Background and Purpose— A number of single gene disorders can cause cerebral small vessel disease. Mutations in the COL4A1 gene encoding the type IV collagen alpha 1 chain, which are already associated with porencephaly and infantile hemiparesis, have been recently recognized as a further monogenic cause of small vessel disease that can present in adulthood. Methods— We performed a systematic review of published data from 1966 to January 8, 2010 to characterize the features of small vessel disease seen with COL4A1 mutations. Results— We identified a total of 52 mutation carriers. A history of stroke was reported in 9 subjects (17.3%); in 6 cases it was attributable to subcortical hemorrhage and in 3 cases it was attributable to lacunar infarction. Stroke often occurred as first presentation of the disease, with a mean age of onset of 36.1 (SD, 12.95; range, 14–49). Hemorrhages, often recurrent, have been associated with physical trauma and activity and anticoagulant therapy. Brain imaging showed frequent leukoaraiosis (63.5%), microbleeds that are usually subcortical (52.9%), lacunar infarction (13.5%), and dilated perivascular spaces (19.2%). Extensive leukoaraiosis was seen in a number of asymptomatic adult mutation carriers. Asymptomatic intracranial aneurysms were common (44.4% of 18 with angiography). Migraine (with and without aura) was reported in 10 subjects, with a mean age at onset of 31.7. Systemic features are also frequent, affecting the eye (10/21, 47.6%), kidney (15.4%), and muscle (15.4%). Conclusions— COL4A1 is a further cause of familial vasculopathy and may present with stroke, ischemic as well as hemorrhagic, in adult life and with radiological features of leukoaraiosis and microbleeds.

www.dissection.co.uk, ISRNCTN44555237.

Background and Purpose-Cerebral small vessel disease (SVD) is the most common cause of vascular dementia. Interest in the use of surrogate markers is increasing. The aims of this study were to determine if brain volume was different between patients with SVD and control subjects, whether it correlated with cognition in SVD, and whether changes in brain volume could be detected during prospective follow-up. Methods-Thirty-five patients (mean age, 68.8 years) who had a lacunar stroke and radiological evidence of confluent leukoaraiosis and 70 age-and gender-matched control subjects were recruited. Whole-brain T1-weighted imaging and neuropsychological testing were performed after 1 year on all patients and after 2 years for the control subjects. Fully automated software was used to determine brain volume and percentage brain volume change. An executive function score was derived. Results-There was a significant difference in brain volume between the patients with SVD and control subjects (meanϮSD [mL] 1529Ϯ84 versus 1573Ϯ69, Pϭ0.019). In the patients with SVD, there was a significant association between brain volume and executive function (rϭ0.501, PϽ0.05). The meanϮSD yearly brain atrophy rate for patients with SVD and control subjects was significantly different (Ϫ0.914%Ϯ0.8% versus Ϫ0.498%Ϯ0. 4%, respectively, Pϭ0.017). No change in executive function score was detected over this period. Key Words: brain atrophy Ⅲ cerebral small vessel disease Ⅲ cognitive impairment Ⅲ longitudinal study Ⅲ MRI Ⅲ surrogate marker C erebral small vessel disease (SVD) is a major cause of stroke, age-related cognitive decline, and vascular dementia. 1 Despite its importance, few studies have specifically investigated treatment in this stroke subtype. 2,3 This is due to a number of issues that complicate assessment of treatment efficacy: the risk of recurrent stroke is relatively low with an annual rate of 0.25%, 4 the rate of progression to dementia is slow, 4 and repeated cognitive testing is associated with a learning effect that reduces sensitivity to longitudinal decline. Therefore, large sample sizes are required to determine treatment efficacy when using stroke and dementia as end points. This has led to the suggestion that imaging may provide useful surrogate markers for SVD to assess therapeutic approaches at an early stage. 5 A number of criteria have been proposed for the definition of an effective surrogate marker for treatment trials. 6 The first criterion is that the marker must be able to predict the natural course of the disease, that is, it should correlate with relevant clinical features, for example, cognitive function, in both crosssectional and longitudinal studies. Conclusions-Brain volume is reduced in SVD andIn multiple sclerosis, imaging parameters have been demonstrated to have high sensitivity for detection of disease activity, which is better than clinical scores. 7 Brain atrophy has been used as an outcome measure in treatment trials. 8,9 In comparison to multiple sclerosis, there are less data on br...

Objective:For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms.Methods:We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations.Results:There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p < 5 × 10−6) from community populations (15 single nucleotide polymorphisms in total) and from stroke patients, 6 independent loci were associated with WMHV in both populations. Four of these are novel associations at the genome-wide level (rs72934505 [NBEAL1], p = 2.2 × 10−8; rs941898 [EVL], p = 4.0 × 10−8; rs962888 [C1QL1], p = 1.1 × 10−8; rs9515201 [COL4A2], p = 6.9 × 10−9).Conclusions:Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease.

