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The University of Southampton
BRAIN UK

Lay Summaries of studies supported by BRAIN UK by category: Cerebrovascular

BRAIN UK Ref: 11/004
Response of stem cells in the human brain to acute/hypoxic injury
Dr N Cohen, University of Bristol 

Injury to the central nervous system through stroke and head injury is common and associated with variable degrees of functional recovery amongst survivors. Tissue damage is mediated by both ischaemia (a reduction in blood flow to the brain) and hypoxia (a reduction in oxygen to the brain) resulting in cell death with an area of the brain called the hippocampus being particularly susceptible to damage. However, the biology underlying recovery is poorly understood in humans although information from models developed in mice seem to indicate that a type of cell (neuronal precursor cells, NPCs) present within the hippocampus act as a potential source of new nerve cells during tissue repair.

The applicant has undertaken a previous investigation into hippocampal-mediated brain repair using a combination of morphological study and special staining methods that demonstrate NPCs. However, some of these methods were not specific for NPCs and staining reliability was variable. The cases used for this initial investigation (post mortem hippocampus from individuals who died from cardiorespiratory arrest with corresponding controls) are to be re-examined and an additional staining method is to be employed to further characterize NPCs and to quantify the brain’s ability to undergo repair after ischaemic and hypoxic-mediated damage.

Project Status: Active

Research Outputs: Abstract

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BRAIN UK Ref: 11/008
ADAM17 in subarachnoid haemorrhage
Dr D Boche, University of Southampton 

Subarachnoid haemorrhage (SAH) is bleeding around the brain typically caused by a ruptured blood vessel. A delay in the lack of blood perfusion (ischaemia) is an important determinant in the outcome of SAH. Biological pathways involved in scavenging the oxygen-binding component of blood (haemoglobin) may therefore be important in the response and recovery of an individual to SAH. A previous study by the researcher demonstrated that the brain is poorly adapted to the scavenging of haemoglobin after SAH. This has led to a particular scavenging pathway (CD163-haptoglobin-haemoglobin system) being identified as one that may respond to pharmacological manipulation in order to improve its efficiency. This may be achieved by increasing the number of cells recruited to this system by inhibiting a particular molecule (ADAM17) which is involved in normal cell signaling and activation.

This study will apply specific staining techniques to cases of SAH and age- and gender-matched controls to demonstrate ADAM17 expression in the brain, demonstrate cells important in haemoglobin scavenging pathways and sites of haemorrhage. Data will be analysed quantitatively in order to establish if any correlations exist between ADAM17 expression and haemaglobin metabolism in SAH in order to determine its use as a potential therapeutic target.

Project Status: Active 

Research Outputs: Publication x 2; Grant Application x 1; Presentation x 1; Poster x 5

DatePublication title
2015 Haemoglobin Scavenging After Subarachnoid Haemorrhage
2016 Heme-Hemopexin Scavenging Is Active in the Brain and Associates With Outcome After Subarachnoid Hemorrhage
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BRAIN UK Ref: 13/007
CAA in subarachnoid haemorrhage
Dr R Carare, University of Southampton

Lay Summary not available.

Project status: Closed.

 

BRAIN UK Ref: 13/009
CAA in autonomic dysfunction
Dr R Carare, University of Southampton 

Alzheimer’s disease is an age related neurodegenerative disorder which affects approximately 24%-33% of the Western population aged 85 and above. Symptoms include profound cognitive decline and memory loss, which can often be explained by a neurotoxicity induced through accumulation of extracellular Aβ depositions. Chronic fatigue syndrome is a condition characterised by a disabling fatigue. Current figures suggest upwards of 250,000 people in the United Kingdom currently suffer from this poorly understood condition. In recent years reputable evidence has identified chronic fatigue syndrome as a model of autonomic dysfunction, resulting in providing support for a neurological basis of chronic fatigue syndrome.
This study aimed to identify whether Aβ deposits were present in cases of autonomic dysfunction and to establish if an Alzheimer’s disease-like neuropathology could be held accountable for a degree of chronic fatigue syndrome symptomology. Using immunohistochemistry, all cases of autonomic dysfunction provided evidence for intracellular deposition of Aβ in cortical regions of the brain. However, the percentage coverage of Aβ was significantly lower than that recorded in severe Alzheimer’s disease.
Future investigations are needed to identify the exact localisation of intracellular deposits and further investigate the effect of autonomic dysfunction on cholinergic acetyltransferase and cholinergic innervation.
It was concluded that chronic fatigue syndrome has a similar neuropathology to that of early-stage Alzheimer’s disease. With these findings, it is hoped such novel findings will evoke enthusiasm for future research and support utilisation of the global wealth of Alzheimer’s disease knowledge, to improve the current understanding and treatment of chronic fatigue syndrome. 

