Research Decoder: Outcome measures II – Imaging

hIn the last Research Decoder, I went over some of the most common clinical outcome measures used to evaluate the efficacy and safety of new or repurposed interventions for MS in clinical trials. Clinical outcome measures are invaluable in that they provide a quantitative measure of how disease course and disability – characteristics that directly affect a participant’s health and quality of life – are influenced by an intervention, but they don’t necessarily tell the complete story. In part II, I’ll be taking a deeper dive into some of the other outcome measures that help to fill in the missing pieces of the puzzle.

Radiological measures

Imaging measures are less tangible and intuitive to study participants compared to changes in clinical measures – after all, while you can tell if your vision in one eye is diminished or if you’re feeling fatigued, you certainly can’t feel a lesion forming inside your brain. Nonetheless, imaging measures can be powerful and non-invasive indicators of how MS disease activity changes in response to an intervention by providing a window into the brain in vivid detail. Radiological endpoints are measured using advanced imaging technologies, including different types of magnetic resonance imaging (MRI) and optical coherence tomography (OCT).

  • Lesion counts and volume: MRI uses a number of different scanning techniques that allow specific tissues to appear vividly in an MRI picture. I won’t go into them in detail since the technology and physics involved can get quite technical, but I’ll give a quick overview: T1 scans with a special contrast that’s injected into the vein show areas of active inflammation – deemed lesions – in the brain and spinal cord due to the leakage of contrast out of the blood vessels in these damaged areas. T2 scans capture both new inflammation and old lesions (scars) and provide a record of both past and ongoing disease. Lesions in the myelin, or white matter, stand out as bright white spots on a T2 scan, and their distinct features also lend themselves to the measurement of their volume (size)

Sometimes the number of lesions will correlate with clinical outcome measures like relapse activity or the extent of disability, but sometimes they won’t since the extent and type of symptoms can depend on the location of the lesions, their size and the brain’s capacity to compensate (see a previous post on neuroplasticity). This frustrating phenomenon is called the “clinico-radiological paradox” and can complicate the interpretation of an MRI scan. Another challenge is determining whether changes in lesion counts correlate with response to a particular treatment during a clinical trial in such a complex disease as MS; in other words, what is their prognostic value?  To date, conventional MRI measures like T1 and T2 scans have demonstrated good prognostic value for disease course in the early stages (i.e. soon after diagnosis), but have produced mixed results for reliably predicting long-term clinical disability and progression (with T2 lesion volume showing some of the better correlation). Newer and less conventional imaging technologies as well as changes in brain volume (see below) are under investigation for their prognostic value relating to disability.

  • Brain volume: Changes in the volume of the brain are an indicator of loss of nerve cells and fibres, and whole-brain atrophy (i.e. a decrease in brain volume) is one of the best available imaging measures of disease progression that can help to test neuroprotective and reparative interventions that target neurodegeneration, especially when measured in tandem with active T2 lesions. This is especially important since neurodegeneration, or the loss of nerve cells, has been identified as a critical factor underlying disability progression in MS. Factors that can complicate interpretation of brain volume changes include fluid-related swelling of the brain and initial anti-inflammatory effects of disease-modifying therapies or other drugs, which must be properly taken into account.
  • Optical Coherence Tomography (OCT): The eye can provide a striking window into the state of the brain, and OCT imaging allows us to measure the thickness of the nerve fibres connecting the retina to the brain, as well as the volume of the macula, a part of the retina rich in light-sensitive cells. Not only can OCT capture loss of optic nerve fibres  related to vision, but changes in OCT measures also correlate well with changes in brain volume that are characteristic of disability progression, positioning OCT as a promising tool for measuring the efficacy of neuroprotective therapies.

In the last part of this Research Decoder, I’ll cover some of the newer outcome measures joining the ranks of clinical and imaging measures that will hopefully complete the full picture of how the disease responds to treatment and maximizes quality of life for people affected by MS.

References

  1. Lavery AM et al. (2014) Outcome Measures in Relapsing-Remitting Multiple Sclerosis: Capturing Disability and Disease Progression in Clinical Trials. Mult Scler Int. 262350.
  2. Gajofatto A et al. (2013) Clinical, MRI, and CSF Markers of Disability Progression in Multiple Sclerosis. Disease Markers. 35(6)687-99

Image credits: © Cornelius20 | Dreamstime.com – Brain Maze Photo

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