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Blood flow, oxygenation and neurological dysfunction

Neurological deficits in multiple sclerosis (MS) have traditionally been attributed to abnormalities in axonal conduction as a result of demyelination, however, increasing evidence suggests that inflammation alone is sufficient to impair function. Research from the laboratory has revealed that the inflamed CNS suffers from a significant reduction in blood flow, resulting in tissue hypoxia, which in turn leads to mitochondrial dysfunction and the expression of deficits. We can monitor oxygen gradients across vessels and tissue using different techniques, including, but not limited to, in vivo confocal microscopy and hyperspectral imaging, allowing us to understand oxygen delivery in the inflamed CNS. We aim to examine different models of MS to determine the downstream effects of impaired blood flow and tissue hypoxia, in order to develop rational therapeutic strategies aimed at restoring function by improving tissue perfusion and oxygenation. 

  • Dr. Roshni Desai, PhD
  • Prof. Kenneth Smith, PhD
  • Zhiyuan Yang, PhD Student
  • Arabella Lukas, MSc Student
  • Elena Rossi, MSc Student
  • Emily Payne, MSc Student  
  • Qiuhan Lang, Visiting student
Pattern III demyelination

Different demyelinating lesion subtypes have been described in MS, based on the mechanism of tissue damage. One particular subtype, Pattern III, has been described as ‘hypoxia-like’ due to the similarities to acute white matter stroke, and has been attributed to nitric oxide-mediated mitochondrial inhibition. We have developed an experimental model of the human Pattern III lesion, and have shown an important role for tissue hypoxia in lesion development. Thus, the model can be used to evaluate the efficacy of novel therapeutic agents, aimed at increasing oxygenation, on the formation of Pattern III demyelination and axonal degeneration.

  • Dr. Roshni Desai, PhD
  • Alice Kingslake, MSc
  • Ayse Gertrude Yenicelik, Visiting student 
  • Prof. Kenneth Smith, PhD
The newly forming lesion

The white matter in MS can appear to be normal upon superficial examination, by eye, or by MRI, but in reality is often highly abnormal, showing biochemical and histological abnormalities. One interesting feature is the presence of clusters or nodules of activated microglial cells that express pro-inflammatory cytokines, are closely associated with stressed oligodendrocytes, and damaged axons. We aim to identify the pathophysiological substrata of microglial nodules and determine factors responsible for their conversion into demyelinating lesions.

  • Dr. Roshni Desai, PhD
  • Prof. Kenneth Smith, PhD
The role of perivascular space in the pathogenesis of cerebral small vessel disease

Cerebral small vessel disease (cSVD) encompasses a range of pathological conditions affecting cerebral vasculature, with heterogenous causes. About half of patients with diagnosis of cSVD go on to develop stroke and/or dementia. Risk factors for cSVD include ageing, hypertension and diabetes.  Our lab is a part of an international consortium supported by Leducq Foundation focusing on the role of perivascular space in the pathogenesis of cSVD. We use spontaneously hypertensive rat to study the development of changes in blood-brain barrier, microglial activation and tissue oxygenation.  In addition, we introduce another risk factor, prediabetes induced with high fat diet, to examine the effect of commonly encountered comorbidities - diabetes and hypertension, on brain vascular function. We use in vivo confocal imaging combined with oxygen-sensitive microspheres to examine cerebral perfusion, and histological techniques to assess tissue pathology.

  • Dr. Marija Sajic, MD, PhD
  • Dr. Roshni Desai, PhD
  • Prof. Kenneth Smith, PhD
  • Miss Susannah Chilton, MSc student 
The role of mitochondrial and calcium homeostasis in the development diabetic polyneuropathy

Diabetic polyneuropathy (DPN) impacts over 50% of people with diabetes. It is a gradually worsening, irreversible disorder with symptoms such as pain, sensory loss, inability to recognise injury, and a 25% life-time risk of ulceration. Mechanisms are not understood and consequently there are no preventative or curative treatments. We focus on the role of mitochondria and calcium homeostasis in the development of DPN. We use high fat diet to induce type 2 diabetes in mice that are transgenically modified to express axonal or mitochondrial fluorescent markers or ratiometric calcium probes. We then visualise changes in mitochondrial morphology and membrane potential or intra-axonal and ER changes in calcium concentration in peripheral axons affected in diabetes, using confocal microscopy, in vivo. At the same time, we use electrophysiology to assess axonal function and/or mimic physiological levels of energy demand. Combining these techniques, we are able to build a comprehensive picture of axonal, mitochondrial and calcium dynamics during disease development. Recently we have extended the research to encompass other neurological complication of diabetes, such as effects of diabetes on central nervous system. We focus on changes in cerebral perfusion, oxygenation, microglia and mitochondrial function in type 2 diabetes. 

