Boom or bust in biomarkers: is the heterogeneity of PD slowing our search?

If we follow the model of progressive neurodegeneration over many years, there is a prolonged period in which largely non-motor symptoms start to make themselves evident -- before neuronal loss is sufficient to cause the clear motor symptoms that lead to clinical diagnosis. 

On a broad interpretation, markers that chart this progress encompass both disease biology and the underlying pathological processes: so they include non-motor (and early motor) signs and symptoms, as well as imaging and biochemical markers. In addition, there are risks of prodromal PD that can be attributed to gene mutations and environmental exposure, as well as age and sex.

But there are clear difficulties, Daniela Berg told the recent conference James Parkinson – An Essay on the Shaking Palsy 1817: A Celebration of 200 Years of Progress, organised by the International Parkinson and Movement Disorder Society (MDS).  A fundamental consideration is the heterogeneity of PD – both manifest and prodromal.

If a clinical diagnosis of PD (with all its phenotypic variability) is a common destination arrived at via many different pathogenetic pathways, then finding markers to plot progress along each route to diagnosis will be complicated.

What if Parkinson’s Disease is not a single entity, but many related disorders?

Combining markers

There are also specific issues, such as the fact that we have different tools for assessing non-motor symptoms, and none has achieved universal acceptance. It is highly likely that we will continue to need a combination of markers, rather than being able to refer to a single definitive one. So REM-sleep behaviour disorder, while clearly relevant, needs the support – for example -- of olfactory deficits, or constipation, or daytime somnolence, or mild motor dysfunction.

That said, progress is being made. The recent MDS paper on research criteria for prodromal PD uses Bayesian statistics to estimate the contribution made by the sequential addition of risk factors and non-motor markers to the diagnosis of probable prodromal PD, defining that as 80% or greater certainty that the condition is present.¹

Body fluids

Turning to markers in body fluids, we do not know whether CSF markers of oxidative stress or immune function, or levels of growth factors, reliably reflect processes in the brain. Findings to date are inconsistent, but blood-derived markers show some promise, with interest in measuring mRNA and plasma apolipoprotein A1 (ApoA1), for example. Low levels of the latter have been associated with lower age of PD onset and greater severity of motor symptoms, suggesting a possible longitudinal marker of progression.²

We need markers to aid diagnosis of prodromal PD and we need markers of progression  

Since Parkinson’s is a disorder of protein aggregation, proteomics is an obvious avenue to explore. But 27 studies have identified a bewildering array of more than five hundred different markers. On the other hand, LeWitt and colleagues have recently published evidence from the DATATOP group suggesting that sequential metabolomic profiling of patients with early PD might yield a biochemical signature strongly related to disease progression.³

Heterogeneous histology and genetics

Among histological markers, there is hope that alpha synuclein deposits in an accessible tissue such as the skin may help. Tolosa and Vilas have suggested that phosphorylated α-synuclein in skin nerve fibres differentiates Parkinson's disease from, for example, multiple system atrophy.⁴

But there is again an overall lack of coherence in the literature. This could be because of different methods of tissue sampling and handling and analysis. More worryingly, it could be because PD is not a single entity but many related disorders, perhaps defined by heterogeneous genetics, and certainly characterised by widely differing ages of onset.

Alberto Espay, of the University of Cincinnati, has suggested that PD may be at least twenty different diseases. If this is anywhere near the true picture, our search for biomarkers will be long and complex.⁵ If we are to succeed in developing neuroprotective agents – rather than symptomatic treatments -- neurology may have to parallel developments in oncology, which took forty years to progress from the earliest cytotoxics to agents targeted at specific molecular lesions.

As a starting point, Espay suggests we distinguish between three levels of diagnostic criteria: a clinical tier defined by meeting the MDS criteria for diagnosis; a pathological tier in which it can be demonstrated that there is alpha-synuclein in the substantia nigra; and a third genetic/molecular tier in which we can show presence of a PD-associated abnormality such as an LRRK2 mutation.

There are now more than four hundred papers on biomarkers in PD – a veritable boom. But it will clearly take more than this to bring us into the era of precision medicine. On the positive side, if we look world-wide, 44 clinical cohorts are under study, containing in total fifteen thousand patients. If information from these various initiatives could be brought together, we would be in a better position to start stratifying patients by likely pathogenetic processes, such as mitochondrial involvement, or inflammatory markers, or dominant motor or non-motor clinical presentation.