Signs Of Small Vessel Disease Research Articles

The Role of Extracellular Matrix and Inflammation in the Stratification of Bleeding and Thrombotic Risk of Atrial Fibrillation on Oral Anticoagulant Therapy: Insights from Strat-Af Study.

In anticoagulated atrial fibrillation (AF) patients, the validity of models recommended for the stratification of the risk ratio between benefits and hemorrhage risk is limited. We hypothesize that both circulating and neuroimaging-based markers might improve the prediction of bleeding and thrombotic risk in anticoagulated AF patients. The Strat-AF study is an observational, prospective, single-center study enrolling 170 patients with AF; recruited patients are evaluated by means of a comprehensive protocol, with clinical, cerebral magnetic resonance imaging and circulating biomarkers assessment. The main outcome is the evaluation of cerebral microangiopathy related to the levels of circulating biomarkers of inflammation and extracellular matrix (ECM) remodeling. At multivariate logistic regression analysis adjusted for age, sex, CHA2DS2-VASc, HAS-BLED and type of anticoagulant, matrix metalloproteinases (MMP)-2 levels were significantly and positively associated with the presence of cerebral microbleeds (CMBs). A significant association between MMP-2, tissue inhibitor of metalloproteinases (TIMP)-1,-2,-4 levels and white matter hyperintensity was also found. Concerning the small vessel disease (SVD) score, MMP-2 and TIMP-1,-2 levels were associated with the presence of two and three or more signs of SVD, whereas TIMP-4 levels were associated with the presence of three signs of SVD with respect to patients with no instrumental signs of SVD. As regarding the presence of enlarged perivascular spaces (EPVS), a significant association was found for high levels of interleukin (IL)-8 and TIMP 1-2-3. These results demonstrate that patients with AF have evidence of impaired ECM degradation, which is an independent risk factor for thrombotic complications of AF patients on oral anticoagulant therapy. The incorporation of these markers in the prognostic schemes might improve their clinical capability in predicting stroke risk and thrombotic complications.

Blood-brain barrier pathology in cerebral small vessel disease.

Cerebral small vessel disease is a neurological disease that affects the brain microvasculature and which is commonly observed among the elderly. Although at first it was considered innocuous, small vessel disease is nowadays regarded as one of the major vascular causes of dementia. Radiological signs of small vessel disease include small subcortical infarcts, white matter magnetic resonance imaging hyperintensities, lacunes, enlarged perivascular spaces, cerebral microbleeds, and brain atrophy; however, great heterogeneity in clinical symptoms is observed in small vessel disease patients. The pathophysiology of these lesions has been linked to multiple processes, such as hypoperfusion, defective cerebrovascular reactivity, and blood-brain barrier dysfunction. Notably, studies on small vessel disease suggest that blood-brain barrier dysfunction is among the earliest mechanisms in small vessel disease and might contribute to the development of the hallmarks of small vessel disease. Therefore, the purpose of this review is to provide a new foundation in the study of small vessel disease pathology. First, we discuss the main structural domains and functions of the blood-brain barrier. Secondly, we review the most recent evidence on blood-brain barrier dysfunction linked to small vessel disease. Finally, we conclude with a discussion on future perspectives and propose potential treatment targets and interventions.

Dilated Virchow-Robin spaces are a marker for arterial disease in multiple sclerosis.

Virchow-Robin spaces (VRS) have been associated with neurodegeneration and neuroinflammation. However, it remains uncertain to what degree non-dilated or dilated VRS reflect specific features of neuroinflammatory pathology. Thus, we aimed at investigating the clinical relevance of VRS as imaging biomarker in multiple sclerosis (MS) and to correlate VRS to their histopathologic signature. In a cohort study comprising 142 MS patients and 30 control subjects, we assessed the association of non-dilated and dilated VRS to clinical and magnetic resonance imaging (MRI) outcomes. Findings were corroborated in a validation cohort comprising 63 MS patients. Brain blocks from 6 MS patients and 3 non-MS controls were histopathologically processed to correlate VRS to their tissue substrate. In our actively treated clinical cohort, the count of dilated centrum semiovale VRS was associated with increased T1 and T2 lesion volumes. There was no systematic spatial colocalization of dilated VRS with MS lesions. At tissue level, VRS mostly corresponded to arteries and were not associated with MS pathological hallmarks. Interestingly, in our exvivo cohort comprising mostly progressive MS patients, dilated VRS in MS were associated with signs of small vessel disease. Contrary to prior beliefs, these observations suggest that VRS in MS do not associate with an accumulation of immune cells. But instead, these findings indicate vascular pathology as a driver and/or consequence of neuroinflammatory pathology for this imaging feature. NIH, Swedish Society for Medical Research, Swiss National Science Foundation and University of Zurich.

