Ischemic White Matter Disease Research Articles

Abstract TMP27: Par1 Mediates Protective Effect of 3K3K-APC After White Matter Stroke in Mice

3K3A-APC is a recombinant variant of activated protein C (APC) with > 90% reduced anticoagulant activity but preserved cell signaling activity. Benefical effects are mediated by its antiapoptotic direct neuronal protective and vasculoprotective effects including protection of blood-brain barrier (BBB) integrity as well as anti-inflammatiory activity as shown in multiple animal models of large ischemic stroke (middle cerebral artery occlusion) and neurodegeneration. These preclinical studies led to a successfully completed phase II clinical trial of 3K3A-APC for ischemic stroke (RHAPSODY). RHAPSODY trial showed that 3K3A-APC is safe and may reduce hemorrhage in patients that were treated with tPA and/or thrombectomy standard of care therapy for stroke. Even though the protective effects of 3K3A-APC are well known to be mediated by biased signaling via protease activated receptor 1 (PAR1) activation, the role of PAR1 has not been studied in ischemic white matter stroke. In the present study, we used a mouse model of white matter stroke induced by injecting a vasoconstrictor N 5 -(1-Iminoethyl)-L-ornithine (L-NIO) into the corpus callosum. Our results suggest that 4 hrs post-treatment with 3K3A-APC (0.2 mg/kg) reduced lesion volumes by about ~67% (cresyl violet staining and T2w MRI), which was associated with reduced BBB leakage (fibrinogen staining and DCE-MRI), and improved function of oligodendrocytes (OLS, Olig2+CNPase+) and oligodendrocyte precursor cell (OPCs, Olig2+PDGFRα+) at 1 and 7 days after stroke. Beneficial effects of 3K3A-APC were associated with reduced axonal damage on diffusion tensor MRI, and improved behavioral performance on adhesive removal and grid walking tests. We next showed that PAR1 is expressed in all major cell types in the white matter (e.g., OLS, OPCs, microglia and astrocytes) and that silencing PAR1 with small interfering RNA (siRNA) abolishes the protective effect of 3K3A-APC in this model. Taken together, our data suggest that 3K3A-APC is protective in ischemic white matter disease via PAR1 mediated signaling, which improves oligovascular integrity and neuronal survival.

Do Cerebral Small Vessel Disease and Multiple Sclerosis Share Common Mechanisms of White Matter Injury?

Background and Purpose- The role of inflammation in ischemic white matter disease is increasingly recognized, and further understanding of the pathophysiology might inform future treatment strategies. Multiple sclerosis (MS) is a chronic autoimmune condition in which inflammation plays a central role that also affects the white matter. We hypothesized that white matter injury might share common mechanisms and used statistical genetics techniques to assess whether having genetically elevated white matter hyperintensity (WMH) volume was associated with increased MS risk. Methods- We investigated the genetic association in 2 cohorts with magnetic resonance imaging-quantified ischemic white matter lesion volume (WMH in stroke; n=2797 and UK Biobank; n=8353) and 14 802 cases of MS and 26 703 controls from the International Multiple Sclerosis Genetics Consortium. We further performed individual-level polygenic risk score calculations for MS and measures of structural white matter disease in UK Biobank. Finally, we looked for evidence of overlapping risk across the whole genome. Results- There was no association of genetic variants influencing MS with WMH volume using summary statistics in the WMH in stroke cohort (relative risk score =1.014; 95% CI, 0.936-1.110) or in the UK Biobank cohort (relative risk score =1.030; 95% CI, 0.932-1.117). Conversely, assessing the contribution of single nucleotide polymorphisms significantly associated with WMH on the risk of MS there was no significant association (relative risk score =0.930; 95% CI, 0.736-1.191). There were no significant associations between polygenic risk scores calculations; these results were robust to the selection of single nucleotide polymorphisms at a range of significance thresholds. Whole genome analysis did not reveal any overlap of risk between the traits. Conclusions- Our results do not provide evidence to suggest a shared mechanism of white matter damage in ischemia and MS. We propose that inflammation acts in distinct pathways because of the differing nature of the primary insult.

