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1
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Huang X, Wen S, Huang Y, Zhang B, Xia Z, Huang Z. Association between cardiometabolic index and the incidence of stroke: a prospective nationwide cohort study in China. J Diabetes Metab Disord 2025; 24:26. [PMID: 39735172 PMCID: PMC11680538 DOI: 10.1007/s40200-024-01530-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 10/12/2024] [Indexed: 12/31/2024]
Abstract
Objectives Cardiometabolic index (CMI), based on triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C) ratio and waist-to-height ratio (WHtR), has been recognized as a novel and practical marker for the assessment of cardiometabolic risk. However, the relationship between CMI and the incidence of stroke remains to be elucidated. This investigation aimed to explore the association between CMI and stroke incidence. Methods The investigation included 6,633 individuals aged over 45 years from the China Health and Retirement Longitudinal Study. Logistic regressions and restricted cubic spline regression were uitilized to determine the relationship between CMI and the incidence of stroke. Weighted quantile sum regression was used to offer a comprehensive explanation of the CMI by calculating the weights of triglyceride-glucose (TG), high-density lipoprotein cholesterol (HDL-C), weight, and height. Results During the 9-year follow-up, 827 (12%) incident stroke participants were identified. With CMI as a continuous variable, the OR (95% CI) for the risk of incident stroke was 1.09 (1.01-1.19) (p = 0.047) after adjusting for potential confounders, indicating a significant link between increased CMI and an elevated incidence of stroke. Additionally, when CMI was categorized into quartiles, compared to the first quartile, the incident stroke was significantly higher in the fourth quartile (OR 1.57, 95%CI 1.22-2.04, p <0.001). The association between CMI and stroke incidence was nonlinear (p overall=0.002, p non-linear = 0.006). TG emerged as the primary contributor when the weights were assigned to the constituent elements of the CMI (weight = 0.645). Conclusions The CMI was independently associated with stroke incidence in middle-aged and elderly Chinese populations. Long-term CMI monitoring is of great importance for early identification and prevention of stroke, with significant implications for clinical practice. Supplementary Information The online version contains supplementary material available at 10.1007/s40200-024-01530-3.
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Affiliation(s)
- Xingjie Huang
- Department of Cardiology, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541000 China
| | - Song Wen
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, 106 Zhongshan 2nd Road, Yuexiu, Guangzhou, Guangdong 510080 China
| | - Yuqing Huang
- Hypertension Laboratory, Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510080 China
| | - Bin Zhang
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, 106 Zhongshan 2nd Road, Yuexiu, Guangzhou, Guangdong 510080 China
| | - Zhonghua Xia
- Department of Cardiology, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541000 China
| | - Zehan Huang
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, 106 Zhongshan 2nd Road, Yuexiu, Guangzhou, Guangdong 510080 China
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Hong H, Tozer DJ, Chen Y, Brown RB, Low A, Markus HS. Perivascular space dysfunction in cerebral small vessel disease is related to neuroinflammation. Brain 2025; 148:1540-1550. [PMID: 39509331 PMCID: PMC12073995 DOI: 10.1093/brain/awae357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 09/09/2024] [Accepted: 10/13/2024] [Indexed: 11/15/2024] Open
Abstract
Enlarged perivascular spaces are a feature of cerebral small vessel disease, and it has been hypothesized that they might reflect impaired glymphatic drainage. The mechanisms underlying enlargement of perivascular spaces are not fully understood, but both increased inflammation and blood-brain barrier (BBB) permeability have been hypothesized to play a role. We investigated the relationship between perivascular spaces and both CNS and peripheral inflammation, in addition to BBB permeability, in cerebral small vessel disease. Fifty-four symptomatic sporadic cerebral small vessel disease patients were studied. Perivascular spaces were quantified both using a visual rating scale and by measurement of the volume of perivascular spaces in the white matter and the basal ganglia. PET-MRI was used to measure microglial activation using the radioligand 11C-PK11195, and simultaneously, BBB permeability was acquired using dynamic contrast-enhanced MRI. We determined 11C-PK11195 binding and BBB permeability in the local vicinity of individual perivascular spaces in concentric shells surrounding the perivascular spaces. In addition, both mean 11C-PK11195 binding and BBB permeability in both the white matter and the basal ganglia were determined. To assess systemic inflammation, a panel of 93 blood biomarkers relating to cardiovascular disease, inflammation and endothelial activation were measured. Within the white matter, tissue in closest proximity to perivascular spaces displayed greater 11C-PK11195 binding (P < 0.001) in the vicinity of perivascular spaces. Higher white matter perivascular spaces burden on the visual rating scale was associated with higher white matter 11C-PK11195 binding (ρ = 0.469, false discovery rate-corrected P = 0.009); values for the volume of perivascular spaces showed a similar trend. In contrast, there were no associations between the burden of basal ganglia perivascular spaces and 11C-PK11195 binding. No marker of perivascular spaces was correlated with blood-brain barrier permeability. There was no association between markers of perivascular spaces and blood biomarkers of systemic inflammation. Our findings demonstrate that white matter perivascular spaces are associated with increased 11C-PK11195 binding, consistent with neuroinflammation playing a role in enlargement of white matter perivascular spaces. Further longitudinal and intervention studies are required to determine whether the relationship between neuroinflammation and enlarged perivascular spaces is causal.
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Affiliation(s)
- Hui Hong
- Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK
- Department of Radiology, Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou 310009, China
| | - Daniel J Tozer
- Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Yutong Chen
- Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Robin B Brown
- Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Audrey Low
- Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Hugh S Markus
- Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK
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Cheng Y, Arteaga‐Reyes C, Clancy U, Garcia DJ, Valdés Hernández MDC, Thrippleton MJ, Stringer MS, Blair GW, Wiseman S, Chappell FM, Zhang J, Liu X, Jochems AC, Maniega SM, Sakka E, Bastin ME, Brown R, Loos CM, Makin SD, Liu M, Wu B, Doubal FN, Wardlaw JM. Clinical Relevance of 'Cap' and 'Track' Development after Recent Small Subcortical Infarct. Ann Neurol 2025; 97:942-955. [PMID: 39821913 PMCID: PMC12010063 DOI: 10.1002/ana.27182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 01/02/2025] [Accepted: 01/02/2025] [Indexed: 01/19/2025]
Abstract
OBJECTIVE After a recent small subcortical infarct (RSSI), some patients develop perilesional or remote hyperintensities ('caps/tracks') to the index infarct on T2/FLAIR MRI. However, their clinical relevance remains unclear. We investigated the clinicoradiological correlates of 'caps/tracks', and their impact on long-term outcomes following RSSI. METHODS We identified participants with lacunar stroke and MRI-confirmed RSSI from 3 prospective studies. At baseline, we collected risk factors, RSSI characteristics, small vessel disease (SVD) features, and microstructural integrity on diffusion imaging. Over 1-year, we repeated MRI and recorded 'caps/tracks' blinded to other data. We evaluated predictors of 'caps/tracks', and their association with 1-year functional (modified Rankin Scale score ≥2), mobility (Timed Up-and-Go), cognitive outcomes (Montreal Cognitive Assessment [MoCA] score <26), and recurrent cerebrovascular events (stroke/transient ischemic attack/incident infarct) using multivariable regression. RESULTS Among 185 participants, 93 (50.3%) developed 'caps/tracks' first detected at median 198 days after stroke. 'Caps/tracks' were independently predicted by baseline factors: larger RSSI, RSSI located in white matter, higher SVD score, and higher mean diffusivity in normal-appearing white matter (odds ratio [OR] [95% confidence interval {CI}], 1.15 [1.07-1.25], 6.01 [2.80-13.57], 1.77 [1.31-2.44], 1.42 [1.01-2.03]). At 1 year, 'cap/track' formation was associated with worse functional outcome (OR: 3.17, 95% CI: 1.28-8.22), slower gait speed (β: 0.13, 95% CI: 0.01-0.25), and recurrent cerebrovascular events (hazard ratio [HR]: 2.05, 95% CI: 1.05-4.02), but not with cognitive impairment. INTERPRETATION 'Caps/tracks' after RSSI are associated with worse clinical outcomes, and may reflect vulnerability to progressive SVD-related injury. Reducing 'caps/tracks' may offer early efficacy markers in trials aiming to improve outcome after lacunar stroke. ANN NEUROL 2025;97:942-955.
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Affiliation(s)
- Yajun Cheng
- Department of NeurologyWest China Hospital, Sichuan UniversityChengduChina
- Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute, University of EdinburghEdinburghUK
| | - Carmen Arteaga‐Reyes
- Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute, University of EdinburghEdinburghUK
| | - Una Clancy
- Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute, University of EdinburghEdinburghUK
| | - Daniela Jaime Garcia
- Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute, University of EdinburghEdinburghUK
| | - Maria Del C. Valdés Hernández
- Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute, University of EdinburghEdinburghUK
| | - Michael J. Thrippleton
- Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute, University of EdinburghEdinburghUK
| | - Michael S. Stringer
- Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute, University of EdinburghEdinburghUK
| | - Gordon W. Blair
- Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute, University of EdinburghEdinburghUK
| | - Stewart Wiseman
- Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute, University of EdinburghEdinburghUK
| | - Francesca M. Chappell
- Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute, University of EdinburghEdinburghUK
| | - Junfang Zhang
- Department of Neurology & Institute of NeurologyRuijin Hospital affiliated with Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xiaodi Liu
- Division of Neurology, Department of MedicineLKS Faculty of Medicine, The University of Hong KongHong KongChina
| | - Angela C.C. Jochems
- Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute, University of EdinburghEdinburghUK
| | - Susana Muñoz Maniega
- Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute, University of EdinburghEdinburghUK
| | - Eleni Sakka
- Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute, University of EdinburghEdinburghUK
| | - Mark E. Bastin
- Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute, University of EdinburghEdinburghUK
| | - Rosalind Brown
- Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute, University of EdinburghEdinburghUK
| | - Caroline M.J. Loos
- Department of NeurologyAntwerp University Hospital and Research Group on Translational NeuroSciences, Faculty of Medicine and Health Sciences, University of AntwerpAntwerpBelgium
| | - Stephen D.J. Makin
- Centre for Rural Health, Institute of Applied Health Sciences, University of AberdeenInvernessUK
| | - Ming Liu
- Department of NeurologyWest China Hospital, Sichuan UniversityChengduChina
| | - Bo Wu
- Department of NeurologyWest China Hospital, Sichuan UniversityChengduChina
| | - Fergus N. Doubal
- Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute, University of EdinburghEdinburghUK
| | - Joanna M. Wardlaw
- Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute, University of EdinburghEdinburghUK
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Kim SA, Kim EY, Wang SJ, Lee MJ. Beyond the "string of beads": case-based exploration of diagnostic pitfalls and solutions in reversible cerebral vasoconstriction syndrome. J Headache Pain 2025; 26:89. [PMID: 40289076 PMCID: PMC12036309 DOI: 10.1186/s10194-025-01978-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 11/29/2024] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND The diagnosis of reversible cerebral vasoconstriction syndrome (RCVS) is challenging due to its varied clinical manifestations and imaging findings. While it typically presents with a sudden, severe thunderclap headache and multifocal constriction of the cerebral arteries, the wide spectrum of radiological presentations may complicate the diagnosis. MAIN BODY This review presents a series of cases that show both typical and atypical presentations of RCVS. Typical cases show the characteristic "string of beads" pattern on angiography, which usually resolves within 3-6 months. However, diagnostic challenges arise when angiography appears normal in the early stages or when imaging artifacts obscure the findings. In addition, the variability in vasoconstriction patterns and the need for a differential diagnosis further complicate the accurate identification. These cases highlight the importance of considering RCVS in patients with recurrent thunderclap headaches, even when the initial imaging is inconclusive. Recognizing these challenges and the variability in presentation, along with the use of high-resolution vessel wall MRI and blood-brain barrier imaging, can improve diagnostic accuracy and improve patient outcomes. CONCLUSION The diagnosis of RCVS requires careful integration of clinical evaluation and advanced imaging techniques, with particular attention to radiological findings that can guide accurate diagnosis and management. Despite challenges, such as normal early stage angiography and imaging variability, maintaining a high suspicion of RCVS is essential, especially in patients with recurrent thunderclap headaches.
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Affiliation(s)
- Seung Ae Kim
- Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
- Graduate School of Translational Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Eung Yeop Kim
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Shuu-Jiun Wang
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
- College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Mi Ji Lee
- Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
- Graduate School of Translational Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
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Boutet A, Son HJ, Malik M, Haile S, Yang AZ, Pai V, Germann J, Mandell DM. Enlarging and shrinking focal perivascular spaces. Neuroradiol J 2025; 38:224-229. [PMID: 38565221 PMCID: PMC11571348 DOI: 10.1177/19714009241242642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2024] Open
Abstract
Background and PurposePerivascular spaces (PVS) are interstitial fluid-filled spaces surrounding blood vessels traversing the deep gray nuclei and white matter of the brain. These are commonly encountered on CT and MR imaging and are generally asymptomatic and of no clinical significance. However, occasional changes in the size of focal PVS, for example, when enlarging, may mimic pathologies including neoplasms and infections, hence potentially confounding radiological interpretation. Given these potential diagnostic issues, we sought to better characterize common clinical and imaging features of focal PVS demonstrating size fluctuations.Materials and MethodsUpon institutional approval, we retrospectively identified 4 cases demonstrating PVS with size changes at our institution. To supplement our cases, we also performed a literature review, which identified an additional 14 cases. Their clinical and imaging data were analyzed to identify characteristic features.ResultsOf the 18 total cases (including the 4 institutional cases), 10 cases increased and 8 decreased in size. These focal PVS ranged from 0.4-4.5 cm in size. Whereas a decrease in size did not represent a diagnostic issue, focal increase in size of PVS led to concerning differential diagnoses in at least 30% of the radiology reports. These enlarging PVS were most found in the basal ganglia and temporal lobe, and in patients with previous brain radiation treatment.ConclusionFocal size change of PVS can occur, especially years after brain radiation treatment. Being cognizant of this benign finding is important to consider in the differential diagnosis to avoid undue patient anxiety or unnecessary medical intervention.
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Affiliation(s)
- Alexandre Boutet
- Joint Department of Medical Imaging, University of Toronto, Canada
| | - Hyo Jin Son
- Temerty Faculty of Medicine, University of Toronto, Canada
| | - Mikail Malik
- Temerty Faculty of Medicine, University of Toronto, Canada
| | - Samuel Haile
- Temerty Faculty of Medicine, University of Toronto, Canada
| | - Andrew Z Yang
- Division of Neurosurgery, University of Toronto, Canada
| | - Vivek Pai
- Joint Department of Medical Imaging, University of Toronto, Canada
- Division of Neuroradiology, Department of Diagnostic Imaging, The Hospital for Sick Children, Canada
| | | | - Daniel M Mandell
- Joint Department of Medical Imaging, University of Toronto, Canada
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Alaqel SI, Imran M, Khan A, Nayeem N. Aging, vascular dysfunction, and the blood-brain barrier: unveiling the pathophysiology of stroke in older adults. Biogerontology 2025; 26:67. [PMID: 40044939 DOI: 10.1007/s10522-025-10209-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Accepted: 02/18/2025] [Indexed: 05/09/2025]
Abstract
The progressive decline of vascular integrity and blood-brain barrier (BBB) function is associated with aging, a major risk factor for stroke. This review describes the cellular and molecular changes in the brain microvasculature of the neurovascular unit (NVU) that contribute to the development of BBB dysfunction in aging, such as endothelial cell senescence, oxidative stress, and degradation of tight junction proteins. Stroke severity and recovery are exacerbated by BBB breakdown, leading to neuroinflammation, neurotoxicity, and cerebral oedema while identifying molecular mechanisms such as the NLRP3 inflammasome, matrix metalloproteinases (MMPs), and non-coding RNAs (e.g., miRNAs and circRNAs) that drive BBB disruption in aging and stroke. Real-time assessment of BBB permeability in stroke pathophysiology is made possible using advanced imaging techniques, such as dynamic contrast-enhanced MRI and positron emission tomography. Furthermore, biomarkers, including claudin-5, PDGFRβ, or albumin concentration, serve as markers of BBB integrity and vascular health. Restoration of BBB function and stroke recovery with emerging therapeutic strategies, including sirtuin modulators (SIRT1 and SIRT3 activators to enhance endothelial function and mitochondrial health), stem cell-derived extracellular vesicles (iPSC-sEVs for BBB repair and neuroprotection), NLRP3 inflammasome inhibitors (MCC950 to attenuate endothelial pyroptosis and inflammation), hydrogen-rich water therapy (to counteract oxidative stress-induced BBB damage), and neuropeptides such as cortistatin (to regulate neuroinflammation and BBB stability), is promising. This review explores the pathophysiological mechanisms of BBB dysfunction in aging and stroke, their relation to potential therapeutic targets, and novel approaches to improve vascular health and neuroprotection.
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Affiliation(s)
- Saleh I Alaqel
- Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, 91911, Rafha, Saudi Arabia.
