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Chen Y, Yang MJ, Huang H, Fang Y, Zhou X, Yu Z, Wang M, Bohnet-Joschko S, Luo X. Associations between white matter hyperintensities and physical activity: A sectional study in UK Biobank participants. J Clin Neurosci 2025; 135:111181. [PMID: 40117767 DOI: 10.1016/j.jocn.2025.111181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 02/13/2025] [Accepted: 03/10/2025] [Indexed: 03/23/2025]
Abstract
White matter hyperintensities (WMH) are key markers of cerebral small vessel disease (CSVD) linked to increased risks of stroke, dementia, and cognitive decline. Physical activity (PA) has been hypothesized to reduce WMH burden and preserve brain health, yet findings across studies remain mixed. This study examines the association between PA and WMH burden, as well as white matter integrity using diffusion tensor imaging (DTI) metrics, in a cohort of 10,868 participants from the UK Biobank. Participants were categorized into low, intermediate, and high PA tertiles based on accelerometer data. WMH volumes, normalized for head size, were classified into quintiles. Multilevel ordered logistic regression models revealed that high PA levels were significantly associated with reduced WMH burden (OR = 0.956, p = 0.026), while low PA levels increased the likelihood of higher WMH burden (OR = 1.148, p < 0.001). Subtype analyses indicated stronger associations between PA and periventricular WMH compared to deep WMH. Furthermore, DTI metrics demonstrated that higher PA levels were correlated with improved fractional anisotropy (FA) and reduced mean diffusivity (MD) in key white matter tracts, such as the corpus callosum and fornix, suggesting better white matter integrity. Our findings emphasize the potential neuroprotective effects of PA, particularly in mitigating WMH progression and preserving cognitive and motor functions. These results underscore the importance of promoting PA, especially in older adults, as a strategy to reduce the burden of CSVD and support brain health. Future longitudinal studies are needed to confirm causality and elucidate underlying mechanisms.
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Affiliation(s)
- Yucun Chen
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Mia Jiming Yang
- Chair of Management and Innovation in Health Care, Faculty of Management, Economics, and Society, Witten/Herdecke University, 58448 Witten, Germany
| | - Hao Huang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, China
| | - YuanYuan Fang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Xirui Zhou
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Zhiyuan Yu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, China
| | - Minghuan Wang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, China
| | - Sabine Bohnet-Joschko
- Chair of Management and Innovation in Health Care, Faculty of Management, Economics, and Society, Witten/Herdecke University, 58448 Witten, Germany
| | - Xiang Luo
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, China.
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Ridha M, Burke JF, Sekar P, Woo D, Hannawi Y. Antihypertensive Medication Class and Functional Outcomes After Nonlobar Intracerebral Hemorrhage. JAMA Netw Open 2025; 8:e2457770. [PMID: 39899295 PMCID: PMC11791703 DOI: 10.1001/jamanetworkopen.2024.57770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 11/26/2024] [Indexed: 02/04/2025] Open
Abstract
Importance Hypertension is the predominant pathology underlying nonlobar intracerebral hemorrhage (ICH), and antihypertensive agents have distinct biological implications for cerebral microvasculature. It is unknown if the class of antihypertensive medications initiated after ICH affects functional outcome beyond blood pressure (BP) control. Objective To ascertain the association between the class of antihypertensive agents initiated during hospitalization and 90-day functional outcome in nonlobar ICH. Design, Setting, and Participants This cohort study uses data from the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study, a case-control cohort study investigating ICH risk factors among Hispanic, non-Hispanic Black (hereafter Black), and non-Hispanic White (hereafter White) populations at 42 US hospitals from 2010 to 2015. Data for this analysis were examined from May to September 2024. ERICH study participants were selected for the present analysis if they survived hospitalization and had available covariate and outcome data. Individuals with complications that would limit antihypertensive choice were excluded. Exposures Initiation of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), calcium channel blocker, β-blocker, thiazide diuretic, and other antihypertensive medications during index hospitalization. Main Outcomes and Measures Primary outcome was a favorable functional outcome, defined as a 90-day (follow-up) modified Rankin Score score of 0 to 2 (score range: 0 [indicating no disability] to 6 [indicating death]). Mixed-effects logistic regression adjusted for demographic characteristics, medical history, ICH characteristics, BP measurement, total number of antihypertensive medications, and hospitalization site was used to calculate the odds of favorable functional outcome. Results Of the 1561 ERICH study participants in the analytic cohort, 1079 had nonlobar and 482 had lobar ICH. Among the 1079 participants in the nonlobar ICH group (mean [SD] age, 58.5 [12.9] years; 676 males [62.6%]; 429 Hispanic [39.8%], 388 Black [36.0%], and 262 White [24.4%] individuals), a total of 407 (37.7%) ACEIs or ARBs, 419 (38.8%) β-blockers, 503 (46.6%) calcium channel blockers, 180 (16.7%) thiazide diuretics, and 277 (25.7%) other antihypertensive classes were initiated during hospitalization (median [IQR], 3 [2-3] agents at discharge). At follow-up, 481 participants (44.6%) had a favorable functional outcome. Initiation of ACEI or ARB was associated with higher odds of favorable functional outcome (adjusted OR [AOR], 1.49; 95% CI, 1.08-2.05; P = .01). No other antihypertensive class was associated with functional outcome. Findings were consistent across several sensitivity analyses. The interaction with ACEI or ARB was mediated by the presence of radiographic features of cerebral small vessel disease (AOR, 3.04; 95% CI, 1.01-9.19; P = .049). No association with class of antihypertensive agent was observed in lobar ICH. Conclusions and Relevance This large cohort study found that initiation of ACEI or ARB was associated with favorable 90-day functional outcomes after nonlobar ICH. This finding supports a medication class-specific benefit in hypertensive arteriopathy.
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Affiliation(s)
- Mohamed Ridha
- Department of Neurology, The Ohio State University, Columbus
| | - James F. Burke
- Department of Neurology, The Ohio State University, Columbus
| | - Padmini Sekar
- Department of Neurology, University of Cincinnati, Cincinnati, Ohio
| | - Daniel Woo
- Department of Neurology, University of Cincinnati, Cincinnati, Ohio
| | - Yousef Hannawi
- Department of Neurology, The Ohio State University, Columbus
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He Z, Sun J. The role of the neurovascular unit in vascular cognitive impairment: Current evidence and future perspectives. Neurobiol Dis 2025; 204:106772. [PMID: 39710068 DOI: 10.1016/j.nbd.2024.106772] [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: 10/17/2024] [Revised: 12/12/2024] [Accepted: 12/16/2024] [Indexed: 12/24/2024] Open
Abstract
Vascular cognitive impairment (VCI) is a progressive cognitive impairment caused by cerebrovascular disease or vascular risk factors. It is the second most common type of cognitive impairment after Alzheimer's disease. The pathogenesis of VCI is complex, and neurovascular unit destruction is one of its important mechanisms. The neurovascular unit (NVU) is responsible for combining blood flow with brain activity and includes endothelial cells, pericytes, astrocytes and many regulatory nerve terminals. The concept of an NVU emphasizes that interactions between different types of cells are essential for maintaining brain homeostasis. A stable NVU is the basis of normal brain function. Therefore, understanding the structure and function of the neurovascular unit and its role in VCI development is crucial for gaining insights into its pathogenesis. This article reviews the structure and function of the neurovascular unit and its contribution to VCI, providing valuable information for early diagnosis and prevention.
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Affiliation(s)
- Zhidong He
- Department of Neurosurgery, China-Japan Union Hospital of Jilin University, No. 126 Xiantai Street, Changchun 130031, Jilin, China
| | - Jing Sun
- Department of Neurology, China-Japan Union Hospital of Jilin University, No. 126 Xiantai Street, Changchun 130031, Jilin, China..
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Blair G, Appleton JP, Mhlanga I, Woodhouse LJ, Doubal F, Bath PM, Wardlaw JM. Design of trials in lacunar stroke and cerebral small vessel disease: review and experience with the LACunar Intervention Trial 2 (LACI-2). Stroke Vasc Neurol 2024; 9:581-594. [PMID: 38569894 PMCID: PMC11791638 DOI: 10.1136/svn-2023-003022] [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: 12/05/2023] [Accepted: 03/02/2024] [Indexed: 04/05/2024] Open
Abstract
Cerebral small vessel disease (cSVD) causes lacunar stroke (25% of ischaemic strokes), haemorrhage, dementia, physical frailty, or is 'covert', but has no specific treatment. Uncertainties about the design of clinical trials in cSVD, which patients to include or outcomes to assess, may have delayed progress. Based on experience in recent cSVD trials, we reviewed ways to facilitate future trials in patients with cSVD.We assessed the literature and the LACunar Intervention Trial 2 (LACI-2) for data to inform choice of Participant, Intervention, Comparator, Outcome, including clinical versus intermediary endpoints, potential interventions, effect of outcome on missing data, methods to aid retention and reduce data loss. We modelled risk of missing outcomes by baseline prognostic variables in LACI-2 using binary logistic regression.Imaging versus clinical outcomes led to larger proportions of missing data. We present reasons for and against broad versus narrow entry criteria. We identified numerous repurposable drugs with relevant modes of action to test in various cSVD subtypes. Cognitive impairment is the most common clinical outcome after lacunar ischaemic stroke but was missing more frequently than dependency, quality of life or vascular events in LACI-2. Assessing cognitive status using Diagnostic and Statistical Manual for Mental Disorders Fifth Edition can use cognitive data from multiple sources and may help reduce data losses.Trials in patients with all cSVD subtypes are urgently needed and should use broad entry criteria and clinical outcomes and focus on ways to maximise collection of cognitive outcomes to avoid missing data.
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Affiliation(s)
| | - Jason P Appleton
- Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK
- Stroke, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Iris Mhlanga
- Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK
| | - Lisa J Woodhouse
- Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK
| | | | - Philip M Bath
- Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK
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Lin CC, Li CI, Liu CS, Lin CH, Yu J, Yang SY, Li TC. Mediation analysis of brain magnetic resonance imaging variables with all-cause and cardiovascular disease-specific mortalities in persons with type 2 diabetes. Acta Diabetol 2024:10.1007/s00592-024-02387-x. [PMID: 39441402 DOI: 10.1007/s00592-024-02387-x] [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: 04/12/2024] [Accepted: 10/02/2024] [Indexed: 10/25/2024]
Abstract
AIM Glucose variation (GV) has emerged as a predictor of morbidity and mortality in persons with diabetes. However, no study has examined whether brain magnetic resonance imaging (MRI) variables mediated the association between mortality and GV. MATERIALS AND METHODS This study was a retrospective cohort comprising 3,961 individuals with type 2 diabetes (T2D), whose electronic medical records were retrieved from a medical center between January 2001 and October 2021. GV was quantified using coefficient of variation of fasting plasma glucose (FPG-CV) and glycated hemoglobin (HbA1c). The MRI variables included the presence or absence of cerebrovascular abnormality and white matter hyperintensity (WMH). All deaths and deaths resulting from expanded cardiovascular disease (CVD) were identified through annual record linkage with National Death Datasets. Cox proportional hazards models were applied to evaluate associations of MRI variable or GV with mortality. Mediation analyses were performed to assess the relative contributions of MRI variables for GV on mortality. RESULTS Among 3,961 patients, 2,114 patients (53.4%) had cerebrovascular abnormality and 1,888 patients (47.7%) had WMH. The results showed cerebrovascular abnormality and WMHs were significantly associated with all-cause and expanded CVD mortality after considering GV. The largest mediated effects of GV on all-cause and expanded CVD mortality were observed by cerebrovascular abnormality (5.26% and 8.49%, respectively). CONCLUSIONS Our study suggests cerebrovascular abnormality and WMHs are important predictors of mortality in patients with T2D after considering GV. In addition, MRI variables of cerebrovascular abnormality expressed weak but significant mediation effect on the associations between GV and mortality.
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Affiliation(s)
- Cheng-Chieh Lin
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chia-Ing Li
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Chiu-Shong Liu
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chih-Hsueh Lin
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Jiaxin Yu
- Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan
| | - Shing-Yu Yang
- Department of Public Health, College of Public Health, China Medical University, No. 100, Sec. 1, Jingmao Rd., Beitun Dist, Taichung, 406040, Taiwan R.O.C
| | - Tsai-Chung Li
- Department of Public Health, College of Public Health, China Medical University, No. 100, Sec. 1, Jingmao Rd., Beitun Dist, Taichung, 406040, Taiwan R.O.C..
- Department of Audiology and Speech-Language Pathology, College of Medical and Health Sciences, Asia University, Taichung, Taiwan.
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Das AS, Mallick A, Mora SA, Keins S, Abramson JR, Castello JP, Pasi M, Kourkoulis CE, Rodriguez-Torres A, Warren AD, Gökçal E, Viswanathan A, Greenberg SM, Anderson CD, Rosand J, Biffi A, Gurol ME. Hypertension control after intracerebral hemorrhage among varying small vessel disease etiologies. Neurol Sci 2024; 45:4913-4921. [PMID: 38772978 DOI: 10.1007/s10072-024-07560-2] [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: 02/17/2024] [Accepted: 04/25/2024] [Indexed: 05/23/2024]
Abstract
INTRODUCTION Intracerebral hemorrhage (ICH) is attributable to cerebral small vessel disease (cSVD), which includes cerebral amyloid angiopathy (CAA) and hypertensive-cSVD (HTN-cSVD). HTN-cSVD includes patients with strictly deep ICH/microbleeds and mixed location ICH/microbleeds, the latter representing a more severe form of HTN-cSVD. We test the hypothesis that more severe forms of HTN-cSVD are related to worse hypertension control in long-term follow-up after ICH. METHODS From consecutive non-traumatic ICH patients admitted to a tertiary care center, we classified the ICH as CAA, strictly deep ICH/microbleeds, and mixed-location ICH/microbleeds. CSVD burden was quantified using a validated MRI-based score (range: 0-6 points). We created a multivariable (linear mixed effects) model adjusting for age, sex, race, year of inclusion, hypertension, and antihypertensive medication usage to investigate the association of average systolic blood pressure (SBP) during follow-up with cSVD etiology/severity. RESULTS 796 ICH survivors were followed for a median of 48.8 months (IQR 41.5-60.4). CAA-related ICH survivors (n = 373) displayed a lower median SBP (138 mmHg, IQR 133-142 mmHg) compared to those of strictly deep ICH (n = 222, 141 mmHg, IQR 136-143 mmHg, p = 0.04), and mixed location ICH/microbleeds (n = 201, 142 mmHg, IQR 135-144 mmHg, p = 0.02). In the multivariable analysis, mixed location ICH/microbleeds (effect: + 3.8 mmHg, SE: 1.3 mmHg, p = 0.01) and increasing cSVD severity (+ 1.8 mmHg per score point, SE: 0.8 mmHg, p = 0.03) were associated with higher SBP in follow-up. CONCLUSION CSVD severity and subtype predicts long-term hypertension control in ICH patients.
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Affiliation(s)
- Alvin S Das
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Lowry Medical Office Building, Ste 9A-05, Boston, MA, 02215, USA.
| | - Akashleena Mallick
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
- Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Samantha A Mora
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
- Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Sophia Keins
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Jessica R Abramson
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Juan Pablo Castello
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Marco Pasi
- Université de Tours, CHU Tours, Tours, France
| | - Christina E Kourkoulis
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Axana Rodriguez-Torres
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Andrew D Warren
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Elif Gökçal
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Anand Viswanathan
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Steven M Greenberg
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Christopher D Anderson
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
- Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jonathan Rosand
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
- Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Alessandro Biffi
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
- Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - M Edip Gurol
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
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Mok VCT, Cai Y, Markus HS. Vascular cognitive impairment and dementia: Mechanisms, treatment, and future directions. Int J Stroke 2024; 19:838-856. [PMID: 39283037 PMCID: PMC11490097 DOI: 10.1177/17474930241279888] [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: 08/17/2024] [Accepted: 08/17/2024] [Indexed: 10/21/2024]
Abstract
Worldwide, around 50 million people live with dementia, and this number is projected to triple by 2050. It has been estimated that 20% of all dementia cases have a predominant cerebrovascular pathology, while perhaps another 20% of vascular diseases contribute to a mixed dementia picture. Therefore, the vascular contribution to dementia affects 20 million people currently and will increase markedly in the next few decades, particularly in lower- and middle-income countries.In this review, we discuss the mechanisms of vascular cognitive impairment (VCI) and review management. VCI refers to the spectrum of cerebrovascular pathologies that contribute to any degree of cognitive impairment, ranging from subjective cognitive decline, to mild cognitive impairment, to dementia. While acute cognitive decline occurring soon after a stroke is the most recognized form of VCI, chronic cerebrovascular disease, in particular cerebral small-vessel disease, can cause insidious cognitive decline in the absence of stroke. Moreover, cerebrovascular disease not only commonly co-occurs with Alzheimer's disease (AD) and increases the probability that AD pathology will result in clinical dementia, but may also contribute etiologically to the development of AD pathologies.Despite its enormous health and economic impact, VCI has been a neglected research area, with few adequately powered trials of therapies, resulting in few proven treatments. Current management of VCI emphasizes prevention and treatment of stroke and vascular risk factors, with most evidence for intensive hypertension control. Reperfusion therapies in acute stroke may attenuate the risk of VCI. Associated behavioral symptoms such as apathy and poststroke emotionalism are common. We also highlight novel treatment strategies that will hopefully lead to new disease course-modifying therapies. Finally, we highlight the importance of including cognitive endpoints in large cardiovascular prevention trials and the need for an increased research focus and funding for this important area.
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Affiliation(s)
- Vincent Chung Tong Mok
- Lau Tat-chuen Research Centre of Brain Degenerative Diseases in Chinese, Therese Pei Fong Chow Research Centre for Prevention of Dementia, Lui Che Woo Institute of Innovative Medicine, Gerald Choa Neuroscience Institute, Li Ka Shing Institute of Health Science, Division of Neurology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Yuan Cai
- Lau Tat-chuen Research Centre of Brain Degenerative Diseases in Chinese, Therese Pei Fong Chow Research Centre for Prevention of Dementia, Lui Che Woo Institute of Innovative Medicine, Gerald Choa Neuroscience Institute, Li Ka Shing Institute of Health Science, Division of Neurology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Hugh S Markus
- Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
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Muir RT, Smith EE. The Spectrum of Cerebral Small Vessel Disease: Emerging Pathophysiologic Constructs and Management Strategies. Neurol Clin 2024; 42:663-688. [PMID: 38937035 DOI: 10.1016/j.ncl.2024.03.003] [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: 06/29/2024]
Abstract
Cerebral small vessel disease (CSVD) is a spectrum of disorders that affect small arterioles, venules, cortical and leptomeningeal vessels, perivascular spaces, and the integrity of neurovascular unit, blood brain barrier, and surrounding glia and neurons. CSVD is an important cause of lacunar ischemic stroke and sporadic hemorrhagic stroke, as well as dementia-which will constitute some of the most substantive population and public health challenges over the next century. This article provides an overview of updated pathophysiologic frameworks of CSVD; discusses common and underappreciated clinical and neuroimaging manifestations of CSVD; and reviews emerging genetic risk factors linked to sporadic CSVD.
