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International Journal of Stroke :... Jan 2023Cerebral small vessel disease (SVD) causes lacunar stroke and intracerebral hemorrhage, and is the most common pathology underlying vascular cognitive impairment.... (Review)
Review
Cerebral small vessel disease (SVD) causes lacunar stroke and intracerebral hemorrhage, and is the most common pathology underlying vascular cognitive impairment. Increasingly, the importance of other clinical features of SVD is being recognized including motor impairment, (vascular) parkinsonism, impaired balance, falls, and behavioral symptoms, such as depression, apathy, and personality change. Epidemiological data show a high prevalence of the characteristic magnetic resonance imaging (MRI) features of white matter hyperintensities and lacunar infarcts in community studies, and recent data suggest that it is also a major health burden in low- and middle-income countries. In this review, we cover advances in diagnosis, imaging, clinical presentations, pathogenesis, and treatment.The two most common pathologies underlying SVD are arteriolosclerosis caused by aging, hypertension, and other conventional vascular risk factors, and cerebral amyloid angiopathy (CAA) caused by vascular deposition of β-amyloid. We discuss the revised Boston criteria of CAA based on MRI features, which have been recently validated. Imaging is providing important insights into pathogenesis, including improved detection of tissue damage using diffusion tensor imaging (DTI) leading to its use to monitor progression and surrogate endpoints in clinical trials. Advanced MRI techniques can demonstrate functional or dynamic abnormalities of the blood vessels, while the high spatial resolution provided by ultrahigh field MRI at 7 T allows imaging of individual perforating arteries for the first time, and the measurement of flow velocity and pulsatility within these arteries. DTI and structural network analysis have highlighted the importance of network disruption in mediating the effect of different SVD pathologies in causing a number of symptoms, including cognitive impairment, apathy, and gait disturbance.Despite the public health importance of SVD, there are few proven treatments. We review the evidence for primary prevention, and recent data showing how intensive blood pressure lowering reduces white matter hyperintensities (WMH) progression and delays the onset of cognitive impairment. There are few treatments for secondary prevention, but a number of trials are currently evaluating novel treatment approaches. Recent advances have implicated molecular processes related to endothelial dysfunction, nitric oxide synthesis, blood-brain barrier integrity, maintenance and repair of the extracellular matrix, and inflammation. Novel treatment approaches are being developed to a number of these targets. Finally, we highlight the importance of large International collaborative initiatives in SVD to address important research questions and cover a number which have recently been established.
Topics: Humans; Diffusion Tensor Imaging; Stroke; Cerebral Small Vessel Diseases; Cognitive Dysfunction; Magnetic Resonance Imaging; Stroke, Lacunar; Cerebral Amyloid Angiopathy
PubMed: 36575578
DOI: 10.1177/17474930221144911 -
Vascular Health and Risk Management 2015Stroke is the leading cause of disability in the USA and a major cause of mortality worldwide. One out of four strokes is recurrent. Secondary stroke prevention starts... (Review)
Review
Stroke is the leading cause of disability in the USA and a major cause of mortality worldwide. One out of four strokes is recurrent. Secondary stroke prevention starts with deciphering the most likely stroke mechanism. In general, one of the main goals in stroke reduction is to control vascular risk factors such as hypertension, diabetes, dyslipidemia, and smoking cessation. Changes in lifestyle like a healthy diet and aerobic exercise are also recommended strategies. In the case of cardioembolism due to atrial fibrillation, mechanical valves, or cardiac thrombus, anticoagulation is the mainstay of therapy. The role of anticoagulation is less evident in the case of bioprosthetic valves, patent foramen ovale, and dilated cardiomyopathy with low ejection fraction. Strokes due to larger artery atherosclerosis account for approximately a third of all strokes. In the case of symptomatic extracranial carotid stenosis, surgical intervention as close as possible in time to the index event seems highly beneficial. In the case of intracranial large artery atherosclerosis, the best medical therapy consists of antiplatelets, high-dose statins, aggressive controls of vascular risk factors, and lifestyle modifications, with no role for intracranial arterial stenting or angioplasty. For patients with small artery occlusion (ie, lacunar stroke), the therapy is similar to that used in patients with intracranial large artery atherosclerosis. Despite the constant new evidence on how to best treat patients who have suffered a stroke, the risk of stroke recurrence remains unacceptably high, thus evidencing the need for novel therapies.
