Originally Posted on MedwireNews | 13 December 2016
Researchers have developed a biochemical test for diagnosing Parkinson’s disease (PD) using technology that detects misfolded α-synuclein (αSyn) oligomers in cerebrospinal fluid (CSF).
Their protein misfolding cyclic amplification (PMCA) platform technology takes advantage of the ability of minute misfolded oligomers, in this case αSyn, to nucleate further aggregation, enabling a very high amplification of the signal.
Initial studies with synthetic αSyn aggregates showed that the technology could detect αSyn oligomers at volumes as low as 0.1 pg/mL. And when tested in the presence of two representative CSF samples from 76 patients with PD, αSyn aggregation was induced with a lag phase of approximately 120 and 220 hours.
The assay’s diagnostic ability was blind tested against CSF samples from 65 individuals with other unrelated neurologic diseases (including two healthy people), such as epilepsy and muscular dystrophy, 14 with Alzheimer’s disease, and 18 with other chronic neurodegenerative brain diseases.
In all, 67 (88%) of the 76 PD samples correctly tested positive for αSyn-PMCA, while 61 (94%) of the 65 samples from patients with unrelated neurologic diseases correctly tested negative.
Claudio Soto (University of Texas-Houston Medical School, USA) and co-researchers note in JAMA Neurology that two of the control individuals who falsely tested positive for αSyn-PMCA went on to develop PD 1 and 4 years after analysis, “indicating that the technology may have the potential to detect disease at the presymptomatic stages.”
The false positive results were slightly higher for the patients with Alzheimer’s disease, at 36%, which the researchers explain is likely due to these patients often having concomitant αSyn abnormalities.
But a low false positive rate among patients with other chronic neurodegenerative brain diseases, at 17%, suggests the assay has specificity for synucleinopathies rather than neurodegeneration in general, they note.
The overall sensitivity and specificity for diagnosing Parkinson’s disease were calculated to be 88.5% and 94.0%, respectively.
The team points out that the technology may also be useful for diagnosing synuclein-aggregation disorders other than just PD. They tested 10 samples from patients with dementia with Lewy bodies (DLB) and 10 from those with multiple system atrophy, of which 10 and eight, respectively, were positive on αSyn-PMCA.
As well as diagnosing Parkinson’s disease, the technology could prove useful for monitoring disease progression and studying treatment efficacy, the researchers say, having found a positive correlation between kinetic factors of αSyn aggregation and disease severity measured on the Hoehn and Yahr scale.
In a related editorial, Tim Bartels (Harvard Medical School, Boston, Massachusetts, USA) notes that the findings “deliver strong evidence that pathologic spread of small diffusible amyloid structures is at least a common feature of the human disease, if not even part of its mechanism.”
He recognizes that “developing a reliable biomarker for PD or synucleinopathies is no small feat,” and says: “The addition of a biochemical test to the clinical diagnosis would therefore benefit the patient in terms of early and correct diagnosis and hence early and appropriate intervention.”