Severe Small Vessel Disease Research Articles

Shape of the Central Sulcus and Disability After Subcortical Stroke: A Motor Reserve Hypothesis.

Both brain and cognitive reserves modulate the clinical impact of chronic brain diseases. Whether a motor reserve also modulates the relationships between stroke and disability is unknown. We aimed to determine whether the shape of the central sulcus, a marker of the development of underlying motor connections, is independently associated with disability in patients with a positive history of small subcortical ischemic stroke. Shapes of central sulci were reconstructed from high-resolution magnetic resonance imaging and ordered without supervision according to a validated algorithm in 166 patients with a positive history of small subcortical ischemic stroke caused by CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy), a severe monogenic cerebral small vessel disease affecting young patients. Ordinal logistic regression modeling was used to test the relationships between modified Rankin scale, a disability scale strongly weighted toward motor disability, and sulcal shape. Modified Rankin scale was strongly associated with sulcal shape, independent of age, sex, and level of education (proportional odds ratio =1.19, 95% confidence interval =1.06-1.35; P=0.002). Results remained significant after further adjustment for brain atrophy, volume of lacunes, and volume of white matter hyperintensities of presumed vascular origin. The severity of disability in patients with a positive history of small subcortical ischemic stroke caused by a severe cerebral small vessel disease is related to the shape of the central sulcus, independently of the main determinants of disability. These results support the concept of a motor reserve that could modulate the clinical severity in patients with a positive history of small subcortical ischemic stroke.

The clinical significance of brain microbleeds in patients with Alzheimer's disease: Preliminary study.

Background:Microbleeds (MBs) are observed frequently in Alzheimer's disease (AD) and suggested to play a crucial role in the pathophysiology, but their clinical significance remains unclear.Materials and Methods:The study recruited 100 patients with AD who were diagnosed at the memory clinic in Seoul Medical Center in 2014. For each patient, baseline characteristics, neuropsychological tests, cerebrovascular risk factors, medial temporal lobe atrophy (MTLA), and severity of small vessel disease (SVD) according to the existence of MBs were evaluated.Results:The prevalence of MBs in patients with AD was 33%. The percentage of male gender, the severity of SVD and MTLA were significantly increased in MB(+) group. The MB(+) group showed more severe MTLA and SVD than MB(−) group.Conclusions:These results suggested that MBs might reflect the burden of amyloid and ischemic vascular pathology.

Leukoaraiosis and lacunes are associated with poor clinical outcomes in ischemic stroke patients treated with intravenous thrombolysis.

The effect of preexisting small vessel disease on outcomes of patients with ischemic stroke treated with i.v. thrombolysis is not fully understood. We aim to investigate the effect of combined leukoaraiosis and lacunes as detected on unenhanced brain computer tomography at baseline on clinical outcomes after i.v. thrombolysis. We analyzed data from the Canadian Alteplase for Stroke Effectiveness Study. Small vessel disease was assessed on baseline computer tomography rating for leukoaraiosis and lacunes. We dichotomized the burden of small vessel disease to "absent or moderate" and "severe." Clinical outcomes at 90 days included excellent outcome (mRS = 0-1), good outcome (mRS = 0-2), and the occurrence of symptomatic intracerebral hemorrhage. Sensitivity analysis was performed on two age groups (≤80 versus >80). We ran logistic regression adjusting for confounders to evaluate independent effect of small vessel disease on outcomes. There were 820 patients with available brain computer tomography with mean age (±SD) of 71.3 (±13.2), 455 (55.5%) were male. Of these, 123 (15%) patients had severe small vessel disease at baseline. Age group analysis revealed significant associations of small vessel disease only in patients aged ≤80. After adjustment for confounders, presence of severe small vessel disease reduced the chances of both excellent (OR = 0.42, 95% CI = 0.24-0.74) and good outcome (OR = 0.35, 95% CI = 0.21-0.58) and with an increased risk of symptomatic intracerebral hemorrhage (OR = 5.91; 95% CI = 2.40-14.57). When considered together as radiological expressions of small vessel disease, presence and severity of severe leukoaraiosis and lacunes on baseline computer tomography scan are associated with poor clinical outcomes in patients treated with i.v. thrombolysis.

