With motor neurone disease (MND), the muscle weakness almost always starts in a single part of the body, with the weakness then spreading to other muscles in an orderly fashion. Neurologists are usually quite good at predicting which muscles will be affected next, slightly less so at predicting when this will happen.
The physical changes on the outside will be reflecting events occurring in the ‘closed box’ that is the brain and spinal cord. The latest imaging techniques are starting to give us more of a picture of what’s happening in the central nervous system as the disease progresses, but further technological advances will still need to be made. The clearest picture still comes from the study of generously donated and incredibly valuable post-mortem tissue.
The second day of the Symposium saw researchers present in the Clinical-Pathological Correlates of Disease Progression session, focussing on how to understand disease progression, the role of prions in neurodegenerative diseases and the relationship between MND and frontotemporal dementia.
Over many years, Dr John Ravits (University of California, San Diego) has examined hundreds of central nervous system (CNS) tissue samples from dozens of MND cases. By carefully comparing pathology with the clinical symptoms, he has managed to build up a picture of disease spread, both up and down the spinal cord as well as from one side to another.
How the disease propagates from one degenerating motor neuron to the neighbouring more healthy motor neurons is not well understood, but some of the clues as to what might be going on come from another family of neurodegenerative diseases called prion diseases. Prion stands for ‘protainaceous infectious particle’ and the best known of these conditions is Creutzfeld-Jacob disease (CJD).
Prion proteins damage neurons by entering nerve cells and interacting with healthy proteins. They cause the healthy proteins to change shape, turning them into prion proteins as well, which can then escape the nerve cell to ‘infect’ another: a process that researchers call ‘seeding’.
So why are CJD and MND very different diseases if they use similar processes?
The answer is because entirely different proteins are at play in different diseases. Indeed, a ‘prion-like’ effect is not just limited to MND: it is also thought to occur in Alzheimer’s disease. Dr Mark Diamond (University of Texas) provided an overview of how a protein called ‘Tau’ appears to be the culprit for conditions such as Alzheimer’s disease and Progressive Supranuclear Palsy.
Dr Diamond has found that the spread of Tau protein occurs well in advance of any significant signs of cellular damage. He has developed a system for measuring the seeding of Tau between cells and finds that different ‘strains’ of Tau protein appear to be associated with different types of disease. The different patterns of strains could also feasibly help to speed up diagnosis in the future.
In addition, if the protein involved in Alzheimer’s disease is different, but the basic process of disease seeding and spread is the same, then similar strategies could be used for different diseases – each aiming at a different specific protein target.
So what is the ‘prion-like’ protein involved in MND?
There may be more than one: SOD is suspected of being able to spread from one cell to another (this work will be discussed in detail by delegates in Session 8A: Mechanisms of Intercellular Propagation on Saturday) but the suspect covered in this session was TDP-43, which shows some structural properties similar to prion proteins.
There are close pathological and genetic links between MND and some forms of frontotemporal dementia (FTD) with a proportion of FTD patients going on to develop MND symptoms. Prof Bill Seeley (University of California) has looked at the part of the brain where the upper motor neurons are found, in FTD patients, and sees the early signs of cellular clumping of TDP-43 protein – the classic pathological hallmarks of MND. He demonstrated using MRI scans of FTD patients, that the spread of pathology from one affected brain area to another may be linked to the connection between these brain regions. In other words, ‘what’s wired together dies together’.
The hope is that if the process of cell-to-cell disease transmission can be understood, then treatment strategies to stop it could mean that the spread of disease symptoms can be slowed. Who knows – if combined with faster and earlier diagnosis, perhaps symptoms could even be localised to the originating part of the body?