Abstract TP567: Identification of Il-17/Cxcl5 as a Novel Regulator of Endothelial-Oligodendrocyte Signaling in Ischemic White Matter Disease

Introduction: Cardiovascular risk factors including obesity accelerate the rate of ischemic white matter lesions through unknown mechanisms. Disruption of the normal signaling between endothelial cells and oligodendrocytes may drive the acceleration of white matter lesions. Here, we performed gain and loss of function studies of the IL-17/CXCL5 signaling cascade in white matter endothelia and determined the effect on oligodendrocytes. Methods: Obesity-induced activation of IL-17 receptor b was blocked using function-blocking anti-IL-17B antibodies injected systemically q3d for 6 weeks. Over-expression of CXCL5 in white matter endothelia was achieved using FLEX lentiviral administration in Tie2-Cre:tdTomato transgenic mice. Endothelial CXCL5 levels, oligodendrocyte number, and maturation were determined using 3D confocal microscopy. Focal white matter ischemic stroke was induced using stereotactic injection of the irreversible eNOS inhibitor L-Nio. Results: IL-17Rb and CXCL5 levels are significantly increased at RNA and protein levels in white matter endothelial cells in obese mice. Endothelial expression of CXCL5 is further increased after focal white matter stroke. Administration of function-blocking anti-IL-17B antibodies to high fat diet mice reduced the level of endothelial CXCL5 by 60.4% without changing endothelial IL-17Rb levels. The total number and mean distance of vessel-associated oligodendrocyte precursor cells (OPCs) was not different in control vs. anti-IL-17B treated animals. In normal weight Tie2-Cre:tdTomato mice, forced over-expression of CXCL5 resulted in an increased number of vessel-associated OPCs compared to control. In obese mice, stroke-responsive OPCs are increased 37% at 7d after focal white matter stroke and remyelination of focal white matter lesions at 28d is impaired. Conclusions: Chronic cardiovascular risk factors such as obesity promote changes in white matter endothelia including activation of IL-17/CXCL5 signaling. Up-regulation of CXCL5 in white matter endothelia attracts OPCs to vessels and exaggerates the injury response to focal white matter stroke. Endothelial-oligodendrocyte signaling may provide novel therapeutic targets for ischemic white matter disease.

Astrocytic connexin 43 potentiates myelin injury in ischemic white matter disease.

Rational: Myelin loss is a characteristic feature of both ischemic white matter disease and its associated vascular dementia, and is a hallmark of chronic cerebral hypoperfusion due to carotid artery stenosis. Yet the cellular mechanisms involved in ischemic dysmyelination are not well-understood, and no effective treatment has emerged to prevent or slow hypoperfusion-related demyelination. In a study employing the bilateral common carotid artery stenosis (BCAS) mouse model, we found reduced cerebral blood flow velocity and arteriolar pulsatility, and confirmed that prolonged BCAS provoked myelin disruption. These pathological features were associated with marked cognitive decline, in the absence of evident damage to axons.Methods: To assess the role of astroglial communication in BCAS-associated demyelination, we investigated the effect of deleting or inhibiting connexin 43 (Cx43), a constituent of astroglial gap junctions and hemichannels.Results: Genetic deletion and pharmacological inhibition of gap junctions both protected myelin integrity and rescued cognitive decline in the BCAS-treated mice. Gap junction inhibition also suppressed the transient increase in extracellular glutamate observed in the callosal white matter of wild-type mice exposed to BCAS.Conclusion: These findings suggest that astrocytic Cx43 may be a viable target for attenuating the demyelination and cognitive decline associated with chronic cerebral hypoperfusion.

Toll-like Receptor 2: A Novel Therapeutic Target for Ischemic White Matter Injury and Oligodendrocyte Death.

Despite paramount clinical significance of white matter stroke, there is a paucity of researches on the pathomechanism of ischemic white matter damage and accompanying oligodendrocyte (OL) death. Therefore, a large gap exists between clinical needs and laboratory researches in this disease entity. Recent works have started to elucidate cellular and molecular basis of white matter injury under ischemic stress. In this paper, we briefly introduce white matter stroke from a clinical point of view and review pathophysiology of ischemic white matter injury characterized by OL death and demyelination. We present a series of evidence that Toll-like receptor 2 (TLR2), one of the membranous pattern recognition receptors, plays a cell-autonomous protective role in ischemic OL death and ensuing demyelination. Moreover, we also discuss our recent findings that its endogenous ligand, high-mobility group box 1 (HMGB1), is released from dying OLs and exerts autocrine trophic effects on OLs and myelin sheath under ischemic condition. We propose that modulation of TLR2 and its endogenous ligand HMGB1 can be a novel therapeutic target for ischemic white matter disease.

