkar, Hong Gao, Clara G Sears, Shesh N Rai, Mathias Basner, Aruni Bhatnagar

{"title":"Carnosine supplementation improves cognitive outcomes in younger participants of the NEAT trial.","authors":"Timothy E O'Toole, Alok R Amraotkar, Hong Gao, Clara G Sears, Shesh N Rai, Mathias Basner, Aruni Bhatnagar","doi":"10.1016/j.neurot.2025.e00541","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00541","url":null,"abstract":"Some prior studies suggested that supplementation with carnosine or β-alanine can improve cognitive abilities and neurodegenerative disorders in certain elderly or at-risk populations. However, the efficacy of carnosine in improving cognitive performance in a healthy, adult population has not been assessed. We examined this as a post-hoc secondary outcome in the placebo-controlled, randomized Nucleophilic Defense Against PM Toxicity (NEAT) clinical trial (NCT03314987). Participants in this trial were instructed to take either cornstarch (placebo) or carnosine capsules (2g daily) for up to 12wk. Cognitive ability was assessed using the Cognition test battery, which consists of ten individual tests known to engage specific brain systems and covering a range of cognitive domains. Speed, accuracy, and efficiency were obtained for the whole battery as well as for each of the ten individual tests. Participant testing occurred at baseline, prior to randomization, after approximately 6wk of supplementation (Follow-up-1), and after approximately 12wk of supplementation (Follow-up-2). Of the 299 participants who were randomized, we obtained useable measures for 242 participants at Follow-up-1 and 231 at Follow-up-2. Age-based stratification (23-35 years, 36-50 years, 51-65 years), showed statistically significant improvements in overall speed and efficiency in the youngest age group stratum at both follow-up visits. This same group also demonstrated significant improvements in seven speed or accuracy scores of the individual tests. The other age groups demonstrated few or no significant improvements. Thus, in a study population largely devoid of susceptibility factors or pre-existing conditions, carnosine supplementation selectively improved high-level cognitive performance in young individuals.","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00541"},"PeriodicalIF":5.6,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fasudil inhibits α-synuclein aggregation through ROCK-inhibition-mediated mechanisms.

IF 5.6 2区医学

Neurotherapeutics Pub Date : 2025-02-05 DOI: 10.1016/j.neurot.2025.e00544

Lucia Lage, Ana I Rodriguez-Perez, Jose Luis Labandeira-Garcia, Antonio Dominguez-Meijide

{"title":"Fasudil inhibits α-synuclein aggregation through ROCK-inhibition-mediated mechanisms.","authors":"Lucia Lage, Ana I Rodriguez-Perez, Jose Luis Labandeira-Garcia, Antonio Dominguez-Meijide","doi":"10.1016/j.neurot.2025.e00544","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00544","url":null,"abstract":"ROCK inhibitors such as fasudil protected against dopaminergic degeneration and other neurodegenerative processes in several experimental models through inhibition of neuroinflammation and activation of survival signaling pathways, and clinical trials have been initiated. More recently, fasudil has been suggested to inhibit α-synuclein aggregation. However, this is controversial, particularly if it is a consequence of direct binding of the fasudil molecule to α-synuclein. We studied the mechanisms involved in the effects of fasudil on α-synuclein aggregation using the α-synuclein-T/V5-synphilin-1 model. Molecule-molecule interactions were studied using real time quaking inducing conversion (RT-QuiC). Fasudil decreased the number of cells with inclusions and the size of inclusions in dopaminergic neurons and glial cells, and inhibited α-synuclein aggregation and microglial endocytosis of aggregates. These changes were not due to changes in α-synuclein protein expression or phosphorylation and were related to ROCK inhibition rather than direct interaction with α-synuclein, as confirmed with a second ROCK inhibitor (Y27632) and ROCK gene silencing. We observed that ROCK inhibition downregulates several factors that are known to promote α-synuclein aggregation such as NADPH-oxidase-derived oxidative stress, intracellular calcium increase, and α-synuclein endocytosis, and promotes autophagy. The present results support that fasudil is a useful drug against Parkinson's disease progression. In addition to other reported neuroprotective properties, fasudil inhibits α-synuclein aggregation and microglial endocytosis of aggregates, which enhances the microglial inflammatory response. The effects of fasudil are mostly related to ROCK inhibition, which we have shown using two structurally different ROCK inhibitors and knockdown data, and further supported by using RT-QuiC.","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00544"},"PeriodicalIF":5.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

From a clinically relevant pain target to a possible analgesic treatment strategy.