Topics: Aged; Aged, 80 and over; Cerebral Angiography; Comorbidity; Female; Humans; Magnetic Resonance Angiography; Male; Middle Aged; Predictive Value of Tests; Recurrence; Risk Assessment; Risk Factors; Risk Reduction Behavior; Secondary Prevention; Stroke; Treatment Outcome; Ultrasonography, Doppler, Transcranial
PubMed: 26300647
DOI: 10.2147/VHRM.S63791 -
Neuromolecular Medicine Dec 2019Biomarkers are objective indicators used to assess normal or pathological processes, evaluate responses to treatment and predict outcomes. Many blood biomarkers already... (Review)
Review
Biomarkers are objective indicators used to assess normal or pathological processes, evaluate responses to treatment and predict outcomes. Many blood biomarkers already guide decision-making in clinical practice. In stroke, the number of candidate biomarkers is constantly increasing. These biomarkers include proteins, ribonucleic acids, lipids or metabolites. Although biomarkers have the potential to improve the diagnosis and the management of patients with stroke, there is currently no marker that has demonstrated sufficient sensitivity, specificity, rapidity, precision, and cost-effectiveness to be used in the routine management of stroke, thus highlighting the need for additional work. A better standardization of clinical, laboratory and statistical procedures between centers is indispensable to optimize biomarker performance. This review focuses on blood biomarkers that have shown promise for translation into clinical practice and describes some newly reported markers that could add to routine stroke care. Avenues for the discovery of new stroke biomarkers and future research are discussed. The description of the biomarkers is organized according to their expected application in clinical practice: diagnosis, treatment decision, and outcome prediction.
Topics: Biomarkers; Blood Proteins; Cerebral Hemorrhage; Diagnosis, Differential; Disease Management; Glutamic Acid; Humans; Ischemic Stroke; Lipids; Nitric Oxide; Prognosis; RNA; Secondary Prevention; Stroke; Stroke, Lacunar; Thrombolytic Therapy; Transcriptome; Treatment Outcome
PubMed: 30830566
DOI: 10.1007/s12017-019-08530-0 -
Journal of Stroke and Cerebrovascular... Aug 2019Lacunar strokes are appropriately named for their ability to cavitate and form ponds or "little lakes" (Latin: lacune -ae meaning pond or pit is a diminutive form of... (Review)
Review
Lacunar strokes are appropriately named for their ability to cavitate and form ponds or "little lakes" (Latin: lacune -ae meaning pond or pit is a diminutive form of lacus meaning lake). They account for a substantial proportion of both symptomatic and asymptomatic ischemic strokes. In recent years, there have been several advances in the management of large vessel occlusions. New therapies such as non-vitamin K antagonist oral anticoagulants and left atrial appendage closure have recently been developed to improve stroke prevention in atrial fibrillation; however, the treatment of small vessel disease-related strokes lags frustratingly behind. Since Fisher characterized the lacunar syndromes and associated infarcts in the late 1960s, there have been no therapies specifically targeting lacunar stroke. Unfortunately, many therapeutic agents used for the treatment of ischemic stroke in general offer only a modest benefit in reducing recurrent stroke while adding to the risk of intracerebral hemorrhage and systemic bleeding. Escalation of antithrombotic treatments beyond standard single antiplatelet agents has not been effective in long-term lacunar stroke prevention efforts, unequivocally increasing intracerebral hemorrhage risk without providing a significant benefit. In this review, we critically review the available treatments for lacunar stroke based on evidence from clinical trials. For several of the major drugs, we summarize the adverse effects in the context of this unique patient population. We also discuss the role of neuroprotective therapies and neural repair strategies as they may relate to recovery from lacunar stroke.
Topics: Humans; Risk Factors; Stroke, Lacunar; Treatment Outcome
PubMed: 31151838
DOI: 10.1016/j.jstrokecerebrovasdis.2019.05.004 -
Neurology Jun 2019CNS small vessel disease (CSVD) causes 25% of strokes and contributes to 45% of dementia cases. Prevalence increases with age, affecting about 5% of people aged 50 years... (Review)
Review
CNS small vessel disease (CSVD) causes 25% of strokes and contributes to 45% of dementia cases. Prevalence increases with age, affecting about 5% of people aged 50 years to almost 100% of people older than 90 years. Known causes and risk factors include age, hypertension, branch atheromatous disease, cerebral amyloid angiopathy, radiation exposure, immune-mediated vasculitides, certain infections, and several genetic diseases. CSVD can be asymptomatic; however, depending on location, lesions can cause mild cognitive dysfunction, dementia, mood disorders, motor and gait dysfunction, and urinary incontinence. CSVD is diagnosed on the basis of brain imaging biomarkers, including recent small subcortical infarcts, white matter hyperintensities, lacunes, cerebral microbleeds, enlarged perivascular spaces, and cerebral atrophy. Advanced imaging modalities can detect signs of disease even earlier than current standard imaging techniques. Diffusion tensor imaging can identify altered white matter connectivity, and blood oxygenation level-dependent imaging can identify decreased vascular reactivity. Pathogenesis is thought to begin with an etiologically specific insult, with or without genetic predisposition, which results in dysfunction of the neurovascular unit. Uncertainties regarding pathogenesis have delayed development of effective treatment. The most widely accepted approach to treatment is to intensively control well-established vascular risk factors, of which hypertension is the most important. With better understanding of pathogenesis, specific therapies may emerge. Early identification of pathologic characteristics with advanced imaging provides an opportunity to forestall progression before emergence of symptoms.
