Post mortem cerebrospinal fluid α-synuclein levels are raised in multiple system atrophy and distinguish this from the other α-synucleinopathies, Parkinson's disease and Dementia with Lewy bodies

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.

Distinct higher-order α-synuclein oligomers induce intracellular aggregation

“…This proposal provides a guide for directing efforts towards the isolation of the toxic forms α-syn in vivo. As such, it would be highly desirable to obtain more comprehensive information about α-syn oligomers that have been detected in the cerebrospinal fluid and sera of PD patients [13][14][15][16] through the epitope mapping used here. The challenge will remain to isolate oligomers from clinical specimens of PD patients or other biological systems under near-native conditions [57,58] and elucidate how the oligomers produced in vivo compare with those observed here.…”

“…α-Syn is expressed as an intracellular protein but has been shown to be directly secreted or released as a result of neuronal death or stress conditions into the extracellular space [12]. Soluble oligomeric forms of α-syn have also been detected in the cerebrospinal fluid and sera of PD patients [13][14][15][16].…”

The role of α-synuclein in neurodegeneration — An update

“…The source of PDlinked AS in human CSF remains unknown, but recent studies suggest that despite the higher levels in peripheral blood products, neurons in the CNS represent the principal source of AS in human CSF [790]. Postmortem CSF levels of oligomeric AS and pAS significantly raised in MSA compared to other controls and other synucleinopaties, but did not distinguish PD and DLB from PSP or control groups [791]. CSF AS levels did not differ significantly between DLB and/or PD and AD [792], but AS levels were reduced in DLB patients with long disease duration or worse cognitive performance [760,792].…”

Candidate biomarkers of multiple system atrophy in cerebrospinal fluid

“…As such, it may be beneficial in the diagnosis of PD but not for MSA. Also, Foulds et al (2012) detected levels of total and oligomeric forms of α-syn as well as phosphorylated and phosphorylated oligomeric forms of α-syn in CSF samples from patients with PD, MSA, DLB, and PSP and healthy controls. They found that, of the four forms of α-syn, only the oligomeric phosphorylated forms of α-syn in CSF could differentiate MSA from PD.…”