Abstract WP107: Molecular Disorganization of Axons Adjacent to Human Cortical Microinfarcts

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Hamza Coban ◽  
Spencer Tung ◽  
Harry V Vinters ◽  
Jason D Hinman
Keyword(s):  
White Matter ◽  
Cerebrovascular Diseases ◽  
Molecular Organization ◽  
Segment Length ◽  
Ischemic Brain ◽  
Ankyrin G ◽  
Autopsy Brain Tissue ◽  
Cortical Regions ◽  
Axon Initial Segments ◽  
Fibrillary Gliosis

Introduction: Ischemic brain lesions are pathologic hallmarks commonly associated with cognitive and cerebrovascular diseases. In particular, cortical microinfarcts are described as microscopically identified wedge shaped ischemic lesions such as cavitations with few remaining macrophages and fibrillary gliosis. These microscopic lesions are observed with high resolution magnetic resonance imaging in aging brains and in patients with cerebrovascular disease (CVD). Recent studies have suggested that strategically located microinfarcts strongly correlate with cognitive deficits, which can contribute to Alzheimer’s Disease (AD) as well as other forms of dementia. Hypothesis: We have recently shown that there is altered axonal molecular organization in white matter areas adjacent to white matter lacunar and microinfarcts. In this study, we hypothesized that similar changes were present in nodal, paranodal, and axon initial segments adjacent to human cortical microinfarcts. Methods: Paraffin-embedded sections of autopsy brain tissue from five patients (post mortem interval range= 4 to 45 h) with cortical microinfarcts reported in their clinical neuropathological examination were immunofluorescently labeled for nodal and paranodal markers including beta-IV spectrin, ankyrin-G, and contactin-associated protein (caspr). High magnification images were generated using confocal microscopy. Results: Cases ranged in age from 73 to 93 years old. Comorbid neuropathologic diagnoses included AD (n=3) and mixed dementia (n=2). Adjacent to cortical microinfarcts, we observed significant elongation of paranodal segments and shortened axon initial segments adjacent to cortical microinfarcts. In adjacent cortical regions without microinfarcts, paranodal segments were less frequently abnormal and axon initial segment length appeared normal. Conclusions: These data indicate that the molecular organization of axons adjacent to human cortical microinfarcts is abnormal providing support for a microinfarct penumbral injury that worsens the effect of these tiny strokes.

METHODS FOR SIMULATION OF ACUTE BRAIN ISCHEMIA: PATHOPHYSIOLOGICAL SUBSTANTIATION OF SELECTION AND IMPORTANCE FOR CLINICAL PRACTICE

2019 ◽  
pp. 142-152
Author(s):  
Б.И. Гельцер ◽  
Э.В. Слабенко ◽  
Ю.В. Заяц ◽  
В.Н. Котельников
Keyword(s):  
Clinical Practice ◽  
Experimental Studies ◽  
Cerebrovascular Diseases ◽  
Experimental Models ◽  
Pathological Process ◽  
Ischemic Brain ◽  
Actual Clinical Practice ◽  
Acute Cerebral Ischemia ◽  
Different Types ◽  
Acute Brain Ischemia

Одним из основных требований к разработке экспериментальных моделей цереброваскулярных заболеваний является их максимальная приближенность к реальной клинической практике. В работе систематизированы данные по основным методам моделирования острой ишемии головного мозга (ОИГМ), представлена их классификация, анализируются данные о преимуществах и недостатках той или иной модели. Обсуждаются результаты экспериментальных исследований по изучению патогенеза ОИГМ с использованием различных моделей (полной и неполной глобальной, локальной и мультифокальной ишемии) и способов их реализации (перевязка артерий, клипирование, коагуляция, эмболизация и др.). Особое внимание уделяется «стабильности» последствий острого нарушения мозгового кровообращения: необратимых ишемических повреждений головного мозга или обратимых с реперфузией заданной продолжительности. Отмечается, что важное значение в этих исследованиях должно принадлежать современным методам прижизненной визуализации очагов острого ишемического повреждения, что позволяет оценивать динамику патологического процесса. Предлагаемый метод отвечает требованиям гуманного обращения с животными. Подчеркивается, что выбор релевантной модели ОИГМ определяется задачами предстоящего исследования и технологическими ресурсами научной лаборатории. Development of experimental models for acute forms of cerebrovascular diseases is essential for implementation of methods for their prevention and treatment. One of the principal requirements to such models is their maximum approximation to actual clinical practice. This review systematized major models of acute cerebral ischemia (ACI), their classification, and presented information about their advantages and shortcomings. Also, the review presented results of experimental studies on pathophysiological mechanisms of different types of modeled ACI (complete and incomplete global, local, and multifocal ischemia) and methods for creating these models (arterial ligation, clipping, coagulation, embolization, etc.). Particular attention was paid to “stability” of the consequences of acutely impaired cerebral circulation - an irreversible ischemic brain injury or a reversible injury with reperfusion of a given duration. The authors emphasized that in such studies, a special significance should be given to intravital imaging of acute ischemic damage foci using modern methods, which allow assessing the dynamics of the pathological process and meet the requirements to humane treatment of animals. The choice of a relevant ACI model is determined by objectives of the planned study and the technological resources available at the research laboratory.

