Projects

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 symptoms. 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
• Kubra Ozturk, PhD student
• Zhiyuan Yang, PhD student
• Yiqing Xia, Visiting scientist

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
• Prof. Kenneth Smith, PhD

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 are exploring 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. We also study potential therapies to protect against the acute and chronic deficits.

• Dr. Erika Aguzzi, PhD 
• Dr. Roshni Desai, PhD
• Prof. Kenneth Smith, PhD 
• Zhiyuan Yang, PhD student

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 
• Prof. Kenneth Smith, PhD  
• Zhiyuan Yang, PhD student 

Cerebral small vessel disease (cSVD) encompasses a range of pathological conditions affecting the cerebral vasculature, with various causes. About half of patients with a 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 the Fondation Leducq focusing on the role of perivascular space in the pathogenesis of cSVD. We use a laboratory model to study the development of changes in blood-brain barrier, microglial activation and tissue oxygenation.  We use in vivo confocal imaging combined with oxygen-sensitive microspheres and near-infrared spectroscopy to examine cerebral perfusion, vascular dysfunction and histological techniques to assess tissue pathology. We also explore the value of agents to improve vascular perfusion in protecting cognitive function and tissue integrity.

• Dr. Roshni Desai, PhD
• Prof. Kenneth Smith, PhD
• Zhiyuan Yang, PhD student 
• Yiqing Xia, Visiting scientist