White Matter Vessels Research Articles

T lymphocytes and cytotoxic astrocyte blebs correlate across autism brains.

Autism spectrum disorder (ASD) affects 1 in 59 children, yet except for rare genetic causes, the etiology in most ASD remains unknown. In the ASD brain, inflammatory cytokine and transcript profiling shows increased expression of genes encoding mediators of the innate immune response. We evaluated postmortem brain tissue for adaptive immune cells and immune cell-mediated cytotoxic damage that could drive this innate immune response in the ASD brain. Standard neuropathology diagnostic methods including histology and immunohistochemistry were extended with automated image segmentation to quantify identified pathologic features in the postmortem brains. We report multifocal perivascular lymphocytic cuffs contain increased numbers of lymphocytes in ~65% of ASD compared to control brains in males and females, across all ages, in most brain regions, and in white and gray matter, and leptomeninges. CD3+ T lymphocytes predominate over CD20+ B lymphocytes and CD8+ over CD4+ T lymphocytes in ASD brains. Importantly, the perivascular cuff lymphocyte numbers correlate to the quantity of astrocyte-derived round membranous blebs. Membranous blebs form as a cytotoxic reaction to lymphocyte attack. Consistent with multifocal immune cell-mediated injury at perivascular cerebrospinal fluid (CSF)-brain barriers, a subset of white matter vessels have increased perivascular space (with jagged contours) and collagen in ASD compared to control brains. CSF-brain barrier pathology is also evident at cerebral cortex pial and ventricular ependymal surfaces in ASD. The findings suggest dysregulated cellular immunity damages astrocytes at foci along the CSF-brain barrier in ASD. ANN NEUROL 2019;86:885-898.

Dependence of resting-state fMRI fluctuation amplitudes on cerebral cortical orientation relative to the direction of B0 and anatomical axes

Functional magnetic resonance imaging (fMRI) is now capable of sub-millimetre scale measurements over the entire human brain, however with such high resolutions each voxel is influenced by the local fine-scale details of the cerebral cortical vascular anatomy. The cortical vasculature is structured with the pial vessels lying tangentially along the grey matter surface, intracortical diving arterioles and ascending venules running perpendicularly to the surface, and a randomly oriented capillary network within the parenchyma. It is well-known that the amplitude of the blood-oxygenation level dependent (BOLD) signal emanating from a vessel depends on its orientation relative to the B0-field. Thus the vascular geometric hierarchy will impart an orientation dependence to the BOLD signal amplitudes and amplitude differences due to orientation differences constitute a bias for interpreting neuronal activity. Here, we demonstrate a clear effect of cortical orientation to B0 in the resting-state BOLD-fMRI amplitude (quantified as the coefficient of temporal signal variation) for 1.1 mm isotropic data at 7T and 2 mm isotropic at 3T. The maximum bias, i.e. the fluctuation amplitude difference between regions where cortex is perpendicular to vs. parallel to B0, is about +70% at the pial surface at 7T and +11% at 3T. The B0 orientation bias declines with cortical depth, becomes progressively smaller closer to the white matter surface, but then increases again to a local maximum within the white matter just beneath the cortical grey matter, suggesting a distinct tangential network of white matter vessels that also generate a BOLD orientation effect. We further found significant (negative) biases with the cortex orientation to the anterior-posterior anatomical axis of the head: a maximum negative bias of about −30% at the pial surface at 7T and about −13% at 3T. The amount of signal variance explained by the low frequency drift, motion and the respiratory cycle also showed a cortical orientation dependence; only the cardiac cycle induced signal variance was independent of cortical orientation, suggesting that the cardiac induced component of the image time-series fluctuations is not related to a significant change in susceptibility. Although these orientation effects represent a signal bias, and are likely to be a nuisance in high-resolution analyses, they may help characterize the vascular influences on candidate fMRI acquisitions and, thereby, may be exploited to improve the neuronal specificity of fMRI.

