Pub Date : 2024-08-01Epub Date: 2024-02-28DOI: 10.1177/0271678X241236014
Christopher A Lear, Benjamin A Lear, Joanne O Davidson, Victoria J King, Yoshiki Maeda, Alice McDouall, Simerdeep K Dhillon, Alistair J Gunn, Laura Bennet
Antenatal hypoxia-ischaemia (HI) in preterm fetal sheep can trigger delayed evolution of severe, cystic white matter injury (WMI), in a similar timecourse to WMI in preterm infants. We therefore examined how severe hypoxia-ischaemia affects recovery of electroencephalographic (EEG) activity. Chronically instrumented preterm fetal sheep (0.7 gestation) received 25 min of complete umbilical cord occlusion (UCO, n = 9) or sham occlusion (controls, n = 9), and recovered for 21 days. HI was associated with a shift to lower frequency EEG activity for the first 5 days with persisting loss of EEG power in the delta and theta bands, and initial loss of power in the alpha and beta bands in the first 14 days of recovery. In the final 3 days of recovery, there was a marked rhythmic shift towards higher frequency EEG activity after UCO. The UCO group spent less time in high-voltage sleep, and in the early evening (7:02 pm ± 47 min) abruptly stopped cycling between sleep states, with a shift to a high frequency state for 2 h 48 min ± 40 min, with tonic electromyographic activity. These findings demonstrate persisting EEG and sleep state dysmaturation after severe hypoxia-ischaemia. Loss of fetal or neonatal sleep state cycling in the early evening may be a useful biomarker for evolving cystic WMI.
{"title":"Dysmaturation of sleep state and electroencephalographic activity after hypoxia-ischaemia in preterm fetal sheep.","authors":"Christopher A Lear, Benjamin A Lear, Joanne O Davidson, Victoria J King, Yoshiki Maeda, Alice McDouall, Simerdeep K Dhillon, Alistair J Gunn, Laura Bennet","doi":"10.1177/0271678X241236014","DOIUrl":"10.1177/0271678X241236014","url":null,"abstract":"<p><p>Antenatal hypoxia-ischaemia (HI) in preterm fetal sheep can trigger delayed evolution of severe, cystic white matter injury (WMI), in a similar timecourse to WMI in preterm infants. We therefore examined how severe hypoxia-ischaemia affects recovery of electroencephalographic (EEG) activity. Chronically instrumented preterm fetal sheep (0.7 gestation) received 25 min of complete umbilical cord occlusion (UCO, n = 9) or sham occlusion (controls, n = 9), and recovered for 21 days. HI was associated with a shift to lower frequency EEG activity for the first 5 days with persisting loss of EEG power in the delta and theta bands, and initial loss of power in the alpha and beta bands in the first 14 days of recovery. In the final 3 days of recovery, there was a marked rhythmic shift towards higher frequency EEG activity after UCO. The UCO group spent less time in high-voltage sleep, and in the early evening (7:02 pm ± 47 min) abruptly stopped cycling between sleep states, with a shift to a high frequency state for 2 h 48 min ± 40 min, with tonic electromyographic activity. These findings demonstrate persisting EEG and sleep state dysmaturation after severe hypoxia-ischaemia. Loss of fetal or neonatal sleep state cycling in the early evening may be a useful biomarker for evolving cystic WMI.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1376-1392"},"PeriodicalIF":4.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139982966","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}
Perioperative neurocognitive disorders (PND) refer to cognitive deterioration that occurs after surgery or anesthesia. Prolonged isoflurane exposure has potential neurotoxicity and induces PND, but the mechanism is unclear. The glymphatic system clears harmful metabolic waste from the brain. This study sought to unveil the functions of glymphatic system in PND and explore the underlying molecular mechanisms. The PND mice model was established by long term isoflurane anesthesia. The glymphatic function was assessed by multiple in vitro and in vivo methods. An adeno-associated virus was used to overexpress AQP4 and TGN-020 was used to inhibit its function. This research revealed that the glymphatic system was impaired in PND mice and the blunted glymphatic transport was closely associated with the accumulation of inflammatory proteins in the hippocampus. Increasing AQP4 polarization could enhance glymphatic transport and suppresses neuroinflammation, thereby improve cognitive function in the PND model mice. However, a marked impaired glymphatic inflammatory proteins clearance and the more severe cognitive dysfunction were observed when decreasing AQP4 polarization. Therefore, long-term isoflurane anesthesia causes blunted glymphatic system by inducing AQP4 depolarization, enhanced the AQP4 polarization can alleviate the glymphatic system malfunction and reduce the neuroinflammatory response, which may be a potential treatment strategy for PND.