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Affiliation(s)
- Ryan T Muir
- Calgary Stroke Program, Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada; Department of Community Health Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 1N4, Canada
| | - Eric E Smith
- Calgary Stroke Program, Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada; Department of Community Health Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
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Abouzari M, Abiri A, Tawk K, Tsang C, Patel B, Khoshsar A, Djalilian HR. White Matter Hyperintensity in Patients with Sudden Sensorineural Hearing Loss. Diagnostics (Basel) 2024; 14:1109. [PMID: 38893635 PMCID: PMC11171904 DOI: 10.3390/diagnostics14111109] [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: 04/09/2024] [Revised: 05/20/2024] [Accepted: 05/24/2024] [Indexed: 06/21/2024] Open
Abstract
OBJECTIVE To compare white matter hyperintensities (WMHs) on T2-weighted magnetic resonance imaging (MRI) of patients with sudden sensorineural hearing loss (SSNHL) and analyze subpopulations with age-matched controls. METHODS T2-weighted MRI scans of 150 patients with SSNHL were assessed for WMHs and compared with the data of 148 healthy age-matched adults. Assessments of WMHs included independent grading of deep white matter hyperintensities (DWMHs) and periventricular hyperintensities (PVHs). WMH severity was visually rated using the Fazekas and Mirsen scales by two independent observers. RESULTS Fazekas grades for PVHs (p < 0.001) and DWMHs (p < 0.001) of SSNHL patients were found to be significantly greater than those of healthy participants. The average Mirsen grades for DWMHs of healthy and SSNHL patients were evaluated to be 0.373 ± 0.550 and 2.140 ± 0.859, respectively. Mirsen grades for DWMHs of SSNHL patients were found to be significantly greater (p < 0.001) than those of healthy participants. The Mirsen scale was found to have higher sensitivity (p < 0.001) than the Fazekas scale in grading PVHs and DWMHs. No significant difference (p = 0.24) was found in specificities between the two scales. CONCLUSIONS Patients with sudden hearing loss have a much higher likelihood of having periventricular and deep white matter hyperintensities compared to age-matched controls. These findings indicate that sudden hearing loss patients are more likely to have microvascular changes in the brain, which may indicate a vascular and/or migraine origin to sudden sensorineural hearing loss.
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Affiliation(s)
- Mehdi Abouzari
- Department of Otolaryngology–Head and Neck Surgery, University of California, Irvine, CA 92697, USA
| | - Arash Abiri
- Department of Otolaryngology–Head and Neck Surgery, University of California, Irvine, CA 92697, USA
- Department of Biomedical Engineering, University of California, Irvine, CA 92697, USA
| | - Karen Tawk
- Department of Otolaryngology–Head and Neck Surgery, University of California, Irvine, CA 92697, USA
| | - Cynthia Tsang
- Department of Otolaryngology–Head and Neck Surgery, University of California, Irvine, CA 92697, USA
| | - Beenish Patel
- Department of Biomedical Engineering, University of California, Irvine, CA 92697, USA
| | - Avissa Khoshsar
- Department of Otolaryngology–Head and Neck Surgery, University of California, Irvine, CA 92697, USA
| | - Hamid R. Djalilian
- Department of Otolaryngology–Head and Neck Surgery, University of California, Irvine, CA 92697, USA
- Department of Biomedical Engineering, University of California, Irvine, CA 92697, USA
- Department of Neurological Surgery, University of California, Irvine, CA 92697, USA
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Sargurupremraj M, Soumaré A, Bis JC, Surakka I, Jürgenson T, Joly P, Knol MJ, Wang R, Yang Q, Satizabal CL, Gudjonsson A, Mishra A, Bouteloup V, Phuah CL, van Duijn CM, Cruchaga C, Dufouil C, Chêne G, Lopez OL, Psaty BM, Tzourio C, Amouyel P, Adams HH, Jacqmin-Gadda H, Ikram MA, Gudnason V, Milani L, Winsvold BS, Hveem K, Matthews PM, Longstreth WT, Seshadri S, Launer LJ, Debette S. Genetic Complexities of Cerebral Small Vessel Disease, Blood Pressure, and Dementia. JAMA Netw Open 2024; 7:e2412824. [PMID: 38776079 PMCID: PMC11112447 DOI: 10.1001/jamanetworkopen.2024.12824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 03/21/2024] [Indexed: 05/25/2024] Open
Abstract
Importance Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain. Objective To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential epidemiologic biases. Design, Setting, and Participants This study first examined the association of genetically determined WMH burden, stroke, and BP levels with Alzheimer disease (AD) in a 2-sample mendelian randomization (2SMR) framework. Second, using population-based studies (1979-2018) with prospective dementia surveillance, the genetic association of WMH, stroke, and BP with incident all-cause dementia was examined. Data analysis was performed from July 26, 2020, through July 24, 2022. Exposures Genetically determined WMH burden and BP levels, as well as genetic liability to stroke derived from genome-wide association studies (GWASs) in European ancestry populations. Main Outcomes and Measures The association of genetic instruments for WMH, stroke, and BP with dementia was studied using GWASs of AD (defined clinically and additionally meta-analyzed including both clinically diagnosed AD and AD defined based on parental history [AD-meta]) for 2SMR and incident all-cause dementia for longitudinal analyses. Results In 2SMR (summary statistics-based) analyses using AD GWASs with up to 75 024 AD cases (mean [SD] age at AD onset, 75.5 [4.4] years; 56.9% women), larger WMH burden showed evidence for a causal association with increased risk of AD (odds ratio [OR], 1.43; 95% CI, 1.10-1.86; P = .007, per unit increase in WMH risk alleles) and AD-meta (OR, 1.19; 95% CI, 1.06-1.34; P = .008), after accounting for pulse pressure for the former. Blood pressure traits showed evidence for a protective association with AD, with evidence for confounding by shared genetic instruments. In the longitudinal (individual-level data) analyses involving 10 699 incident all-cause dementia cases (mean [SD] age at dementia diagnosis, 74.4 [9.1] years; 55.4% women), no significant association was observed between larger WMH burden and incident all-cause dementia (hazard ratio [HR], 1.02; 95% CI, 1.00-1.04; P = .07). Although all exposures were associated with mortality, with the strongest association observed for systolic BP (HR, 1.04; 95% CI, 1.03-1.06; P = 1.9 × 10-14), there was no evidence for selective survival bias during follow-up using illness-death models. In secondary analyses using polygenic scores, the association of genetic liability to stroke, but not genetically determined WMH, with dementia outcomes was attenuated after adjusting for interim stroke. Conclusions These findings suggest that WMH is a primary vascular factor associated with dementia risk, emphasizing its significance in preventive strategies for dementia. Future studies are warranted to examine whether this finding can be generalized to non-European populations.
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Affiliation(s)
- Muralidharan Sargurupremraj
- Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France
- Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio
| | - Aicha Soumaré
- Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France
| | - Joshua C. Bis
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle
| | - Ida Surakka
- Department of Internal Medicine, University of Michigan, Ann Arbor
| | - Tuuli Jürgenson
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Pierre Joly
- Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France
| | - Maria J. Knol
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Ruiqi Wang
- School of Public Health, Boston University and the National Heart, Lung, and Blood Institute Framingham Heart Study, Boston, Massachusetts
- Department of Neurology, Boston University School of Medicine, Boston, Massachusetts
| | - Qiong Yang
- School of Public Health, Boston University and the National Heart, Lung, and Blood Institute Framingham Heart Study, Boston, Massachusetts
- Department of Neurology, Boston University School of Medicine, Boston, Massachusetts
| | - Claudia L. Satizabal
- Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio
- School of Public Health, Boston University and the National Heart, Lung, and Blood Institute Framingham Heart Study, Boston, Massachusetts
- Department of Neurology, Boston University School of Medicine, Boston, Massachusetts
| | | | - Aniket Mishra
- Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France
| | - Vincent Bouteloup
- Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France
| | - Chia-Ling Phuah
- Department of Neurology, Washington University School of Medicine & Barnes-Jewish Hospital, St Louis, Missouri
- NeuroGenomics and Informatics Center, Washington University in St Louis, St Louis, Missouri
| | - Cornelia M. van Duijn
- Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Carlos Cruchaga
- NeuroGenomics and Informatics Center, Washington University in St Louis, St Louis, Missouri
- Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri
- Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, Missouri
| | - Carole Dufouil
- Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France
| | - Geneviève Chêne
- Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France
- Department of Public Health, CHU de Bordeaux, Bordeaux, France
| | - Oscar L. Lopez
- Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Bruce M. Psaty
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle
- Department of Epidemiology, University of Washington, Seattle
- Department of Health Systems and Population Health, University of Washington, Seattle
| | - Christophe Tzourio
- Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France
- Department of Public Health, CHU de Bordeaux, Bordeaux, France
| | - Philippe Amouyel
- INSERM U1167, University of Lille, Institut Pasteur de Lille, Lille, France
- Department of Epidemiology and Public Health, CHRU de Lille, Lille, France
| | - Hieab H. Adams
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
- Latin American Brain Health (BrainLat), Universidad Adolfo Ibáñez, Santiago, Chile
| | - Hélène Jacqmin-Gadda
- Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France
| | - Mohammad Arfan Ikram
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Vilmundur Gudnason
- Icelandic Heart Association, Kopavogur, Iceland
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Lili Milani
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Bendik S. Winsvold
- Division of Clinical Neuroscience, Department of Research and Innovation, Oslo University Hospital, Oslo, Norway
- K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Department of Neurology, Oslo University Hospital, Oslo, Norway
| | - Kristian Hveem
- K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- HUNT Research Centre, Department of Public Health and Nursing, Norwegian University of Science and Technology, Levanger, Norway
| | - Paul M. Matthews
- Department of Brain Sciences, Imperial College London, London, United Kingdom
- UK Dementia Research Institute, Imperial College London, London, United Kingdom
- Data Science Institute, Imperial College London, London, United Kingdom
| | - W. T. Longstreth
- Department of Epidemiology, University of Washington, Seattle
- Department of Neurology, University of Washington, Seattle
| | - Sudha Seshadri
- Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio
- School of Public Health, Boston University and the National Heart, Lung, and Blood Institute Framingham Heart Study, Boston, Massachusetts
- Department of Neurology, Boston University School of Medicine, Boston, Massachusetts
| | - Lenore J. Launer
- Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, Bethesda, Maryland
| | - Stéphanie Debette
- Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France
- School of Public Health, Boston University and the National Heart, Lung, and Blood Institute Framingham Heart Study, Boston, Massachusetts
- Institute for Neurodegenerative Diseases, Department of Neurology, Bordeaux University Hospital, Bordeaux, France
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11
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Huang WQ, Lin Q, Tzeng CM. Leukoaraiosis: Epidemiology, Imaging, Risk Factors, and Management of Age-Related Cerebral White Matter Hyperintensities. J Stroke 2024; 26:131-163. [PMID: 38836265 PMCID: PMC11164597 DOI: 10.5853/jos.2023.02719] [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: 08/18/2023] [Accepted: 01/15/2024] [Indexed: 06/06/2024] Open
Abstract
Leukoaraiosis (LA) manifests as cerebral white matter hyperintensities on T2-weighted magnetic resonance imaging scans and corresponds to white matter lesions or abnormalities in brain tissue. Clinically, it is generally detected in the early 40s and is highly prevalent globally in individuals aged >60 years. From the imaging perspective, LA can present as several heterogeneous forms, including punctate and patchy lesions in deep or subcortical white matter; lesions with periventricular caps, a pencil-thin lining, and smooth halo; as well as irregular lesions, which are not always benign. Given its potential of having deleterious effects on normal brain function and the resulting increase in public health burden, considerable effort has been focused on investigating the associations between various risk factors and LA risk, and developing its associated clinical interventions. However, study results have been inconsistent, most likely due to potential differences in study designs, neuroimaging methods, and sample sizes as well as the inherent neuroimaging heterogeneity and multi-factorial nature of LA. In this article, we provided an overview of LA and summarized the current knowledge regarding its epidemiology, neuroimaging classification, pathological characteristics, risk factors, and potential intervention strategies.
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Affiliation(s)
- Wen-Qing Huang
- Department of Central Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qing Lin
- Department of Neurology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Xiamen Clinical Research Center for Neurological Diseases, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Fujian Provincial Clinical Research Center for Brain Diseases, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- The Third Clinical College, Fujian Medical University, Fuzhou, Fujian, China
| | - Chi-Meng Tzeng
- Translational Medicine Research Center, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China
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12
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Boockvar KS, Huan T, Curyto K, Lee S, Intrator O. Increase in blood pressure precedes distress behavior in nursing home residents with dementia. PLoS One 2024; 19:e0298281. [PMID: 38687764 PMCID: PMC11060555 DOI: 10.1371/journal.pone.0298281] [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: 07/13/2023] [Accepted: 01/22/2024] [Indexed: 05/02/2024] Open
Abstract
BACKGROUND Distress behaviors in dementia (DBD) likely increase sympathetic nervous system activity. The aim of this study was to examine the associations among DBD, blood pressure (BP), and intensity of antihypertensive treatment, in nursing home (NH) residents with dementia. METHODS We identified long-stay Veterans Affairs NH residents with dementia in 2019-20 electronic health data. Each individual with a BP reading and a DBD incident according to a structured behavior note on a calendar day (DBD group) was compared with an individual with a BP reading but without a DBD incident on that same day (comparison group). In each group we calculated daily mean BP from 14 days before to 7 days after the DBD incident day. We then calculated the change in BP between the DBD incident day and, as baseline, the 7-day average of BP 1 week prior, and tested for differences between DBD and comparison groups in a generalized estimating equations multivariate model. RESULTS The DBD and comparison groups consisted of 707 and 2328 individuals, respectively. The DBD group was older (74 vs. 72 y), was more likely to have severe cognitive impairment (13% vs. 8%), and had worse physical function scores (15 vs. 13 on 28-point scale). In the DBD group, mean systolic BP on the DBD incident day was 1.6 mmHg higher than baseline (p < .001), a change that was not observed in the comparison group. After adjusting for covariates, residents in the DBD group, but not the comparison group, had increased likelihood of having systolic BP > = 160 mmHg on DBD incident days (OR 1.02; 95%CI 1.00-1.03). Systolic BP in the DBD group began to rise 7 days before the DBD incident day and this rise persisted 1 week after. There were no significant changes in mean number of antihypertensive medications over this time period in either group. CONCLUSIONS NH residents with dementia have higher BP when they experience DBD, and BP rises 7 days before the DBD incident. Clinicians should be aware of these findings when deciding intensity of BP treatment.
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Affiliation(s)
- Kenneth S. Boockvar
- Division of Gerontology, Geriatrics, and Palliative Care, University of Alabama, Birmingham, Alabama, United States of America
- Geriatrics Research, Education, and Clinical Center, Birmingham VA Health Care System, Birmingham, Alabama, United States of America
- Institute on Aging, The New Jewish Home, New York, New York, United States of America
| | - Tianwen Huan
- University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America
- Geriatrics & Extended Care Data Analysis Center, Canandaigua VAMC, Canandaigua, New York, United States of America
| | - Kimberly Curyto
- VA Western New York Healthcare System, Center for Integrated Healthcare, Buffalo, New York, United States of America
| | - Sei Lee
- University of California, San Francisco, California, United States of America
- San Francisco VA Health Care System, San Francisco, California, United States of America
| | - Orna Intrator
- University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America
- Geriatrics & Extended Care Data Analysis Center, Canandaigua VAMC, Canandaigua, New York, United States of America
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13
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Ip BYM, Ko H, Lam BYK, Au LWC, Lau AYL, Huang J, Kwok AJ, Leng X, Cai Y, Leung TWH, Mok VCT. Current and Future Treatments of Vascular Cognitive Impairment. Stroke 2024; 55:822-839. [PMID: 38527144 DOI: 10.1161/strokeaha.123.044174] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2024]
Affiliation(s)
- Bonaventure Yiu Ming Ip
- Division of Neurology, Department of Medicine and Therapeutics (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Li Ka Shing Institute of Health Sciences (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Margaret K. L. Cheung Research Centre for Management of Parkinsonism (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., C.Y., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Lau Tat-Chuen Research Centre of Brain Degenerative Diseases in Chinese (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., C.Y., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., C.Y., V.C.T.M.)
- Kwok Tak Seng Centre for Stroke Research and Intervention, Hong Kong SAR, China (B.Y.M.I., X.L., T.W.H.L.)
| | - Ho Ko
- Division of Neurology, Department of Medicine and Therapeutics (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Li Ka Shing Institute of Health Sciences (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Margaret K. L. Cheung Research Centre for Management of Parkinsonism (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., C.Y., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Lau Tat-Chuen Research Centre of Brain Degenerative Diseases in Chinese (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., C.Y., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., C.Y., V.C.T.M.)
| | - Bonnie Yin Ka Lam
- Division of Neurology, Department of Medicine and Therapeutics (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Li Ka Shing Institute of Health Sciences (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Margaret K. L. Cheung Research Centre for Management of Parkinsonism (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., C.Y., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Lau Tat-Chuen Research Centre of Brain Degenerative Diseases in Chinese (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., C.Y., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., C.Y., V.C.T.M.)
| | - Lisa Wing Chi Au
- Division of Neurology, Department of Medicine and Therapeutics (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Li Ka Shing Institute of Health Sciences (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Margaret K. L. Cheung Research Centre for Management of Parkinsonism (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., C.Y., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Lau Tat-Chuen Research Centre of Brain Degenerative Diseases in Chinese (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., C.Y., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., C.Y., V.C.T.M.)
| | - Alexander Yuk Lun Lau
- Division of Neurology, Department of Medicine and Therapeutics (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Margaret K. L. Cheung Research Centre for Management of Parkinsonism (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., C.Y., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Lau Tat-Chuen Research Centre of Brain Degenerative Diseases in Chinese (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., C.Y., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
| | - Junzhe Huang
- Division of Neurology, Department of Medicine and Therapeutics (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Li Ka Shing Institute of Health Sciences (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Margaret K. L. Cheung Research Centre for Management of Parkinsonism (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., C.Y., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Lau Tat-Chuen Research Centre of Brain Degenerative Diseases in Chinese (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., C.Y., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., C.Y., V.C.T.M.)
| | - Andrew John Kwok
- Division of Neurology, Department of Medicine and Therapeutics (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Li Ka Shing Institute of Health Sciences (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Lau Tat-Chuen Research Centre of Brain Degenerative Diseases in Chinese (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., C.Y., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., C.Y., V.C.T.M.)
| | - Xinyi Leng
- Division of Neurology, Department of Medicine and Therapeutics (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Li Ka Shing Institute of Health Sciences (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Kwok Tak Seng Centre for Stroke Research and Intervention, Hong Kong SAR, China (B.Y.M.I., X.L., T.W.H.L.)
| | - Yuan Cai
- Division of Neurology, Department of Medicine and Therapeutics (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Li Ka Shing Institute of Health Sciences (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Margaret K. L. Cheung Research Centre for Management of Parkinsonism (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., C.Y., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Lau Tat-Chuen Research Centre of Brain Degenerative Diseases in Chinese (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., C.Y., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., C.Y., V.C.T.M.)
| | - Thomas Wai Hong Leung
- Division of Neurology, Department of Medicine and Therapeutics (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Li Ka Shing Institute of Health Sciences (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Kwok Tak Seng Centre for Stroke Research and Intervention, Hong Kong SAR, China (B.Y.M.I., X.L., T.W.H.L.)
| | - Vincent Chung Tong Mok
- Division of Neurology, Department of Medicine and Therapeutics (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Li Ka Shing Institute of Health Sciences (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., X.L., C.Y., T.W.H.L., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Margaret K. L. Cheung Research Centre for Management of Parkinsonism (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., C.Y., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Lau Tat-Chuen Research Centre of Brain Degenerative Diseases in Chinese (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., A.Y.L.L., J.H., A.J.K., C.Y., V.C.T.M.), Faculty of Medicine, The Chinese University of Hong Kong
- Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong (B.Y.M.I., H.K., B.Y.K.L., L.W.C.A., J.H., A.J.K., C.Y., V.C.T.M.)