Abstract WP88: Relationship Between Small Vessel Ischemic White Matter Disease and Collateral Recruitment in Patients With Acute Embolic Ischemic Stroke

Introduction: White matter hyperintensities (WMH) is the most prominent neuroimaging feature of small vessel disease (SVD). SVD is thought to be a result of arteriolosclerosis, chronic hypoperfusion of white matter, selective oligodendrocyte death and degeneration of myelinated fibers. The risk of ischemic stroke is significantly increased with the presence of WMH. The presence of intracranial collaterals is a strong predictor of salvageable neurological function in acute stroke; however, the factors affecting the ability to recruit collaterals are poorly understood. We wanted to study if the presence and severity of small vessel white matter disease had an adverse effect on cerebral collateral flow in acute embolic large vessel stroke. Methods: We identified a consecutive series of adult subjects with acute embolic large vessel strokes confirmed on CT angiography (CTA) from a 10-year institutional database. Patients without a brain MRI within six months of CTA were excluded. Collateral scores of the affected hemisphere were calculated on CTA using the modified Tan scale (0-4) by two independent trained reviewers and confirmed by a neuroradiologist. The WMH was quantified using the Fazekas scale (0-3) incorporating both deep and periventricular components. Areas of restricted diffusion on brain MRI in the peri-stroke period were eliminated from the assessment of Fazekas score. Spearman’s correlation tests were performed for the association between collateral scores and WMH. Results: A total of 234 patients (mean age 70±14 years, 47% [110/234] women) satisfied the inclusion criteria. The prevalence of periventricular and deep WMH was 83% and 87% respectively. Aging had a significant impact on periventricular WMH (r=0.48, p <0.001) and deep WMH (r=0.47, p <0.001). However, collateral scores exhibited no statistically significant relationship with the presence or severity of periventricular scores (r=0.08, p=0.17) or deep WMH scores (r=0.01, p=0.77). Conclusions: Our results indicate that the presence of SVD does not affect cerebral collateral flow. The vascular niche and risk factors of SVD appear to be distinct from that of intracranial vessels responsible for collateral reperfusion of ischemic territory in acute large vessel embolic stroke.

Use of Laser in Arteriovenous Malformation Surgery.

Arteriovenous malformation surgery is particularly demanding owing to the need to control bleeding of small, deep white matter vessels during and after removal of the nidus; this is probably one of the most critical moments of arteriovenous malformation surgery. The aim of this article is to describe a useful technique based on the use of tweezers to temporarily stop the blood flow followed by coagulation with the thulium laser. Surgery was performed in 20 patients with unruptured cerebral arteriovenous malformations. In each case, the superficial feeder vessels were easily coagulated with nonstick bipolar tips. The finer and deeper feeder vessels were coagulated with use of tweezers and thulium laser. All patients were treated successfully. Optimal intraoperative hemostasis was achieved. Results were good with no postoperative complications. Our results could encourage a more standardized use of the described technique.

Structure of the Medullary Veins of the Cerebral Hemisphere and Related Disorders.

Deep medullary veins drain into subependymal veins with four convergence zones and show parallel distribution patterns adjacent to the body or inferior horn and a radial pattern in the frontal horn or trigon of the lateral ventricle. As white matter imaging develops such as diffusion tensor imaging or susceptibility-weighted imaging, requirements for understanding of white matter structures are increasing, not only for understanding of neuronal tracts but also for that of other structures including the fine anatomy of white matter vessels. Some disorders are related to deep medullary veins and show characteristic distributions of the lesions indicating the relationship to the medullary veins. When lesions show a parallel or radial distribution pattern in the certebral deep white matter, disorders related to deep medullary veins should be considered for differential diagnosis. In this review, we discuss disorders related to deep medullary veins, including (a) anomalies of the medullary veins, (b) hemorrhagic disorders related to the medullary veins (diffuse vascular injury due to high-energy trauma, deep medullary vein engorgement/thrombosis in neonates), (c) inflammatory changes that spread along the medullary veins, (d) neoplasms within the medullary veins, and (e) metabolic changes that lead to altered visualization of medullary veins. Understanding the anatomic structure of medullary veins in the cerebral hemisphere and becoming familiar with disorders in which the medullary veins play a major role in disease development may be helpful in the interpretation of brain images. ©RSNA, 2017.

