Abstract
Parkinson's disease (PD) is the most frequent of all Lewy body diseases, a family of progressive neurodegenerative disorders characterized by intra-neuronal cytoplasmic inclusions of α-synuclein. Its most defining features are bradykinesia, tremor, rigidity and postural instability. By the time PD manifests with motor signs, 70% of dopaminergic midbrain neurons are lost, and the disease is already in the middle or late stage. However, there are various non-motor symptoms occurring up to 20 years before the actual parkinsonism that are closely associated with profound deficiency of myocardial noradrenaline content and peripheral sympathetic denervation, as evidenced by neuroimaging experiments in recent years. Additionally, there is an inherent autotoxicity of catecholamines in the neuronal cells in which they are produced, forming toxic catecholaldehyde intermediates that make α-synuclein prone to aggregation, initiating a cascade of events that ultimately leads to neuronal death. The etiopathogenesis of PD and related synucleinopathies thus may well be a prototypical example of a catecholamine-regulated neurodegeneration, given that the synucleinopathy in PD spreads in synergy with central and peripheral catecholaminergic dysfunction from the earliest phases onward. That is why catecholamines and their metabolites, precursors, or derivatives in cerebrospinal fluid or plasma could be of particular interest as biomarkers for prodromal and de novo PD. Because there is great demand for such markers, this mini-review summarizes all catecholamine-related studies to date, in addition to providing profound neurochemical evidence on a systemic and cellular level to further emphasize this hypothesis and with emphasis on extracellular vesicles as a novel diagnostic and therapeutic incentive.
Highlights
Parkinson’s disease (PD) is recognized as the second most common neurodegenerative disorder following Alzheimer’s disease (AD), with an approximate incidence rate of 10–18 per 100,000 person-years
The threshold theory acknowledges that the earliest symptoms are caused by catecholaminergic deficiency of the peripheral/autonomic nervous system, followed by a central dopaminergic depletion
The hypothesis of DOPAL- and DOPEGALinduced synucleinopathy and a consequentially altered metabolic route of DA and NA are in agreement with a handful of studies so far that indicated cerebrospinal fluid (CSF) dihydroxyphenylacetic acid (DOPAC) and plasma DHPG/MHPG to be of potential interest as biomarkers for prodromal PD in particular
Summary
Parkinson’s disease (PD) is recognized as the second most common neurodegenerative disorder following Alzheimer’s disease (AD), with an approximate incidence rate of 10–18 per 100,000 person-years. The autotoxicity theory clarifies the selective vulnerability of central and peripheral catecholaminergic neurons, converting a stabile negative feedback-regulated in-cell system to a fragile, unstoppable positive feedback loop [33] This context naturally provides rationale for the development of biofluid markers of dopaminergic/noradrenergic origin. The same group performed similar research in early-stage PD patients, complying with three out of four clinical PD criteria, that were off levodopa or MAO inhibitor treatments, as confirmed by TABLE 1 | Enlistment of studies evaluating biofluid catecholamines and their derivatives or precursors as potential markers for prodromal, de novo, or early-stage Parkinson’s disease. Goldstein et al [43] Figura et al [44] Goldstein et al [45] Kim et al [46] D’Andrea et al [47]
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