Project Status: Closed

BRAIN UK Ref: 14/001
CAA and Dystroglycanopathies
Dr R Carare, University of Southampton

Research has implicated the basement membrane (BM) in the route for the perivascular elimination of amyloid-β, the failure of which is believed to contribute to Alzheimer’s disease (AD) pathogenesis. Collagen IV is a ubiquitous BM component with structural and functional roles. Laminin connects collagen IV to the dystrophin glycoprotein complex (DGC), a transmembrane structure essential for embryonic BM development. In the human brain the DGC is located in perivascular astrocyte end-feet where it acts as an anchor to aquaporin 4 (AQP4), a water channel reported to aid elimination of toxins such as amyloid-β from the brain via convective bulk flow.
Dystroglycanopathies are a clinically heterogenous group of muscular dystrophies caused by an abnormality with the α-dystroglycan component of the DGC. Dystroglycanopathies are used in this study as a model of disrupted BMs to explore their potential for use in future AD research where the analysis of amyloid-β along compromised BMs is valuable. Additionally, the literature is currently lacking an understanding of how the DGC influences the development of collagen IV in rebrovascular BMs.
This study investigates how the general morphology and contours of vessels is altered in dystroglycanopathies in human brain tissue by immunohistochemical staining for collagen IV and will involve a quantitative comparison of both staining and blood vessel diameter between dystroglycanopathies and normal tissue. Dystroglycanopathies exhibit observably weaker staining and a statistically significant greater blood vessel diameter with a mean difference of 3.17um (2.72, 3.62, P<0.001), possibly due to a thickened BM. It was observed that dystroglycanopathy BMs appear to be more rugged and tortuous indicating structural irregularities which may result in a functional deficit.

Project Status: Closed

BRAIN UK Ref: 14/017
Electron microscopic study of CAA
Dr. R Carare, University of Southampton

The basement membranes of capillaries and arteries (BM) are the route for the perivascular elimination of amyloid-β, the failure of which is believed to contribute to Alzheimer’s disease (AD) pathogenesis. Collagen IV is a ubiquitous BM component with structural and functional roles. Laminin connects collagen IV to the dystrophin glycoprotein complex (DGC. Dystroglycanopathies are a clinically heterogenous group of muscular dystrophies caused by an abnormality with the α-dystroglycan component of the DGC. Dystroglycanopathies are used in this study as a model of disrupted BMs to explore their potential for use in future AD research where the analysis of amyloid-β along compromised BMs is valuable.
This study investigates how the general morphology and contours of vessels is altered in dystroglycanopathies in human brain tissue by immunohistochemical staining for collagen IV involves a comparison of both staining and blood vessel diameter between dystroglycanopathies and normal tissue. Our results so far demonstrate that Dystroglycanopathies exhibit observably weaker staining for collagen IV and a statistically significant greater blood vessel diameter possibly due to a thickened BM. BMs in dystroglycanopathies appear to be more rugged and tortuous indicating structural irregularities which may result in a functional deficit. Using these observations we will employ experimental studies on mice with disrupted dystroglycan complex to stud the capacity for removal of amyloid from the brain.

Project Status: Closed

Research Outputs: Publication

DatePhD Thesis
2015 The Pathway of Elimination of Amyloid β from the Brain: Significance for the Pathogenesis of Alzheimer’s Disease & Cerebral Amyloid Angiopathy

BRAIN UK Ref: 15/004
Possible ectopic Endothelin secretion in liver cancer resulting in PRES
Dr A Salek-Haddadi, Royal London Hospital – Barts Health NHS Trust

Small investigation of an unusual neurological complication of a liver tumour (Posterior Reversible Encephalopathy Syndrome – PRES) to see if ectoptic Endothelin production/secretion by the liver tumour may have had a role to play.

Project Status: Closed

BRAIN UK Ref: 15/018
A morphological assessment of the white matter in CAA
Dr. R Carare, University of Southampton 

The build up of waste products like amyloid plaques, which are protein pieces, in the walls of arteries is a common cause of stroke and is also commonly observed in Alzheimer’s disease. The build up of amyloid is an indicator of the brain’s failing ability to remove waste along the walls of blood vessels. Some arteries do not develop amyloid deposits but rather have enlarged spaces around them that can be observed on MRI scans. We are fortunate to have brain tissue from two patients with amyloid deposits. In this project we propose to apply our expertise in the analysis of blood vessels of the brain together with advanced microscopy to compare the structure of blood vessels in the same patient between amyloid-laden arteries and arteries with enlarged spaces around them. We will also compare this tissue with some from ‘healthy’ brains. The findings will allow to identify unique differences that will shed light on why the enlarged spaces appear around some vessels in the same patient that also has amyloid deposits.