Abstract WP260: The Dramatic Alteration of Microvascular Complexity and Endothelial Cell Gene Expression in Mice With Metabolic Syndrome

Introduction: Obesity is a leading public health problem in the US. More than one-third of adult are obese. It is closely related to development of the metabolic syndrome, which produces various vascular risk factors, including hyperglycemia, hyperlipidemia, hypertension and low high-density lipoprotein. All these factors increase the risk of developing chronic vascular diseases, particularly cerebral vascular disease. Studies show that patients with metabolic syndrome have a six-fold increase in the risk of developing microvascular infarcts in the brain, which predominantly injure white matter leading to dementia, disability and even death. Hypothesis: The purpose of this study is to assess the effects of metabolic syndrome on cerebral microvasculature and unveil the molecular mechanisms that regulate these changes. Methods: Transgenic mice (Tie2-Cre:flox-stop tdtomato plus flox-RiboTAG) were fed with 60%kCal from fat diet to induce metabolic syndrome for 12 weeks at 2 months age and 10%kCal from fat diet was used as control. The volume of cerebral vasculature in white matter was evaluated by reporter gene expression in endothelial cells of Tie2-Cre:flox-stop tdtomato mice. Transcriptomes from cerebral endothelial cells were isolated using Ribotag ribosomal immunoprecipitation technology (Tie2-Cre:flox-RiboTAG). Following ribosomal associated transcriptome isolation, RNA-seq was performed. Results: Metabolic syndrome results in a significant decrease in white matter vascular volume in both large (30±2.2%, P< 0.04) and micro vessel (23±3.7%, P<0.01). Transcriptional profiling of white matter endothelial cells reveal a difference of expression profile between normal mice and mice with metabolic syndrome. The significant changes in endothelial cell gene expression are associated with the decreased volume of vessels in white matter with metabolic syndrome through changes in angiogenic receptor ligands. Conclusion: Metabolic syndrome decreases the volumes of large and micro vessels in white matter and significantly changes endothelial cell gene expression. These findings help to develop molecular therapeutic approaches for patients with metabolic syndrome to prevent cerebral microvascular complications including stroke.

Feasibility and potential role of ferumoxytol-enhanced neuroimaging in HIV-associated neurocognitive disorder

We assessed ferumoxytol-enhanced brain MRI to identify monocyte/macrophage accumulation in HIV-associated neurocognitive disorder (HAND). Four HIV-infected subjects with undetectable HIV RNA levels on antiretroviral therapy, HIV DNA level in CD14+ cells ≥10 copies/10(6) cells, and cognitive impairment underwent ferumoxytol-enhanced brain MRI. On post-ferumoxytol susceptibility-weighted images, all HIV-infected subjects demonstrated a diffuse "tram track" appearance in the perivascular regions of cortical and deep white matter vessels suggesting ferumoxytol uptake in monocytes/macrophages. This finding was not present in an HIV-seronegative control. While ferumoxytol may have potential as an imaging biomarker for monocyte/macrophage accumulation in patients with HAND, future study is needed.