- King Salman Center for Disability Research, 11614, Riyadh, Saudi Arabia.
| | - Mohd Imran
- Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, 91911, Rafha, Saudi Arabia
- Center For Health Research, Northern Border University, Arar, Saudi Arabia
| | - Abida Khan
- Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, 91911, Rafha, Saudi Arabia
- Center For Health Research, Northern Border University, Arar, Saudi Arabia
| | - Naira Nayeem
- Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, 91911, Rafha, Saudi Arabia
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Song H, Zhang S, Xie Q, Zhu Z, Li L, Zhao H. Compromised cerebrovascular reactivity related to presence of white matter hyperintensities in cryptogenic stroke with right-to-left shunts. J Stroke Cerebrovasc Dis 2025; 34:108223. [PMID: 39778666 DOI: 10.1016/j.jstrokecerebrovasdis.2025.108223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 12/11/2024] [Accepted: 01/01/2025] [Indexed: 01/11/2025] Open
Abstract
OBJECTIVE This study investigates cerebrovascular reactivity (CVR) changes in cryptogenic stroke (CS) patients with right-to-left shunts (RLS) and evaluates the relationship between CVR and white matter hyperintensities (WMHs). METHODS The breath-holding index (BHI), representing CVR, was measured from the middle cerebral artery (MCA) using the breath-holding method. WMHs were defined as clearly hyperintense areas on 3T magnetic resonance imaging (MRI), assessed separately as periventricular hyperintensities (PVH) and deep white matter hyperintensities (DWMH). RLS was diagnosed based on a contrast-enhanced transcranial Doppler (c-TCD) examination. RESULTS Among 260 CS patients and 128 controls, BHI was significantly lower in CS groups (0.68±0.27 vs. 0.83±0.31, P<0.001), particularly in those with RLS (0.64±0.28 vs. 0.71±0.25,P = 0.030). CS patients with WMHs exhibited lower BHI than those without WMHs (0.50±0.22 vs.0.60±0.35, P = 0.012), and PVH showed lower BHI compared to DWMH (0.45±0.24 vs.0.58±0.16, P = 0.003). A negative correlation was found between WMH severity and BHI (0.60±0.35 vs.0.51±0.21 vs.0.48±0.20 vs.0.38±0.28, P = 0.025). Reduced BHI was an independent risk factor for WMHs (OR = 0.283; 95 % CI = 0.081-0.995, P = 0.049). CONCLUSION CS patients, especially those with RLS, show reduced CVR, which correlates with the location and severity of WMHs. These findings suggest that RLS may significantly contribute to WMH development in CS patients.
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Affiliation(s)
- Huizhen Song
- Department of Neurology, The Third People's Hospital of Heze, Heze 274000, Shandong, PR China; Department of Neurology, The Affiliated Hospital of Qingdao Univeisity, Qingdao 266000, Shandong, PR China
| | - Shuang Zhang
- Department of Cardiology, Heze Traditional Chinese Medicine Hospital, Heze 274000, Shandong, PR China
| | - Qianqian Xie
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan 250000, Shandong, PR China
| | - Zhoujie Zhu
- Medical Department,The Third People's Hospital of Heze, Heze 274000, Shandong, PR China
| | - Linger Li
- Department of Neurology, The Affiliated Hospital of Qingdao Univeisity, Qingdao 266000, Shandong, PR China
| | - Hongqin Zhao
- Department of Neurology, The Affiliated Hospital of Qingdao Univeisity, Qingdao 266000, Shandong, PR China.
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Wu Q, Chen J, Yang X, Zhang X, He W, Xia J. Associations of ventriculomegaly and white matter hyperintensities with glymphatic dysfunction in idiopathic normal pressure hydrocephalus. Eur Radiol 2025:10.1007/s00330-024-11320-3. [PMID: 39836203 DOI: 10.1007/s00330-024-11320-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 10/26/2024] [Accepted: 11/28/2024] [Indexed: 01/22/2025]
Abstract
OBJECTIVES To investigate glymphatic function in idiopathic normal pressure hydrocephalus (iNPH) using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method and to explore the associations of ALPS index with ventriculomegaly and white matter hyperintensities (WMH). MATERIALS AND METHODS This study included 41 patients with iNPH and 40 age- and sex-matched normal controls (NCs). All participants underwent brain MRI. Based on DTI, we then calculated the ALPS index to obtain the water diffusivity along the perivascular space. Ventricular volume and WMH were also determined. Differences in the diffusivities and ALPS indexes between the iNPH and NC groups were investigated; associations of the DTI-ALPS index with ventriculomegaly and WMH were analysed. RESULTS Patients with iNPH had a lower ALPS index than NCs (p < 0.001). The ALPS index was significantly correlated with the normalised ventricular volume (r = -0.446, p = 0.004), but not with total WMH volume (r = -0.246, p = 0.126). Further regression analyses indicated that the reduced ALPS index was associated with increased ventricular volume (β = -7.158, p = 0.016), but not with normalised WMH volume (β = -2.796, p = 0.161). The receiver operating characteristic analysis demonstrated the ALPS index's excellent diagnostic performance for iNPH (the optimal cut-off point = 1.322; sensitivity, 100.0%; specificity, 87.5%; AUC = 0.980). CONCLUSIONS Patients with iNPH had a lower ALPS index, which may suggest impaired glymphatic function. This study demonstrated an association of DTI-ALPS index with ventriculomegaly, but not WMH in patients with iNPH. KEY POINTS Question Glymphatic dysfunction is crucial in idiopathic normal pressure hydrocephalus (iNPH) development, yet its associations with neuroimaging features remains unclear. Findings Diffusion tensor image analysis along the perivascular space (DTI-ALPS) revealed a reduced ALPS index in idiopathic normal pressure hydrocephalus, negatively correlating with ventricular volume. Clinical relevance DTI-ALPS enables non-invasive assessment of glymphatic function and its relationship with neuroimaging characteristics in idiopathic normal pressure hydrocephalus, facilitating the investigation of glymphatic dysfunction in iNPH pathophysiology.
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Affiliation(s)
- Qian Wu
- Department of Radiology, The First Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Jiakuan Chen
- Department of Radiology, South China Hospital, Medical School, Shenzhen University, Shenzhen, China
| | - Xiaolin Yang
- Longgang Central Hospital of Shenzhen, Shenzhen, China
| | - Xiejun Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Wenjie He
- Department of Radiology, The First Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.
| | - Jun Xia
- Department of Radiology, The First Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.
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Sasannia S, Leigh R, Bastani PB, Shin HG, van Zijl P, Knutsson L, Nyquist P. Blood-brain barrier breakdown in brain ischemia: Insights from MRI perfusion imaging. Neurotherapeutics 2025; 22:e00516. [PMID: 39709246 PMCID: PMC11840350 DOI: 10.1016/j.neurot.2024.e00516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 12/11/2024] [Accepted: 12/11/2024] [Indexed: 12/23/2024] Open
Abstract
Brain ischemia is a major cause of neurological dysfunction and mortality worldwide. It occurs not only acutely, such as in acute ischemic stroke (AIS), but also in chronic conditions like cerebral small vessel disease (cSVD). Any other conditions resulting in brain hypoperfusion can also lead to ischemia. Ischemic events can cause blood-brain barrier (BBB) disruption and, ultimately, white matter alterations, contributing to neurological deficits and long-term functional impairments. Hence, understanding the mechanisms of BBB breakdown and white matter injury across various ischemic conditions is critical for developing effective interventions and improving patient outcomes. This review discusses the proposed mechanisms of ischemia-related BBB breakdown. Moreover, magnetic resonance imaging (MRI) based perfusion-weighted imaging (PWI) techniques sensitive to BBB permeability changes are described, including dynamic contrast-enhanced (DCE-MRI) and dynamic susceptibility contrast MRI (DSC-MRI), two perfusion-weighted imaging (PWI). These PWI techniques provide valuable insights that improve our understanding of the complex early pathophysiology of brain ischemia, which can lead to better assessment and management. Finally, in this review, we explore the implications of the mentioned neuroimaging findings, which emphasize the potential of neuroimaging biomarkers to guide personalized treatment and inform novel neuroprotective strategies. This review highlights the importance of investigating BBB changes in brain ischemia and the critical role of advanced neuroimaging in improving patient care and advancing stroke research.
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Affiliation(s)
- Sarvin Sasannia
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States; F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, Baltimore, MD, United States.
| | - Richard Leigh
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
| | - Pouya B Bastani
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
| | - Hyeong-Geol Shin
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, Baltimore, MD, United States; Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
| | - Peter van Zijl
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, Baltimore, MD, United States; Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
| | - Linda Knutsson
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States; F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, Baltimore, MD, United States; Department of Medical Radiation Physics, Lund University, Lund, Sweden.
| | - Paul Nyquist
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Neurocritical Care Division, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, MD, United States; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
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10
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Hannawi Y. Cerebral Small Vessel Disease: a Review of the Pathophysiological Mechanisms. Transl Stroke Res 2024; 15:1050-1069. [PMID: 37864643 DOI: 10.1007/s12975-023-01195-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 06/02/2023] [Accepted: 09/18/2023] [Indexed: 10/23/2023]
Abstract
Cerebral small vessel disease (cSVD) refers to the age-dependent pathological processes involving the brain small vessels and leading to vascular cognitive impairment, intracerebral hemorrhage, and acute lacunar ischemic stroke. Despite the significant public health burden of cSVD, disease-specific therapeutics remain unavailable due to the incomplete understanding of the underlying pathophysiological mechanisms. Recent advances in neuroimaging acquisition and processing capabilities as well as findings from cSVD animal models have revealed critical roles of several age-dependent processes in cSVD pathogenesis including arterial stiffness, vascular oxidative stress, low-grade systemic inflammation, gut dysbiosis, and increased salt intake. These factors interact to cause a state of endothelial cell dysfunction impairing cerebral blood flow regulation and breaking the blood brain barrier. Neuroinflammation follows resulting in neuronal injury and cSVD clinical manifestations. Impairment of the cerebral waste clearance through the glymphatic system is another potential process that has been recently highlighted contributing to the cognitive decline. This review details these mechanisms and attempts to explain their complex interactions. In addition, the relevant knowledge gaps in cSVD mechanistic understanding are identified and a systematic approach to future translational and early phase clinical research is proposed in order to reveal new cSVD mechanisms and develop disease-specific therapeutics.
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Affiliation(s)
- Yousef Hannawi
- Division of Cerebrovascular Diseases and Neurocritical Care, Department of Neurology, The Ohio State University, 333 West 10th Ave, Graves Hall 3172C, Columbus, OH, 43210, USA.
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11
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Gulej R, Nyúl-Tóth Á, Csik B, Patai R, Petersen B, Negri S, Chandragiri SS, Shanmugarama S, Mukli P, Yabluchanskiy A, Conley S, Huffman D, Tarantini S, Csiszar A, Ungvari Z. Young blood-mediated cerebromicrovascular rejuvenation through heterochronic parabiosis: enhancing blood-brain barrier integrity and capillarization in the aged mouse brain. GeroScience 2024; 46:4415-4442. [PMID: 38727872 PMCID: PMC11336025 DOI: 10.1007/s11357-024-01154-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 04/05/2024] [Indexed: 06/15/2024] Open
Abstract
Age-related cerebromicrovascular changes, including blood-brain barrier (BBB) disruption and microvascular rarefaction, play a significant role in the development of vascular cognitive impairment (VCI) and neurodegenerative diseases. Utilizing the unique model of heterochronic parabiosis, which involves surgically joining young and old animals, we investigated the influence of systemic factors on these vascular changes. Our study employed heterochronic parabiosis to explore the effects of young and aged systemic environments on cerebromicrovascular aging in mice. We evaluated microvascular density and BBB integrity in parabiotic pairs equipped with chronic cranial windows, using intravital two-photon imaging techniques. Our results indicate that short-term exposure to young systemic factors leads to both functional and structural rejuvenation of cerebral microcirculation. Notably, we observed a marked decrease in capillary density and an increase in BBB permeability to fluorescent tracers in the cortices of aged mice undergoing isochronic parabiosis (20-month-old C57BL/6 mice [A-(A)]; 6 weeks of parabiosis), compared to young isochronic parabionts (6-month-old, [Y-(Y)]). However, aged heterochronic parabionts (A-(Y)) exposed to young blood exhibited a significant increase in cortical capillary density and restoration of BBB integrity. In contrast, young mice exposed to old blood from aged parabionts (Y-(A)) rapidly developed cerebromicrovascular aging traits, evidenced by reduced capillary density and increased BBB permeability. These findings underscore the profound impact of systemic factors in regulating cerebromicrovascular aging. The rejuvenation observed in the endothelium, following exposure to young blood, suggests the existence of anti-geronic elements that counteract microvascular aging. Conversely, pro-geronic factors in aged blood appear to accelerate cerebromicrovascular aging. Further research is needed to assess whether the rejuvenating effects of young blood factors could extend to other age-related cerebromicrovascular pathologies, such as microvascular amyloid deposition and increased microvascular fragility.
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Affiliation(s)
- Rafal Gulej
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Ádám Nyúl-Tóth
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary
| | - Boglarka Csik
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary
| | - Roland Patai
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary
| | - Benjamin Petersen
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Sharon Negri
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Siva Sai Chandragiri
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Santny Shanmugarama
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Peter Mukli
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary
| | - Andriy Yabluchanskiy
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA
| | - Shannon Conley
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Derek Huffman
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Stefano Tarantini
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA
| | - Anna Csiszar
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Zoltan Ungvari
- Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary.
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA.
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12
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van Dinther M, Voorter PHM, Zhang E, van Kuijk SMJ, Jansen JFA, van Oostenbrugge RJ, Backes WH, Staals J. The neurovascular unit and its correlation with cognitive performance in patients with cerebral small vessel disease: a canonical correlation analysis approach. GeroScience 2024; 46:5061-5073. [PMID: 38888875 PMCID: PMC11335703 DOI: 10.1007/s11357-024-01235-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 05/31/2024] [Indexed: 06/20/2024] Open
Abstract
Growing evidence indicates an important role of neurovascular unit (NVU) dysfunction in the pathophysiology of cerebral small vessel disease (cSVD). Individually measurable functions of the NVU have been correlated with cognitive function, but a combined analysis is lacking. We aimed to perform a unified analysis of NVU function and its relation with cognitive performance. The relationship between NVU function in the white matter and cognitive performance (both latent variables composed of multiple measurable variables) was investigated in 73 patients with cSVD (mean age 70 ± 10 years, 41% women) using canonical correlation analysis. MRI-based NVU function measures included (1) the intravoxel incoherent motion derived perfusion volume fraction (f) and microvascular diffusivity (D*), reflecting cerebral microvascular flow; (2) the IVIM derived intermediate volume fraction (fint), indicative of the perivascular clearance system; and (3) the dynamic contrast-enhanced MRI derived blood-brain barrier (BBB) leakage rate (Ki) and leakage volume fraction (VL), reflecting BBB integrity. Cognitive performance was composed of 13 cognitive test scores. Canonical correlation analysis revealed a strong correlation between the latent variables NVU function and cognitive performance (r 0.73; p = 0.02). For the NVU, the dominating variables were D*, fint, and Ki. Cognitive performance was driven by multiple cognitive tests comprising different cognitive domains. The functionality of the NVU is correlated with cognitive performance in cSVD. Instead of focusing on individual pathophysiological mechanisms, future studies should target NVU dysfunction as a whole to acquire a coherent understanding of the complex disease mechanisms that occur in the NVU in cSVD.Trial registration: NTR3786 (Dutch Trial Register).
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Affiliation(s)
- Maud van Dinther
- Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.