{"title":"Long-term isoflurane anesthesia induces cognitive deficits via AQP4 depolarization mediated blunted glymphatic inflammatory proteins clearance.","authors":"Rui Dong, Yuqiang Han, Pin Lv, Linhao Jiang, Zimo Wang, Liangyu Peng, Shuai Liu, Zhengliang Ma, Tianjiao Xia, Bing Zhang, Xiaoping Gu","doi":"10.1177/0271678X241237073","DOIUrl":"10.1177/0271678X241237073","url":null,"abstract":"<p><p>Perioperative neurocognitive disorders (PND) refer to cognitive deterioration that occurs after surgery or anesthesia. Prolonged isoflurane exposure has potential neurotoxicity and induces PND, but the mechanism is unclear. The glymphatic system clears harmful metabolic waste from the brain. This study sought to unveil the functions of glymphatic system in PND and explore the underlying molecular mechanisms. The PND mice model was established by long term isoflurane anesthesia. The glymphatic function was assessed by multiple in vitro and in vivo methods. An adeno-associated virus was used to overexpress AQP4 and TGN-020 was used to inhibit its function. This research revealed that the glymphatic system was impaired in PND mice and the blunted glymphatic transport was closely associated with the accumulation of inflammatory proteins in the hippocampus. Increasing AQP4 polarization could enhance glymphatic transport and suppresses neuroinflammation, thereby improve cognitive function in the PND model mice. However, a marked impaired glymphatic inflammatory proteins clearance and the more severe cognitive dysfunction were observed when decreasing AQP4 polarization. Therefore, long-term isoflurane anesthesia causes blunted glymphatic system by inducing AQP4 depolarization, enhanced the AQP4 polarization can alleviate the glymphatic system malfunction and reduce the neuroinflammatory response, which may be a potential treatment strategy for PND.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1450-1466"},"PeriodicalIF":4.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140039462","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}
Pub Date : 2024-08-01Epub Date: 2024-03-14DOI: 10.1177/0271678X241237733
Severin Schramm, Corinna Börner, Miriam Reichert, Gabriel Hoffmann, Stephan Kaczmarz, Michael Griessmair, Kirsten Jung, Maria T Berndt, Claus Zimmer, Thomas Baum, Florian Heinen, Michaela V Bonfert, Nico Sollmann
Arterial spin labeling (ASL) is a non-invasive magnetic resonance imaging (MRI) method for the assessment of cerebral blood flow (CBF). This review summarizes recent ASL-based investigations in adult and pediatric patients with migraine with aura, migraine without aura, and chronic migraine. A systematic search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted within PubMed and reference sections of articles identified from April 2014 to November 2022. Out of 236 initial articles, 20 remained after filtering, encompassing data from 1155 subjects in total. Cross-sectional studies in adults showed inconsistent results, while longitudinal studies demonstrated that cerebral perfusion changes over the migraine cycle can be tracked using ASL. The most consistent findings were observed in ictal states among pediatric migraine patients, where studies showed hypoperfusion matching aura symptoms during early imaging followed by hyperperfusion. Overall, ASL is a useful but currently underutilized modality for evaluating cerebral perfusion in patients with migraine. The generalizability of results is currently limited by heterogeneities regarding study design and documentation of clinical variables (e.g., relation of attacks to scanning timepoint, migraine subtypes). Future MRI studies should consider augmenting imaging protocols with ASL to further elucidate perfusion dynamics in migraine.
动脉自旋标记(ASL)是一种评估脑血流(CBF)的无创磁共振成像(MRI)方法。本综述总结了近期对先兆偏头痛、无先兆偏头痛和慢性偏头痛的成人和儿童患者进行的基于 ASL 的研究。根据系统综述和元分析首选报告项目(PRISMA)指南,在PubMed和参考文献中对2014年4月至2022年11月期间的文章进行了系统检索。在 236 篇初始文章中,经过筛选后保留了 20 篇,共包含 1155 名受试者的数据。成人横断面研究显示的结果并不一致,而纵向研究则表明,偏头痛周期内的脑灌注变化可通过 ASL 追踪。在小儿偏头痛患者的发作状态下观察到的结果最为一致,研究显示,在早期成像时,脑灌注不足与先兆症状相匹配,随后出现脑灌注亢进。总之,ASL 是评估偏头痛患者脑灌注情况的一种有用但目前未得到充分利用的方法。目前,研究设计和临床变量记录(如发作与扫描时间点的关系、偏头痛亚型)方面的异质性限制了研究结果的推广性。未来的 MRI 研究应考虑使用 ASL 增强成像方案,以进一步阐明偏头痛的灌注动态。
