Cerebrospinal fluid α‐synuclein levels in Parkinson's disease – changed or unchanged?

Parkinsonian disorders represent a large group of agerelated neurodegenerative diseases. In addition to common Parkinson’s disease (PD), they include the rarer atypical parkinsonian disorders such as multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and dementia with Lewy bodies [1]. The differential diagnosis may be challenging, especially in early disease stages. As an accurate initial diagnosis has profound implications for the management of these devastating disorders, there is an unmet need for better diagnostic tools. Predominantly expressed in the pre-synapse, a-synuclein, 140 amino acids long, has been found to be the major constituent of the intracellular aggregates in Lewy bodies, the pathological hallmark of PD and dementia with Lewy bodies, and in the glial cytoplasmic inclusions of multiple system atrophy [2,3]. These diseases have accordingly been grouped as synucleinopathies. Intracellular a-synuclein has been shown to be released into the extracellular space [4] and may be transmitted between neurons [5]. The exact roles of a-synuclein in biology and neurotoxicity remain unclear but genetic data, including duplications and triplications of the a-synuclein-encoding SNCA gene in PD, clearly suggest a primary involvement of the protein in neurodegeneration [6–8]. Full-length a-synuclein has been detected in biological fluids, including cerebrospinal fluid (CSF), plasma, conditioned cell media and most recently saliva [4,9,10]. The quantification of a-synuclein in CSF, the fluid that surrounds the brain and communicates freely with the brain interstitial fluid, has been proposed as a potential biomarker for a-synuclein-related diseases [11]. There are discrepant findings, however, by a number of investigators using several different platforms and standard operating procedures, as well as a tremendous overlap of values across studies. Nevertheless, as more and more data accumulate a trend towards reduced CSF a-synuclein levels in PD and other synucleinopathies can be spotted in the literature. In this context, the new study by van Dijk et al. [12] in the current issue of European Journal of Neurology is important. van Dijk and colleagues employed a time-resolved F€ orster’s resonance energy transfer assay to measure CSF a-synuclein in 53 PD patients and 50 healthy controls and detected reduced levels in the former group. Moreover, they assessed CSF a-synuclein levels in relation to disease duration and severity, as well as imaging data of dopamine transporters, without finding any associations. The study was carefully conducted and the authors excluded CSF samples with blood contamination; a common reason for erroneously elevated CSF a-synuclein concentration is high amounts of the protein in red blood cells [13]. The data by van Dijk et al. corroborate the view that CSF a-synuclein is indeed reduced in PD, although with an overlap against controls making the diagnostic accuracy suboptimal. Including these latest data, we performed a metaanalysis of cross-sectional PD control studies on CSF a-synuclein. All studies reporting mean and standard deviations for CSF a-synuclein were included (for those reporting median and range, we contacted the authors) [12,14–28]. Fold change in the biomarker level between PD patients and controls was used as the effect metric to factor out method-related differences in absolute a-synuclein levels across studies. Studies on oligomeric a-synuclein were excluded. The meta-analysis clearly shows that CSF a-synuclein is reduced in PD (Fig. 1). The question now is whether this reduction correlates with Lewy body counts in the brain and whether it can be fine-tuned to better reflect pathology, e.g. by developing specific assays against N-terminally acetylated and C-terminally truncated a-synuclein forms that are found in brain tissue [29]. Perhaps CSF a-synuclein will develop into a biomarker that correlates with pathology in a manner similar to how the 42 amino acid isoform of amyloid b (Ab42) correlates with senile plaque pathology? It should be noted that CSF levels of total Ab did not associate with plaque pathology; it was not until specific assays for the aggregationprone Ab42 variant were developed that such correlations became evident [30]. In any case, van Dijk and colleagues’ assay holds real promise in large sample series, including other parkinsonian disorders and in longitudinal sample series with serial CSF examinations.