Development 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 microangiopathy in men with obstructive sleep apnea syndrome

To determine factors associated with the development of small vessel disease (SVD) in patients with obstructive sleep apnea syndrome (OSA). One hundred and fifty-two patients with risk factors for the development of cerebrovascular diseases were examined. Based on the results of polysomnography, patients were divided into groups with- (n=84) and without (n=68) OSA. The groups were matched by age, prevalence of arterial hypertension and diabetes mellitus. SVD was diagnosed using brain MRI. Laboratory tests included an assessment of parameters of lipid metabolism, glucose metabolism, concentration of C-reactive protein (CRP), levels of homocysteine and creatinine with the calculation of glomerular filtration rate (GFR). Patients with OSA, compared with those without OSA, were characterized by a statistically significant number of gliosis foci, with their large sizes, more frequent changes on the Fazekas scales and the Hassan scale. The most severe degree of damage according to the Hassan scale in patients with OSA was detected more often (55 (66%) and 27 (39%) OR=2.89, 95% CI 1.47-5.67, p=0.002). More pronounced atrophic changes in the brain, an increase in the size of the III ventricle and the index of the anterior horns, significantly lower GFR and higher levels of CRP were noted in the OSA group. Patients with OSA and duration of nocturnal hypoxia for more than 2 minutes were more likely to have hyperintensity of subcortical regions. In patients with OSAS, pronounced manifestations of SMD were associated with a significantly higher level of morning systolic blood pressure (MAP): 140 [120; 150] vs. 127 [120; 130] p=0.029; increased levels of blood homocysteine: 14 [11; 17.8] vs. 13 [9.7; 12.5] p=0.049; a decrease in GFR: 79 [71; 87.3] vs. 89.8 [80.3; 94] p=0.002, respectively. OSA and intermittent nocturnal hypoxia are independent risk factors for SMD. A more severe micro-focal vascular lesion in OSA is associated with a decrease in renal filtration function, an increase in morning blood pressure and an elevation in homocysteine level.

The role of the fibrinolytic system laboratory markers in the assessment of the cerebral small vessel disease severity

Background: Small vessel disease (SVD) is a common brain disease causing about 40% of all dementias and about 25% of ischemic strokes, which makes important the study of its pathophysiology and the search for its biomarkers. A number of studies have shown a significant role of endothelial dysfunction and nonspecific inflammation, as well as of some individual parameters of hemostasis disorders in the development of SVD.&#x0D; Aim: To identify the role of the laboratory markers of fibrinolytic system in the assessment of the severity of white matter lesions in patients with SVD.&#x0D; Materials and methods: This single center cross-sectional non-controlled observational study included 117 patients with dyscirculatory encephalopathy (chronic brain ischemia), with a mean ( SD) age of 57.7 11.5 years. Laboratory tests of the fibrinolytic system, endothelial dysfunction, markers of inflammation and for an integral assessment of plasma hemostasis were performed in all patients, including XIIa-dependent fibrinolysis, levels of plasminogen, alpha2-antiplasmin, plasminogen activator inhibitor 1 (PAI-1), fibrinogen, von Willebrand factor (vWF) and activity of blood coagulation factor VIII (FVIII), highly sensitive C-reactive protein and parameters of the thrombodynamics assay. In all the patients, brain magnetic resonance imaging was performed with the assessment of the white matter lesions by the Fazecas scale.&#x0D; Results: Depending on the identified neuroimaging SVD markers (assessed with the Fazecas scale), the patients were divided into the SVD group (n = 54) and no-SVD group (n = 63). Those with SVD were older than those without (65 9 vs 51 10 years; p 0.001), had higher prevalence of arterial hypertension (p 0.001), diabetes mellitus (p = 0.029) and past thrombotic events (p 0.001). The SVD patients, compared to those without SVD, had a higher time of XIIa-dependent fibrinolysis (7.6 2.9 vs 6.5 1.7 min, p = 0.032), higher alpha2-antiplasmin levels (111 [95117] vs 105 [95111]%, p = 0.016) and higher clot density (D) (22789 [2056726411] vs 20627 [1832422650] U, p 0.001), although the parameters were within the reference ranges. As far as the thrombodynamics is concerned, the SVD group had higher values for all test parameters, as well as higher levels of the inflammation and endothelial dysfunction markers. Increased time of XIIa-dependent fibrinolysis was associated with higher probability of periventricular and subcortical leukoareosis grade 2 by the Fazecas scale (odds ratio 1.31 [1.071.60], p = 0.009), including an increase in the size and number of gliosis areas. Higher plasminogen levels were associated with a lower probability of leukoareosis by the Fazecas scale (odds ratio 0.97 [0.950.98], p 0.001).&#x0D; Conclusion: The severity of fibrinolytic and hemostatic abnormalities correlates with the severity of brain SVD, thus forming the hypofibrinolytic and prothrombotic status of the patients with this disorder.

