Abstract
The therapy of neurodegenerative diseases such as Parkinson’s disease (PD) is still limited to the treatment of symptoms and primarily aimed at compensating for dopaminergic hypofunction. Numerous disease-modifying therapies currently in the pipeline attempt to modify the underlying pathomechanisms. In recent decades, the results of molecular genetics and biomarker research have raised hopes of earlier diagnosis and new neuroprotective therapeutic approaches. As the disease-causing processes in monogenetic forms of PD are better understood than in sporadic PD, these disease subsets are likely to benefit first from disease-modifying therapies. Recent studies have suggested that disease-relevant changes found in genetically linked forms of PD (i.e., PARK-LRRK2, PARK-GBA) can also be reproduced in patients in whom no genetic cause can be found, i.e., those with sporadic PD. It can, therefore, be assumed that as soon as the first causal therapy for genetic forms of PD is approved, more patients with PD will undergo genetic testing and counseling. Regarding future neuroprotective trials in neurodegenerative diseases and objective parameters such as biomarkers with high sensitivity and specificity for the diagnosis and course of the disease are needed. These biomarkers will also serve to monitor treatment success in clinical trials. Promising examples in PD, such as alpha-synuclein species, lysosomal enzymes, markers of amyloid and tau pathology, and neurofilament light chain, are under investigation in blood and CSF. This paper provides an overview of the opportunities and current limitations of monogenetic diagnostic and biomarker research in PD and aims to build a bridge between current knowledge and association with PD genetics and biomarkers.
Highlights
Parkinson’s disease (PD) [sporadic andgenetic forms of PD] represents a heterogeneous group of disorders with the pathophysiological shared end of a dopaminergic deficit
Another study reported significantly elevated in vitro kinase activity of LRRK2 in peripheral blood mononuclear cells (PBMCs) from LRRK2 G2019S mutation carriers in comparison to non-carriers, while the phosphorylation is at serine 935 (pS935)-LRRK2 level was increased in sPD compared to controls (Melachroinou et al, 2020)
A biomarker with a high sensitivity and specificity that could be introduced into clinical routine is currently not available
Summary
Parkinson’s disease (PD) [sporadic (sPD) and (mono)genetic forms of PD (gPD)] represents a heterogeneous group of disorders with the pathophysiological shared end of a dopaminergic deficit. Biomarkers from body fluids, skin biopsies, or imaging studies have the advantage of identifying the risk for future PD, diagnosing PD early, and monitoring disease progression, and can serve to monitor possible treatment success in clinical trials. Recent studies have suggested that disease-relevant changes found in genetically linked forms of PD (i.e., PARK-LRRK2, PARK-GBA) can be reproduced in patients in whom no genetic cause can be found (Di Maio et al, 2018). Even if these patients with gPD currently represent only a small group (approximately 10%) (Cook et al, 2021), it is expected that availability of a causal therapy for genetic forms of PD will substantially increase demand for genetic testing and counseling.
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