No evidence for increased brain iron deposition in patients with ischemic white matter disease

Besides specific iron accumulation in some neurodegenerative disorders, increased iron deposition in cerebral deep gray matter (DGM) is found in multiple sclerosis. As this is considered largely a white matter (WM) disease, we speculated that patients with more severe ischemic WM hyperintensities (WMH) might also have an increased iron concentration in DGM structures and tested this assumption by using magnetic resonance imaging–based quantitative R2* relaxometry. WMH severity was measured in 61 patients with acute transient neurological symptoms (mean age: 71.5 ± 8.3 years) undergoing 3-Tesla magnetic resonance imaging. Despite a 6-year higher age of patients with more severe (i.e., early confluent or confluent) WMH, their DGM R2* rates did not differ from patients with punctate or no WMH. In the globus pallidum, R2* rates were even lower in patients with severe WMH. WMH volume was not correlated with R2* levels in any of the analyzed DGM structures. These findings argue against WM damage per se causing increased DGM iron deposition in multiple sclerosis and suggest no role of iron accumulation in ischemic small vessel disease.

Extreme Deep White Matter Hyperintensity Volumes Are Associated with African American Race

Background: African Americans (AAs) have a higher prevalence of extreme ischemic white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) than do European Americans (EAs) based on the Cardiovascular Health Study (CHS) score. Ischemic white matter disease, limited to the deep white matter, may be biologically distinct from disease in other regions and may reflect a previously observed trend toward an increased risk of subcortical lacunar infarcts in AAs. We hypothesized that extreme deep WMH volume (DWMV) or periventricular volume (PV) may also have a higher prevalence in AAs. Thus, we studied extreme CHS scores and extreme DWMV and PV in a healthy population enriched for cardiovascular disease risk factors. Methods: We imaged the brains of 593 subjects who were first-degree relatives of probands with early onset coronary disease prior to 60 years of age. WMHs were manually delineated on 3-tesla cranial MRI by a trained radiology reader; the location and volume of lesions were characterized using automated software. DWMV and PV were measured directly with automated software, and the CHS score was determined by a neuroradiologist. Volumes were characterized as being in the upper 25% versus lower 75% of total lesion volume. Volumes in the upper versus the remaining quartiles were examined for AA versus EA race using multiple logistic regression (generalized estimating equations adjusted for family relatedness) and adjusted for major vascular disease risk factors including age ≥55 years versus <55, sex, current smoking, obesity, hypertension, diabetes and low-density lipoprotein >160 mg/dl. Results: Participants were 58% women and 37% AAs, with a mean age of 51.5 ± 11.0 years (range, 29-74 years). AAs had significantly higher odds of having extreme DWMVs (odds ratio, OR, 1.8; 95% confidence interval, CI, 1.2-2.9; p = 0.0076) independently of age, sex, hypertension and all other risk factors. AAs also had significantly higher odds of having extreme CHS scores ≥3 (OR, 1.3; 95% CI, 1.1-3.6; p = 0.025). Extreme PV was not significantly associated with AA race (OR, 1.3; 95% CI, 0.81-2.1; p = 0.26). Conclusions: AAs from families with early-onset cardiovascular disease are more likely to have extreme DWMVs (a subclinical form of cerebrovascular disease) and an extreme CHS score, but not extreme PV, independently of age and other cardiovascular disease risk factors. These findings suggest that this AA population is at an increased risk for DWMV and may be at an increased risk for future subcortical stroke. Longitudinal studies are required to see if DWMV is predictive of symptomatic subcortical strokes in this population.

