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MR Imaging

Overview

There is an active and expanding programme of MRI research in the Molecular Neurogenetics Group. MRI can lead to a better understanding of the ways in which the brain is damaged in cerebrovascular disease, for example by revealing small areas of unsuspected haemorrhage or the true extent of ischaemic damage. Measuring the severity of damage, and monitoring its progression over time, can be helpful in clinical trials to work out whether new treatments are slowing progression. Research in the group has already shown just how useful MRI might be in this setting.

Brain imaging can also help us to investigate the mechanisms of cognitive impairment: this is a major focus of our future research. We are beginning to explore the pattern and severity of brain injury in much more detail, using both modern imaging techniques and advanced methods for computerised image analysis. The main new questions are:

  • How damage within certain regions of the brain like the frontal lobes, or particularly important structures like the hippocampus, may be linked to problems with certain important cognitive functions like executive functions or memory
  • The inter-relationships between different types of structural changes, such as the relationship between damage in white matter tracts and shrinkage or atrophy of the cortical regions that these tracts connect together

We are especially interested in the effects of disease in the cerebral blood vessels leading to forms of “vascular” dementia. This is commonly seen linked to high blood pressure, diabetes or other risk factors. To explore these aspects we are studying a disease called CADASIL, which is a rare, pure form of cerebrovascular disease caused by mutations in a gene called Notch3.

Paris-Munich study

This collaborative study builds on previous work by centres with two of the largest cohorts of CADASIL patients worldwide. The study aims to recruit approximately 300 patients with CADASIL and perform detailed MRI and cognitive assessments over a 3 year follow-up period.

In addition to the collaborating research groups in Paris and Munich, the study is being performed in co-operation with Theralys – an image analysis company based in Lyon. In this way, many of the lesion quantification techniques implemented are the same state of the art techniques applied in large clinical trials in diseases like MS.

So far, approximately 250 patients have been enrolled in the study and some of the cross-sectional data has already been published in journals including Brain (see below).

The Paris-Munich study involves close co-operation between research teams in Paris, Munich, and at Theralys. The team members at the present time include:-

  • Professor Hugues Chabriat (group leader - Hopital Lariboisiere, Paris) (articles )
  • PD Dr Martin Dichgans (group leader - Klinikum Großhadern, Munich) (articles )
  • Dr Chahin Pachai (CEO - Theralys)
  • Dr Frederique Buffon (Paris)
  • Dr Andreas Gschwendtner (Munich)
  • Dr Marco Düring (Munich)
  • Dr Eric Jouvent (Paris)
  • Dr Mike O'Sullivan (Munich and London)
  • Dr Anand Viswanathan (Paris and Massachussetts General Hospital, Boston, USA)

Advanced MR Imaging

Quantitative Lesion Measurements

Many studies continue to use simple visual rating scales for the extent of white matter lesions, which is likely to be insensitive and may not be well-suited to longitudinal studies. Full quantitative analysis of lesion burden has been performed by the group for a number of years. By applying these techniques, it has been possible to explore the relationship of lesions with cognitive status, assess potential sample sizes for clinical trials, and more recently determine the contribution of genetic factors other than the CADASIL mutation on disease progression.

Fully quantitative assessment of lesion burden is currently carried out by the image analysis company Theralys, with whom we have close links.

Current interests of the group include:-

  • the true nature of ‘lacunar lesions’ and their evolution over time
  • the influence of different lesion types – lacunar lesions and white matter lesions – on the clinical and cognitive features of CADASIL
  • the relationships between lesions and cerebral atrophy

Diffusion Tensor Imaging (DTI)

DTI is an advanced method that is well adapted to measuring structural change in cerebral white matter. Studies with DTI in ageing, sporadic small vessel disease and CADASIL have shown that the technique is able to detect changes in regions that appear normal to the naked eye, and more importantly, that changes on DTI correlate more powerfully with cognitive performance than visible lesion burden.

Brain Atrophy

For a number of years, accelerated shrinkage of the brain, or atrophy, has been recognised as a feature of degenerative dementias like Alzheimer’s disease. The degree of shrinkage has also been found to relate well to the clinical and cognitive progression of the disease. More recently, it has also been discovered that this is true of primarily white matter diseases like CADASIL. We have shown that atrophy is potentially a very good marker of disease progression for use in clinical trials. Atrophy has a number of potential advantages as a marker for trials:

  • Face validity. What this means is that when the brain is shrinking more rapidly than usual it is hard to argue that this is not necessarily a bad thing or does not reflect a more serious disease course.
  • Atrophy can be thought of as a final common pathway of various types of brain damage
  • It is becoming increasingly possible to measure atrophy with very high accuracy and reliability. Techniques to do this are becoming widely available. The most commonly used techniques are freely available to the scientific community.

Within the department we use two common and freely available image analysis packages to measure atrophy – SIENA (part of the FSL software, centre for functional MRI of the brain, University of Oxford) and SPM (Statistical Parametric Mapping, University College London). Please see the respective websites for more details:

Team Members

Collaborators

  • Dr Mike O'Sullivan (London)
  • Dr Philipp Sämann (Max Planck Institute of Psychiatry, Munich)

Selected Publications

O'Sullivan M, Jouvent E, Saemann PG, Mangin JF, Viswanathan A, Gschwendtner A, Bracoud L, Pachai C, Chabriat H, Dichgans M. Measurement of brain atrophy in subcortical vascular disease: a comparison of different approaches and the impact of ischaemic lesions. Neuroimage. 2008 Nov 1;43(2):312-20.

O'Sullivan M, Ngo E, Viswanathan A, Jouvent E, Gschwendtner A, Saemann PG, Duering M, Pachai C, Bousser MG, Chabriat H, Dichgans M. Hippocampal volume is an independent predictor of cognitive performance in CADASIL. Neurobiol Aging. 2007 Oct 24. Pubmed ExternerLink

Opherk C, Peters N, Holtmannspoetter M, Gschwendtner A, Mueller-Myhsok B, Dichgans M. Heritability of MRI lesion volume in CADASIL: evidence for genetic modifiers. Stroke. 2006 Nov;37(11):2684-9. Pubmed ExternerLink

Peters N, Holtmannspoetter M, Opherk C, Gschwendtner A, Herzog J, Saemann P, Dichgans M. Brain volume changes in CADASIL: a serial MRI study in pure subcortical ischemic vascular disease. Neurology. 2006 May 23;66(10):1517-22. Pubmed ExternerLink

Holtmannspoetter M, Peters N, Opherk C, Martin D, Herzog J, Brückmann H, Sämann P, Gschwendtner A, Dichgans M. Diffusion magnetic resonance histograms as a surrogate marker and predictor of disease progression in CADASIL: a two-year follow-up study.
Stroke. 2005 Dec;36(12):2559-65. Pubmed ExternerLink

Dichgans M, Holtmannspoetter M, Herzog J, Peters N, Bergmann M, Yousry TA. Cerebral microbleeds in CADASIL: a gradient-echo magnetic resonance imaging and autopsy study. Stroke. 2002 Jan;33(1):67-7. Pubmed ExternerLink