IF 5.6 2区医学

Neurotherapeutics Pub Date : 2025-02-04 DOI: 10.1016/j.neurot.2025.e00542

Alban Latremoliere

引用次数: 0

3,3'-Diindolylmethane improves pathology and neurological outcome following traumatic brain injury.

IF 5.6 2区医学

Neurotherapeutics Pub Date : 2025-02-04 DOI: 10.1016/j.neurot.2025.e00531

Carlos A Dallera, Fabiola Placeres-Uray, Patrizzia Mastromatteo-Alberga, Maria Dominguez-Torres, Alyssa F Balleste, Aditi S Gorthy, Tyler S Rahimzadeh, Isabelle Aliancin, W Dalton Dietrich, Juan Pablo de Rivero Vaccari, Irwin C Jacobs, Elizabeth A Chlipala, Hannah Benton, Michael A Zeligs, Coleen M Atkins

{"title":"3,3'-Diindolylmethane improves pathology and neurological outcome following traumatic brain injury.","authors":"Carlos A Dallera, Fabiola Placeres-Uray, Patrizzia Mastromatteo-Alberga, Maria Dominguez-Torres, Alyssa F Balleste, Aditi S Gorthy, Tyler S Rahimzadeh, Isabelle Aliancin, W Dalton Dietrich, Juan Pablo de Rivero Vaccari, Irwin C Jacobs, Elizabeth A Chlipala, Hannah Benton, Michael A Zeligs, Coleen M Atkins","doi":"10.1016/j.neurot.2025.e00531","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00531","url":null,"abstract":"3,3'-Diindolylmethane (DIM), a naturally occurring bis-indole found in cruciferous vegetables and produced in small amounts in the normal flora of the human gut, has demonstrated neuroprotective benefits in models of CNS hypoxia and stroke. In the CNS, DIM modulates the activation of the aryl hydrocarbon receptor (AhR) and inhibits its pro-inflammatory effects. Although capable of crossing the blood brain barrier, DIM's bioavailability is limited by its low solubility. Dispersed BR4044 provides a nanoscale high-solubility DIM suspension with the potential for treating traumatic brain injury (TBI). The present study aimed to determine whether BR4044 treatment could reduce pathology and improve behavioral recovery following moderate TBI. Male Sprague Dawley rats received moderate fluid percussion injury or sham surgery followed by vehicle or BR4044 treatment in the acute recovery period. TBI BR4044 animals showed significantly reduced cortical and hippocampal edema and lower levels of serum-derived extracellular vesicles compared to TBI Vehicle animals. BR4044 treatment of TBI animals preserved sensorimotor function and associative fear memory. Cortical contusion size and neuronal loss in the parietal cortex and CA3 region of the hippocampus were also significantly reduced with BR4044 treatment. BR4044 also decreased microbleeding and nuclear AhR at the contusion site. This translational study demonstrates that BR4044 ameliorates pathology and improves neurological outcomes following TBI by reducing brain edema, lowering acute extracellular vesicle release, modulating AhR, preserving cortical and hippocampal neurons, reducing red blood cell (RBC) extravasation into the injured brain, and promoting behavioral recovery.","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00531"},"PeriodicalIF":5.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fibrinogen degradation products exacerbate alpha-synuclein aggregation by inhibiting autophagy via downregulation of Beclin1 in multiple system atrophy. 在多系统萎缩中，纤溶酶原降解产物通过下调Beclin1抑制自噬，从而加剧α-突触核蛋白的聚集。

IF 5.6 2区医学

Neurotherapeutics Pub Date : 2025-02-03 DOI: 10.1016/j.neurot.2025.e00538

Huanzhu Liu, Ruoyang Yu, Muwei Zhang, Xiaoyan Zheng, Lizi Zhong, Wanlin Yang, Yuqi Luo, Zifeng Huang, Jialing Zheng, Hui Zhong, Xiaobo Wei, Wenhua Zheng, Yinghua Yu, Qing Wang