Abstract 43: Increased Activation of Inflammatory Genes in Monocytes of Healthy People with Ischemic White Matter Disease

Introduction: White matter hyperintensities (WMH) on MRI represent small vessel ischemic cerebrovascular disease. Greater WMH burden is associated with higher levels of circulating inflammatory cytokines in persons &gt; 65 years with dementia, suggesting a pro-inflammatory vascular process. We hypothesized that middle-aged, asymptomatic, apparently healthy high risk people with high WMH burden would demonstrate increased inflammatory gene expression in monocytes analyzed with microarray. Methods: Subjects (N=70) were identified from a larger MRI study in 593 healthy family members of persons with early-onset CAD (&lt; 60 years). We obtained monocytes and examined gene expression in all subjects (mean age 58.1 ± 10 years, range 30-73; 55% female; 36% African American). These included 35 subjects with the greatest WMH burden using volumetric methods in the larger study, and 35 unrelated age-sex-race matched controls with the lowest WMH burden. Monocyte mRNA was analyzed on Illumina Human HT12 v4 microarrays. We performed unsupervised principal component analysis (PCA) followed by ANOVA between high and low WMH groups. Genes with 2 SD differences in expression between groups were included for Gene Ontology permutation analysis using 1000 permutations within “GoMiner”. Only genes with the lowest false discovery rate (FDR) were summarized. Results: PCA identified no significant clustering. A total of 1,315 genes were included in gene ontology analysis and resulted in 10 ontological categories with an FDR&lt;0.01%. This included 164 genes all showing greater expression in the high WMH group. These were key inflammatory genes, such as tumor necrosis factor (TNF), interleukin-6 (IL-6), interleukin-8 (IL-8), toll like receptor 5 and 7 (TLR5, TLR7) and integrin alpha 5 and M (ITGA5, ITGAM). Conclusions: Gene microarray ontological analysis of monocytes in healthy middle aged high risk people with greater WMH burden shows increased activation of genes of known innate inflammatory pathways. These findings likely reflect greater pro-inflammatory processes in persons with greater WMH, consistent with the presence of inflammation-mediated occult small vessel cerebrovascular disease in a healthy middle-aged population at increased risk for vascular diseases.

Vascular Cognitive Impairment and Dementia Expenditures: 7–Year Inpatient Cost Description in Community Dwellers

Background: Vascular cognitive impairment (VCI) and vascular dementia (VaD) are prevalent conditions with a growing impact on health care expenses. Few studies have addressed expenditures on cognitive vascular disease. We quantify the expenses of tertiary–care inpatients with VCI and VaD and provide the first report on the specific cost of care in community–dwelling patients with small– and large–vessel ischemic cognitive disease. Methods: This is a cost–description study of inpatient expenditures from the Spanish National Health Institute and regional government perspectives. We retrospectively analyzed the expenses in a prospective cohort of 122 community dwellers with VCI who developed small–vessel disease with ischemic white matter disease (Binswanger's disease) (n = 60), lacunar state (n = 26), or large–vessel disease (n = 36). Admissions with a primary or secondary diagnosis of transient ischemic attack or stroke, cognitive impairment or dementia, and other diagnoses related to cerebrovascular disease were assessed. Results: The average cost per patient was $33 740. The costs per VCI admission were similar across groups (∼$9545). The average number of admissions increased during the progression of the disease (VCI, 1.2; VaD, 2.5) and contributed to higher expenses per patient during the VaD stage (∼$22 631) compared with the VCI stage (∼$11 110). Half of patients (n = 61; 50%) progressed without isch–emic events during the VCI stage. These patients incurred lower per–patient costs during the VCI stage ($9750 vs $12 464), and costs increased during the post–VaD diagnosis stage ($28 528 vs $16 734). Conclusion: Large– and small–vessel cerebrovascular diseases are common and costly conditions. Vascular cognitive impairment presenting with stroke may incur greater expenses than VCI onset without stroke. Thus, patients with large–vessel disease incurred higher costs during the VCI stage. Care became more onerous at an advanced VaD stage in all groups. During the VaD stage, the expenditures of patients with Binswanger's disease were significantly higher and eventually counterbalanced the initially lower costs seen during the VCI stage.

Retinal vasoreactivity as a marker for chronic ischemic white matter disease?

