Abstract
Parkinson's disease (PD) is the most common neurodegenerative movement disorder that affects extensive regions of the nervous system. Its current clinical diagnosis is based on motor symptoms that appear late during disease progression when substantial proportions of the nigrostriatal dopaminergic neuron population are lost already. Although disturbances in sleep and other biofunctions often surface years prior to motor impairments and point to a long prodromal phase, these phenotypic signs in a person's midlife lack predictive power. They do, however, signal the unfolding of the disease and suggest molecular correlates that begin deviating early on. Revealing such trajectories, hence, promises not only a better understanding of prodromal PD but may also enable a much-needed earlier diagnosis. A nexus that may harbor such molecular trajectories is the epigenome as key etiological factors of PD—genetics, age, and environment—influence this substrate. An earlier diagnosis would also allow earlier interventions and lifestyle adjustments to improve brain function and reduce symptoms. In this review, we describe the challenges of diagnosing PD early on and highlight the opportunities that may arise from steering research efforts towards comprehensive interrogations of molecular layers during the long-time neglected midlife phase. In particular, we emphasize how existing cohorts of at-risk individuals, available animal models, and suitable markers may come together and aid in revealing molecular trajectories that offer diagnostic utility for PD in its prodromal stage.
Highlights
Neurodegenerative disorders are a growing health threat in demographically aging societies
The pathological hallmark of Parkinson’s disease (PD) are misfolded alpha-synuclein protein structures accumulating in cellular inclusions known as Lewy bodies [8]
Typically at the age of 55–65, most idiopathic patients experience years or sometimes decades of unspecific symptomology, indicating the existence of a long prodromal phase. While these prodromal symptoms lack diagnostic specificity [19], they signal an early unfolding of pathology and, are likely accompanied by molecular correlates that deviate from the healthy norm
Summary
Neurodegenerative disorders are a growing health threat in demographically aging societies. Typically at the age of 55–65, most idiopathic patients experience years or sometimes decades of unspecific symptomology, indicating the existence of a long prodromal phase While these prodromal symptoms lack diagnostic specificity [19], they signal an early unfolding of pathology and, are likely accompanied by molecular correlates that deviate from the healthy norm. Research has explored a number of potential molecular markers for PD that center on measures that directly or indirectly assess the degree of mitochondrial dysfunction, oxidative stress, Lewy bodies formation, neuroinflammation, and other core pathological characteristics of PD in readily accessible biofluids or biopsies [62] Their utility in diagnosing or prognosing the disease early on, has remained limited [63, 64]. This issue may largely result from the relatively low prevalence of PD on which sensitivity, specificity, and the predictive values of these measures are dependent [77] and has been discussed before [78,79,80]
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