Genotype-phenotype of PSEN1 p.CYS263PHE carriers in Flanders-Belgian Alzheimer's disease patients.

We identified 13 unrelated index patients carrying the presenilin 1 (PSEN1) missense mutation, p.Cys263Phe in a Flanders-Belgian cohort of Alzheimer's disease (AD) patients. Seven affected relatives in three different families also carried the PSEN1 p.Cys263Phe mutation (n=20). We aimed to delineate a clinicopathological phenotype of p.Cys263Phe carriers. We compared the p.Cys263Phe genotype-phenotype with that of AD patients carrying autosomal dominant mutations i.e. PSEN1 (n=29), PSEN2 (n=1), and APP (n=5). Reviewing of medical records of autosomal dominant mutation carriers to obtain clinical and pathological data for defining genotype-phenotype data. Mean onset age of the p.Cys263Phe carriers is 63.9±5.5 years (range 53-79), with a disease duration of 7.0±3.5 years (range 4-13). APOE genotypes have no significant effects on onset age. A positive familial history is present in 92.9% of the carriers. Segregation with disease is present in two families with autosomal dominant inheritance of AD (figure 1). In all carriers the clinical presentation is predominantly amnestic, although 35.7% (5/14) of the patients also show significant frontal symptoms. Structural neuroimaging displays diffuse (sub)cortical atrophy with evident hippocampal atrophy in 26.7% (4/15) of the carriers. In 40.0% (6/15) of the patients we observe severe signs of small vessel disease. Brain perfusion SPECT or fluorodeoxyglucose PET imaging shows bilateral temporoparietal involvement in 57.1% (4/7) of carriers. Cerebrospinal fluid AD biomarkers were analyzed in eight carriers, and all are characteristic for AD. Neuropathological examination in three carriers shows severe levels of hallmark AD lesions combined with pronounced cerebral amyloid angiopathy (CAA) and multiple intracerebral hemorrhages in one patient. Carriers of p.Cys263Phe have a later age at onset (63.9 years) compared to PSEN1 carriers (50.9 years) and other PSEN1, PSEN2 and APP mutation carriers (51.4 years) (figure 2). PSEN1 p.Cys263Phe carriers present with early-onset familial AD with autosomal dominant co-segregation. Important is that frontal symptoms are seen in 35.7% of the carrier while neuropathological examination reveals severe levels of AD neuropathology with prominent presence of CAA. The disease onset of PSEN1 p.Cys263Phe carriers is later in comparison with other autosomal dominant gene mutation carriers.

White matter integrity of watershed areas is potentially influenced by hypoperfusion in the presence permanent atrial fibrillation

Aim. To test a hypothesis of hypoperfusion-induced white matter changes in patients with atrial fibrillation (AFib) and to present statistics to compute sample size for the upcoming studies.Material and methods. We included 30 inpatients with AFib and investigated them with magnetic resonance imaging (MRI) with standard sequencies and diffusion tensor imaging (DTI). DTI data were analyzed with conventional ROI analysis in the Olea Sphere software and with watershed areas (WSA) mask in the FSL toolbox after nonlinear transformation of images to the Montreal Neurological Institute (MNI) space. Wilcoxon test was used to compare diffusion characteristics across subgroups.Results. Median age of participants was 73 years (69-78), 18 (60%) patients had moderate signs of small vessel disease with Fazekas score of one. Twenty-one patients had paroxysmal AFib. Analysis of WSA revealed decreased white matter integrity in the parieto-occipital cortical WSA with a pattern of significantly increased mean diffusivity (p=0,039), and marginally significant decrease in fractional anisotropy (p=0,056). Rank-based effect size across areas under comparison was either small (0,2) or negligible, and with statistical power in the range of 0,05-1.Conclusion. Atrial fibrillation could have pathophysiologically feasible mechanism to affect white matter integrity in the watershed areas.

