We also expect that, due to interlaboratory variation and different producers/vendors of kits/platforms for measuring CSF biomarkers, it will be difficult to have defined and validated cut-off for each marker.

The planned systematic review and meta-analysis will be the first summary of the evidence in the field with an IPD approach.

Background

Idiopathic Parkinson’s disease (PD) is a progressive neurodegenerative disorder related to α-synuclein misfolding and aggregation. For this reason, it belongs to the family of ‘synucleinopathies’, which also includes some other neurological diseases, such as multiple system atrophy (MSA) and dementia with Lewy bodies. Clinical diagnosis of PD is based on the presence of bradykinesia accompanied by at least one other characteristic, such as tremor, rigidity and impaired postural reflexes.1 Typically, patients suffering from PD show a good response to symptomatic treatment with dopaminergic therapies. However, in addition to PD, several disorders cause parkinsonism, including atypical parkinsonian disorders such as progressive supranuclear palsy, corticobasal degeneration and MSA, and the different parkinsonian disorders are often difficult to distinguish from each other, especially during the early clinical stages.2 3 Although imaging and ancillary investigations may be helpful in the diagnostic workup,4–6 the accurate diagnosis of PD mostly relies on the clinician’s expertise and consequently objective diagnostic methods are needed. Furthermore, there is a need today for markers that can track the disease progression in PD, which might improve the evaluation of novel disease-modifying therapies. In the last decades, an increasing number of studies have been performed with the purpose of finding useful diagnostic and prognostic biomarkers for PD.

The cerebrospinal fluid (CSF) has been widely investigated as a source of reliable biomarkers for neurodegenerative diseases, especially for Alzheimer’s disease but also for PD and atypical parkinsonian disorders, because CSF is the biological fluid closest to the brain. Unlike plasma, CSF is not separated from the brain by the blood–brain barrier. Hence, proteins linked to brain-specific activities or to disease processes are more represented in the CSF than in other fluids or tissues. The investigation of CSF biomarkers for PD diagnosis began in the 60s. Many CSF proteins were tested as biomarkers for the diagnosis of PD. Several have received attention and have been listed (with a non-exhaustive purpose, see Magdalinou et al 1): total, oligomeric and phosphorylated α-synuclein; Aβ-42; total and phosphorylated tau; neurofilament light-chain protein; oxidative stress markers (DJ-1, 8-OHdG and urate); and lysosomal dysfunction (β-glucocerebrosidase).

Rationale for a systematic review and an individual participant data meta-analysis We propose a systematic review and an individual participant data (IPD) meta-analysis for the evaluation of the diagnostic and prognostic utility of CSF biomarkers in PD. Despite the increasing number of published studies, few systematic reviews with meta-analysis were identified.7–10 All the evidence synthesis is about the diagnostic role of synuclein species in PD and other parkinsonisms. No evidence exists regarding the role of other CSF markers or for evaluating prognostic accuracy. IPD represents the gold standard of meta-analysis and offers several advantages that could be of primary interest in the field of CSF biomarkers in PD11: an increase in the total sample size, thus reducing the risk of false-positive findings and increasing the precision of study results; an increase in the case mix variability and the potential generalisability of prediction models across subgroups, settings and countries; the standardisation of the statistical analysis methods across IPD sets; more complex associations can be investigated, such as non-linearity of predictor effects, predictor interactions and time-varying predictor effects.