Abstract
Differentiating clinically between Parkinson's disease (PD) and the atypical parkinsonian syndromes of Progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and multiple system atrophy (MSA) is challenging but crucial for patient management and recruitment into clinical trials. Because PD (and the related disorder Dementia with Lewy bodies (DLB)) and MSA are characterised by the deposition of aggregated forms of α-synuclein protein (α-syn) in the brain, whereas CBS and PSP are tauopathies, we have developed immunoassays to detect levels of total and oligomeric forms of α-syn, and phosphorylated and phosphorylated oligomeric forms of α-syn, within body fluids, in an attempt to find a biomarker that will differentiate between these disorders. Levels of these 4 different forms of α-syn were measured in post mortem samples of ventricular cerebrospinal fluid (CSF) obtained from 76 patients with PD, DLB, PSP or MSA, and in 20 healthy controls. Mean CSF levels of total and oligomeric α-syn, and phosphorylated α-syn, did not vary significantly between the diagnostic groups, whereas mean CSF levels of phosphorylated oligomeric α-syn did differ significantly (p<0.001) amongst the different diagnostic groups. Although all 4 measures of α-syn were higher in patients with MSA compared to all other diagnostic groups, these were only significantly raised (p<0.001) in MSA compared to all other diagnostic groups, for phosphorylated oligomeric forms of α-syn. This suggests that this particular assay may have utility in differentiating MSA from control subject and patients with other α-synucleinopathies. However, it does not appear to be of help in distinguishing patients with PD and DLB from those with PSP or from control subjects. Western blots show that the principal form of α-syn within CSF is phosphorylated, and the finding that the phosphorylated oligomeric α-syn immunoassay appears to be the most informative of the 4 assays would be consistent with this observation.
Highlights
Idiopathic Parkinson's disease (PD) is one of several neurodegenerative disorders that can present with similar clinical symptoms, parkinsonism which is a combination of tremor, rigidity and bradykinesia
We have shown by immunoblotting that both phosphorylated and non-phosphorylated forms of α-syn can be detected in cerebrospinal fluid (CSF) of patients with PD, Dementia with Lewy bodies (DLB), Progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and in control individuals, and that the levels of these can be measured by immunoassay
This finding is based on a relatively small number of MSA cases, and may be considered preliminary, the distinction between MSA and other patient groups was robust, and higher α-syn levels were consistently seen across all 4 assays in MSA compared to PD/DLB and other non-synucleinopathies
Summary
Idiopathic Parkinson's disease (PD) is one of several neurodegenerative disorders that can present with similar clinical symptoms, parkinsonism which is a combination of tremor, rigidity and bradykinesia. In vivo diagnosis of PD and atypical Parkinsonian disorders relies on clinical criteria (Poewe and Wenning, 2002). None of these disorders is currently curable, it is important to make the correct diagnosis as early as possible since the symptomatic therapeutic approaches differ, and future (causative) therapies might be targeted directly against the underlying pathological process in each of these disorders. Considerable effort currently goes into the development of biomarkers for PD and the atypical parkinsonian disorders that would reliably allow the clinician to distinguish between them at an early stage
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