Post-mortem assessment of hypoperfusion of cerebral cortex in Alzheimer's disease and vascular dementia.

Perfusion is reduced in the cerebral neocortex in Alzheimer's disease. We have explored some of the mechanisms, by measurement of perfusion-sensitive and disease-related proteins in post-mortem tissue from Alzheimer's disease, vascular dementia and age-matched control brains. To distinguish physiological from pathological reduction in perfusion (i.e. reduction exceeding the decline in metabolic demand), we measured the concentration of vascular endothelial growth factor (VEGF), a protein induced under conditions of tissue hypoxia through the actions of hypoxia-inducible factors, and the myelin associated glycoprotein to proteolipid protein 1 (MAG:PLP1) ratio, which declines in chronically hypoperfused brain tissue. To evaluate possible mechanisms of hypoperfusion, we also measured the levels of amyloid-β40, amyloid-β42, von Willebrand factor (VWF; a measure of microvascular density) and the potent vasoconstrictor endothelin 1 (EDN1); we assayed the activity of angiotensin I converting enzyme (ACE), which catalyses the production of another potent vasoconstrictor, angiotensin II; and we scored the severity of arteriolosclerotic small vessel disease and cerebral amyloid angiopathy, and determined the Braak tangle stage. VEGF was markedly increased in frontal and parahippocampal cortex in Alzheimer's disease but only slightly and not significantly in vascular dementia. In frontal cortex the MAG:PLP1 ratio was significantly reduced in Alzheimer's disease and even more so in vascular dementia. VEGF but not MAG:PLP1 increased with Alzheimer's disease severity, as measured by Braak tangle stage, and correlated with amyloid-β42 and amyloid-β42: amyloid-β40 but not amyloid-β40. Although MAG:PLP1 tended to be lowest in cortex from patients with severe small vessel disease or cerebral amyloid angiopathy, neither VEGF nor MAG:PLP1 correlated significantly with the severity of structural vascular pathology (small vessel disease, cerebral amyloid angiopathy or VWF). However, MAG:PLP1 showed a significant negative correlation with the level of EDN1, which we previously showed to be elevated in the cerebral cortex Alzheimer's disease. These finding are in contrast with the previously demonstrated reduction in EDN1, and positive correlation with MAG:PLP1, in the hypoperfused white matter in Alzheimer's disease. The decline in MAG:PLP1 strongly suggests pathological hypoperfusion of the frontal cortex in Alzheimer's disease. Although severe small vessel disease or cerebral amyloid angiopathy may contribute in some cases, abnormal vascular contractility mediated by EDN1 is likely to be a more important overall contributor. Both amyloid-β accumulation and hypoperfusion are likely to cause the upregulation of VEGF.

Frontotemporal lobar degeneration FTLD-tau: preclinical lesions, vascular, and Alzheimer-related co-pathologies

Frontotemporal lobar degeneration with τ pathology (FTLD-tau) is one of a group of neurodegenerative diseases that manifests with cognitive decline. Alzheimer (AD) and cerebrovascular lesions are commonly noted in the brains of most elderly individuals, begging the question as to whether (a) coexisting AD and vascular pathology or age contribute to the development of FTLD-tau disorders and vice versa and (b) FTLD-tau-like pathology can be found in non-diseased individuals. We studied brains of FTLD-tau cases exhibiting (a) argyrophilc grain disease (AGD), (b) progressive supranuclear palsy (PSP), (c) corticobasal degeneration (CBD), or (d) Pick's disease (PiD) for coexisting AD and vascular pathology for comparison with that of non-diseased individuals and AD patients. We confirmed that AGD lowered the threshold for AD pathology to cause dementia. Such an effect was not seen in PSP, CBD, or PiD. In PiD, white matter degeneration and demyelination was observed in the frontal and temporal lobes in association with small vessel disease (SVD)-related changes in white matter arteries. Age at death varied among the four types of FTLD-tau. PiD cases were youngest at death followed by CBD, PSP, and finally AGD. In 9.8% of non-diseased controls, we found grains, coiled bodies, and/or τ-positive astrocytes mimicking an AGD-like pattern. Moreover, the prevalence of FTLD-tau pathology in non-diseased individuals increased with age. In summary, this study demonstrates that age impacts of the diversity of neuropathological changes in FTLD-tau. The age-related coexistence of AD-related pathology is, thereby, associated with AGD but not with PSP, CBD, and PiD. Moreover, severe SVD and white matter demyelination is associated with PiD indicating a role of vascular copathology in this type of FTLD-tau. Finally, our finding that FTLD-tau-related pathological lesions occur in non-diseased individuals suggests that preclinical stages of FTLD-tau exist. As such, our results indicate that age, together with vascular and AD-related copathology, contributes to the morphological appearance of FTLD-tau.

