AD/PD 2023 | Latest developments in Parkinson’s disease biomarkers
Andrea Pilotto, MD, University of Brescia, Brescia, Italy, explains the major ongoing research regarding digital and fluid biomarkers for use in Parkinson’s disease (PD) diagnosis, monitoring, and prognostication. There is a huge interest in seed amplification assays (RT-QuIC) that detect misfolded ɑ-synuclein in the CSF, as they have demonstrated high sensitivity and specificity. However, its ability to detect ɑ-synuclein in PD and dementia with Lewy bodies (DLB), as well as other conditions such as Alzheimer’s disease, limits its use for PD differential diagnosis. Although some reports are conflicting, neurofilament light (NfL) appears to be useful in discriminating between typical and atypical parkinsonisms, as well as providing prognostic information on cognitive and motor progression. However, NfL does not change much over time in PD, and therefore there is still research into new markers in plasma that are able to track the neurodegenerative process, especially in prodromal phases. Digital technology able to detect subtle changes in motor performance that are not otherwise visible is also promising in this space. This interview took place at the AD/PD™ 2023 congress in Gothenburg, Sweden.
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Transcript (edited for clarity)
Regarding the CSF biomarkers in Parkinson’s disease, there is a huge discussion, but it’s still questioned the value of ⍺-synuclein in CSF but also in plasma, so the total ⍺-synuclein. Conversely, there is a huge interest in the research community for seed amplification assays, the so-called RT-QuIC for ⍺-synuclein, which has been demonstrated to be very sensitive and very solid for the diagnosis of either Parkinson’s or Lewy...
Regarding the CSF biomarkers in Parkinson’s disease, there is a huge discussion, but it’s still questioned the value of ⍺-synuclein in CSF but also in plasma, so the total ⍺-synuclein. Conversely, there is a huge interest in the research community for seed amplification assays, the so-called RT-QuIC for ⍺-synuclein, which has been demonstrated to be very sensitive and very solid for the diagnosis of either Parkinson’s or Lewy. What is of high interest is probably that these assays are highly sensitive even in other conditions, so we are, for example, demonstrating that even in Alzheimer’s disease there are a lot of patients who resulted positive to ⍺-synuclein with the seed amplification assay. So then it’s not easy to use this in differential diagnosis. Of course it is of interest to evaluate at a single patient level the amount of ⍺-synuclein at different phases of the disease, but we still need probably very good markers for distinguishing Parkinson’s disease from other conditions.
And regarding prognostic and differential diagnosis, NfL is quite an old marker now because there are a lot of different studies showing that an increase in NfL is not related with typical Parkinson’s disease. But this can really help in the early diagnostic phases because if I have a patient with a mild or even moderate parkinsonism with normal NfL, then I know that it’s probably really an idiopathic Parkinson’s disease and with the same patient with a very increased level of NfL, then the majority of patients are probably in an early phase of an atypical parkinsonism such as DLB or corticobasal syndrome, MSA or PSP.
And if we consider then the prognostic value of different markers and we are presenting also an abstract, Dr. Lupini is presenting an abstract in Gothenburg looking at this. So if we evaluate the different markers of progression in Parkinson’s disease, again, NfL is by far the best marker with a little contribution of p-tau and the little contribution of GFAP probably. So they might add a little bit of understanding, probably in a subset of patients with an increased astrocytic or inflammatory reaction, or co-pathology of Alzheimer’s disease probably. But again the robustness of NfL in predicting the progression, the motor but also cognitive progression in Parkinson’s, at the moment, NfL is the best marker ever for predicting this. We are still looking for new markers in plasma which are able to track also the neurodegenerative process because we know that the NfL is not changing a lot over time in Parkinson’s disease.
Also a very interesting question is, how can we track the progression of Parkinson’s in prodromal phases? So we know that the idiopathic REM sleep behavior disorders are a perfect model of prodromal Parkinson’s disease but also prodromal Lewy, so prodromal ⍺-synucleinopathies. In this phase it is very difficult to track the progression because there are not really very clear symptoms and probably, they are just very subtle motor symptoms we cannot track in an easy way and we are presenting in the Gothenburg one important study evaluating the subtle motor symptoms using mobile technology. So digital markers of mobility alteration in this phase. And we found indeed that the clinician was not able to see any difference in subjects with idiopathic REM sleep behavior disorder but when we looked at the digital markers then it appeared very clear that they indeed have a slowness of some movements, particularly on turning and gait and probably we can track over time the conversion to Parkinson’s disease, but also potentially the response to treatment or non-pharmacological approaches using this mobile technology. We think we now have the potential to apply digital technology in larger samples because the cost but also the accuracy is better. And so we should think about the inclusion of digital markers also in prospective cohorts.
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