scholarly journals Arterial stiffness and progression of cerebral white matter hyperintensities in patients with type 2 diabetes and matched controls: a 5-year cohort study

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Kristian L. Funck ◽  
Esben Laugesen ◽  
Pernille Høyem ◽  
Brian Stausbøl-Grøn ◽  
Won Y. Kim ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cohort Study ◽  
White Matter ◽  
Arterial Stiffness ◽  
White Matter Hyperintensities ◽  
Cerebrovascular Diseases ◽  
Study Data ◽  
Cerebral White Matter ◽  
Intracranial Volume

Abstract Background Stroke is a serious complication in patients with type 2 diabetes (T2DM). Arterial stiffness may improve stroke prediction. We investigated the association between carotid-femoral pulse wave velocity [PWV] and the progression of cerebral white matter hyperintensities (WMH), a marker of stroke risk, in patients with T2DM and controls. Methods In a 5-year cohort study, data from 45 patients and 59 non-diabetic controls were available for analysis. At baseline, participants had a mean (± SD) age of 59  ±  10 years and patients had a median (range) diabetes duration of 1.8 (0.8–3.2) years. PWV was obtained by tonometry and WMH volume by an automated segmentation algorithm based on cerebral T2-FLAIR and T1 MRI (corrected by intracranial volume, cWMH). High PWV was defined above 8.94 m/s (corresponding to the reference of high PWV above 10 m/s using the standardized path length method). Results Patients with T2DM had a higher PWV than controls (8.8  ±  2.2 vs. 7.9  ±  1.4 m/s, p  <  0.01). WMH progression were similar in the two groups (p  =  0.5). One m/s increase in baseline PWV was associated with a 16% [95% CI 1–32%], p  <  0.05) increase in cWMH volume at 5 years follow-up after adjustment for age, sex, diabetes, pulse pressure and smoking. High PWV was associated with cWMH progression in the combined cohort (p  <  0.05). We found no interaction between diabetes and PWV on cWMH progression. Conclusions PWV is associated with cWMH progression in patients with type 2 diabetes and non-diabetic controls. Our results indicate that arterial stiffness may be involved early in the pathophysiology leading to cerebrovascular diseases.

Abstract 14655: Diffusion Neuroimaging of Adults With D-Transposition of the Great Arteries Reveal White Matter Alterations in the Connectomic Rich Club

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ai Wern Chung ◽  
Borjan Gagoski ◽  
Jane W Newburger ◽  
P. Ellen Grant ◽  
Michelle GURVITZ
Keyword(s):  
White Matter ◽  
Structural Integrity ◽  
Circulatory Arrest ◽  
A Priori ◽  
Group Differences ◽  
High Angular Resolution ◽  
Central System ◽  
Rich Club ◽  
Apparent Diffusion ◽  
Cortical Regions

Introduction: The population of adults with d-transposition of the great arteries (TGA) continue to grow. As this group has underlying neurocognitive impairment and longer-term neurovascular damage, advanced neuroimaging to identify markers for treatment is required. Diffusion (d)MRI tractography quantifies the structural integrity of white matter (WM) pathways in the brain - where lower FA (fractional anisotropy) and higher ADC (apparent diffusion coefficient) typify WM damage. The brain’s structural backbone is its rich club (RC), a set of highly interconnected regions established before birth and vital for effective cognitive function. Moreover, there are Feeder and Seeder subnetworks peripheral to the RC, which are thought to form later and may be more adaptive. Hypothesis: We hypothesize that adults with TGA have alterations in both the brain’s structural RC and in peripheral connections. Methods: Subjects were TGA adults from the Boston Circulatory Arrest Study (n = 25, mean age 28.46 ± 1.14yr) and Controls (n = 13, 28.35 ± 1.70). Multi-shell, high-angular resolution dMRI data were acquired and fitted with a multi-fiber model (Fig). After tractography, a connectome of the number of tracts connecting pairwise cortical regions was computed. A priori RC regions were bilateral superior frontal and parietal frontal gyri, precuneus, posterior cingulate and insular regions. Connections were grouped into subnetworks and mean FA and ADC computed. Results: Cohorts were age-matched (p=0.801, unpaired t-test). Overall, patients had lower FA and greater ADC than controls in all subnetworks. Group differences (unpaired t-tests) were significant in the RC (ADC p=0.029), Feeder subnetwork (FA p=0.041; ADC p=0.042), with trends in Seeder subnetworks (FA p=0.061; ADC p=0.062). Conclusions: Widespread WM alterations exist in adults with TGA not only in the brain’s most central system, but also connections feeding into the RC suggesting prenatal and adaptive changes.