Examination of the Clinicopathologic Continuum of Alzheimer Disease in the Autopsy Cohort of the National Alzheimer Coordinating Center

To test the hypothesis that Alzheimer disease (AD) is a clinical and pathologic continuum between normal aging and end-stage dementia, we selected a convenience sample of subjects from the National Alzheimer Coordinating Center 2005 to 2012 autopsy cohort (n = 2,083) with the last clinical evaluation within 2 years before autopsy and no other primary neuropathologic diagnosis. Demographic and neuropathologic characteristics were correlated with the Clinical Dementia Rating-Sum of Boxes in the 835 subjects meeting these criteria. Both neuritic plaques and neurofibrillary tangles independently predicted Clinical Dementia Rating-Sum of Boxes. Severe small-vessel disease, severe amyloid angiopathy, and hippocampal sclerosis were also independently associated with the degree of cognitive impairment. By contrast, education was a strong independent protective factor against cognitive deficits. The cause of mild to moderate dementia remained uncertain in 14% of the patients. Inverse probability weighting suggests the generalizability of these results to nonautopsied cohorts. These data indicate that plaques and tangles independently contribute to cognitive impairment, that concurrent vascular disease strongly correlates with cognitive dysfunction even in a sample selected to represent the AD pathologic continuum, and that education further modifies clinical expression. Thus, multiple concomitant etiologies of brain damage and premorbid characteristics contribute to the uncertainty of AD clinicopathologic correlations based only on tangles and plaques.

Circulating Markers of Endothelial Dysfunction and Platelet Activation in Patients with Severe Symptomatic Cerebral Small Vessel Disease

Background: Small deep infarcts (SDI), also called lacunar infarcts, resulting from the occlusion of deep branch arteries, account for 25% of ischemic strokes. The physiopathology of the disease remains largely unknown. However, evidence about the role of endothelial dysfunction has emerged. Whereas chronic platelet activation is of major importance in acute thrombosis of large atherosclerotic arteries, its role in SDI remains unclear. Frequently associated risk factors are hypertension and diabetes mellitus. The aim of this study was to determine platelet and endothelial activation in patients with recent SDI in comparison to population-based control subjects matched for age, sex and vascular risk factors. Methods: Platelet activation markers (activated glycoprotein IIb/IIIa, P-selectin and platelet microparticles), shear-induced platelet aggregation (SIPA) studied in the SIPAgreg device at 4,000 s^-1, endothelial activation markers [including von Willebrand factor (vWF) antigen and homocysteine] and high-sensitivity C-reactive protein (hsCRP) were measured in 74 consecutive patients with recent SDI, in whom detectable large artery atherosclerosis or cardiac embolism had been ruled out. Blood samples were collected 1 and 3 months after symptom onset. These factors were also measured in 74 population-based controls with no stroke history and matched for age, sex, hypertension and diabetes. Results: One month after symptom onset, the patients had similar levels of platelet activation to matched controls (p > 0.40 for all comparisons). In contrast, endothelial activation parameters were increased in patients in comparison to controls (vWF: p = 0.002 and homocysteinemia/creatinemia: p = 0.025). The level of hsCRP was slightly increased in patients compared to controls (p = 0.059). At 3 months, we observed a significant decrease in vWF and hsCRP levels in patients (median change in vWF = 10%, p = 0.004; median change in hsCRP = 0.4 mg/l, p = 0.02). Homocysteine levels and all platelet parameters remained unchanged at this time compared to at 1 month. Conclusions: Our results confirm that chronic platelet activation, when compared to controls matched for age, sex and vascular risk factors, did not seem to play a central role in the pathophysiology of lacunar stroke. In contrast, we found markers of endothelial dysfunction, the role of which in the occurrence of lacunar infarction has still to be clarified in further studies.