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14
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Scheuermann BC, Parr SK, Schulze KM, Kunkel ON, Turpin VG, Liang J, Ade CJ. Associations of Cerebrovascular Regulation and Arterial Stiffness With Cerebral Small Vessel Disease: A Systematic Review and Meta-Analysis. J Am Heart Assoc 2023; 12:e032616. [PMID: 37930079 PMCID: PMC10727345 DOI: 10.1161/jaha.123.032616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 10/24/2023] [Indexed: 11/07/2023]
Abstract
BACKGROUND Cerebral small vessel disease (cSVD) is a major contributing factor to ischemic stroke and dementia. However, the vascular pathologies of cSVD remain inconclusive. The aim of this systematic review and meta-analysis was to characterize the associations between cSVD and cerebrovascular reactivity (CVR), cerebral autoregulation, and arterial stiffness (AS). METHODS AND RESULTS MEDLINE, Web of Science, and Embase were searched from inception to September 2023 for studies reporting CVR, cerebral autoregulation, or AS in relation to radiological markers of cSVD. Data were extracted in predefined tables, reviewed, and meta-analyses performed using inverse-variance random effects models to determine pooled odds ratios (ORs). A total of 1611 studies were identified; 142 were included in the systematic review, of which 60 had data available for meta-analyses. Systematic review revealed that CVR, cerebral autoregulation, and AS were consistently associated with cSVD (80.4%, 78.6%, and 85.4% of studies, respectively). Meta-analysis in 7 studies (536 participants, 32.9% women) revealed a borderline association between impaired CVR and cSVD (OR, 2.26 [95% CI, 0.99-5.14]; P=0.05). In 37 studies (27 952 participants, 53.0% women) increased AS, per SD, was associated with cSVD (OR, 1.24 [95% CI, 1.15-1.33]; P<0.01). Meta-regression adjusted for comorbidities accounted for one-third of the AS model variance (R2=29.4%, Pmoderators=0.02). Subgroup analysis of AS studies demonstrated an association with white matter hyperintensities (OR, 1.42 [95% CI, 1.18-1.70]; P<0.01). CONCLUSIONS The collective findings of the present systematic review and meta-analyses suggest an association between cSVD and impaired CVR and elevated AS. However, longitudinal investigations into vascular stiffness and regulatory function as possible risk factors for cSVD remain warranted.
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Affiliation(s)
| | - Shannon K. Parr
- Department of KinesiologyKansas State UniversityManhattanKSUSA
| | | | | | | | - Jia Liang
- Department of Biostatistics, St. Jude Children’s Research HospitalMemphisTNUSA
| | - Carl J. Ade
- Department of KinesiologyKansas State UniversityManhattanKSUSA
- Department of Physician’s Assistant Studies, Kansas State UniversityManhattanKSUSA
- Johnson Cancer Research CenterKansas State UniversityManhattanKSUSA
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15
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Busby N, Newman-Norlund R, Wilmskoetter J, Johnson L, Rorden C, Gibson M, Roth R, Wilson S, Fridriksson J, Bonilha L. Longitudinal Progression of White Matter Hyperintensity Severity in Chronic Stroke Aphasia. Arch Rehabil Res Clin Transl 2023; 5:100302. [PMID: 38163020 PMCID: PMC10757197 DOI: 10.1016/j.arrct.2023.100302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024] Open
Abstract
Objective To determine whether longitudinal progression of small vessel disease in chronic stroke survivors is associated with longitudinal worsening of chronic aphasia severity. Design A longitudinal retrospective study. Severity of white matter hyperintensities (WMHs) as a marker for small vessel disease was assessed on fluid-attenuated inversion recovery (FLAIR) scans using the Fazekas scale, with ratings for deep WMHs (DWMHs) and periventricular WMHs (PVHs). Setting University research laboratories. Participants This study includes data from 49 chronic stroke survivors with aphasia (N=49; 15 women, 34 men, age range=32-81 years, >6 months post-stroke, stroke type: [46 ischemic, 3 hemorrhagic], community dwelling). All participants completed the Western Aphasia Battery-Revised (WAB) and had FLAIR scans at 2 timepoints (average years between timepoints: 1.87 years, SD=3.21 years). Interventions Not applicable. Main Outcome Measures Change in white matter hyperintensity severity (calculated using the Fazekas scale) and change in aphasia severity (difference in Western Aphasia Battery scores) were calculated between timepoints. Separate stepwise regression models were used to identify predictors of WMH severity change, with lesion volume, age, time between timepoints, body mass index (BMI), and presence of diabetes as independent variables. Additional stepwise regression models investigated predictors of change in aphasia severity, with PVH change, DWMH change, lesion volume, time between timepoints, and age as independent predictors. Results 22.5% of participants (11/49) had increased WMH severity. Increased BMI was associated with increases in PVH severity (P=.007), whereas the presence of diabetes was associated with increased DWMH severity (P=.002). Twenty-five percent of participants had increased aphasia severity which was significantly associated with increased severity of PVH (P<.001, 16.8% variance explained). Conclusion Increased small vessel disease burden is associated with contributing to chronic changes in aphasia severity. These findings support the idea that good cardiovascular risk factor control may play an important role in the prevention of long-term worsening of aphasic symptoms.
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Affiliation(s)
- Natalie Busby
- Department of Communication Sciences and Disorders, University of South Carolina, Columbia, SC
| | | | - Janina Wilmskoetter
- Department of Neurology, Medical University of South Carolina, Charleston, SC
| | - Lisa Johnson
- Department of Communication Sciences and Disorders, University of South Carolina, Columbia, SC
| | - Chris Rorden
- Department of Psychology, University of South Carolina, Columbia, SC
| | - Makayla Gibson
- Department of Communication Sciences and Disorders, University of South Carolina, Columbia, SC
| | - Rebecca Roth
- Department of Neurology, Emory University, Atlanta, GA
| | - Sarah Wilson
- Department of Communication Sciences and Disorders, University of South Carolina, Columbia, SC
| | - Julius Fridriksson
- Department of Communication Sciences and Disorders, University of South Carolina, Columbia, SC
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16
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Busby N, Wilson S, Wilmskoetter J, Newman-Norlund R, Sayers S, Newman-Norlund S, Roth R, Rorden C, Fridriksson J, Bonilha L. White matter hyperintensity load mediates the relationship between age and cognition. Neurobiol Aging 2023; 132:56-66. [PMID: 37729770 DOI: 10.1016/j.neurobiolaging.2023.08.007] [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: 04/25/2023] [Revised: 08/14/2023] [Accepted: 08/21/2023] [Indexed: 09/22/2023]
Abstract
To elucidate the relationship between age and cognitive decline, it is important to consider structural brain changes such as white matter hyperintensities (WMHs), which are common in older age and may affect behavior. Therefore, we aimed to investigate if WMH load is a mediator of the relationship between age and cognitive decline. Healthy participants (N = 166, 20-80 years) completed the Montreal Cognitive Assessment (MoCA). WMHs were manually delineated on FLAIR scans. Mediation analysis was conducted to determine if WMH load mediates the relationship between age and cognition. Older age was associated with worse cognition (p < 0.001), but this was an indirect effect: older participants had more WMHs, and, in turn, increased WMH load was associated with worse MoCA scores. WMH load mediates the relationship between age and cognitive decline. Importantly, this relationship was not moderated by age (i.e., increased WMH severity is associated with poorer MoCA scores irrespective of age). Across all ages, high cholesterol was associated with increased WMH severity.
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Affiliation(s)
- Natalie Busby
- Department of Communication Sciences and Disorders, University of South Carolina, Columbia, SC, USA.
| | - Sarah Wilson
- Department of Communication Sciences and Disorders, University of South Carolina, Columbia, SC, USA
| | - Janina Wilmskoetter
- Department of Health and Rehabilitation Sciences, Medical University of South Carolina, Charleston, SC, USA
| | | | - Sara Sayers
- Department of Communication Sciences and Disorders, University of South Carolina, Columbia, SC, USA
| | - Sarah Newman-Norlund
- Department of Communication Sciences and Disorders, University of South Carolina, Columbia, SC, USA
| | - Rebecca Roth
- Department of Neurology, Emory University, Atlanta, GA, USA
| | - Chris Rorden
- Department of Psychology, University of South Carolina, Columbia, SC, USA
| | - Julius Fridriksson
- Department of Communication Sciences and Disorders, University of South Carolina, Columbia, SC, USA
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17
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Miyagi T, Ishida A, Shinzato T, Ohya Y. Arterial Stiffness Is Associated With Small Vessel Disease Irrespective of Blood Pressure in Stroke-Free Individuals. Stroke 2023; 54:2814-2821. [PMID: 37846566 DOI: 10.1161/strokeaha.123.042512] [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: 01/09/2023] [Accepted: 08/03/2023] [Indexed: 10/18/2023]
Abstract
BACKGROUND Arterial stiffness and hypertension are important risk factors for cerebral small vessel disease (CSVD). Clinically, there are hypertensive patients with low pulse wave velocity (PWV) and nonhypertensive individuals with high PWV. We aimed to determine the effects of arterial stiffness on CSVD in normotensive individuals. METHODS An observational cross-sectional study was conducted in 1894 stroke-free participants who underwent brain magnetic resonance imaging and brachial-ankle pulse wave velocity (baPWV) measurements at a health checkup between 2013 and 2020. CSVD was defined as any of following: white matter hyperintensities, cerebral microbleeds, silent lacunar infarcts, and enlarged perivascular spaces. baPWV was measured using an automatic oscillometric device. Participants were divided into 4 groups according to the following cutoff points: low blood pressure (BP, <120/80 mm Hg) with low baPWV (<14.63 m/s, a cutoff value that predicted CSVD); high BP (≥120/80 mm Hg) with low baPWV; low BP with high baPWV (≥14.63 m/s); and high BP with high baPWV. RESULTS The mean age of the participants was 57±13 years (41% women). The prevalence of CSVD was 718 (38%), which was higher in the low BP with high baPWV (56%) and high BP with high baPWV (55%) groups than in the high BP with low baPWV (24%) and low BP with low baPWV (22%) groups. Compared with the low BP with low baPWV group, the low BP with high baPWV group (odds ratio, 1.63 [95% CI, 1.09-2.43]) and the high BP with high baPWV group (odds ratio, 1.86 [95% CI, 1.39-2.49]) had a significantly higher multivariable-adjusted risk for CSVD. CONCLUSIONS Individuals with a high baPWV had a higher prevalence of CSVD, independent of BP status. Higher arterial stiffness is likely to be a more important risk factor for CSVD than BP status in stroke-free individuals.
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Affiliation(s)
- Tomo Miyagi
- Department of Cardiovascular Medicine, Nephrology and Neurology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan (T.M., A.I., Y.O.)
| | - Akio Ishida
- Department of Cardiovascular Medicine, Nephrology and Neurology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan (T.M., A.I., Y.O.)
| | | | - Yusuke Ohya
- Department of Cardiovascular Medicine, Nephrology and Neurology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan (T.M., A.I., Y.O.)
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18
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Liu S, Wang M, Gu D, Li Y, Zhang X, Li H, Ji C, Nie X, Liu J. Optimal systolic and diastolic blood pressure threshold that associated with lower risk of white matter hyperintensity progression. Front Aging Neurosci 2023; 15:1254463. [PMID: 37927340 PMCID: PMC10620971 DOI: 10.3389/fnagi.2023.1254463] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 10/05/2023] [Indexed: 11/07/2023] Open
Abstract
Background The optimal control thresholds for systolic blood pressure (SBP) and diastolic blood pressure (DBP) in patients with white matter hyperintensity (WMH) are still unclear. Method A longitudinal retrospective study of patients with brain magnetic resonance imaging (MRI) scans with intervals of more than 3 years was conducted. Blood pressure records during hospitalization and from outpatient visits between baseline and the last MRI scan were collected. The outcome was the change in total WMH from baseline to the final visit. Results Among the 965 patients with MRI scans, 457 patients with detailed longitudinal blood pressure records were ultimately included and classified into the WMH absent group (n = 121), mild WMH group (n = 126), and moderate to severe WMH group (n = 210). Both baseline and longitudinal mean SBP, DBP, and SBP SD were significantly associated with WMH severity (p < 0.05). An average SBP of 130-140 mmHg [vs. <130 mmHg, aOR, 1.80, (95% CI, 1.05-3.07), p = 0.03] was associated with a higher risk of WMH progression. DBP ≥ 90 mmHg [vs. <80 mmHg, OR, 1.81, (95% CI, 0.88-3.74), p = 0.02, aOR, 1.54, (95% CI, 0.66-3.53), p = 0.32] was associated with a higher risk of WMH progression, but was not after adjusted for other covariates. Longitudinal BP variability was not significantly associated with WMH progression. Conclusion Both SBP and DBP had a stronger relationship with the severity of WMH. A target mean SBP of <130 mmHg and mean DBP of <80 mmHg was associated with a lower risk of WMH progression.
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Affiliation(s)
- Sibo Liu
- Intensive Care Unit, Dalian Municipal Central Hospital Affiliated Dalian University of Technology, Dalian, China
| | - Mengxing Wang
- China National Clinical Research Center for Neurological Diseases Beijing China, Beijing, China
| | - De’an Gu
- Department of Neurology, Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Cancer Hospital, Qingdao, China
| | - Yanzhao Li
- Department of Neurosurgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Xin Zhang
- Department of General Medicine, Dalian Municipal Central Hospital Affiliated Dalian University of Technology, Dalian, China
| | - Hang Li
- Department of Geriatrics, Affiliated Dalian Friendship Hospital of Dalian Medical University, Dalian, China
| | - Chenhua Ji
- Department of General Medicine, Dalian Municipal Central Hospital Affiliated Dalian University of Technology, Dalian, China
| | - Ximing Nie
- Neurocritical Care Unit, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Jinjie Liu
- Department of General Medicine, Dalian Municipal Central Hospital Affiliated Dalian University of Technology, Dalian, China
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19
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Nash PS, Simister RJ, Wheeler DC, Werring DJ. Hypertension and small vessel disease: do the drugs work? Br J Hosp Med (Lond) 2023; 84:1-11. [PMID: 37769262 DOI: 10.12968/hmed.2023.0092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/30/2023]
Abstract
Associations of hypertension with ischaemic stroke and intracerebral haemorrhage, particularly when attributed to cerebral small vessel disease, are well established. While it seems plausible that treating hypertension should prevent small vessel disease from developing or progressing, there is limited evidence demonstrating this. This article critically appraises the evidence answering this clinical question. Hypertension is also closely associated with chronic kidney disease, with anatomical and functional similarities between the vasculature of the brain and kidneys leading to the hypothesis that shared multi-system pathophysiological processes may be involved. Therefore, the article also summarises data on prevention of progression of chronic kidney disease. Evidence supports a target blood pressure of <130/80 mmHg to optimally prevent progression of both small vessel disease and chronic kidney disease. However, future studies are needed to determine long-term effects of more intensive blood pressure treatment targets on small vessel disease progression and incident dementia.
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Affiliation(s)
- Philip S Nash
- Comprehensive Stroke Service, National Hospital for Neurology and Neurosurgery, University College London, London, UK
- UCL Stroke Research Centre, Department of Brain Repair and Rehabilitation, University College London Queen Square Institute of Neurology, London, UK
| | - Rob J Simister
- Comprehensive Stroke Service, National Hospital for Neurology and Neurosurgery, University College London, London, UK
- UCL Stroke Research Centre, Department of Brain Repair and Rehabilitation, University College London Queen Square Institute of Neurology, London, UK
| | - David C Wheeler
- Department of Renal Medicine, University College London, London, UK
| | - David J Werring
- Comprehensive Stroke Service, National Hospital for Neurology and Neurosurgery, University College London, London, UK
- UCL Stroke Research Centre, Department of Brain Repair and Rehabilitation, University College London Queen Square Institute of Neurology, London, UK
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20
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Zhao B, Jia W, Yuan Y, Li Z, Fu X. Effects of intensive blood pressure control on cognitive function in patients with cerebral small vessel disease. J Stroke Cerebrovasc Dis 2023; 32:107289. [PMID: 37544058 DOI: 10.1016/j.jstrokecerebrovasdis.2023.107289] [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: 01/26/2023] [Revised: 07/28/2023] [Accepted: 07/31/2023] [Indexed: 08/08/2023] Open
Abstract
OBJECTIVE This study aimed to investigate the effects of intensive blood pressure control on cognitive function in elderly patients with cerebral small vessel disease (CSVD). METHODS From May 2020 to June 2022, 140 outpatients and inpatients with CSVD and hypertension in the Department of Neurology of Beijing Shijingshan Hospital were selected. They were randomly divided into the standard and intensive blood pressure control groups, and the dosage of antihypertensive drugs was adjusted to reduce the blood pressure to the target level. The patients were followed up for 2 years. The medical records or data at "enrollment" and "2-year follow-up" were analyzed and evaluated. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to evaluate cognitive function. Cranial magnetic resonance imaging was performed to evaluate lacunar infarctions (LIs) and white matter hyperintensity (WMH). Multiple linear regression was used to analyze the correlation between MMSE scores and blood pressure, WMH, and LIs. RESULTS (1) The MMSE and MoCA scores in the standard group were significantly lower than those at enrollment. The WMH score in the standard group was significantly higher than that at enrollment. (2) After the 2-year follow-up, the 24-h systolic blood pressure (SBP), 24-h diastolic blood pressure (DBP), daytime mean SBP, daytime mean DBP, and nighttime mean SBP in the two groups significantly decreased, which had significant statistical significance (P < 0.05). (3) The correlation between blood pressure and MMSE score was analyzed using multiple linear regression analysis. The WMH score, LIs, 24-h SBP, and 24-h DBP were independently correlated with MMSE scores. CONCLUSION In elderly patients with hypertension, a decrease in SBP to 126 mmHg, compared with 134 mmHg, can delay cognitive impairment as well as reduce LIs and cerebral WMH lesions in patients with CSVD.
