Biomarkers for Parkison's disease: Tools to assess Parkinson's disease onset and progression

Abstract

Reliable and well-validated biomarkers for PD to identify individuals "at risk" before motor symptoms, accurately diagnose individuals at the threshold of clinical PD, and monitor PD progression throughout its course would dramatically accelerate research into both PD cause and therapeutics. Biomarkers offer the potential to provide a window onto disease mechanism, potentially generating therapeutic targets for disease. In particular, biomarkers enable investigation of the premotor period of PD before typical symptoms are manifest, but while degeneration has already begun. Given the multiple genetic causes for PD already identified, the marked variability in the loss of dopaminergic markers measured by imaging at motor symptom onset and the clear heterogeneity of clinical symptoms in PD onset and clinical progression, it is likely many biomarkers with a focus ranging from clinical symptoms to PD pathobiology to molecular genetic mechanisms will be necessary to fully map PD risk and progression. Biomarkers are also critical in new drug development for PD, both in early validation studies to assess drug dosing and to determine drug penetrance into the brain, and in later efficacy studies to complement PD clinical outcomes. During the past two decades, much progress has been made in identifying and assessing PD biomarkers, but as yet, no fully validated biomarker for PD is currently available. Nonetheless, there is increasing evidence that molecular genetics, focused -omic (proteomic, metabolomic, and transcriptomic) assessment of blood and cerebrospinal fluid, and advanced in vivo brain imaging will provide critical clues to assist in the diagnosis and medical management of PD patients.

Progression from Unilateral to Bilateral Parkinsonism in Early Parkinson Disease: Implication of Mesocortical Dopamine Dysfunction by PET

“…These reports indicate the difficulty of making a precise evaluation of possible PD cases based solely on clinical data. In contrast, depicting abnormalities of the dopamine system on a molecular basis has a greater advantage (6,(20)(21)(22)(23)(24)(25). Previous studies showed that the progression of PD was associated with a similar rate of dopaminergic losses in all striatal subregions (26).…”

MPTP Induces Systemic Parkinsonism in Middle-Aged Cynomolgus Monkeys: Clinical Evolution and Outcomes

“…The clinical severity corresponding to the Kurlan score at the end of the rapid progress stage in this study may represent the initial level of damage to the dopaminergic system induced by MPTP. The score of the monkey manifesting spontaneous recovery was 14 at the end of rapid progress stage, much lower than that of the other animals (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Studies have suggested that stable Parkinsonism occurs in severe cases despite varying degrees of response to MPTP treatment [20].…”

“…Clinical symptoms appear when 50%-60% of dopaminergic neurons and [70%-80% of striatal nerve terminals have degenerated or died. The concept of a clinical symptom threshold is based on data derived from decreased dopamine levels in post-mortem tissue from humans and altered dopaminergic function observed in radioisotopic brain imaging [26,32,33].…”

Feature Extraction Methods for Studying Surface Electromyography and Kinematic Measurements in Parkinson’s Disease

“…Clinicopathological studies from the UK and Canada have shown that the disease is diagnosed incorrectly in about 25 % of patients [48]. The pre-motor period before diagnosis may be long (5-20 years) and at the time of the diagnosis already 50-60 % of the dopaminergic neurons may be lost [22,38].…”