  • Dr. Marija Sajic, MD, PhD 
  • Prof. Kenneth Smith, PhD
  • Sophie Newton, MSc student 
  • Nikolaos Monios, MSc student 
  • Prof. Francis Edwards, collaborator 
  • Jonathan Brenton, PhD student collaborator
Neuroprotective strategies to prevent slow degeneration in a new model of multiple sclerosis

Multiple sclerosis (MS) is a central, neuroinflammatory demyelinating disease that causes neurological deficits due primarily to impaired neuro/axonal function in the short term, and primarily due to slowly progressive neuro/axonal degeneration in the longer term. Current evidence suggests that the acute neurological deficit can arise from inflammation, even in the absence of demyelination, although the mechanism(s) remain uncertain. Equally uncertain, is the cause of the slowly progressive degeneration. We aim to explore the mechanisms responsible for both acute and chronic deficit by studying a new model of MS that expresses a period of acute inflammation, and then a slowly progressive degeneration of the grey matter, which resembles the slow and progressive grey matter degeneration in MS. Simultaneously we intend to study different potential therapies to protect against the acute and chronic deficits. 

  • Erika Aguzzi, MSc, PhD student
  • Dr. Roshni Desai, PhD
  • Prof. Kenneth Smith, PhD 
Overcoming tissue hypoxia - a new role for oxygen and enhanced perfusion in the therapy of optic neuritis

The earliest symptoms of MS are often in the visual system and due to optic neuritis. The optic nerve lesions are typically demyelinating, and associated with neuro/axonal degeneration.  If degeneration is substantial, the visual disturbances will be permanent. Our research aims to study whether improved oxygenation of the lesion by increasing oxygen or blood supply can reduce the retinal and optic nerve pathology, as assessed by electrophysiological and histological examination. We plan clinical trials to examine our novel therapies, guided by our new finding that an energy insufficiency is an important and hitherto unappreciated cause of damage.

  • Dr. Cristina Marcoci, MD, PhD student 
  • Prof. Kenneth Smith, PhD  
The effects of iron deficiency and iron repletion on mitochondrial morphology and function in a model of disease

Iron is a vital micronutrient that is an essential component in many biological processes, including energy production within the mitochondria. Iron deficiency is the leading cause of anemia worldwide and is a serious condition which affects the body globally. We aim to understand the understudied effects of iron deficiency and iron repletion on the mitochondria, using various techniques including enzyme-linked immunosorbent assays (ELISAs), immunohistochemistry and microscopy.

  • Katerina Cabolis, MSc, PhD student 
  • Dr. Marija Sajic, MD, PhD 
  • Mr. Toby Richards, MD, FRCS, collaborator
  • Prof. Kenneth Smith, PhD
  • Elika Darvishi, MRes student
  • Sabrina Weber, Visiting student 
Studying auditory function in neuroinflammatory disease

Hearing impairment can be an early symptom of MS and its onset has been correlated with disease relapses. Whether this hearing deficit is correlated with central or peripheral involvement of the auditory pathways is still unknown. An MS model is being used to evaluate the location of the lesions responsible for hearing impairment, and which areas of the auditory pathways (central or peripheral) are involved. The efficacy of vasodilation in reducing hearing impairment will be assessed using electrophysiology.

The prevalence of hearing and balance symptoms in MS is currently unclear and the symptoms are often underestimated. To determine their prevalence we are using a simple questionnaire to understand the experience of patients with particular symptoms.

  • Dr. Arianna Di Stadio, MD, PhD 
  • Prof. Kenneth Smith, PhD 
  • Prof. Jeremy Chataway, MA, PhD, FRCP
  • Dr. Thomas Williams, Clinical Research Fellow