A Ferret Model of Encephalopathy of Prematurity

There is an ongoing need for relevant animal models in which to test therapeutic interventions for infants with neurological sequelae of prematurity. The ferret is an attractive model species as it has a gyrified brain with a white-to-gray matter ratio similar to that in the human brain. A model of encephalopathy of prematurity was developed in postnatal day 10 (P10) ferret kits, considered to be developmentally equivalent to infants of 24–26 weeks’ gestation. Cross-fostered P10 ferret kits received 5 mg/kg of lipopolysaccharide (LPS) before undergoing consecutive hypoxia-hyperoxia-hypoxia (60 min at 9%, 120 min at 60%, and 30 min at 9%). Control animals received saline vehicle followed by normoxia. The development of basic reflexes (negative geotaxis, cliff aversion, and righting) as well as gait coordination on an automated catwalk were assessed between P28 and P70, followed by ex vivo magnetic resonance imaging (MRI) and immunohistochemical analysis. Compared to controls, injured animals had slower overall reflex development between P28 and P40, as well as smaller hind-paw areas consistent with “toe walking” at P42. Injured animals also displayed significantly greater lateral movement during CatWalk assessment as a result of reduced gait coordination. Ex vivo MRI showed widespread white-matter hyperintensity on T2-weighted imaging as well as altered connectivity patterns. This coincided with white-matter dysmaturation characterized by increased intensity of myelin basic protein staining, white-matter thinning, and loss of oligodendrocyte transcription factor 2 (OLIG2)-positive cells. These results suggest both pathological and motor deficits consistent with premature white-matter injury. This newborn ferret model can therefore provide an additional platform to assess potential therapies before translation to human clinical trials.

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[P2-420]: A COMPARISON OF BRAIN WHITE MATTER HYPERINTENSITY BURDEN ASSESSED IN VIVO AND EX VIVO

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.06.1076 ◽

2017 ◽

Vol 13 (7S_Part_16) ◽

pp. P794-P795

Author(s):

Arman P. Kulkarni ◽

Arnold M. Evia ◽

Julie A. Schneider ◽

David A. Bennett ◽

Konstantinos Arfanakis

Keyword(s):

White Matter ◽

Ex Vivo ◽

White Matter Hyperintensity ◽

Brain White Matter

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Trial of remote ischaemic preconditioning in vascular cognitive impairment (TRIC-VCI): protocol

BMJ Open ◽

10.1136/bmjopen-2020-040466 ◽

2020 ◽

Vol 10 (10) ◽

pp. e040466

Author(s):

Aravind Ganesh ◽

Philip Barber ◽

Sandra E Black ◽

Dale Corbett ◽

Thalia S Field ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Cognitive Impairment ◽

White Matter ◽

Diffusion Tensor ◽

Vascular Cognitive Impairment ◽

White Matter Injury ◽

White Matter Hyperintensity ◽

Limb Ischaemia ◽

Ischaemic Brain

IntroductionCerebral small vessel disease (cSVD) accounts for 20%–25% of strokes and is the most common cause of vascular cognitive impairment (VCI). In an animal VCI model, inducing brief periods of limb ischaemia-reperfusion reduces subsequent ischaemic brain injury with remote and local protective effects, with hindlimb remote ischaemic conditioning (RIC) improving cerebral blood flow, decreasing white-matter injury and improving cognition. Small human trials suggest RIC is safe and may prevent recurrent strokes. It remains unclear what doses of chronic daily RIC are tolerable and safe, whether effects persist after treatment cessation, and what parameters are optimal for treatment response.Methods and analysisThis prospective, open-label, randomised controlled trial (RCT) with blinded end point assessment and run-in period, will recruit 24 participants, randomised to one of two RIC intensity groups: one arm treated once daily or one arm twice daily for 30 consecutive days. RIC will consistent of 4 cycles of blood pressure cuff inflation to 200 mm Hg for 5 min followed by 5 min deflation (total 35 min). Selection criteria include: age 60–85 years, evidence of cSVD on brain CT/MRI, Montreal Cognitive Assessment (MoCA) score 13–24 and preserved basic activities of living. Outcomes will be assessed at 30 days and 90 days (60 days after ceasing treatment). The primary outcome is adherence (completing ≥80% of sessions). Secondary safety/tolerability outcomes include the per cent of sessions completed and pain/discomfort scores from patient diaries. Efficacy outcomes include changes in cerebral blood flow (per arterial spin-label MRI), white-matter hyperintensity volume, diffusion tensor imaging, MoCA and Trail-Making tests.Ethics and disseminationResearch Ethics Board approval has been obtained. The results will provide information on feasibility, dose, adherence, tolerability and outcome measures that will help design a phase IIb RCT of RIC, with the potential to prevent VCI. Results will be disseminated through peer-reviewed publications, organisations and meetings.Trial registration numberNCT04109963.