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Affiliation(s)
- Bingqing Zhao
- Department of Neurology, Beijing Shijingshan Hospital, Shijingshan Teaching Hospital of Capital Medical University, China.
| | - Weihua Jia
- Department of Neurology, Beijing Shijingshan Hospital, Shijingshan Teaching Hospital of Capital Medical University, China
| | - Ye Yuan
- Department of Neurology, Beijing Shijingshan Hospital, Shijingshan Teaching Hospital of Capital Medical University, China
| | - Zheng Li
- Department of Neurology, Beijing Shijingshan Hospital, Shijingshan Teaching Hospital of Capital Medical University, China
| | - Xinran Fu
- Department of Neurology, Beijing Shijingshan Hospital, Shijingshan Teaching Hospital of Capital Medical University, China
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21
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Sargurupremraj M, Soumare A, Bis JC, Surakka I, Jurgenson T, Joly P, Knol MJ, Wang R, Yang Q, Satizabal CL, Gudjonsson A, Mishra A, Bouteloup V, Phuah CL, van Duijn CM, Cruchaga C, Dufouil C, Chêne G, Lopez O, Psaty BM, Tzourio C, Amouyel P, Adams HH, Jacqmin-Gadda H, Ikram MA, Gudnason V, Milani L, Winsvold BS, Hveem K, Matthews PM, Longstreth WT, Seshadri S, Launer LJ, Debette S. Complexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.08.08.23293761. [PMID: 37790435 PMCID: PMC10543241 DOI: 10.1101/2023.08.08.23293761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/05/2023]
Abstract
Importance There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear. Objective To disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist. To account for potential epidemiological biases inherent to late-onset conditions like dementia. Design Setting and Participants This study first explored the association of genetically determined WMH, BP levels and stroke risk with AD using summary-level data from large genome-wide association studies (GWASs) in a two-sample Mendelian randomization (MR) framework. Second, leveraging individual-level data from large longitudinal population-based cohorts and biobanks with prospective dementia surveillance, the association of weighted genetic risk scores (wGRSs) for WMH, BP, and stroke with incident all-cause-dementia was explored using Cox-proportional hazard and multi-state models. The data analysis was performed from July 26, 2020, through July 24, 2022. Exposures Genetically determined levels of WMH volume and BP (systolic, diastolic and pulse blood pressures) and genetic liability to stroke. Main outcomes and measures The summary-level MR analyses focused on the outcomes from GWAS of clinically diagnosed AD (n-cases=21,982) and GWAS additionally including self-reported parental history of dementia as a proxy for AD diagnosis (ADmeta, n-cases=53,042). For the longitudinal analyses, individual-level data of 157,698 participants with 10,699 incident all-cause-dementia were studied, exploring AD, vascular or mixed dementia in secondary analyses. Results In the two-sample MR analyses, WMH showed strong evidence for a causal association with increased risk of ADmeta (OR, 1.16; 95%CI:1.05-1.28; P=.003) and AD (OR, 1.28; 95%CI:1.07-1.53; P=.008), after accounting for genetically determined pulse pressure for the latter. Genetically predicted BP traits showed evidence for a protective association with both clinically defined AD and ADmeta, with evidence for confounding by shared genetic instruments. In longitudinal analyses the wGRSs for WMH, but not BP or stroke, showed suggestive association with incident all-cause-dementia (HR, 1.02; 95%CI:1.00-1.04; P=.06). BP and stroke wGRSs were strongly associated with mortality but there was no evidence for selective survival bias during follow-up. In secondary analyses, polygenic scores with more liberal instrument definition showed association of both WMH and stroke with all-cause-dementia, AD, and vascular or mixed dementia; associations of stroke, but not WMH, with dementia outcomes were markedly attenuated after adjusting for interim stroke. Conclusion These findings provide converging evidence that WMH is a leading vascular contributor to dementia risk, which may better capture the brain damage caused by BP (and other etiologies) than BP itself and should be targeted in priority for dementia prevention in the population.
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Affiliation(s)
- Muralidharan Sargurupremraj
- University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, Bordeaux, France
- Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX
| | - Aicha Soumare
- University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, Bordeaux, France
| | - Joshua C Bis
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Ida Surakka
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Tuuli Jurgenson
- Estonian Genome Centre, Institute of Genomics, University of Tartu
| | - Pierre Joly
- University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, Bordeaux, France
| | | | - Ruiqi Wang
- Boston University and the NHLBI's Framingham Heart Study, Boston, MA
- Department of Neurology, Boston University School of Medicine, Boston, MA, USA
| | - Qiong Yang
- Boston University and the NHLBI's Framingham Heart Study, Boston, MA
- Department of Neurology, Boston University School of Medicine, Boston, MA, USA
| | - Claudia L Satizabal
- Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX
- Boston University and the NHLBI's Framingham Heart Study, Boston, MA
- Department of Neurology, Boston University School of Medicine, Boston, MA, USA
| | | | - Aniket Mishra
- University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, Bordeaux, France
| | - Vincent Bouteloup
- University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, Bordeaux, France
| | - Chia-Ling Phuah
- Department of Neurology, Washington University School of Medicine & Barnes-Jewish Hospital, St. Louis, Missouri, USA
- NeuroGenomics and Informatics Center, Washington University in St Louis, Missouri, USA
| | | | - Carlos Cruchaga
- NeuroGenomics and Informatics Center, Washington University in St Louis, Missouri, USA
- Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA
- The Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Carole Dufouil
- University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, Bordeaux, France
| | - Geneviève Chêne
- University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, Bordeaux, France
| | - Oscar Lopez
- Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Bruce M Psaty
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, Washington, USA
- Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA
| | - Christophe Tzourio
- University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, Bordeaux, France
| | - Philippe Amouyel
- INSERM U1167, Lille, France
- Department of Epidemiology and Public Health, Pasteur Institute of Lille, France
| | | | - Hélène Jacqmin-Gadda
- University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, Bordeaux, France
| | | | - Vilmundur Gudnason
- Icelandic Heart Association, 201 Kopavogur,Iceland
- University of Iceland, Faculty of Medicine, 101 Reykjavik , Iceland
| | - Lili Milani
- Estonian Genome Centre, Institute of Genomics, University of Tartu
| | - Bendik S Winsvold
- Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway
- K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Department of Neurology, Oslo University Hospital, Oslo, Norway
| | - Kristian Hveem
- K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- HUNT Research Centre, Department of Public Health and Nursing, Norwegian University of Science and Technology, Levanger, Norway
| | - Paul M Matthews
- Department of Brain Sciences, Imperial College London, UK
- UK Dementia Research Institute, London, UK
- Data Science Institute, Imperial College London
| | - W T Longstreth
- Department of Neurology, University of Washington, Seattle, Washington, USA
- Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Sudha Seshadri
- Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX
- Boston University and the NHLBI's Framingham Heart Study, Boston, MA
- Department of Neurology, Boston University School of Medicine, Boston, MA, USA
| | - Lenore J Launer
- Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA
| | - Stéphanie Debette
- University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, Bordeaux, France
- Department of Neurology, Boston University School of Medicine, Boston, MA, USA
- Department of Neurology, Institute for Neurodegenerative Diseases, Bordeaux University Hospital, Bordeaux, France
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22
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Rashid T, Li K, Toledo JB, Nasrallah I, Pajewski NM, Dolui S, Detre J, Wolk DA, Liu H, Heckbert SR, Bryan RN, Williamson J, Davatzikos C, Seshadri S, Launer LJ, Habes M. Association of Intensive vs Standard Blood Pressure Control With Regional Changes in Cerebral Small Vessel Disease Biomarkers: Post Hoc Secondary Analysis of the SPRINT MIND Randomized Clinical Trial. JAMA Netw Open 2023; 6:e231055. [PMID: 36857053 PMCID: PMC9978954 DOI: 10.1001/jamanetworkopen.2023.1055] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/02/2023] Open
Abstract
IMPORTANCE Little is known about the associations of strict blood pressure (BP) control with microstructural changes in small vessel disease markers. OBJECTIVE To investigate the regional associations of intensive vs standard BP control with small vessel disease biomarkers, such as white matter lesions (WMLs), fractional anisotropy (FA), mean diffusivity (MD), and cerebral blood flow (CBF). DESIGN, SETTING, AND PARTICIPANTS The Systolic Blood Pressure Intervention Trial (SPRINT) is a multicenter randomized clinical trial that compared intensive systolic BP (SBP) control (SBP target <120 mm Hg) vs standard control (SBP target <140 mm Hg) among participants aged 50 years or older with hypertension and without diabetes or a history of stroke. The study began randomization on November 8, 2010, and stopped July 1, 2016, with a follow-up duration of approximately 4 years. A total of 670 and 458 participants completed brain magnetic resonance imaging at baseline and follow-up, respectively, and comprise the cohort for this post hoc analysis. Statistical analyses for this post hoc analysis were performed between August 2020 and October 2022. INTERVENTIONS At baseline, 355 participants received intensive SBP treatment and 315 participants received standard SBP treatment. MAIN OUTCOMES AND MEASURES The main outcomes were regional changes in WMLs, FA, MD (in white matter regions of interest), and CBF (in gray matter regions of interest). RESULTS At baseline, 355 participants (mean [SD] age, 67.7 [8.0] years; 200 men [56.3%]) received intensive BP treatment and 315 participants (mean [SD] age, 67.0 [8.4] years; 199 men [63.2%]) received standard BP treatment. Intensive treatment was associated with smaller mean increases in WML volume compared with standard treatment (644.5 mm3 vs 1258.1 mm3). The smaller mean increases were observed specifically in the deep white matter regions of the left anterior corona radiata (intensive treatment, 30.3 mm3 [95% CI, 16.0-44.5 mm3]; standard treatment, 80.5 mm3 [95% CI, 53.8-107.2 mm3]), left tapetum (intensive treatment, 11.8 mm3 [95% CI, 4.4-19.2 mm3]; standard treatment, 27.2 mm3 [95% CI, 19.4-35.0 mm3]), left superior fronto-occipital fasciculus (intensive treatment, 3.2 mm3 [95% CI, 0.7-5.8 mm3]; standard treatment, 9.4 mm3 [95% CI, 5.5-13.4 mm3]), left posterior corona radiata (intensive treatment, 26.0 mm3 [95% CI, 12.9-39.1 mm3]; standard treatment, 52.3 mm3 [95% CI, 34.8-69.8 mm3]), left splenium of the corpus callosum (intensive treatment, 45.4 mm3 [95% CI, 25.1-65.7 mm3]; standard treatment, 83.0 mm3 [95% CI, 58.7-107.2 mm3]), left posterior thalamic radiation (intensive treatment, 53.0 mm3 [95% CI, 29.8-76.2 mm3]; standard treatment, 106.9 mm3 [95% CI, 73.4-140.3 mm3]), and right posterior thalamic radiation (intensive treatment, 49.5 mm3 [95% CI, 24.3-74.7 mm3]; standard treatment, 102.6 mm3 [95% CI, 71.0-134.2 mm3]). CONCLUSIONS AND RELEVANCE This study suggests that intensive BP treatment, compared with standard treatment, was associated with a slower increase of WMLs, improved diffusion tensor imaging, and FA and CBF changes in several brain regions that represent vulnerable areas that may benefit from more strict BP control. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01206062.
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Affiliation(s)
- Tanweer Rashid
- Neuroimage Analytics Laboratory and the Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Science Center San Antonio, San Antonio
| | - Karl Li
- Neuroimage Analytics Laboratory and the Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Science Center San Antonio, San Antonio
| | - Jon B. Toledo
- Department of Neurology, University of Florida, Gainesville
- Department of Neurology, Houston Methodist Hospital, Houston, Texas
| | - Ilya Nasrallah
- Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia
- Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia
| | - Nicholas M. Pajewski
- Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Sudipto Dolui
- Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia
| | - John Detre
- Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia
- Department of Neurology, University of Pennsylvania, Philadelphia
| | - David A. Wolk
- Department of Neurology, University of Pennsylvania, Philadelphia
| | - Hangfan Liu
- Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia
| | | | - R. Nick Bryan
- Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia
| | - Jeff Williamson
- Section of Gerontology and Geriatric Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Christos Davatzikos
- Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia
- Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia
| | - Sudha Seshadri
- Neuroimage Analytics Laboratory and the Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Science Center San Antonio, San Antonio
| | - Lenore J. Launer
- Intramural Research Program, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Bethesda, Maryland
| | - Mohamad Habes
- Neuroimage Analytics Laboratory and the Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Science Center San Antonio, San Antonio
- Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia
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23
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Dawson J, Robertson M, Dickie DA, Bath P, Forbes K, Quinn T, Broomfield NM, Dani K, Doney A, Houston G, Lees KR, Muir KW, Struthers A, Walters M, Barber M, Bhalla A, Cameron A, Dyker A, Guyler P, Hassan A, Kearney MT, Keegan B, Lakshmanan S, Macleod MJ, Randall M, Shaw L, Subramanian G, Werring D, McConnachie A. Xanthine oxidase inhibition and white matter hyperintensity progression following ischaemic stroke and transient ischaemic attack (XILO-FIST): a multicentre, double-blinded, randomised, placebo-controlled trial. EClinicalMedicine 2023; 57:101863. [PMID: 36864979 PMCID: PMC9972492 DOI: 10.1016/j.eclinm.2023.101863] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/25/2023] [Accepted: 01/26/2023] [Indexed: 02/18/2023] Open
Abstract
BACKGROUND People who experience an ischaemic stroke are at risk of recurrent vascular events, progression of cerebrovascular disease, and cognitive decline. We assessed whether allopurinol, a xanthine oxidase inhibitor, reduced white matter hyperintensity (WMH) progression and blood pressure (BP) following ischaemic stroke or transient ischaemic attack (TIA). METHODS In this multicentre, prospective, randomised, double-blinded, placebo-controlled trial conducted in 22 stroke units in the United Kingdom, we randomly assigned participants within 30-days of ischaemic stroke or TIA to receive oral allopurinol 300 mg twice daily or placebo for 104 weeks. All participants had brain MRI performed at baseline and week 104 and ambulatory blood pressure monitoring at baseline, week 4 and week 104. The primary outcome was the WMH Rotterdam Progression Score (RPS) at week 104. Analyses were by intention to treat. Participants who received at least one dose of allopurinol or placebo were included in the safety analysis. This trial is registered with ClinicalTrials.gov, NCT02122718. FINDINGS Between 25th May 2015 and the 29th November 2018, 464 participants were enrolled (232 per group). A total of 372 (189 with placebo and 183 with allopurinol) attended for week 104 MRI and were included in analysis of the primary outcome. The RPS at week 104 was 1.3 (SD 1.8) with allopurinol and 1.5 (SD 1.9) with placebo (between group difference -0.17, 95% CI -0.52 to 0.17, p = 0.33). Serious adverse events were reported in 73 (32%) participants with allopurinol and in 64 (28%) with placebo. There was one potentially treatment related death in the allopurinol group. INTERPRETATION Allopurinol use did not reduce WMH progression in people with recent ischaemic stroke or TIA and is unlikely to reduce the risk of stroke in unselected people. FUNDING The British Heart Foundation and the UK Stroke Association.
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Affiliation(s)
- Jesse Dawson
- School of Cardiovascular and Metabolic Health, College of Medical, Veterinary & Life Sciences, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, G51 4TF, UK
- Corresponding author.
| | - Michele Robertson
- Robertson Centre for Biostatistics, School of Health and Wellbeing, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK
| | - David Alexander Dickie
- School of Cardiovascular and Metabolic Health, College of Medical, Veterinary & Life Sciences, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, G51 4TF, UK
- DD Analytics Cubed Ltd, 73 Union Street, Greenock, Scotland, PA16 8BG, UK
| | - Phillip Bath
- Stroke Trials Unit, Mental Health & Clinical Neuroscience, University of Nottingham, Nottingham, NG7 2UH, UK
| | - Kirsten Forbes
- Department of Neuroradiology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, 1345 Govan Road, Glasgow, G51 4TF, UK
| | - Terence Quinn
- School of Cardiovascular and Metabolic Health, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK
| | - Niall M. Broomfield
- Department of Clinical Psychology and Psychological Therapies, Norwich Medical School, University of East Anglia, NR4 7TJ, UK
| | - Krishna Dani
- Department of Neurology, Institute of Neurological Sciences Glasgow, Queen Elizabeth University Hospital, 1345 Govan Road, Glasgow, G51 4TF, UK
| | - Alex Doney
- Medicine Monitoring Unit (MEMO), School of Medicine, University of Dundee. Ninewells Hospital, Dundee, DD1 9SY, UK
| | - Graeme Houston
- Division of Imaging and Science Technology, School of Medicine, Ninewells Hospital, Dundee, DD1 9SY, UK
| | - Kennedy R. Lees
- School of Medicine, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK
| | - Keith W. Muir
- School of Psychology and Neuroscience, College of Medical, Veterinary & Life Sciences, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, G51 4TF, UK
| | - Allan Struthers
- Division of Molecular and Clinical Medicine, University of Dundee, UK
| | - Matthew Walters
- School of Medicine, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK
| | - Mark Barber
- University Department of Stroke Care, University Hospital Monklands, Airdrie, ML6 OJS, UK
| | - Ajay Bhalla
- Department of Stroke, Ageing and Health, Guy's and St Thomas NHS Foundation Trust, St Thomas' Hospital, Lambeth Palace Rd, London, SE1 7EH, UK
| | - Alan Cameron
- School of Cardiovascular and Metabolic Health, College of Medical, Veterinary & Life Sciences, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, G51 4TF, UK
| | - Alexander Dyker
- Wolfson Unit of Clinical Pharmacology, Royal Victoria Infirmary, Newcastle Upon Tyne, UK
| | - Paul Guyler
- Department of Stroke Medicine, Mid and South Essex University Hospitals Group, Southend University Hospital, Prittlewell Chase, Westcliff-on-Sea, Essex, SS0 0RY, UK
| | - Ahamad Hassan
- Department of Neurology, Leeds General Infirmary, Leeds, UK
| | - Mark T. Kearney
- Leeds Institute of Cardiovascular and Metabolic Medicine, The University of Leeds, Leeds, UK
| | - Breffni Keegan
- Department of Medicine, South West Acute Hospital, Enniskillen, BT74 6DN, UK
| | - Sekaran Lakshmanan
- Department of Stroke Medicine The Luton and Dunstable University Hospital, Bedfordshire, NHSFT, Lewsey Road, Luton, LU4 0DZ, UK
| | | | - Marc Randall
- Department of Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Louise Shaw
- Department of Stroke Medicine, Royal United Hospital, Combe Park, Bath, BA1 3NG, UK
| | - Ganesh Subramanian
- Department of Stroke Medicine, Nottingham University Hospitals, Nottingham, NG5 1PB, UK
| | - David Werring
- Stroke Research Centre, UCL Queen Square Institute of Neurology, London, UK
- Comprehensive Stroke Service, National Hospital for Neurology and Neurosurgery, Queen Square, University College Hospitals NHS Foundation Trust, London, UK
| | - Alex McConnachie
- Robertson Centre for Biostatistics, School of Health and Wellbeing, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK
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24
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Chung CP, Ihara M, Hilal S, Chen LK. Targeting cerebral small vessel disease to promote healthy aging: Preserving physical and cognitive functions in the elderly. Arch Gerontol Geriatr 2023; 110:104982. [PMID: 36868073 DOI: 10.1016/j.archger.2023.104982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 02/15/2023] [Accepted: 02/22/2023] [Indexed: 02/27/2023]
Abstract
Cerebral small vessel disease (SVD), which is highly age-related, is the most common neuroimaging finding in community-dwelling elderly individuals. In addition to increasing the risk of dementia and stroke, SVD is associated with cognitive and physical (particularly gait speed) functional impairments in the elderly. Here, we provide evidence suggesting covert SVD, e.g. without clinically evident stroke or dementia, as a critical target to preserve the functional ability that enables well-being in older age. First, we discuss the relationship between covert SVD and geriatric syndrome. SVD lesions found in non-demented, stroke-free elderly are actually not "silent" but are associated with accelerated age-related functional decline. We also review the brain structural and functional abnormalities associated with covert SVD and the possible mechanisms underlying their contributions to SVD-related cognitive and physical functional impairments. Finally, we reveal current data, though limited, on the management of elderly patients with covert SVD to prevent SVD lesion progression and functional decline. Although it is important in aging health, covert SVD is still under-recognized or misjudged by physicians in both neurological and geriatric professions. Improving the acknowledgment, detection, interpretation, and understanding of SVD would be a multidisciplinary priority to maintain cognitive and physical functions in the elderly. The dilemmas and future directions of clinical practice and research for the elderly with covert SVD are also included in the present review.