- CARIM-School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.
| | - Paulien H M Voorter
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- MHeNs-School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands
| | - Eleana Zhang
- Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Sander M J van Kuijk
- Department of Epidemiology and Medical Technology Assessment (KEMTA), Maastricht University, Maastricht, the Netherlands
| | - Jacobus F A Jansen
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- MHeNs-School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands
| | - Robert J van Oostenbrugge
- Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands
- CARIM-School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands
- MHeNs-School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands
| | - Walter H Backes
- CARIM-School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- MHeNs-School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands
| | - Julie Staals
- Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands
- CARIM-School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands
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13
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Clancy U, Arteaga-Reyes C, Jaime Garcia D, Hewins W, Locherty R, Valdés Hernández MDC, Wiseman SJ, Stringer MS, Thrippleton M, Chappell FM, Jochems ACC, Liu X, Cheng Y, Zhang J, Rudilosso S, Kampaite A, Hamilton OKL, Brown R, Bastin ME, Muñoz Maniega S, Hamilton I, Job D, Doubal FN, Wardlaw JM. Incident Infarcts in Patients With Stroke and Cerebral Small Vessel Disease: Frequency and Relation to Clinical Outcomes. Neurology 2024; 103:e209750. [PMID: 39159417 PMCID: PMC11361828 DOI: 10.1212/wnl.0000000000209750] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 06/25/2024] [Indexed: 08/21/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Factors associated with cerebral small vessel disease (SVD) progression, including incident infarcts, are unclear. We aimed to determine the frequency of incident infarcts over 1 year after minor stroke and their relation to baseline SVD burden, vascular risks, and recurrent stroke and cognitive outcomes. METHODS We recruited patients with lacunar or nondisabling cortical stroke. After diagnostic imaging, we repeated structural MRI at 3-6 monthly intervals for 12 months, visually assessing incident infarcts on diffusion-weighted imaging or FLAIR. We used logistic regression to determine associations of baseline vascular risks, SVD score, and index stroke subtype with subsequent incident infarcts. We assessed cognitive and functional outcomes at 1 year using Montreal Cognitive Assessment (MoCA) and modified Rankin scale (mRS), adjusting for baseline age, mRS, MoCA, premorbid intelligence, and SVD score. RESULTS We recruited 229 participants, mean age 65.9 (SD 11.1). Over half of all participants, 131 of 229 (57.2%) had had an index lacunar stroke. From baseline to 1-year MRI, we detected 117 incident infarcts in n = 57/229 (24.8%) participants. Incident infarcts were mainly of the small subcortical (86/117 [73.5%] in n = 38/57 [66.7%]) vs cortical infarct subtype (n = 19/57 [33.3%]). N = 39/57 participants had incident infarcts at 1 visit; 18 of 57 at 2 or more visits; and 19 of 57 participants had multiple infarcts at a single visit. Only 7 of 117 incident infarcts corresponded temporally to clinical stroke syndromes. The baseline SVD score was the strongest predictor of incident infarcts (adjusted odds ratio [OR] 1.87, 95% CI 1.39-2.58), while mean arterial pressure was not associated. All participants with incident infarcts were prescribed an antiplatelet or anticoagulant. Lower 1-year MoCA was associated with lower baseline MoCA (β 0.47, 95% CI 0.33-0.61), lower premorbid intelligence, and older age. Higher 1-year mRS was associated with higher baseline mRS only (OR 5.57 [3.52-9.10]). Neither outcome was associated with incident infarcts. DISCUSSION In the year after stroke in a population enriched for lacunar stroke, incident infarcts occurred in one-quarter and were associated with worse baseline SVD. Most incident infarcts detected on imaging did not correspond to clinical stroke/transient ischemic attack. Worse 1-year cognition and function were not associated with incident infarcts.
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Affiliation(s)
- Una Clancy
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Carmen Arteaga-Reyes
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Daniela Jaime Garcia
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Will Hewins
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Rachel Locherty
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Maria Del C Valdés Hernández
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Stewart J Wiseman
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Michael S Stringer
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Michael Thrippleton
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Francesca M Chappell
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Angela C C Jochems
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Xiaodi Liu
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Yajun Cheng
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Junfang Zhang
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Salvatore Rudilosso
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Agniete Kampaite
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Olivia K L Hamilton
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Rosalind Brown
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Mark E Bastin
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Susana Muñoz Maniega
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Iona Hamilton
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Dominic Job
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Fergus N Doubal
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
| | - Joanna M Wardlaw
- From the Row Fogo Centre for Research into Ageing and the Brain, Centre for Clinical Brain Sciences, and UK Dementia Research Institute (U.C., C.A.-R., D.J.G., W.H., R.L., M.D.C.V.H., S.J.W., M.S.S., M.T., F.M.C., A.C.C.J., A.K., O.K.L.H., R.B., M.E.B., S.M.M., I.H., D.J., F.N.D., J.M.W.), University of Edinburgh; Division of Neurology (X.L.), Department of Medicine, The University of Hong Kong; Department of Neurology (Y.C.), West China Hospital, Sichuan University, Chengdu, China; Department of Neurology (J.Z.), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China; Comprehensive Stroke Center (S.R.), Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi i Sunyer Biomedical Research Institute, Spain; and MRC/CSO Social and Public Health Sciences Unit (O.K.L.H.), School of Health and Wellbeing, University of Glasgow, United Kingdom
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14
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Mena Romo L, Mengual JJ, Avellaneda-Gómez C, García-Sánchez SM, Font MÀ, Montull C, Castrillo L, Lleixa M, Bargalló N, Laredo C, Amaro S, Armario P, Gómez-Choco M. Association between blood-brain barrier permeability and changes in pulse wave velocity following a recent small subcortical infarct. Hypertens Res 2024; 47:2495-2502. [PMID: 38942814 DOI: 10.1038/s41440-024-01764-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 03/27/2024] [Accepted: 06/04/2024] [Indexed: 06/30/2024]
Abstract
Cerebral small vessel disease (cSVD) is associated with increased blood-brain barrier (BBB) permeability. We sought to evaluate whether arterial stiffness might be associated with BBB permeability in patients with cSVD. We assessed BBB permeability using Dynamic Contrast-Enhanced MRI (DCE-MRI) in 29 patients that had suffered a recent small subcortical infarct (RSSI). BBB permeability in the whole brain (WB), gray matter (GM) and white matter (WM) was assessed with the parameter Ktrans. We used ambulatory blood pressure monitoring to measure 24-h systolic blood pressure (24-h SBP), diastolic blood pressure (24-h DBP), and pulse wave velocity (24-h PWV) both after stroke and following a 2-year follow-up. The differences between both measurements were calculated as Δ24-h SBP, Δ24-h DBP and Δ24-h PWV. DCE-MRI was acquired at a median (IQR) of 24 (19-27) months after stroke. Median age was 66.7 (9.7) years, and 24 (83%) patients were men. Median (IQR) Δ24-h PWV was 0.3 (-0.1, 0.5) m/s. WB-Ktrans, GM-Ktrans, and WM-Ktrans were associated with Δ24-h PWV (Spearman's, r [95% CI], WB 0.651 [0.363-0.839]; GM 0.657 [0.373-0.845], WM 0.530[0.197-0.777]) but not with Δ24-h SBP or Δ24-h DBP. These associations remained significant after adjustment with linear regression models, controlling for age, sex, body mass index, and Δ24-h SBP (b[95% CI], WB 0.725[0.384-1.127], GM 0.629 [0.316-1.369], WM 0.865 [0.455-0.892]) or Δ24-h DBP (b[95% CI], WM 0.707 [0.370-1.103], GM 0.643 [0.352-1.371], WM 0.772 [0.367-0.834]). Our results suggest that an increment on arterial stiffness in the months following a RSSI might increase BBB permeability.
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Affiliation(s)
- Luis Mena Romo
- Neurology Department, Complex Hospitalari Universitari Moisès Broggi, Sant Joan Despí, Spain
| | - Juan José Mengual
- Neurology Department, Complex Hospitalari Universitari Moisès Broggi, Sant Joan Despí, Spain
| | - Carla Avellaneda-Gómez
- Neurology Department, Complex Hospitalari Universitari Moisès Broggi, Sant Joan Despí, Spain
| | - Sonia María García-Sánchez
- Neurology Department, Complex Hospitalari Universitari Moisès Broggi, Sant Joan Despí, Spain
- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Spain
| | | | - Caterina Montull
- Radiology Department, Complex Hospitalari Universitari Moisès Broggi, Sant Joan Despí, Spain
| | - Laura Castrillo
- Radiology Department, Complex Hospitalari Universitari Moisès Broggi, Sant Joan Despí, Spain
| | - Mercè Lleixa
- Neurology Department, Complex Hospitalari Universitari Moisès Broggi, Sant Joan Despí, Spain
| | - Nuria Bargalló
- Radiology Department CDIC, Neuroradiology section, Hospital Clínic de Barcelona., Barcelona, Spain
| | - Carlos Laredo
- Magnetic Resonance Imaging Core Facility, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Sergio Amaro
- Comprehensive Stroke Center, Institute of Neuroscience, Hospital Clínic de Barcelona, Barcelona, Spain
- Neurociéncies Clíniques i Experimentals, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Pedro Armario
- Internal Medicine Department, Complex Hospitalari Universitari Moisès Broggi, Sant Joan Despí, Spain
- Universitat de Barcelona, Barcelona, Spain
| | - Manuel Gómez-Choco
- Neurology Department, Complex Hospitalari Universitari Moisès Broggi, Sant Joan Despí, Spain.
- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Spain.
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15
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Gibbon S, Low A, Hamid C, Reid‐Schachter M, Muniz‐Terrera G, Ritchie CW, Trucco E, Dhillon B, O'Brien JT, MacGillivray TJ. Association of optic disc pallor and RNFL thickness with cerebral small vessel disease in the PREVENT-Dementia study. ALZHEIMER'S & DEMENTIA (AMSTERDAM, NETHERLANDS) 2024; 16:e12633. [PMID: 39119001 PMCID: PMC11307169 DOI: 10.1002/dad2.12633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 07/05/2024] [Accepted: 07/16/2024] [Indexed: 08/10/2024]
Abstract
INTRODUCTION We tested associations between two retinal measures (optic disc pallor, peripapillary retinal nerve fiber layer [pRNFL] thickness) and four magnetic resonance imaging markers of cerebral small vessel disease (SVD; lacunes, microbleeds, white matter hyperintensities, and enlarged perivascular spaces [ePVSs]). METHODS We used PallorMetrics to quantify optic disc pallor from fundus photographs, and pRNFL thickness from optical coherence tomography scans. Linear and logistic regression assessed relationships between retinal measures and SVD markers. Participants (N = 108, mean age 51.6) were from the PREVENT Dementia study. RESULTS Global optic disc pallor was linked to ePVSs in the basal ganglia in both left (β = 0.12, standard error [SE] = 0.05, P < 0.05) and right eyes (β = 0.13, SE = 0.05, P < 0.05). Associations were also noted in different disc sectors. No pRNFL associations with SVD markers were found. DISCUSSION Optic disc pallor correlated with ePVSs in the basal ganglia, suggesting retinal examination may be a useful method to study brain health changes related to SVD. Highlights Optic disc pallor is linked to enlarged perivascular spaces in basal ganglia.There is no association between peripapillary retinal nerve fiber layer thickness and cerebral small vessel disease markers.Optic disc examination could provide insights into brain health.The sample included 108 midlife adults from the PREVENT Dementia study.
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Affiliation(s)
- Samuel Gibbon
- Centre for Clinical Brain SciencesChancellor's BuildingEdinburghUK
- Robert O Curle Ophthalmology SuiteInstitute for Regeneration and RepairEdinburghUK
| | - Audrey Low
- Department of PsychiatrySchool of Clinical MedicineUniversity of CambridgeCambridgeUK
| | - Charlene Hamid
- Centre for Clinical Brain SciencesChancellor's BuildingEdinburghUK
- Robert O Curle Ophthalmology SuiteInstitute for Regeneration and RepairEdinburghUK
| | - Megan Reid‐Schachter
- Centre for Clinical Brain SciencesChancellor's BuildingEdinburghUK
- Robert O Curle Ophthalmology SuiteInstitute for Regeneration and RepairEdinburghUK
| | | | - Craig W. Ritchie
- Centre for Clinical Brain SciencesChancellor's BuildingEdinburghUK
| | - Emanuele Trucco
- VAMPIRE project, Computing (SSEN)University of DundeeQueen Mother BuildingDundeeUK
| | - Baljean Dhillon
- Centre for Clinical Brain SciencesChancellor's BuildingEdinburghUK
- Robert O Curle Ophthalmology SuiteInstitute for Regeneration and RepairEdinburghUK
- Princess Alexandra Eye PavilionEdinburghUK
| | - John T. O'Brien
- Department of PsychiatrySchool of Clinical MedicineUniversity of CambridgeCambridgeUK
| | - Thomas J. MacGillivray
- Centre for Clinical Brain SciencesChancellor's BuildingEdinburghUK
- Robert O Curle Ophthalmology SuiteInstitute for Regeneration and RepairEdinburghUK
- Edinburgh ImagingThe Queen's Medical Research InstituteUniversity of EdinburghEdinburghUK
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16
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Dupré N, Drieu A, Joutel A. Pathophysiology of cerebral small vessel disease: a journey through recent discoveries. J Clin Invest 2024; 134:e172841. [PMID: 38747292 PMCID: PMC11093606 DOI: 10.1172/jci172841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2024] Open
Abstract
Cerebral small vessel disease (cSVD) encompasses a heterogeneous group of age-related small vessel pathologies that affect multiple regions. Disease manifestations range from lesions incidentally detected on neuroimaging (white matter hyperintensities, small deep infarcts, microbleeds, or enlarged perivascular spaces) to severe disability and cognitive impairment. cSVD accounts for approximately 25% of ischemic strokes and the vast majority of spontaneous intracerebral hemorrhage and is also the most important vascular contributor to dementia. Despite its high prevalence and potentially long therapeutic window, there are still no mechanism-based treatments. Here, we provide an overview of the recent advances in this field. We summarize recent data highlighting the remarkable continuum between monogenic and multifactorial cSVDs involving NOTCH3, HTRA1, and COL4A1/A2 genes. Taking a vessel-centric view, we discuss possible cause-and-effect relationships between risk factors, structural and functional vessel changes, and disease manifestations, underscoring some major knowledge gaps. Although endothelial dysfunction is rightly considered a central feature of cSVD, the contributions of smooth muscle cells, pericytes, and other perivascular cells warrant continued investigation.
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Affiliation(s)
- Nicolas Dupré
- Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Paris, France
| | - Antoine Drieu
- Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Paris, France
| | - Anne Joutel
- Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Paris, France
- GHU-Paris Psychiatrie et Neurosciences, Hôpital Sainte Anne, Paris, France
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17
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Huang H, Liao X, Zhang A, Qiu B, Mei F, Liu F, Zeng K, Yang C, Ma H, Ding W, Qi S, Bao Y. Cerebrospinal Fluid from Patients After Craniotomy with the Appearance of Interleukin-6 Storm Can Activate Microglia to Damage the Hypothalamic Neurons in Mice. Mol Neurobiol 2024; 61:2707-2718. [PMID: 37924484 DOI: 10.1007/s12035-023-03693-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 10/04/2023] [Indexed: 11/06/2023]
Abstract
We monitored CSF (cerebrospinal fluid) for Th1/Th2 inflammatory cytokines in a patient with unexplained postoperative disturbance of consciousness after craniotomy and found that the level of IL-6 (interleukin-6) concentrations was extremely high, meeting the traditional criteria for an inflammatory cytokine storm. Subsequently, the cerebrospinal fluid specimens of several patients were tested, and it was found that IL-6 levels were increased in different degrees after craniotomy. Previous studies have focused more on mild and long-term IL-6 elevation, but less on the effects of this short-term IL-6 inflammatory cytokine storm. Cerebrospinal fluid rich in IL-6 may play a significant role in patients after craniotomy. The objective is to explore the degree of IL-6 elevation and the incidence of IL-6 inflammatory cytokine storm in patients after craniotomy, as well as the effect of IL-6 elevation on the brain. In this study, the levels and clinical manifestations of inflammatory factors in cerebrospinal fluid after craniotomy were statistically classified, and the underlying mechanisms were discussed preliminarily. CSF specimens of patients after craniotomy were collected, IL-6 level was measured at 1, 5, and 10 days after operation, and cognitive function was analyzed at 1, 10, and 180 days after surgery. Craniotomy mouse model, cerebrospinal fluid of patients with the appearance of IL-6 storm after craniotomy, and IL-6 at the same concentration stimulation model were established. Behavioral tests, fluorescence in situ hybridization (FISH), pathological means, western blot, and ELISA (enzyme-linked immune-sorbent assay) were performed for verification. CSF from patients after craniotomy caused disturbance of consciousness in mice, affected neuronal damage in the hypothalamus, activation of microglia in the hypothalamus, and decreased expression of barrier proteins in the hypothalamus and brain. The large amount of interleukin-6 in CSF after craniotomy was found to be mainly derived from astrocytes. The IL-6 level in CSF after craniotomy correlated inversely with patients' performance in MoCA test. High levels of IL-6 in the cerebrospinal fluid derived from astrocytes after craniotomy may lead to disruption of the brain-cerebrospinal fluid barrier, most notably around the hypothalamus, which might result in inflammatory activation of microglia to damage the hypothalamic neurons and impaired cognitive function/more gradual cognitive repairment in patients after craniotomy with the appearance of IL-6 storm.
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Affiliation(s)
- Haorun Huang
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China
| | - Xixian Liao
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China
| | - An Zhang
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China
| | - Binghui Qiu
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China
| | - Fen Mei
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China
| | - Fan Liu
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China
| | - Kai Zeng
- The First Clinical College, Southern Medical University, Guangzhou City, Guangdong Province, China
| | - Chunen Yang
- The First Clinical College, Southern Medical University, Guangzhou City, Guangdong Province, China
| | - Haidie Ma
- The First Clinical College, Southern Medical University, Guangzhou City, Guangdong Province, China
| | - Wenjie Ding
- The First Clinical College, Southern Medical University, Guangzhou City, Guangdong Province, China
| | - Songtao Qi
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China.
| | - Yun Bao
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China.
