Increased CSF DOPA Decarboxylase Correlates with Lower DaT-SPECT Binding: Analyses in Biopark and PPMI Cohorts.

BACKGROUND: Recent studies identified increased cerebrospinal fluid (CSF) DOPA decarboxylase (DDC) as a promising biomarker for parkinsonian disorders, suggesting a compensation to dying dopaminergic neurons. A correlation with 123I-FP-CIT-SPECT (DaT-SPECT) imaging could shed light on this link. OBJECTIVE: The objective is to assess the relationship between CSF DDC levels and DaT-SPECT binding values. METHODS: A total of 51 and 72 Parkinson's disease (PD) subjects with available DaT-SPECT and CSF DDC levels were selected from the PPMI and Biopark cohorts, respectively. DDC levels were analyzed using proximity extension assay and correlated with DaT-SPECT striatal binding ratios (SBR). All analyses were corrected for age and sex. RESULTS: CSF DDC levels in PD patients correlated negatively with DaT-SPECT SBR in both putamen and caudate nucleus. Additionally, SBR decreased with increased DDC levels over time in PD patients. CONCLUSION: CSF DDC levels negatively correlate with DaT-SPECT SBR in levodopa-treated PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Large-scale proximity extension assay reveals CSF midkine and DOPA decarboxylase as supportive diagnostic biomarkers for Parkinson's disease.

BACKGROUND: There is a need for biomarkers to support an accurate diagnosis of Parkinson's disease (PD). Cerebrospinal fluid (CSF) has been a successful biofluid for finding neurodegenerative biomarkers, and modern highly sensitive multiplexing methods offer the possibility to perform discovery studies. Using a large-scale multiplex proximity extension assay (PEA) approach, we aimed to discover novel diagnostic protein biomarkers allowing accurate discrimination of PD from both controls and atypical Parkinsonian disorders (APD). METHODS: CSF from patients with PD, corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), multiple system atrophy and controls, were analysed with Olink PEA panels. Three cohorts were used in this study, comprising 192, 88 and 36 cases, respectively. All samples were run on the Cardiovascular II, Oncology II and Metabolism PEA panels. RESULTS: Our analysis revealed that 26 and 39 proteins were differentially expressed in the CSF of test and validation PD cohorts, respectively, compared to controls. Among them, 6 proteins were changed in both cohorts. Midkine (MK) was increased in PD with the strongest effect size and results were validated with ELISA. Another most increased protein in PD, DOPA decarboxylase (DDC), which catalyses the decarboxylation of DOPA (L-3,4-dihydroxyphenylalanine) to dopamine, was strongly correlated with dopaminergic treatment. Moreover, Kallikrein 10 was specifically changed in APD compared with both PD and controls, but unchanged between PD and controls. Wnt inhibitory factor 1 was consistently downregulated in CBS and PSP patients in two independent cohorts. CONCLUSIONS: Using the large-scale PEA approach, we have identified potential novel PD diagnostic biomarkers, most notably MK and DDC, in the CSF of PD patients.

Complement system changes in blood in Parkinson's disease and progressive Supranuclear Palsy/Corticobasal Syndrome.

Parkinson's Disease (PD) is diagnosed clinically, and early PD is often challenging to differentiate from atypical parkinsonian disorders such as the Four-repeat (4R-) Tauopathies Progressive Supranuclear Palsy and Corticobasal Syndrome. Diagnostic biomarkers are needed, and proteomic studies have suggested that the plasma complement system is altered in PD, but validation studies are lacking. In this study, plasma from 148 individuals (PD, 4R-Tauopathies, and healthy controls (HC)) were used to quantify 12 complement proteins with immunoassays, and CH50 classical pathway complement activity was quantified in sera from further 78 individuals (PD and HC). Complement factors C1q and C3 in plasma were lower in individuals with 4R-Tauopathies (ANOVA, p = 0.0041, p = 0.0057 respectively) compared to both PD and HC. None of the complement proteins were altered between PD and HC, however a few proteins correlated with clinical parameters within the PD group. Notably, levels of C3 correlated with non-motor symptoms in female patients. Classical pathway complement activity was not altered in PD serum, but did correlate with mental fatigue. In conclusion, individuals with 4R-Tauopathies showed lower plasma C1q and C3 compared PD and HC. Neither complement levels nor CH50 activity were significantly altered in PD versus HC but may associate with PD symptom severity.

Impaired migratory phenotype of CD4+ T cells in Parkinson's disease.

Dysfunctions in the immune system appear implicated in both disease onset and progression of Parkinson's disease (PD). Neurodegeneration observed in the brain of PD patients has been associated with neuroinflammation that is linked to alterations in peripheral adaptive immunity, where CD4+ T cells are key players. In the present study, we elucidated the immunological aspect of PD by employing a wide range of cellular assays, immunocytochemistry and flow cytometry to examine CD4+ T cells. We particularly investigated the role of CD4+ T cell migration in the proper functioning of the adaptive immune system. Our data reveal the altered migration potential of CD4+ T cells derived from PD patients, along with impaired mitochondrial positioning within the cell and reduced mitochondrial functionality. In addition, a cross-sectional study of p11 levels in CD4+ T cell subsets showed a differentially increased level of p11 in Th1, Th2 and Th17 populations. Taken together, these results demonstrate major impairments in the functionality of peripheral CD4+ T cells in PD.

Mitochondrial biogenesis, telomere length and cellular senescence in Parkinson's disease and Lewy body dementia.

Progressive age is the single major risk factor for neurodegenerative diseases. Cellular aging markers during Parkinson's disease (PD) have been implicated in previous studies, however the majority of studies have investigated the association of individual cellular aging hallmarks with PD but not jointly. Here, we have studied the association of PD with three aging hallmarks (telomere attrition, mitochondrial dysfunction, and cellular senescence) in blood and the brain tissue. Our results show that PD patients had 20% lower mitochondrial DNA copies but 26% longer telomeres in blood compared to controls. Moreover, telomere length in blood was positively correlated with medication (Levodopa Equivalent Daily Dose, LEDD) and disease duration. Similar results were found in brain tissue, where patients with Parkinson's disease (PD), Parkinson's disease dementia (PDD) and Dementia with Lewy Bodies (DLB) showed (46-95%) depleted mtDNA copies, but (7-9%) longer telomeres compared to controls. In addition, patients had lower mitochondrial biogenesis (PGC-1α and PGC-1ß) and higher load of a cellular senescence marker in postmortem prefrontal cortex tissue, with DLB showing the highest effect among the patient groups. Our results suggest that mitochondrial dysfunction (copy number and biogenesis) in blood might be a valuable marker to assess the risk of PD. However, further studies with larger sample size are needed to evaluate these findings.

Plasma IL-6 and IL-17A Correlate with Severity of Motor and Non-Motor Symptoms in Parkinson's Disease.

The nature of the inflammatory response in Parkinson's disease (PD) remains to be better understood. Here, we used highly sensitive Single Molecule Array (SIMOA) technology to measure the levels of the inflammatory mediators Interleukin 6 (IL-6), Interleukin 17A (IL-17A), Tumour Necrosis Factor α (TNFα) and Transforming Growth Factor ß (TGFß) in plasma from PD patients and age- and gender-matched healthy controls. We report that IL-17A correlates with non-motor symptoms (NMS) scores, while IL-6 positively correlates with motor scores. We found no correlations between cytokines and disease duration suggesting that IL-6 and IL-17A are associated with disease severity rather than disease duration in this cohort, furthermore IL-17A may be involved in the underlying pathophysiology of NMS in PD.