Could salt intake directly affect the cerebral microvasculature in hypertension?

ObjectivesExcess dietary salt and chronic kidney disease (CKD) are acknowledged stroke risk factors. The development of small vessel disease, similarly affecting the cerebral and renal microvasculatures, may be an important mechanistic link underlying this interaction. Therefore, we aimed to evaluate if the dietary salt intake and markers of CKD (estimated glomerular filtration rate, albuminuria) relate to transcranial Doppler (TCD) markers of cerebral small vessel disease (CSVD) in hypertensive patients. Materials and methodsFifty-six hypertensive patients (57% with diabetes) underwent TCD monitoring in the middle (MCA) and posterior (PCA) cerebral arteries for evaluating neurovascular coupling (NVC), dynamic cerebral autoregulation (dCA), and vasoreactivity to carbon dioxide (VRCO2). We investigated the relation between renal parameters and TCD studies using Pearson's correlation coefficient and linear regression analyses. ResultsThere were no associations between dCA, VRCO2, NVC, and renal function tests. However, there was a negative association between the daily salt intake and the natural frequency during visual stimulation (r2=0.101, ß=-0.340, p=0.035), indicative of increased rigidity of the cerebral resistance vessels that react to cognitive activation. ConclusionsIn this cross-sectional study, we found an association between excess dietary salt consumption and CSVD in hypertensive patients. Future research is needed to evaluate whether the natural frequency could be an early, non-invasive, surrogate marker for microvascular dysfunction in hypertension.

Small Resistance Artery Disease and ACE2 in Hypertension: A New Paradigm in the Context of COVID-19

Cardiovascular disease causes almost one third of deaths worldwide, and more than half are related to primary arterial hypertension (PAH). The occurrence of several deleterious events, such as hyperactivation of the renin–angiotensin system (RAS), and oxidative and inflammatory stress, contributes to the development of small vessel disease in PAH. Small resistance arteries are found at various points through the arterial tree, act as the major site of vascular resistance, and actively regulate local tissue perfusion. Experimental and clinical studies demonstrate that alterations in small resistance artery properties are important features of PAH pathophysiology. Diseased small vessels in PAH show decreased lumens, thicker walls, endothelial dysfunction, and oxidative stress and inflammation. These events may lead to altered blood flow supply to tissues and organs, and can increase the risk of thrombosis. Notably, PAH is prevalent among patients diagnosed with COVID-19, in whom evidence of small vessel disease leading to cardiovascular pathology is reported. The SARS-Cov2 virus, responsible for COVID-19, achieves cell entry through an S (spike) high-affinity protein binding to the catalytic domain of the angiotensin-converting enzyme 2 (ACE2), a negative regulator of the RAS pathway. Therefore, it is crucial to examine the relationship between small resistance artery disease, ACE2, and PAH, to understand COVID-19 morbidity and mortality. The scope of the present review is to briefly summarize available knowledge on the role of small resistance artery disease and ACE2 in PAH, and critically discuss their clinical relevance in the context of cardiovascular pathology associated to COVID-19.