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Cougo P, Colares H, Farinhas JG, Hämmerle M, Neves P, Bezerra R, Balduino A, Wu O, Pontes-Neto OM. Subtle white matter intensity changes on fluid-attenuated inversion recovery imaging in patients with ischaemic stroke. Brain Commun 2024; 6:fcae089. [PMID: 38529359 PMCID: PMC10963121 DOI: 10.1093/braincomms/fcae089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 01/12/2024] [Accepted: 03/11/2024] [Indexed: 03/27/2024] Open
Abstract
Leukoaraiosis is a neuroimaging marker of small-vessel disease that is characterized by high signal intensity on fluid-attenuated inversion recovery MRI. There is increasing evidence from pathology and neuroimaging suggesting that the structural abnormalities that characterize leukoaraiosis are actually present within regions of normal-appearing white matter, and that the underlying pathophysiology of white matter damage related to small-vessel disease involves blood-brain barrier damage. In this study, we aim to verify whether leukoaraiosis is associated with elevated signal intensity on fluid-attenuated inversion recovery imaging, a marker of brain tissue free-water accumulation, in normal-appearing white matter. We performed a cross-sectional study of adult patients admitted to our hospital with a diagnosis of acute ischaemic stroke or transient ischaemic attack. Leukoaraiosis was segmented using a semi-automated method involving manual outlining and signal thresholding. White matter regions were segmented based on the probabilistic tissue maps from the International Consortium for Brain Mapping 152 atlas. Also, normal-appearing white matter was further segmented based on voxel distance from leukoaraiosis borders, resulting in five normal-appearing white matter strata at increasing voxel distances from leukoaraiosis. The relationship between mean normalized fluid-attenuated inversion recovery signal intensity on normal-appearing white matter and leukoaraiosis volume was studied in a multivariable statistical analysis using linear mixed modelling, having normal-appearing white matter strata as a clustering variable. One hundred consecutive patients meeting inclusion and exclusion criteria were selected for analysis (53% female, mean age 68 years). Mean normalized fluid-attenuated inversion recovery signal intensity on normal-appearing white matter was higher in the vicinity of leukoaraiosis and progressively lower at increasing distances from leukoaraiosis. In a multivariable analysis, the mean normalized fluid-attenuated inversion recovery signal intensity on normal-appearing white matter was positively associated with leukoaraiosis volume and age (B = 0.025 for each leukoaraiosis quartile increase; 95% confidence interval 0.019-0.030). This association was found similarly across normal-appearing white matter strata. Voxel maps of the mean normalized fluid-attenuated inversion recovery signal intensity on normal-appearing white matter showed an increase in signal intensity that was not adjacent to leukoaraiosis regions. Our results show that normal-appearing white matter exhibits subtle signal intensity changes on fluid-attenuated inversion recovery imaging that are related to leukoaraiosis burden. These results suggest that diffuse free-water accumulation is likely related to the aetiopathogenic processes underlying the development of white matter damage related to small-vessel disease.
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Affiliation(s)
- Pedro Cougo
- Instituto Americas, Neurology Division, Rio de Janeiro 22775-001, Brazil
- Hospital Samaritano Barra, Department of Neurology, Rio de Janeiro 22775-001, Brazil
| | - Heber Colares
- Hospital Samaritano Barra, Department of Radiology, Rio de Janeiro, 22775-001, Brazil
| | - João Gabriel Farinhas
- Instituto Americas, Neurology Division, Rio de Janeiro 22775-001, Brazil
- Hospital Samaritano Barra, Department of Neurology, Rio de Janeiro 22775-001, Brazil
| | - Mariana Hämmerle
- Hospital Samaritano Barra, Department of Neurology, Rio de Janeiro 22775-001, Brazil
| | - Pedro Neves
- Hospital Samaritano Barra, Department of Radiology, Rio de Janeiro, 22775-001, Brazil
| | - Raquel Bezerra
- Hospital Samaritano Barra, Department of Radiology, Rio de Janeiro, 22775-001, Brazil
| | - Alex Balduino
- Instituto Americas, Neurology Division, Rio de Janeiro 22775-001, Brazil
| | - Ona Wu
- Athinoula A. Martinos Centre for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA 02129, USA
| | - Octavio M Pontes-Neto
- Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto 14040-900, Brazil
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19
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Akhtar N, Singh R, Kamran S, Joseph S, Morgan D, Uy RT, Treit S, Shuaib A. Association between serum triglycerides and stroke type, severity, and prognosis. Analysis in 6558 patients. BMC Neurol 2024; 24:88. [PMID: 38443844 PMCID: PMC10913234 DOI: 10.1186/s12883-024-03572-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 02/15/2024] [Indexed: 03/07/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Hypertriglyceridemia (HT) may increase the risk of stroke. Limited studies have shown that stroke severity and infarction size are smaller in patients with HT. We explored the relationship between triglyceride levels and stroke risk factors, severity and outcome in a large prospective database. DESIGN Prospective Cross-sectional study. SETTING We retrospectively interrogated the Qatar Stroke Database in all patients admitted between 2014-2022 with acute ischemic stroke and evaluated the relationship between triglyceride, diabetes, stroke severity (measured on NIHSS), stroke type (TOAST classification) and the short- (mRS at 90 days) and long-term outcomes (MACE at 1 year) in patients with HT. PARTICIPANTS Six thousand five hundred fifty-eight patients ≥20 years were included in this study RESULTS: Six thousand five hundred fifty-eight patients with ischemic stroke [mean age 54.6 ± 12. 9; male 82.1%) were included. Triglyceride levels upon admission were low-normal (≤1.1 mmol/L) in 2019 patients, high-normal (1.2-1.7 mmol/L) in 2142 patients, borderline-high (1.8-2.2 mmol/L) in 1072 patients and high (≥2.3 mmol/L) in 1325 patients. Higher triglyceride levels were associated with stroke and increased likelihood of having diabetes, obesity, active smoking, and small vessel/lacunar stroke type. An inverse relationship was noted whereby higher triglyceride levels were associated with lower stroke severity and reduced likelihood of poorer outcome (mRS 3-6) at discharge and 90 days. Long-term MACE events were less frequent in patients with higher triglyceride levels. After adjusting age, gender, diabetes, prior stroke, CAD, and obesity, multivariate analysis showed that hypertension and triglyceride levels were higher in mild ischemic strokes patients. CONCLUSIONS Increasing triglycerides are associated with higher risk of small vessel disease and requires further prospective cohort studies for confirmation.
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Affiliation(s)
- Naveed Akhtar
- Hamad Medical Corporation, Neurology, North Tower, Doha, Qatar
| | - Rajvir Singh
- Hamad Medical Corporation, Neurology, North Tower, Doha, Qatar
| | - Saadat Kamran
- Hamad Medical Corporation, Neurology, North Tower, Doha, Qatar
| | - Sujatha Joseph
- Hamad Medical Corporation, Neurology, North Tower, Doha, Qatar
| | - Deborah Morgan
- Hamad Medical Corporation, Neurology, North Tower, Doha, Qatar
| | - Ryan Ty Uy
- Hamad Medical Corporation, Neurology, North Tower, Doha, Qatar
| | - Sarah Treit
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Ashfaq Shuaib
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
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20
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Tian Y, Wang M, Pan Y, Meng X, Zhao X, Liu L, Wang Y, Wang Y. In patients who had a stroke or TIA, enlarged perivascular spaces in basal ganglia may cause future haemorrhagic strokes. Stroke Vasc Neurol 2024; 9:8-17. [PMID: 37188388 PMCID: PMC10956113 DOI: 10.1136/svn-2022-002157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 03/10/2023] [Indexed: 05/17/2023] Open
Abstract
INTRODUCTION It remains unclear whether enlarged perivascular spaces (EPVS) predict poor clinical outcomes in patients with acute ischaemic stroke (AIS) or transient ischaemic attack (TIA). METHOD Data were obtained from the Third China National Stroke Registry study. We estimated EPVS in basal ganglia (BG) and centrum semiovale (CSO) using a semiquantified scale (Grade from 0 to 4). Using Cox and logistic regression analyses, the associations of EPVS with 3-month and 1-year adverse outcomes (including recurrent stroke, ischaemic stroke, haemorrhagic stroke, combined vascular event, disability and mortality) were explored. Sensitivity analyses of any association of cerebral small vessel disease at baseline and development of a small arterial occlusion (SAO) were conducted. RESULT Among 12 603 patients with AIS/TIA, median age was 61.7±11.6 years, and 68.2% were men. After adjusting for all potential confounders, frequent-to-severe BG-EPVS was associated with a decreased risk of recurrent ischaemic stroke (HR 0.71, 95% CI 0.55 to 0.92, p=0.01) but an increased risk of haemorrhagic stroke (HR 1.99, 95% CI 1.11 to 3.58, p=0.02) at 1 year after AIS/TIA, compared with none-to-mild BG-EPVS. Patients with frequent-to-severe CSO-EPVS had a decreased risk of disability (OR 0.76, 95% CI 0.62 to 0.92, p=0.004) and all-cause death (HR 0.55, 95% CI 0.31 to 0.98, p=0.04) within 3-month but not 1-year follow-ups, compared with those with none-to-mild BG-EPVS. Sensitivity analyses showed that both BG-EPVS (HR 0.43, 95% CI 0.21 to 0.87, p=0.02) and CSO-EPVS (HR 0.58, 95% CI 0.35 to 0.95, p=0.03) were associated with a decreased risk of subsequent ischaemic stroke in patients with SAO during 1-year follow-up. CONCLUSION BG-EPVS increased the risk of haemorrhagic stroke in patients already with AIS/TIA within 1 year. Therefore, caution is recommended when selecting antithrombotic agents for secondary stroke prevention in patients with AIS/TIA and more severe BG-EPVS.
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Affiliation(s)
- Yu Tian
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Chinese Institute for Brain Research, Beijing, China
- National Center for Neurological Diseases, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Mengxing Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Chinese Institute for Brain Research, Beijing, China
- National Center for Neurological Diseases, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Yuesong Pan
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Chinese Institute for Brain Research, Beijing, China
- National Center for Neurological Diseases, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Xia Meng
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Chinese Institute for Brain Research, Beijing, China
- National Center for Neurological Diseases, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Xingquan Zhao
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Chinese Institute for Brain Research, Beijing, China
- National Center for Neurological Diseases, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Liping Liu
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Chinese Institute for Brain Research, Beijing, China
- National Center for Neurological Diseases, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Yongjun Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Chinese Institute for Brain Research, Beijing, China
- National Center for Neurological Diseases, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Yilong Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Chinese Institute for Brain Research, Beijing, China
- National Center for Neurological Diseases, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
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21
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Low A, van Winden S, Cai L, Kessels RPC, Maas MC, Morris RG, Nus M, Tozer DJ, Tuladhar A, van der Kolk A, Wolters R, Mallat Z, Riksen NP, Markus H, de Leeuw FE. Immune regulation and blood-brain barrier permeability in cerebral small vessel disease: study protocol of the INflammation and Small Vessel Disease (INSVD) study - a multicentre prospective cohort study. BMJ Open 2024; 14:e084303. [PMID: 38413153 PMCID: PMC10900331 DOI: 10.1136/bmjopen-2024-084303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 02/12/2024] [Indexed: 02/29/2024] Open
Abstract
INTRODUCTION The INflammation and Small Vessel Disease (INSVD) study aims to investigate whether peripheral inflammation, immune (dys)regulation and blood-brain barrier (BBB) permeability relate to disease progression in cerebral small vessel disease (SVD). This research aims to pinpoint specific components of the immune response in SVD relating to disease progression. This could identify biomarkers of SVD progression, as well as potential therapeutic targets to inform the development and repurposing of drugs to reduce or prevent SVD, cognitive decline and vascular dementia. METHODS AND ANALYSIS INSVD is a prospective observational multicentre cohort study in individuals with symptomatic SVD. This longitudinal study combines comprehensive immunophenotyping of the peripheral blood immune compartment with advanced neuroimaging markers of SVD and BBB permeability. The main SVD marker of interest is white matter microstructure as determined by diffusion tensor imaging, a valuable marker of disease progression owing to its sensitivity to early alterations to white matter integrity. The research is being conducted in two sites-in the UK (Cambridge) and the Netherlands (Nijmegen)-with each site recruiting 100 participants (total n=200). Participants undergo clinical and cognitive assessments, blood draws, and brain MRI at baseline and 2-year follow-up. ETHICS AND DISSEMINATION This study received ethical approval from the local ethics boards (UK: East of England-Cambridge Central Research Ethics Committee (REC) ref: 22/EE/00141, Integrated Research Application System (IRAS) ID: 312 747. Netherlands: Medical Research Ethics Committee (MREC) Oost-Nederland, ref: 2022-13623, NL-number: NL80258.091.22). Written informed consent was obtained from all subjects before the study. Any participant-derived benefits resulting from this research, such as new insights into disease mechanisms or possible novel therapies, will be disseminated to study participants, patient groups and members of the public. TRIAL REGISTRATION NUMBER NCT05746221.
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Affiliation(s)
- Audrey Low
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Sanne van Winden
- Department of Neurology, Radboudumc, Nijmegen, The Netherlands
- Radboud University Donders Institute for Brain Cognition and Behaviour, Nijmegen, The Netherlands
| | - Lupei Cai
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Roy P C Kessels
- Radboud University Donders Institute for Brain Cognition and Behaviour, Nijmegen, The Netherlands
- Vincent Van Gogh Instituut, Venray, The Netherlands
| | - Marnix C Maas
- Department of Radiology and Nuclear Medicine, Radboudumc, Nijmegen, The Netherlands
| | - Robin G Morris
- Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK
| | - Meritxell Nus
- Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
- The Victor Phillip Dahdaleh Heart and Lung Research Institute, Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge Medicine, Cambridge, UK
| | - Daniel J Tozer
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Anil Tuladhar
- Department of Neurology, Radboudumc, Nijmegen, The Netherlands
- Radboud University Donders Institute for Brain Cognition and Behaviour, Nijmegen, The Netherlands
| | - Anja van der Kolk
- Department of Radiology and Nuclear Medicine, Radboudumc, Nijmegen, The Netherlands
| | - Rowan Wolters
- Department of Neurology, Radboudumc, Nijmegen, The Netherlands
| | - Ziad Mallat
- The Victor Phillip Dahdaleh Heart and Lung Research Institute, Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge Medicine, Cambridge, UK
| | - Niels P Riksen
- Department of Internal Medicine, Radboudumc, Nijmegen, The Netherlands
| | - Hugh Markus
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Frank-Erik de Leeuw
- Department of Neurology, Radboudumc, Nijmegen, The Netherlands
- Radboud University Donders Institute for Brain Cognition and Behaviour, Nijmegen, The Netherlands
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22
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Rowsthorn E, Pham W, Nazem-Zadeh MR, Law M, Pase MP, Harding IH. Imaging the neurovascular unit in health and neurodegeneration: a scoping review of interdependencies between MRI measures. Fluids Barriers CNS 2023; 20:97. [PMID: 38129925 PMCID: PMC10734164 DOI: 10.1186/s12987-023-00499-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 12/05/2023] [Indexed: 12/23/2023] Open
Abstract
The neurovascular unit (NVU) is a complex structure that facilitates nutrient delivery and metabolic waste clearance, forms the blood-brain barrier (BBB), and supports fluid homeostasis in the brain. The integrity of NVU subcomponents can be measured in vivo using magnetic resonance imaging (MRI), including quantification of enlarged perivascular spaces (ePVS), BBB permeability, cerebral perfusion and extracellular free water. The breakdown of NVU subparts is individually associated with aging, pathology, and cognition. However, how these subcomponents interact as a system, and how interdependencies are impacted by pathology remains unclear. This systematic scoping review identified 26 studies that investigated the inter-relationships between multiple subcomponents of the NVU in nonclinical and neurodegenerative populations using MRI. A further 112 studies investigated associations between the NVU and white matter hyperintensities (WMH). We identify two putative clusters of NVU interdependencies: a 'vascular' cluster comprising BBB permeability, perfusion and basal ganglia ePVS; and a 'fluid' cluster comprising ePVS, free water and WMH. Emerging evidence suggests that subcomponent coupling within these clusters may be differentially related to aging, neurovascular injury or neurodegenerative pathology.
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Affiliation(s)
- Ella Rowsthorn
- Department of Neuroscience, Central Clinical School, Monash University, 99 Commercial Road, Melbourne, VIC, 3004, Australia
- Turner Institute for Brain and Mental Health & School of Psychological Sciences, Monash University, 18 Innovation Walk, Clayton, VIC, 3168, Australia
| | - William Pham
- Department of Neuroscience, Central Clinical School, Monash University, 99 Commercial Road, Melbourne, VIC, 3004, Australia
| | - Mohammad-Reza Nazem-Zadeh
- Department of Neuroscience, Central Clinical School, Monash University, 99 Commercial Road, Melbourne, VIC, 3004, Australia
| | - Meng Law
- Department of Neuroscience, Central Clinical School, Monash University, 99 Commercial Road, Melbourne, VIC, 3004, Australia
- Department of Radiology, Alfred Health, 99 Commercial Road, Melbourne, VIC, 3004, Australia
- Department of Electrical and Computer Systems Engineering, Monash University, 14 Alliance Lane, Clayton, VIC, 3168, Australia
| | - Matthew P Pase
- Turner Institute for Brain and Mental Health & School of Psychological Sciences, Monash University, 18 Innovation Walk, Clayton, VIC, 3168, Australia
- Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA
| | - Ian H Harding
- Department of Neuroscience, Central Clinical School, Monash University, 99 Commercial Road, Melbourne, VIC, 3004, Australia.
- Monash Biomedical Imaging, Monash University, 762-772 Blackburn Road, Clayton, VIC, 3168, Australia.