Abstract W MP87: PDGF Contributes to BMSC Treatment Induced Neurogenesis and White Matter and Axonal Remodeling in T2DM Stroke Rats

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Alex Zacharek ◽  
Tao Yan ◽  
Michael Chopp` ◽  
Poornima Venkat ◽  
Ruizhou Ning ◽  
...  
Keyword(s):  
Cell Migration ◽  
White Matter ◽  
Artery Occlusion ◽  
Border Zone ◽  
Axonal Outgrowth ◽  
Ischemic Brain ◽  
Neuroblast Migration ◽  
Gene And Protein Expression ◽  
Underlying Mechanisms

Objective: Our previous studies have found that bone-marrow-stromal cell (BMSC) treatment of stroke in Type two DM (T2DM) rats, initiated at 3 days after stroke, improved functional recovery. Neurogenesis and white matter (WM) remodeling play an important role in neurorestorative effects after stroke. In this study, we tested whether BMSCs regulate neurogenesis and WM remodeling and the underlying mechanisms of BMSC induced neurorestorative effects in T2DM stroke rats. Methods: T2DM was induced with streptozotocin injection in addition to a high fat diet. T2DM rats were subjected to 2h of middle cerebral artery occlusion (MCAo), then treated with human BMSCs (5X106) or vehicle control (n=8/group) initiated at 3 days after MCAo and rats were monitored for 28 days. Neuroblast migration, WM changes, and gene and protein expression were measured in the ischemic brain. Subventricular zone (SVZ) explant cell migration and primary cortical neuron (PCN) axonal outgrowth measurements were performed in vitro. Results: BMSC treatment in T2DM rats significantly improves functional outcome and increases WM remodeling identified by increased myelin and axonal density. BMSCs also increase the neuroblast migration protein doublecortin (DCX, 25.0±4.3% vs control: 4.5±1.1%), platelet-derived growth factor (PDGF)-AA, and bFGF expression in the ischemic border zone. Angiogenic ELISA array data are consistent with the immunostaining data, showing that BMSC treatment increases PDGF-AA (2.1 fold), PDGF-BB (2.5 fold) and bFGF (1.8 fold) in the ischemic brain. Using an in vitro cell culture model, we found that BMSCs secrete high levels of PDGF. PDGF treatment significantly increases SVZ explant cell migration (1.7 fold) and PCN axonal outgrowth (1.9 fold) compared to non-treatment control. Inhibition of PDGF with neutralized anti-PDGF antibody significantly attenuates BMSC conditioned medium induced SVZ cell migration and PCN axon outgrowth. Conclusion: BMSC treatment of stroke in T2DM increases WM remodeling and neurogenesis as well as increases PDGF expression. PDGF not only promotes neuronal migration, but also increases axonal outgrowth. Therefore, increasing PDGF likely contributes to BMSC induced neurogenesis and WM remodeling in T2DM stroke rats.

scholarly journals Cognitive features of white matter lesions accompanied by different risk factors of cerebrovascular diseases

2019 ◽  
Vol 28 (12) ◽  
pp. 1705-1710
Author(s):  
Yafei Shangguan ◽  
Tao Xiong ◽  
Changwei Jiang ◽  
Wei Chen ◽  
Yan Zhang ◽  
...  
Keyword(s):  
Risk Factors ◽  
White Matter ◽  
White Matter Lesions ◽  
Cerebrovascular Diseases

scholarly journals Neural correlates of polygenic risk score for autism spectrum disorders in general population

