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UCL Queen Square Institute of Neurology

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Research

We have several topics of research focus:

Hypoxia

hypoxia image

Particular current interests derive from our discovery that neuroinflammatory lesions can be hypoxic, and sufficiently hypoxic to impair mitochondrial metabolism.  This impairment is especially likely in an inflammatory environment containing nitric oxide and superoxide. The hypoxia and energy deficit directly contribute to three of the cardinal features of MS, namely loss of function (symptoms), demyelination and degeneration.  Based on this realisation, our research explores novel protective treatment strategies that we are developing for clinical trial. One approach is to reduce energy demand by partial blockade of sodium channels. This therapy is also effective in dampening the activation of microglial cells (these cells can damage brain tissue), and we have recently shown the efficacy of one clinically relevant drug in this respect.  Therapies based on this new understanding have been examined in recent and ongoing clinical trials in MS and related diseases.  Encouragingly, such therapies can be very effective in neuroprotection, and they are also inexpensive and safe for long term administration.

Image: Inflamed spinal cord showing strong labelling for hypoxia in the grey matter.

Blood Flow

Blood flow in vessels indicated by fluorescent streaks
Impaired blood flow or hypoperfusion is becoming an increasing focus of our research, as it is likely to be the primary cause of the tissue hypoxia observed in neuroinflammation. Hypoperfusion is well established in MS with reports of reduced flow affecting both grey and white matter. The white matter (composed of myelinated nerve fibres) is particularly vulnerable to disturbances in blood flow, explaining why MS lesions have a predilection to form at sites known to have a vulnerable blood supply. Our evidence is that therapies aimed at maintaining or restoring blood flow improve neurological function and reduce structural damage, with major implications for the way MS is treated.

Image: Blood flow in vessels indicated by fluorescent streaks.  Long streaks (upper image) show fast flow through normal tissue, and short streaks (lower) show slow flow through inflamed tissue.

Mitochondria

Mitochondria are of particular interest in our research.  In the normal nervous system we have found that mitochondrial trafficking along axons is highly influenced by the level of impulse activity along the axons, which has implications for neurodegenerative disease.  In the inflamed nervous system we have discovered that many axonal mitochondria become non-functional, which starves the axons of energy.  In fact our evidence is that the energy insufficiency can cause conduction failure (and hence symptoms) and ultimately degeneration.  We have also investigated how mitochondria become damaged in diabetic axons, and how this damage contributes to diabetic neuropathy.

retinal vasculature

Image: Retinal vasculature revealed as a shadow over green fluorescence due to ongoing retinal mitochondrial respiration.

excessive superoxide production

Image: Excessive superoxide production in inflamed tissue on the left of the spinal cord.

Model of the early MS lesion

early lesion
We have developed and characterised a model of the Pattern III (hypoxic) type of demyelination found in early MS lesions.  The model lesion demonstrates the prominent role of innate immune mechanisms in lesion formation. The lesion provides an excellent opportunity to test the efficacy of putative therapeutic agents.

Image: Pattern III demyelination (circled), as occurs in early MS lesions.

Model of ‘slow-burning’ neurodegeneration

Model of slow-burning neurodegeneration
Among our experimental models is a new focal lesion of ‘slow burning’ degeneration of the grey matter, consequent to a neuroinflammatory event.  The lesion commences after a short delay following induction and it causes slowly progressive disability that advances hand in hand with progressive neurodegeneration and atrophy of the grey matter.  The lesion shares many features with progressive MS, and we are exploring the underlying mechanisms in the belief that this will indicate rational neuroprotective strategies.

Image: Grey matter atrophy (left) and mitochondrial failure (asterisk) in a lesion of slowly progressive neurodegeneration.

Techniques employed

  • electron microscopy
    Confocal microscopy to monitor mitochondrial dynamics and membrane potential (a measure of mitochondrial metabolism/health), blood flow, tissue metabolism and inflammation in real time
  • Electrophysiology to monitor changes in neurological function
  • Light and electron microscopy, including a range of immunohistological methods to determine the metabolic and cellular consequences of inflammation
  • Tissue oxygen monitoring by ratiometric oxygen sensitive fluorescent tracer, optical probe and immunohistochemical methods
  • Near-Infrared Spectroscopy (NIRS) using non-invasive methods to monitor mitochondrial function and tissue oxygenation within the brain
  • Multispectral Imaging for non-invasive monitoring of retinal tissue oxygen concentration

Image: Electron microscope image showing a normal myelinated axon (left) and a demyelinated axon (right).