Early markers and predictors of cerebrovascular diseases in a group of young and middle-aged employees of the EMERCOM of Russia

Introduction. Typical basis of chronic cerebral ischemia in young people is small vessel disease (SVD) diagnosed by micro-focal lesions and microstructural damage of cerebral white matter (WM), reduction of fractional anisotropy (FA) in diffusion tensor MRI (DT-MRI). Previous studies showed that increased dopplerographic pulsatility and resistivity indices in middle cerebral artery (MCA PI-RI) correlated with SVD manifestations and cognitive impairment in middle-aged and elderly patients. Aim – to determine early markers and predictors of asymptomatic SVD in young and middle-aged individuals without cognitive impairment. Materials and methods. 52 male employees of the EMERCOM, 47.3±7.6 years, without neurological or cognitive deficits were examined. Duplex scanning with MCA PI-RI calculation, MRI with WM damage assessment according to Fazekas scale, DT-MRI FA definition were completed. Results. All those examed showed MRI signs of SVD. Two groups were formed according to Fazekas: 0 points (n-38) and 1-2 points (n-14). The 2nd group showed higher MCA PI-RI (p<0.002 and p<0.05). Multivariate logistical regression analysis showed significant correlation of PI in MCA (OR: 2.33; 95% CI: 1.13- 4.81; p=0.02) with WM lesion according to Fazekas. The FA in cognitively important tracts was lower in group 2 (p<0,001). A stepwise multiple linear regression model revealed that the strongest predictors of FA reduction were PI and RI. The values of psychomotor speed and attention span were lower in group 2. Conclusion. MCA PI-RI are early markers of focal lesions and microstructural changes in WM and predictors of cognitive impairment in the young and middle-aged with asymptomatic SVD.

Small vessel disease and biomarkers of endothelial dysfunction after ischaemic stroke.

Although pathogenesis of small vessel disease is poorly understood, increasing evidence suggests that endothelial dysfunction may have a relevant role in development and progression of small vessel disease. In this cross-sectional study, we investigated the associations between imaging signs of small vessel disease and blood biomarkers of endothelial dysfunction at two different time points in a population of ischaemic stroke patients. In stroke patients treated with intravenous thrombolysis, we analysed blood levels of von Willebrand factor, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and vascular endothelial growth factor. Three reviewers independently assessed small vessel disease features using computed tomography. At baseline and 90 days after the index stroke, we tested the associations between single and combined small vessel disease features and levels of blood biomarkers using linear regression analysis adjusting for age, sex, hypertension, diabetes, smoke. A total of 263 patients were available for the analysis. Mean age (±SD) was 69 (±13) years, 154 (59%) patients were male. We did not find any relation between small vessel disease and endothelial dysfunction at baseline. At 90 days, leukoaraiosis was independently associated with intercellular adhesion molecule-1 (β = 0.21; p = 0.016) and vascular cell adhesion molecule-1 (β = 0.22; p = 0.009), and lacunes were associated with vascular endothelial growth factor levels (β = 0.21; p = 0.009) whereas global small vessel disease burden was associated with vascular endothelial growth factor (β = 0.26; p = 0.006). Leukoaraiosis and lacunes were associated with endothelial dysfunction, which could play a key role in pathogenesis of small vessel disease. Small vessel disease features and total burden were associated with endothelial dysfunction 90 days after the stroke, whereas there was no relation during the acute phase. Our results suggest that endothelial dysfunction, particularly vascular endothelial growth factor, is involved in pathological process of small vessel disease.

Small Vessel Disease on Neuroimaging in a 75-Year-Old Cohort (PIVUS): Comparison With Cognitive and Executive Tests.

