The burden of neurodegenerative conditions, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), is a major challenge facing society and the scientific community.

In the United States alone¹, 5 million people have AD and a further 1 million live with PD. Without further intervention, it is estimated that more than 12 million people in the United States will have a neurodegenerative disease within 30 years.

With no cure currently available for any neurodegenerative disease, there is an urgent need to develop new diagnostics and treatments that can make a meaningful difference to disease progression.

One of the major challenges to achieving this is the fact that neurodegenerative diseases take years to develop. Molecular changes can occur years before symptom onset², at which point interventions may simply be too late.

Indeed, one suggested reason³ for the failure of clinical trials for AD is the fact that once patients have symptoms and are eligible for a trial, it is not possible to reverse the damage and rescue cognitive function.

To change this outlook, we need to see what is happening in the brain much earlier on in the disease process. There is an urgent need to identify robust biomarkers of aging and neurodegeneration to effectively target interventions that will slow or reverse these destructive processes.

However, while DNA sequencing has revealed a number of genes linked to the risk of neurodegenerative disease such as APOE in AD⁴, these variants are not highly predictive. They don’t accurately reflect the phenotype and pathology of the aging brain.

Only the proteome – the ultimate output of the genome – provides a true view of what’s going on at a biological level in health and disease.

Accessing the Brain Through Proteomics

It is challenging to get a direct window into the brain compared with other parts of the body. While it is sometimes possible to obtain post-mortem or surgical biopsies, you are unlikely to be allowed to biopsy the brain in a living patient. And although tools such as MRI provide a useful insight into anatomy, imaging is expensive and typically cannot reveal molecular-level changes.

This is where biofluids – including blood and cerebrospinal fluid (CSF) – become extremely useful. Both blood and CSF contain a host of molecules, including proteins, which can indicate and track disease progress in neurodegenerative disease – and there are many more to be discovered.

At Biognosys, our mass spectrometry-based TrueDiscovery™ platform offers a Biofluid Biomarker Discovery solution that provides an unbiased profile of the proteins in biofluids, including plasma and CSF, at an unprecedented scale, depth, and sensitivity.

CSF is a known reservoir of neurologically relevant peptides. However, conventional methods of biomarker quantification in CSF face a compromise between sensitivity and multiplexing.

Our TrueDiscovery™ platform offers robust and unbiased whole proteome analysis at <pg/mL sensitivity in CSF.

We are now able to identify and quantify 5,000 proteins in CSF. This is more than double the depth of analysis we obtained in our 2020 pilot study in AD. It revealed more than 70 dysregulated proteins that we used to define a novel biomarker panel for effective patient stratification.

Furthermore, although the blood-brain barrier separates the brain from many compounds found in blood, there are still biological clues to neurological health and disease in the bloodstream. There is also mounting evidence to suggest that systemic events measurable in blood – such as inflammation⁵ and metabolic dysfunction⁶ – affect the risk of neurodegenerative disease.

Our Biofluid Biomarker Discovery solution for plasma provides unprecedented depth and sensitivity across the whole proteome. As a result, it offers the opportunity to identify biomarkers of neurological disease onset, progression, and treatment response that could be more easily monitored through blood testing than CSF sampling.

In addition, where brain tissue samples are available, our industry-leading Tissue Biomarker Discovery solution can reliably identify and quantify up to 13,000 proteins, including multiple post-translational modifications, in both formalin-fixed and fresh-frozen samples.

Whether you’re exploring CSF, plasma, or brain tissue, our proteomics solutions provide a detailed exploration of biologically relevant and highly informative neurological and pathological biomarkers across the whole proteome.

An Unbiased Map of the Proteome in Aging and Neurodegeneration

Our latest research, in collaboration with Abhay Moghekar, Research Director of the Cerebrospinal Fluid Center, Department of Neurology at Johns Hopkins University School of Medicine, Baltimore, and presented at ADPD this year, applies the approach before AD has been diagnosed.

We analyzed 133 matched blood plasma and CSF sample pairs in people undergoing healthy aging and those in the earliest stages of AD, known as mild cognitive impairment⁷.

After processing the samples and performing analysis using our SpectroMine™ and Spectronaut™ software, we were able to identify and quantify more than 50,000 peptides associated with around 4,800 proteins in CSF. We measured a further 35,000 peptides associated with around 2,800 proteins in plasma.

Several of the proteins we identified have well-characterized links to neurodegenerative disease. For example, amyloid-precursor protein⁸, tau⁹, and beta-secretase 1¹⁰ have roles in AD, alpha-synuclein¹¹, which forms aggregates in PD, and the neurofilament proteins¹², which are valuable biomarkers in a range of neurological disorders.

We also assessed numerous post-translational modifications, truncations, and isoforms, all of which can affect protein function.

Bringing Hidden Pathways to Light

As our latest research shows, insights from proteomics can identify and validate biomarkers for neurodegeneration in both CSF and blood plasma, including novel markers of disease progression.

As well as identifying biomarkers for early diagnosis and response to treatment, proteomics can also improve our fundamental understanding of the disease process, which could lead to new targets for research and drug development.

What’s more, our proteomics technology is completely transferable across samples and species. As a result, it has a diversity of applications in research across the entire drug discovery journey, from lab to clinic.

Ultimately, the data provided by our TrueDiscovery™ platform in CSF, plasma, and tissue have the potential to generate new insights into the underlying biology of neurodegeneration. In turn, this could better identify and stratify patients and – crucially – help deliver treatments to patients when it is still possible to make a difference to their outcome.

Get in touch with our Director of Scientific Alliances, Yuehan Feng, Ph.D., for more information.

References

1. https://neurodiscovery.harvard.edu/challenge
2. years before symptom onset
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966425/
4. APOE in AD
5. https://www.frontiersin.org/articles/10.3389/fimmu.2021.796867/full
6. https://pubmed.ncbi.nlm.nih.gov/29562518/
7. https://www.nia.nih.gov/health/what-mild-cognitive-impairment
8. https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=351
9. https://www.ncbi.nlm.nih.gov/gene/4137
10. https://www.ncbi.nlm.nih.gov/gene/23621
11. https://www.ncbi.nlm.nih.gov/gene/6622
12. https://www.nature.com/articles/s41582-018-0058-z

[Sources – for info only]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027455/
https://www.sciencedirect.com/science/article/pii/S1053811920311617
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966425/
https://www.nature.com/articles/s41380-021-01249-0