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Affiliation(s)
- Chih-Ping Chung
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; Center for Health Longevity and Aging Sciences, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan
| | - Masafumi Ihara
- Department of Neurology, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Saima Hilal
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore; Memory Aging and Cognition Center, National University Health System, Singapore
| | - Liang-Kung Chen
- Center for Health Longevity and Aging Sciences, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan; Taipei Municipal Gan-Dau Hospital (managed by Taipei Veterans General Hospital), Taipei, Taiwan.
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25
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Maillard P, Hillmer LJ, Lu H, Arfanakis K, Gold BT, Bauer CE, Kramer JH, Staffaroni AM, Stables L, Wang DJ, Seshadri S, Satizabal CL, Beiser A, Habes M, Fornage M, Mosley TH, Rosenberg GA, Singh B, Singh H, Schwab K, Helmer KG, Greenberg SM, DeCarli C, Caprihan A. MRI free water as a biomarker for cognitive performance: Validation in the MarkVCID consortium. ALZHEIMER'S & DEMENTIA (AMSTERDAM, NETHERLANDS) 2022; 14:e12362. [PMID: 36523847 PMCID: PMC9745638 DOI: 10.1002/dad2.12362] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/11/2022] [Accepted: 08/29/2022] [Indexed: 12/15/2022]
Abstract
Introduction To evaluate the clinical validity of free water (FW), a diffusion tensor imaging-based biomarker kit proposed by the MarkVCID consortium, by investigating the association between mean FW (mFW) and executive function. Methods Baseline mFW was related to a baseline composite measure of executive function (EFC), adjusting for relevant covariates, in three MarkVCID sub-cohorts, and replicated in five, large, independent legacy cohorts. In addition, we tested whether baseline mFW predicted accelerated EFC score decline (mean follow-up time: 1.29 years). Results Higher mFW was found to be associated with lower EFC scores in MarkVCID legacy and sub-cohorts (p-values < 0.05). In addition, higher baseline mFW was associated significantly with accelerated decline in EFC scores (p = 0.0026). Discussion mFW is a sensitive biomarker of cognitive decline, providing a strong clinical rational for its use as a marker of white matter (WM) injury in multi-site observational studies and clinical trials of vascular cognitive impairment and dementia (VCID).
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Affiliation(s)
- Pauline Maillard
- Department of NeurologyUniversity of CaliforniaDavisCaliforniaUSA
| | - Laura J. Hillmer
- Department of NeurologyUniversity of New MexicoAlbuquerqueNew MexicoUSA
| | - Hanzhang Lu
- Department of RadiologyJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Konstantinos Arfanakis
- Department of Biomedical EngineeringIllinois Institute of TechnologyChicagoIllinoisUSA
- Rush Alzheimer's Disease CenterDepartment of Diagnostic Radiology and Nuclear MedicineRush University Medical CenterChicagoIllinoisUSA
| | - Brian T. Gold
- Department of NeuroscienceUniversity of KentuckyLexingtonKentuckyUSA
| | | | - Joel H. Kramer
- Department of NeurologyMemory and Aging CenterWeill Institute for NeurosciencesUniversity of CaliforniaSan FranciscoCaliforniaUSA
| | - Adam M. Staffaroni
- Department of NeurologyMemory and Aging CenterWeill Institute for NeurosciencesUniversity of CaliforniaSan FranciscoCaliforniaUSA
| | - Lara Stables
- Department of NeurologyMemory and Aging CenterWeill Institute for NeurosciencesUniversity of CaliforniaSan FranciscoCaliforniaUSA
| | - Danny J.J. Wang
- Laboratory of FMRI Technology (LOFT)Stevens Neuroimaging and Informatics InstituteKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Sudha Seshadri
- Department of NeurologyBoston University School of MedicineBostonMassachusettsUSA
- Glenn Biggs Institute for Alzheimer's & Neurodegenerative DiseasesUniversity of Texas Health San AntonioSan AntonioTexasUSA
| | - Claudia L. Satizabal
- Department of NeurologyBoston University School of MedicineBostonMassachusettsUSA
- Glenn Biggs Institute for Alzheimer's & Neurodegenerative DiseasesUniversity of Texas Health San AntonioSan AntonioTexasUSA
- Department of Population Health SciencesUniversity of Texas Health San AntonioSan AntonioTexasUSA
| | - Alexa Beiser
- Department of NeurologyBoston University School of MedicineBostonMassachusettsUSA
- Department of BiostatisticsBoston University School of Public HealthBostonMassachusettsUSA
| | - Mohamad Habes
- Glenn Biggs Institute for Alzheimer's & Neurodegenerative DiseasesUniversity of Texas Health San AntonioSan AntonioTexasUSA
| | - Myriam Fornage
- Brown Foundation Institute of Molecular MedicineMcGovern Medical SchoolSchool of Public HealthThe University of Texas Health Science Center at HoustonHoustonTexasUSA
- Human Genetics CenterSchool of Public HealthThe University of Texas Health Science Center at HoustonHoustonTexasUSA
| | - Thomas H. Mosley
- MIND CenterUniversity of Mississippi Medical CenterJacksonMississippiUSA
| | - Gary A. Rosenberg
- Department of NeurologyUniversity of New MexicoAlbuquerqueNew MexicoUSA
| | - Baljeet Singh
- Department of NeurologyUniversity of CaliforniaDavisCaliforniaUSA
| | - Herpreet Singh
- Department of NeurologyMassachusetts General HospitalBostonMassachusettsUSA
| | - Kristin Schwab
- Department of NeurologyMassachusetts General HospitalBostonMassachusettsUSA
| | - Karl G. Helmer
- Department of RadiologyHarvard Medical SchoolBostonMassachusettsUSA
- Department of RadiologyMassachusetts General HospitalBostonMassachusettsUSA
| | | | - Charles DeCarli
- Department of NeurologyUniversity of CaliforniaDavisCaliforniaUSA
| | - Arvind Caprihan
- The Mind Research NetworkAlbuquerqueNew MexicoAlbuquerqueNew MexicoUSA
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26
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Lespinasse J, Chêne G, Mangin J, Dubois B, Blanc F, Paquet C, Hanon O, Planche V, Gabelle A, Ceccaldi M, Annweiler C, Krolak‐Salmon P, Godefroy O, Wallon D, Sauvée M, Bergeret S, Chupin M, Proust‐Lima C, Dufouil C. Associations among hypertension, dementia biomarkers, and cognition: The MEMENTO cohort. Alzheimers Dement 2022. [PMID: 36464896 DOI: 10.1002/alz.12866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 09/12/2022] [Accepted: 10/05/2022] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Approximately 40% of dementia cases could be delayed or prevented acting on modifiable risk factors including hypertension. However, the mechanisms underlying the hypertension-dementia association are still poorly understood. METHODS We conducted a cross-sectional analysis in 2048 patients from the MEMENTO cohort, a French multicenter clinic-based study of outpatients with either isolated cognitive complaints or mild cognitive impairment. Exposure to hypertension was defined as a combination of high blood pressure (BP) status and antihypertensive treatment intake. Pathway associations were examined through structural equation modeling integrating extensive collection of neuroimaging biomarkers and clinical data. RESULTS Participants treated with high BP had significantly lower cognition compared to the others. This association was mediated by higher neurodegeneration and higher white matter hyperintensities load but not by Alzheimer's disease (AD) biomarkers. DISCUSSION These results highlight the importance of controlling hypertension for prevention of cognitive decline and offer new insights on mechanisms underlying the hypertension-dementia association. HIGHLIGHTS Paths of hypertension-cognition association were assessed by structural equation models. The hypertension-cognition association is not mediated by Alzheimer's disease biomarkers. The hypertension-cognition association is mediated by neurodegeneration and leukoaraiosis. Lower cognition was limited to participants treated with uncontrolled blood pressure. Blood pressure control could contribute to promote healthier brain aging.
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Affiliation(s)
- Jérémie Lespinasse
- Inserm Research Center « Bordeaux Population Health », Bordeaux School of Public Health, CIC 1401‐EC Bordeaux University Bordeaux France
- Pôle de santé publique Centre Hospitalier Universitaire (CHU) de Bordeaux Bordeaux France
| | - Geneviève Chêne
- Inserm Research Center « Bordeaux Population Health », Bordeaux School of Public Health, CIC 1401‐EC Bordeaux University Bordeaux France
- Pôle de santé publique Centre Hospitalier Universitaire (CHU) de Bordeaux Bordeaux France
| | - Jean‐Francois Mangin
- CATI, US52‐UAR2031, CEA, ICM, SU, CNRS, INSERM, APHP Paris France
- Université Paris‐Saclay, CEA, CNRS, Neurospin, UMR9027 Baobab Gif‐sur‐Yvette France
| | - Bruno Dubois
- Sorbonne Université, CNRS, INSERM Laboratoire d'Imagerie Biomédicale Paris France
- Sorbonne‐Université, Service des maladies cognitives et comportementales et Institut de la mémoire et de la maladie d'Alzheimer (IM2A) Hôpital de la Salpêtrière Paris AP‐PH France
| | - Frederic Blanc
- Univ. Strasbourg, CNRS, ICube laboratory, UMR 7357, Fédération de Médecine Translationnelle de Strasbourg, Centre Mémoire de Ressources et de Recherches Departement de Gériatrie Strasbourg France
| | - Claire Paquet
- Univ. Paris, Inserm U1144, GHU APHP Nord Lariboisière Fernand‐Widal Paris France
| | - Olivier Hanon
- Univ. de Paris, EA 4468, Service de Gériatrie, AP‐HP Hôpital Broca Paris France
| | - Vincent Planche
- Univ. Bordeaux, CNRS UMR 5293, Institut des Maladies Neurodégénératives, Centre Mémoire de Ressources et de Recherches Pôle de Neurosciences Cliniques, CHU de Bordeaux Bordeaux France
| | - Audrey Gabelle
- Univ. Montpellier, i‐site MUSE, Inserm U1061, Centre Mémoire de Ressources et de Recherches, Pôle de Neurosciences Département de Neurologie, CHU de Montpellier Montpellier France
| | - Mathieu Ceccaldi
- Univ. Aix Marseille, Inserm UMR 1106, Institut de Neurosciences des Systèmes, Centre Mémoire de Ressources et de Recherches Département de Neurologie et de Neuropsychologie, AP‐HM Marseille France
| | - Cedric Annweiler
- Univ. Angers, UPRES EA 4638, Centre Mémoire de Ressources et de Recherches, Département de Gériatrie, CHU d'Angers Angers France
| | - Pierre Krolak‐Salmon
- Univ. Lyon, Inserm U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, Centre Mémoire Ressource et Recherche de Lyon (CMRR), Hôpital des Charpennes Hospices Civils de Lyon Lyon France
| | - Olivier Godefroy
- Neurology Departement and Functional Neurosciences Lab. (UR UPJV 4559) Amiens University Hospital Amiens France
| | - David Wallon
- Normandie Univ, UNIROUEN, Inserm U1245, CHU Rouen, Department of Neurology and CNR‐MAJ, Normandy Center for Genomic and Personalized Medicine CIC‐CRB1404 Rouen France
| | - Mathilde Sauvée
- CMRR Grenoble Arc Alpin CHU Grenoble Grenoble France
- Laboratoire de Psychologie et NeuroCognition: LPNC CNRS 5105 Université Grenoble Alpes Grenoble France
| | - Sébastien Bergeret
- Département de Médecine NucléaireAP‐HP, Hôpital Pitié‐Salpêtrière ParisFrance
| | - Marie Chupin
- CATI, US52‐UAR2031, CEA, ICM, SU, CNRS, INSERM, APHP Paris France
| | - Cécile Proust‐Lima
- Inserm Research Center « Bordeaux Population Health », Bordeaux School of Public Health, CIC 1401‐EC Bordeaux University Bordeaux France
| | - Carole Dufouil
- Inserm Research Center « Bordeaux Population Health », Bordeaux School of Public Health, CIC 1401‐EC Bordeaux University Bordeaux France
- Pôle de santé publique Centre Hospitalier Universitaire (CHU) de Bordeaux Bordeaux France
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Pauls MMH, Binnie LR, Benjamin P, Betteridge S, Clarke B, Dhillon MPK, Ghatala R, Hainsworth FAH, Howe FA, Khan U, Kruuse C, Madigan JB, Moynihan B, Patel B, Pereira AC, Rostrup E, Shtaya ABY, Spilling CA, Trippier S, Williams R, Young R, Barrick TR, Isaacs JD, Hainsworth AH. The PASTIS trial: Testing tadalafil for possible use in vascular cognitive impairment. Alzheimers Dement 2022; 18:2393-2402. [PMID: 35135037 PMCID: PMC10078742 DOI: 10.1002/alz.12559] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 10/13/2021] [Accepted: 12/07/2021] [Indexed: 01/31/2023]
Abstract
INTRODUCTION There are few randomized clinical trials in vascular cognitive impairment (VCI). This trial tested the hypothesis that the PDE5 inhibitor tadalafil, a widely used vasodilator, increases cerebral blood flow (CBF) in older people with symptomatic small vessel disease, the main cause of VCI. METHODS In a double-blind, placebo-controlled, cross-over trial, participants received tadalafil (20 mg) and placebo on two visits ≥7 days apart (randomized to order of treatment). The primary endpoint, change in subcortical CBF, was measured by arterial spin labelling. RESULTS Tadalafil increased CBF non-significantly in all subcortical areas (N = 55, age: 66.8 (8.6) years) with greatest treatment effect within white matter hyperintensities (+9.8%, P = .0960). There were incidental treatment effects on systolic and diastolic blood pressure (-7.8, -4.9 mmHg; P < .001). No serious adverse events were observed. DISCUSSION This trial did not identify a significant treatment effect of single-administration tadalafil on subcortical CBF. To detect treatment effects may require different dosing regimens.
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Affiliation(s)
- Mathilde M H Pauls
- Molecular & Clinical Sciences Research Institute, St George's University of London, London, UK.,Department of Neurology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Lauren R Binnie
- Molecular & Clinical Sciences Research Institute, St George's University of London, London, UK
| | - Philip Benjamin
- Molecular & Clinical Sciences Research Institute, St George's University of London, London, UK.,Department of Neuroradiology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Shai Betteridge
- Department of Neuropsychology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Brian Clarke
- Department of Neurology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Mohani-Preet K Dhillon
- Molecular & Clinical Sciences Research Institute, St George's University of London, London, UK
| | - Rita Ghatala
- South London Stroke Research Network, London, UK
| | - Fearghal A H Hainsworth
- Molecular & Clinical Sciences Research Institute, St George's University of London, London, UK
| | - Franklyn A Howe
- Molecular & Clinical Sciences Research Institute, St George's University of London, London, UK
| | - Usman Khan
- Department of Neurology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Christina Kruuse
- Department of Neurology and Neurovascular Research Unit, Herlev Gentofte Hospital, Hellerup, Denmark
| | - Jeremy B Madigan
- Department of Neuroradiology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Barry Moynihan
- Department of Neurology, St George's University Hospitals NHS Foundation Trust, London, UK.,Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Bhavini Patel
- Department of Neurology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Anthony C Pereira
- Molecular & Clinical Sciences Research Institute, St George's University of London, London, UK.,Department of Neurology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Egill Rostrup
- Mental Health Centre, University of Copenhagen, Glostrup, Denmark
| | - Anan B Y Shtaya
- Molecular & Clinical Sciences Research Institute, St George's University of London, London, UK
| | - Catherine A Spilling
- Molecular & Clinical Sciences Research Institute, St George's University of London, London, UK
| | | | | | - Robin Young
- Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK
| | - Thomas R Barrick
- Molecular & Clinical Sciences Research Institute, St George's University of London, London, UK
| | - Jeremy D Isaacs
- Molecular & Clinical Sciences Research Institute, St George's University of London, London, UK.,Department of Neurology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Atticus H Hainsworth
- Molecular & Clinical Sciences Research Institute, St George's University of London, London, UK.,Department of Neurology, St George's University Hospitals NHS Foundation Trust, London, UK
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Association between Serum Amyloid A Level and White Matter Hyperintensity Burden: a Cross-Sectional Analysis in Patients with Acute Ischemic Stroke. Neurol Ther 2022; 12:161-175. [PMID: 36374429 PMCID: PMC9837367 DOI: 10.1007/s40120-022-00415-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 10/17/2022] [Indexed: 11/16/2022] Open
Abstract
INTRODUCTION This work aimed to determine the potential link between white matter hyperintensity (WMH) burden and serum amyloid A (SAA) level in patients with acute ischemic stroke. METHODS Consecutive patients with acute large artery atherosclerosis (LAA) stroke between April 2021 and May 2022 were included. WMH volumes (periventricular, deep, and total) were measured using the Fazekas score and a semiautomated volumetric analysis on fluid-attenuated inversion recovery-magnetic resonance imaging. The burdens of WMH were scored to assess the dose-dependent association between SAA and WMH volume. Multivariate regression and a two-piecewise linear regression model were used to evaluate whether SAA levels are an independent predictor of WMH, and to discover the threshold effect or saturation effect of SAA levels with respect to WMH volume. RESULTS The mean age of patients was 63.2 ± 11.5 years, with 65.9% men. The median SAA level was 3.93 mg/L and the total WMH volume of 6.86 cm3. In the multivariable analysis, SAA remained an independent predictor of total WMH volume [β = 0.82, 95% confidence interval (CI) = 0.49-1.07, p < 0.001], periventricular WMH volume (adjusted β = 0.76, 95% CI = 0.46-1.07, p < 0.001), and deep WMH volume (adjusted β = 0.26, 95% CI = 0.06-0.45, p = 0.011) after controlling for confounders. Furthermore, SAA levels were associated with periventricular Fazekas score, deep Fazekas score, and Fazekas grades. Threshold effect and saturation effect analyses demonstrated a nonlinear relationship between SAA levels and periventricular white matter hyperintensity (PVWMH) volumes, with SAA levels (2.12-19.89 mg/L) having significant dose-dependent relationships with periventricular WMH volumes (adjusted β = 1.98, 95% CI = 1.12-2.84, p < 0.001). CONCLUSION SAA level ranging from 2.12 to 19.89 mg/L is dose-dependently associated with periventricular WMH development. These findings point the way forward for future research into the pathophysiology of WMH.