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23
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Morton L, Arndt P, Garza AP, Henneicke S, Mattern H, Gonzalez M, Dityatev A, Yilmazer-Hanke D, Schreiber S, Dunay IR. Spatio-temporal dynamics of microglia phenotype in human and murine cSVD: impact of acute and chronic hypertensive states. Acta Neuropathol Commun 2023; 11:204. [PMID: 38115109 PMCID: PMC10729582 DOI: 10.1186/s40478-023-01672-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 10/19/2023] [Indexed: 12/21/2023] Open
Abstract
Vascular risk factors such as chronic hypertension are well-established major modifiable factors for the development of cerebral small vessel disease (cSVD). In the present study, our focus was the investigation of cSVD-related phenotypic changes in microglia in human disease and in the spontaneously hypertensive stroke-prone rat (SHRSP) model of cSVD. Our examination of cortical microglia in human post-mortem cSVD cortical tissue revealed distinct morphological microglial features specific to cSVD. We identified enlarged somata, an increase in the territory occupied by thickened microglial processes, and an expansion in the number of vascular-associated microglia. In parallel, we characterized microglia in a rodent model of hypertensive cSVD along different durations of arterial hypertension, i.e., early chronic and late chronic hypertension. Microglial somata were already enlarged in early hypertension. In contrast, at late-stage chronic hypertension, they further exhibited elongated branches, thickened processes, and a reduced ramification index, mirroring the findings in human cSVD. An unbiased multidimensional flow cytometric analysis revealed phenotypic heterogeneity among microglia cells within the hippocampus and cortex. At early-stage hypertension, hippocampal microglia exhibited upregulated CD11b/c, P2Y12R, CD200R, and CD86 surface expression. Detailed analysis of cell subpopulations revealed a unique microglial subset expressing CD11b/c, CD163, and CD86 exclusively in early hypertension. Notably, even at early-stage hypertension, microglia displayed a higher association with cerebral blood vessels. We identified several profound clusters of microglia expressing distinct marker profiles at late chronic hypertensive states. In summary, our findings demonstrate a higher vulnerability of the hippocampus, stage-specific microglial signatures based on morphological features, and cell surface protein expression in response to chronic arterial hypertension. These results indicate the diversity within microglia sub-populations and implicate the subtle involvement of microglia in cSVD pathogenesis.
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Affiliation(s)
- Lorena Morton
- Institute of Inflammation and Neurodegeneration, Medical Faculty, Health Campus Immunology, Infectiology, and Inflammation (GC-I3), Otto-von-Guericke University, Leipziger Straße 44, 39120, Magdeburg, Germany
| | - Philipp Arndt
- Department of Neurology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- German Center for Neurodegenerative Diseases (DZNE) Helmholtz Association, Magdeburg, Germany
| | - Alejandra P Garza
- Institute of Inflammation and Neurodegeneration, Medical Faculty, Health Campus Immunology, Infectiology, and Inflammation (GC-I3), Otto-von-Guericke University, Leipziger Straße 44, 39120, Magdeburg, Germany
| | - Solveig Henneicke
- Department of Neurology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- German Center for Neurodegenerative Diseases (DZNE) Helmholtz Association, Magdeburg, Germany
| | - Hendrik Mattern
- German Center for Neurodegenerative Diseases (DZNE) Helmholtz Association, Magdeburg, Germany
- Faculty of Natural Sciences, Biomedical Magnetic Resonance, Otto-von-Guericke University, Magdeburg, Germany
- Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany
| | - Marilyn Gonzalez
- Institute of Inflammation and Neurodegeneration, Medical Faculty, Health Campus Immunology, Infectiology, and Inflammation (GC-I3), Otto-von-Guericke University, Leipziger Straße 44, 39120, Magdeburg, Germany
| | - Alexander Dityatev
- German Center for Neurodegenerative Diseases (DZNE) Helmholtz Association, Magdeburg, Germany
- Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany
- Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany
| | - Deniz Yilmazer-Hanke
- Clinical Neuroanatomy, Department of Neurology, Institute for Biomedical Research, Ulm University, Ulm, Germany
| | - Stefanie Schreiber
- Department of Neurology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- German Center for Neurodegenerative Diseases (DZNE) Helmholtz Association, Magdeburg, Germany
- Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany
- Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health (C-I-R-C), Jena-Magdeburg-Halle, Germany
| | - Ildiko R Dunay
- Institute of Inflammation and Neurodegeneration, Medical Faculty, Health Campus Immunology, Infectiology, and Inflammation (GC-I3), Otto-von-Guericke University, Leipziger Straße 44, 39120, Magdeburg, Germany.
- Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
- Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany.
- Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health (C-I-R-C), Jena-Magdeburg-Halle, Germany.
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24
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Wang Z, Li XN, Yang SN, Wang Y, Gao KJ, Han B, Ma AJ. Exosomal miR-320e through wnt2targeted inhibition of the Wnt/β-catenin pathway allevisate cerebral small vessel disease and cognitive impairment. World J Psychiatry 2023; 13:630-644. [PMID: 37771642 PMCID: PMC10523201 DOI: 10.5498/wjp.v13.i9.630] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/20/2023] [Accepted: 07/14/2023] [Indexed: 09/15/2023] Open
Abstract
BACKGROUND Exosomal miRNAs play crucial roles in many central nervous system diseases. Cerebral small vessel disease (CVSD) is a small vessel disease that is affected by various factors. This study aimed to investigate the role of exosomal miR-320e in the Wnt/β-catenin pathway stimulated by oxidative stress and assess its clinical correlation with psychiatric symptoms in patients with CVSD. AIM To explore whether exosomal miR-320e could suppress the Wnt/β-catenin pathway and play a protective role in CVSD progression, as well as examine its potential correlation with cognitive impairment and depression in patients with CVSD. METHODS Differentially expressed exosomal miRNAs were filtered by sequencing plasma exosomes from patients with CVSD and healthy controls. Bioinformatics and dual luciferase analyses were used to confirm the binding of miR-320e to Wnt2, and the mRNA and protein levels of downstream components in the Wnt/β-catenin pathway were evaluated when overexpressed or with knockdown of miR-320e under H2O2-induced oxidative stress. In addition, Wnt2-targeting siRNA was used to confirm the role of miR-320e in the Wnt2-mediated inhibition of the Wnt/β-catenin pathway. A retrospective analysis was conducted among patients with CVSD to confirm the correlation between miR-320e expression and the severity of cognitive impairment and depression, which were quantified using the Montreal Cognitive Assessment (MoCA)/Executive Function Assessment (EFA), and the Hamilton Depression Scale (HAMD)/Beck Depression Inventory (BDI), respectively. RESULTS High-throughput sequencing revealed that exosomal miR-320e was downregulated in patients with CVSD. Bioinformatics analysis and dual-luciferase reporter gene experiments showed that exosomal miR-320e inhibited the Wnt/β-catenin pathway in response to oxidative stress by targeting the 3' noncoding region of Wnt2. Uptake of exosomes carrying miR-320e into endothelial cells could also target Wnt2 and inhibit the Wnt2/β-catenin pathway. Elevated miR-320e expression may protect patients with CVSD from relatively severe cognitive impairment and depression, as it was found to have a positive correlation with the MoCA/EFA and HAMD/BDI scores. CONCLUSION Our results suggest that exosomal miR-320e suppresses the Wnt/β-catenin pathway and may play a protective role in CVSD progression.
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Affiliation(s)
- Zheng Wang
- Department of Internal Medicine-Neurology, Affiliated Hospital of Qingdao University, Qingdao 266001, Shandong Province, China
| | - Xue-Ning Li
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266001, Shandong Province, China
| | - Shao-Nan Yang
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266001, Shandong Province, China
| | - Yuan Wang
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266001, Shandong Province, China
| | - Ke-Jin Gao
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266001, Shandong Province, China
| | - Bin Han
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266001, Shandong Province, China
| | - Ai-Jun Ma
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266001, Shandong Province, China
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25
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Rudilosso S, Stringer MS, Thrippleton M, Chappell F, Blair GW, Jaime Garcia D, Doubal F, Hamilton I, Janssen E, Kopczak A, Ingrisch M, Kerkhofs D, Backes WH, Staals J, Duering M, Dichgans M, Wardlaw JM. Blood-brain barrier leakage hotspots collocating with brain lesions due to sporadic and monogenic small vessel disease. J Cereb Blood Flow Metab 2023; 43:1490-1502. [PMID: 37132279 PMCID: PMC10414006 DOI: 10.1177/0271678x231173444] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 03/02/2023] [Accepted: 03/21/2023] [Indexed: 05/04/2023]
Abstract
Blood-brain barrier (BBB) is known to be impaired in cerebral small vessel disease (SVD), and is measurable by dynamic-contrast enhancement (DCE)-MRI. In a cohort of 69 patients (42 sporadic, 27 monogenic SVD), who underwent 3T MRI, including DCE and cerebrovascular reactivity (CVR) sequences, we assessed the relationship of BBB-leakage hotspots to SVD lesions (lacunes, white matter hyperintensities (WMH), and microbleeds). We defined as hotspots the regions with permeability surface area product highest decile on DCE-derived maps within the white matter. We assessed factors associated with the presence and number of hotspots corresponding to SVD lesions in multivariable regression models adjusted for age, WMH volume, number of lacunes, and SVD type. We identified hotspots at lacune edges in 29/46 (63%) patients with lacunes, within WMH in 26/60 (43%) and at the WMH edges in 34/60 (57%) patients with WMH, and microbleed edges in 4/11 (36%) patients with microbleeds. In adjusted analysis, lower WMH-CVR was associated with presence and number of hotspots at lacune edges, and higher WMH volume with hotspots within WMH and at WMH edges, independently of the SVD type. In conclusion, SVD lesions frequently collocate with high BBB-leakage in patients with sporadic and monogenic forms of SVD.
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Affiliation(s)
- Salvatore Rudilosso
- Comprehensive Stroke Center, Department of Neuroscience, Hospital Clinic and August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Michael S Stringer
- Centre for Clinical Brain Sciences, UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK
| | - Michael Thrippleton
- Centre for Clinical Brain Sciences, UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK
| | - Francesca Chappell
- Centre for Clinical Brain Sciences, UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK
| | - Gordon W Blair
- Centre for Clinical Brain Sciences, UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK
| | - Daniela Jaime Garcia
- Centre for Clinical Brain Sciences, UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK
| | - Fergus Doubal
- Centre for Clinical Brain Sciences, UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK
| | - Iona Hamilton
- Centre for Clinical Brain Sciences, UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK
| | - Esther Janssen
- Department of Neurology, Radboud University Medical Centre (Radboudumc), Nijmegen, The Netherlands
| | - Anna Kopczak
- Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany
| | - Michael Ingrisch
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Danielle Kerkhofs
- Department of Neurology and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Walter H Backes
- Department of Radiology & Nuclear Medicine, Schools for Mental Health & Neuroscience and School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Julie Staals
- Department of Neurology and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Marco Duering
- Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany
- Medical Image Analysis Center (MIAC AG) and Department of Biomedical Engineering, University of Basel, Basel, Switzerland
| | - Martin Dichgans
- Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany
- Munich Cluster for Systems Neurology, Munich, Germany
- German Center for Neurodegenerative Diseases, Munich, Germany
| | - Joanna M Wardlaw
- Centre for Clinical Brain Sciences, UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK
| | - on behalf of the SVDs@target consortium
- Comprehensive Stroke Center, Department of Neuroscience, Hospital Clinic and August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- Centre for Clinical Brain Sciences, UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK
- Department of Neurology, Radboud University Medical Centre (Radboudumc), Nijmegen, The Netherlands
- Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
- Department of Neurology and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center+, Maastricht, The Netherlands
- Department of Radiology & Nuclear Medicine, Schools for Mental Health & Neuroscience and School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, Netherlands
- Medical Image Analysis Center (MIAC AG) and Department of Biomedical Engineering, University of Basel, Basel, Switzerland
- Munich Cluster for Systems Neurology, Munich, Germany
- German Center for Neurodegenerative Diseases, Munich, Germany
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26
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Rajeev V, Chai YL, Poh L, Selvaraji S, Fann DY, Jo DG, De Silva TM, Drummond GR, Sobey CG, Arumugam TV, Chen CP, Lai MKP. Chronic cerebral hypoperfusion: a critical feature in unravelling the etiology of vascular cognitive impairment. Acta Neuropathol Commun 2023; 11:93. [PMID: 37309012 PMCID: PMC10259064 DOI: 10.1186/s40478-023-01590-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 05/25/2023] [Indexed: 06/14/2023] Open
Abstract
Vascular cognitive impairment (VCI) describes a wide spectrum of cognitive deficits related to cerebrovascular diseases. Although the loss of blood flow to cortical regions critically involved in cognitive processes must feature as the main driver of VCI, the underlying mechanisms and interactions with related disease processes remain to be fully elucidated. Recent clinical studies of cerebral blood flow measurements have supported the role of chronic cerebral hypoperfusion (CCH) as a major driver of the vascular pathology and clinical manifestations of VCI. Here we review the pathophysiological mechanisms as well as neuropathological changes of CCH. Potential interventional strategies for VCI are also reviewed. A deeper understanding of how CCH can lead to accumulation of VCI-associated pathology could potentially pave the way for early detection and development of disease-modifying therapies, thus allowing preventive interventions instead of symptomatic treatments.
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Affiliation(s)
- Vismitha Rajeev
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Memory Aging and Cognition Centre, National University Health System, Singapore, Singapore
| | - Yuek Ling Chai
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Memory Aging and Cognition Centre, National University Health System, Singapore, Singapore
| | - Luting Poh
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Memory Aging and Cognition Centre, National University Health System, Singapore, Singapore
| | - Sharmelee Selvaraji
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Memory Aging and Cognition Centre, National University Health System, Singapore, Singapore
- Integrative Sciences and Engineering Programme, NUS Graduate School, National University of Singapore, Singapore, Singapore
| | - David Y Fann
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Dong-Gyu Jo
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
| | - T Michael De Silva
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria, Australia
| | - Grant R Drummond
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria, Australia
| | - Christopher G Sobey
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria, Australia
| | - Thiruma V Arumugam
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria, Australia
| | - Christopher P Chen
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Memory Aging and Cognition Centre, National University Health System, Singapore, Singapore
- NUS Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Mitchell K P Lai
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Memory Aging and Cognition Centre, National University Health System, Singapore, Singapore.
- NUS Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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27
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Okar SV, Hu F, Shinohara RT, Beck ES, Reich DS, Ineichen BV. The etiology and evolution of magnetic resonance imaging-visible perivascular spaces: Systematic review and meta-analysis. Front Neurosci 2023; 17:1038011. [PMID: 37065926 PMCID: PMC10098201 DOI: 10.3389/fnins.2023.1038011] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 03/15/2023] [Indexed: 04/03/2023] Open
Abstract
ObjectivesPerivascular spaces have been involved in neuroinflammatory and neurodegenerative diseases. Upon a certain size, these spaces can become visible on magnetic resonance imaging (MRI), referred to as enlarged perivascular spaces (EPVS) or MRI-visible perivascular spaces (MVPVS). However, the lack of systematic evidence on etiology and temporal dynamics of MVPVS hampers their diagnostic utility as MRI biomarker. Thus, the goal of this systematic review was to summarize potential etiologies and evolution of MVPVS.MethodsIn a comprehensive literature search, out of 1,488 unique publications, 140 records assessing etiopathogenesis and dynamics of MVPVS were eligible for a qualitative summary. 6 records were included in a meta-analysis to assess the association between MVPVS and brain atrophy.ResultsFour overarching and partly overlapping etiologies of MVPVS have been proposed: (1) Impairment of interstitial fluid circulation, (2) Spiral elongation of arteries, (3) Brain atrophy and/or perivascular myelin loss, and (4) Immune cell accumulation in the perivascular space. The meta-analysis in patients with neuroinflammatory diseases did not support an association between MVPVS and brain volume measures [R: −0.15 (95%-CI −0.40–0.11)]. Based on few and mostly small studies in tumefactive MVPVS and in vascular and neuroinflammatory diseases, temporal evolution of MVPVS is slow.ConclusionCollectively, this study provides high-grade evidence for MVPVS etiopathogenesis and temporal dynamics. Although several potential etiologies for MVPVS emergence have been proposed, they are only partially supported by data. Advanced MRI methods should be employed to further dissect etiopathogenesis and evolution of MVPVS. This can benefit their implementation as an imaging biomarker.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=346564, identifier CRD42022346564.
