Biofluid Biomarkers in Parkinson's Disease: Clarity Amid Controversy

Vieira, Sophia R.L.; Toffoli, Marco; Campbell, Philip; Schapira, Anthony H.V.

doi:10.1002/mds.28030

Cited by 6 publications

(6 citation statements)

References 52 publications

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“…Whether lipidic and metabolic profiles are influenced by genotype remains elusive. Furthermore, the application of validated biomarkers to the prodrome and progression of PD in general remains a controversial area ( 71 ).…”

Section: Genotype–phenotype Correlation With Nonclinical Biomarkers In Gba -Parkinson Diseasementioning

confidence: 99%

Exploring the Genotype–Phenotype Correlation in GBA-Parkinson Disease: Clinical Aspects, Biomarkers, and Potential Modifiers

Menozzi

Schapira

2021

Front. Neurol.

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Variants in the glucocerebrosidase (GBA) gene are the most common genetic risk factor for Parkinson disease (PD). These include pathogenic variants causing Gaucher disease (GD) (divided into “severe,” “mild,” or “complex”—resulting from recombinant alleles—based on the phenotypic effects in GD) and “risk” variants, which are not associated with GD but nevertheless confer increased risk of PD. As a group, GBA-PD patients have more severe motor and nonmotor symptoms, faster disease progression, and reduced survival compared with noncarriers. However, different GBA variants impact variably on clinical phenotype. In the heterozygous state, “complex” and “severe” variants are associated with a more aggressive and rapidly progressive disease. Conversely, “mild” and “risk” variants portend a more benign course. Homozygous or compound heterozygous carriers usually display severe phenotypes, akin to heterozygous “complex” or “severe” variants carriers. This article reviews genotype–phenotype correlations in GBA-PD, focusing on clinical and nonclinical aspects (neuroimaging and biochemical markers), and explores other disease modifiers that deserve consideration in the characterization of these patients.

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Section: Genotype–phenotype Correlation With Nonclinical Biomarkers In Gba -Parkinson Diseasementioning

confidence: 99%

Exploring the Genotype–Phenotype Correlation in GBA-Parkinson Disease: Clinical Aspects, Biomarkers, and Potential Modifiers

Menozzi

Schapira

2021

Front. Neurol.

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“…5 Unfortunately, there are currently limited means of separating this group in vivo without biopsy, but potential biomarker proxies include SNCA, as discussed. While these promising methods are currently limited by substantial interindividual and technical variability, 28 they have the future potential to stratify subtypes of G2019S disease based on pathophysiology. Regardless, if the therapeutic intervention is upstream of the LB pathology and there is a shared mechanism for the onset of disease, then agents for LRRK2 could work in both pathologic outcomes.…”

Section: Phenotypic Biomarkersmentioning

confidence: 99%

“…1,2,4 Potential for LRRK2-Specific and GBA-Specific Biomarkers Biomarkers can serve multiple roles including aiding to stratify groups during study enrollment, tracking target and pathway engagement, and determining subgroups in post hoc analysis. 28,29 The elucidation of the LRRK2-related and GBA1-related PD models has led to the identification of several promising biomarkers that may facilitate prevention trials.…”

Section: Gba1mentioning

confidence: 99%

“…1,2,4 Severe variants exhibit the lowest levels of CSF SNCA, which has been correlated with impaired cognitive function and REM behavior disorder (RBD). 27 While synuclein imaging is still under development, SNCA oligomers in CSF, skin, 32 and other tissues, 28 including a novel method using real-time quaking-induced conversion, demonstrate promise in identifying individuals with early SNCA deposition in GBA trials. 19…”

Section: Fluid and Tissue Biomarkersmentioning

confidence: 99%

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Who to Enroll in Parkinson Disease Prevention Trials?