Glial Vascular Degeneration in CADASIL

CADASIL is a genetic vascular dementia caused by mutations in the Notch 3 gene on Chromosome 19. However, little is known about the mechanisms of vascular degeneration. We characterized upstream components of Notch signaling pathways that may be disrupted in CADASIL, by measuring expression of insulin, IGF-1, and IGF-2 receptors, Notch 1, Notch 3, and aspartyl-(asparaginyl)-β-hydroxylase (AAH) in cortex and white matter from 3 CADASIL and 6 control brains. We assessed CADASIL-associated cell loss by measuring mRNA corresponding to neurons, oligodendroglia, and astrocytes, and indices of vascular degeneration by measuring smooth muscle actin (SMA) and endothelin-1 expression in isolated vessels. Immunohistochemical staining was used to assess SMA degeneration. Significant abnormalities, including reduced cerebral white matter mRNA levels of Notch 1, Notch 3, AAH, SMA, IGF receptors, myelin-associated glycoproteins, and glial fibrillary acidic protein, and reduced vascular expression of SMA, IGF receptors, Notch 1, and Notch 3 were detected in CADASIL-lesioned brains. In addition, we found CADASIL-associated reductions in SMA, and increases in ubiquitin immunoreactivity in the media of white matter and meningeal vessels. No abnormalities in gene expression or immunoreactivity were observed in CADASIL cerebral cortex. In conclusion, molecular abnormalities in CADASIL are largely restricted to white matter and white matter vessels, corresponding to the distribution of neuropathological lesions. These preliminary findings suggest that CADASIL is mediated by both glial and vascular degeneration with reduced expression of IGF receptors and AAH, which regulate Notch expression and function.

３Ｔ‐ＭＲＩによるｓｔｒｏｋｅ ＭＲＩの有用性と問題点

We report usefulness of 3 tesla MRI and new ischemic findings on gradient echo-type T2*-weighted images (T2*-WI) in patients with acute ischemic stroke We defined two ischemic findings regarding the vessels (cortical vessel enlargement sign; hypointensity of the cortical vessels and brush sign; hypointensity of the deep white matter vessels) and a decreased intensity in the ischemic parenchyma (tissue ischemic sign) on the T2*-WI. These ischemic findings were compared with the hypoperfused area detected by the FAIR images and the ROI comparison between the hypoperfusion on the FAIR imaging and the “tissue ischemic sign” on the T2*-WI was conducted by calculating the asymmetry ratios. This cortical vessel enlargement sign was seen in all patients with ICA or MCA occlusion. The area of the vessel ischemic signs was almost the same or less than the hypoperfused area shown by the PWI images. In patients who showed tissue ischemic sign, the ROI measurement demonstrated more hypoperfusion by PWI than in the sign (-) group. 3T MRI is therefore useful to evaluate ischemic conditions in acute stroke patients.

Breakdown of the blood–brain barrier to proteins in white matter of the developing brain following systemic inflammation

Compromised blood-brain barrier permeability resulting from systemic inflammation has been implicated as a possible cause of brain damage in fetuses and newborns and may underlie white matter damage later in life. Rats at postnatal day (P) 0, P8 and P20 and opossums (Monodelphis domestica) at P15, P20, P35, P50 and P60 and adults of both species were injected intraperitoneally with 0.2-10 mg/kg body weight of 055:B5 lipopolysaccharide. An acute-phase response occurred in all animals. A change in the permeability of the blood-brain barrier to plasma proteins during a restricted period of postnatal development in both species was determined immunocytochemically by the presence of proteins surrounding cerebral blood vessels and in brain parenchyma. Blood vessels in white matter, but not grey matter, became transiently permeable to proteins between 10 and 24 h after lipopolysaccharide injection in P0 and P8 rats and P35-P60 opossums. Brains of Monodelphis younger than P35, rats older than P20 and adults of both species were not affected. Permeability of the blood-cerebrospinal fluid (CSF) barrier to proteins was not affected by systemic inflammation for at least 48 h after intraperitoneal injection of lipopolysaccharide. These results show that there is a restricted period in brain development when the blood-brain barrier, but not the blood-CSF barrier, to proteins is susceptible to systemic inflammation; this does not appear to be attributable to barrier "immaturity" but to its stage of development and only occurs in white matter.