Abstract TP298: Acute Intracerebral Hemorrhage: Prospective Evaluation ofaA Pragmatic Stepwise Diagnostic Algorithm for Underlying Vascular Pathologies

BACKGROUND: Intracerebral hemorrhage (ICH) is one of the deadliest form of stroke, but the diagnostic work-up has only been insufficiently defined. We tested the unsefulness of a pragmatic step-wise diagnostic algorithm including CT/CTA, MRI/MRA, and digital subtraction angiography (DSA) on the detection of acutely treatment-relevant underlying pathologies. PATIENTS AND METHODS: We analyzed 114 consecutive patients (42% women, mean age 66 years +/-12) hospitalized for spontaneous ICH. All patients had initial CT with or without CTA. Those without evident underlying cause and no contraindication underwent MRI/MRA. Finally, diagnostic DSA was performed in cases without evident ICH etiology on prior imaging. RESULTS: Of the 114 ICH patients, 2 showed deep ICH with CT evidence of severe small vessel disease. In 2 cases, CTA revealed cerebral venous thrombosis. The remaining 107 (95%) patients without contraindication (n=2 had a pacemaker) underwent subsequent MRI/MRA allowing detection of underlying small vessel disease in 36 (32%) and 14 (12%) with acutely treatment relevant pathology: one cerebral venous thrombosis, six secondary hemorrhagic infarcts, three cavernous malformations, two brain tumors, and two patients had reversible acute vasoconstriction syndrome. Fifty-seven patients (50%) remained without diagnosis of any underlying pathology and underwent DSA revealing 2 dural arteriovenous fistula, 2 arteriovenous malformation, 1 moyamoya syndrome, 1 ruptured aneurysm, and 1 acute cerebral vasoconstriction syndrome. CONCLUSION: Our findings suggest the diagnostic sensitivity of brain CT alone is insufficient for the diagnostic work-up in ICH patients. A pragmatic, stepwise imaging algorithm based on additional CTA, MRI/MRA and DSA lead to the diagnosis of an underlying pathology in 52%, including the detection of acutely treatment-relevant pathologies in 19% (22 of 114 patients).

Statins and Cerebral Hemodynamics

HMG-CoA reductase inhibitors (statins) are associated with improved stroke outcome. This observation has been attributed in part to the palliative effect of statins on cerebral hemodynamics and cerebral autoregulation (CA), which are mediated mainly through the upregulation of endothelium nitric oxide synthase (eNOS). Several animal studies indicate that statin pretreatment enhances cerebral blood flow after ischemic stroke, although this finding is not further supported in clinical settings. Cerebral vasomotor reactivity, however, is significantly improved after long-term statin administration in most patients with severe small vessel disease, aneurysmal subarachnoid hemorrhage, or impaired baseline CA.

Cerebral White Matter Lesions and Lacunar Infarcts Contribute to the Presence of Mild Parkinsonian Signs

Mild parkinsonian signs (MPS) are common in elderly people and may be an early stage of parkinson(ism). They might be related to cerebral small-vessel disease, although this association remains incompletely understood. To identify subjects at early stages of the disease, we investigated whether the presence of MPS was dependent on the severity and location of small-vessel disease, including white matter lesions and lacunar infarcts. Four hundred thirty individuals, with small-vessel disease, aged between 50 and 85 years, without dementia or parkinsonism, were included in this analysis and underwent MRI scanning. The number and location of lacunar infarcts were rated. White matter lesion volume was assessed by manual segmentation with automated delineating of different regions. Presence of MPS was based on the motor section of the Unified Parkinson's Disease Rating Scale. Associations were determined using logistic regression analysis adjusted for age, sex, and total brain volume. Severe white matter lesions and the presence of lacunar infarcts were independently associated with the presence of MPS (OR, 2.6; 95% CI, 1.3-4.9 and OR, 1.8; 95% CI, 1.0-3.0). Frontal and parietal white matter lesions and, to a lesser extent, lacunar infarcts in the thalamus were associated with a higher risk of MPS. The presence of lacunar infarcts was independently related to the bradykinesia category of parkinsonian signs. This study shows that severe small-vessel disease, especially at certain locations, is associated with MPS signs in older adults. Our findings suggest that small-vessel disease interrupts basal ganglia-thalamocortical circuits involving both the frontal and parietal lobes and hence may result in MPS.