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Affiliation(s)
- Serhat V. Okar
- Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Fengling Hu
- Department of Biostatistics, Epidemiology, and Informatics, Penn Statistics in Imaging and Visualization Center, University of Pennsylvania, Philadelphia, PA, United States
| | - Russell T. Shinohara
- Department of Biostatistics, Epidemiology, and Informatics, Penn Statistics in Imaging and Visualization Center, University of Pennsylvania, Philadelphia, PA, United States
| | - Erin S. Beck
- Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Daniel S. Reich
- Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Benjamin V. Ineichen
- Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
- Department of Neuroradiology, Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Center for Reproducible Science, University of Zurich, Zurich, Switzerland
- *Correspondence: Benjamin V. Ineichen, , ; orcid.org/0000-0003-1362-4819
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28
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Uchida Y, Kan H, Sakurai K, Oishi K, Matsukawa N. Contributions of blood-brain barrier imaging to neurovascular unit pathophysiology of Alzheimer's disease and related dementias. Front Aging Neurosci 2023; 15:1111448. [PMID: 36861122 PMCID: PMC9969807 DOI: 10.3389/fnagi.2023.1111448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 01/26/2023] [Indexed: 02/11/2023] Open
Abstract
The blood-brain barrier (BBB) plays important roles in the maintenance of brain homeostasis. Its main role includes three kinds of functions: (1) to protect the central nervous system from blood-borne toxins and pathogens; (2) to regulate the exchange of substances between the brain parenchyma and capillaries; and (3) to clear metabolic waste and other neurotoxic compounds from the central nervous system into meningeal lymphatics and systemic circulation. Physiologically, the BBB belongs to the glymphatic system and the intramural periarterial drainage pathway, both of which are involved in clearing interstitial solutes such as β-amyloid proteins. Thus, the BBB is believed to contribute to preventing the onset and progression for Alzheimer's disease. Measurements of BBB function are essential toward a better understanding of Alzheimer's pathophysiology to establish novel imaging biomarkers and open new avenues of interventions for Alzheimer's disease and related dementias. The visualization techniques for capillary, cerebrospinal, and interstitial fluid dynamics around the neurovascular unit in living human brains have been enthusiastically developed. The purpose of this review is to summarize recent BBB imaging developments using advanced magnetic resonance imaging technologies in relation to Alzheimer's disease and related dementias. First, we give an overview of the relationship between Alzheimer's pathophysiology and BBB dysfunction. Second, we provide a brief description about the principles of non-contrast agent-based and contrast agent-based BBB imaging methodologies. Third, we summarize previous studies that have reported the findings of each BBB imaging method in individuals with the Alzheimer's disease continuum. Fourth, we introduce a wide range of Alzheimer's pathophysiology in relation to BBB imaging technologies to advance our understanding of the fluid dynamics around the BBB in both clinical and preclinical settings. Finally, we discuss the challenges of BBB imaging techniques and suggest future directions toward clinically useful imaging biomarkers for Alzheimer's disease and related dementias.
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Affiliation(s)
- Yuto Uchida
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States,*Correspondence: Yuto Uchida, ; Noriyuki Matsukawa,
| | - Hirohito Kan
- Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Keita Sakurai
- Department of Radiology, National Center for Geriatrics and Gerontology, Ōbu, Aichi, Japan
| | - Kenichi Oishi
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Noriyuki Matsukawa
- Department of Neurology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan,*Correspondence: Yuto Uchida, ; Noriyuki Matsukawa,
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29
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Wan S, Dandu C, Han G, Guo Y, Ding Y, Song H, Meng R. Plasma inflammatory biomarkers in cerebral small vessel disease: A review. CNS Neurosci Ther 2022; 29:498-515. [PMID: 36478511 PMCID: PMC9873530 DOI: 10.1111/cns.14047] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 10/24/2022] [Accepted: 11/22/2022] [Indexed: 12/12/2022] Open
Abstract
Cerebral small vessel disease (CSVD) is a group of pathological processes affecting small arteries, arterioles, capillaries, and small veins of the brain. It is one of the most common subtypes of cerebrovascular diseases, especially highly prevalent in elderly populations, and is associated with stroke occurrence and recurrence, cognitive impairment, gait disorders, psychological disturbance, and dysuria. Its diagnosis mainly depends on MRI, characterized by recent small subcortical infarcts, lacunes, white matter hyperintensities (WMHs), enlarged perivascular spaces (EPVS), cerebral microbleeds (CMBs), and brain atrophy. While the pathophysiological processes of CSVD are not fully understood at present, inflammation is noticed as playing an important role. Herein, we aimed to review the relationship between plasma inflammatory biomarkers and the MRI features of CSVD, to provide background for further research.
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Affiliation(s)
- Shuling Wan
- Department of Neurology, National Center for Neurological Disorders, Xuanwu HospitalCapital Medical UniversityBeijingChina,Advanced Center of StrokeBeijing Institute for Brain DisordersBeijingChina
| | - Chaitu Dandu
- Department of NeurosurgeryWayne State University School of MedicineDetroitMichiganUSA
| | - Guangyu Han
- Department of Neurology, National Center for Neurological Disorders, Xuanwu HospitalCapital Medical UniversityBeijingChina,Advanced Center of StrokeBeijing Institute for Brain DisordersBeijingChina
| | - Yibing Guo
- Department of Neurology, National Center for Neurological Disorders, Xuanwu HospitalCapital Medical UniversityBeijingChina,Advanced Center of StrokeBeijing Institute for Brain DisordersBeijingChina
| | - Yuchuan Ding
- Department of NeurosurgeryWayne State University School of MedicineDetroitMichiganUSA
| | - Haiqing Song
- Department of Neurology, National Center for Neurological Disorders, Xuanwu HospitalCapital Medical UniversityBeijingChina,Advanced Center of StrokeBeijing Institute for Brain DisordersBeijingChina
| | - Ran Meng
- Department of Neurology, National Center for Neurological Disorders, Xuanwu HospitalCapital Medical UniversityBeijingChina,Advanced Center of StrokeBeijing Institute for Brain DisordersBeijingChina,Department of NeurosurgeryWayne State University School of MedicineDetroitMichiganUSA
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30
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Datta A, Chen C, Gao YG, Sze SK. Quantitative Proteomics of Medium-Sized Extracellular Vesicle-Enriched Plasma of Lacunar Infarction for the Discovery of Prognostic Biomarkers. Int J Mol Sci 2022; 23:ijms231911670. [PMID: 36232970 PMCID: PMC9569577 DOI: 10.3390/ijms231911670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 09/23/2022] [Accepted: 09/26/2022] [Indexed: 11/16/2022] Open
Abstract
Lacunar infarction (LACI), a subtype of acute ischemic stroke, has poor mid- to long-term prognosis due to recurrent vascular events or incident dementia which is difficult to predict using existing clinical data. Herein, we aim to discover blood-based biomarkers for LACI as a complementary prognostic tool. Convalescent plasma was collected from forty-five patients following a non-disabling LACI along with seventeen matched control subjects. The patients were followed up prospectively for up to five years to record an occurrence of adverse outcome and grouped accordingly (i.e., LACI-no adverse outcome, LACI-recurrent vascular event, and LACI-cognitive decline without any recurrence of vascular events). Medium-sized extracellular vesicles (MEVs), isolated from the pooled plasma of four groups, were analyzed by stable isotope labeling and 2D-LC-MS/MS. Out of 573 (FDR < 1%) quantified proteins, 146 showed significant changes in at least one LACI group when compared to matched healthy control. A systems analysis revealed that major elements (~85%) of the MEV proteome are different from the proteome of small-sized extracellular vesicles obtained from the same pooled plasma. The altered MEV proteins in LACI patients are mostly reduced in abundance. The majority of the shortlisted MEV proteins are not linked to commonly studied biological processes such as coagulation, fibrinolysis, or inflammation. Instead, they are linked to oxygen-glucose deprivation, endo-lysosomal trafficking, glucose transport, and iron homeostasis. The dataset is provided as a web-based data resource to facilitate meta-analysis, data integration, and targeted large-scale validation.
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Affiliation(s)
- Arnab Datta
- Laboratory of Translational Neuroscience, Division of Neuroscience, Yenepoya Research Center, Yenepoya (Deemed to be University), University Road, Deralakatte, Mangalore 575018, Karnataka, India
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
- Correspondence: or (A.D.); (S.K.S.)
| | - Christopher Chen
- Memory, Aging and Cognition Centre, National University Health System, Singapore 119228, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
| | - Yong-Gui Gao
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
| | - Siu Kwan Sze
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
- Department of Health Sciences, Faculty of Applied Health Sciences, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, ON L2S 3A1, Canada
- Correspondence: or (A.D.); (S.K.S.)
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31
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Yao XY, Gao MC, Bai SW, Xie L, Song YY, Ding J, Wu YF, Xue CR, Hao Y, Zhang Y, Guan YT. Enlarged perivascular spaces, neuroinflammation and neurological dysfunction in NMOSD patients. Front Immunol 2022; 13:966781. [PMID: 36248814 PMCID: PMC9557144 DOI: 10.3389/fimmu.2022.966781] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 08/31/2022] [Indexed: 11/22/2022] Open
Abstract
Background and objectives Cerebrospinal fluid (CSF) and interstitial fluid exchange along a brain-wide network of perivascular spaces (PVS) termed the ‘glymphatic system’. The aquaporin-4 (AQP4) water channels abundantly expressed on astrocytic endfeet play a key role in the CSF circulation in the glymphatic system. Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating autoimmune disease of the central nervous system (CNS) featured with a specific autoantibody directed against AQP4 in most of patients. Anti-AQP4 antibodies are likely resulting in the impairment of the brain glymphatic system and the enlargement of PVS in NMOSD patients. In the current study, we aimed to demonstrate the features of EPVS detected by MRI and its association with the CSF anti-AQP4 antibody titer, CNS inflammatory markers, and disease severity in NMOSD patients. Methods We conducted a retrospective review of a consecutive cohort of 110 patients with NMOSD who had brain MRI. We assessed the correlation of EPVS with markers of neuroinflammation, blood-brain barrier (BBB) function and severity of neurological dysfunction in patients. We used multivariate logistic regression analysis to determine the independent variables associated with disease severity. Results The median number of total-EPVS was 15.5 (IQR, 11-24.2) in NMOSD patients. The number of total-EPVS was significantly related to EDSS score after correcting for the effects of age and hypertension (r=0.353, p<0.001). The number of total-EPVS was also significantly associated with the titer of CSF anti-AQP4 antibody, the albumin rate (CSF/serum ratios of albumin), the CSF albumin, IgG and IgA levels. Logistic regression analysis showed that total-EPVS and serum albumin level were two independent factors to predict disease severity in NMOSD patients (OR=1.053, p=0.028; OR=0.858, p=0.009 respectively). Furthermore, ROC analysis achieved AUC of 0.736 (0.640-0.831, p<0.001) for total-EPVS to determine severe NMOSD (EDSS 4.5-9.5). Discussion In our cohort, we found a relationship between EPVS and neuroinflammation and BBB function in NMOSD. Moreover, EPVS might independently predict neurological dysfunction in patients with NMOSD.
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Affiliation(s)
- Xiao-Ying Yao
- Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Mei-Chun Gao
- Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shu-Wei Bai
- Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Li Xie
- Clinical Research Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ya-Ying Song
- Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jie Ding
- Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yi-Fan Wu
- Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chun-Ran Xue
- Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yong Hao
- Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Zhang
- Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yang-Tai Guan
- Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- *Correspondence: Yang-Tai Guan,
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32
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Huo Y, Wang Y, Guo C, Liu Q, Shan L, Liu M, Wu H, Li G, Lv H, Lu L, Zhou Y, Feng J, Han Y. Deep white matter hyperintensity is spatially correlated to MRI-visible perivascular spaces in cerebral small vessel disease on 7 Tesla MRI. Stroke Vasc Neurol 2022; 8:144-150. [PMID: 36170993 PMCID: PMC10176991 DOI: 10.1136/svn-2022-001611] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 09/14/2022] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND The association between perivascular space (PVS) and white matter hyperintensity (WMH) has been unclear. Normal-appearing white matter (NAWM) around WMH is also found correlated with the development of focal WMH. This study aims to investigate the topological connections among PVS, deep WMH (dWMH) and NAWM around WMH using 7 Tesla (7T) MRI. METHODS Thirty-two patients with non-confluent WMHs and 16 subjects without WMHs were recruited from our department and clinic. We compared the PVS burden between patients with and without WMHs using a 5-point scale. Then, the dilatation and the number of PVS within a radius of 1 cm around each dWMH were compared with those of a reference site (without WMH) in the contralateral hemisphere. In this study, we define NAWM as an area within the radius of 1 cm around each dWMH. Furthermore, we assessed the spatial relationship between dWMH and PVS. RESULTS Higher PVS scores in the centrum semiovale were found in patients with >5 dWMHs (median 3) than subjects without dWMH (median 2, p = 0.014). We found there was a greater dilatation and a higher number of PVS in NAWM around dWMH than at the reference sites (p<0.001, p<0.001). In addition, 79.59% of the dWMHs were spatially connected with PVS. CONCLUSION dWMH, NAWM surrounding WMH and MRI-visible PVS are spatially correlated in the early stage of cerebral small vessel disease. Future study of WMH and NAWM should not overlook MRI-visible PVS.
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Affiliation(s)
- Yajing Huo
- Department of Neurology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yilin Wang
- Georgetown Preparatory School, North Bethesda, Maryland, USA
| | - Cen Guo
- Department of Neurology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qianyun Liu
- Department of Neurology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lili Shan
- Department of Neurology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mingyuan Liu
- Department of Neurology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Haibo Wu
- Department of Neurology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guanwu Li
- Department of Radiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Huihui Lv
- Department of Neurology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lingdan Lu
- Department of Neurology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yintin Zhou
- Department of Neurology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jianfeng Feng
- Institute of Science and Technology for Brain-inspired Intelligence, Fudan University, Shanghai, China
| | - Yan Han
- Department of Neurology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Cliteur MP, Sondag L, Wolsink A, Rasing I, Meijer FJA, Jolink WMT, Wermer MJH, Klijn CJM, Schreuder FHBM. Cerebral small vessel disease and perihematomal edema formation in spontaneous intracerebral hemorrhage. Front Neurol 2022; 13:949133. [PMID: 35968312 PMCID: PMC9372363 DOI: 10.3389/fneur.2022.949133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 07/07/2022] [Indexed: 12/02/2022] Open
Abstract
Objective Blood-brain barrier (BBB) dysfunction is implicated in the pathophysiology of cerebral small vessel disease (cSVD)-related intracerebral hemorrhage (ICH). The formation of perihematomal edema (PHE) is presumed to reflect acute BBB permeability following ICH. We aimed to assess the association between cSVD burden and PHE formation in patients with spontaneous ICH. Methods We selected patients with spontaneous ICH who underwent 3T MRI imaging within 21 days after symptom onset from a prospective observational multicenter cohort study. We rated markers of cSVD (white matter hyperintensities, enlarged perivascular spaces, lacunes and cerebral microbleeds) and calculated the composite score as a measure of the total cSVD burden. Perihematomal edema formation was measured using the edema extension distance (EED). We assessed the association between the cSVD burden and the EED using a multivariable linear regression model adjusting for age, (log-transformed) ICH volume, ICH location (lobar vs. non-lobar), and interval between symptom onset and MRI. Results We included 85 patients (mean age 63.5 years, 75.3% male). Median interval between symptom onset and MRI imaging was 6 days (IQR 1–19). Median ICH volume was 17.0 mL (IQR 1.4–88.6), and mean EED was 0.54 cm (SD 0.17). We found no association between the total cSVD burden and EED (B = −0.003, 95% CI −0.003–0.03, p = 0.83), nor for any of the individual radiological cSVD markers. Conclusion We found no association between the cSVD burden and PHE formation. This implies that mechanisms other than BBB dysfunction are involved in the pathophysiology of PHE.
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Affiliation(s)
- Maaike P. Cliteur
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Lotte Sondag
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Axel Wolsink
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Ingeborg Rasing
- Department of Neurology & Neurosurgery, Leiden University Medical Center, Leiden, Netherlands
| | - F. J. A. Meijer
- Department of Medical Imaging, Radboud University Medical Centre, Nijmegen, Netherlands
| | | | - Marieke J. H. Wermer
- Department of Neurology & Neurosurgery, Leiden University Medical Center, Leiden, Netherlands
| | - Catharina J. M. Klijn
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Floris H. B. M. Schreuder
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands
- *Correspondence: Floris H. B. M. Schreuder
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Gao Y, Deng W, Sun J, Yue D, Zhang B, Feng Y, Han J, Shen F, Hu J, Fu Y. The Association of Nocturnal Blood Pressure Patterns and Other Influencing Factors With Lacunes and Enlarged Perivascular Spaces in Hypertensive Patients. Front Neurol 2022; 13:879764. [PMID: 35677332 PMCID: PMC9168463 DOI: 10.3389/fneur.2022.879764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 04/12/2022] [Indexed: 11/13/2022] Open
Abstract
PurposeNocturnal blood pressure dipping patterns have been associated with an increased risk of Cerebral Small Vessel Disease (CSVD), which has not been well-studied. This study is aimed to explore the association of dipping patterns and other factors with lacunes and enlarged perivascular spaces (EPVS) in patients with hypertension.MethodsWe enrolled a total of 1,322 patients with essential hypertension in this study. Magnetic resonance imaging (MRI) scans and 24-h ambulatory blood pressure (BP) monitoring were completed. Nocturnal BP decline was calculated, and then dipping patterns were classified. Patients were classified into four groups according to the performance of lacunes and EPVS in the MRI scan for statistical analysis.Results(1) Nocturnal BP decline showed independent negative correlation with both lacunes and EPVS while mean systolic BP (mSBP) level showed an independent positive correlation with them (P < 0.05). (2) The frequency of reverse-dippers in the control group was significantly lower than that in other groups; the frequency of non-dippers in the lacunes group and EPVS group was significantly lower than that in the control group; the frequency of extreme-dippers in the EPVS group was significantly higher than that in the mixed (lacunes with EPVS) group (P < 0.05).ConclusionsBoth mSBP and dipping patterns might play an important role in developing lacunes and EPVS in patients with hypertension.