Perivascular clustering in temporal lobe epilepsy: oligodendroglial cells of unknown function

Marked perivascular clustering (PC), i.e., groups and rows of small round cells along white matter vessels, is seen in temporal lobe epilepsy (TLE) specimens obtained by surgery. This study focuses on the constituting cell types and discusses clinical significance and pathogenesis of PC, which are so far unknown. Based on a series of 59 nonlesional TLE surgical specimens, we characterized PC by immunohistochemistry and correlated the amount of PC with clinical parameters. PC cells were variably positive for galactocerebroside, myelin basic protein and S-100 protein, while glial fibrillary acidic protein, vimentin, nestin and neuronal antigens were not expressed. There was no correlation between the amount of PC and any clinical feature, including age at surgery, age at epilepsy onset, duration of epilepsy, preoperative seizure frequency, childhood febrile convulsions, family history of epilepsy, and postsurgical outcome. Our findings suggest oligodendroglial differentiation of PC, while its primary (dysplastic) versus secondary (reactive) pathogenesis remains unresolved.

P3-181 Decreasing numbers of small white matter vessels parallelled increasing severity of white matter disease in Alzheimer's disease

P3-181 Decreasing numbers of small white matter vessels parallelled increasing severity of white matter disease in Alzheimer's disease

Role of aberrant nitric oxide synthase-3 expression in cerebrovascular degeneration and vascular-mediated injury in Alzheimer's disease.

Nitric oxide (NO) is an important signaling molecule that is generated through the catalytic activity of nitric oxide synthase (NOS). In the brain, NO mediates neuronal survival, synaptic plasticity, vascular smooth muscle relaxation, and endothelial cell permeability. Previous studies demonstrated aberrant expression of the NOS-III gene in neurons and glial cells in brains with Alzheimer's disease (AD). Since NOS-III is also expressed in vascular cells, and cerebrovascular disease (CVD) frequently complicates the pathology of AD, we investigated the role of NOS-III in relation to CVD in AD. Vasculopathy in AD + CVD was characterized by thickening and hyalinization of the media of small and medium-size vessels, variable degrees of beta-amyloid (A beta) deposition, and increased apoptosis of vascular smooth muscle and endothelial cells, particularly involving white matter vessels. These abnormalities were correlated with reduced levels of NOS-III expression in cerebral vessels. Double-labeling studies demonstrated that the low levels of cerebrovascular NOS-III were associated with increased levels of the pro-apoptosis gene product, p53 in smooth muscle and endothelial cells, suggesting a role for altered NOS-III expression in AD-associated vascular degeneration. Constitutively reduced cerebrovascular NOS-III expression and NO production could also lead to cerebral hypoperfusion due to impaired vasodilation responses, and diminished capacity to remove respiratory waste products and toxins from the extracellular space due to reduced capillary permeability. The role for phosphodiesterases as modulators of NOS activity is discussed, as these molecules represent potential therapeutic targets given their cell type and cyclic nucleotide specificities of action.

Could Wallerian degeneration contribute to "leuko-araiosis" in subjects free of any vascular disorder?

To determine the possible role of Wallerian degeneration secondary to the grey matter neuronal loss in the pathogenesis of "leuko-araiosis", computerised tomography (CT) of the brain was studied in 98 normotensive and non diabetic subjects free of cardiac diseases: 32 with Alzheimer's disease, 36 with Parkinson's disease, eight with progressive supranuclear palsy, and 22 controls. In Alzheimer's disease, leuko-araiosis scores were greater than in control subjects. Leuko-araiosis was more prominent in anterior periventricular areas in Parkinson's disease and progressive supranuclear palsy, and in posterior periventricular areas in Alzheimer's disease. In two patients with Alzheimer's disease and leuko-araiosis, necropsy revealed diffuse white matter pallor, mild fibrillary astrocytosis, and in one patient limited hyaline thickening of small white matter vessels, without any infarction or hypertensive change. Changes were more severe in white matter close to cortical areas with a great density of neurofibrillary tangles. Leuko-araiosis was more severe or more widespread in Alzheimer's disease than in Parkinson's disease, progressive supranuclear palsy and normal ageing. Differences in the location of leuko-araiosis between the four groups might be due to differences in the location of the grey matter disorder and Wallerian degeneration rather than amyloid in Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy and normal ageing. Wallerian degeneration might be another cause of leuko-araiosis in neuro-degenerative disorders beside previously reported extra-cerebral predisposing factors and amyloid angiopathy.