Project Status: Closed

BRAIN UK Ref: 16/006
Identification of early onset cerebral amyloid angiopathy (CAA)
Prof. S Brandner, University College London 

A proportion of strokes with bleeding into the brain (so-called haemorrhages or haematomas) are caused by the deposition of an aggregated protein called amyloid-beta in the walls of the blood vessels, which makes them brittle, and prone to rupture and bleed. The vast majority of such amyloid-beta deposition occurs without known cause and a smaller proportion is caused by genetic risk factors and can be predicted to some degree. However, in addition there is a distinct possibility that amyloid-beta deposition can be transmitted through medical procedures. Such transmission is extremely rare and has so far been shown only in patients who had received medical treatments containing human-derived tissue.

Here, we want to investigate if similar changes can also be found in patients who underwent surgical or neurosurgical procedures in the distant past. This would raise the concern that amyloid-beta pathology may also be transmitted through contaminated surgical instruments. Identification of potential sources of contamination are important for adequate risk assessment and evaluation of the methods used for surgical instrument decontamination and thus will have a significant impact on public health.

Project Status: Active

 DatePublication title
 2018  Evidence of amyloid-β cerebral amyloid angiopathy transmission through neurosurgery.
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BRAIN UK Ref: 17/015
Inflammatory and vascular changes after brain haemorrhage: a neuropathological assessment of human tissue
Dr Anan Shtaya, St George's, University of London 

Bleeding into the brain (a brain haemorrhage) happens in 10 to 15% of all strokes. It is also called ICH (intracerebral haemorrhage). When this happens the chances of dying or being disabled are much higher than a stroke caused by a blood clot (an ischaemic stroke). ICH is a medical emergency because of the high risk of brain injury and dying of brain cells. In certain situations surgery may be a treatment option. If surgery can be done quickly, the blood mass in the brain (haematoma) can be reduced, which reduces the inflammation and swelling in the brain. This potentially can reduce nerve cell death but the overall benefit from surgery to date is limited.

While clinical trials have explored the role of surgical removal of the blood mass and/or dissolving it, the reaction of the brain while trying to resolve the blood mass and repair the damage is still unclear. Animal studies have shown activation of not only an inflammation process but also an anti-inflammation (repair) process following ICH. If the anti-inflammation process is activated in human that ICH can be better treated. In our study, we would like to investigate the inflammatory and anti-inflammatory responses after ICH in post-mortem human brains to help understand how the human brain repairs itself and absorbs the haematoma. Our results may guide future studies and/or treatment approaches to treat ICHs.

Project Status: Active

 DatePublication title
 2019 Rapid neuroinflammatory changes in human acute intracerebral haemorrhage. 
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BRAIN UK Ref: 19/006
Quantitative analysis of brain vascular pathology in cerebrovascular cases of the Corsellis Brain Collection
Prof Raj Kalaria, Newcastle University NHS Hospitals Trust 

The West London NHS Trust has provided 240 cases of fixed brain tissue from the Corsellis Collection, a historic collection dating from 1950’s to the 1990’s which has now been disbanded.  Newcastle will use the tissue to quantify the extent of brain vascular pathology in terms of the number and location of strokes of different sizes, small bleeds and large brain haemorrhages.  We, specifically aim to address the following questions:

1) Is the distribution of cerebrovascular changes (changes affecting the flow of blood through the brain) in the older Corsellis collection different from that in the more recent Newcastle collection from the Cognitive Function After Stroke (CogFAST) and Vascular Dementia (VaD) studies? 

2) What are the frequencies (and degree of artery narrowing) of intracranial atherosclerosis and arteriolosclerosis (the thickening and stiffening of the arteries due to the build-up of fats, cholesterol and other substances in and on your artery walls (plaque), which can restrict blood flow)?  The comparison would be in brains from the Corsellis collection and the cerebrovascular cases (participants who have strokes and other brain and blood vessel conditions) in Newcastle, collected two decades later.  This may relate to changes in discernible vascular health and lifestyle factors.  

3) Determine frequencies of cognitive impairment no dementia (individuals whose cognitive functioning falls below normal but who do not meet dementia criteria) and dementia cases in the Corsellis collection with those in the CogFAST and VaD studies to determine thresholds for dementia. The study will help us define the critical causes of brain vascular changes which cause dementia. 

Project Status: Active

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