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Kuller LH, Snitz BE, Hughes TM, Chang Y, Cohen AD, Mathis CA, Aizenstein HJ, Lopez OL. Low untreated systolic blood pressure over 18 years is associated with survival free of dementia age 90. Alzheimers Dement 2022; 18:2176-2187. [PMID: 35089640 PMCID: PMC9787390 DOI: 10.1002/alz.12493] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 08/11/2021] [Indexed: 01/31/2023]
Abstract
INTRODUCTION We hypothesized that lower untreated systolic blood pressure (SBP) would be associated with a lower risk of dementia and death up to age 95. METHODS SBP measured between 2000 and 2006 was evaluated in relationship to dementia risk and brain biomarkers from 2009-2020 (n = 177) in the Gingko Evaluation of Memory Study (GEMS), mean age 95 in 2020. Participants had measurements of brain amyloid beta (Aβ) and repeat clinical-cognitive evaluations every 6 months. RESULTS By 2020, only 9 of 177 patients (5%) were alive and cognitively unimpaired (CU). Mean SBP from 2000 to 2006 was 120 mm Hg for nine alive/CU, 125 mm Hg for alive/mild cognitive impairment (MCI), and 130 mm Hg for alive/dementia (P = .03). The amount of Aβ was directly related to SBP levels. In multivariate analysis, Aβ+ in 2009 and thinner cortex were significant predictors of dementia. Excluding Aβ, SBP became a significant predictor of dementia. DISCUSSION Low SBP untreated by antihypertensive medications was associated with significant decreased risk of dementia and less Aβ.
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Affiliation(s)
- Lewis H. Kuller
- Department of EpidemiologyGraduate School of Public HealthUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Beth E. Snitz
- Department of NeurologyUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Timothy M. Hughes
- Department of Internal MedicineSection on Gerontology and Geriatric MedicineWake Forest School of MedicineWinston‐SalemNorth CarolinaUSA
| | - Yuefang Chang
- Department of NeurosurgeryUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Ann D. Cohen
- Department of PsychiatryUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Chester A. Mathis
- Department of RadiologyUniversity of PittsburghPittsburghPennsylvaniaUSA
| | | | - Oscar L. Lopez
- Department of NeurologyUniversity of PittsburghPittsburghPennsylvaniaUSA
- Department of PsychiatryUniversity of PittsburghPittsburghPennsylvaniaUSA
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HUNG STANLEYHUGHWA, KHLIF MOHAMEDSALAH, KRAMER SHARON, WERDEN EMILIO, BIRD LAURAJ, CAMPBELL BRUCECV, BRODTMANN AMY. Poststroke White Matter Hyperintensities and Physical Activity: A CANVAS Study Exploratory Analysis. Med Sci Sports Exerc 2022; 54:1401-1409. [DOI: 10.1249/mss.0000000000002946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Del Cuore A, Pacinella G, Riolo R, Tuttolomondo A. The Role of Immunosenescence in Cerebral Small Vessel Disease: A Review. Int J Mol Sci 2022; 23:ijms23137136. [PMID: 35806140 PMCID: PMC9266569 DOI: 10.3390/ijms23137136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 06/20/2022] [Accepted: 06/24/2022] [Indexed: 11/16/2022] Open
Abstract
Cerebral small vessel disease (CSVD) is one of the most important causes of vascular dementia. Immunosenescence and inflammatory response, with the involvement of the cerebrovascular system, constitute the basis of this disease. Immunosenescence identifies a condition of deterioration of the immune organs and consequent dysregulation of the immune response caused by cellular senescence, which exposes older adults to a greater vulnerability. A low-grade chronic inflammation status also accompanies it without overt infections, an “inflammaging” condition. The correlation between immunosenescence and inflammaging is fundamental in understanding the pathogenesis of age-related CSVD (ArCSVD). The production of inflammatory mediators caused by inflammaging promotes cellular senescence and the decrease of the adaptive immune response. Vice versa, the depletion of the adaptive immune mechanisms favours the stimulation of the innate immune system and the production of inflammatory mediators leading to inflammaging. Furthermore, endothelial dysfunction, chronic inflammation promoted by senescent innate immune cells, oxidative stress and impairment of microglia functions constitute, therefore, the framework within which small vessel disease develops: it is a concatenation of molecular events that promotes the decline of the central nervous system and cognitive functions slowly and progressively. Because the causative molecular mechanisms have not yet been fully elucidated, the road of scientific research is stretched in this direction, seeking to discover other aberrant processes and ensure therapeutic tools able to enhance the life expectancy of people affected by ArCSVD. Although the concept of CSVD is broader, this manuscript focuses on describing the neurobiological basis and immune system alterations behind cerebral aging. Furthermore, the purpose of our work is to detect patients with CSVD at an early stage, through the evaluation of precocious MRI changes and serum markers of inflammation, to treat untimely risk factors that influence the burden and the worsening of the cerebral disease.
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Affiliation(s)
- Alessandro Del Cuore
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialised Medicine (PROMISE) G. D’Alessandro, University of Palermo, 90133 Palermo, Italy; (G.P.); (R.R.); (A.T.)
- Internal Medicine and Stroke Care Ward, Policlinico “P. Giaccone”, 90127 Palermo, Italy
- Correspondence: ; Tel.: +39-091-655-2197
| | - Gaetano Pacinella
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialised Medicine (PROMISE) G. D’Alessandro, University of Palermo, 90133 Palermo, Italy; (G.P.); (R.R.); (A.T.)
- Internal Medicine and Stroke Care Ward, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Renata Riolo
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialised Medicine (PROMISE) G. D’Alessandro, University of Palermo, 90133 Palermo, Italy; (G.P.); (R.R.); (A.T.)
- Internal Medicine and Stroke Care Ward, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Antonino Tuttolomondo
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialised Medicine (PROMISE) G. D’Alessandro, University of Palermo, 90133 Palermo, Italy; (G.P.); (R.R.); (A.T.)
- Internal Medicine and Stroke Care Ward, Policlinico “P. Giaccone”, 90127 Palermo, Italy
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Chung CP, Lee WJ, Chou KH, Lee PL, Peng LN, Wang PN, Lin CP, Chen LK. Frailty and dementia risks in asymptomatic cerebral small vessel disease: A longitudinal cohort study. Arch Gerontol Geriatr 2022; 102:104754. [PMID: 35728329 DOI: 10.1016/j.archger.2022.104754] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/12/2022] [Accepted: 06/13/2022] [Indexed: 11/30/2022]
Abstract
OBJECTIVES Frailty has been shown to predict adverse outcomes in several diseases. We aimed to evaluate the associations between frailty profiles, both severity and subtype, and dementia risk in a community-based population with asymptomatic (without stroke and dementia) cerebral small vessel disease (CSVD). METHODS Individuals with asymptomatic CSVD were recruited from the community-based I-Lan Longitudinal Aging Study between 2011 and 2014 (baseline) and were followed up between 2018 and 2019. All participants underwent CSVD assessment by 3T brain MRI, as well as physical and cognitive assessments at baseline. Univariate and multivariate logistic regression analyses were performed to evaluate the associations between each factor and dementia conversion at follow-up. RESULTS Among 261 participants with asymptomatic CSVD (64.8 [50.0-89.1, 8.4] years; 136 [52.1%] men), 13 (5.0%) developed dementia during a mean follow-up of 5.7 (0.7) years. Dementia converters were less likely to be robust (30.8% vs. 61.5%) and more likely to be pre-frail/frail (69.2% vs. 38.5%) than non-converters (p = 0.040). Meanwhile, there was significantly more frequent mobility frailty (53.8% vs. 19.8%, p = 0.009), but a similar prevalence of non-mobility frailty in dementia converters compared with non-converters. Univariate analyses showed that neither frailty severity nor CSVD burden was associated with a higher risk of dementia; it was the frailty subtype, the mobility frailty, which was significantly associated with dementia conversion in participants with asymptomatic CSVD, with an odds-ratio of 4.8 (95% CI = 1.5-14.8, p = 0.007). The significance remained after adjusting for age, sex, education and baseline cognitive function, respectively. CONCLUSION Mobility frailty was associated with a higher risk of incident dementia in individuals with subclinical CSVD. Mobility frailty might be involved in the pathology of cognitive decline in CSVD and potentially serve as a marker to identify people at risk of cognitive impairment at an early stage of CSVD.
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Affiliation(s)
- Chih-Ping Chung
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, No. 201, Section 2, Shipai Road, Beitou District, Taipei City 112, Taiwan; School of Medicine, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan.
| | - Wei-Ju Lee
- Aging and Health Research Center, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan; Department of Family Medicine, Taipei Veterans General Hospital Yuanshan Branch, Yi-Lan, Taiwan
| | - Kun-Hsien Chou
- Institute of Neuroscience, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan; Brain Research Center, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan
| | - Pei-Lin Lee
- Institute of Neuroscience, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan; Brain Research Center, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan
| | - Li-Ning Peng
- Aging and Health Research Center, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan; Center for Geriatric and Gerontology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Pei-Ning Wang
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, No. 201, Section 2, Shipai Road, Beitou District, Taipei City 112, Taiwan; Aging and Health Research Center, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan; Brain Research Center, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan
| | - Ching-Po Lin
- Institute of Neuroscience, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan; Brain Research Center, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan
| | - Liang-Kung Chen
- Aging and Health Research Center, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan; Taipei Municipal Gan-Dau Hospital (managed by Taipei Veterans General Hospital), Taipei, Taiwan
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Chi NF, Chung CP, Cheng HM, Liu CH, Lin CJ, Hsu LC, Tang SC, Lee JT, Po HL, Jeng JS, Wang TD, Lee IH. 2021 Taiwan Stroke Society Guidelines of blood pressure control for ischemic stroke prevention. J Chin Med Assoc 2022; 85:651-664. [PMID: 35507097 DOI: 10.1097/jcma.0000000000000738] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Since the publication of the 2015 Taiwan Stroke Society Blood Pressure for Treatment and Prevention of Stroke Guideline (2015 TSS BP Guideline), several new clinical studies have addressed whether a stricter blood pressure (BP) target would be effective for stroke prevention. METHODS TSS guideline consensus group provides recommendations on BP targets for stroke prevention based on updated evidences. RESULTS The present guideline covers five topics: (1) diagnosis of hypertension; (2) BP control and primary prevention of ischemic stroke; (3) BP control and secondary prevention of ischemic stroke; (4) BP control and secondary prevention of large artery atherosclerosis ischemic stroke; and (5) BP control and secondary prevention of small vessel occlusion ischemic stroke. CONCLUSION The BP target for most stroke patients with hypertension is <130/80 mm Hg.
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Affiliation(s)
- Nai-Fang Chi
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Neurology in School of Medicine, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan, ROC
| | - Chih-Ping Chung
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Neurology in School of Medicine, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan, ROC
| | - Hao-Ming Cheng
- Center for Evidence-based Medicine & Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Medicine, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan, ROC
- Institute of Public Health, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan, ROC
| | - Chi-Hung Liu
- Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan City, Taiwan, ROC
| | - Chun-Jen Lin
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Neurology in School of Medicine, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan, ROC
| | - Li-Chi Hsu
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Neurology in School of Medicine, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan, ROC
| | - Sung-Chun Tang
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan, ROC
| | - Jiunn-Tay Lee
- Department of Neurology, Tri-Service General Hospital, Taipei, Taiwan, ROC
| | - Helen L Po
- Department of Neurology, Mackay Memorial Hospital, Taipei, Taiwan, ROC
| | - Jiann-Shing Jeng
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan, ROC
| | - Tzung-Dau Wang
- Department of Cardiology, National Taiwan University, Taipei, Taiwan, ROC
| | - I-Hui Lee
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Neurology in School of Medicine, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan, ROC
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Rundek T, Tolea M, Ariko T, Fagerli EA, Camargo CJ. Vascular Cognitive Impairment (VCI). Neurotherapeutics 2022; 19:68-88. [PMID: 34939171 PMCID: PMC9130444 DOI: 10.1007/s13311-021-01170-y] [Citation(s) in RCA: 123] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/06/2021] [Indexed: 01/03/2023] Open
Abstract
Vascular cognitive impairment (VCI) is predominately caused by vascular risk factors and cerebrovascular disease. VCI includes a broad spectrum of cognitive disorders, from mild cognitive impairment to vascular dementia caused by ischemic or hemorrhagic stroke, and vascular factors alone or in a combination with neurodegeneration including Alzheimer's disease (AD) and AD-related dementia. VCI accounts for at least 20-40% of all dementia diagnosis. Growing evidence indicates that cerebrovascular pathology is the most important contributor to dementia, with additive or synergistic interactions with neurodegenerative pathology. The most common underlying mechanism of VCI is chronic age-related dysregulation of CBF, although other factors such as inflammation and cardiovascular dysfunction play a role. Vascular risk factors are prevalent in VCI and if measured in midlife they predict cognitive impairment and dementia in later life. Particularly, hypertension, high cholesterol, diabetes, and smoking at midlife are each associated with a 20 to 40% increased risk of dementia. Control of these risk factors including multimodality strategies with an inclusion of lifestyle modification is the most promising strategy for treatment and prevention of VCI. In this review, we present recent developments in age-related VCI, its mechanisms, diagnostic criteria, neuroimaging correlates, vascular risk determinants, and current intervention strategies for prevention and treatment of VCI. We have also summarized the most recent and relevant literature in the field of VCI.
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Affiliation(s)
- Tatjana Rundek
- Department of Neurology and Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Magdalena Tolea
- Department of Neurology and Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Taylor Ariko
- Department of Neurology and Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Eric A Fagerli
- Department of Neurology and Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Christian J Camargo
- Department of Neurology and Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, Miami, FL, USA
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Design of Stroke-Related Clinical Trials. Stroke 2022. [DOI: 10.1016/b978-0-323-69424-7.00065-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Kang P, Ying C, Chen Y, Ford AL, An H, Lee JM. Oxygen Metabolic Stress and White Matter Injury in Patients With Cerebral Small Vessel Disease. Stroke 2021; 53:1570-1579. [PMID: 34886686 PMCID: PMC9038643 DOI: 10.1161/strokeaha.121.035674] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND AND PURPOSE Chronic hypoxia-ischemia is a putative mechanism underlying the development of white matter hyperintensities (WMH) and microstructural disruption in cerebral small vessel disease. WMH fall primarily within deep white matter (WM) watershed regions. We hypothesized that elevated oxygen extraction fraction (OEF), a signature of hypoxia-ischemia, would be detected in the watershed where WMH density is highest. We further hypothesized that OEF would be elevated in regions immediately surrounding WMH, at the leading edge of growth. METHODS In this cross-sectional study conducted from 2016 to 2019 at an academic medical center in St Louis, MO, participants (age >50) with a range of cerebrovascular risk factors underwent brain magnetic resonance imaging using pseudocontinuous arterial spin labeling, asymmetric spin echo, fluid-attenuated inversion recovery and diffusion tensor imaging to measure cerebral blood flow (CBF), OEF, WMH, and WM integrity, respectively. We defined the physiologic watershed as a region where CBF was below the 10th percentile of mean WM CBF in a young healthy cohort. We conducted linear regression to evaluate the relationship between CBF and OEF with structural and microstructural WM injury defined by fluid-attenuated inversion recovery WMH and diffusion tensor imaging, respectively. We conducted ANOVA to determine if OEF was increased in proximity to WMH lesions. RESULTS In a cohort of 42 participants (age 50-80), the physiologic watershed region spatially overlapped with regions of highest WMH lesion density. As CBF decreased and OEF increased, WMH density increased. Elevated watershed OEF was associated with greater WMH burden and microstructural disruption, after adjusting for vascular risk factors. In contrast, WM and watershed CBF were not associated with WMH burden or microstructural disruption. Moreover, OEF progressively increased while CBF decreased, in concentric contours approaching WMH lesions. CONCLUSIONS Chronic hypoxia-ischemia in the watershed region may contribute to cerebral small vessel disease pathogenesis and development of WMH. Watershed OEF may hold promise as an imaging biomarker to identify individuals at risk for cerebral small vessel disease progression.
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Affiliation(s)
- Peter Kang
- Department of Neurology, Washington University School of Medicine. (P.K., Y.C., A.L.F., H.A., J.-M.L.)
| | - Chunwei Ying
- Department of Biomedical Engineering, Washington University (C.Y., H.A., J.-M.L.)
| | - Yasheng Chen
- Department of Neurology, Washington University School of Medicine. (P.K., Y.C., A.L.F., H.A., J.-M.L.)
| | - Andria L Ford
- Department of Neurology, Washington University School of Medicine. (P.K., Y.C., A.L.F., H.A., J.-M.L.).,Mallinckrodt Institute of Radiology, Washington University School of Medicine. (A.L.F., H.A., J.-M.L.)
| | - Hongyu An
- Department of Neurology, Washington University School of Medicine. (P.K., Y.C., A.L.F., H.A., J.-M.L.).,Mallinckrodt Institute of Radiology, Washington University School of Medicine. (A.L.F., H.A., J.-M.L.).,Department of Biomedical Engineering, Washington University (C.Y., H.A., J.-M.L.)
| | - Jin-Moo Lee
- Department of Neurology, Washington University School of Medicine. (P.K., Y.C., A.L.F., H.A., J.-M.L.).,Mallinckrodt Institute of Radiology, Washington University School of Medicine. (A.L.F., H.A., J.-M.L.).,Department of Biomedical Engineering, Washington University (C.Y., H.A., J.-M.L.)
