Parkinson’s Disease (PD) is a debilitating progressive neurodegenerative disease that affects about 145,000 people in the UK and between 7-10 million people worldwide. Typified by tremors, slow movements and stiff or inflexible muscles, PD is caused by the lack of dopamine in the brain as nerve cells are lost from an area of the brain called the substantia nigra. Alongside the characteristic symptoms of PD, many patients also experience problems with balance, memory, sleeping, loss of smell and depression and anxiety. Whilst common in the elderly, PD can afflict people much younger, in their 40s-50s and even younger, up to 10% of patients diagnosed are aged less than 50 years. To date, treatment for PD has focussed on increasing or replacing dopamine.
In the early stages of disease, stimulating remaining dopaminergic neurons with dopamine agonists such as pramipexole or ropinirole to increase cellular dopamine is a key approach. These are taken either alone or in combination with the most common treatment for PD, levodopa (L-dopa), which artificially increases the levels of dopamine in the brain. Levodopa however is a double-edged sword, with its ability to treat PD symptoms diminishing over time as it contributes to motor complications and dyskinesias compromising patient functionality and well-being. To assist the efficacy of levodopa COMT inhibitors (Catechol-O-methyl transferase inhibitors) may be added to prevent the body breaking down levodopa before it reaches the brain to facilitate levodopa’s action. These drugs can reduce the impact of levodopa ‘wearing off’ leading people to be frozen. All of these approaches attempt to increase the levels of dopamine in the brain through the body’s own reserves or artificially. Yet despite these medications, for many patients with PD, their lives remain blighted with dyskinesias, somnolence, development of compulsive behaviours and psychosis.
Parkinson’s Disease – emerging and future treatments
Treatments that explore other avenues are emerging and are exciting. One of these already in clinical practice is deep brain stimulation (DBS), which stimulates the brain to treat motor symptoms such as tremor. It’s not suitable for everyone and has high cost implications for healthcare systems but for those patients for whom it is effective the impact on their lives can be transformative…a theme we will return to.
Immunity and the gut
Misfolding of proteins like α-synuclein is a key component in PD besides dopamine loss and the ability of the body to stage an immune attack against genetically abnormal proteins such as α-synuclein in PD has been shown to potentially aggravate disease progression. Similarly, could α-synuclein be trafficked by the gut-brain super highway via the vagus nerve from the intestine to the brain? Would that mean PD is triggered by the gut and not the brain? Research in 2018 suggested that in the gut α-synuclein is useful in the intestines to fight invading gut pathogens and that they, and bacteria themselves, can promote protein misfolding.
Interestingly, patients with PD often have glucose intolerance and research suggests a correlation between glucose intolerance and misfolded α-synuclein. Studies of anti-diabetic drugs such as exenatide suggest a positive effect on PD OFF period scores, results of which need to be examined in longer term studies.
To explore the role of the gut, research into the role of anti-diabetic drugs like liraglutide and exenatide and the role of bacteria in the gut microbiome are ongoing with the prospect of positive results very exciting. Drugs to target the immune system already exist and more are in the pipeline. One such immunotherapy in development is the antibody BIIB054 by Biogen which is under investigation but has shown positive results in a preclinical study to limit α-synuclein aggregation, reduce dopamine neuron loss and reduce motor symptoms.
Harnessing the future with natural growth factors?
One of the most exciting developments however is a recent study, the subject of a BBC documentary, that explored the role of glial cell line-derived neurotrophic factor (GDNF) using direct brain delivery through a skull mounted transcutaneous port over 5 years. GDNF is a naturally occurring growth factor that can protect and promote the survival of dopaminergic neurons, and has been explored using nanospheres as a delivery vehicle in animal models. The challenge has always been how to deliver it directly to the brain…potentially overcome by direct delivery.
Results by Wohne et al. from the study population overall were not clear cut but suggested that OFF periods were reduced compared with placebo (17.3% compared with 11.8%) although this was not significant across the population overall (p=0.41). And, in patients treated with GDNF, improvements continued with a reduction in OFF periods of 27.6% at 40 weeks which stabilised up to 80 weeks where the reduction was 26.7%.
If you look at the cohort and the study overall, the primary endpoint was missed. However, it’s clear that if you look at individuals within the study, some patients experienced very significant improvements whilst others did not and GDNF elicited significant increases in dopamine in the brain as measured by PET scans. As above, for those for whom GNDF was effective, the impact on their lives was transformative. The key now is to understand why GDNF works for some and not all and how future studies might be designed. It was clear that across the patient cohort there is the potential to increase the delivered dose of GDNF and future studies will need to be long-term 80-week studies (at least) in order to really understand the real effects. Read the story of one of those study participants at www.cureparkinson.org.uk.
Be precise in PD – is it now time?
It seems evident, looking at treatment outcomes and research studies, including recent GDNF data from the group in Bristol UK, that PD is not a ‘one size fits all’ disease. Rather it is a multifaceted disease with multiple pathologies leading to the complex motor and non-motor symptoms observed in patients. Should we now consider how the treatment of neurodegenerative diseases like PD need to be individualised, taking into account each patient’s genetic and disease progression profile so that new treatments such as GDNF can be used effectively?
What is absolutely true is that research in PD will remain challenging, and at times hugely frustrating, and will require an integrated approach from patient groups, pharmaceutical companies and scientists to take treatment to the next stage. However, data from the last few years give us a glimpse of some truly exciting developments with the potential to help people triumph over PD rather than sometimes feeling PD has the upper hand.
Michael J Fox Foundation – www.michaeljfox.org
Parkinson’s Disease Net – www.parkinsonsdisease.net
Parkinson’s UK – www.parkinsons.org.uk
Scheperjans F et al. J Parkinsons Dis 2018;8(Suupl 1):S31-S39
Stolzenberg E et al. J Innate Immun 2017;9:456-63
The Cure Parkinsons Trust – www.cureparkinsons.org.uk
Weihofen A et al. Neurobiol Dis 2019;124:276-288 – (Access the paper at: https://www.sciencedirect.com/science/article/pii/S0969996118304480?via%3Dihub)
Wohne A et al. Brain 2019;142:512-25 – (Access the paper at: www.ncbi.nlm.nih.gov/pmc/articles/PMC6391602/pdf/awz023.pdf)
Wohne A et al. J Parkinsons Dis 2019;Feb 26. Doi:10.3233/JPD-191576