Cause Of Small Vessel Disease Research Articles

Methylenetetrahydrofolate reductase polymorphisms and elevated plasma homocysteine levels in small vessel disease.

Despite its public health importance, the causes of small vessel disease (SVD) are not fully understood. The presence of SVD in monogenic twins indicates the involvement of genetic factors in the pathogenesis of this disease. The purpose of this study was to investigate the association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with SVD risk. Patients with SVD and matched controls were recruited from Tianjin Union Medical Center and Tianjin Huanhu Hospital. Clinical and laboratory data were collected. Plasma total homocysteine (tHcy) and folate levels were measured, and MTHFR rs1801133 (C677T) and rs1801131 (A1298C) single-nucleotide polymorphisms were genotyped. We analyzed potential associations among SVD and MTHFR polymorphisms, tHcy, and folate levels. Patients with SVD displayed significantly decreased plasma folate levels (Z=-3.537, p<.001) and increased tHcy levels (Z=4.910, p<.001) compared with controls. Significantly different plasma tHcy levels were associated with rs1801133 (χ2 =6.664, p=.036), and post hoc analysis indicated higher plasma tHcy levels in individuals carrying the TT allele compared with levels in those carrying the TC allele (Z=2.478, p=.013). No significant differences in tHcy levels were observed for rs1801131 alleles. The genotype and allele frequencies of rs1801133 were different between SVD and control groups (χ2 =9.378, p=.009). There was no significant difference in distributions of rs1801131 genotypes between the two groups, and multivariable logistic regression analysis showed that rs1801131 and rs1801133 were not significantly associated with the risk of SVD. Our study indicates that an elevated plasma tHcy level is independently associated with the development of SVD. Although MTHFR rs1801133 is linked to increased plasma homocysteine (Hcy) levels, it is not a risk factor for SVD. rs1801131 is not related to Hcy levels or SVD risk.

Cerebral arterial pulsatility is associated with features of small vessel disease in patients with acute stroke and TIA: a 4D flow MRI study

Cerebral small vessel disease (SVD) is a major cause of stroke and cognitive impairment. However, the underlying mechanisms behind SVD are still poorly understood. High cerebral arterial pulsatility has been suggested as a possible cause of SVD. In population studies, arterial pulsatility has been linked to white matter hyperintensities (WMH), cerebral atrophy, and cognitive impairment, all features of SVD. In stroke, pulsatility data are scarce and contradictory. The aim of this study was to investigate the relationship between arterial pulsatility and SVD in stroke patients. With a cross-sectional design, 89 patients with acute ischemic stroke or TIA were examined with MRI. A neuropsychological assessment was performed 1 year later. Using 4D flow MRI, pulsatile indices (PI) were calculated for the internal carotid artery (ICA) and middle cerebral artery (M1, M3). Flow volume pulsatility (FVP), a measure corresponding to the cyclic expansion of the arterial tree, was calculated for the same locations. These parameters were assessed for associations with WMH volume, brain volume and cognitive function. ICA-FVP was associated with WMH volume (β = 1.67, 95% CI: [0.1, 3.24], p = 0.037). M1-PI and M1-FVP were associated with decreasing cognitive function (β = − 4.4, 95% CI: [− 7.7, − 1.1], p = 0.009 and β = − 13.15, 95% CI: [− 24.26, − 2.04], p = 0.02 respectively). In summary, this supports an association between arterial pulsatility and SVD in stroke patients, and provides a potential target for further research and preventative treatment. FVP may become a useful biomarker for assessing pulsatile stress with PCMRI and 4D flow MRI.

ASSOCIATIONS OF PLASMA AMYLOID BETA LEVELS WITH SEVERITY AND PROGRESSION OF CEREBRAL SMALL VESSEL DISEASE

Cerebral small vessel disease (SVD) is a frequent pathology in aging and contributor to the development of dementia. Cerebral amyloid angiopathy (CAA) is one of the potential causes of SVD, characterized by deposition of amyloid β (Aβ) proteins in cerebral blood vessels. Plasma Aβ levels may be useful as an early non-invasive marker of CAA. We investigated the association of plasma Aβ levels with severity and progression of SVD markers in non-demented elderly with SVD. We studied 487 participants from the RUN DMC cohort study of whom 258 participants underwent three MRI assessments over a period of nine years. We determined baseline plasma levels of Aβ38, Aβ40 and Aβ42 peptides using ELISAs. We assessed volume of white matter hyperintensities (WMH) by semi-automatic segmentation, and manually rated lacunes and microbleeds as markers of SVD. We analyzed associations between plasma Aβ and SVD markers by ANCOVA with adjustments for age, sex and hypertension. Plasma Aβ40 levels were elevated in participants with microbleeds (mean 205.4 vs. 186.4 pg/ml; p<0.01), lacunes (mean 194.8 vs. 181.2 pg/ml; p<0.05) and moderate to severe WMH (mean 201.8 vs. 183.3 pg/ml; p<0.05) compared to participants without these SVD markers. High plasma Aβ40 levels were associated with increased risk of incident lacunes and progression of WMH. Elevated plasma Aβ42 levels were associated with incident microbleeds over nine years (p<0.05). Plasma Aβ levels are associated with both presence and progression of neuroimaging markers of SVD. These data suggest that plasma Aβ levels could possibly serve as inexpensive and non-invasive measure for identifying individuals with increased risk for SVD. This study was part of the CAVIA project: Cerebral Amyloid Angiopathy: Vascular Imaging and fluid markers of Amyloid deposition.