The cerebral microvasculature cannot be easily studied non-invasively. Because the retina and brain share embryological, anatomical and physiological similarities, studies of retinal blood vessels may prove to be useful as a surrogate marker for cerebrovascular disease. In epidemiological studies abnormal retinal arteriovenous ratios (AVRs) predict the risk of stroke and vascular dementia. However, the association between retinal vasoreactivity, cerebral small vessel ischemic disease, and cerebral blood vessel function remains unknown. Study GoalsTo examine (1) the association between cerebral ischemic white matter disease (WMD) and retinal microvessel behavior and (2) the relationship between retinal blood vessel reactivity and measures of cerebrovascular function. MethodsCohort study of 12 patients with ischemic WMD and 14 healthy controls. Retinal vasoreactivity was measured following high frequency flicker light stimulation. Middle cerebral artery (MCA) vasoreactivity was measured using transcranial Doppler ultrasound (TCD). Magnetic resonance imaging scans (MRIs) were reviewed for evidence of ischemic WMD. ResultsPatients with ischemic WMD had attenuated retinal venous (2.2%±0.27 SD, vs. controls 6%±0.7 SD, p=0.002, CI 95%) and arterial (1.9%±0.8 SD, vs. controls 4.9%±0.8 SD, p=0.004, CI 95%) vasoreactivity compared to controls. An attenuated retinal venous light flicker response was associated with a significant decrease of MCA vasoreactivity (r=0.45, p=0.05, CI 95%). Decreased AVRs, an indicator for altered retinal vessel architecture in patients with cerebral chronic ischemic WMD, were also significantly correlated with dysfunction of cerebral vasoreactivity (r=0.69, p=0.001, CI 95%). ConclusionIn this study functional and structural impairment of the retinal microvasculature were associated with ischemic WMD and measures of cerebral vascular function. Microvascular dysfunction in the eye may predict cerebral small vessel disease, but validation by larger studies is needed.

Cerebrovascular Diseases Complicating Ventriculoperitoneal Shunt Response in Secondary Normal Pressure Hydrocephalus (P07.191)

Objective: To describe outcomes in two patients with cerebrovascular disease and secondary normal pressure hydrocephalus (NPH) with poor response to ventriculoperitoneal shunting (VPS). Background The prediction of VPS response in secondary NPH remains challenging, given its complex etiologies and comorbidities. Cerebrovascular disease (CVD) is a common comorbidity in NPH, and previous CVD insults may contribute to the development of secondary NPH, making it an important consideration in patient selection and outcome of VPS in secondary NPH. Design/Methods: We report the pre-operative and post-operative clinical features, surgical, neuroimaging, and ancillary testing data in two such cases, with videotaped exam in the second case. Results: Patient #1, a 79-year- old woman with known basilar tip aneurysm and pituitary macroadenoma, developed progressive gait disturbance/ataxia, cognitive decline, and urinary and fecal incontinence in the setting of moderate ventriculomegaly and transependymal CSF migration on brain MRI. Right-sided occipital VPS provided minimal improvement and post-operative imaging demonstrate enlarging basilar tip aneurysm with mild midbrain compression. Clinically, three months after VPS, she developed mild features of akinetic mutism. Patient #2, an 81- year- old woman with recent history of a right-sided subdural hematoma and evacuation, who upon recovery developed fluctuating cognition with mildly decreased interactiveness and gait dysfunction, was found to have significant ventriculomegaly and moderate ischemic white matter disease on head CT. After a robust response in gait speed to a large volume lumbar puncture, a right pre-coronal VPS was placed, with only temporary benefits. After shunt malfunctions were revised twice, benefits could not be recaptured, and she developed significant akinetic mutism. Conclusions: Decisions to place a VPS in secondary NPH in the setting of CVD, large artery aneurysms, and after subdural hematomas are challenging and may prove to be negative predictive factors to shunt response. Disclosure: Dr. Rao-Frisch has nothing to disclose. Dr. Shams has nothing to disclose. Dr. Smyth has nothing to disclose. Dr. Lerner has nothing to disclose.