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Affiliation(s)
- Yang Gao
- Department of Neurology, The First Hospital of Jiaxing and The Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Weiping Deng
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jialan Sun
- Department of Neurology, Pudong New Area Gongli Hospital, Shanghai, China
| | - Dongqi Yue
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bei Zhang
- Department of Radiology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yulan Feng
- Department of Neurology, Minhang Hospital, Fudan University, Shanghai, China
| | - Jun Han
- Department of Radiology, The First Hospital of Jiaxing and The Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Fanxia Shen
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jin Hu
- Department of Neurology, The First Hospital of Jiaxing and The Affiliated Hospital of Jiaxing University, Jiaxing, China
- Jin Hu
| | - Yi Fu
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Yi Fu
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Brown RB, Tozer DJ, Loubière L, Hong YT, Fryer TD, Williams GB, Graves MJ, Aigbirhio FI, O’Brien JT, Markus HS. MINocyclinE to Reduce inflammation and blood brain barrier leakage in small Vessel diseAse (MINERVA) trial study protocol. Eur Stroke J 2022; 7:323-330. [PMID: 36082255 PMCID: PMC9445404 DOI: 10.1177/23969873221100338] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 04/24/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Cerebral small vessel disease (SVD) is a common cause of stroke and cognitive impairment. Recent data has implicated neuroinflammation and increased blood-brain barrier (BBB) permeability in its pathogenesis, but whether such processes are causal and can be therapeutically modified is uncertain. In a rodent model of SVD, minocycline was associated with reduced white matter lesions, inflammation and BBB permeability. Aims: To determine whether blood-brain barrier permeability (measured using dynamic contrast-enhanced MRI) and microglial activation (measured by positron emission tomography using the radioligand 11C-PK11195) can be modified in SVD. Design: Phase II randomised double blind, placebo-controlled trial of minocycline 100 mg twice daily for 3 months in 44 participants with moderate to severe SVD defined as a clinical lacunar stroke and confluent white matter hyperintensities. Outcomes: Primary outcome measures are volume and intensity of focal increases of blood-brain barrier permeability and microglial activation determined using PET-MRI imaging. Secondary outcome measures include inflammatory biomarkers in serum, and change in conventional MRI markers and cognitive performance over 1 year follow up. Discussion: The MINERVA trial aims to test whether minocycline can influence novel pathological processes thought to be involved in SVD progression, and will provide insights into whether central nervous system inflammation in SVD can be therapeutically modulated.
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Affiliation(s)
- Robin B Brown
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Daniel J Tozer
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Laurence Loubière
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Young T Hong
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
- Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, UK
| | - Tim D Fryer
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
- Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, UK
| | - Guy B Williams
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
- Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, UK
| | - Martin J Graves
- Department of Radiology, University of Cambridge, Cambridge, UK
| | - Franklin I Aigbirhio
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
- Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, UK
| | - John T O’Brien
- Department of Psychiatry, University of Cambridge, Cambridge, UK
| | - Hugh S Markus
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
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Fu W, Zhou X, Wang M, Li P, Hou J, Gao P, Wang J. Fundus Changes Evaluated by OCTA in Patients With Cerebral Small Vessel Disease and Their Correlations: A Cross-Sectional Study. Front Neurol 2022; 13:843198. [PMID: 35547389 PMCID: PMC9081972 DOI: 10.3389/fneur.2022.843198] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
Objective To detect fundus changes in patients with cerebral small vessel disease (CSVD) using optical coherence tomography angiography (OCTA) and to investigate the correlations between CSVD and fundus changes. Methods From January 2019 to January 2020, patients diagnosed with CSVD by magnetic resonance imaging (MRI) were enrolled in our study and received fundus examinations using OCTA. CSVD was defined as white matter hyperintensities, enlarged perivascular spaces, lacunes, or microbleeds on MRI. OCTA parameters included foveal avascular zone areas, retinal nerve fiber layer thickness, and capillary densities of the superficial retinal capillary plexuses, deep retinal capillary plexuses, and the radial peripapillary capillary network of the disc. Univariate and multivariate logistic regression analyses were performed to explore the correlation between CSVD and fundus changes. Results A total of 115 patients (40% male) were enrolled and analyzed, and the mean age was 65.11 ± 11.23 years. After multivariate logistic regression analysis, the radial peripapillary capillary network density was negatively correlated with severity of deep white matter lesions (OR: 0.909; 95% CI: 0.828-0.998; p = 0.046) and perivascular spaces (OR: 0.881; 95% CI: 0.779-0.995; p = 0.041). Parafoveal vessel densities of the superficial retinal capillary plexuses were independently correlated with lacunes (OR: 0.889; 95% CI: 0.817-0.967; p = 0.006). Conclusion OCTA parameters were correlated with CSVD, indicating that OCTA is a potential method for CSVD screening.
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Affiliation(s)
- Wang Fu
- Department of Neurology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaoyu Zhou
- Department of Neurology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Minli Wang
- Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ping Li
- Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jingjing Hou
- Tongji University School of Medicine, Shanghai, China
| | - Peng Gao
- Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jue Wang
- Educational Office, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
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Moretti R, Caruso P. Small Vessel Disease: Ancient Description, Novel Biomarkers. Int J Mol Sci 2022; 23:3508. [PMID: 35408867 PMCID: PMC8998274 DOI: 10.3390/ijms23073508] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/20/2022] [Accepted: 03/21/2022] [Indexed: 12/22/2022] Open
Abstract
Small vessel disease (SVD) is one of the most frequent pathological conditions which lead to dementia. Biochemical and neuroimaging might help correctly identify the clinical diagnosis of this relevant brain disease. The microvascular alterations which underlie SVD have common origins, similar cognitive outcomes, and common vascular risk factors. Nevertheless, the arteriolosclerosis process, which underlines SVD development, is based on different mechanisms, not all completely understood, which start from a chronic hypoperfusion state and pass through a chronic brain inflammatory condition, inducing a significant endothelium activation and a consequent tissue remodeling action. In a recent review, we focused on the pathophysiology of SVD, which is complex, involving genetic conditions and different co-morbidities (i.e., diabetes, chronic hypoxia condition, and obesity). Currently, many points still remain unclear and discordant. In this paper, we wanted to focus on new biomarkers, which can be the expression of the endothelial dysfunction, or of the oxidative damage, which could be employed as markers of disease progression or for future targets of therapies. Therefore, we described the altered response to the endothelium-derived nitric oxide-vasodilators (ENOV), prostacyclin, C-reactive proteins, and endothelium-derived hyperpolarizing factors (EDHF). At the same time, due to the concomitant endothelial activation and chronic neuroinflammatory status, we described hypoxia-endothelial-related markers, such as HIF 1 alpha, VEGFR2, and neuroglobin, and MMPs. We also described blood-brain barrier disruption biomarkers and imaging techniques, which can also describe perivascular spaces enlargement and dysfunction. More studies should be necessary, in order to implement these results and give them a clinical benefit.
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Affiliation(s)
- Rita Moretti
- Neurology Clinic, Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy;
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Di Chiara T, Del Cuore A, Daidone M, Scaglione S, Norrito RL, Puleo MG, Scaglione R, Pinto A, Tuttolomondo A. Pathogenetic Mechanisms of Hypertension-Brain-Induced Complications: Focus on Molecular Mediators. Int J Mol Sci 2022; 23:2445. [PMID: 35269587 PMCID: PMC8910319 DOI: 10.3390/ijms23052445] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 02/03/2022] [Accepted: 02/10/2022] [Indexed: 02/06/2023] Open
Abstract
There is growing evidence that hypertension is the most important vascular risk factor for the development and progression of cardiovascular and cerebrovascular diseases. The brain is an early target of hypertension-induced organ damage and may manifest as stroke, subclinical cerebrovascular abnormalities and cognitive decline. The pathophysiological mechanisms of these harmful effects remain to be completely clarified. Hypertension is well known to alter the structure and function of cerebral blood vessels not only through its haemodynamics effects but also for its relationships with endothelial dysfunction, oxidative stress and inflammation. In the last several years, new possible mechanisms have been suggested to recognize the molecular basis of these pathological events. Accordingly, this review summarizes the factors involved in hypertension-induced brain complications, such as haemodynamic factors, endothelial dysfunction and oxidative stress, inflammation and intervention of innate immune system, with particular regard to the role of Toll-like receptors that have to be considered dominant components of the innate immune system. The complete definition of their prognostic role in the development and progression of hypertensive brain damage will be of great help in the identification of new markers of vascular damage and the implementation of innovative targeted therapeutic strategies.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Antonino Tuttolomondo
- Department of Health Promotion, Maternal and Infant Care, Internal Medicine and Medical Specialties, “G. D’Alessandro”, University of Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy; (T.D.C.); (A.D.C.); (M.D.); (S.S.); (R.L.N.); (M.G.P.); (R.S.); (A.P.)
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Wardlaw JM, Benveniste H, Williams A. Cerebral Vascular Dysfunctions Detected in Human Small Vessel Disease and Implications for Preclinical Studies. Annu Rev Physiol 2022; 84:409-434. [PMID: 34699267 DOI: 10.1146/annurev-physiol-060821-014521] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Cerebral small vessel disease (SVD) is highly prevalent and a common cause of ischemic and hemorrhagic stroke and dementia, yet the pathophysiology is poorly understood. Its clinical expression is highly varied, and prognostic implications are frequently overlooked in clinics; thus, treatment is currently confined to vascular risk factor management. Traditionally, SVD is considered the small vessel equivalent of large artery stroke (occlusion, rupture), but data emerging from human neuroimaging and genetic studies refute this, instead showing microvessel endothelial dysfunction impacting on cell-cell interactions and leading to brain damage. These dysfunctions reflect defects that appear to be inherited and secondary to environmental exposures, including vascular risk factors. Interrogation in preclinical models shows consistent and converging molecular and cellular interactions across the endothelial-glial-neural unit that increasingly explain the human macroscopic observations and identify common patterns of pathology despite different triggers. Importantly, these insights may offer new targets for therapeutic intervention focused on restoring endothelial-glial physiology.
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Affiliation(s)
- Joanna M Wardlaw
- Division of Neuroimaging Sciences, Centre for Clinical Brain Sciences; UK Dementia Research Institute; and Edinburgh Imaging, University of Edinburgh, Edinburgh, United Kingdom;
| | - Helene Benveniste
- Department of Anesthesiology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Anna Williams
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom
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40
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Clancy U, Makin SD, McHutchison CA, Cvoro V, Chappell FM, Hernández MDCV, Sakka E, Doubal F, Wardlaw JM. Impact of Small Vessel Disease Progression on Long-term Cognitive and Functional Changes After Stroke. Neurology 2022; 98:e1459-e1469. [PMID: 35131905 PMCID: PMC8992602 DOI: 10.1212/wnl.0000000000200005] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 01/03/2022] [Indexed: 11/30/2022] Open
Abstract
Background and Objectives The severity of white matter hyperintensities (WMH) at presentation with stroke is associated with poststroke dementia and dependency. However, WMH can decrease or increase after stroke; prediction of cognitive decline is imprecise; and there are few data assessing longitudinal interrelationships among changing WMH, cognition, and function after stroke, despite the clinical importance. Methods We recruited patients within 3 months of a minor ischemic stroke, defined as NIH Stroke Scale (NIHSS) score <8 and not expected to result in a modified Rankin Scale (mRS) score >2. Participants repeated MRI at 1 year and cognitive and mRS assessments at 1 and 3 years. We ran longitudinal mixed-effects models assessing change in Addenbrooke’s Cognitive Examination–Revised (ACE-R) and mRS scores. For mRS score, we assessed longitudinal WMH volumes (cube root; percentage intracranial volume [ICV]), adjusting for age, NIHSS score, ACE-R, stroke subtype, and time to assessment. For ACE-R score, we additionally adjusted for ICV, mRS, premorbid IQ, and vascular risk factors. We then used a multivariate model to jointly assess changing cognition/mRS score, adjusted for prognostic variables, using all available data. Results We recruited 264 patients; mean age was 66.9 (SD 11.8) years; 41.7% were female; and median mRS score was 1 (interquartile range 1–2). One year after stroke, normalized WMH volumes were associated more strongly with 1-year ACE-R score (β = −0.259, 95% CI −0.407 to −0.111 more WMH per 1-point ACE-R decrease, p = 0.001) compared to subacute WMH volumes and ACE-R score (β = 0.105, 95% CI −0.265 to 0.054, p = 0.195). Three-year mRS score was associated with 3-year ACE-R score (β = −0.272, 95% CI −0.429 to −0.115, p = 0.001). Combined change in baseline-1-year jointly assessed ACE-R/mRS scores was associated with fluctuating WMH volumes (F = 9.3, p = 0.03). Discussion After stroke, fluctuating WMH mean that 1-year, but not baseline, WMH volumes are associated strongly with contemporaneous cognitive scores. Covarying longitudinal decline in cognition and independence after stroke, central to dementia diagnosis, is associated with increasing WMH volumes.
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Affiliation(s)
- Una Clancy
- Centre for Clinical Brain Sciences, Edinburgh Imaging and the UK Dementia Research Institute, University of Edinburgh, United Kingdom
| | - Stephen Dj Makin
- Centre for Clinical Brain Sciences, Edinburgh Imaging and the UK Dementia Research Institute, University of Edinburgh, United Kingdom.,Centre For Rural Health, Institute of Applied Health Sciences, University of Aberdeen, United Kingdom
| | - Caroline A McHutchison
- Centre for Clinical Brain Sciences, Edinburgh Imaging and the UK Dementia Research Institute, University of Edinburgh, United Kingdom
| | - Vera Cvoro
- Centre for Clinical Brain Sciences, Edinburgh Imaging and the UK Dementia Research Institute, University of Edinburgh, United Kingdom
| | - Francesca M Chappell
- Centre for Clinical Brain Sciences, Edinburgh Imaging and the UK Dementia Research Institute, University of Edinburgh, United Kingdom
| | - Maria Del C Valdés Hernández
- Centre for Clinical Brain Sciences, Edinburgh Imaging and the UK Dementia Research Institute, University of Edinburgh, United Kingdom
| | - Eleni Sakka
- Centre for Clinical Brain Sciences, Edinburgh Imaging and the UK Dementia Research Institute, University of Edinburgh, United Kingdom
| | - Fergus Doubal
- Centre for Clinical Brain Sciences, Edinburgh Imaging and the UK Dementia Research Institute, University of Edinburgh, United Kingdom
| | - Joanna M Wardlaw
- Centre for Clinical Brain Sciences, Edinburgh Imaging and the UK Dementia Research Institute, University of Edinburgh, United Kingdom
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Neuroinflammation and Neuropathology. NEUROSCIENCE AND BEHAVIORAL PHYSIOLOGY 2022; 52:196-201. [PMID: 35317271 PMCID: PMC8930459 DOI: 10.1007/s11055-022-01223-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 01/18/2021] [Indexed: 11/25/2022]
Abstract
This review addresses the current understanding of the role of autoimmune neuroinflammation in the pathogenesis of vascular, neurodegenerative, and other diseases of the nervous system. The mechanisms of responses of resident CNS cells (glial cells, astrocytes) and peripheral immune system cells are presented. The therapeutic potentials of phosphodiesterase inhibitors, which have antiaggregant properties and can suppress autoimmune inflammation, are discussed. The phosphodiesterase inhibitor dipyridamole is regarded as a potential drug for this purpose.
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Barisano G, Montagne A, Kisler K, Schneider JA, Wardlaw JM, Zlokovic BV. Blood-brain barrier link to human cognitive impairment and Alzheimer's Disease. NATURE CARDIOVASCULAR RESEARCH 2022; 1:108-115. [PMID: 35450117 PMCID: PMC9017393 DOI: 10.1038/s44161-021-00014-4] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 12/21/2021] [Indexed: 01/18/2023]
Abstract
Vascular dysfunction is frequently seen in disorders associated with cognitive impairment, dementia and Alzheimer's disease (AD). Recent advances in neuroimaging and fluid biomarkers suggest that vascular dysfunction is not an innocent bystander only accompanying neuronal dysfunction. Loss of cerebrovascular integrity, often referred to as breakdown in the blood-brain barrier (BBB), has recently shown to be an early biomarker of human cognitive dysfunction and possibly underlying mechanism of age-related cognitive decline. Damage to the BBB may initiate or further invoke a range of tissue injuries causing synaptic and neuronal dysfunction and cognitive impairment that may contribute to AD. Therefore, better understanding of how vascular dysfunction caused by BBB breakdown interacts with amyloid-β and tau AD biomarkers to confer cognitive impairment may lead to new ways of thinking about pathogenesis, and possibly treatment and prevention of early cognitive impairment, dementia and AD, for which we still do not have effective therapies.