Diabetic rats are more susceptible to cognitive decline in a model of microemboli-mediated vascular contributions to cognitive impairment and dementia

Vascular disease plays an important role in all kinds of cognitive impairment and dementia. Diabetes increases the risk of vascular disease and dementia. However, it is not clear how existing vascular disease in the brain accelerates the development of small vessel disease and promotes cognitive dysfunction in diabetes. We used microemboli (ME) injection model in the current study to test the hypothesis that cerebrovascular dysfunction in diabetes facilitates entrapment of ME leading to inflammation and cognitive decline. We investigated cognitive function, axonal/white matter (WM) changes, neurovascular coupling, and microglial activation in control and diabetic male and female Wistar rats subjected to sham or low/high dose ME injection. Diabetic male animals had cognitive deficits, WM demyelination and greater microglial activation than the control animals even at baseline. Functional hyperemia gradually declined in diabetic male animals after ME injection. Both low and high ME injection worsened WM damage and increased microglial activation in diabetic male and female animals. Low ME did not cause cognitive decline in controls, while promoting learning/memory deficits in diabetic female rats and no further decline in diabetic male animals. High ME led to cognitive decline in control male rats and exacerbated the deficits in diabetic cohort. These results suggest that the existing cerebrovascular dysfunction in diabetes may facilitate ME-mediated demyelination leading to cognitive decline. It is important to integrate comorbidities/sex as a biological variable into experimental models for the development of preventive or therapeutic targets.

Pulmonary Hypertension in Patients After Permanent Pacemaker Implantation

Abstract Permanent pacemaker (PPM) implantation can lead to thromboembolic events at different times after the procedure. According to literature, 1.7% of patients with pulmonary embolism have an implantable cardiac device. This frequency is higher than reported so far, from 0.16 to 0.47% of the total population. The pathophysiologic mechanism of pulmonary embolism in chronic thromboembolic pulmonary hypertension (CTEPH) is multifactorial. Recently, there is evidence that not only the organisation of thrombotic deposits in the proximal pulmonary arterial vessels is important, but also the development of small vessel disease, which plays an important role in the evolution and progression of the disease. The role of thrombosis in medical devices in contact with blood flow, such as stents, vascular grafts, heart valves, has been well studied and documented in scientific literature on biomaterials. It is clear that implantable cardiac devices such as pacemakers, similarly to other foreign surfaces exposed to blood flow, promote blood clotting and complement activation. Numerous studies to date have addressed the potential risk of distal vascular involvement of pulmonary circulation in the presence of a pacemaker, but none has conclusively proven this hypothesis. Over the last decade, there has been significant progress in the therapeutic potential of CTEPH. Pulmonary endarterectomy remains the only therapeutic method that can lead to lasting clinical improvement in these patients while achieving a good quality of life. This method is operational, with high financial value and is associated with the presence of a highly specialised team of specialists. This justifies the search for ways to prevent the onset of the disease rather than treat the consequences.

Midlife Atherosclerosis and Development of Alzheimer or Vascular Dementia.