Background and Purpose: Signs of small vessel disease (SVD) are commonly seen on magnetic resonance imaging (MRI) of the brain in cognitively healthy elderly individuals, and the clinical relevance of these are often unclear. We have previously described three different MRI manifestations of SVD as well as cerebral perfusion in a longitudinal study of non-demented 75-year-old subjects. The purpose of the present study was to evaluate the relationship of these findings to cognition and executive function at age 75 and changes after 5 years.Methods: In all, 406 subjects from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study were examined with MRI of the brain at age 75 years. Two-hundred and fifty of the subjects were re-examined 5 years later. White matter hyperintensities (WMHs) and lacunar infarcts (LIs) were assessed on both occasions, but microbleeds (MBs) and perfusion only at age 75. Cognitive function was screened by the Mini Mental State Examination (MMSE). Trail Making Test A and B (TMT-A and TMT-B) were performed at baseline and at follow-up at age 80.Results: At baseline, 93% performed >27 points in the MMSE. The TMT-B at age 75 was significantly related to WMH visual scoring after adjustment for sex, education and cerebrovascular disease risk factors (+80 s (95% CI 0.3–161 s), P < 0.05 for grade 2–3 vs. grade 0). Neither MMSE nor TMT-A was significantly related to WMH scoring. There was no relation between any test performance and WMH volume, white matter volume, number of MBs or brain perfusion at age 75. Subjects who had sustained a new LI (n = 26) showed a greater increase of the time to perform TMT-A at the 5-year follow-up (+25 s vs. +4 s in LI-free subjects, P = 0.003). Changes in MMSE or TMT-A and -B test performance between ages 75 and 80 were not related to changes in WMH scoring or volume during the 5 years follow-up, or to brain perfusion at age 75.Conclusion: In this cognitively healthy community-based population, moderate-severe WMHs and incident LIs on brain MRI in individuals aged 75–80 years were associated with a mild impairment of processing speed and executive function.

Small Vessel Disease Is Associated with Tissue Inhibitor of Matrix Metalloproteinase-4 After Ischaemic Stroke.

Small vessel disease (SVD) is frequent in aging and stroke patients. Inflammation and remodeling of extracellular matrix have been suggested as concurrent mechanisms of SVD. We investigated the relationship between imaging features of SVD and circulating metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in patients with ischaemic stroke. In patients treated with intravenous thrombolysis, we took blood samples before intravenous thrombolysis and 90days after the acute stroke and analysed levels of MMPs and TIMPs. We assessed leukoaraiosis, number of lacunes and brain atrophy on pre-treatment CT scan and graded global SVD burden combining such features. We investigated associations between single features, global SVD and MMPs and TIMPs at baseline and at follow-up, retaining univariate statistically significant associations in multivariate linear regression analysis and adjusting for clinical confounders. A total of 255 patients [mean (±SD) = 68.6 (± 12.7) years, 154 (59%) males] were included, 107 (42%) had no signs of SVD; 47 (19%) had from moderate to severe SVD burden.A total of 107 (42%) patients had no signs of SVD; 47 (19%) had from moderate to severe SVD burden. After adjustment, only TIMP-4 proved associations with SVD features. Brain atrophy was associated with baseline TIMP-4 (β = 0.20;p = 0.019) and leukoaraiosis with 90days TIMP-4 (β = 0.19; p = 0.013). Global SVD score was not associated with baseline TIMP-4 levels (β = 0.10; p = 0.072), whereas was associated with 90days TIMP-4 levels (β = 0.21; p = 0.003). Total SVD burden was associated with higher TIMP-4 levels 90days after stroke, whereas was not during the acute phase. Our results support a biological relationship between SVD grade and TIMP-4.

Enlarged perivascular spaces are associated with health-related quality of life in patients with acute ischemic stroke.