{"title":"Perfusion imaging by arterial spin labeling in migraine: A literature review.","authors":"Severin Schramm, Corinna Börner, Miriam Reichert, Gabriel Hoffmann, Stephan Kaczmarz, Michael Griessmair, Kirsten Jung, Maria T Berndt, Claus Zimmer, Thomas Baum, Florian Heinen, Michaela V Bonfert, Nico Sollmann","doi":"10.1177/0271678X241237733","DOIUrl":"10.1177/0271678X241237733","url":null,"abstract":"<p><p>Arterial spin labeling (ASL) is a non-invasive magnetic resonance imaging (MRI) method for the assessment of cerebral blood flow (CBF). This review summarizes recent ASL-based investigations in adult and pediatric patients with migraine with aura, migraine without aura, and chronic migraine. A systematic search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted within PubMed and reference sections of articles identified from April 2014 to November 2022. Out of 236 initial articles, 20 remained after filtering, encompassing data from 1155 subjects in total. Cross-sectional studies in adults showed inconsistent results, while longitudinal studies demonstrated that cerebral perfusion changes over the migraine cycle can be tracked using ASL. The most consistent findings were observed in ictal states among pediatric migraine patients, where studies showed hypoperfusion matching aura symptoms during early imaging followed by hyperperfusion. Overall, ASL is a useful but currently underutilized modality for evaluating cerebral perfusion in patients with migraine. The generalizability of results is currently limited by heterogeneities regarding study design and documentation of clinical variables (e.g., relation of attacks to scanning timepoint, migraine subtypes). Future MRI studies should consider augmenting imaging protocols with ASL to further elucidate perfusion dynamics in migraine.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1253-1270"},"PeriodicalIF":4.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140119616","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}
Pub Date : 2024-08-01Epub Date: 2024-03-04DOI: 10.1177/0271678X241237427
Clara Correa-Paz, María Pérez-Mato, Mathys Bellemain-Sagnard, Marco González-Domínguez, Pauline Marie, Lara Pérez-Gayol, Esteban López-Arias, Lucia Del Pozo-Filíu, Sonia López-Amoedo, Ana Bugallo-Casal, María Luz Alonso-Alonso, María Candamo-Lourido, María Santamaría-Cadavid, Susana Arias-Rivas, Manuel Rodríguez-Yañez, Ramón Iglesias-Rey, José Castillo, Denis Vivien, Marina Rubio, Francisco Campos
Alteplase (rtPA) remains the standard thrombolytic drug for acute ischemic stroke. However, new rtPA-derived molecules, such as tenecteplase (TNK), with prolonged half-lives following a single bolus administration, have been developed. Although TNK is currently under clinical evaluation, the limited preclinical data highlight the need for additional studies to elucidate its benefits. The toxicities of rtPA and TNK were evaluated in endothelial cells, astrocytes, and neuronal cells. In addition, their in vivo efficacy was independently assessed at two research centers using an ischemic thromboembolic mouse model. Both therapies were tested via early (20 and 30 min) and late administration (4 and 4.5 h) after stroke. rtPA, but not TNK, caused cell death only in neuronal cultures. Mice were less sensitive to thrombolytic therapies than humans, requiring doses 10-fold higher than the established clinical dose. A single bolus dose of 2.5 mg/kg TNK led to an infarct reduction similar to perfusion with 10 mg/kg of rtPA. Early administration of TNK decreased the hemorrhagic transformations compared to that by the early administration of rtPA; however, this result was not obtained following late administration. These two independent preclinical studies support the use of TNK as a promising reperfusion alternative to rtPA.
{"title":"Pharmacological preclinical comparison of tenecteplase and alteplase for the treatment of acute stroke.","authors":"Clara Correa-Paz, María Pérez-Mato, Mathys Bellemain-Sagnard, Marco González-Domínguez, Pauline Marie, Lara Pérez-Gayol, Esteban López-Arias, Lucia Del Pozo-Filíu, Sonia López-Amoedo, Ana Bugallo-Casal, María Luz Alonso-Alonso, María Candamo-Lourido, María Santamaría-Cadavid, Susana Arias-Rivas, Manuel Rodríguez-Yañez, Ramón Iglesias-Rey, José Castillo, Denis Vivien, Marina Rubio, Francisco Campos","doi":"10.1177/0271678X241237427","DOIUrl":"10.1177/0271678X241237427","url":null,"abstract":"<p><p>Alteplase (rtPA) remains the standard thrombolytic drug for acute ischemic stroke. However, new rtPA-derived molecules, such as tenecteplase (TNK), with prolonged half-lives following a single <i>bolus</i> administration, have been developed. Although TNK is currently under clinical evaluation, the limited preclinical data highlight the need for additional studies to elucidate its benefits. The toxicities of rtPA and TNK were evaluated in endothelial cells, astrocytes, and neuronal cells. In addition, their <i>in