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Endothelial-derived exosomes demonstrate a link between endothelial innate inflammation and brain dysfunction and injury in aging

10.1101/670083 ◽

2019 ◽

Cited By ~ 1

Author(s):

F.M. Elahi ◽

D. Harvey ◽

M. Altendahl ◽

K.B. Casaletto ◽

N. Fernandes ◽

...

Keyword(s):

White Matter ◽

Human Subjects ◽

Positive Association ◽

Regulatory Proteins ◽

White Matter Injury ◽

White Matter Hyperintensity ◽

Grey Matter Volume ◽

Older Individuals ◽

Significant Positive Association

ABSTRACTWe test the hypothesis that endothelial cells take on an inflammatory phenotype in functionally intact human subjects with radiographic evidence of white matter injury. Markers within all three complement effector pathways and regulatory proteins were quantified from endothelial-derived exosomes (EDE) of subjects (age 70-82) with (n=11) and without (n=16) evidence of white matter hyperintensity on MRI. Group differences and associations with systemic markers of immune activation (IL6, ICAM1), cognition and neuroimaging were calculated via regression modelling.EDE complement factors within the alternative and classical pathways were found to be higher and regulatory proteins lower in subjects with WMH. EDE levels of several factors demonstrated significant associations with cognitive slowing and systolic blood pressure. The inhibitor of the membrane attack complex, CD46, showed a significant positive association with cerebral grey matter volume. Systemic inflammatory markers, IL6 and ICAM1, were positively associated with EDE levels of several factors.These findings provide the first in vivo evidence of the association of endothelial cell inflammation with white matter injury, cognition, and brain degeneration in functionally normal older individuals, and form the basis for future biomarker development in early or preclinical stages of vascular cognitive impairment and dementia.

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Modified behavioural tests to detect white matter injury- induced motor deficits after intracerebral haemorrhage in mice

Scientific Reports ◽

10.1038/s41598-019-53263-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Weixiang Chen ◽

Min Xia ◽

Chao Guo ◽

Zhengcai Jia ◽

Jie Wang ◽

...

Keyword(s):

White Matter ◽

Grip Strength ◽

Motor Function ◽

Intracerebral Haemorrhage ◽

Strength Test ◽

White Matter Injury ◽

Motor Deficit ◽

Motor Deficits ◽

Walking Test ◽

Behavioural Tests

AbstractMotor function deficit induced by white matter injury (WMI) is one of the most severe complications of intracerebral haemorrhage (ICH). The degree of WMI is closely related to the prognosis of patients after ICH. However, the current behavioural assessment of motor function used in the ICH mouse model is mainly based on that for ischaemic stroke and lacks the behavioural methods that accurately respond to WMI. Here, a series of easy-to-implement behavioural tests were performed to detect motor deficits in mice after ICH. The results showed that the grip strength test and the modified pole test not only can better distinguish the degree of motor dysfunction between different volumes of blood ICH models than the Basso Mouse Scale and the beam walking test but can also accurately reflect the severity of WMI characterized by demyelination, axonal swelling and the latency of motor-evoked potential delay induced by ICH. In addition, after ICH, the results of grip tests and modified pole tests, rather than the Basso Mouse Scale and the beam walking test, were worse than those observed after intraventricular haemorrhage (IVH), which was used as a model of brain haemorrhage in non-white matter areas. These results indicate that the grip strength test and the modified pole test have advantages in detecting the degree of motor deficit induced by white matter injury after ICH in mice.

