Selecting the best patient groups for clinical trials: insights from the CamPaIGN study of Parkinson’s disease

This post was inspired by a talk given by Prof Roger Barker, to whom all credit for the ideas below must be attributed. His group are also doing some very exciting work on cell based therapies and viral-RNA based therapies for PD which I plan to write about in the future.
 

In addition to identifying PD as early as possible, being able to identify those with a more severe, rapidly-progressing form of the disease would help with deciding who should be entered into clinical trials of disease-modifying therapies.

Longitudinal studies of patients with PD (such as the CamPaIGN study) have shown that while some patients with PD may have ‘good’ outcomes (no dementia or postural instability) even 10 years after their diagnosis, others may progress much more rapidly to getting dementia or postural instability [1].

This second group with a more rapidly-progressing underlying disease process, would be the ideal group with which to trial new potentially disease-modifying therapies, whereas those with a more ‘benign’ form of PD are likely to do well with dopaminergic based therapies.

Therefore, being able to predict whether a patient will have a benign or rapidly-progressing disease course is important, not only for patients’ and their families’ own information, but also to optimise who gets what treatment.

Luckily, the CamPaIGN study managed to identify a few factors which predict a rapid progression to Parkinson’s disease dementia, including:

• Age 
• Poor semantic fluency [1] – reduced ability to name as many animals as possible from memory in 90 seconds
• Poor overlapping pentagon drawing – poor ability to replicate the overlapping
• Having two copies of the H1 variant of the gene ‘MAPT’. This encodes a protein called ‘Tau’ which has been implicated in a number of neurodegenerative diseases, including Alzheimer’s [2]
• Having a single abnormal copy of the GBA gene. ALL the patients with a single GBA mutation in the CamPaiGN study developed dementia by 8 years. (GBA is a gene which causes Gaucher’s disease when two mutated copies are inherited. People with a single mutation do not develop Gaucher’s and are otherwise healthy, they are known to have an increased risk of developing PD)

 

This is a great example of how epidemiological evidence can inform clinical practice (by allowing doctors to more accurately assess prognosis), add to our understanding of the mechanisms of disease (in this case, by suggest a role for Tau in the pathology of Parkinson’s disease dementia) and help optimise our efforts to find new treatments for a disease (by helping to select the best patients for trials of new therapies).

References:

1. Williams-Gray CH, Mason SL, Evans JR, Foltynie T, Brayne C, Robbins TW, Barker RA: The CamPaIGN study of Parkinson's disease: 10-year outlook in an incident population-based cohort. J Neurol Neurosurg Psychiatry 2013.

2. Goris A, Williams-Gray CH, Clark GR, Foltynie T, Lewis SJ, Brown J, Ban M, Spillantini MG, Compston A, Burn DJ, et al.: Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson's disease. Ann Neurol 2007, 62:145-153.