Abstract 2891: Severity of Amyloid Deposition is Associated with Ischemic White Matter Disease in Cerebral Amyloid Angiopathy but Not in Healthy Elderly: a PET/MRI Correlative Study

Background and Purpose: Cerebral Amyloid Angiopathy (CAA), characterized by accumulation of amyloid beta proteins in the walls of cortical/leptomeningeal vessels, is increasingly recognized as a cause of ischemic brain injury in addition to its classical role in lobar cerebral hemorrhages (ICH). Pittsburgh Compound B (PiB) is a PET ligand that has been shown to label the vascular amyloid deposits of CAA, allowing invivo quantification of the severity of CAA pathology. We hypothesized that there would be a dose-dependent relationship between vascular amyloid burden (measured by PiB) and brain ischemia (measured by extent of MRI markers of chronic ischemia) in patients diagnosed with CAA but not in healthy elderly without evidence of advanced CAA. Methods: Thirty-five non-demented patients (9 women) with a diagnosis of CAA according to Boston Criteria and 50 healthy elderly subjects (29 women) without lobar microhemorrhages or history of stroke/dementia who underwent a brain MRI scan and PiB-PET imaging were analyzed. Global cortical PiB retention was calculated using cerebellar cortex as the reference tissue input function and expressed as the distribution volume ratio (DVR). Quantitative analysis of white matter T2-hyperintensity (WMH) volume on MRI FLAIR sequences was performed using computer-assisted techniques. Presence of lacunar infarcts was also recorded in each subject. Multivariate linear regression was used to assess the association between PiB retention and WMH volume while controlling for other vascular risk factors within each group. Results: CAA patients were younger than healthy elderly (67±10 vs 73±7, p=0.004) but had higher amounts of WMH (19ml IQR:6.7-31.8 vs 3.2ml IQR:2-5.6, p&lt;0.001) and mean global DVR (1.34±0.19 vs 1.17±0.13, p&lt;0.001). In bivariate analyses, global DVR and WMH showed a strong correlation (Spearman's rho=0.52, p&lt;0.001) in the CAA cohort. This association did not substantially change in a multivariate model that included age, gender, and vascular risk factors as covariates. Global DVR and WMH were not correlated (Spearman's rho=0.01, p=0.95) in the healthy elderly group. Nine CAA patients (26%) had a lacunar infarction on imaging against only 1 healthy control (2%), p=0.001. CAA patients with lacunes had higher mean DVR (p=0.03), but this association did not remain independent after adjustment for age. Conclusions: Our results indicate that global PiB retention independently correlates with volume of white matter disease on FLAIR in patients with CAA but not in healthy elderly. These findings support the idea that vascular amyloid burden directly contributes to chronic cerebral ischemia in the CAA population and highlights the possible utility of amyloid imaging as a marker of CAA severity.

Abstract 17265: The Relationship Between Subclinical Coronary Artery Atheroscelrosis and Brain Ischemic White Matter Disease in Healthy Individuals from High Risk Families

Background: Ischemic white matter disease (IWMD) is associated with incident stroke. Similarly subclinical coronary artery disease is associated with incident coronary artery disease (CAD) events. Although, atherogenesis in both vascular beds likely shares common mechanisms, the extent to which subclinical CAD is associated with preclinical IWMD in a young to middle-aged healthy asymptomatic high risk population with a family history of premature CAD remains unknown. Methods: We screened 405 apparently healthy participants in Genetic Study of Atherosclerotic Risk (GeneSTAR) (mean age 51.6 ± 10.6 years, 60% female, 36% African American) for CAD risk factors, and for the presence of calcified and noncalcified coronary plaque using dual-source 256 multi-detector cardiac CT angiography. The presence of IWMD was assessed by 3 Tesla brain MRI and the ischemic white-matter volume to brain volume (WVBV) ratio was calculated using direct measurements. A multivariate linear regression analysis predicting WVBV was performed for the presence of CAD, adjusting for age, sex, race, traditional CAD risk factors, and intrafamilial correlations using a generalized estimating equation (GEE). Results: Subclinical CAD was highly prevalent (43.0%). Individuals with coronary plaque had a higher ratio of WVBV (median 0.11, interquartile range [0.04 to 0.33]) as compared to those without coronary plaque (median 0.05 [0.01 to 0.14], p&lt;0.001). In the fully adjusted analysis, the presence of subclinical CAD was a significant predictor of WVBV (p=0.05), as was age (p&lt;0.001). Conclusion: This is the first study to show a strong association of subclinical CAD and occult ischemic white mater disease in healthy high-risk young to middle aged individuals, independent of traditional CAD risk factors, including age. The findings support the premise of shared causal pathways in the two vascular beds in families at increased risk for both CAD and stroke.

