Results of a proof-of-concept study have yielded the first potential biomarker for Parkinson disease (PD).1 Investigators in Japan and Germany collaboratively developed a novel assay with sensitivity and specificity high enough to accurately detect small quantities of α-synuclein (αSyn) oligomers — the keystone neuropathology associated with the development of clinical PD — in cerebrospinal fluid (CSF).1
The investigators collected CSF samples from blinded cohorts of 96 patients with neurodegenerative disorders involving αSyn deposits, including 76 patients with clinically probable PD, 10 with dementia with Lewy bodies (DLB), and 10 with multiple system atrophy (MSA). The control group included 14 patients with Alzheimer’s disease, 18 affected by neurodegenerative diseases not associated with αSyn (frontotemporal dementia, ataxia, Huntington disease, amyotrophic lateral sclerosis, and progressive supranuclear palsy), 65 with other neurologic diseases (epilepsy, cervical spondylosis, muscular dystrophy, viral myositis, and myelopathy), and 2 without any signs of neurological disease.
Despite nearly 2 decades of research into the role of misfolded αSyn in the formation of Lewy bodies that correlate with motor and cognitive signs of PD,2,3 attempts to quantify the activity of αSyn in vivo have been heavily hampered by relatively low levels of the protein available in CSF.4 In an accompanying editorial, Tim Bartels, PhD, pointed out that this is further complicated by problems in antibody selectivity, making it difficult to distinguish normal from abnormal forms of αSyn.4
To overcome this challenge, the investigators adapted an amplification technology previously used in prion diseases to create the protein misfolded cyclic amplification (PMCA) assay to measure seeding activity of αSyn.5 The assay was highly effective in determining the presence of misfolded αSyn in CSF with an 88% sensitivity for a diagnosis of PD, 100% for DLB and 80% for MSA. In addition, it demonstrated a 97% specificity for PD compared with 94% for other neurological diseases. Individual results showed direct correlations between αSyn-PMCA and Hoehn and Yahr measures of disease severity (Japanese cohort: rs = −0.54, P =.006; German cohort: rs = −0.36, P =.02).
Broad Clinical Implications
The clinical implications of this research are important in a number of ways. First, the αSyn-PMCA test was not only effective for the diagnosis of PD, but the investigators reported that their findings show “a positive correlation between disease severity and the kinetic factors of αSyn aggregation, suggesting that αSyn-PMCA might be useful to monitor disease progression and possibly to study the efficacy of therapeutic interventions.” Second, the high accuracy of αSyn-PMCA technology in identifying all negative samples correctly and 2 positive samples that converted later to PD suggests the potential to identify the disease in preclinical stages. Finally, the combined application of the αSyn-PMCA with prion protein-PMCA, Aβ-PMCA, and evolving technology for detection of tau and TDP-43 aggregates offers the potential for effective early diagnostic testing across a full range of neurological disorders.
- Shahnawaz M, Tokuda T, Waragai M, et al. Development of a biochemical diagnosis of Parkinson disease by detection of α-synuclein misfolded aggregates in cerebrospinal fluid. JAMA Neurol. 2017;74:163-172.
- Baba M, Nakajo S, Tu PH, et al. Aggregation of α-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am J Pathol. 1998;152:879-884.
- Wood SJ, Wypych J, Steavenson S, et al. α-Synuclein fibrillogenesis is nucleation-dependent: implications for the pathogenesis of Parkinson’s disease. J Biol Chem. 1999;274:19509-19512.
- Bartels T. Conformation-specific detection of α-synuclein: the search for a biomarker in parkinson disease. JAMA Neurol. 2017;74:146-147.
- Saborio GP, Permanne B, Soto C. Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature. 2001;411:810-813.