Parkinson's Disease: Biomarkers for Diagnosis and Disease Progression

Abstract

Parkinson's disease (PD) is a progressive neurological disease that causes both motor and nonmotor symptoms. While our understanding of putative mechanisms has advanced significantly, it remains challenging to verify biomarkers with sufficient evidence for regular clinical use. Clinical symptoms are the primary basis for diagnosing the disease, which can be mild in the early stages and overlap with other neurological disorders. As a result, clinical testing and medical records are mostly relied upon for diagnosis, posing substantial challenges during both the initial diagnosis and the continuous disease monitoring. Recent biochemical, neuroimaging, and genetic biomarkers have helped us understand the pathophysiology of Parkinson's disease. This comprehensive study focuses on these biomarkers, which were chosen based on their relevance, methodological excellence, and contribution to the field. Biochemical biomarkers, including α-synuclein and glial fibrillary acidic protein (GFAP), can predict disease severity and progression. The dopaminergic system is widely used as a neuroimaging biomarker to diagnose PD. Numerous genes and genome wide association study (GWAS) sites have been related to the development of PD. Recent research on the SNCA gene and leucine-rich repeat protein kinase 2 (LRRK2) has shown promising results. By evaluating current studies, this review intends to uncover gaps in biomarker validation and use, while also highlighting promising improvements. It emphasizes the need for dependable and reproducible indicators in improving PD diagnosis and prognosis. These biomarkers may open up new avenues for early diagnosis, disease progression tracking, and the development of personalized treatment programs.

Keywords: Parkinson’s disease; biochemical; biomarker; genetic; neuroimaging; α-synuclein.

Figure 1

Schematic representation of PD biomarkers. The three primary categories of PD biomarkers are genetic, biochemical, and neuroimaging biomarkers, each leading to insights into disease mechanisms and progression. Created with www.BioRender.com.

Figure 2

Possible blood-based biomarker of Parkinson’s disease. This figure provides evidence supporting the potential of the blood-based biomarker for Parkinson’s disease, shows significant differences in levels between PD patients and controls, good diagnostic accuracy, correlation with disease severity, dynamic changes over time, and reproducibility in an independent cohort. Total α-synuclein levels show inconsistent results, with some studies reported increase (↑), others decrease (↓), and some no significant difference (↔) between PD patients and HC. This variability may stem from differences in sample sources or detection methods. Phosphorylated α-synuclein is consistently elevated (↑) in PD patients as compared to HC. Levels of oligomeric forms of α-synuclein are increased (↑) in PD patients' plasma, serum, and red blood cells, which is more closely associated with neurotoxicity and PD pathology. Exosomal α-synuclein is also elevated (↑) in PD patients compared to HC, supporting its role as a biomarker for PD. Blood NfL levels are significantly higher (↑) in advanced stages of PD, reflecting neurodegeneration and disease progression. Tau protein levels, both in plasma and serum, are generally increased (↑) in PD, but other studies report no significant change (↔). Aβ42 levels in PD are unchanged (↔) or reduced (↓) compared to HC, reflecting study variability and potential differences in disease mechanisms. Levels of phosphorylated tau (p-tau) and Aβ42 are increased (↑) in FTD patients compared to PD or APS. CRP protein levels, both in whole blood and serum, are generally elevated (↑) in PD patients as compared to HC. PD; Parkinson’s disease, HC; Healthy control, FTD; Frontotemporal dementia, APS; Atypical parkinsonian syndromes, CRP; C-Reactive protein, Aβ42; amyloid-beta 42, NfL; Neurofilament light chain, ↑; upregulated, ↓; downregulated, ↔; unchanged.

Figure 3

Cerebrospinal fluid (CSF) biomarkers of PD. This figure illustrates the complex pathways involved in PD pathology and highlights key cerebrospinal fluid (CSF) biomarkers associated with the disease. The molecular mechanisms underlying PD facilitate early diagnosis and the development of targeted therapies.