vivo</i> efficacy was independently assessed at two research centers using an ischemic thromboembolic mouse model. Both therapies were tested via early (20 and 30 min) and late administration (4 and 4.5 h) after stroke. rtPA, but not TNK, caused cell death only in neuronal cultures. Mice were less sensitive to thrombolytic therapies than humans, requiring doses 10-fold higher than the established clinical dose. A single <i>bolus</i> dose of 2.5 mg/kg TNK led to an infarct reduction similar to perfusion with 10 mg/kg of rtPA. Early administration of TNK decreased the hemorrhagic transformations compared to that by the early administration of rtPA; however, this result was not obtained following late administration. These two independent preclinical studies support the use of TNK as a promising reperfusion alternative to rtPA.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1306-1318"},"PeriodicalIF":4.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140021877","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}
Pub Date : 2024-08-01Epub Date: 2024-03-04DOI: 10.1177/0271678X241237072
Slim Fellah, Chunwei Ying, Yan Wang, Kristin P Guilliams, Melanie E Fields, Yasheng Chen, Josiah Lewis, Amy Mirro, Rachel Cohen, Nkemdilim Igwe, Cihat Eldeniz, Dengrong Jiang, Hanzhang Lu, William J Powers, Jin-Moo Lee, Andria L Ford, Hongyu An
Abnormal oxygen extraction fraction (OEF), a putative biomarker of cerebral metabolic stress, may indicate compromised oxygen delivery and ischemic vulnerability in patients with sickle cell disease (SCD). Elevated OEF was observed at the tissue level across the brain using an asymmetric spin echo (ASE) MR method, while variable global OEFs were found from the superior sagittal sinus (SSS) using a T2-relaxation-under-spin-tagging (TRUST) MRI method with different calibration models. In this study, we aimed to compare the average ASE-OEF in the SSS drainage territory and TRUST-OEF in the SSS from the same SCD patients and healthy controls. 74 participants (SCD: N = 49; controls: N = 25) underwent brain MRI. TRUST-OEF was quantified using the Lu-bovine, Bush-HbA and Li-Bush-HbS models. ASE-OEF and TRUST-OEF were significantly associated in healthy controls after controlling for hematocrit using the Lu-bovine or the Bush-HbA model. However, no association was found between ASE-OEF and TRUST-OEF in patients with SCD using either the Bush-HbA or the Li-Bush-HbS model. Plausible explanations include a discordance between spatially volume-averaged oxygenation brain tissue and flow-weighted volume-averaged oxygenation in SSS or sub-optimal calibration in SCD. Further work is needed to refine and validate non-invasive MR OEF measurements in SCD.
{"title":"Comparison of cerebral oxygen extraction fraction using ASE and TRUST methods in patients with sickle cell disease and healthy controls.","authors":"Slim Fellah, Chunwei Ying, Yan Wang, Kristin P Guilliams, Melanie E Fields, Yasheng Chen, Josiah Lewis, Amy Mirro, Rachel Cohen, Nkemdilim Igwe, Cihat Eldeniz, Dengrong Jiang, Hanzhang Lu, William J Powers, Jin-Moo Lee, Andria L Ford, Hongyu An","doi":"10.1177/0271678X241237072","DOIUrl":"10.1177/0271678X241237072","url":null,"abstract":"<p><p>Abnormal oxygen extraction fraction (OEF), a putative biomarker of cerebral metabolic stress, may indicate compromised oxygen delivery and ischemic vulnerability in patients with sickle cell disease (SCD). Elevated OEF was observed at the tissue level across the brain using an asymmetric spin echo (ASE) MR method, while variable global OEFs were found from the superior sagittal sinus (SSS) using a T2-relaxation-under-spin-tagging (TRUST) MRI method with different calibration models. In this study, we aimed to compare the average ASE-OEF in the SSS drainage territory and TRUST-OEF in the SSS from the same SCD patients and healthy controls. 74 participants (SCD: N = 49; controls: N = 25) underwent brain MRI. TRUST-OEF was quantified using the Lu-bovine, Bush-HbA and Li-Bush-HbS models. ASE-OEF and TRUST-OEF were significantly associated in healthy controls after controlling for hematocrit using the Lu-bovine or the Bush-HbA model. However, no association was found between ASE-OEF and TRUST-OEF in patients with SCD using either the Bush-HbA or the Li-Bush-HbS model. Plausible explanations include a discordance between spatially volume-averaged oxygenation brain tissue and flow-weighted volume-averaged oxygenation in SSS or sub-optimal calibration in SCD. Further work is needed to refine and validate non-invasive MR OEF measurements in SCD.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1404-1416"},"PeriodicalIF":4.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140021876","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}
