Premotor biomarkers for Parkinson's disease - a promising direction of research

Abstract

The second most serious neurodegenerative disease is Parkinson's disease (PD). Over the past several decades, a strong body of evidence suggests that PD can begin years before the hallmark clinical motor symptoms appear. Biomarkers for PD are urgently needed to differentiate between neurodegenerative disorders, screen novel therapeutics, and predict eventual clinical PD before the onset of symptoms. Some clinical evaluations and neuroimaging techniques have been developed in the last several years with some success in this area. Moreover, other strategies have been utilized to identify biochemical and genetic markers associated with PD leading to the examination of PD progression and pathogenesis in cerebrospinal fluid, blood, or saliva. Finally, interesting results are surfacing from preliminary studies using known PD-associated genetic mutations to assess potential premotor PD biomarkers. The current review highlights recent advances and underscores areas of potential advancement.

Figure 1

Evolution of PD. During the course of normal aging (green line), small but slow dopaminergic degeneration occurs without any motor symptoms. Typically idiopathic PD (iPD) (blue line) is of unknown origin but is thought to develop gradually over time with a slow degeneration of dopaminergic neurons leading to the emergence of the classic PD motor symptoms later in life. Another model of dopamingeric neurodegeneration leading to PD motor symptoms involves repeated exposure to environmental toxicants over time in combination with a genetic predisposition to dopaminergic neuron loss (yellow line). Early-onset PD (red line), as caused by mutations in the parkin gene, involves a precipitous decline in dopaminergic neuron number where PD motor symptoms can present decades prior to those in iPD. One more scenario (not shown) of PD-motor symptom development involves possible in utero environmental toxicants or genetic factors leading to an atypically low number of dopaminergic neurons at birth and increased susceptibility to PD development.

Figure 2

The Search for Premotor PD Biomarkers. 1. In order to discover premotor PD biomarkers, it is necessary to first enrich for patient population more likely to develop PD. Patients with genetic susceptibility markers, for example, parkin and LRRK2 mutations, and clinical biomarkers, hyposmia, RBD, constipation, and depression. 2. Patients with genetic markers and clinical phenotypes will undergo screening for neuroimaging changes known to correlate with PD. 3. After verification with neuroimaging, various patient tissues where the presence of biochemical markers has already been verified will be acquired (blood, CSF, saliva, and skin). 4. Premotor PD biomarker assessment and identification will use changes in the levels of known biochemical markers, i.e., α-synuclein, uric acid, DJ-1, in addition to others identified through unbiased profiling.