Ongoing Microinfarction in Patients with Intracerebral Hemorrhage (S23.002)

Objective: To determine whether cerebral microinfarcts (CMI) occur beyond the acute post-hemorrhage time window in patients with intracerebral hemorrhage (ICH). Background Clinically silent CMIs have been observed with high incidence on diffusion weighted imaging (DWI) of patients with primary ICH. Most CMIs have been detected shortly after acute hemorrhage, raising the question of whether CMIs are solely a byproduct of the acute ICH or rather are an ongoing process occurring throughout the course of severe small vessel disease. Design/Methods: We retrospectively analyzed 476 MRI scans obtained in the acute (≤7 days after ICH) or nonacute (>14 days after ICH) phases from 117 subjects with deep and 293 with lobar ICH (53% males, mean age 72.1±13.3 years). DWI, apparent diffusion coefficient maps, FLAIR and T2* MRIs were reviewed for the presence of CMIs. Results: One or more CMIs were identified in 24 (12.5%) of 192 subjects in the nonacute phase and 43 (19.7%) of 218 subjects in the acute post-ICH phase (risk ratio for CMIs on acute vs nonacute scans 1.58, 95%CI 0.99-2.5, p=0.06). Separate analyses of lobar and deep ICH yielded similar risk ratios for CMIs on acute vs nonacute images (RR= 1.46, 95%CI 0.86-2.5, p=0.2 for lobar ICH, RR= 1.94, 95%CI 0.76-4.98, p=0.21 for deep). In paired analysis of 66 subjects with both acute and nonacute MRIs, CMIs were present on 8 acute and 9 nonacute scans (RR= 0.98, 95%CI 0.71-1.36, p=1). The overall proportion of subjects with incident CMIs was 16% for lobar and 17% for deep ICH patients (p=0.77). Conclusions: Incident CMIs appear to occur commonly throughout the course of primary ICH. Although the data suggest these lesions may be more common in the acute post-ICH phase, CMIs are also frequent nonacutely, suggesting they might contribute to small vessel-related cognitive impairment. Disclosure: Dr. Auriel has nothing to disclose. Dr. Gurol has nothing to disclose. Dr. Ayres has nothing to disclose. Dr. Schwab has nothing to disclose. Dr. Vashkevich has nothing to disclose. Dr. Rosand has nothing to disclose. Dr. Viswanathan has received personal compensation for activities with Athena Diagnostics. Dr. Greenberg has received personal compensation for activities with Hoffman-Laroche Ltd. as a committee member.

Multiple subcortical acute ischemic lesions reflect small vessel disease rather than cardiogenic embolism

Multiple acute ischemic lesions in different hemispheres or vascular territories are mainly considered to be of proximal embolic origin. However, despite careful diagnostic work-up, the etiological classification often stays undetermined. We propose that multiple acute ischemic lesions can sometimes be a phenomenon observed in small vessel disease (SVD). From a prospectively collected database of more than 7,000 stroke patients, 173 patients with acute bihemispheric infarction were identified. We analyzed those subjects with multiple small (< 15 mm Ø) subcortical acute ischemic lesions on diffusion-weighted MRI (DWI) and concomitant severe small vessel disease (Fazekas grades II-III) without a proximal embolic source as evaluated by cardiological investigations. Twenty patients (mean age 66 ± 12 years, 12 men) with a mean number of 2.95 ± 1.24 acute lesions on DWI (range of 2-7 lesions per patient) were identified (n = 5 Fazekas II°, n = 15 Fazekas III°). Most of the lesions were located in typical areas of lacunar infarction. The mean NIHSS score on admission was 2.95 ± 2.0 (range 0-8). Multiple acute ischemic lesions in different vascular territories might not always be of proximal cardiovascular embolic origin. Simultaneous small subcortical ischemic lesions may reflect remote ischemia due to small vessel disease reflecting simultaneous hemorheological dysfunction.