The first Greek case of heterozygous cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy: An atypical clinico-radiological presentation.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) was previously considered a rare, early-onset recessive form of small-vessel disease (SVD) caused by biallelic mutations in the serine protease gene HTRA1 with subsequent loss of its activity. However, very recently, there is growing interest of research showing heterozygous HTRA1 mutations as causes of SVD with a dominant inheritance pattern. This first Greek heterozygous CARASIL case with unusual clinico-radiological presentation extends our very recent knowledge on how heterozygous CARASIL mutations may be associated with cerebral SVD. Our findings highlight heterozygous HTRA1 mutations as an important cause of familial SVD, and that screening of HTRA1 should be considered in all patients with a hereditary SVD of unknown aetiology.

Impaired Retinal Vasoreactivity: An Early Marker of Stroke Risk in Diabetes.

Diabetes is a common cause of small vessel disease leading to stroke and vascular dementia. While the function and structure of large cerebral vessels can be easily studied, the brain's microvasculature remains difficult to assess. Previous studies have demonstrated that structural changes in the retinal vessel architecture predict stroke risk, but these changes occur at late disease stages. Our goal was to examine whether retinal vascular status can predict cerebral small vessel dysfunction during early stages of diabetes. Retinal vasoreactivity and cerebral vascular function were measured in 78 subjects (19 healthy controls, 22 subjects with prediabetes, and 37 with type-2 diabetes) using a new noninvasive retinal imaging device (Dynamic Vessel Analyzer) and transcranial Doppler studies, respectively. Cerebral blood vessel responsiveness worsened with disease progression of diabetes. Similarly, retinal vascular reactivity was significantly attenuated in subjects with prediabetes and diabetes compared to healthy controls. Subjects with prediabetes and diabetes with impaired cerebral vasoreactivity showed mainly attenuation of the retinal venous flicker response. This is the first study to explore the relationship between retinal and cerebral vascular function in diabetes. Impairment of venous retinal responsiveness may be one of the earliest markers of vascular dysfunction in diabetes possibly indicating subsequent risk of stroke and vascular dementia.

Monogenic causes of stroke: now and the future.

Most stroke is multifactorial with multiple polygenic risk factors each conferring small increases in risk interacting with environmental risk factors, but it can also arise from mutations in a single gene. This review covers single-gene disorders which lead to stroke as a major phenotype, with a focus on those which cause cerebral small vessel disease (SVD), an area where there has been significant recent progress with findings that may inform us about the pathogenesis of SVD more broadly. We also discuss the impact that next generation sequencing technology (NGST) is likely to have on clinical practice in this area. The most common form of monogenic SVD is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, due to the mutations in the NOTCH3 gene. Several other inherited forms of SVD include cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy, collagen type IV α1 and α2 gene-related arteriopathy and FOXC1 deletion related arteriopathy. These monogenic forms of SVD, with overlapping clinical phenotypes, are beginning to provide insights into how the small arteries in the brain can be damaged and some of the mechanisms identified may also be relevant to more common sporadic SVD. Despite the discovery of these disorders, it is often challenging to clinically and radiologically distinguish between syndromes, while screening multiple genes for causative mutations that can be costly and time-consuming. The rapidly falling cost of NGST may allow quicker diagnosis of these rare causes of SVD, and can also identify previously unknown disease-causing variants.

Small vessel disease: not a small problem.