Recent work has focused on cell transplantation as a therapeutic option following ischemic stroke, based on animal studies showing that cells transplanted to the brain not only survive, but also lead to functional improvement. Neural degeneration after ischemia is not selective but involves different neuronal populations, as well as glial and endothelial cell types. In models of stroke, the principal mechanism by which any improvement has been observed, has been attributed to the release of trophic factors, possibly promoting endogenous repair mechanisms, reducing cell death and stimulating neurogenesis and angiogenesis. Initial human studies indicate that stem cell therapy may be technically feasible in stroke patients, however, issues still need to be addressed for use in human subjects.

BackgroundSeveral lines of evidence support the involvement of the lectin pathway of complement (LP) in the pathogenesis of acute ischemic stroke. The aim of this multicenter observational study was to assess the prognostic value of different circulating LP initiators in acute stroke.MethodsPlasma levels of the LP initiators ficolin-1, -2, and -3 and mannose-binding lectin (MBL) were measured in 80 stroke patients at 6 h only and in 85 patients at 48 h and later. Sixty-one age- and sex-matched healthy individuals served as controls. Stroke severity was measured on admission using the National Institutes of Health Stroke Scale (NIHSS). The outcome was measured at 90 days by the modified Rankin Scale (mRS).ResultsFicolin-1 was decreased in patients compared with controls measured at 6 h (median 0.13 vs 0.33 μg/ml, respectively, p < 0.0001). At 48 h, ficolin-1 was significantly higher (0.45 μg/ml, p < 0.0001) compared to the 6 h samples and to controls. Likewise, ficolin-2 was decreased at 6 h (2.70 vs 4.40 μg/ml, p < 0.0001) but not at 48 h. Ficolin-3 was decreased both at 6 and 48 h (17.3 and 18.23 vs 21.5 μg/ml, p < 0.001 and <0.05, respectively). For MBL no difference was detected between patients and controls or within patients at the different time points. In multivariate analysis, early ficolin-1 was independently associated with unfavorable mRS outcome (adjusted odds ratio (OR): 2.21, confidence interval (CI) 95 % 1.11–4.39, p = 0.023). Early ficolin-1 improved the discriminating ability of an outcome model including NIHSS and age (area under the curve (AUC) 0.95, CI 95 % 0.90–0.99, p = 0.0001).ConclusionsThe ficolins are consumed within 6 h after stroke implicating activation of the LP. Early ficolin-1 is selectively related to 3-month unfavorable outcome.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0481-2) contains supplementary material, which is available to authorized users.

Data from pre-clinical and clinical studies provide evidence that colony-stimulating factors (CSFs) and other growth factors (GFs) can improve stroke outcome by reducing stroke damage through their anti-apoptotic and anti-inflammatory effects, and by promoting angiogenesis and neurogenesis. This review provides a critical and up-to-date literature review on CSF use in stroke. We searched for experimental and clinical studies on haemopoietic GFs such as granulocyte CSF, erythropoietin, granulocyte-macrophage colony-stimulating factor, stem cell factor (SCF), vascular endothelial GF, stromal cell-derived factor-1α and SCF in ischemic stroke. We also considered studies on insulin-like growth factor-1 and neurotrophins. Despite promising results from animal models, the lack of data in human beings hampers efficacy assessments of GFs on stroke outcome. We provide a comprehensive and critical view of the present knowledge about GFs and stroke, and an overview of ongoing and future prospects.

Background: Cerebral cavernous malformations (CCMs) are vascular malformations characterized by clusters of enlarged leaky capillaries in the central nervous system. They may result in intracranial haemorrhage, epileptic seizure(s), or focal neurological deficits, and potentially lead to severe disability. Globally, CCMs represent the second most common intracranial vascular malformation in humans, and their familial form (FCCMs) accounts for one-fifth of cases. Neurosurgical excision, and perhaps stereotactic radiosurgery, is the only available therapeutic option. Case reports suggest that propranolol might modify disease progression. Methods: Treat_CCM is a prospective, randomized, open-label, blinded endpoint (PROBE), parallel-group trial involving six Italian clinical centres with central reading of brain magnetic resonance imaging (MRI) and adverse events. Patients with symptomatic FCCMs are randomized (2:1 ratio) either to propranolol (40-80 mg twice daily) in addition to standard care or to standard care alone (i.e. anti-epileptic drugs or headache treatments). The primary outcome is intracranial haemorrhage or focal neurological deficit attributable to CCMs. The secondary outcomes are MRI changes over time (i.e. de novo CCM lesions, CCM size and signal characteristics, iron deposition, and vascular leakage as assessed by quantitative susceptibility mapping and dynamic contrast enhanced permeability), disability, health-related quality of life, depression severity, and anxiety (SF-36, BDI-II, State-Trait Anxiety Inventory). Discussion: Treat_CCM will evaluate the safety and efficacy of propranolol for CCMs following promising case reports in a randomized controlled trial. The direction of effect on the primary outcome and the consistency of effects on the secondary outcomes (even if none of them yield statistically significant differences) of this external pilot study may lead to a larger sample size in a definitive phase 2 trial. Trial registration: ClinicalTrails.gov, NCT03589014. Retrospectively registered on 17 July 2018.