This study explored the association between enlarged perivascular spaces (EPVS) and the health-related quality of life (HRQoL) in patients with acute ischemic stroke. This was an observational study of consecutively screened patients with acute ischemic stroke from March 2010 to March 2015. EPVS were rated in the basal ganglia and the centrum semiovale with a validated scale. The HRQoL was assessed 3months after the stroke onset using the Stroke-Specific Quality of Life (SSQoL). Linear regression models were used to study the association between EPVS and HRQoL. The study included 648 patients (mean age 65.8years; 40.0% women) with mild to moderately severe stroke (median NIHSS score 2), of whom 640 (98.8%) exhibited signs of small vessel disease. The median EPVS scores in the basal ganglia and the centrum semiovale were 1 each. In linear regression analysis, EPVS in the basal ganglia were associated with a lower total SSQoL score (P=0.02) and lower mobility (P=0.01), mood (P=0.03), and self-care (P<0.01). EPVS in the centrum semiovale were associated only with a lower SSQoL work/productivity subscore (P=0.002). EPVS are associated with lower HRQoL in patients with mild to moderate acute ischemic stroke. Early identification and intervention of EPVS may improve HRQoL in stroke survivors.

Elevated Concentrations of Neurofilament Light Chain in the Cerebrospinal Fluid of Bipolar Disorder Patients

Bipolar disorder (BD) is characterized by mood swings between manic and depressive states. The etiology and pathogenesis of BD is unclear, but many of the affected cognitive domains, as well as neuroanatomical abnormalities, resemble symptoms and signs of small vessel disease. In small vessel disease, cerebrospinal fluid (CSF) markers reflecting damages in different cell types and subcellular structures of the brain have been established. Hence, we hypothesized that CSF markers related to small vessel disease may also be applicable as biomarkers for BD. To investigate this hypothesis, we sampled CSF from 133 patients with BD and 86 healthy controls. The concentrations of neurofilament light chain (NF-L), myelin basic protein (MBP), S100B, and heart-type fatty acid binding protein (H-FABP) were measured in CSF and analyzed in relation to diagnosis, clinical characteristics, and ongoing medications. Hereby we found an elevation of the marker of subcortical axonal damage, NF-L, in bipolar subjects. We also identified positive associations between NF-L and treatment with atypical antipsychotics, MBP and lamotrigine, and H-FABP and lithium. These findings indicate axonal damage as an underlying neuropathological component of bipolar disorder, although the clinical value of elevated NF-L remains to be validated in follow-up studies. The associations between current medications and CSF brain injury markers might aid in the understanding of both therapeutic and adverse effects of these drugs.

Subcortical hyperintensity volumetrics in Alzheimer's disease and normal elderly in the Sunnybrook Dementia Study: correlations with atrophy, executive function, mental processing speed, and verbal memory.

IntroductionSubcortical hyperintensities (SHs) are radiological entities commonly observed on magnetic resonance imaging (MRI) of patients with Alzheimer’s disease (AD) and normal elderly controls. Although the presence of SH is believed to indicate some form of subcortical vasculopathy, pathological heterogeneity, methodological differences, and the contribution of brain atrophy associated with AD pathology have yielded inconsistent results in the literature.MethodsUsing the Lesion Explorer (LE) MRI processing pipeline for SH quantification and brain atrophy, this study examined SH volumes of interest and cognitive function in a sample of patients with AD (n = 265) and normal elderly controls (n = 100) from the Sunnybrook Dementia Study.ResultsCompared with healthy controls, patients with AD were found to have less gray matter, less white matter, and more sulcal and ventricular cerebrospinal fluid (all significant, P <0.0001). Additionally, patients with AD had greater volumes of whole-brain SH (P <0.01), periventricular SH (pvSH) (P <0.01), deep white SH (dwSH) (P <0.05), and lacunar lesions (P <0.0001). In patients with AD, regression analyses revealed a significant association between global atrophy and pvSH (P = 0.02) and ventricular atrophy with whole-brain SH (P <0.0001). Regional volumes of interest revealed significant correlations with medial middle frontal SH volume and executive function (P <0.001) in normal controls but not in patients with AD, global pvSH volume and mental processing speed (P <0.01) in patients with AD, and left temporal SH volume and memory (P <0.01) in patients with AD.ConclusionsThese brain-behavior relationships and correlations with brain atrophy suggest that subtle, yet measurable, signs of small vessel disease may have potential clinical relevance as targets for treatment in Alzheimer’s dementia.