2022

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Therapies that prevent the occurrence of Parkinson disease (PD) (primary prevention) or mitigate the progression of symptoms in those with early disease (secondary prevention) are a critical unmet need in disease management. Despite great promise, PD prevention trials have not yet demonstrated success. Initiation of treatment too late in the disease course and the heterogeneity of disease are obstacles that may have contributed to the failure. Genetically stratified groups offer many advantages to primary and secondary prevention trials. In addition to their ease of identification, they decrease disease heterogeneity on several levels. Particularly, they comprise a phenotypically and pathologically enriched group with defined clinical features, pathogenic mechanisms and associated proteins that may serve as specific trial endpoints, therapeutic targets and biomarkers for disease state, and pharmacodynamic and pharmacokinetic status. However, challenges arise from genetic variant heterogeneity, from reduced penetrance whereby many carriers will not develop PD, and in recruiting a population that will meet the desired outcome in the proposed study duration. In this review, we discussed the opportunities afforded by the enrollment of genetically stratified cohorts (i.e., leucine-rich repeat kinase 2 and glucocerebrosidase 1) into prevention trials with a primary focus on primary prevention trials. We also outlined challenges surrounding the enrollment of these cohorts and offered suggestions to leverage their many advantages.

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“…Because slowing down or halting PD still remains the principal goal of the research [15,58], a major challenge regards the possibility to uncover exactly when and how the first signs of the disease do appear, in order to develop therapeutic strategies to mitigate or stop the progressive DAergic neuronal death. To this end, considerable effort is devoted to the screening of valuable clinical PD biomarkers, to reveal early aspects of disease pathogenesis and eventually to develop diagnostic methods to prevent and treat PD [59][60][61][62][63]. Investigations aimed at identifying preclinical PD biomarkers represent an important step towards the development of more efficacious neuroprotective therapies.…”

Section: Parkinson's Disease: An Aging Related Disordermentioning

confidence: 99%

Extracellular Vesicles as Novel Diagnostic and Prognostic Biomarkers for Parkinson’s Disease

et al. 2021

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The elderly population will significantly increase in the next decade and, with it, the proportion of people affected by age-related diseases. Among them, one of the most invalidating is Parkinson's disease (PD), characterized by motor-and non-motor dysfunctions which strongly impair the quality of life of affected individuals. PD is characterized by the progressive degeneration of dopaminergic neurons, with consequent dopamine depletion, and the accumulation of misfolded α-synuclein aggregates. Although 150 years have passed since PD first description, no effective therapies are currently available, but only palliative treatments. Importantly, PD is often diagnosed when the neuronal loss is elevated, making difficult any therapeutic intervention. In this context, two key challenges remain unanswered: (i) the early diagnosis to avoid the insurgence of irreversible symptoms; and (ii) the reliable monitoring of therapy efficacy. Research strives to identify novel biomarkers for PD diagnosis, prognosis, and therapeutic follow-up. One of the most promising sources of biomarkers is represented by extracellular vesicles (EVs), a heterogeneous population of nanoparticles, released by all cells in the microenvironment. Brain-derived EVs are able to cross the blood-brain barrier, protecting their payload from enzymatic degradation, and are easily recovered from biofluids. Interestingly, EV content is strongly influenced by the specific pathophysiological status of the donor cell. In this manuscript, the role of EVs as source of novel PD biomarkers is discussed, providing all recent findings concerning relevant proteins and miRNAs carried by PD patient-derived EVs, from several biological specimens. Moreover, the contribution of mitochondria-derived EVs will be dissected. Finally, the promising possibility to use EVs as source of markers to monitor PD therapy efficacy will be also examined. In the future, larger cohort studies will help to validate these EV-associated candidates, that might be effectively used as non-invasive and robust source of biomarkers for PD.

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Biofluid Biomarkers in Parkinson's Disease: Clarity Amid Controversy

Cited by 6 publications

References 52 publications

Exploring the Genotype–Phenotype Correlation in GBA-Parkinson Disease: Clinical Aspects, Biomarkers, and Potential Modifiers

Exploring the Genotype–Phenotype Correlation in GBA-Parkinson Disease: Clinical Aspects, Biomarkers, and Potential Modifiers

Who to Enroll in Parkinson Disease Prevention Trials?

Extracellular Vesicles as Novel Diagnostic and Prognostic Biomarkers for Parkinson’s Disease

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