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Brown R, Low A, Markus HS. Rate of, and risk factors for, white matter hyperintensity growth: a systematic review and meta-analysis with implications for clinical trial design. J Neurol Neurosurg Psychiatry 2021; 92:1271-1277. [PMID: 34344790 DOI: 10.1136/jnnp-2021-326569] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 07/05/2021] [Indexed: 11/04/2022]
Abstract
BACKGROUND White matter hyperintensities (WMHs) are a highly prevalent MRI marker of cerebral small vessel disease (SVD), which predict stroke and dementia risk, and are being increasingly used as a surrogate marker in clinical trials. However, the influence of study population selection on WMH progression rate has not been studied and the effect of individual patient factors for WMH growth are not fully understood. METHODS We performed a systematic review and meta-analysis of the literature on progression of WMHs in longitudinal studies to determine rates of WMH growth, and how these varied according to population characteristics and cardiovascular risk factors. We used these data to calculate necessary sample sizes for clinical trials using WMH as an endpoint. RESULTS WMH growth rate was highest in SVD (2.50cc/year), intermediate in unselected stroke patients (1.29cc/year) and lower in patients with non-stroke cardiovascular disease, and with cognitive impairment. Age was significantly associated with progression (correlation coefficient 0.15cc/year, 95% CI 0.02 to 0.28cc/year) as was baseline lesion volume (0.6cc/year, 95% CI 0.13 to 1.06 cc/year). Both hypertension (OR 1.72, 95% CI 1.19 to 2.46) and current smoking (OR 1.48, 95% CI 1.02 to 2.16) were associated with WMH growth. Sample sizes for a clinical trial varied greatly with patient population selection and baseline lesion volume; estimates are provided. CONCLUSIONS WMH progression varies markedly according to the characteristics of the population being studied and this will have a major impact on sample sizes required in a clinical trial. Our sample size estimates provide data for planning clinical trials using WMH as an outcome measure. PROSPERO REGISTRATION NUMBER CRD42020191781.
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Affiliation(s)
- Robin Brown
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Audrey Low
- Department of Psychiatry, University of Cambridge, Cambridge, UK
| | - Hugh S Markus
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
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Hotz I, Deschwanden PF, Mérillat S, Liem F, Kollias S, Jäncke L. Associations of subclinical cerebral small vessel disease and processing speed in non-demented subjects: A 7-year study. Neuroimage Clin 2021; 32:102884. [PMID: 34911190 PMCID: PMC8633374 DOI: 10.1016/j.nicl.2021.102884] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/26/2021] [Accepted: 11/16/2021] [Indexed: 12/22/2022]
Abstract
Markers of cerebral small vessel disease (CSVD) have previously been associated with age-related cognitive decline. Using longitudinal data of cognitively healthy, older adults (N = 216, mean age at baseline = 70.9 years), we investigated baseline status and change in white matter hyperintensities (WMH) (total, periventricular, deep), normal appearing white matter (NAWM), brain parenchyma volume (BPV) and processing speed over seven years as well as the impact of different covariates by applying latent growth curve (LGC) models. Generally, we revealed a complex pattern of associations between the different CSVD markers. More specifically, we observed that changes of deep WMH (dWMH), as compared to periventricular WMH (pWMH), were more strongly related to the changes of other CSVD markers and also to baseline processing speed performance. Further, the number of lacunes rather than their volume reflected the severity of CSVD. With respect to the studied covariates, we revealed that higher education had a protective effect on subsequent total WMH, pWMH, lacunar number, NAWM volume, and processing speed performance. The indication of antihypertensive drugs was associated with lower lacunar number and volume at baseline and the indication of antihypercholesterolemic drugs came along with higher processing speed performance at baseline. In summary, our results confirm previous findings, and extend them by providing information on true within-person changes, relationships between the different CSVD markers and brain-behavior associations. The moderate to strong associations between changes of the different CSVD markers indicate a common pathological relationship and, thus, support multidimensional treatment strategies.
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Affiliation(s)
- Isabel Hotz
- Division of Neuropsychology, Department of Psychology, University of Zurich, Zurich, Switzerland; University Research Priority Program (URPP), Dynamics of Healthy Aging, University of Zurich, Zurich, Switzerland.
| | - Pascal Frédéric Deschwanden
- University Research Priority Program (URPP), Dynamics of Healthy Aging, University of Zurich, Zurich, Switzerland
| | - Susan Mérillat
- University Research Priority Program (URPP), Dynamics of Healthy Aging, University of Zurich, Zurich, Switzerland
| | - Franziskus Liem
- University Research Priority Program (URPP), Dynamics of Healthy Aging, University of Zurich, Zurich, Switzerland
| | - Spyridon Kollias
- Department of Neuroradiology, University Hospital Zurich, Zurich, Switzerland
| | - Lutz Jäncke
- Division of Neuropsychology, Department of Psychology, University of Zurich, Zurich, Switzerland; University Research Priority Program (URPP), Dynamics of Healthy Aging, University of Zurich, Zurich, Switzerland.
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Narasimhan M, Schwartz R, Halliday G. Parkinsonism and cerebrovascular disease. J Neurol Sci 2021; 433:120011. [PMID: 34686356 DOI: 10.1016/j.jns.2021.120011] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/01/2021] [Accepted: 09/29/2021] [Indexed: 11/27/2022]
Abstract
The relationship between cerebrovascular disease and parkinsonism is commonly seen in everyday clinical practice but remains ill-defined and under-recognised with little guidance for the practising neurologist. We attempt to define this association and to illustrate key clinical, radiological and pathological features of the syndrome of Vascular Parkinsonism (VaP). VaP is a major cause of morbidity in the elderly associated with falls, hip fractures and cognitive impairment. Although acute parkinsonism is reported in the context of an acute cerebrovascular event, the vast majority of VaP presents as an insidious syndrome usually in the context of vascular risk factors and radiological evidence of small vessel disease. There may be an anatomic impact on basal ganglia neuronal networks, however the effect of small vessel disease (SVD) on these pathways is not clear. There are now established reporting standards for radiological features of SVD on MRI. White matter hyperintensities and lacunes have been thought to be the representative radiological features of SVD but other features such as the perivascular space are gaining more importance, especially in context of the glymphatic system. It is important to consider VaP in the differential diagnosis of Parkinson disease (PD) and in these situations, neuroimaging may offer diagnostic benefit especially in those patients with atypical presentations or refractoriness to levodopa. Proactive management of vascular risk factors, monitoring of bone density and an exercise program may offer easily attainable therapeutic targets in PD and VaP. Levodopa therapy should be considered in patients with VaP, however the dose and effect may be different from use in PD. This article is part of the Special Issue "Parkinsonism across the spectrum of movement disorders and beyond" edited by Joseph Jankovic, Daniel D. Truong and Matteo Bologna.
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Affiliation(s)
- Manisha Narasimhan
- Brain and Mind Centre and Faculty of Health and Medical Sciences, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia.
| | - Raymond Schwartz
- Brain and Mind Centre and Faculty of Health and Medical Sciences, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia
| | - Glenda Halliday
- Brain and Mind Centre and Faculty of Health and Medical Sciences, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia
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Morys F, Dadar M, Dagher A. Association Between Midlife Obesity and Its Metabolic Consequences, Cerebrovascular Disease, and Cognitive Decline. J Clin Endocrinol Metab 2021; 106:e4260-e4274. [PMID: 33677592 PMCID: PMC8475210 DOI: 10.1210/clinem/dgab135] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Indexed: 01/08/2023]
Abstract
CONTEXT Chronic obesity is associated with several complications, including cognitive impairment and dementia. However, we have only piecemeal knowledge of the mechanisms linking obesity to central nervous system damage. Among candidate mechanisms are other elements of obesity-associated metabolic syndrome, such as hypertension, dyslipidemia, and diabetes, but also systemic inflammation. While there have been several neuroimaging studies linking adiposity to changes in brain morphometry, a comprehensive investigation of the relationship has so far not been done. OBJECTIVE To identify links between adiposity and cognitive dysfunction. METHODS This observational cohort study (UK Biobank), with an 8-year follow-up, included more than 20 000 participants from the general community, with a mean age of 63 years. Only participants with data available on both baseline and follow-up timepoints were included. The main outcome measures were cognitive performance and mediator variables: hypertension, diabetes, systemic inflammation, dyslipidemia, gray matter measures, and cerebrovascular disease (volume of white matter hyperintensities on magnetic resonance imaging). RESULTS Using structural equation modeling, we found that body mass index, waist-to-hip ratio, and body fat percentage were positively related to higher plasma C-reactive protein, dyslipidemia, hypertension, and diabetes. In turn, hypertension and diabetes were related to cerebrovascular disease. Finally, cerebrovascular disease was associated with lower cortical thickness and volume and higher subcortical volumes, but also cognitive deficits (largest significant pcorrected = 0.02). CONCLUSIONS We show that adiposity is related to poor cognition, with metabolic consequences of obesity and cerebrovascular disease as potential mediators. The outcomes have clinical implications, supporting a role for the management of adiposity in the prevention of late-life dementia and cognitive decline.
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Affiliation(s)
- Filip Morys
- Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada
- Correspondence: Filip Morys, Ph.D., Université McGill, 3801 University Street, H3A 2B4 Montreal, Canada.
| | - Mahsa Dadar
- Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada
- Department of Radiology and Nuclear Medicine, Faculty of Medicine, Laval University, Québec, Canada
| | - Alain Dagher
- Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada
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Robinson AC, Roncaroli F, Chew-Graham S, Davidson YS, Minshull J, Horan MA, Payton A, Pendleton N, Mann DMA. The Contribution of Vascular Pathology Toward Cognitive Impairment in Older Individuals with Intermediate Braak Stage Tau Pathology. J Alzheimers Dis 2021; 77:1005-1015. [PMID: 32804131 DOI: 10.3233/jad-200339] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The pathological features of Alzheimer's disease (AD) are well described but little is known as to how both neurodegeneration and vascular changes might interact in causing cognitive impairment. OBJECTIVE The present study aims to investigate relationships between vascular and AD pathology in cognitively healthy and cognitively impaired individuals with a particular emphasis on those at intermediate Braak tau stages. METHODS We investigated the interplay between Braak tau stage and measures of vascular pathology as described by the vascular cognitive impairment neuropathology guidelines (VCING) in 185 brains from the Brains for Dementia Research programme and The University of Manchester Longitudinal Study of Cognition in Healthy Old Age. VCING asserts that at least one large (>10 mm) infarct, moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, and moderate/severe arteriosclerosis in occipital white matter accurately predicts the contribution of cerebrovascular pathology to cognitive impairment. RESULTS We found that the extent of arteriosclerosis in the occipital white matter did not differ between cognitive groups at intermediate (III-IV) Braak stages whereas moderate/severe leptomeningeal occipital cerebral amyloid angiopathy was greater in cognitively impaired than normal individuals at Braak stage III-IV. This finding remained significant after controlling for effects of age, sex, CERAD score, Thal phase, presence/severity of primary age-related tauopathy, presence/severity of limbic-predominant age-related TDP43 encephalopathy and small vessel disease in basal ganglia. CONCLUSION Interventions targeting cerebral amyloid angiopathy may contribute to delay the onset of cognitive impairment in individuals with intermediate Alzheimer's type pathology.
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Affiliation(s)
- Andrew C Robinson
- Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK
| | - Federico Roncaroli
- Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK.,Manchester Academic Health Science Centre (MAHSC), Manchester, UK
| | - Stephen Chew-Graham
- Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK
| | - Yvonne S Davidson
- Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK
| | - James Minshull
- Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK
| | - Michael A Horan
- Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK
| | - Antony Payton
- Division of Informatics, Imaging & Data Sciences, Faculty of Biology, Medicine and Health, School of Health Sciences, The University of Manchester, Manchester, UK
| | - Neil Pendleton
- Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK
| | - David M A Mann
- Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK
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Su C, Wu H, Yang X, Zhao B, Zhao R. The relation between antihypertensive treatment and progression of cerebral small vessel disease: A systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore) 2021; 100:e26749. [PMID: 34397717 PMCID: PMC8322490 DOI: 10.1097/md.0000000000026749] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 06/29/2021] [Accepted: 07/08/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Cerebral small vessel disease is relevant to hypertension. We tried to figure out whether antihypertensive treatment is beneficial for this disease. METHODS We systematically searched PubMed, Embase, and Cochrane electronic databases for randomized controlled trials about white matter hyperintensities (WMH), brain atrophy, microbleeds, and lacunar infarcts with antihypertensive treatment and performed a meta-analysis. RESULTS We identified 7 trials on white matter hyperintensities and brain atrophy with antihypertensive treatment. Pooled analysis showed antihypertensive treatment performed positively in the progression of WMH (standardized mean difference, -0.22; 95% CI, -0.36 to -0.07, I^2 = 52%). And in the subgroup meta-analysis, only lower SBP controlled level (110-129 mm Hg) had effect on the progression of WMH (standardized mean difference, -0.37; 95% CI, -0.54 to -0.29, I^2 =0). The meta-regression showed larger difference of SBP in treatment groups having a smaller WMH progression. Antihypertensive treatment is not significant in the progression of brain atrophy (standardized mean difference, -0.02; 95% CI, -0.26 to 0.30, I^2 = 85%). Only 1 trial reported the new patients of lacunar infarcts in the follow-up, no association with antihypertensive treatment (odds ratio, 2.2; 95% CI, 0.4-12.1; P = .36). CONCLUSIONS Antihypertensive treatment is beneficial for cerebral small vessel disease on white matter hyperintensities progression, but no impact on brain atrophy. And lower SBP level is more effective on the progression of WMH. There is not enough evidence to prove the relationship between antihypertensive treatment and lacunar stroke, microbleeds.
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Affiliation(s)
- Chen Su
- Neurology Department, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Hao Wu
- Neurology Department, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Xiaoyu Yang
- Neurology Department, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Bing Zhao
- Neurology Department, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, Shandong Province, China
| | - Renliang Zhao
- Neurology Department, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
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Medrano-Martorell S, Capellades J, Jiménez-Conde J, González-Ortiz S, Vilas-González M, Rodríguez-Campello A, Ois Á, Cuadrado-Godia E, Avellaneda C, Fernández I, Merino-Peña E, Roquer J, Martí-Fàbregas J, Giralt-Steinhauer E. Risk factors analysis according to regional distribution of white matter hyperintensities in a stroke cohort. Eur Radiol 2021; 32:272-280. [PMID: 34117555 DOI: 10.1007/s00330-021-08106-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/18/2021] [Accepted: 05/27/2021] [Indexed: 01/11/2023]
Abstract
OBJECTIVES The spectrum of distribution of white matter hyperintensities (WMH) may reflect different functional, histopathological, and etiological features. We examined the relationships between cerebrovascular risk factors (CVRF) and different patterns of WMH in MRI using a qualitative visual scale in ischemic stroke (IS) patients. METHODS We assembled clinical data and imaging findings from patients of two independent cohorts with recent IS. MRI scans were evaluated using a modified visual scale from Fazekas, Wahlund, and Van Swieten. WMH distributions were analyzed separately in periventricular (PV-WMH) and deep (D-WMH) white matter, basal ganglia (BG-WMH), and brainstem (B-WMH). Presence of confluence of PV-WMH and D-WMH and anterior-versus-posterior WMH predominance were also evaluated. Statistical analysis was performed with SPSS software. RESULTS We included 618 patients, with a mean age of 72 years (standard deviation [SD] 11 years). The most frequent WMH pattern was D-WMH (73%). In a multivariable analysis, hypertension was associated with PV-WMH (odds ratio [OR] 1.79, 95% confidence interval [CI] 1.29-2.50, p = 0.001) and BG-WMH (OR 2.13, 95% CI 1.19-3.83, p = 0.012). Diabetes mellitus was significantly related to PV-WMH (OR 1.69, 95% CI 1.24-2.30, p = 0.001), D-WMH (OR 1.46, 95% CI 1.07-1.49, p = 0.017), and confluence patterns of D-WMH and PV-WMH (OR 1.62, 95% CI 1.07-2.47, p = 0.024). Hyperlipidemia was found to be independently related to brainstem distribution (OR 1.70, 95% CI 1.08-2.69, p = 0.022). CONCLUSIONS Different CVRF profiles were significantly related to specific WMH spatial distribution patterns in a large IS cohort. KEY POINTS • An observational study of WMH in a large IS cohort was assessed by a modified visual evaluation. • Different CVRF profiles were significantly related to specific WMH spatial distribution patterns. • Distinct WMH anatomical patterns could be related to different pathophysiological mechanisms.
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Affiliation(s)
- Santiago Medrano-Martorell
- Department of Neuroradiology, Hospital Clínic i Provincial, Villarroel, 170, Barcelona, Spain.
- Department of Neuroradiology, Hospital del Mar, Department of Medicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
| | - Jaume Capellades
- Department of Neuroradiology, Hospital del Mar, Department of Medicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Jordi Jiménez-Conde
- Department of Neurology, Hospital del Mar; Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona (UAB)/DCEXS-Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Sofía González-Ortiz
- Department of Neuroradiology, Hospital Clínic i Provincial, Villarroel, 170, Barcelona, Spain
- Department of Neuroradiology, Hospital del Mar, Department of Medicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Marta Vilas-González
- Department of Neuroradiology, Hospital del Mar, Department of Medicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Ana Rodríguez-Campello
- Department of Neurology, Hospital del Mar; Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona (UAB)/DCEXS-Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Ángel Ois
- Department of Neurology, Hospital del Mar; Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona (UAB)/DCEXS-Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Elisa Cuadrado-Godia
- Department of Neurology, Hospital del Mar; Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona (UAB)/DCEXS-Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Carla Avellaneda
- Department of Neurology, Hospital del Mar; Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona (UAB)/DCEXS-Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Isabel Fernández
- Department of Neurology, Hospital del Mar; Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona (UAB)/DCEXS-Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Elisa Merino-Peña
- Department of Neuroradiology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Jaume Roquer
- Department of Neurology, Hospital del Mar; Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona (UAB)/DCEXS-Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Joan Martí-Fàbregas
- Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Eva Giralt-Steinhauer
- Department of Neurology, Hospital del Mar; Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona (UAB)/DCEXS-Universitat Pompeu Fabra (UPF), Barcelona, Spain
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Zee B, Wong Y, Lee J, Fan Y, Zeng J, Lam B, Wong A, Shi L, Lee A, Kwok C, Lai M, Mok V, Lau A. Machine-learning method for localization of cerebral white matter hyperintensities in healthy adults based on retinal images. Brain Commun 2021; 3:fcab124. [PMID: 34222872 PMCID: PMC8249101 DOI: 10.1093/braincomms/fcab124] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 03/26/2021] [Accepted: 04/14/2021] [Indexed: 11/12/2022] Open
Abstract
Retinal vessels are known to be associated with various cardiovascular and cerebrovascular disease outcomes. Recent research has shown significant correlations between retinal characteristics and the presence of cerebral small vessel disease as measured by white matter hyperintensities from cerebral magnetic resonance imaging. Early detection of age-related white matter changes using retinal images is potentially helpful for population screening and allow early behavioural and lifestyle intervention. This study investigates the ability of the machine-learning method for the localization of brain white matter hyperintensities. All subjects were age 65 or above without any history of stroke and dementia and recruited from local community centres and community networks. Subjects with known retinal disease or disease influencing vessel structure in colour retina images were excluded. All subjects received MRI on the brain, and age-related white matter changes grading was determined from MRI as the primary endpoint. The presence of age-related white matter changes on each of the six brain regions was also studied. Retinal images were captured using a fundus camera, and the analysis was done based on a machine-learning approach. A total of 240 subjects are included in the study. The analysis of various brain regions included the left and right sides of frontal lobes, parietal–occipital lobes and basal ganglia. Our results suggested that data from both eyes are essential for detecting age-related white matter changes in the brain regions, but the retinal parameters useful for estimation of the probability of age-related white matter changes in each of the brain regions may differ for different locations. Using a classification and regression tree approach, we also found that at least three significant heterogeneous subgroups of subjects were identified to be essential for the localization of age-related white matter changes. Namely those with age-related white matter changes in the right frontal lobe, those without age-related white matter changes in the right frontal lobe but with age-related white matter changes in the left parietal–occipital lobe, and the rest of the subjects. Outcomes such as risks of severe grading of age-related white matter changes and the proportion of hypertension were significantly related to these subgroups. Our study showed that automatic retinal image analysis is a convenient and non-invasive screening tool for detecting age-related white matter changes and cerebral small vessel disease with good overall performance. The localization analysis for various brain regions shows that the classification models on each of the six brain regions can be done, and it opens up potential future clinical application.
