Differences in Blood and Cerebrospinal Fluid Between Parkinson's Disease and Related Diseases

Abstract

It is difficult to distinguish Parkinson's disease (PD) in the early stage from those of various disorders including atypical Parkinson's syndrome (APS), vascular parkinsonism (VP), and even essential tremor (ET), because of the overlap of symptoms. Other, more challenging problems will arise when Parkinson's disease develops into Parkinson's disease dementia (PDD) in the middle and late stages. At this time, the differential diagnosis of PDD and DLB becomes thorny. These complicate the diagnostic process for PD, which traditionally heavily relies on symptomatic assessment and treatment response. Recent advances have identified several biomarkers in the blood and cerebrospinal fluid (CSF), including α-synuclein, lysosomal enzymes, fatty acid-binding proteins, and neurofilament light chain, whose concentration differs in PD and the related diseases. However, not all these molecules can effectively discriminate PD from related disorders. This review advocates for a paradigm shift toward biomarker-based diagnosis to effectively distinguish between PD and similar conditions. These biomarkers may reflect the diversity that exist among different diseases and provide an effective way to accurately understand their mechanisms. This review focused on blood and CSF biomarkers of PD that may have differential diagnostic value and the related molecular measurement methods with high diagnostic performance due to emerging technologies.

Keywords: Atypical Parkinsonian disorders; Biomarkers; Dementia and movement disorders; Differential diagnosis; Parkinson’s disease.

Fig. 1

Flow diagram of the different types of PD’s differential diagnostic biomarkers. CNS central nervous system, DDC DOPA decarboxylase, GFAP glial fibrillary acidic protein, NfL neurofilament light chain protein, FABP3 fatty acid-binding protein 3, heart type, Hcy homocysteine

Fig. 2

α-Syn seeds show a specificity of deeper aspects. The differences in three dimensions make this biomarker show extremely high specificity in discriminating PD and MSA. PD Parkinson’s disease, MSA multiple system atrophy, plateau height: the peak at which the interaction of amyloid-binding dyes and α-syn aggregates ultimately reaches, aggregation time: speed of interaction between amyloid-binding dyes and α-syn aggregates, fluorescence maximum: the final intensity of fluorescence when the binding peak is reached, counts of spectral peaks: the wavelengths corresponding to the peaks of the derived two seed fibrils in the spectrum, fiber width: fibrils width in Cryo-ET (cryo-electron tomography), twist length: the length between the twisted nodes, reflecting the number of twists, the longer the length, the lower the twist frequency

Fig. 3

Concentrations of NfL in PD were considerably different from those in APS, PDD, and ET, with NfL concentrations higher in APS and PDD than in PD and the opposite in APS (VP is not included). This may suggest a different pathogenesis of its disease at the molecular level. NfL Neurofilament light protein, PD Parkinson’s disease, APS atypical Parkinson’s syndrome, PSP progressive supranuclear palsy, CBS corticobasal syndrome, MSA multiple system atrophy, PDD Parkinson’s disease dementia, ET essential tremor

Fig. 4

The relative proportion of statistically significant content reported in the key literatures (represented by mean content of biomarkers). PD Parkinson’s disease, MSA multiple system atrophy, PSP progressive supranuclear palsy, ET essential tremor, APS atypical Parkinson’s syndrome, PDD Parkinson’s disease dementia, DLB dementia with Lewy bodies, DDC DOPA decarboxylase, SIRT1 NAD-dependent deacetylase sirtuin-1, GFAP glial fibrillary acidic protein, NfL neurofilament light chain protein, FABP3 fatty acid-binding protein 3, heart type, Hcy homocysteine