Pub Date : 2024-08-01Epub Date: 2024-03-07DOI: 10.1177/0271678X241237624
Zahra Shirzadi, Rory Boyle, Wai-Ying W Yau, Gillian Coughlan, Jessie Fanglu Fu, Michael J Properzi, Rachel F Buckley, Hyun-Sik Yang, Catherine E Scanlon, Stephanie Hsieh, Rebecca E Amariglio, Kathryn Papp, Dorene Rentz, Julie C Price, Keith A Johnson, Reisa A Sperling, Jasmeer P Chhatwal, Aaron P Schultz
In addition to amyloid and tau pathology, elevated systemic vascular risk, white matter injury, and reduced cerebral blood flow contribute to late-life cognitive decline. Given the strong collinearity among these parameters, we proposed a framework to extract the independent latent features underlying cognitive decline using the Harvard Aging Brain Study (N = 166 cognitively unimpaired older adults at baseline). We used the following measures from the baseline visit: cortical amyloid, inferior temporal cortex tau, relative cerebral blood flow, white matter hyperintensities, peak width of skeletonized mean diffusivity, and Framingham Heart Study cardiovascular disease risk. We used exploratory factor analysis to extract orthogonal factors from these variables and their interactions. These factors were used in a regression model to explain longitudinal Preclinical Alzheimer Cognitive Composite-5 (PACC) decline (follow-up = 8.5 ±2.7 years). We next examined whether gray matter volume atrophy acts as a mediator of factors and PACC decline. Latent factors of systemic vascular risk, white matter injury, and relative cerebral blood flow independently explain cognitive decline beyond amyloid and tau. Gray matter volume atrophy mediates these associations with the strongest effect on white matter injury. These results suggest that systemic vascular risk contributes to cognitive decline beyond current markers of cerebrovascular injury, amyloid, and tau.
除了淀粉样蛋白和 tau 病理学之外,全身血管风险升高、白质损伤和脑血流量减少也是导致晚年认知能力下降的原因。鉴于这些参数之间存在很强的共线性,我们提出了一个框架,利用哈佛大学老年脑研究(N = 166 名基线认知功能未受损的老年人)来提取认知功能衰退的独立潜在特征。我们使用了基线访问中的以下测量指标:皮层淀粉样蛋白、下颞皮层 tau、相对脑血流量、白质高密度、骨架化平均扩散峰值宽度和弗雷明汉心脏研究心血管疾病风险。我们使用探索性因子分析从这些变量及其交互作用中提取正交因子。这些因素被用于回归模型,以解释临床前阿尔茨海默氏症认知综合征-5(PACC)的纵向衰退(随访时间 = 8.5 ± 2.7 年)。接下来,我们研究了灰质体积萎缩是否是各种因素与 PACC 下降之间的中介。除淀粉样蛋白和tau外,全身血管风险、白质损伤和相对脑血流量等潜在因素也能独立解释认知能力的下降。灰质体积萎缩介导了这些关联,对白质损伤的影响最大。这些结果表明,除了目前的脑血管损伤、淀粉样蛋白和 tau 标记之外,系统性血管风险也是认知能力下降的原因之一。
{"title":"Vascular contributions to cognitive decline: Beyond amyloid and tau in the Harvard Aging Brain Study.","authors":"Zahra Shirzadi, Rory Boyle, Wai-Ying W Yau, Gillian Coughlan, Jessie Fanglu Fu, Michael J Properzi, Rachel F Buckley, Hyun-Sik Yang, Catherine E Scanlon, Stephanie Hsieh, Rebecca E Amariglio, Kathryn Papp, Dorene Rentz, Julie C Price, Keith A Johnson, Reisa A Sperling, Jasmeer P Chhatwal, Aaron P Schultz","doi":"10.1177/0271678X241237624","DOIUrl":"10.1177/0271678X241237624","url":null,"abstract":"<p><p>In addition to amyloid and tau pathology, elevated systemic vascular risk, white matter injury, and reduced cerebral blood flow contribute to late-life cognitive decline. Given the strong collinearity among these parameters, we proposed a framework to extract the independent latent features underlying cognitive decline using the Harvard Aging Brain Study (N = 166 cognitively unimpaired older adults at baseline). We used the following measures from the baseline visit: cortical amyloid, inferior temporal cortex tau, relative cerebral blood flow, white matter hyperintensities, peak width of skeletonized mean diffusivity, and Framingham Heart Study cardiovascular disease risk. We used exploratory factor analysis to extract orthogonal factors from these variables and their interactions. These factors were used in a regression model to explain longitudinal Preclinical Alzheimer Cognitive Composite-5 (PACC) decline (follow-up = 8.5 ±2.7 years). We next examined whether gray matter volume atrophy acts as a mediator of factors and PACC decline. Latent factors of systemic vascular risk, white matter injury, and relative cerebral blood flow independently explain cognitive decline beyond amyloid and tau. Gray matter volume atrophy mediates these associations with the strongest effect on white matter injury. These results suggest that systemic vascular risk contributes to cognitive decline beyond current markers of cerebrovascular injury, amyloid, and tau.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1319-1328"},"PeriodicalIF":4.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059482","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}