ObjectiveTo investigate whether midlife atherosclerosis is associated with different dementia subtypes and related underlying pathologies.MethodsParticipants comprised the cardiovascular cohort of the Swedish prospective population‐based Malmö Diet and Cancer Study (N = 6,103). Carotid plaques and intima media thickness (IMT) were measured at baseline (1991–1994). Dementia incidence until 2014 was obtained from national registers. Diagnoses were reviewed and validated in medical records. In a cognitively unimpaired subcohort (n = 330), β‐amyloid42 and tau were quantified in cerebrospinal fluid (CSF), and white matter hyperintensity volume, lacunar infarcts, and cerebral microbleeds were estimated on magnetic resonance imaging (2009–2015).ResultsDuring 20 years of follow‐up, 462 individuals developed dementia (mean age at baseline = 57.5 ± 5.9 years, 58% women). Higher IMT in midlife was associated with an increased hazard ratio (HR) of all‐cause dementia (adjusted HR = 1.14 [95% confidence interval (CI) = 1.03–1.26]) and vascular dementia (adjusted HR = 1.32 [95% CI = 1.10–1.57]) but not Alzheimer disease (AD) dementia (adjusted HR = 0.95 [95% CI = 0.77–1.17]). Carotid plaques were associated with vascular dementia when assessed as a 3‐graded score (adjusted HR = 1.90 [95% CI = 1.07–3.38]). In the cognitively unimpaired subcohort (53.8 ± 4.6 years at baseline, 60% women), higher IMT in midlife was associated with development of small vessel disease (adjusted odds ratio [OR] = 1.47 [95% CI = 1.05–2.06]) but not significantly with abnormal CSF AD biomarkers (adjusted OR = 1.28 [95% CI = 0.87–1.90] for Aβ42 and 1.35 [95% CI = 0.86–2.13] for Aβ42/p‐tau). Carotid plaques revealed no significant association with any of the underlying brain pathologies.InterpretationOur findings support an association between midlife atherosclerosis and development of vascular dementia and cerebral small vessel disease but not between atherosclerosis and subsequent AD dementia or AD pathology. ANN NEUROL 2020;87:52–62

4095Exercise and vascular ageing: a cross-sectional and randomized controlled trial

Abstract Background Vascular ageing can be quantified at subclinical stages by use of sensitive vascular biomarkers of the macro- and microcirculation. Detection of vascular impairments enables initiation of timely treatment strategies to counteract development of CV disease and improve CV outcome. Purpose To (a) compare large artery stiffness and retinal microvascular diameters in healthy life-long active and healthy sedentary older adults with CV risk patients, and (b) to assess the effects of short-term high-intensity exercise training on vascular health in these patients. Methods Seven hundred and eighty-three participants were screened for their CV risk and physical activity profile. We included 38 healthy active (HA, mean age 60±7 years) and 36 healthy sedentary (HS, mean age 60±7 years) as well as 84 sedentary patients with ≥2 CV risk factors (SR, mean age 59±6 years) in the cross-sectional approach. SR were randomized to a 12-week high-intensity interval training (HIIT) or physical activity recommendations after the baseline assessment. Carotid-femoral PWV (cfPWV) was measured as a marker of large artery stiffness and the central retinal arteriolar (CRAE) and venular (CRVE) diameters as well as the retinal arteriolar-to-venular diameter ratio (AVR) were measured as a marker of the microcirculation. Standard procedures of anthropometric measurements were implemented. Results Anthropometric parameters differed between the groups according to the inclusion criteria. cfPWV was highest in SR (8.2±1.4m/s) compared to HS (7.5±1.6m/s) and HA (7.0±1.1 m/s). HA had a lower cfPWV compared to HS (p&lt;0.05) and SR (p&lt;0.001). HA had wider CRAE (179±14μm) and narrower CRVE (204±17μm) compared to HS (CRAE: 172±11 μm; CRVE: 209±11 μm) resulting in a higher AVR in HA (0.88±0.05) compared to HS (0.83±0.04, p&lt;0.001). By contrast, SR showed narrower CRAE (171±14 μm) and wider CRVE (218±16μm, p&lt;0.05) compared to HS resulting in a lower AVR (0.79±0.05, p&lt;0.001) compared to HS and HA. HIIT in SR improved most classic CV risk factors. Additionally, CRAE increased (pre: 175±14μm vs post: 181±13μm, p=0.001) and CRVE decreased (pre: 222±14μm vs post: 220±14μm, p=0.007) in the HIIT group without changes in the cfPWV. PWV was significantly but moderately associated with AVR (r=−0.2, p=0.01). Conclusions Life-long physical activity and fitness were associated with lower arterial stiffness and favourable retinal vessel diameters in healthy individuals. CV patients had higher arterial stiffness and lower AVR. Short-term HIIT improved retinal microvascular phenotype without changes in large artery stiffness. Retinal vessel diameters are sensitive diagnostic tool for CV risk stratification and subclinical vascular disease monitoring in CV patients. Short-term HIIT may postpone development of small vessel disease in older patients. Acknowledgement/Funding Swiss National Science Foundation, Nora van Meeuwen-Häfliger Stiftung

