Defining Parkinson's Disease: Past and Future

Abstract

Parkinson's disease (PD) is the second most common still relentlessly progressive neurodegenerative disorder with a long period in which the pathophysiological process is already spreading but cardinal motor symptoms are not present. This review outlines the major developments and milestones in our understanding of PD that have shaped the way we define this disorder. Past criteria and definitions of PD have been based on clinical motor manifestations enabling diagnosis of the disease only in later symptomatic stages. Nevertheless, with advancing knowledge of disease pathophysiology and aim of early disease detection, a major shift of the diagnostic paradigm is being advocated towards a biological definition similar to other neurodegenerative disorders including Alzheimer's disease and Huntington's disease, with the ultimate goal of an earlier, disease course modifying therapy. We summarize the major pillars of this possible approach including in vivo detection of neuronal α-synuclein aggregation, neurodegeneration and genetics and outline their possible application in different contexts of use in the frame of biological PD definition.

Keywords: Parkinson’s disease; biomarkers; genetics; neurodegeneration; synuclein.

Fig. 1

Defining Parkinson’s disease – historical milestones, complexity of PD-related neurodegeneration and corresponding evolution of diagnostic criteria and definitions. PD, Parkinson’s disease; SN, substantia nigra, MPTP, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine; DBS, deep brain stimulation; SNCA, synuclein alpha gene; LB, Lewy bodies; α-syn, α-synuclein; SAA, seed amplification assays; GWAS, genome-wide association study; ANS, autonomic nervous system; ENS, enteric nervous system; GABA, gamma-aminobutyric acid; PIGD, postural instability and gait disturbance; UK, United Kingdom; MDS, International Parkinson and Movement Disorders Society; SynNeurGe, synuclein-neurodegeneration-genetics; NSD-ISS, neuronal α-synuclein disease integrated staging system. Created with BioRender.com.