Pub Date : 2024-08-01Epub Date: 2024-05-31DOI: 10.1177/0271678X241259551
Hasan Sawan, Chenyang Li, Sagar Buch, Evanthia Bernitsas, E Mark Haacke, Yulin Ge, Yongsheng Chen
Studying the relationship between cerebral oxygen utilization and cognitive impairment is essential to understanding neuronal functional changes in the disease progression of multiple sclerosis (MS). This study explores the potential of using venous susceptibility in internal cerebral veins (ICVs) as an imaging biomarker for cognitive impairment in relapsing-remitting MS (RRMS) patients. Quantitative susceptibility mapping derived from fully flow-compensated MRI phase data was employed to directly measure venous blood oxygen saturation levels (SvO2) in the ICVs. Results revealed a significant reduction in the susceptibility of ICVs (212.4 ± 30.8 ppb vs 239.4 ± 25.9 ppb) and a significant increase of SvO2 (74.5 ± 1.89% vs 72.4 ± 2.23%) in patients with RRMS compared with age- and sex-matched healthy controls. Both the susceptibility of ICVs (r = 0.508, p = 0.031) and the SvO2 (r = -0.498, p = 0.036) exhibited a moderate correlation with cognitive decline in these patients assessed by the Paced Auditory Serial Addition Test, while no significant correlation was observed with clinical disability measured by the Expanded Disability Status Scale. The findings suggest that venous susceptibility in ICVs has the potential to serve as a specific indicator of oxygen metabolism and cognitive function in RRMS. .
研究脑氧利用率与认知障碍之间的关系对于了解多发性硬化症(MS)疾病进展过程中神经元的功能变化至关重要。本研究探讨了利用大脑内静脉(ICV)的静脉易感性作为复发缓解型多发性硬化症(RRMS)患者认知障碍的成像生物标志物的潜力。利用完全血流补偿磁共振成像相位数据得出的定量易感性图谱直接测量了ICV中静脉血氧饱和度(SvO2)水平。结果显示,与年龄和性别匹配的健康对照组相比,RRMS 患者 ICV 的易感性明显降低(212.4 ± 30.8 ppb vs 239.4 ± 25.9 ppb),SvO2 明显升高(74.5 ± 1.89% vs 72.4 ± 2.23%)。ICV 的易感性(r = 0.508,p = 0.031)和 SvO2(r = -0.498,p = 0.036)与步调听觉连续加法测试(Paced Auditory Serial Addition Test)评估的这些患者的认知能力下降呈中度相关,而与扩展残疾状况量表(Expanded Disability Status Scale)测量的临床残疾无明显相关。研究结果表明,ICV 中的静脉易感性有可能成为 RRMS 患者氧代谢和认知功能的特定指标。.
{"title":"Reduced oxygen extraction fraction in deep cerebral veins associated with cognitive impairment in multiple sclerosis.","authors":"Hasan Sawan, Chenyang Li, Sagar Buch, Evanthia Bernitsas, E Mark Haacke, Yulin Ge, Yongsheng Chen","doi":"10.1177/0271678X241259551","DOIUrl":"10.1177/0271678X241259551","url":null,"abstract":"<p><p>Studying the relationship between cerebral oxygen utilization and cognitive impairment is essential to understanding neuronal functional changes in the disease progression of multiple sclerosis (MS). This study explores the potential of using venous susceptibility in internal cerebral veins (ICVs) as an imaging biomarker for cognitive impairment in relapsing-remitting MS (RRMS) patients. Quantitative susceptibility mapping derived from fully flow-compensated MRI phase data was employed to directly measure venous blood oxygen saturation levels (S<sub>v</sub>O<sub>2</sub>) in the ICVs. Results revealed a significant reduction in the susceptibility of ICVs (212.4 ± 30.8 ppb vs 239.4 ± 25.9 ppb) and a significant increase of S<sub>v</sub>O<sub>2</sub> (74.5 ± 1.89% vs 72.4 ± 2.23%) in patients with RRMS compared with age- and sex-matched healthy controls. Both the susceptibility of ICVs (<i>r = </i>0.508, <i>p = </i>0.031) and the S<sub>v</sub>O<sub>2</sub> (<i>r</i> = -0.498, <i>p = </i>0.036) exhibited a moderate correlation with cognitive decline in these patients assessed by the Paced Auditory Serial Addition Test, while no significant correlation was observed with clinical disability measured by the Expanded Disability Status Scale. The findings suggest that venous susceptibility in ICVs has the potential to serve as a specific indicator of oxygen metabolism and cognitive function in RRMS. .</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1298-1305"},"PeriodicalIF":4.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141183722","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}
Pub Date : 2024-08-01Epub Date: 2024-02-05DOI: 10.1177/0271678X241230741
Cecilia Björnfot, Anders Eklund, Jenny Larsson, William Hansson, Johan Birnefeld, Anders Garpebring, Sara Qvarlander, Lars-Owe D Koskinen, Jan Malm, Anders Wåhlin