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Affiliation(s)
- Giuseppe Barisano
- Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, USA
- These authors contributed equally: Giuseppe Barisano and Axel Montagne
| | - Axel Montagne
- Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- These authors contributed equally: Giuseppe Barisano and Axel Montagne
| | - Kassandra Kisler
- Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Julie A. Schneider
- Departments of Pathology and Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - Joanna M. Wardlaw
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
- UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK
| | - Berislav V. Zlokovic
- Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Alzheimer’s Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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Rudilosso S, Rodríguez-Vázquez A, Urra X, Arboix A. The Potential Impact of Neuroimaging and Translational Research on the Clinical Management of Lacunar Stroke. Int J Mol Sci 2022; 23:1497. [PMID: 35163423 PMCID: PMC8835925 DOI: 10.3390/ijms23031497] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/20/2022] [Accepted: 01/24/2022] [Indexed: 12/21/2022] Open
Abstract
Lacunar infarcts represent one of the most frequent subtypes of ischemic strokes and may represent the first recognizable manifestation of a progressive disease of the small perforating arteries, capillaries, and venules of the brain, defined as cerebral small vessel disease. The pathophysiological mechanisms leading to a perforating artery occlusion are multiple and still not completely defined, due to spatial resolution issues in neuroimaging, sparsity of pathological studies, and lack of valid experimental models. Recent advances in the endovascular treatment of large vessel occlusion may have diverted attention from the management of patients with small vessel occlusions, often excluded from clinical trials of acute therapy and secondary prevention. However, patients with a lacunar stroke benefit from early diagnosis, reperfusion therapy, and secondary prevention measures. In addition, there are new developments in the knowledge of this entity that suggest potential benefits of thrombolysis in an extended time window in selected patients, as well as novel therapeutic approaches targeting different pathophysiological mechanisms involved in small vessel disease. This review offers a comprehensive update in lacunar stroke pathophysiology and clinical perspective for managing lacunar strokes, in light of the latest insights from imaging and translational studies.
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Affiliation(s)
- Salvatore Rudilosso
- Comprehensive Stroke Center, Hospital Clínic of Barcelona, 08036 Barcelona, Spain; (S.R.); (A.R.-V.); (X.U.)
| | - Alejandro Rodríguez-Vázquez
- Comprehensive Stroke Center, Hospital Clínic of Barcelona, 08036 Barcelona, Spain; (S.R.); (A.R.-V.); (X.U.)
| | - Xabier Urra
- Comprehensive Stroke Center, Hospital Clínic of Barcelona, 08036 Barcelona, Spain; (S.R.); (A.R.-V.); (X.U.)
| | - Adrià Arboix
- Cerebrovascular Division, Department of Neurology, Hospital Universitari del Sagrat Cor, Universitat de Barcelona, 08034 Barcelona, Spain
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44
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Jung DH, Park B, Lee YJ. Relationship of the Triglyceride-Glucose Index with Subclinical White Matter Hypersensitivities of Presumed Vascular Origin Among Community-Dwelling Koreans. Int J Gen Med 2022; 15:603-608. [PMID: 35068939 PMCID: PMC8766995 DOI: 10.2147/ijgm.s346997] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 01/07/2022] [Indexed: 12/15/2022] Open
Abstract
Purpose The triglyceride-glucose (TyG) index, a widely accessible measure, has been a surrogate indicator of peripheral insulin resistance, and its clinical importance continues to grow in East Asia. We hypothesized that the TyG index is relevant to subclinical white matter hypersensitivities (WMHs) of presumed vascular origin among community-dwelling Koreans. Methods We investigated the relationship between the TyG index and WMHs on brain magnetic resonance imaging scans in 2417 Koreans over 45 years of age without a history of cancer, stroke, or ischemic heart disease. The study population was divided into four groups according to the TyG index quartiles. Using multiple logistic regression analysis, we assessed the odds ratios (ORs) and 95% confidence intervals (95% CIs) for WMHs across the TyG index quartiles. Results The prevalence of WMHs was significantly higher in the fourth TyG index quartile, with an overall rate of 9.3%. After adjusting for potential confounding variables, the ORs of WMHs for the TyG index quartiles were 1.00, 1.47 (95% CI, 0.91–2.40), 1.76 (95% CI, 1.05–2.97), and 6.79 (95% CI, 3.85–1.54), respectively. Conclusion We found that higher TyG index values were associated with the brain’s WMHs of presumed vascular origin. Our findings suggest that the serum TyG index could be an additional valuable biomarker for assessing the risk of cerebral small vessel disease in the preclinical stage.
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Affiliation(s)
- Dong-Hyuk Jung
- Department of Family Medicine, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Byoungjin Park
- Department of Family Medicine, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Yong-Jae Lee
- Department of Family Medicine, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
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45
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Poh L, Sim WL, Jo DG, Dinh QN, Drummond GR, Sobey CG, Chen CLH, Lai MKP, Fann DY, Arumugam TV. The role of inflammasomes in vascular cognitive impairment. Mol Neurodegener 2022; 17:4. [PMID: 35000611 PMCID: PMC8744307 DOI: 10.1186/s13024-021-00506-8] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 12/02/2021] [Indexed: 12/11/2022] Open
Abstract
There is an increasing prevalence of Vascular Cognitive Impairment (VCI) worldwide, and several studies have suggested that Chronic Cerebral Hypoperfusion (CCH) plays a critical role in disease onset and progression. However, there is a limited understanding of the underlying pathophysiology of VCI, especially in relation to CCH. Neuroinflammation is a significant contributor in the progression of VCI as increased systemic levels of the proinflammatory cytokine interleukin-1β (IL-1β) has been extensively reported in VCI patients. Recently it has been established that CCH can activate the inflammasome signaling pathways, involving NLRP3 and AIM2 inflammasomes that critically regulate IL-1β production. Given that neuroinflammation is an early event in VCI, it is important that we understand its molecular and cellular mechanisms to enable development of disease-modifying treatments to reduce the structural brain damage and cognitive deficits that are observed clinically in the elderly. Hence, this review aims to provide a comprehensive insight into the molecular and cellular mechanisms involved in the pathogenesis of CCH-induced inflammasome signaling in VCI.
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Affiliation(s)
- Luting Poh
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Wei Liang Sim
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Dong-Gyu Jo
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
| | - Quynh Nhu Dinh
- Centre for Cardiovascular Biology and Disease Research, Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC Australia
| | - Grant R. Drummond
- Centre for Cardiovascular Biology and Disease Research, Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC Australia
| | - Christopher G. Sobey
- Centre for Cardiovascular Biology and Disease Research, Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC Australia
| | - Christopher Li-Hsian Chen
- Memory Aging and Cognition Centre, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Mitchell K. P. Lai
- Memory Aging and Cognition Centre, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - David Y. Fann
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Centre for Healthy Longevity, National University Health System (NUHS), Singapore, Singapore
| | - Thiruma V. Arumugam
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
- Centre for Cardiovascular Biology and Disease Research, Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC Australia
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46
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Lee KH, Kang KM. Association between Cerebral Small Vessel and Alzheimer’s Disease. JOURNAL OF THE KOREAN SOCIETY OF RADIOLOGY 2022; 83:486-507. [PMID: 36238505 PMCID: PMC9514514 DOI: 10.3348/jksr.2022.0041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/15/2022] [Accepted: 05/16/2022] [Indexed: 11/15/2022]
Abstract
뇌소혈관질환은 뇌 자기공명영상에서 흔히 관찰되는 혈관성 변화로 뇌백질 고신호강도, 뇌미세출혈, 열공성 경색, 혈관주위공간 등을 포함한다. 이러한 혈관성 변화가 알츠하이머병(Alzheimer’s disease; 이하 AD)의 발병 및 진행과 관련되어 있고, 대표 병리인 베타 아밀로이드 및 타우 단백의 침착과도 연관되어 있다는 증거들이 축적되고 있다. 혈관성 변화는 생활 습관 개선이나 약물 치료를 통해 예방과 개선이 가능하기 때문에 뇌소혈관질환과 AD 및 AD 생체지표의 관련성을 연구하는 것이 중요하다. 본 종설에서는 AD와 AD 생체지표에 대해 간략히 소개하고, AD와 혈관성 변화의 관련성에 대해 축적된 증거들을 제시한 다음, 뇌소혈관질환의 병태 생리와 MR 영상 소견을 설명하고자 한다. 또 뇌소혈관질환과 AD 진단의 위험도 및 AD 생체지표와의 관련성에 대한 기존 연구 결과들을 정리하고자 한다.
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Affiliation(s)
- Kyung Hoon Lee
- Department of Radiology, Seoul National University Hospital, Seoul, Korea
| | - Koung Mi Kang
- Department of Radiology, Seoul National University Hospital, Seoul, Korea
- Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
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47
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Li S, Li G, Luo X, Huang Y, Wen L, Li J. Endothelial Dysfunction and Hyperhomocysteinemia-Linked Cerebral Small Vessel Disease: Underlying Mechanisms and Treatment Timing. Front Neurol 2021; 12:736309. [PMID: 34899561 PMCID: PMC8651556 DOI: 10.3389/fneur.2021.736309] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 11/01/2021] [Indexed: 02/05/2023] Open
Abstract
Cerebral small vessel disease (cSVD)—a common cause of stroke and vascular dementia—is a group of clinical syndromes that affects the brain's small vessels, including arterioles, capillaries, and venules. Its pathogenesis is not fully understood, and effective treatments are limited. Increasing evidence indicates that an elevated total serum homocysteine level is directly and indirectly associated with cSVD, and endothelial dysfunction plays an active role in this association. Hyperhomocysteinemia affects endothelial function through oxidative stress, inflammatory pathways, and epigenetic alterations at an early stage, even before the onset of small vessel injuries and the disease. Therefore, hyperhomocysteinemia is potentially an important therapeutic target for cSVD. However, decreasing the homocysteine level is not sufficiently effective, possibly due to delayed treatment, which underlying reason remains unclear. In this review, we examined endothelial dysfunction to understand the close relationship between hyperhomocysteinemia and cSVD and identify the optimal timing for the therapy.
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Affiliation(s)
- Shuang Li
- Department of Neurology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Guangjian Li
- Department of Neurology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xia Luo
- Department of Neurology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yan Huang
- Department of Neurology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Lan Wen
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jinglun Li
- Department of Neurology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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Nguyen B, Bix G, Yao Y. Basal lamina changes in neurodegenerative disorders. Mol Neurodegener 2021; 16:81. [PMID: 34876200 PMCID: PMC8650282 DOI: 10.1186/s13024-021-00502-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 11/17/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Neurodegenerative disorders are a group of age-associated diseases characterized by progressive degeneration of the structure and function of the CNS. Two key pathological features of these disorders are blood-brain barrier (BBB) breakdown and protein aggregation. MAIN BODY The BBB is composed of various cell types and a non-cellular component---the basal lamina (BL). Although how different cells affect the BBB is well studied, the roles of the BL in BBB maintenance and function remain largely unknown. In addition, located in the perivascular space, the BL is also speculated to regulate protein clearance via the meningeal lymphatic/glymphatic system. Recent studies from our laboratory and others have shown that the BL actively regulates BBB integrity and meningeal lymphatic/glymphatic function in both physiological and pathological conditions, suggesting that it may play an important role in the pathogenesis and/or progression of neurodegenerative disorders. In this review, we focus on changes of the BL and its major components during aging and in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). First, we introduce the vascular and lymphatic systems in the CNS. Next, we discuss the BL and its major components under homeostatic conditions, and summarize their changes during aging and in AD, PD, and ALS in both rodents and humans. The functional significance of these alterations and potential therapeutic targets are also reviewed. Finally, key challenges in the field and future directions are discussed. CONCLUSIONS Understanding BL changes and the functional significance of these changes in neurodegenerative disorders will fill the gap of knowledge in the field. Our goal is to provide a clear and concise review of the complex relationship between the BL and neurodegenerative disorders to stimulate new hypotheses and further research in this field.
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Affiliation(s)
- Benjamin Nguyen
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA, USA
| | - Gregory Bix
- Clinical Neuroscience Research Center, Tulane University School of Medicine, New Orleans, Louisiana, USA
- Departments of Neurosurgery and Neurology, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Yao Yao
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA, USA.
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, MDC 8, Tampa, Florida, 33612, USA.
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Song R, Pan KY, Xu H, Qi X, Buchman AS, Bennett DA, Xu W. Association of cardiovascular risk burden with risk of dementia and brain pathologies: A population-based cohort study. Alzheimers Dement 2021; 17:1914-1922. [PMID: 34310004 PMCID: PMC10266491 DOI: 10.1002/alz.12343] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 03/03/2021] [Accepted: 03/11/2021] [Indexed: 01/30/2023]
Abstract
INTRODUCTION The impact of cardiovascular risk burden on brain pathologies remains unclear. We aimed to examine the association of the Framingham General Cardiovascular Risk Score (FGCRS) with dementia risk, and brain pathologies. METHODS Within the Rush Memory and Aging Project, 1588 dementia-free participants were assessed on FGCRS at baseline and followed up to 21 years. During the follow-up, 621 participants died and underwent autopsies. RESULTS The multi-adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) of FGCRS were 1.03 (1.00-1.07) for dementia and 1.04 (1.01-1.07) for Alzheimer's disease (AD) dementia. Further, a higher FGCRS was associated with higher gross chronic cerebral infarctions (odds ratio [OR] 1.08, 95% CI 1.02-1.14), cerebral atherosclerosis (OR 1.10, 95% CI 1.03-1.17), and global AD pathology (OR 1.06, 95% CI 1.01-1.12). CONCLUSIONS A higher FGCRS is associated with an increased risk of dementia and AD dementia. Both vascular and AD pathologies in the brain may underlie this association.
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Affiliation(s)
- Ruixue Song
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
- Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin, China
| | - Kuan-Yu Pan
- Amsterdam University Medical Center, Vrije Universiteit, Department of Psychiatry, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands
| | - Hui Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
- Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin, China
| | - Xiuying Qi
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
- Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin, China
| | - Aron S. Buchman
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, 60612, USA
| | - David A. Bennett
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, 60612, USA
| | - Weili Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
- Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin, China
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
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50
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Liao FF, Lin G, Chen X, Chen L, Zheng W, Raghow R, Zhou FM, Shih AY, Tan XL. Endothelial Nitric Oxide Synthase-Deficient Mice: A Model of Spontaneous Cerebral Small-Vessel Disease. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:1932-1945. [PMID: 33711310 PMCID: PMC8647425 DOI: 10.1016/j.ajpath.2021.02.022] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 02/04/2021] [Accepted: 02/24/2021] [Indexed: 02/08/2023]
Abstract
Age-related cerebral small-vessel disease (CSVD) is a major cause of stroke and dementia. Despite a widespread acceptance of small-vessel arteriopathy, lacunar infarction, diffuse white matter injury, and cognitive impairment as four cardinal features of CSVD, a unifying pathologic mechanism of CSVD remains elusive. Herein, we introduce partial endothelial nitric oxide synthase (eNOS)-deficient mice as a model of age-dependent, spontaneous CSVD. These mice developed cerebral hypoperfusion and blood-brain barrier leakage at a young age, which progressively worsened with advanced age. Their brains exhibited elevated oxidative stress, astrogliosis, cerebral amyloid angiopathy, microbleeds, microinfarction, and white matter pathology. Partial eNOS-deficient mice developed gait disturbances at middle age, and hippocampus-dependent memory deficits at older ages. These mice also showed enhanced expression of bone morphogenetic protein 4 (BMP4) in brain pericytes before myelin loss and white matter pathology. Because BMP4 signaling not only promotes astrogliogenesis but also blocks oligodendrocyte differentiation, we posit that paracrine actions of BMP4, localized within the neurovascular unit, promote white matter disorganization and neurodegeneration. These observations point to BMP4 signaling pathway in the aging brain vasculature as a potential therapeutic target. Finally, because studies in partial eNOS-deficient mice corroborated recent clinical evidence that blood-brain barrier disruption is a primary cause of white matter pathology, the mechanism of impaired nitric oxide signaling-mediated CSVD warrants further investigation.
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Affiliation(s)
- Francesca-Fang Liao
- Department of Pharmacology, Addiction Science, Toxicology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee.
| | - Geng Lin
- Department of Pharmacology, Addiction Science, Toxicology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee; Department of Histology and Embryology, Basic Medical University, China Medical University, Shenyang, China
| | - Xingyong Chen
- Department of Pharmacology, Addiction Science, Toxicology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee; Department of Neurology, Fujian Provincial Hospital, Provincial Clinical College of Fujian Medical University, Fuzhou, China
| | - Ling Chen
- Department of Pharmacology, Addiction Science, Toxicology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee; Department of Cell Biology and Genetics, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Wei Zheng
- Department of Pharmacology, Addiction Science, Toxicology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee; Department of Histology and Embryology, Basic Medical University, China Medical University, Shenyang, China
| | - Rajendra Raghow
- Department of Pharmacology, Addiction Science, Toxicology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee
| | - Fu-Ming Zhou
- Department of Pharmacology, Addiction Science, Toxicology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee
| | - Andy Y Shih
- Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington
| | - Xing-Lin Tan
- Department of Pharmacology, Addiction Science, Toxicology, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee; Department of Neurology, Nanhai Hospital of Southern Medical University, Foshan, China
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