Abstract TP564: Diabetic but Not Control Rats Develop White Matter Injury and Cognitive Deficits in a Microemboli Injection Model of VCID

Diabetes doubles the risk of vascular cognitive impairment and dementia (VCID), a disease is associated with small vessel disease (SVD) of the brain. Given that diabetes mediates early cerebrovascular dysfunction, and microemboli are common in the cerebral circulation and can penetrate into the brain parenchymal arterioles without causing an infarction, we tested the hypothesis that entrapment of microemboli in dysfunctional vessel walls accelerates the development of SVD ultimately resulting in VCID in diabetes. Diabetes was induced by a high fat diet and low dose streptozotocin (35 mg/kg, IP) injection in male Wistar rats. Cholesterol crystal microemboli [40-70 μm, 3000 (Group A) or 6000 (Group B) per 200 μl saline] were injected 8 weeks later through internal carotid artery. Cognitive function was monitored by the novel object recognition (NOR) test. White matter injury was assessed by Luxol fast blue (LFB) and hematoxylin/eosin (HE) staining in Group A. Cerebral blood flow (CBF), white matter hyperintensities (T2 map), microbleeds (T2 asterisk), and microinfarcts (T2 W) were assessed by MRI in Group B. In Group A, there was increased white matter degeneration in diabetic animals compared to controls. This degeneration was aggravated by microembolic injection. We found that cognitive function was exacerbated in Group B diabetes animals. MRI results showed these animals also had decreased CBF but no change on microinfarcts or microbleed. These results suggest that white matter degeneration starts in the early stages of diabetes, and that microemboli exacerbate these pathological changes even before the appearance of any neurobehavioral deficits. Additional studies are needed to examine the precise time course for development of cerebral neurovascular changes relative to appearance of behavioral deficits and explore potential therapeutic targets for VCI in diabetes.

Tissue-type plasminogen activator and MRI features of cerebral small vessel disease

Introduction. Сerebral small vessel disease (SVD) is a one of the leading causes of cognitive decline, and of ischemic and hemorrhagic stroke. It is diagnosed with the MRI criteria elaborated by international society (STRIVE, 2013). The development of SVD is closely related with endothelial dysfunction. Of special importance are studies of factors produced by endothelium and participating in the pathogenesis of SVD. Objective: to clarify the relationships of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1) with MRI signs of SVD. Materials and methods. Seventy-one patients (23 males and 48 females, mean age 60.5±6.9) with SVD diagnosed according to the STRIVE criteria were examined. Arterial hypertension of grade 1 was revealed in 12 patients, grade 2 in 7, and grade 3 in 37 patients. White matter hyperintensities (WMH), according to Fazekas (F) scale, were graded stage F1 in 17 patients, F2 in 23, and F3 in 30 patients. Control group comprised 21 age- and sex-matched individuals with normal brain MRI. Brain MRI (3 Tl) was performed in all patients, with the assessment of the following SVD features: WMH, lacunes, microbleeds, and enlarged perivascular spaces. Blood levels of t-PA and PAI-1 were measured by enzyme immunoassay. An ANOVA variance analysis was used (p 0.05). PAI-1 levels were not associated (p>0.05) with t-PA levels or MRI features of SVD. Conclusion. The determined effect of t-PA level on the severity of WMH and perivascular spaces, the SVD features associated with increased blood-brain permeability, confirms the role of endothelial dysfunction in the development of SVD and the involvement of t-PA in the mechanisms of brain injury.