White matter hyperintensities (WMH), perivascular spaces (PVS) and lacunes are common MRI features of small vessel disease (SVD). However, no shared underlying pathological mechanism has been identified. We investigated whether SVD burden, in terms of WMH, PVS and lacune status, was related to changes in the cerebral arterial wall by applying global cerebral pulse wave velocity (gcPWV) measurements, a newly described marker of cerebral vascular stiffness. In a population-based cohort of 190 individuals, 66-85 years old, SVD features were estimated from T1-weighted and FLAIR images while gcPWV was estimated from 4D flow MRI data. Additionally, the gcPWV's stability to variations in field-of-view was analyzed. The gcPWV was 10.82 (3.94) m/s and displayed a significant correlation to WMH and white matter PVS volume (r = 0.29, p < 0.001; r = 0.21, p = 0.004 respectively from nonparametric tests) that persisted after adjusting for age, blood pressure variables, body mass index, ApoB/A1 ratio, smoking as well as cerebral pulsatility index, a previously suggested early marker of SVD. The gcPWV displayed satisfactory stability to field-of-view variations. Our results suggest that SVD is accompanied by changes in the cerebral arterial wall that can be captured by considering the velocity of the pulse wave transmission through the cerebral arterial network.
{"title":"Cerebral arterial stiffness is linked to white matter hyperintensities and perivascular spaces in older adults - A 4D flow MRI study.","authors":"Cecilia Björnfot, Anders Eklund, Jenny Larsson, William Hansson, Johan Birnefeld, Anders Garpebring, Sara Qvarlander, Lars-Owe D Koskinen, Jan Malm, Anders Wåhlin","doi":"10.1177/0271678X241230741","DOIUrl":"10.1177/0271678X241230741","url":null,"abstract":"<p><p>White matter hyperintensities (WMH), perivascular spaces (PVS) and lacunes are common MRI features of small vessel disease (SVD). However, no shared underlying pathological mechanism has been identified. We investigated whether SVD burden, in terms of WMH, PVS and lacune status, was related to changes in the cerebral arterial wall by applying global cerebral pulse wave velocity (gcPWV) measurements, a newly described marker of cerebral vascular stiffness. In a population-based cohort of 190 individuals, 66-85 years old, SVD features were estimated from T1-weighted and FLAIR images while gcPWV was estimated from 4D flow MRI data. Additionally, the gcPWV's stability to variations in field-of-view was analyzed. The gcPWV was 10.82 (3.94) m/s and displayed a significant correlation to WMH and white matter PVS volume (r = 0.29, p < 0.001; r = 0.21, p = 0.004 respectively from nonparametric tests) that persisted after adjusting for age, blood pressure variables, body mass index, ApoB/A1 ratio, smoking as well as cerebral pulsatility index, a previously suggested early marker of SVD. The gcPWV displayed satisfactory stability to field-of-view variations. Our results suggest that SVD is accompanied by changes in the cerebral arterial wall that can be captured by considering the velocity of the pulse wave transmission through the cerebral arterial network.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1343-1351"},"PeriodicalIF":4.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139691962","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}
Pub Date : 2024-08-01Epub Date: 2024-03-05DOI: 10.1177/0271678X241237484
Manon Leclerc, Cyntia Tremblay, Philippe Bourassa, Julie A Schneider, David A Bennett, Frédéric Calon
The brain is a highly demanding organ, utilizing mainly glucose but also ketone bodies as sources of energy. Glucose transporter-1 (GLUT1) and monocarboxylates transporter-1 (MCT1) respectively transport glucose and ketone bodies across the blood-brain barrier. While reduced glucose uptake by the brain is one of the earliest signs of Alzheimer's disease (AD), no change in the uptake of ketone bodies has been evidenced yet. To probe for changes in GLUT1 and MCT1, we performed Western immunoblotting in microvessel extracts from the parietal cortex of 60 participants of the Religious Orders Study. Participants clinically diagnosed with AD had lower cerebrovascular levels of GLUT1, whereas MCT1 remained unchanged. GLUT1 reduction was associated with lower cognitive scores. No such association was found for MCT1. GLUT1 was inversely correlated with neuritic plaques and cerebrovascular β-secretase-derived fragment levels. No other significant associations were found between both transporters, markers of Aβ and tau pathologies, sex, age at death or apolipoprotein-ε4 genotype. These results suggest that, while a deficit of GLUT1 may underlie the reduced transport of glucose to the brain in AD, no such impairment occurs for MCT1. This study thus supports the exploration of ketone bodies as an alternative energy source for the aging brain.
