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Biomarkers – ever closer in PD

For some time now, researchers have been seeking effective biomarkers for the diagnosis and management of Parkinson’s disease. And so far, such biomarkers have remained largely elusive. However, the work continues, as was reported at MDS 2018, and efforts are at last showing signs of yielding dividends.

Biomarkers – why do we need them?

Brit Mollenhauer, Germany, presented a case probably familiar to many neurologists. It concerned a patient who appeared to be in the early stages of Parkinson’s disease (PD). After a thorough and exhaustive work-up, all the available diagnostic criteria supported a diagnosis of PD. He responded well to levodopa, yet 2 years later, following his death, an autopsy revealed he had had multiple system atrophy. Clearly, his condition had been misdiagnosed.

53% of patients with early PD responsive to medication (<5 years) are misdiagnosed

What are the implications? It depends from whose perspective you view the situation. From the patient’s family’s point of view, having an accurate diagnosis would have allowed them to prepare better. From the doctor’s perspective, the management of the patient would likely have been different. From the pharmaceutical company’s perspective, he wouldn’t have been enrolled in a clinical study investigating de novo PD.

Misdiagnosis in PD is too frequent

Unfortunately, it appears that misdiagnosis is not an uncommon occurrence in PD. Adler et al. estimate that 53% of patients with early PD responsive to medication (<5 years) are misdiagnosed. This confirms the need for tissue or other diagnostic biomarkers in PD. 1

Properties of a good biomarker
  • Proximity to the disease/pathophysiology
  • Can be objectively measured
  • Independent validation optimally in an independent cohort and independent group/laboratory
  • Clinically meaningful e.g. correlates with clinical progression
  • Easy to collect and to process
  • Less affected by technical variability
  • High sensitivity for a diagnostic and a risk/screening marker 
  • High specificity for a marker of progressing alpha-synuclein pathology

However, as yet, Dr Mollenhauer did not consider any available biomarker fulfilled the criteria of a good biomarker. She urged all clinicians to join the Parkinson’s Progression Markers Initiative - PMMI - and to become biomarker researchers!

So what exactly is the state of play in biomarker research?

Fluids

Alpha-synuclein (a-syn) is an obvious target.  And substantial progress has been made in measuring normal and abnormal forms of a-syn in CSF, Douglas Galasko, USA, reported. Although there is still some way to go to overcome some of the limitations encountered, two approaches (RT-QUic and PMCA) appear highly sensitive and specific.

RT-QuIC and PMCA appear highly sensitive and specific in detecting alpha-synuclein aggregates in CFS

RT-QuIC – really quick detection of a-syn

Real-time quaking induced conversion (RT-QuIC) is a test developed by the NIH to allow the early diagnosis of prion disease. This test has been modified, hopefully to allow the early diagnosis of PD and dementia with Lewy bodies (DLB). The modified marker was used to test 60 samples of CSF collected from patients with PD, DLB and controls (a proportion of which has AD). The test correctly excluded all the controls and diagnosed PD and DLB with 93% accuracy.2

A-syn Protein Misfolding Cyclic Amplification (PCMA) permits the detection of tiny quantities of a-syn aggregates in CSF. In a comparison of CSF samples taken from 76 patients with PD and 97 patients with other neurological conditions, a-syn PCMA showed 88.5% sensitivity and 96.9% specificity for PD. Levels of a-syn PCMA measured also correlated with severity of clinical symptoms in PD. The authors suggest that a-syn PCMA could potentially form the basis of a non-invasive test for PD.3

Alpha-synuclein PCMA could potentially form the basis of a non-invasive test for PD

Solids

In terms of solid biomarkers, skin and salivary gland samples stained for phosphorylated- a-syn also show diagnostic promise. 4, 5 However, predictive and prognostic markers for PD are still lacking.

NfL – game on?

In terms of differential diagnosis, neurofilament light chain (NfL) protein in CSF is a promising marker for atypical PD. It has been shown that the CSF concentration of NfL is increased in atypical PD but not in PD. Hansson et al. have developed an ultra-sensitive single molecule array (Simoa) immunoassay for NfL and have shown that blood measurements of NfL can differentiate patients with PD from those with progressive supranuclear palsy, multiple system atrophy, and corticobasal syndrome. Thus, Nfl offers great potential as a blood based biomarker rather than CSF based biomarker that may be of use in differential diagnosis.6

Neurofilament light chain (NfL) protein in CSF is a promising marker for atypical PD

Imaging PD

As Antonio Strafella, Canada, reported there has been an explosion of papers in the past 5 years demonstrating the keen interest in finding new imaging biomarkers in PD. Given this level of interest, for many imaging biomarkers it’s still early days but three papers suggest there is reason for optimism.7-9

Multimodal approach may be beneficial

A-syn aggregation is thought to start in autonomic nerve terminals and spread to the spinal cord and brainstem. Much of this activity occurs before the onset of motor symptoms. Knudsen et al. investigated patients with REM sleep behavior disorder, a prodromal feature of PD, using multimodal imaging techniques that not only assessed dopaminergic but also sympathetic, parasympathetic and noradrenergic neuronal pathways. 7

It appears that in this group of patients with no motor symptoms of PD, pathology was already present in the peripheral autonomic nervous system and the locus coerulus. Furthermore, it was present at a similar level to what is seen in PD patients. While this paper supports the theory that pathology spreads from the periphery to the brainstem, Professor Strafella suggested that a multimodal approach could be useful in quantifying the changes that occur during the early stages of PD.

A multimodal approach could be useful in quantifying the changes that occur during the early stages of PD

The study of PD progression over time was also featured in a paper investigating a family carrying the LRRK2 (R1441C) mutation – a well known gene defect in PD. In this study, it was possible to follow dopaminergic dysfunction and disease progression in asymptomatic family members using multi-tracer PET.8

Both these papers suggest ways of following early disease progression over time and offer a means of monitoring any neuroprotective effect new agents might offer in PD

References
  1. General- Poewe W. Nature Reviews Disease Primers 2017;3: article 17013
  2. Adler CH et al. Neurology 2014;83:406-12
  3. Groveman B. JAMA Neurol 2017;74:163-172
  4. Shahnawaz M et al. JAMA Neurol 2017;74:163-172
  5. Doppler K Acta Neuropathol 2017;133:535-545
  6. Kang et al. Sci Rep 2016;133:28143]
  7. Hansson O. Neurology 2017;88:930-937
  8. Knudsen Lancet Neurol 2018;17:618-628
  9. Nandhagopal R et al. Neurology 2008;71:1790-1795
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