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Budhachandra Khundrakpam ◽  
Uku Vainik ◽  
Jinnan Gong ◽  
Noor Al-Sharif ◽  
Neha Bhutani ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
White Matter ◽  
General Population ◽  
Cortical Thickness ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Risk Scores ◽  
Polygenic Risk ◽  
Cortical Regions ◽  
White Matter Connectivity

Abstract Autism spectrum disorder is a highly prevalent and highly heritable neurodevelopmental condition, but studies have mostly taken traditional categorical diagnosis approach (yes/no for autism spectrum disorder). In contrast, an emerging notion suggests a continuum model of autism spectrum disorder with a normal distribution of autistic tendencies in the general population, where a full diagnosis is at the severe tail of the distribution. We set out to investigate such a viewpoint by investigating the interaction of polygenic risk scores for autism spectrum disorder and Age2 on neuroimaging measures (cortical thickness and white matter connectivity) in a general population (n = 391, with age ranging from 3 to 21 years from the Pediatric Imaging, Neurocognition and Genetics study). We observed that children with higher polygenic risk for autism spectrum disorder exhibited greater cortical thickness for a large age span starting from 3 years up to ∼14 years in several cortical regions localized in bilateral precentral gyri and the left hemispheric postcentral gyrus and precuneus. In an independent case–control dataset from the Autism Brain Imaging Data Exchange (n = 560), we observed a similar pattern: children with autism spectrum disorder exhibited greater cortical thickness starting from 6 years onwards till ∼14 years in wide-spread cortical regions including (the ones identified using the general population). We also observed statistically significant regional overlap between the two maps, suggesting that some of the cortical abnormalities associated with autism spectrum disorder overlapped with brain changes associated with genetic vulnerability for autism spectrum disorder in healthy individuals. Lastly, we observed that white matter connectivity between the frontal and parietal regions showed significant association with polygenic risk for autism spectrum disorder, indicating that not only the brain structure, but the white matter connectivity might also show a predisposition for the risk of autism spectrum disorder. Our findings showed that the fronto-parietal thickness and connectivity are dimensionally related to genetic risk for autism spectrum disorder in general population and are also part of the cortical abnormalities associated with autism spectrum disorder. This highlights the necessity of considering continuum models in studying the aetiology of autism spectrum disorder using polygenic risk scores and multimodal neuroimaging.

scholarly journals Accelerated longitudinal gray/white matter contrast decline in aging in lightly myelinated cortical regions

2016 ◽  
Vol 37 (10) ◽  
pp. 3669-3684 ◽  
Author(s):  
Didac Vidal-Piñeiro ◽  
Kristine B. Walhovd ◽  
Andreas B. Storsve ◽  
Håkon Grydeland ◽  
Darius A. Rohani ◽  
...  
Keyword(s):  
White Matter ◽  
Cortical Regions

scholarly journals Nodes of Ranvier and axon initial segments are ankyrin G–dependent domains that assemble by distinct mechanisms

2007 ◽  
Vol 177 (5) ◽  
pp. 857-870 ◽  
Author(s):  
Yulia Dzhashiashvili ◽  
Yanqing Zhang ◽  
Jolanta Galinska ◽  
Isabel Lam ◽  
Martin Grumet ◽  
...  
Keyword(s):  
Schwann Cells ◽  
Sodium Channels ◽  
Cytoskeletal Proteins ◽  
Action Potential Generation ◽  
Potential Generation ◽  
Nodes Of Ranvier ◽  
Ankyrin G ◽  
Sites Of Action ◽  
Axon Initial Segments ◽  
Inside Out

Axon initial segments (AISs) and nodes of Ranvier are sites of action potential generation and propagation, respectively. Both domains are enriched in sodium channels complexed with adhesion molecules (neurofascin [NF] 186 and NrCAM) and cytoskeletal proteins (ankyrin G and βIV spectrin). We show that the AIS and peripheral nervous system (PNS) nodes both require ankyrin G but assemble by distinct mechanisms. The AIS is intrinsically specified; it forms independent of NF186, which is targeted to this site via intracellular interactions that require ankyrin G. In contrast, NF186 is targeted to the node, and independently cleared from the internode, by interactions of its ectodomain with myelinating Schwann cells. NF186 is critical for and initiates PNS node assembly by recruiting ankyrin G, which is required for the localization of sodium channels and the entire nodal complex. Thus, initial segments assemble from the inside out driven by the intrinsic accumulation of ankyrin G, whereas PNS nodes assemble from the outside in, specified by Schwann cells, which direct the NF186-dependent recruitment of ankyrin G.

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