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Affiliation(s)
- Benny Zee
- Centre for Clinical Research and Biostatistics, Jockey Club School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.,Clinical Trials and Biostatistics Lab, CUHK Shenzhen Research Institute, Shenzhen, China
| | - Yanny Wong
- Margaret KL Cheung Research Centre for Management of Parkinsonism, Therese Pei Fong Chow Research Centre for Prevention of Dementia and Gerald Choa Neuroscience Centre, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.,Division of Neurology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Jack Lee
- Centre for Clinical Research and Biostatistics, Jockey Club School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.,Clinical Trials and Biostatistics Lab, CUHK Shenzhen Research Institute, Shenzhen, China
| | - Yuhua Fan
- Department of Neurology, First Affiliated Hospital of Sun Yat-Sen University, Guangdong, China.,Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department, National Key Discipline, Guangzhou 510080, China
| | - Jinsheng Zeng
- Department of Neurology, First Affiliated Hospital of Sun Yat-Sen University, Guangdong, China.,Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department, National Key Discipline, Guangzhou 510080, China
| | - Bonnie Lam
- Margaret KL Cheung Research Centre for Management of Parkinsonism, Therese Pei Fong Chow Research Centre for Prevention of Dementia and Gerald Choa Neuroscience Centre, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.,Division of Neurology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Adrian Wong
- Margaret KL Cheung Research Centre for Management of Parkinsonism, Therese Pei Fong Chow Research Centre for Prevention of Dementia and Gerald Choa Neuroscience Centre, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.,Division of Neurology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Lin Shi
- BrainNow Research Institute, Shenzhen, Guangdong Province, China.,Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Allen Lee
- Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Chloe Kwok
- Centre for Clinical Research and Biostatistics, Jockey Club School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Maria Lai
- Centre for Clinical Research and Biostatistics, Jockey Club School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Vincent Mok
- Margaret KL Cheung Research Centre for Management of Parkinsonism, Therese Pei Fong Chow Research Centre for Prevention of Dementia and Gerald Choa Neuroscience Centre, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.,Division of Neurology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Alexander Lau
- Margaret KL Cheung Research Centre for Management of Parkinsonism, Therese Pei Fong Chow Research Centre for Prevention of Dementia and Gerald Choa Neuroscience Centre, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.,Division of Neurology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China
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Wardlaw JM, Debette S, Jokinen H, De Leeuw FE, Pantoni L, Chabriat H, Staals J, Doubal F, Rudilosso S, Eppinger S, Schilling S, Ornello R, Enzinger C, Cordonnier C, Taylor-Rowan M, Lindgren AG. ESO Guideline on covert cerebral small vessel disease. Eur Stroke J 2021; 6:CXI-CLXII. [PMID: 34414301 PMCID: PMC8370079 DOI: 10.1177/23969873211012132] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 04/02/2021] [Indexed: 12/11/2022] Open
Abstract
'Covert' cerebral small vessel disease (ccSVD) is common on neuroimaging in persons without overt neurological manifestations, and increases the risk of future stroke, cognitive impairment, dependency, and death. These European Stroke Organisation (ESO) guidelines provide evidence-based recommendations to assist with clinical decisions about management of ccSVD, specifically white matter hyperintensities and lacunes, to prevent adverse clinical outcomes. The guidelines were developed according to ESO standard operating procedures and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. We prioritised the clinical outcomes of stroke, cognitive decline or dementia, dependency, death, mobility and mood disorders, and interventions of blood pressure lowering, antiplatelet drugs, lipid lowering, lifestyle modifications, glucose lowering and conventional treatments for dementia. We systematically reviewed the literature, assessed the evidence, formulated evidence-based recommendations where feasible, and expert consensus statements. We found little direct evidence, mostly of low quality. We recommend patients with ccSVD and hypertension to have their blood pressure well controlled; lower blood pressure targets may reduce ccSVD progression. We do not recommend antiplatelet drugs such as aspirin in ccSVD. We found little evidence on lipid lowering in ccSVD. Smoking cessation is a health priority. We recommend regular exercise which may benefit cognition, and a healthy diet, good sleep habits, avoiding obesity and stress for general health reasons. In ccSVD, we found no evidence for glucose control in the absence of diabetes or for conventional Alzheimer dementia treatments. Randomised controlled trials with clinical endpoints are a priority for ccSVD.
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Affiliation(s)
- Joanna M Wardlaw
- Centre for Clinical Brain Sciences, UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK
| | - Stephanie Debette
- Bordeaux Population Health Center, University of Bordeaux, INSERM, UM1219, Team VINTAGE
- Department of Neurology, Institute for Neurodegenerative Disease, Bordeaux University Hospital, Bordeaux, France
| | - Hanna Jokinen
- HUS Neurocenter, Division of Neuropsychology, Helsinki University Hospital, University of Helsinki and Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Finland
| | - Frank-Erik De Leeuw
- Radboud University Medical Center, Department of Neurology; Donders Center for Medical Neuroscience, Nijmegen, The Netherlands
| | - Leonardo Pantoni
- Stroke and Dementia Lab, 'Luigi Sacco' Department of Biomedical and Clinical Sciences, University of Milan, Milano, Italy
| | - Hugues Chabriat
- Department of Neurology, Hopital Lariboisiere, APHP, INSERM U 1161, FHU NeuroVasc, University of Paris, Paris, France
| | - Julie Staals
- Department of Neurology, School for Cardiovascular Diseases (CARIM), Maastricht UMC+, AZ Maastricht, the Netherlands
| | - Fergus Doubal
- Centre for Clinical Brain Sciences, UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK
- Dept of Medicine for the Elderly, University of Edinburgh, Edinburgh, UK
| | - Salvatore Rudilosso
- Comprehensive Stroke Center, Department of Neuroscience, Hospital Clínic, Barcelona, Spain
| | - Sebastian Eppinger
- University Clinic of Neurology, Medical University of Graz, Graz, Austria
| | - Sabrina Schilling
- Bordeaux Population Health Center, University of Bordeaux, INSERM, UM1219, Team VINTAGE
| | - Raffaele Ornello
- Department of Applied Clinical Sciences and Biotechnology, University of L’Aquila, L’Aquila, Italy
| | - Christian Enzinger
- University Clinic of Neurology, Medical University of Graz, Graz, Austria
| | - Charlotte Cordonnier
- Univ. Lille, INSERM, CHU Lille, U1172, LilNCog – Lille Neuroscience & Cognition, Lille, France
| | - Martin Taylor-Rowan
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Arne G Lindgren
- Department of Clinical Sciences Lund, Neurology, Lund University; Section of Neurology, Skåne University Hospital, Lund, Sweden
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46
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Wartolowska KA, Webb AJS. Blood Pressure Determinants of Cerebral White Matter Hyperintensities and Microstructural Injury: UK Biobank Cohort Study. Hypertension 2021; 78:532-539. [PMID: 34058855 PMCID: PMC8260341 DOI: 10.1161/hypertensionaha.121.17403] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Supplemental Digital Content is available in the text. Small vessel disease and related stroke and dementia risks are linked to aging and hypertension, but it is unclear whether the pulsatile or steady blood pressure (BP) component is more important for the development of macrostructural hyperintensities and microstructural white matter damage. This was a cross-sectional analysis of the UK Biobank cohort study of community-based adults from 22 UK centers. Linear associations were determined between neuroimaging markers (white matter hyperintensity [WMH] volume and diffusion imaging indices) and mean arterial pressure and pulse pressure (PP), both unadjusted and adjusted for age, sex, cardiovascular risk factors, antihypertensive medication, BP source, and assessment center. In 37 041 participants aged 45 to 82 years (53% female), univariable analyses demonstrated that increases in both BP components were associated with greater WMH volume and white matter injury on diffusion indices, with a larger effect for PP (standardized effect size for WMH: mean arterial BP: 0.182 [95% CIs, 0.170–0.193]; PP: 0.285 [95% CIs, 0.274–0.296]). In multivariable analyses, associations with mean arterial pressure remained similar, but associations with PP diminished, reflecting covariance with age and risk factors (standardized effect size for WMH: mean arterial BP: 0.106 [95% CIs, 0.095–0.117]; PP: 0.011 [95% CIs, −0.001 to 0.023]). The synergistic interaction between PP and age increased the effect of age on WMH and diffusion indices. Both macrostructural and microstructural white matter injury had similar associations with the pulsatile and steady components of hypertension, although PP accentuated the relationship between age and white matter damage.
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Affiliation(s)
- Karolina A Wartolowska
- Wolfson Centre for Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom
| | - Alastair J S Webb
- Wolfson Centre for Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom
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47
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Yang W, Luo H, Ma Y, Si S, Zhao H. Effects of Antihypertensive Drugs on Cognitive Function in Elderly Patients with Hypertension: A Review. Aging Dis 2021; 12:841-851. [PMID: 34094646 PMCID: PMC8139194 DOI: 10.14336/ad.2020.1111] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 11/11/2020] [Indexed: 12/13/2022] Open
Abstract
Hypertension is a common comorbidity that contributes to the development of various cardiovascular disorders in elderly patients. Moreover, hypertension has been associated with cognitive decline and dementia. Cognitive impairment leads to increased morbidity and mortality in elderly patients with hypertension. However, previous studies investigating the association between blood pressure (BP), BP variability (BPV), and antihypertensive drug use and the risk of cognitive impairment in elderly patients with hypertension have reported inconsistent findings. Given the global burden of hypertension, the aging population, and the low quality of life associated with cognitive impairment, a more comprehensive understanding of the association between hypertension and cognitive decline is needed. In this review, we summarized the current preclinical evidence and clinical research regarding the association of BP control, BPV, and antihypertensive drug use and cognitive function. We particularly focused on the differences among categories of antihypertensive drugs. We concluded that the correlation of BP and risk of cognitive function is non-linear and dependent on a patient's age. Intensive BP control is generally not recommended, particularly for the oldest-old. Increased BPV and characteristics of orthostatic hypotension in the elderly also increase the risk of cognitive decline. The current evidence does not support one category of antihypertensive drugs as superior to others for preventing dementia in elderly patients with hypertension.
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Affiliation(s)
- Wei Yang
- Department of Geriatric Medicine, Xuan Wu Hospital, Capital Medical University, Beijing 100053, China
| | - Hongyu Luo
- Department of Geriatric Medicine, Xuan Wu Hospital, Capital Medical University, Beijing 100053, China
| | - Yixin Ma
- Department of Geriatric Medicine, Xuan Wu Hospital, Capital Medical University, Beijing 100053, China
| | - Sicong Si
- Department of Geriatric Medicine, Xuan Wu Hospital, Capital Medical University, Beijing 100053, China
| | - Huan Zhao
- Department of Geriatric Medicine, Xuan Wu Hospital, Capital Medical University, Beijing 100053, China
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48
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Grosu S, Lorbeer R, Hartmann F, Rospleszcz S, Bamberg F, Schlett CL, Galie F, Selder S, Auweter S, Heier M, Rathmann W, Mueller-Peltzer K, Ladwig KH, Peters A, Ertl-Wagner BB, Stoecklein S. White matter hyperintensity volume in pre-diabetes, diabetes and normoglycemia. BMJ Open Diabetes Res Care 2021; 9:9/1/e002050. [PMID: 34183320 PMCID: PMC8240582 DOI: 10.1136/bmjdrc-2020-002050] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 06/01/2021] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION As white matter hyperintensities (WMHs) of the brain are associated with an increased risk of stroke, cognitive decline, and depression, elucidating the associated risk factors is important. In addition to age and hypertension, pre-diabetes and diabetes may play important roles in the development of WMHs. Previous studies have, however, shown conflicting results. We aimed to investigate the effect of diabetes status and quantitative markers of glucose metabolism on WMH volume in a population-based cohort without prior cardiovascular disease. RESEARCH DESIGN AND METHODS 400 participants underwent 3 T MRI. WMHs were manually segmented on 3D fluid-attenuated inversion recovery images. An oral glucose tolerance test (OGTT) was administered to all participants not previously diagnosed with diabetes to assess 2-hour serum glucose concentrations. Fasting glucose concentrations and glycated hemoglobin (HbA1c) levels were measured. Zero-inflated negative binomial regression analyses of WMH volume and measures of glycemic status were performed while controlling for cardiovascular risk factors and multiple testing. RESULTS The final study population comprised 388 participants (57% male; age 56.3±9.2 years; n=98 with pre-diabetes, n=51 with diabetes). Higher WMH volume was associated with pre-diabetes (p=0.001) and diabetes (p=0.026) compared with normoglycemic control participants after adjustment for cardiovascular risk factors. 2-hour serum glucose (p<0.001), but not fasting glucose (p=0.389) or HbA1c (p=0.050), showed a significant positive association with WMH volume after adjustment for cardiovascular risk factors. CONCLUSION Our results indicate that high 2-hour serum glucose concentration in OGTT, but not fasting glucose levels, may be an independent risk factor for the development of WMHs, with the potential to inform intensified prevention strategies in individuals at risk of WMH-associated morbidity.
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Affiliation(s)
- Sergio Grosu
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Roberto Lorbeer
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Felix Hartmann
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Susanne Rospleszcz
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
- Department of Epidemiology, Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Fabian Bamberg
- Department of Diagnostic and Interventional Radiology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Christopher L Schlett
- Department of Diagnostic and Interventional Radiology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Franziska Galie
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Sonja Selder
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Sigrid Auweter
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Margit Heier
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
- KORA Study Centre, University Hospital of Augsburg, Augsburg, Germany
| | - Wolfgang Rathmann
- Institute for Biometrics and Epidemiology, German Diabetes Center, Duesseldorf, Germany
- German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany
| | - Katharina Mueller-Peltzer
- Department of Diagnostic and Interventional Radiology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Karl-Heinz Ladwig
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
- Department of Psychosomatic Medicine and Psychotherapy, Hospital Rechts der Isar, Technical University Munich, Munich, Germany
| | - Annette Peters
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
- Department of Epidemiology, Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Birgit B Ertl-Wagner
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
- Department of Radiology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Sophia Stoecklein
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
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49
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Shah C, Srinivasan D, Erus G, Schmitt JE, Agarwal A, Cho ME, Lerner AJ, Haley WE, Kurella Tamura M, Davatzikos C, Bryan RN, Fan Y, Nasrallah IM. Changes in brain functional connectivity and cognition related to white matter lesion burden in hypertensive patients from SPRINT. Neuroradiology 2021; 63:913-924. [PMID: 33404789 PMCID: PMC8286444 DOI: 10.1007/s00234-020-02614-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 11/25/2020] [Indexed: 12/17/2022]
Abstract
PURPOSE Hypertension is a risk factor for cognitive impairment; however, the mechanisms leading to cognitive changes remain unclear. In this cross-sectional study, we evaluate the impact of white matter lesion (WML) burden on brain functional connectivity (FC) and cognition in a large cohort of hypertensive patients from the Systolic Blood Pressure Intervention Trial (SPRINT) at baseline. METHODS Functional networks were identified from baseline resting state functional MRI scans of 660 SPRINT participants using independent component analysis. WML volumes were calculated from structural MRI. Correlation analyses were carried out between mean FC of each functional network and global WML as well as WML within atlas-defined white matter regions. For networks of interest, voxel-wise-adjusted correlation analyses between FC and regional WML volume were performed. Multiple variable linear regression models were built for cognitive test performance as a function of network FC, followed by mediation analysis. RESULTS Mean FC of the default mode network (DMN) was negatively correlated with global WML volume, and regional WML volume within the precuneus. Voxel-wise correlation analyses revealed that regional WML was negatively correlated with FC of the DMN's left lateral temporal region. FC in this region of the DMN was positively correlated to performance on the Montreal Cognitive Assessment and demonstrated significant mediation effects. Additional networks also demonstrated global and regional WML correlations; however, they did not demonstrate an association with cognition. CONCLUSION In hypertensive patients, greater WML volume is associated with lower FC of the DMN, which in turn is related to poorer cognitive test performance. TRIAL REGISTRATION NCT01206062.
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Affiliation(s)
- Chintan Shah
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.
- Department of Radiology, Imaging Institute, Cleveland Clinic, 9500 Euclid Ave, Mail code L10-428, Cleveland, OH, 44195, USA.
| | - Dhivya Srinivasan
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA
- Center for Biomedical Image Computing and Analytics, University of Pennsylvania, PA, Philadelphia, USA
| | - Guray Erus
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA
- Center for Biomedical Image Computing and Analytics, University of Pennsylvania, PA, Philadelphia, USA
| | - James E Schmitt
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA
| | - Adhish Agarwal
- Division of Nephrology and Hypertension, University of Utah, Salt Lake City, UT, USA
| | - Monique E Cho
- Division of Nephrology and Hypertension, University of Utah, Salt Lake City, UT, USA
| | - Alan J Lerner
- University Hospitals Cleveland Medical Center, Department of Neurology, Case Western Reserve University, Cleveland, OH, USA
| | - William E Haley
- Department of Nephrology and Hypertension, Mayo Clinic, Jacksonville, FL, USA
| | - Manjula Kurella Tamura
- Division of Nephrology, Stanford University, Palo Alto, CA, USA
- VA Palo Alto Geriatric Research and Education Clinical Center, Palo Alto, CA, USA
| | - Christos Davatzikos
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA
- Center for Biomedical Image Computing and Analytics, University of Pennsylvania, PA, Philadelphia, USA
| | - Robert N Bryan
- Dell Medical School, Department of Diagnostic Medicine, University of Texas at Austin, Austin, TX, USA
| | - Yong Fan
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA
- Center for Biomedical Image Computing and Analytics, University of Pennsylvania, PA, Philadelphia, USA
| | - Ilya M Nasrallah
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA
- Center for Biomedical Image Computing and Analytics, University of Pennsylvania, PA, Philadelphia, USA
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50
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Landau SM, Harrison TM. A Link Between Cardiovascular Risk Management and Alzheimer Disease Is Still Elusive. JAMA Neurol 2021; 78:524-526. [PMID: 33683302 DOI: 10.1001/jamaneurol.2021.0083] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Affiliation(s)
- Susan M Landau
- Helen Wills Neuroscience Institute, University of California, Berkeley
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