Small infarcts in the subcortical area (lacunar infarction) have been considered a relatively simple condition. In most cases, complications associated with warfarin are not a cause for worry, the superiority of angioplasty or stenting need not be disputed, and performing craniectomy is unnecessary; we simply administer an antihypertensive drug and aspirin. However, small subcortical infarcts are not easy to manage. No solid evidence has been presented to support the effectiveness of antiplatelet agents or statin, while the incidence of hemorrhagic complication after the use of antiplatelets is high in this condition. More importantly, the consequences of accumulated small vessel diseases are dismal; many patients suffer from progressively worsening gait difficulty and cognitive/emotional problems. The presence of small vessel disease even worsens the outcome of other stroke subtypes. Last, although genetic causes of small vessel disease are being studied, the existing knowledge on its pathogenesis, diagnosis, and treatment is far from satisfactory. These issues were amply discussed in the International Conference Stroke Update (ICSU) that was held on November 6-8, 2014, in Jeju Island, South Korea. In this issue and in subsequent May issue, we will publish a series of articles regarding small vessel diseases. Most speakers kindly agreed to write on each of the subjects presented at the ICSU 2014. In these papers, the seriousness of small vessel disease will be correctly elucidated. Small vessel disease seems to be more common among Asians than among Caucasians, and rapidly aging populations in this region will considerably increase the burden of accumulating cases of small vessel disease. One of the missions of the Journal of Stroke (JOS) is to more actively present Asian issues, and the series of articles will certainly contribute to this endeavor. Finally, I am pleased to inform you that the JOS was enlisted as an (E) by Thomson Reuters on October 22, 2014. For this, I am indebted to the editorial board members, authors, and members of the Korean Stroke Society, who are excellent, enthusiastic, and devoted contributors and advisers. I am happy to say that all of your articles published in the JOS to date can now be considered SCI papers. This excellent news will result in our papers gaining more attention and will attract submission of articles from all over the world. I believe that our constant efforts will make the JOS a truly world-class journal. For this, I would like to suggest a toast!

Sensitivity of Diffusion- and Perfusion-Weighted Imaging for Diagnosing Acute Ischemic Stroke Is 97.5%

MRI using diffusion-weighted imaging (DWI) is the most sensitive diagnostic imaging modality for early detection of ischemia, but how accurate is it and how much does perfusion-weighted imaging (PWI) add to the sensitivity have to be known. In this single-center study, we collected epidemiological, imaging, and outcome data on all patients with stroke undergoing MRI-based treatment with intravenous tissue-type plasminogen activator at our center from 2004 to 2010. The DWI negative patients were identified, and we calculated the sensitivity and specificity of DWI and additional PWI for diagnosing acute ischemic stroke. We compared DWI positive and negative patients to identify characteristics associated with DWI negativity. Five hundred sixty-nine consecutive patients were treated with intravenous tissue-type plasminogen activator on the basis of an acute MRI. A DWI lesion was evident in 518 patients. Forty-seven patients were DWI negative; however, a relevant PWI lesion was found in 33 of these patients. Four stroke mimics were treated with intravenous tissue-type plasminogen activator and 1 of these patients had a DWI lesion. Thus, 8% of all patients with stroke were DWI negative. The combination of DWI and PWI resulted in a sensitivity of 97.5% for the ischemic stroke diagnosis. DWI negativity was associated with less severe strokes, location in the posterior circulation, a longer time from onset to scan, and an improved 90-day outcome. The cause of small-vessel disease was more likely to be DWI negative. The combination of DWI and PWI before intravenous tissue-type plasminogen activator confirms the diagnosis in 97.5% of all ischemic strokes.

White Matter Lesions and Vascular Cognitive Impairment

While the diagnosis of vascular dementia rests on established radiomorphological criteria, the term vascular cognitive impairment hitherto is less clear cut and hence the interpretation of white matter changes (WMC) widely held to be caused by vascular disease is pivotal. Part one of this review deals with the description of WMC and the underlying vascular etiologies. To some degree magnetic resonance (MR) imaging seems capable of differentiating these lesions by technical means and by depicting anatomical detail. Microangiopathy, notoriously causing white matter lesions, is focused in a broader sense, including inflammatory and hereditary causes of small vessel disease and corresponding to vascular diseases of the young. Accordingly, interpretation of a given lesion could fail if clinical aspects, such as age, guiding symptoms and acuteness are not taken into account.

Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease

The most common monogenic cause of small-vessel disease leading to ischemic stroke and vascular dementia is the neurodegenerative syndrome cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is associated with mutations in the Notch 3 receptor. CADASIL pathology is characterized by vascular smooth muscle cell degeneration and accumulation of diagnostic granular osmiophilic material (GOM) in vessels. The functional nature of the Notch 3 mutations causing CADASIL and their mechanistic connection to small-vessel disease and GOM accumulation remain enigmatic. To gain insight into how Notch 3 function is linked to CADASIL pathophysiology, we studied two phenotypically distinct mutations, C455R and R1031C, respectively associated with early and late onset of stroke, by using hemodynamic analyses in transgenic mouse models, receptor activity assays in cell culture, and proteomic examination of postmortem human tissue. We demonstrate that the C455R and R1031C mutations define different hypomorphic activity states of Notch 3, a property linked to ischemic stroke susceptibility in mouse models we generated. Importantly, these mice develop osmiophilic deposits and other age-dependent phenotypes that parallel remarkably the human condition. Proteomic analysis of human brain vessels, carrying the same CADASIL mutations, identified clusterin and collagen 18 α1/endostatin as GOM components. Our findings link loss of Notch signaling with ischemic cerebral small-vessel disease, a prevalent human condition. We determine that CADASIL pathophysiology is associated with hypomorphic Notch 3 function in vascular smooth muscle cells and implicate the accumulation of clusterin and collagen 18 α1/endostatin in brain vessel pathology.