The Effect of Hypercholesterolemia on the Characteristics of Cerebral Microvasculature

Aim: It remains unclear whether the increase of LDL cholesterol (LDL-C) is a risk factor for cerebral vascular disease (CVD). To clarify the effects of hypercholesterolemia on cerebral small vessel disease (SVD), we investigate the characteristics of microvasculature including lenticulostriate arteries (LSA) using high resolution brain magnetic resonance imaging (MRI) in subjects with familial hypercholesterolemia (FH). Methods: Twenty-seven patients with FH and 25 patients with type2 diabetes (DM), 25 healthy controls underwent 7Tesla (7T) brain MRI. The prevalence of SVD and LSA structural changes, vessel wall plaque images were determined in each group. Results: The prevalence of SVD, including white matter hyperintensities and lacunar infarctions, significantly increased in DM compared with both FH and controls. In addition, the average numbers of stems of LSA were significantly smaller in DM than FH as well as controls. Interestingly, both SVD prevalence and LSA structural changes showed no difference between FH and controls. Next, we examined the vessel wall imaging analyses of middle cerebral arteries (MCA) and vertebral-basilar arteries (VA-BA). The prevalence of vessel wall plaque on both horizontal segment of MCA (FH vs. controls; 51.8% vs. 20.0%, p&amp;lt;0.05) and VA-BA (37.0% vs. 12.0%, p&amp;lt;0.05) were significantly higher in FH than controls. Conclusion: The prevalence of SVD and LSA structural impairment definitely increased in DM, suggesting that DM was strong risk for CVD compared to hypercholesterolemia. On the other hand, the prevalence of vessel wall plaque on MCA and VA-BA were significantly high in FH compared to controls. These results suggested long-term increase of LDL-C induced the plaque formation in cerebral microvasculature. Image analyses using 7T MRI enables us to investigate the characteristics of cerebral microvasculature prior to the development of SVD, leading to earlier interventions aimed at the prevention of atherosclerotic events. Disclosure Y. Todate: None. Y. Ishigaki: None.

Abstract WP417: Novel Animal Model for Cerebral Small Vessel Disease

Introduction: Cerebral small vessel disease (SVD) is a common finding in patients with stroke. It can manifest as white matter hyperintensities (WMH), microbleeds or lacunar strokes. Presence of SVD is an independent risk factor for stroke and is considered a poor prognostic factor in stroke recovery. In addition, SVD has been associated with vascular dementia, depression and gait disorder. There are no good animal models to study SVD. Hypothesis: The precise mechanism behind development of SVD is not clearly understood. It’s likely a result of multiple different processes including decreased blood flow, inflammation with blood brain barrier disruption, degeneration and myelin breakdown. We try to study the role of reduced blood flow and inflammation in the development of SVD with the eventual goal of developing an agent that may prevent the development or progression of SVD. Methods: We remodeled a novel murine SVD model - asymmetric common carotid artery surgery (ACAS), published recently. We placed an ameroid constrictor around the right common carotid artery (CCA) which gradually narrows and eventually occludes vessels by releasing hygroscopic casein material, and a microcoil around the left CCA in mice. This model causes gradual narrowing of the vessels and a significant reduction of cerebral blood flow as detected by Laser Speckle Imager. These mice were compared to sham control which underwent a sham surgery without any vessel occlusion (n=7 per group). Animals were monitored for 30 days. Results: In the ACAS group, the model caused morbidity in all mice and death in 2 of 7 mice. Histologically, we observed marked vacuoles in white matter evaluated by H&amp;E staining. We devised a severity score based on the extent of white matter damage and presence of infarcts under microscope. Based on this score, the damage was significantly worse in the ACAS group as compared with sham controls. Conclusions: These findings demonstrate the role of gradual blood flow reduction in development of SVD. We plan to further study the mechanisms behind SVD and develop novel treatments with the goal of preventing SVD.

A comparison of location of acute symptomatic vs. 'silent' small vessel lesions.

