The Challenge of Disease-Modifying Therapies in Parkinson’s Disease: Role of CSF Biomarkers

Paoletti, Federico Paolini; Gaetani, Lorenzo; Parnetti, Lucilla

doi:10.3390/biom10020335

Cited by 29 publications

(15 citation statements)

References 81 publications

(94 reference statements)

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“…CSF biomarkers can also provide clues to identify the pathophysiological pathways involved in disease progression. Moreover, they can also help in the development of potential targets for disease-modifying treatments [ 10 ]. As such, exploring CSF biomarkers of MSA is significant.…”

Section: Introductionmentioning

confidence: 99%

Cerebrospinal Fluid Biomarkers in Multiple System Atrophy Relative to Parkinson’s Disease: A Meta-Analysis

Xie

Feng

Huang

et al. 2021

Behavioural Neurology

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Objective. To investigate the differences of candidate cerebrospinal fluid (CSF) biomarkers associated with multiple system atrophy (MSA) and Parkinson’s disease (PD). Method. Here, a systematic review and meta-analysis were conducted on studies related to CSF biomarkers associated with MSA and PD obtained from PubMed, Web of Science, Embase, and Cochrane databases. Data were pooled where appropriate and used to calculate standardized mean differences (SMDs) with 95% confidence intervals (CI). Heterogeneity was assessed using the I 2 statistic while Egger’s test was used to test for existing publication bias. Results. MSA patients had higher CSF t-tau ( SMD = 0.41 , 95% CI: 0.10 to 0.72) and YKL-40 ( SMD = 0.63 , 95% CI 0.12 to1.15) as well as DJ-1 ( SMD = 1.05 , 95% CI 0.67 to 1.42) levels than PD patients, while CSF p-tau ( SMD = − 0.17 , 95% CI, -0.31 to -0.02) and Aβ-42 ( SMD = − 0.33 , 95% CI, -0.55 to -0.12) levels in MSA patients were lower than those in PD patients. There were no differences in CSF’s GFAP and Flt3 ligand levels in both MSA and PD patients. Conclusion. The study revealed the differences in CSF biomarker levels between MSA and PD cohorts that can be further explored to clinically distinguish MSA from PD.

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Section: Introductionmentioning

confidence: 99%

Cerebrospinal Fluid Biomarkers in Multiple System Atrophy Relative to Parkinson’s Disease: A Meta-Analysis

Xie

Feng

Huang

et al. 2021

Behavioural Neurology

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“…Until now, no disease-modifying treatments have been approved. Due to the lack of progression biomarkers and the heterogeneous pathophysiology, a change in disease progression cannot yet be measured easily [ 20–22 ]. We need to look further than clinical and imaging assessments and need to develop tools more apt to identify small but significant changes in disease progression.…”

Section: Discussionmentioning

confidence: 99%

Parkinson’s Disease Drug Development Since 1999: A Story of Repurposing and Relative Success

Boucherie

Duarte

Machado

et al. 2021

JPD

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Background: A global overview of drug development programs in Parkinson’s disease over the last few decades is lacking, while such programs are challenging given the multifaceted and heterogeneous nature of the disease. Objective: To indirectly assess drug development programs in Parkinson’s disease, exploring some factors associated with compound attrition at different trial phases. Methods: We assessed all Parkinson’s disease trials in the WHO trials portal, from inception (1999) to September 2019. Independent authors selected trials and extracted data. The success rate was the number of compounds that progressed to the next drug development phase divided by the number of compounds in that phase. Results: Overall, 357 trials (studying 152 compounds) fulfilled our inclusion criteria, with 62 (17.3%) phase 1 trials, 135 (37.8%) phase 2 trials, 85 (23.8%) phase 3 trials, and 53 (14.8%) phase 4 trials. The success rate was 42.4% from phase 2 to 3. Original compounds received regulatory approval by the FDA in 21.4% of cases, compared with 6.7% of repurposed compounds, representing an overall success rate of 14.9%. We found 172 trials (48.2%) conducted for repurposing previously licensed compounds. These figures were approximately the same regarding approval by the EMA. Most compounds were approved to treat parkinsonism and motor fluctuations. Conclusion: We found a moderate-to-high success rate in all phases of drug development. This was largely based on the success of original compounds, despite almost half of the identified trials attempting compound repurposing.

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“…Another strategy could be the enhancement of α-syn clearance by increasing its intracellular degradation through autophagy-related pathways and the ubiquitin-proteasome system [ 184 ]. The different disease-modifying therapies tested for PD are described elsewhere [ 184 , 185 , 196 , 197 ].…”

Section: Epigenetic Changes As a Therapeutic Target For Lbdmentioning

confidence: 99%

“…However, not all clinical trials have reached satisfactory results in PD [ 197 ]. One reason could be the heterogeneity of the disease, and another, that it is often assumed that each targeted mechanism of disease applies for most patients with the same clinical diagnosis [ 199 ].…”

Section: Epigenetic Changes As a Therapeutic Target For Lbdmentioning

confidence: 99%

Epigenetics in Lewy Body Diseases: Impact on Gene Expression, Utility as a Biomarker, and Possibilities for Therapy

Urbizu

Beyer

2020

IJMS

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Lewy body disorders (LBD) include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). They are synucleinopathies with a heterogeneous clinical manifestation. As a cause of neuropathological overlap with other neurodegenerative diseases, the establishment of a correct clinical diagnosis is still challenging, and clinical management may be difficult. The combination of genetic variation and epigenetic changes comprising gene expression-modulating DNA methylation and histone alterations modifies the phenotype, disease course, and susceptibility to disease. In this review, we summarize the results achieved in the deciphering of the LBD epigenome. To provide an appropriate context, first LBD genetics is briefly outlined. Afterwards, a detailed review of epigenetic modifications identified for LBD in human cells, postmortem, and peripheral tissues is provided. We also focus on the difficulty of identifying epigenome-related biomarker candidates and discuss the results obtained so far. Additionally, epigenetic changes as therapeutic targets, as well as different epigenome-based treatments, are revised. The number of studies focusing on PD is relatively limited and practically inexistent for DLB. There is a lack of replication studies, and some results are even contradictory, probably due to differences in sample collection and analytical techniques. In summary, we show the current achievements and directions for future research.

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The Challenge of Disease-Modifying Therapies in Parkinson’s Disease: Role of CSF Biomarkers

Cited by 29 publications

References 81 publications

Cerebrospinal Fluid Biomarkers in Multiple System Atrophy Relative to Parkinson’s Disease: A Meta-Analysis

Cerebrospinal Fluid Biomarkers in Multiple System Atrophy Relative to Parkinson’s Disease: A Meta-Analysis

Parkinson’s Disease Drug Development Since 1999: A Story of Repurposing and Relative Success

Epigenetics in Lewy Body Diseases: Impact on Gene Expression, Utility as a Biomarker, and Possibilities for Therapy

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