Paroxysmal Nocturnal Hemoglobinuria and Thrombosis Before and After Eculizumab

Thrombosis, mainly venous but also arterial, is the leading threat in Paroxysmal Nocturnal Hemoglobinuria (PNH) patients, caused by the continuous hemolysis. It constitutes the first cause of death in all reported series. Since 1964, a total of 56 patients with PNH clone were evaluated in our Hematology Unit. According with PNH Parker´s Classification, most of the patients were Classical type (28 patients), and the remaining included in the other subsets: 21 in the setting of another bone marrow failure syndrome (BMFS) and 7 subclinical.Since November 2007, Eculizumab (an anti-C5 antibody) is employed in the disease to abrogate the hemolysis in our patients. In the last years, sixteen patients have been treated with this drug in our series. PNH patients previously anticoagulated with warfarin because thrombosis, continued on therapy after the addition of Eculizumab. Also, patients with more than 50 % PNH clone (established by Cytometry with FLAER on granulocytes) and platelets >50 x109/L received oral anticoagulation.The incidence and localization of thrombotic events in the patients without Eculizumab was as follows:Parker's ClassificationClassicalBMFSSubclinical28216Thrombosis cases (%)14 (50)4 (20)2 (33)Thrombotic episodes:2675Deep calf642Multiple cerebral ischemic infarcts212 (1 death)Large Cerebrovascular311Budd-Chiari11 (1 death)Portal2 (1 death)Retinal2Cava1Pulmonary thromboembolism2 (1 death)Myocardial infarction3 (1 death)Arterial ischemia2 (1 amputation)Skin ischemic2 (vasculitis, livedo reticularis)After introduction of Eculizumab, sixteen patients have been treated with this drug and active thrombosis resolved in all cases, as was the case of a patient with a large persistent thrombosis in the inferior cava vein despite the isolated anticoagulation therapy. Only one patient on Eculizumab therapy experienced a thrombotic event and suffered a transient ischemic attack with aphasia after a prolonged catheter ablation procedure for an atrial fibrillation. This patient had previous signs of small vessel disease in MR imaging techniques. The episode occurs despite heparin anticoagulation and anticipated additional Eculizumab dose and resolves thereafter.Eculizumab had a clear favourable impact in preventing thrombosis complications in our series of PNH patients. Careful monitoring of LDH levels and shortening the Eculizumab interval doses it is indicated in any chirurgical or invasive procedures in these patients. Disclosures:Pastrana:Alexion Pharmaceuticals: Speakers Bureau. Ojeda:Alexion Pharmaceuticals: Consultancy, Speakers Bureau.

Statin-treated familial hypercholesterolemia patients with coronary heart disease and pronounced atherosclerosis do not have more brain lesions than healthy controls in later middle age

Clinically silent brain lesions detected with magnetic resonance imaging (MRI) are associated with increased risk for stroke, while stroke risk is controversial in familial hypercholesterolemia (FH). To determine whether the occurrence and size of clinically silent brain lesions in FH patients with coronary heart disease (CHD) is higher than in neurologically healthy controls without CHD. Brain MRI (1.5T) was performed on 19 DNA-test-verified FH patients with CHD and on 29 cardiovascularly and neurologically healthy controls, all aged 48 to 64 years. All patients were on cardiovascular medication. Intracranial arteries were evaluated by MR angiography. Infarcts, including lacunas, and white matter T2 hyperintensities (WMHI), considered as signs of small vessel disease, were recorded. A venous blood sample was obtained for assessment of risk factors. Carotid and femoral intima-media thicknesses (IMT), assessed with ultrasound, were indicators of overall atherosclerosis. On intracranial MR angiography, three patients showed irregular walls or narrowed lumens in intracranial carotid arteries. No silent infarcts appeared, and no differences in numbers or sizes of WMHIs between groups were recorded. Patients had greater carotid and femoral IMTs, and a greater number of carotid and femoral plaques. Cholesterol-years score, level of low-density lipoprotein (LDL) cholesterol, and level of high-sensitivity C-reactive protein (hsCRP) of the FH-North Karelia patients were higher than those of the controls, while the level of high-density lipoprotein (HDL) cholesterol in controls was higher. FH patients with CHD and adequate cardiovascular risk-factor treatment showed no difference in the amount or size of clinically silent brain lesions compared to controls, despite patients' more severe atherosclerosis.