BackgroundAcute lacunar ischaemic stroke, white matter hyperintensities, and lacunes are all features of cerebral small vessel disease. It is unclear why some small vessel disease lesions present with acute stroke symptoms, whereas others typically do not.AimTo test if lesion location could be one reason why some small vessel disease lesions present with acute stroke, whereas others accumulate covertly.MethodsWe identified prospectively patients who presented with acute lacunar stroke symptoms with a recent small subcortical infarct confirmed on magnetic resonance diffusion imaging. We compared the distribution of the acute infarcts with that of white matter hyperintensity and lacunes using computational image mapping methods.ResultsIn 188 patients, mean age 67 ± standard deviation 12 years, the lesions that presented with acute lacunar ischaemic stroke were located in or near the main motor and sensory tracts in (descending order): posterior limb of the internal capsule (probability density 0·2/mm3), centrum semiovale (probability density = 0·15/mm3), medial lentiform nucleus/lateral thalamus (probability density = 0·09/mm3), and pons (probability density = 0·02/mm3). Most lacunes were in the lentiform nucleus (probability density = 0·01–0·04/mm3) or external capsule (probability density = 0·05/mm3). Most white matter hyperintensities were in centrum semiovale (except for the area affected by the acute symptomatic infarcts), external capsules, basal ganglia, and brainstem, with little overlap with the acute symptomatic infarcts (analysis of variance, P < 0·01).ConclusionsLesions that present with acute lacunar ischaemic stroke symptoms may be more likely noticed by the patient through affecting the main motor and sensory tracts, whereas white matter hyperintensity and asymptomatic lacunes mainly affect other areas. Brain location could at least partly explain the symptomatic vs. covert development of small vessel disease.

Plasma Fibrinogen, Global Cognitive Function, and Cerebral Small Vessel Disease: Results of a Cross-Sectional Study in Community-Dwelling Japanese Elderly

Recent studies suggest that hemostatic and endothelial factors play a pivotal role in the development of cerebral small vessel disease (SVD). Although plasma fibrinogen is an essential factor in the coagulation cascade, the relationship among fibrinogen, cognitive function, and SVD has not been clarified in community-based Asian populations. Because fibrinogen levels of Asians have been reported to be lower than these of Caucasians, the impact of fibrinogen on the development of SVD or dementia in Asians may be different from that of Caucasians. We performed a cross-sectional study using MRI to determine the relationships among fibrinogen, cognitive function, and subclinical SVD in community-based Japanese elderly. Subjects with raised fibrinogen levels tended to have more lacunes and higher grades of white matter lesions (WMLs). Additionally, an independent association between fibrinogen and WMLs was determined by logistic regression analyses. Subjects with high fibrinogen levels accompanied by high von Willebrand factors or thrombomodulin levels had an increased tendency for the presence of WMLs. The relationship between the mean Mini-Mental State Examination (MMSE) scores and the quartiles of fibrinogen levels was not statistically significant after controlling for age, gender, and WMLs; however, the mean MMSE scores in subjects without WML were related to the tertiles of the fibrinogen levels even after adjusting for conventional risks and high sensitivity C-reactive protein. The present study suggests that there is a close relationship between fibrinogen levels and subclinical WMLs, which are independent of conventional risk factors and inflammation, in community-based Japanese elderly.

Platelet survival in patients with diabetes mellitus.

Platelet survival by 51chromium labeling was determined in six normal control subjects and in twelve patients with diabetes mellitus, before and after improved glucose control (mean HbA1c 10.5 +/- 2.2% and 7.1 +/- 1.8%, respectively). Mean platelet survival was 9.47 +/- 0.85 days for the normal subjects and 9.04 +/- 1.40 and 9.90 +/- 1.05 for the diabetic subjects in hyperglycemic and improved glycemic states, respectively. The differences between these values were not statistically significant. However, platelet survivals performed in three diabetic patients who had severe retinal disease requiring photocoagulation were significantly shortened compared with nonsmoking control subjects (P less than 0.05) or to patients without severe retinopathy (P less than 0.01). These observations imply that measurable changes in in vivo platelet survival occur after the development of small vessel disease. It remains to be determined whether abnormalities described for diabetic platelets in vitro or changes in in vivo platelet physiology contribute to the initiation or propagation of vascular disease in the hyperglycemic individual.