Cortical plasticity is preserved in nondemented older individuals with severe ischemic small vessel disease

Ischemic small vessel disease (SVD) is a common finding on routine scans in older people, but cognitive sequelae vary considerably. To improve understanding of mechanisms underlying decline or preservation of cognitive function in this condition, we assessed cognition and cortical plasticity in 20 elderly subjects with severe SVD and 20 age-matched controls without SVD, as rated on conventional MRI. Cognitive status was determined with a neuropsychological test battery, cortical plasticity induced with a paired associative stimulation protocol. Microstructural white matter changes were further analyzed for fractional anisotrophy using diffusion tensor imaging. We found that cortical plasticity as well as memory functions were preserved in severe SVD, while executive functions showed trendwise or significant decreases. Within the SVD group, lower white matter integrity in parahippocampal regions and posterior parts of the corpus callosum was associated with larger cortical plasticity, an association not seen for prefrontal white matter tracts. Enhanced cortical plasticity in subjects with lower white matter integrity in memory-relevant areas might thus indicate a compensatory mechanism to counteract memory decline in severe SVD.

Abstract 3280: Cystatin C, a Novel Indicator of Kidney Function, Reflects Severity of Cerebral Small Vessel Disease

Background: Recent studies reported that lacunar infarction, white mater lesions (WMLs) and microbleeds (MBs) might be associated with kidney disease. Cystatin C is, competitive inhibitors of lysosomal cysteine protease, suggested to be a more accurate and sensitive indicator of kidney function, compared to creatinine, creatinine based estimated glomerular filtration rate (GFR). We investigated whether Cystatin C might reflect the severity of cerebral small disease. Methods: Data prospectively collected on subjects with ischemic stroke or transient ischemic attack to a university medical center was analyzed between January 2008 and May 2011. The severity of WMLs was rated using visual rating scale: normal, no lesion or single one, moderate, multiple focal lesion, extensive, multiple confluent lesion scattered throughout white mater. That of MBs was graded according to the number of MB: normal, absence of MB, mild, 1-4, moderate, 5-9, severe, ≥10. GFR were classified to four categories based on the chronic kidney disease criteria. Multivariable ordinal logistic regression analysis, adjusted confounders-age, gender, hypertension, diabetes, hyperlipidemia, smoking, history of stroke, heart disease and total cholesterol, was performed to determine the association between Cystatin C and severity of small vessel disease. Results: A total of 699 subjects were enrolled in this study. Subjects with more severe small vessel disease were likely to be older, have hypertension and history of stroke. The proportion of higher grade of WMLs and MBs was increased according to quartiles of Cystatin C. Compared to lowest quartiles(&lt;47.2 nmol/L), higher Cystatin C quartiles (47.2 -54.7, 54.7-65.7, 65.7≥nmol/L) were likely to have more severe WML grades. [Adjusted OR (95%CI), 1.38(0.93, 2.04), 2.67( 1.81, 3.95), 3.32(2.23, 4.93)]. In addition, higher Cystatin C quartiles tended to have more severe MB grades [adjusted OR (95%CI), 0.98(0.61, 1.51), 1.57(1.00, 2.44), 2.19(1.40, 3.40)]. Compared to the lowest categories of estimated GFR (≥60 ml/min/1.73m2), higher categories of estimated GFR(45.0- 60.0, 15.0-45.0, ≤15.0 ml/min/1.73m2) did not show significant association with the grades of small vessel disease. Conclusion: Vascular beds of brain and kidney had similar characteristics. Patients with impaired kidney function would have also cerebral small vessel disease. Cystatin C is more accurate indicator of kidney function to detect subclinical kidney disease. In this present study, Serum Cystatin C reflects severity of cerebral small vessel disease, independent of estimated GFR.