Endothelin 1, an endothelium-derived peptide, is expressed in neurons of the human spinal cord and dorsal root ganglia.

The localization of endothelin 1 mRNA and endothelin-like immunoreactivity was investigated in samples of neurologically normal nervous system tissue from 10 adults by using in situ hybridization and immunocytochemistry. Tissue sections of spinal cord and dorsal root ganglia were hybridized with an 35S-radiolabeled endothelin 1 complementary RNA probe. Autoradiograms showed labeled neurons in the spinal cord (laminae IV-VI and many motoneurons) and numerous small and large neurons in the dorsal root ganglia. Endothelin 1 transcripts were also found in association with the endothelial layer of some blood vessels in the white matter of the spinal cord. A similar distribution of immunoreactivity was seen using three antisera to endothelin 1, but fewer cells were immunostained than were labeled after the hybridization. Two other endothelin 1 antisera immunostained the endothelial lining of blood vessels in the spinal cord white matter but not neurons. In the ganglia, endothelin 1 transcripts were localized to all cells expressing beta-preprotachykinin and most expressing calcitonin gene-related peptide mRNAs; in the majority of the motoneurons, coexistence of endothelin 1 and calcitonin gene-related peptide mRNAs was noted. There was a similar pattern of coexistence for respective peptide immunoreactivities in the ganglia and spinal cord. The expression of endothelin 1 mRNA in distinct neuronal cell types suggests that this peptide plays a part in neural transmission/modulation and adds a further dimension to the known vascular-related actions of endothelin 1.

Angioarchitecture in Experimental Hydrocephalus

Angioarchitecture was investigated by using scanning electron microscopy of microcorrosion casts in 12 hydrocephalic rats and 5 normal control rats to observe changes in the vascular bed of the cerebral mantle in hydrocephalus. Hydrocephalus was induced by infusion of kaolin into the cisterna magna using puncture through the occipital bone. After injecting polyester resin into the brain vessels from the aortic arch, the head was cut into serial sagittal sections close to the midline to observe the ventricle size. Among the hydrocephalic rats, two showed advanced ventricular size and 10 moderate. Brain tissue, dura mater, cranium and muscle were corroded together to prevent destruction of the microvascular casts. Reduction in the number and caliber of the capillaries in the white matter was the most remarkable change in the hydrocephalic rats. This change increased in proportion to the severity of hydrocephalus. Similar changes were observed in the basal ganglia. Changes in the cortical capillaries were mild, but cortical “palisade” patterns disappeared in some hydrocephalic cases. The crossing and pressing phenomena of the white matter vessels were characteristic, and not seen in the control rats. Three dimentional consideration of the angioarchitecture by using microvascular casts in rat hydrocephalus is discussed, compared with the m icroan gio graphic techniques.

Effect of acetylcholine and vasoactive intestinal peptide on cerebral blood flow.

These experiments were performed to determine whether the neurotransmitters acetylcholine (ACh) and vasoactive intestinal peptide (VIP) increase cerebral blood flow (CBF). In anesthetized dogs, infusion of very large doses of ACh (500 microgram/min) into the carotid artery increased CBF (measured with microspheres) 50%. Anatomical limitations prevented adequate testing of cerebrovascular responses in dogs. In anesthetized rabbits, infusion of ACh (10 microgram/min) into the carotid artery produced a twofold increase in CBF. Vessels in gray matter were more responsive than vessels in white matter. ACh did not alter cerebral oxygen consumption, which indicates that the dilator effect of the drug is not an indirect effect mediated through an increase in metabolism. The vasodilator response to ACh was attenuated by atropine (1 mg iv). Intracarotid infusion of VIP in rabbits increased blood flow to cerebral gray matter: infusion of VIP (10 microgram/min) incresed flow 33%. We conclude that 1) cerebral vasodilator responses to ACh and VIP are larger than previously recognized and 2) responses to these drugs occur primarily in cerebral gray matter. Because the neurotransmitters increase CBF significantly, these studies should encourage further studies concerning effects of cholinergic and peptidergic nerves on cerebral vessels.