Topics: Antihypertensive Agents; CADASIL; Cerebral Amyloid Angiopathy; Cerebral Small Vessel Diseases; Dementia; Diffusion Magnetic Resonance Imaging; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Magnetic Resonance Imaging; Platelet Aggregation Inhibitors; Stroke, Lacunar
PubMed: 31142635
DOI: 10.1212/WNL.0000000000007654 -
JAMA Neurology Oct 2018Stroke is the second leading cause of death in the world, and nearly one-third of ischemic strokes are lacunar strokes (LSs) or small subcortical infarcts. Although... (Review)
Review
IMPORTANCE
Stroke is the second leading cause of death in the world, and nearly one-third of ischemic strokes are lacunar strokes (LSs) or small subcortical infarcts. Although smaller in size, they create large problems, leaving many patients with intellectual and physical disabilities. Because there are limitations in understanding the underlying pathophysiology of LS, the development of novel therapies has been slow.
OBSERVATIONS
When the term lacune was described in the 1800s, its underlying pathophysiological basis was obscure. In the 1960s, C. Miller Fisher, MD, performed autopsy studies that showed that vessels supplying lacunes displayed segmental arteriolar disorganization, characterized by vessel enlargement, hemorrhage, and fibrinoid deposition. For these pathologic changes, he coined the term lipohyalinosis. Since that time, few attempts have been made to reconcile this pathologic description with modern mechanisms of cerebral small vessel disease (CSVD). During the past 6 years, progress has been made in understanding the clinical mechanisms, imaging characteristics, and genetic basis of LS.
CONCLUSIONS AND RELEVANCE
Questions persist regarding the order of events related to the initiation and progression of CSVD, how LS is related to other sequelae of CSVD, and whether LS is part of a systemic disease process. The relative roles of aging, oxidative stress, mechanical stress, genetic predisposition, and other vascular risk factors should be further studied, especially in the era of widespread antihypertensive use. Although understanding of endothelial dysfunction has increased, future work on the role of media and adventitial dysfunction should be explored. Recent advances in mapping the brain vasculome may generate new hypotheses. The investigation of new therapeutic targets, aimed at reversing CSVD processes and promoting neural repair after LS, depends upon further understanding these basic mechanisms.
Topics: Humans; Stroke, Lacunar
PubMed: 30167649
DOI: 10.1001/jamaneurol.2018.1073 -
JAMA Neurology Jul 2023Cerebral small vessel disease (cSVD) is a common cause of stroke (lacunar stroke), is the most common cause of vascular cognitive impairment, and impairs mobility and... (Randomized Controlled Trial)
Randomized Controlled Trial
Isosorbide Mononitrate and Cilostazol Treatment in Patients With Symptomatic Cerebral Small Vessel Disease: The Lacunar Intervention Trial-2 (LACI-2) Randomized Clinical Trial.
IMPORTANCE
Cerebral small vessel disease (cSVD) is a common cause of stroke (lacunar stroke), is the most common cause of vascular cognitive impairment, and impairs mobility and mood but has no specific treatment.
OBJECTIVE
To test the feasibility, drug tolerability, safety, and effects of 1-year isosorbide mononitrate (ISMN) and cilostazol treatment on vascular, functional, and cognitive outcomes in patients with lacunar stroke.
DESIGN, SETTING, AND PARTICIPANTS
The Lacunar Intervention Trial-2 (LACI-2) was an investigator-initiated, open-label, blinded end-point, randomized clinical trial with a 2 × 2 factorial design. The trial aimed to recruit 400 participants from 26 UK hospital stroke centers between February 5, 2018, and May 31, 2021, with 12-month follow-up. Included participants had clinical lacunar ischemic stroke, were independent, were aged older than 30 years, had compatible brain imaging findings, had capacity to consent, and had no contraindications to (or indications for) the study drugs. Data analysis was performed on August 12, 2022.
INTERVENTIONS
All patients received guideline stroke prevention treatment and were randomized to ISMN (40-60 mg/d), cilostazol (200 mg/d), ISMN-cilostazol (40-60 and 200 mg/d, respectively), or no study drug.