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Lasting Pure-Motor Deficits after Focal Posterior Internal Capsule White-Matter Infarcts in Rats

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.7 ◽

2015 ◽

Vol 35 (6) ◽

pp. 977-984 ◽

Cited By ~ 10

Author(s):

Francesco Blasi ◽

Michael J Whalen ◽

Cenk Ayata

Keyword(s):

White Matter ◽

Internal Capsule ◽

Experimental Models ◽

White Matter Injury ◽

Motor Deficits ◽

Sprague Dawley ◽

Term Outcome ◽

Long Term Outcome ◽

Endothelin 1 ◽

Pure Motor

Small white-matter infarcts of the internal capsule are clinically prevalent but underrepresented among currently available animal models of ischemic stroke. In particular, the assessment of long-term outcome, a primary end point in clinical practice, has been challenging due to mild deficits and the rapid and often complete recovery in most experimental models. We, therefore, sought to develop a focal white-matter infarction model that can mimic the lasting neurologic deficits commonly observed in stroke patients. The potent vasoconstrictor endothelin-1 ( n = 24) or vehicle ( n = 9) was stereotactically injected into the internal capsule at one of three antero-posterior levels (1, 2, or 3 mm posterior to bregma) in male Sprague-Dawley rats. Endothelin-injected animals showed highly focal (~1 mm3) and reproducible ischemic infarcts, with severe axonal and myelin loss accompanied by cellular infiltration when examined 2 and 4 weeks after injection. Only those rats injected with endothelin-1 at the most posterior location developed robust and pure-motor deficits in adhesive removal, cylinder and foot-fault tests that persisted at 1 month, without detectable sensory impairments. In summary, we present an internal capsule stroke model optimized to produce lasting pure-motor deficits in rats that may be suitable to study neurologic recovery and rehabilitation after white-matter injury.

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P1-290: NEUROPATHOLOGIES LINKED TO BRAIN WHITE MATTER HYPERINTENSITY VOLUME IN OLDER ADULTS: AN EX-VIVO MRI AND PATHOLOGY INVESTIGATION

Alzheimer s & Dementia ◽

10.1016/j.jalz.2014.05.530 ◽

2014 ◽

Vol 10 ◽

pp. P416-P417

Author(s):

Aikaterini Kotrotsou ◽

Konstantinos Arfanakis ◽

David Bennett ◽

Julie Schneider ◽

Sue Leurgans

Keyword(s):

Older Adults ◽

White Matter ◽

Ex Vivo ◽

White Matter Hyperintensity ◽

Brain White Matter

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Abstract TP208: Fazekas Scores Correspond With Specific Volumes of White Matter Hyperintensity

Stroke ◽

10.1161/str.51.suppl_1.tp208 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Ariana Andere ◽

Anusha Boyanpally ◽

Scott Collins ◽

Michael Reznik ◽

Ali Mahta ◽

...

Keyword(s):

White Matter ◽

Univariate Analysis ◽

Tertiary Care ◽

Volumetric Analysis ◽

Subcortical White Matter ◽

White Matter Hyperintensity ◽

3D Slicer ◽

Tertiary Care Institution ◽

Magnetic Resonance Imaging Mri ◽

Fazekas Scale

Background: White matter hyperintensity (WMH), also known as leukoaraiosis, is commonly visualized as abnormal T2 signal in the deep and subcortical white matter on Magnetic Resonance Imaging (MRI). It is also commonly associated with aging, diabetes, hypertension and cerebrovascular disease. The Fazekas (F) scoring system is a subjective tool commonly used to assess WMH, but no volumetric analysis has been published showing how the scores correspond to true quantities of white matter disease. Methods: MRIs performed on inpatients and outpatients at our tertiary care institution between 2015 and 2017 were reviewed and their relative WMH was scored by one author trained in using the Fazekas scale. Using 3D Slicer 4.9, manual segmentations of WMH were completed and a 3D model was created to quantify the amount of WMH. Univariate analysis and ANOVA tests were run to determine the association of each Fazekas score with volume of WMH. Results: Among the 198 patients in our study (53% female), 163 had WMH (F1 n=66, F2 n=49, F3 n=48). Ranges of WMH in each group were 0.1-8.3 mL in Fazekas 1 (mean = 3.7, SD = 2.3), 6.0-17.7 mL in Fazekas 2 (mean = 10.8, SD = 3.1), and 14.2-77.2 mL in Fazekas 3 (mean = 35.2, SD = 17.9); if 11 outliers above 50 mL were excluded, the range for Fazekas 3 was 14.2-47.0 mL (mean = 27.1, SD = 8.9). When comparing data between groups, both the comparison between F1+2 (t-value = 14.1, p<0.001) and F2+F3 (t-value = 9.62, p<0.001) were significant. Moreover, when comparing between the three groups, each range of values was found to be significant from one another (F = 151.3, p<0.001). Conclusion: When accurately trained in assigning Fazekas scores to patient’s WMH, each of the scores appears to represent an approximate range of distinct volumes for WMH. Studies have shown that the presence and extent of WMH is a predictor for future development of stroke. These results should be validated in subsequent studies.

