The Challenge of Disease-Modifying Therapies in Parkinson's Disease: Role of CSF Biomarkers

Abstract

The development of disease modifying strategies in Parkinson's disease (PD) largely depends on the ability to identify suitable populations after accurate diagnostic work-up. Therefore, patient molecular profiling and disease subtyping are mandatory. Thus far, in clinical trials, PD has been considered to be a "single entity". Conversely, in front of the common feature of nigro-striatal degeneration, PD is pathogenically heterogeneous with a series of several biological and molecular pathways that differently contribute to clinical development and progression. Currently available diagnostic criteria for PD mainly rely on clinical features and imaging biomarkers, thus missing to identify the contribution of pathophysiological pathways, also failing to catch abnormalities occurring in the early stages of disease. Cerebrospinal fluid (CSF) is a promising source of biomarkers, with the high potential for reflecting early changes occurring in PD brain. In this review, we provide an overview on CSF biomarkers in PD, discussing their association with different molecular pathways involved either in pathophysiology or progression in detail. Their potential application in the field of disease modifying treatments is also discussed.

Keywords: Parkinson’s disease; genetic risk factor; neuronal death mechanisms; targets for neuroprotection.

Figure 1

Schematic representation of molecular mechanisms related to α-synuclein metabolism (synthesis, aggregation, intracellular degradation, and extracellular degradation) and potential disease-modifying strategies targeting these mechanisms.

Figure 2

The figure shows a series of cerebrospinal fluid biomarkers which can be potentially used to face up current limits and open issues related to disease-modifying strategies for Parkinson’s disease. Aβ-40: amyloid beta 40 protein; Aβ-42: amyloid beta 42 protein; α-syn: α-synuclein; GCase: β-glucocerebrosidase; LRRK2: leucine-rich repeat kinase 2; MCP-1: monocyte chemoattractant protein 1; NfL: neurofilament light chain; o-α-syn: oligomeric α-synuclein; p-α-syn: phosphorylated α-synuclein; PD: Parkinson’s disease; p-tau: phosphorylated tau protein; t-α-syn: total α-synuclein; t-tau: total tau protein; YKL-40: Chitinase-3-like protein 1.