{"title":"Fibrinogen degradation products exacerbate alpha-synuclein aggregation by inhibiting autophagy via downregulation of Beclin1 in multiple system atrophy.","authors":"Huanzhu Liu, Ruoyang Yu, Muwei Zhang, Xiaoyan Zheng, Lizi Zhong, Wanlin Yang, Yuqi Luo, Zifeng Huang, Jialing Zheng, Hui Zhong, Xiaobo Wei, Wenhua Zheng, Yinghua Yu, Qing Wang","doi":"10.1016/j.neurot.2025.e00538","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00538","url":null,"abstract":"Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease arising from accumulation of the α-synuclein and aberrant protein clearance in oligodendrocytes. The mechanisms of autophagy involved in the progression of MSA remain poorly understood. It is reported that MSA patients have blood-brain barrier impairments, which may increase the entry of fibrinogen into the brain. However, the roles of fibrinogen and its degradation products (FDPs) on autophagy and α-synuclein accumulation in MSA remain unknown. Here, we established the MSA animal model by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) and 3-nitropropionic acid (3-NP), and cellular models by adding fibrillar α-syn into oligodendrocytes to investigate the mechanisms of FDPs on autophagy and accumulation of α-synuclein in oligodendrocytes. We found that FDPs inhibit the entry of α-synuclein into lysosomes for degradation, increasing aggregation of α-synuclein in oligodendrocytes (OLN-93). Our findings indicated that in OLN-93, FDPs inhibited the expressions of Beclin1 and Bif-1, which could promote the fusion of autophagosomes with lysosomes. Furthermore, the expression of α-synuclein was elevated in FDPs-injected mice, accompanied by an increase in the protein level of p62. We detected elevated expression of FDPs in the striatum of MSA mice. Finally, FDPs inhibited the expression of Beclin1 and Bif-1, which led to aberrant autophagic degradation and increased aggregation of α-synuclein and phospho-α-synuclein in MSA mice. Our study illustrates that FDPs can cause aggregation of α-synuclein in MSA by inhibiting Beclin1-mediated autophagy, which may exacerbate disease progression. These results provide a new therapeutic approach for MSA, that targets the inhibitory effect of FDPs on oligodendrocyte autophagy.","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00538"},"PeriodicalIF":5.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification and development of cGAS inhibitors and their uses to treat Alzheimer's disease.

IF 5.6 2区医学

Neurotherapeutics Pub Date : 2025-01-31 DOI: 10.1016/j.neurot.2025.e00536

Jazmin Alarcón-Espósito, Ravi Kumar Nagiri, Li Gan, Subhash C Sinha

{"title":"Identification and development of cGAS inhibitors and their uses to treat Alzheimer's disease.","authors":"Jazmin Alarcón-Espósito, Ravi Kumar Nagiri, Li Gan, Subhash C Sinha","doi":"10.1016/j.neurot.2025.e00536","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00536","url":null,"abstract":"Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a key component of the evolutionary conserved immune response pathway, acting upstream stimulator of interferon genes (STING). It is implicated in various human diseases, including Alzheimer's Disease (AD) and other neurodegenerative disorders. Recent studies have shown that pharmacological inhibition of cGAS in tauopathy mice reduces cytokine expression and ameliorates memory and cognition function. This review summarizes the development and application of high-throughput screening (HTS) strategies for identifying cGAS inhibitor hits and transitioning from hits to leads. Such efforts have provided diverse array of potent cGAS inhibitors that may be beneficial in treating central nervous system (CNS) disorders, such as AD and other neurodegenerative diseases. We describe three HTS strategies: the classical HTS using a chemical library of drug like compounds by cell-free or cell-based assays and the fragment-based screening, where the activity of potential inhibitors was determined by measuring the levels of unreacted ATP or assessing the production of cGAMP or pyrophosphate (PPi). These methods were instrumental in discovering cGAS inhibitor hits and subsequent modifications produced potent leads. Finally, we discuss various post-translational modifications of cGAS and consider whether some of these modifications may serve as useful targets for inhibiting cGAS activity or for promoting protein degradation.","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00536"},"PeriodicalIF":5.6,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Perivascular brain clearance as a therapeutic target in cerebral amyloid angiopathy and Alzheimer's disease.

IF 5.6 2区医学

Neurotherapeutics Pub Date : 2025-01-30 DOI: 10.1016/j.neurot.2025.e00535

Orla Bonnar, Beth Eyre, Susanne J van Veluw

引用次数: 0

Cardiovascular safety of transcutaneous spinal cord stimulation in cervical spinal cord injury.

IF 5.6 2区医学

Neurotherapeutics Pub Date : 2025-01-29 DOI: 10.1016/j.neurot.2025.e00528

Soshi Samejima, Raza N Malik, Jennifer Ge, Lucas Rempel, Kawami Cao, Sameer Desai, Claire Shackleton, Anahita Kyani, Parisa Sarikhani, Jessica M D'Amico, Andrei V Krassioukov

