Last week, Nature magazine published a paper detailing an in-situ study of Parkinson’s disease (PD), showing protein structural changes in cerebrospinal fluid (CSF) between healthy individuals and Parkinson’s patients. There is potential that these structural changes could allow for a new method of differentiating different disease subtypes, thus expanding the scope for new PD therapeutics.
PD is a neurodegenerative disease associated with loss of motor function and cognitive impairment. In 2022, the World Health Organisation reported that the incidence of PD has doubled in the last 25 years with PD being the most prevalent movement disorder. The increased prevalence of PD is commonly identified as a symptom of an ageing society, affecting 1% of the world population over the age of 60.
Identifying Parkinson’s disease subpopulations
There is currently no cure for PD as current PD therapeutics only target the symptoms of the disease. The default Parkinson’s therapeutic is Sinemet (levodopa-carbidopa) which acts by replacing the body’s missing dopamine, thus improving motor control. However, Sinemet is only effective in those with Lewy body pathologies of PD. In PD pathophysiology, Lewy bodies are deposits which interact with chemical in the brain to cause neurodegeneration. This can later lead to PD-related dementia.
Currently, the majority of PD therapeutics and biomarkers are developed to diagnose and treat PD patients that show Lewy body pathology. However, according to the International Parkinson and Movement Disorder Society this accounts for 89% of PD patients, leaving the remaining 11% with scarce PD biomarkers available and thus scarce treatment options.
In the Nature article, 76 CSF proteins were found to be structurally altered in individuals with PD relative to healthy individuals, identifying a new PD biomarker. The study suggested that with further research, this biomarker could account for the diagnosis of the 11% of PD patients who lack Lewy body pathology and introduces the concept that global protein structural analyses could identify a new type of structural biomarker of a human disease.
Dr Alfonso Fasano, the chair in neuromodulation and multi-disciplinary care at the University of Toronto and University Health Network, commented on the growth in PD biomarker research saying, “There’s a lot of interest, in trying to figure out what biomarker can be reliable, sensitive, specific and more importantly, non-invasive, so that they can be used on a large scale and can be used more times in a single subject”. Thus, in recent years there has been major growth in PD biomarker research, aiming to allow the development of new diagnostic measures and new treatment strategies.
The search for Parkinson’s biomarkers
CSF biomarkers have been a popular area of interest in neurodegenerative disease research with previous studies related to Alzheimer’s and Multiple Sclerosis exploring the potential of their use. In PD clinical research, many biomarkers, such as neurofilament, can be measured within the CSF using a lumbar puncture. Technology such as RT QuIC has been developed to detect alpha synuclein within CSF. However, this is an invasive procedure, involving a spinal tap or a lumbar puncture. Furthermore, this biomarker only indicates the prevalence of PD, without giving any information about the patient’s stage of disease progression.
“There are many other biomarkers at this point under investigations. Non-invasive biomarkers in terms of brain MRI biomarkers or MRI technology are increasing. We can now look into brain physiology way better and there are several labs, trying to see whether we can use MRI to detect particular metabolites in the brain for example” says Fasano. However, such biomarkers do not give a specific indication of the patient’s PD subtype, which is important in the consideration of different treatment strategies.
Genetic biomarkers are being investigated to aid in the development of precision medicine for PD. “There are now a number of genes known to cause Parkinson’s disease when mutated or to increase the risk of developing the disease. So, the next logical step is to see what these genes do and try to correct deficit using drugs”, says Fasano. According to GlobalData, genetic mutations such as the GBA mutation are now being targeted in PD therapeutics with three GBA therapies in Phase II clinical trials.
GlobalData is the parent company of Pharmaceutical Technology.
However, issues remain when using genetic biomarkers in the development of PD therapies and PD research. “The problem with this is that not every patient will be eligible for these therapies. Because genetic forms of Parkinson’s disease are a minority of Parkinson’s disease patients, usually the early onset ones because the older the patient, the more heterogeneous is the variety of causes”, says Fasano. Thus, new biomarkers are being explored which may be more useful in identifying PD subtypes which are inclusive of older patients.
New CSF biomarkers
Fasano explains that a wealth of biomarkers allows for a better understanding of disease manifestation, early diagnosis, and subtyping of individuals with the disease is essential to direct the choice of treatment.
The recent Nature article detailed a study that used limited proteolysis-mass spectrometry to analyse the CSF of 52 PD patients and 51 healthy individuals. Researchers collected brain tissue samples from each participant, analysing the variability of protein structures between healthy individuals and individuals with PD. The research team identified 117 highly variable peptides originating from 64 unique proteins. Furthermore, the results showed that variable regions were more disordered, were more accessible to solvents, and had a higher propensity for mediating protein-protein interactions than non-variable regions. Out of these proteins, there were 76 structurally altered proteins in the CSF of individuals with PD with two of those corresponding to PD linked genes.
From these findings, it was shown that protein structural alterations in human CSF were able to distinguish those with PD from healthy individuals. The results also provided information correlating to the specific alpha-synuclein levels within a certain individual with 91% accuracy. Translation of this concept to clinical research will require validation in further independent cohorts as well as testing for specificity to PD versus other neurodegenerative diseases. However, these findings may indicate a new biomarker representing the 11% of the PD population that lacks Lewy body pathology and may also be helpful in research into different PD subtypes and late-stage PD.
With such studies into new biomarkers underway, Fasano expressed his optimism for PD clinical research saying, “We’re learning a lot and we learn something new day by day. So, I’m pretty positive we’ll get there”.