COL4A1 Mutations as a Monogenic Cause of Cerebral Small Vessel Disease

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. 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. 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%). 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.

Clinical and brain MRI follow-up study of a family with COL4A1 mutation

To better delineate the clinical spectrum and the natural history of COL4A1 mutations, a newly defined genetic cause of small vessel disease including the brain and retina. Clinical and brain MRI follow-up study of a family with COL4A1 mutation. During a 7-year period, two affected members died from intracranial hemorrhage. Four other members had a COL4A1 mutation (age ranges 25 to 74 years). None reported stroke or retinal hemorrhage or hematuria and none had dementia according to Diagnostic and Statistical Manual of Mental Disorders-IV criteria. Follow-up brain MRI showed grade 3 diffuse leukoencephalopathy in three out of four patients. All had dilated perivascular spaces and three out of four had silent microbleeds mainly in the deep white matter. MRI signal abnormalities did not change in severity, number, or location between baseline and follow-up imaging. COL4A1 mutation carriers have great diversity in the clinical expression of the disease within the same family. Some affected family members may remain asymptomatic during several years of follow-up and have no evidence of progression of vascular changes on brain MRI.

Arterialized venous perfusion of composite tissue

The results of our experiment prove that arterialized venous perfusion is a viable means of nourishing complex composite tissue without using the arterial tree. Previous laboratory findings [36], coupled with the results of this experiment, demonstrate that as long as proximal arterial inflow is ensured, both the arterial and venous trees need not be intact to keep tissue alive. Rather, it seems that the prerequisites for tissue survival are that at least one of the two systems be intact and that there be sufficient inflow and outflow channels available. Whether these channels are arteries or veins is probably not important. The use of properly placed efferent or afferent arteriovenous fistulas allows one system to provide both physiologic functions. Whether the efferent arterial anastomosis stays open over the long term appears to be inconsequential. Survival is ensured by either direct perfusion with oxygen delivery through the venous tree or through the eventual ingrowth of recipient vessels into the flap by way of the delay phenomena. This perfusion technique is ideally suited for tissue with an inadequate arterial tree but with an intact venous system devoid of venous valves (most veins less than 1.5 mm in diameter). A well-vascularized recipient bed capable of providing vessel ingrowth into transferred tissue may be important in the case of delayed arteriovenous fistula occlusion secondary to intimal hyperplasia; therefore, further experimental study of these flaps must be undertaken before arterialized venous flaps can be recommended for placement in recipient sites compromised due to radiation, ischemia, diabetes, or other causes of small vessel disease in the recipient bed. Although efferent arteriovenous fistulas are currently used to provide arterialized venous perfusion in selected cases of end stage arterial occlusive and vasospastic disease, perhaps their greatest role is in the management of tissue transfer with an inadequate arterial tree. Much knowledge must be gained to understand the physiologic principles and requirements for optimal perfusion. Many questions are left unanswered. For example, in those arteriovenous fistulas that narrow or occlude secondary to neointimal hyperplasia or other causes, which channels (veins or arteries?) are used for perfusion during recipient vessel growth? Can intimai hyperplasia be reversed or prevented by drug therapy and would this be advantageous? Can venous valves be made incompetent so that this technique can be used for larger vessels? Will arterialized venous tissue transfers survive after delayed arteriovenous fistula occlusion in a compromised recipient bed? Are arterialized venous flaps more prone to infection than conventionally perfused flaps? Can this method of perfusion be used with predictable success for visceral organs [26,27]? Anatomic studies on the venous tree must be undertaken to map out the microvenous territories of those veins capable of supporting tissue for transplantation. A search for venous flaps may yield new sources of complex composite tissues for transfer with minimal donor site morbidity and functional and aesthetic drawbacks. Clearly the limits of arterialized venous perfusion have not been realized. Hopefully, this alternative nonconventional method for tissue perfusion will broaden the horizons of transplantation, replantation, trauma, and reconstructive surgery, shedding new light on old frustrations.