Genetic susceptibility to ischemic stroke

Clinicians who treat patients with stroke need to be aware of several single-gene disorders that have ischemic stroke as a major feature, including sickle cell disease, Fabry disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and retinal vasculopathy with cerebral leukodystrophy. The reported genome-wide association studies of ischemic stroke and several related phenotypes (for example, ischemic white matter disease) have shown that no single common genetic variant imparts major risk. Larger studies with samples numbering in the thousands are ongoing to identify common variants with smaller effects on risk. Pharmacogenomic studies have uncovered genetic determinants of response to warfarin, statins and clopidogrel. Despite increasing knowledge of stroke genetics, incorporating this new knowledge into clinical practice remains a challenge. The goals of this article are to review common single-gene disorders relevant to ischemic stroke, summarize the status of candidate gene and genome-wide studies aimed at discovering genetic stroke risk factors, and to briefly discuss pharmacogenomics related to stroke treatment.

Clinical characteristics in subcortical ischemic white matter disease

Vascular white matter lesions (WML) represent one of the main neuroimage findings in individuals older than 65 years and its clinical significance is still partially understood. To describe and analyze the clinical profile of a high severity sample with WML focusing on the frontal executive control. Outpatients (n=20) with high severity WML evaluated with magnetic resonance imaging were selected using the Fazekas scale. Most patients (n=17; 85%) presented an altered Trail Making Test ratio (section B/section A); on verbal fluency, 15 individuals (75%) performed below the cutoff score. Apathy (5.9 +/- 4.65) and depression (3.05+/-3.67) were frequent as assessed by the Neuropsychiatric Inventory. The impairment in functional activities strongly correlated with apathy (r=0.814, p<0.001) and verbal fluency (r=0.744, p<0.001). Executive dysfunction, apathy, and ratio depression were the main characteristics found. Extension of WML may have distinct impact on the clinical picture, but further studies with methodological adjustments are necessary to provide more definitive conclusions.

Understanding White Matter Disease

Most strokes are covert and observed incidentally on brain scans, but their presence increases risk of overt stroke and dementia. Amyloid angiopathy, associated with Alzheimer Disease (AD) causes stroke, and when even small strokes coexist with AD, they lower the threshold for dementia. Diffuse ischemic white matter disease impairs executive functioning, information processing speed, and gait. Neuroimaging techniques, such as tissue segmentation, Diffusion Tensor Imaging, MR Spectroscopy, functional MRI and amyloid PET, probe microstructural integrity, molecular biology, and activation patterns, providing new insights into brain-behavior relationships. MR-pathological studies of periventricular hyperintensity (leukoaraiosis) in aging and dementia reveal arteriolar tortuosity, reduced vessel density, and occlusive venous collagenosis which causes venous insufficiency and vasogenic edema. Activated microglia, oligodendroglial apoptosis, clasmatodendritic astrocytosis, and upregulated hypoxia-markers are seen on immunohistochemistry. Further research is needed to understand and treat this chronic subcortical vascular disease, which is epidemic in our aging population.

Chronic ischemic cerebral white matter disease is a risk factor for nonfocal neurologic injury after total aortic arch replacement