Chronic Small Vessel Disease Affects Clinical Outcome in Patients with Acute Striatocapsular Stroke

Background: Recovery from stroke is presumed to be a function of a cerebral network. Chronic small vessel disease (SVD) has been shown to disrupt this network’s integrity and has been proposed as a predictor of poor outcome after stroke. We studied this hypothesis in patients with acute ischemic stroke of the striatocapsular region, an area of pronounced cortical and subcortical connectivity. Methods: We identified 62 patients with isolated striatocapsular stroke from our stroke registry. The standardized workup included clinical rating according to the modified Rankin Scale (mRS) and MRI, rated according to the Fazekas scale for the extent of SVD, ranging from grade 0 to III. MRS at admission, at discharge, and a short-term recovery parameter (the difference between mRS at admission and discharge) were correlated with the extent of SVD. Comorbidity was assessed with the Charlson comorbidity index (CCI). Results: SVD was graded 0 in 7%, I in 60%, II in 18%, and III in 16% of patients. The median mRS at discharge for the groups was 2, 1, 2 and 4, and the median recovery parameter was 2, 1, 1 and 0.5, respectively. The extent of SVD significantly correlated with both the mRS at discharge and the recovery parameter. While age was also a significant predictor of these outcome parameters, SVD severity was a significant predictor even after correction for age or CCI. Conclusions: SVD is a predictor of poor outcome and recovery in striatocapsular stroke, independent of age or comorbidity. Severe SVD disturbs the integrity of the cerebral network leading to aggravation of and poor recovery from neurological deficits.

Enhanced Rapid-Onset Cortical Plasticity in CADASIL as a Possible Mechanism of Preserved Cognition

Ischemic small vessel disease (SVD) may lead to cognitive impairment, but cognitive deficits with a given burden of SVD vary significantly. The underlying mechanisms of impaired or preserved cognition are unknown. Here, we investigated the impact of ischemic SVD on rapid-onset cortical plasticity, as induced with a paired-associative stimulation protocol. To exclude concomitant effects of aging, we examined 12 middle-aged patients (48.3 ± 8.3 years) with cerebral autosomal dominant arteriopathy with subcortical infarctions and leucoencephalopathy (CADASIL) who suffered from severe ischemic SVD and a group of 12 age-matched controls (49.9 ± 8.3 years). Cognitive status, motor performance and learning, and motor cortex excitability in response to cathodal transcranial direct current stimulation (ctDCS) were assessed. White matter integrity was analyzed by conventional magnetic resonance imaging and diffusion tensor imaging. We found that cognitive and motor functions were largely preserved in CADASIL patients, while rapid-onset cortical plasticity was significantly higher in the CADASIL group compared with controls (repeated measures analysis of variance [group × time] interaction: P = 0.03). This finding was even more pronounced in patients with higher white matter lesion load. ctDCS revealed no evidence of cortical dysplasticity. We conclude that increased rapid-onset cortical plasticity may contribute to largely preserved cognitive and motor function despite extensive ischemic SVD.

Cerebral Microbleeds Are Uncommon in Ischemic Stroke Associated with Nonvalvular Atrial Fibrillation

Patients with cardioembolic ischemic stroke from nonvalvular atrial fibrillation (NVAF) are candidates for long-term anticoagulation. This study examines the prevalence of cerebral microbleeds (MBs) in stroke patients with NVAF. A total of 132 consecutive ischemic stroke patients with NVAF admitted to our Stroke Unit were recruited if complete magnetic resonance (MR) imaging studies including T2* imaging had been performed within less than 72 hours. National Institutes of Health Stroke Scale scores were documented and cerebrovascular risk factors were monitored. Among 132 patients (mean age 74.1±9.8 years), only 9 (6.8%) had MBs (mean number 6.2) as detected on T2* MR images. No statistically significant differences between patients without versus with MBs were observed regarding arterial hypertension, diabetes, hyperlipidemia, and coronary heart disease. However, small vessel disease (SVD) was significantly more frequent in patients with MBs than without MBs (44.4% vs. 12.2%; P<.05) and significantly more patients with MBs experienced repeated strokes (44.4% vs. 14.6%; P<.05). In contrast to studies reflecting a high incidence of MBs in stroke patients of various subtypes, MBs occurred less frequently in patients with cardioembolic acute ischemic stroke associated with NVAF. In patients with severe SVD or repeated cerebrovascular events, special caution should be taken regarding oral anticoagulation.