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Abstract 19890: Pre-operative Cerebral Hemodynamics From Birth Until Surgery in Neonates With Critical Congenital Heart Disease

Circulation ◽

10.1161/circ.132.suppl_3.19890 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Jennifer M Lynch ◽

John J Newland ◽

Madeline Winters ◽

David R Busch ◽

Ann L McCarthy ◽

...

Keyword(s):

Congenital Heart Disease ◽

Heart Disease ◽

White Matter ◽

Congenital Heart ◽

White Matter Injury ◽

Therapeutic Interventions ◽

Metabolic Demand ◽

Critical Congenital Heart Disease ◽

Therapeutic Algorithms ◽

Increased Risk

Introduction: Neonates with critical congenital heart disease (CHD) exhibit a high prevalence of white matter injury (WMI). Recent work in neonates with hypoplastic left heart syndrome has shown that a longer wait from birth to surgery was associated with lower cerebral tissue oxygen saturations (StO2) on the morning of surgery and an increased risk for postoperative white matter injury (WMI). Understanding the daily preoperative changes in cerebral physiology during this vulnerable period may lead to new therapeutic algorithms aimed at prevention of WMI. Methods: Term neonates with critical CHD were recruited for this study. Frequency domain diffuse optical spectroscopy was employed to noninvasively quantify StO2. Daily StO2 measurements were made from day of recruitment until the day of surgery. Results: We studied 37 neonates with critical CHD. Operations were performed at 1-8 days of life. Non-elective reasons for timing of surgery resulted only in earlier surgery in this cohort. The subjects were placed in 2 groups depending on if they had a normal arch (N=20) or obstructed arch (N=17). In a linear mixed-effects model, StO2 decreased as a function of time from birth but was not specific to diagnostic group. Conclusions: Observed longitudinal daily decline in StO2 from birth until surgery supports our earlier findings and extends them to other groups of CHD. These results suggest that reported increases in risk for WMI with time-to-surgery could be due to mismatched oxygen delivery to metabolic demand. Therapeutic interventions such as increasing cerebral blood flow or decreasing cerebral oxygen demand may be considered when earlier surgery is not possible.

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Adrenomedullin Deficiency and Aging Exacerbate Ischemic White Matter Injury after Prolonged Cerebral Hypoperfusion in Mice

BioMed Research International ◽

10.1155/2014/861632 ◽

2014 ◽

Vol 2014 ◽

pp. 1-13 ◽

Cited By ~ 3

Author(s):

Yumiko Mitome-Mishima ◽

Nobukazu Miyamoto ◽

Ryota Tanaka ◽

Tatsuo Shimosawa ◽

Hidenori Oishi ◽

...

Keyword(s):

Oxidative Stress ◽

White Matter ◽

Immunohistochemical Analysis ◽

White Matter Injury ◽

Cerebral Hypoperfusion ◽

Oligodendrocyte Progenitor Cells ◽

Dependent Manner ◽

Wild Type ◽

White Matter Damage ◽

Aged Mice

Adrenomedullin was originally isolated from pheochromocytoma cells and reduces insulin resistance by decreasing oxidative stress. White matter lesions induced by aging and hyperglycemia play a crucial role in cognitive impairment in poststroke patients. Here, we examine whether adrenomedullin deficiency and aging exacerbate ischemic white matter injury after prolonged cerebral hypoperfusion. Adrenomedullin heterozygous, wild-type young/aged mice were subjected to prolonged hypoperfusion. Prolonged cerebral hypoperfusion followed by immunohistochemical analysis was used to evaluate white matter injury. After prolonged hypoperfusion, white matter damage progressed in a time-dependent manner in AM+/−group compared with the wild-type group. The number of oligodendrocyte progenitor cells gradually increased after prolonged hypoperfusion, whereas oligodendrocytes decreased following a transient increase, but the ratio of increase was mild in the AM+/−group(P<0.05). Oxidative stress was detected in oligodendrocytes, with a larger increase in the AM+/−group(P<0.05). Aged mice showed the same tendency, but white matter damage was worse, especially in the aged AM+/−group. Our results demonstrated that white matter injury was increased in adrenomedullin deficiency, which induced oxidative stress. White matter injury was more exacerbated because of hyperglycemia in aged AM+/−group. Adrenomedullin may be an important target in the control of ischemic white matter injury.

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