Leukoaraiosis (chronic ischemic white matter changes) on preoperative brain magnetic resonance imaging is common in patients having aortic arch surgery. This study sought to determine whether it is associated with adverse neurologic outcome in the postoperative period. Data were collected from a retrospective chart review of 142 patients in whom total aortic arch replacement was planned at the Cleveland Clinic between April 2000 and December 2004. All patients had preoperative brain magnetic resonance imaging evaluation. Leukoaraiosis severity was rated semiquantitatively using the Schelten's scale. Postoperative neurologic injuries were investigated by clinical examination and appropriate neuroimaging. They were stratified as type 1 (focal ischemic stroke) and type 2 (nonfocal neurocognitive changes, generalized seizures) injuries. The following were independent predictors of type 1 neurologic injury: age (odds ratio 1.06 [1.01-1.13], P = .02) and moderate to severe aortic atheroma (odds ratio 4.4 [1.4-9.7], P = .012). Total white matter scores (odds ratio 1.16 [1.06-1.27], P = .002) and higher preoperative hemoglobin A1c levels (odds ratio 1.8 [1.00-3.50], P = .05) were significantly associated with type 2 neurologic injuries. Survival was 96%, and 4.2% had persistent focal neurologic deficits at the time of hospital discharge. Leukoaraiosis is a significant independent predictor of nonfocal postoperative neurologic morbidity following aortic arch replacement surgery. Preoperative evaluation with magnetic resonance imaging allows identification of a patient subgroup at risk and implementation of strategies aimed at improving neurologic outcome.

Locus ceruleus degeneration is ubiquitous in Alzheimer’s disease: Possible implications for diagnosis and treatment

Degeneration of the locus ceruleus (LC) and decreased cortical levels of norepinephrine are common findings in Alzheimer's disease (AD), but their significance is unknown. Because the noradrenergic system is accessible to pharmacological intervention, the role of LC degeneration and noradrenergic dysfunction in the pathogenesis and clinical manifestations of AD needs clarification. Hypothetically, loss of noradrenergic innervation could cause microvascular dysfunction and manifest as ischemia. The objectives of this study were to develop a scale for assessment of LC degeneration and to determine whether degeneration of the LC correlates quantitatively with either duration of clinical dementia, overall severity of AD pathology or with measures of ischemic non-focal white matter disease (WMD) in AD. This report is a pathological follow-up of a clinical longitudinal dementia study of 66 consecutive cases of AD without admixture of vascular dementia (VaD) from the Lund Longitudinal Dementia Study, neuropathologically diagnosed between 1990 and 1999. Ten cases of VaD were included for comparative purposes. No correlation between degree of LC degeneration and duration of dementia, AD or WMD severity was found. LC degeneration was significantly more severe in the AD group than in the VaD group. Even though LC degeneration was not associated with WMD or the severity of AD pathology in this AD material, we suggest that clinical studies on the consequences of noradrenergic dysfunction are warranted. Treatment augmenting noradrenergic signaling is available and safe. The marked difference in the level of LC degeneration between AD and VaD cases suggests that LC degeneration could be used as a diagnostic marker of AD.

Positional Nystagmus of Central Origin

Audiometric, electrophysiologic, and radiographic findings for a 68-year-old male with an "imbalance" concern are presented. This paper has a two-fold purpose: (1) to present an unusual electronystagmography case study and (2) to highlight the importance of test conditions in lesion localization. The specific disease pathophysiology remains obscure. Repeated hearing tests documented a known hearing impairment with worsening word-recognition ability of the right ear. An initial electronystagmographic exam was normal except for a mild ageotropic direction-changing positional nystagmus with eyes open and fixed. No repeatable click-evoked auditory brainstem response waveforms could be collected. A magnetic resonance imaging of the brain documents diffuse ischemic white matter disease. A repeated vestibular examination some months later supports the initial findings. The case illustrates the importance of following diagnostic protocol, of repeated measures, and of using both a visual fixation and a nonfixation condition for select electronystagmographic subtests.

Lakunäre Infarkte

Lacunar infarcts, small deep infarcts resulting from occlusion of a penetrating artery, account for about a quarter of all ischemic strokes. The view of lacunar infarcts as a benign and rather innocent vascular lesion has been modified during the last years. Although the prognosis is more favourable than other subtypes during the first years, probably due to the small lesion size, in a longer perspective there is an excess risk of death, continual occurrence of recurrent stroke, and development of cognitive dysfunction. The risk of recurrent stroke is similar to most other types of stroke, and patients are at increased risk to develop cognitive decline and dementia. Increasing age, vascular risk factors, and high nocturnal blood pressure have significant prognostic implications for almost all outcomes. Lacunar infarcts and ischemic white-matter disease, the two main types of cerebral small-vessel disease, frequently co-exist and have synergistic effects on prognosis and risk of cognitive decline. Antiplatelet therapy and risk factor modification are the cornerstones in secondary prevention after a lacunar infarct.