{"title":"Cardiovascular safety of transcutaneous spinal cord stimulation in cervical spinal cord injury.","authors":"Soshi Samejima, Raza N Malik, Jennifer Ge, Lucas Rempel, Kawami Cao, Sameer Desai, Claire Shackleton, Anahita Kyani, Parisa Sarikhani, Jessica M D'Amico, Andrei V Krassioukov","doi":"10.1016/j.neurot.2025.e00528","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00528","url":null,"abstract":"This study evaluated whether cervical transcutaneous spinal cord stimulation (tSCS) in conjunction with rehabilitation on upper extremity function alters blood pressure regulation in individuals with cervical spinal cord injury. This study is a secondary analysis of the Up-LIFT trial, a prospective single-arm multicenter trial designed to evaluate the safety and efficacy of tSCS in conjunction with rehabilitation (tSCS + rehab) on upper extremity function in individuals with chronic cervical spinal cord injury. Utilizing this large data set obtained from 60 individuals across 14 international sites, we compared blood pressure and heart rate measurements obtained before, during and after each training session during both the wash-in Rehab alone period and the tSCS + rehab period of the trial. Blood pressure and heart rate were recorded during each session throughout the protocol in all participants. Sessions of tSCS + rehab did not cause significant changes in blood pressure or heart rate compared to Rehab alone (p > 0.05). Further, blood pressure medications did not have an effect on these cardiovascular responses to tSCS (p > 0.05). This study supports the safety profile of cervical tSCS paired with rehabilitation in individuals with cervical spinal cord injury. The lack of adverse effects on blood pressure and heart rate during the intervention, together with the previously reported clinically meaningful improvements in upper extremity strength and function strongly supports the utility of tSCS in this patient population. Further work is required to elucidate potential long-term effects of targeted tSCS on cardiovascular function in people with spinal cord injury.","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00528"},"PeriodicalIF":5.6,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Quantitative imaging outperforms No-reflow in predicting functional outcomes in a translational stroke model.

IF 5.6 2区医学

Neurotherapeutics Pub Date : 2025-01-29 DOI: 10.1016/j.neurot.2025.e00529

Justine Debatisse, Lucie Chalet, Omer Faruk Eker, Tae-Hee Cho, Guillaume Becker, Océane Wateau, Marlène Wiart, Nicolas Costes, Inés Mérida, Christelle Léon, Jean-Baptiste Langlois, Sophie Lancelot, François Lux, Timothé Boutelier, Norbert Nighoghossian, Laura Mechtouff, Emmanuelle Canet-Soulas

{"title":"Quantitative imaging outperforms No-reflow in predicting functional outcomes in a translational stroke model.","authors":"Justine Debatisse, Lucie Chalet, Omer Faruk Eker, Tae-Hee Cho, Guillaume Becker, Océane Wateau, Marlène Wiart, Nicolas Costes, Inés Mérida, Christelle Léon, Jean-Baptiste Langlois, Sophie Lancelot, François Lux, Timothé Boutelier, Norbert Nighoghossian, Laura Mechtouff, Emmanuelle Canet-Soulas","doi":"10.1016/j.neurot.2025.e00529","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00529","url":null,"abstract":"Microvascular dysfunction and no-reflow are considered a major cause of secondary damage despite revascularization in acute ischemic stroke (AIS), ultimately affecting patient outcomes. We used quantitative PET-MRI imaging to characterize early microvascular damages in a preclinical non-human primate model mimicking endovascular mechanical thrombectomy (EVT). During occlusion, PET perfusion and MRI diffusion were used to measure ischemic and lesion core volumes respectively. Following revascularization, multiparametric PET-MRI included perfusion, diffusion, blood-brain barrier (BBB) permeability MRI, and 15O-oxygen metabolism PET. Lesion growth on MRI was evaluated at one week, and the neurological score was assessed daily; a poor outcome was defined as a score>6 (0-normal, 60-death) after one week. Early after recanalization, the gold-standard PET ischemic threshold (<0.2 mL/min/g) identified post-EVT hypoperfusion in 67 % of the cases (14/21) located in the occlusion acute lesion. Acquired 110 min post-EVT, the area of MRI Tmax hypoperfusion was larger and even more frequent (18/20) and was also located within the acute lesion. Eight of the total cases (38 %) had a poor outcome, and all of them had no-reflow (7/8 MRI no-reflow and 6/8 PET no-reflow). Diffusion ADC alterations and post-EVT oxygen extraction fraction (OEF) values were significantly different in PET no-reflow cases compared to those without no-reflow, exhibiting an inverse correlation. Independently of no-reflow, long perfusion Tmax and post-EVT high BBB Ktrans in the lesion core were the hallmarks of poor outcome and infarct growth. This early quantitative imaging signature may predict infarct growth and poor outcome and help to identify neuroprotection targets.","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00529"},"PeriodicalIF":5.6,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0