A Critical Review of Aspirin in the Secondary Prevention of Noncardioembolic Ischaemic Stroke

Both secondary prevention (such as lifestyle modifications, pharmacotherapy or surgery) and an understanding of the influence of risk factors (including the different aetiologic mechanisms of cerebral ischaemia) play a pivotal role in reducing the burden of recurrent stroke. Regarding the types of preventative treatments available, variations exist across all clinical studies, including differences in target populations (including the type of cerebral ischaemia), risk factors, length of follow-up, drop-out rates and outcomes, which makes translating the results of clinical trials to individual patients difficult. However, with such limitations in mind, this critical albeit nonsystematic review, which compared aspirin with other antiplatelets and in combination with other drugs, showed that the benefit from aspirin treatment is consistently shown in ischaemic stroke, while harms are limited. Furthermore, no definite superiority is apparent across different antiplatelet therapies. Dual antiplatelet regimens may expose to a slight but measurable higher risk of haemorrhagic complications, perhaps in selective groups of patients (i.e. those with severe small-vessel disease or in selective racial groups). Based on our analysis, the indication of aspirin as the first-line choice, also recommended by several acknowledged international or national guidelines, may be confirmed. However, the complex nature of patients at risk of recurrent ischaemic stroke necessitates a comprehensive approach, which should be driven by the primary care physician, whose role is central to successful actions for secondary stroke prevention.

Neuroimaging predictors for depressive symptoms in cerebral small vessel disease

Although cerebral small vessel disease (SVD) is closely associated with late life depression, patients with even severe SVD may have no depressive symptoms. We postulate that concurrent brain atrophy may also involve in the pathogenesis of depressive symptoms in SVD. We aimed to investigate the relevance of brain atrophy in predicting depressive symptoms among patients with severe SVD. We recruited 45 lacunar stroke patients who had diffuse white matter lesion (WML) and varying severity levels of depressive symptoms. We used a quantitative hybrid warping method to determine the volume of 99 brain regions for each patient. We assessed severity of depressive symptoms using the depression score of the hospital anxiety and depression scale (HADS-D). We first performed correlation analysis of each brain variable with the depression score. Significant variables were then entered separately into linear regression analysis to explore predictors of HADS-D, with adjustment of relevant clinical variables. The mean age (SD) of the 45 participants was 74.6 (8.3) years. The mean HADS-D score was 3.5, with score ranging from 0 to 15. Variables that had a significant correlation coefficient with HADS-D were gender, hypertension, Oxford handicap scale, left inferior frontal gyrus, right subthalamic nucleus, left posterior limb of internal capsule, and right cerebellum. Regression analyses showed that only left inferior frontal gyrus atrophy (β = -0.354, p = 0.017) predicted HADS-D score after adjusted for other relevant clinical variables. Concurrent atrophy of left inferior frontal gyrus is associated with depressive symptoms in elderly patients with severe SVD.

Rapid appearance of new cerebral microbleeds after acute ischemic stroke

It is unknown whether the development of cerebral microbleeds (MBs), small areas of signal loss on T2*-weighted gradient-echo imaging (GRE), follows a slow or a rapid process. We hypothesized that MBs may develop rapidly after certain critical events, such as strokes, and investigated the frequency, location, and factors associated with the formation of new MBs after acute ischemic stroke. We retrospectively examined 237 consecutive acute ischemic stroke patients who underwent MRI within 24 hours and follow-up MRI during the week after symptom onset. We defined new MBs as MBs that newly appeared on follow-up GRE outside the infarcted area. We examined the association of new MBs with demographics, risk factors, laboratory data, baseline MBs, and small vessel disease (SVD; leukoaraiosis and lacunar infarctions). Seventy-five patients (31.6%) had baseline MBs, and 30 (12.7%) developed new MBs. Multiple logistic regression analysis indicated that the presence of baseline MBs (odds ratio [OR] 5.72, 95% confidence interval [CI] 2.12-15.42, p = 0.001) and severe SVD (OR 2.94, 95% CI 1.12-7.77, p = 0.03) independently predicted the development of new MBs. Of the 56 new MBs, 29 (51.8%) appeared in the lobar location, 17 (30.4%) appeared in the deep location, and 10 (17.9%) appeared in the infratentorial location. This study suggests that new microbleeds (MBs) can develop rapidly after acute ischemic stroke. Baseline MBs and severe small vessel disease are predictors for the development of new MBs. Further studies will be needed to investigate the clinical implications and mechanisms of these findings.