{"title":"Lower GLUT1 and unchanged MCT1 in Alzheimer's disease cerebrovasculature.","authors":"Manon Leclerc, Cyntia Tremblay, Philippe Bourassa, Julie A Schneider, David A Bennett, Frédéric Calon","doi":"10.1177/0271678X241237484","DOIUrl":"10.1177/0271678X241237484","url":null,"abstract":"<p><p>The brain is a highly demanding organ, utilizing mainly glucose but also ketone bodies as sources of energy. Glucose transporter-1 (GLUT1) and monocarboxylates transporter-1 (MCT1) respectively transport glucose and ketone bodies across the blood-brain barrier. While reduced glucose uptake by the brain is one of the earliest signs of Alzheimer's disease (AD), no change in the uptake of ketone bodies has been evidenced yet. To probe for changes in GLUT1 and MCT1, we performed Western immunoblotting in microvessel extracts from the parietal cortex of 60 participants of the Religious Orders Study. Participants clinically diagnosed with AD had lower cerebrovascular levels of GLUT1, whereas MCT1 remained unchanged. GLUT1 reduction was associated with lower cognitive scores. No such association was found for MCT1. GLUT1 was inversely correlated with neuritic plaques and cerebrovascular β-secretase-derived fragment levels. No other significant associations were found between both transporters, markers of Aβ and tau pathologies, sex, age at death or apolipoprotein-ε4 genotype. These results suggest that, while a deficit of GLUT1 may underlie the reduced transport of glucose to the brain in AD, no such impairment occurs for MCT1. This study thus supports the exploration of ketone bodies as an alternative energy source for the aging brain.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1417-1432"},"PeriodicalIF":4.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140028187","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}
Pub Date : 2024-08-01Epub Date: 2024-03-05DOI: 10.1177/0271678X241237974
Tommaso Volpi, Erica Silvestri, Marco Aiello, John J Lee, Andrei G Vlassenko, Manu S Goyal, Maurizio Corbetta, Alessandra Bertoldo
Brain glucose metabolism, which can be investigated at the macroscale level with [18F]FDG PET, displays significant regional variability for reasons that remain unclear. Some of the functional drivers behind this heterogeneity may be captured by resting-state functional magnetic resonance imaging (rs-fMRI). However, the full extent to which an fMRI-based description of the brain's spontaneous activity can describe local metabolism is unknown. Here, using two multimodal datasets of healthy participants, we built a multivariable multilevel model of functional-metabolic associations, assessing multiple functional features, describing the 1) rs-fMRI signal, 2) hemodynamic response, 3) static and 4) time-varying functional connectivity, as predictors of the human brain's metabolic architecture. The full model was trained on one dataset and tested on the other to assess its reproducibility. We found that functional-metabolic spatial coupling is nonlinear and heterogeneous across the brain, and that local measures of rs-fMRI activity and synchrony are more tightly coupled to local metabolism. In the testing dataset, the degree of functional-metabolic spatial coupling was also related to peripheral metabolism. Overall, although a significant proportion of regional metabolic variability can be described by measures of spontaneous activity, additional efforts are needed to explain the remaining variance in the brain's 'dark energy'.
{"title":"The brain's \"dark energy\" puzzle: How strongly is glucose metabolism linked to resting-state brain activity?","authors":"Tommaso Volpi, Erica Silvestri, Marco Aiello, John J Lee, Andrei G Vlassenko, Manu S Goyal, Maurizio Corbetta, Alessandra Bertoldo","doi":"10.1177/0271678X241237974","DOIUrl":"10.1177/0271678X241237974","url":null,"abstract":"<p><p>Brain glucose metabolism, which can be investigated at the macroscale level with [<sup>18</sup>F]FDG PET, displays significant regional variability for reasons that remain unclear. Some of the functional drivers behind this heterogeneity may be captured by resting-state functional magnetic resonance imaging (rs-fMRI). However, the full extent to which an fMRI-based description of the brain's spontaneous activity can describe local metabolism is unknown. Here, using two multimodal datasets of healthy participants, we built a multivariable multilevel model of functional-metabolic associations, assessing multiple functional features, describing the 1) rs-fMRI signal, 2) hemodynamic response, 3) static and 4) time-varying functional connectivity, as predictors of the human brain's metabolic architecture. The full model was trained on one dataset and tested on the other to assess its reproducibility. We found that functional-metabolic spatial coupling is nonlinear and heterogeneous across the brain, and that local measures of rs-fMRI activity and synchrony are more tightly coupled to local metabolism. In the testing dataset, the degree of functional-metabolic spatial coupling was also related to peripheral metabolism. Overall, although a significant proportion of regional metabolic variability can be described by measures of spontaneous activity, additional efforts are needed to explain the remaining variance in the brain's 'dark energy'.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1433-1449"},"PeriodicalIF":4.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140039463","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}