MAIN OUTCOMES
The primary outcome was recruitment feasibility, including retention at 12 months. Secondary outcomes were safety (death), efficacy (composite of vascular events, dependence, cognition, and death), drug adherence, tolerability, recurrent stroke, dependence, cognitive impairment, quality of life (QOL), and hemorrhage.
RESULTS
Of the 400 participants planned for this trial, 363 (90.8%) were recruited. Their median age was 64 (IQR, 56.0-72.0) years; 251 (69.1%) were men. The median time between stroke and randomization was 79 (IQR, 27.0-244.0) days. A total of 358 patients (98.6%) were retained in the study at 12 months, with 257 of 272 (94.5%) taking 50% or more of the allocated drug. Compared with those participants not receiving that particular drug, neither ISMN (adjusted hazard ratio [aHR], 0.80 [95% CI, 0.59 to 1.09]; P = .16) nor cilostazol (aHR, 0.77 [95% CI, 0.57 to 1.05]; P = .10) alone reduced the composite outcome in 297 patients. Isosorbide mononitrate reduced recurrent stroke in 353 patients (adjusted odds ratio [aOR], 0.23 [95% CI, 0.07 to 0.74]; P = .01) and cognitive impairment in 308 patients (aOR, 0.55 [95% CI, 0.36 to 0.86]; P = .008). Cilostazol reduced dependence in 320 patients (aHR, 0.31 [95% CI, 0.14 to 0.72]; P = .006). Combination ISMN-cilostazol reduced the composite (aHR, 0.58 [95% CI, 0.36 to 0.92]; P = .02), dependence (aOR, 0.14 [95% CI, 0.03 to 0.59]; P = .008), and any cognitive impairment (aOR, 0.44 [95% CI, 0.23 to 0.85]; P = .02) and improved QOL (adjusted mean difference, 0.10 [95% CI, 0.03 to 0.17]; P = .005) in 153 patients. There were no safety concerns.
CONCLUSIONS AND RELEVANCE
These results show that the LACI-2 trial was feasible and ISMN and cilostazol were well tolerated and safe. These agents may reduce recurrent stroke, dependence, and cognitive impairment after lacunar stroke, and they could prevent other adverse outcomes in cSVD. Therefore, both agents should be tested in large phase 3 trials.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03451591.
Topics: Male; Humans; Aged; Middle Aged; Female; Cilostazol; Quality of Life; Stroke, Lacunar; Stroke; Cerebral Small Vessel Diseases; Treatment Outcome
PubMed: 37222252
DOI: 10.1001/jamaneurol.2023.1526 -
BMC Medicine Jun 2022Previous genome-wide association studies (GWAS) have identified numerous risk genes for lacunar stroke, but it is challenging to decipher how they confer risk for the...
BACKGROUND
Previous genome-wide association studies (GWAS) have identified numerous risk genes for lacunar stroke, but it is challenging to decipher how they confer risk for the disease. We employed an integrative analytical pipeline to efficiently transform genetic associations to identify novel proteins for lacunar stroke.
METHODS
We systematically integrated lacunar stroke genome-wide association study (GWAS) (N=7338) with human brain proteomes (N=376) to perform proteome-wide association studies (PWAS), Mendelian randomization (MR), and Bayesian colocalization. We also used an independent human brain proteomic dataset (N=152) to annotate the new genes.
RESULTS
We found that the protein abundance of seven genes (ICA1L, CAND2, ALDH2, MADD, MRVI1, CSPG4, and PTPN11) in the brain was associated with lacunar stroke. These seven genes were mainly expressed on the surface of glutamatergic neurons, GABAergic neurons, and astrocytes. Three genes (ICA1L, CAND2, ALDH2) were causal in lacunar stroke (P < 0.05/proteins identified for PWAS; posterior probability of hypothesis 4 ≥ 75 % for Bayesian colocalization), and they were linked with lacunar stroke in confirmatory PWAS and independent MR. We also found that ICA1L is related to lacunar stroke at the brain transcriptome level.
CONCLUSIONS
Our present proteomic findings have identified ICA1L, CAND2, and ALDH2 as compelling genes that may give key hints for future functional research and possible therapeutic targets for lacunar stroke.
Topics: Bayes Theorem; Brain; Genome-Wide Association Study; Humans; Proteome; Proteomics; Stroke; Stroke, Lacunar
PubMed: 35733147
DOI: 10.1186/s12916-022-02408-y -
The Lancet. Neurology May 2021The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease.
METHODS
We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation.
FINDINGS
Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke.
INTERPRETATION
Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk.
FUNDING
British Heart Foundation.
Topics: Australia; Europe; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Magnetic Resonance Imaging; Stroke, Lacunar; United States
PubMed: 33773637
DOI: 10.1016/S1474-4422(21)00031-4