Objective/Rationale:
Our proposal aims to determine the optimum combination of techniques to detect rate of cognitive decline in people with newly diagnosed Parkinson’s disease (PD). We will apply neuropsychological testing, brain imaging (MRI), analysis of cerebrospinal fluid obtained via lumbar puncture and a simple neurophysiological technique to characterise patterns of cognitive impairment in people with PD and explore how well these tests (also known as biomarkers) predict rate of cognitive decline.
Project Description:
We will recruit approximately 150 people with newly diagnosed PD into this study and obtain their consent to undertake MRI brain scanning, lumbar puncture and neurophysiological testing. These participants will be followed up will be every 18 months. We will measure cognitive function using a battery of detailed tests at first visit and then at each 18 month visit. The study is being “piggy-backed” onto a Parkinson’s UK funded programme, thus providing significant value for money to both the UK funder as well as The Michael J Fox Foundation. Consequently, over 120 subjects have already been recruited, thus making our objectives feasible and realistic.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Finding the best combination of biomarkers is important to predict clinical course, increase diagnostic accuracy and monitor the biological effects of new treatments. The techniques used in this study are widely available and should clarify which combination can best characterise different sub-groups of cognitive impairment in people with PD, and their relevance to prognosis. Additional valuable information will be available through extended follow up and pathological study, both of which are integral to the overall project.
Anticipated Outcome:
Through this work we hope to determine:
(a) The correlation of biomarker outcomes at baseline with cognitive profiles.
(b) The predictive value of deficits in specific cognitive domains (for example, forgetfulness, difficulties in planning tasks) for global cognitive decline at 18 months.
(c) The additional sensitivity and specificity that biomarkers (i.e. MRI outcomes, cerebrospinal fluid proteins and a neurophysiological value believed to reflect chemical changes in the brain), either alone or in combination, bring to the clinical assessment in predicting global cognitive decline at 18 months.
(d) Whether biomarker changes over 18 months correlate with change in cognitive performance, and which measure, either alone, or in combination, is most sensitive to clinical outcome.
Final Outcome
Our first major finding was that mild memory problems (so called “mild cognitive impairment”) were common, even in early Parkinson’s disease, with 42.5% of our participants affected. Those with evidence of mild cognitive impairment tended to be older, were more severely affected by their Parkinson’s disease and had higher depression scores than those without mild cognitive impairment. In a subset of patients who underwent examination of their cerebrospinal fluid by means of a lumbar puncture, lower levels of a specific protein (amyloid) were found in those who had mild cognitive impairment, indicating that future ‘disease-modifying’ treatments could be aimed at these participants. In addition, this gives us added information as to why some people develop dementia in Parkinson’s disease, and suggests that some of the pathology seen in Alzheimer’s disease may also be present.
A number of patients also had electrophysiological tests, which involved magnetic stimulation of the brain with electrical stimulation of a nerve in the arm, which showed that those with problems with their thinking and memory had lower levels of acetylcholine (a neurotransmitter). Again this highlights patients with Parkinson’s disease who may be at risk of dementia in the future. Lastly, some participants underwent an MRI of their head, which showed definite differences between the groups with and without cognitive changes. These data are at baseline assessment, with further analysis ongoing for when the participants were seen at 18 months.
Researchers
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David John Burn, FRCP, MD, MA, MB BS