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Acta Neuropathologica Mar 2024Parkinson's disease (PD) starts at the molecular and cellular level long before motor symptoms appear, yet there are no early-stage molecular biomarkers for diagnosis,...
Parkinson's disease (PD) starts at the molecular and cellular level long before motor symptoms appear, yet there are no early-stage molecular biomarkers for diagnosis, prognosis prediction, or monitoring therapeutic response. This lack of biomarkers greatly impedes patient care and translational research-L-DOPA remains the standard of care more than 50 years after its introduction. Here, we performed a large-scale, multi-tissue, and multi-platform proteomics study to identify new biomarkers for early diagnosis and disease monitoring in PD. We analyzed 4877 cerebrospinal fluid, blood plasma, and urine samples from participants across seven cohorts using three orthogonal proteomics methods: Olink proximity extension assay, SomaScan aptamer precipitation assay, and liquid chromatography-mass spectrometry proteomics. We discovered that hundreds of proteins were upregulated in the CSF, blood, or urine of PD patients, prodromal PD patients with DAT deficit and REM sleep behavior disorder or anosmia, and non-manifesting genetic carriers of LRRK2 and GBA mutations. We nominate multiple novel hits across our analyses as promising markers of early PD, including DOPA decarboxylase (DDC), also known as L-aromatic acid decarboxylase (AADC), sulfatase-modifying factor 1 (SUMF1), dipeptidyl peptidase 2/7 (DPP7), glutamyl aminopeptidase (ENPEP), WAP four-disulfide core domain 2 (WFDC2), and others. DDC, which catalyzes the final step in dopamine synthesis, particularly stands out as a novel hit with a compelling mechanistic link to PD pathogenesis. DDC is consistently upregulated in the CSF and urine of treatment-naïve PD, prodromal PD, and GBA or LRRK2 carrier participants by all three proteomics methods. We show that CSF DDC levels correlate with clinical symptom severity in treatment-naïve PD patients and can be used to accurately diagnose PD and prodromal PD. This suggests that urine and CSF DDC could be a promising diagnostic and prognostic marker with utility in both clinical care and translational research.
Topics: Humans; Parkinson Disease; Dopa Decarboxylase; Proteomics; Biomarkers; Plasma; Oxidoreductases Acting on Sulfur Group Donors; Aromatic-L-Amino-Acid Decarboxylases
PubMed: 38467937
DOI: 10.1007/s00401-024-02706-0 -
ACS Applied Materials & Interfaces May 2024The need for improved wet adhesives has driven research on mussel-inspired materials incorporating dihydroxyphenylalanine (DOPA) and related analogs of the parent...
The need for improved wet adhesives has driven research on mussel-inspired materials incorporating dihydroxyphenylalanine (DOPA) and related analogs of the parent catechol, but their susceptibility to oxidation limits practical application of these functionalities. Here, we investigate the molecular-level adhesion of the catechol analogs dihydroxybenzamide (DHB) and hydroxypyridinone (HOPO) as a function of pH. We find that the molecular structure of the catechol analogs influences their susceptibility to oxidation in alkaline conditions, with HOPO emerging as a particularly promising candidate for pH-tolerant adhesives for diverse environmental conditions.
PubMed: 38622496
DOI: 10.1021/acsami.4c01740 -
Frontiers in Aging Neuroscience 2023Parkinson's disease (PD) is recognized as the second most prevalent progressive neurodegenerative disease among the elderly. However, the relationship between PD and...
BACKGROUND
Parkinson's disease (PD) is recognized as the second most prevalent progressive neurodegenerative disease among the elderly. However, the relationship between PD and plasma homocysteine (Hcy), vitamin B12, and folate has yielded inconsistent results in previous studies. Hence, in order to address this ambiguity, we conducted a meta-analysis to summarize the existing evidence.
METHODS
Suitable studies published prior to May 2023 were identified by searching PubMed, EMBASE, Medline, Ovid, and Web of Science. The methodological quality of eligible studies was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS). Meta-analysis and publication bias were then performed using R version 4.3.1.
RESULTS
The results of our meta-analysis, consisting of case-control and cross-sectional studies, showed that PD patients had lower folate and vitamin B12 levels (SMD [95%CI]: -0.30[-0.39, -0.22], < 0.001 for Vitamin B12; SMD [95%CI]: -0.20 [-0.28, -0.13], < 0.001 for folate), but a significant higher Hcy level (SMD [95%CI]: 0.86 [0.59, 1.14], < 0.001) than healthy people. Meanwhile, PD was significantly related to hyperhomocysteinemia (SMD [95%]: 2.02 [1.26, 2.78], < 0.001) rather than plasma Hcy below 15 μmol/L (SMD [95%]: -0.31 [-0.62, 0.00], = 0.05). Subgroup analysis revealed associations between the Hcy level of PD patients and region ( = 0.03), age ( = 0.03), levodopa therapy ( = 0.03), Hoehn and Yahr stage ( < 0.001), and cognitive impairment ( < 0.001). However, gender ( = 0.38) and sample size ( = 0.49) were not associated.
CONCLUSION
Hcy, vitamin B12, and folic acid potentially predict the onset and development of PD. Additionally, multiple factors were linked to Hcy levels in PD patients. Further studies are needed to comprehend their roles in PD.
PubMed: 37941998
DOI: 10.3389/fnagi.2023.1254824 -
NPJ Parkinson's Disease Oct 2023It remains unclear which adjunctive drug for Parkinson's disease (PD) in combination with levodopa is more effective, tolerable, and safe. We aimed to compare the...
It remains unclear which adjunctive drug for Parkinson's disease (PD) in combination with levodopa is more effective, tolerable, and safe. We aimed to compare the efficacy, tolerability, and safety among anti-PD drugs from several classes in patients with fluctuating PD who received levodopa through network meta-analysis (NMA). Twelve anti-PD drugs belonging to 4 different drug classes (dopamine agonists, monoamine oxidase type B inhibitors, catechol-O-methyl transferase inhibitors, and an adenosine A2A receptor antagonist) were selected. We systematically searched PubMed, Embase, and the Cochrane Library for eligible randomized controlled trials (RCTs) comparing placebo with anti-PD drug or among anti-PD drugs in patients with PD who experienced motor fluctuations or wearing-off and received levodopa. We included 54 RCTs in the analysis. The NMA was performed under a frequentist framework using a random-effects model. The efficacy outcome was change in daily off-time, and the tolerability outcome was discontinuation due to all causes. Safety outcomes included discontinuation due to adverse events (AEs) and the incidence of AEs, dyskinesia, hallucination, and orthostatic hypotension. According to the surface under the cumulative ranking curve (SUCRA) in the NMA, ropinirole transdermal patch (SUCRA, 0.861) ranked the highest in efficacy, followed by pramipexole (0.762), ropinirole extended release (ER) (0.750), and safinamide (0.691). In terms of tolerability, ropinirole (0.954) ranked the highest, followed by pramipexole (0.857), safinamide (0.717), and ropinirole ER (0.708). Each anti-PD drug had different SUCRA ranking profiles for the safety outcomes. These findings suggest that ropinirole, pramipexole, and safinamide are well-balanced anti-PD drugs that satisfy both efficacy and tolerability outcomes.
PubMed: 37853009
DOI: 10.1038/s41531-023-00589-8 -
Journal of Neural Transmission (Vienna,... Nov 2023Device-aided therapies (DAT), which include deep brain stimulation and pump-based continuous dopaminergic stimulation with either levodopa or apomorphine, are among the... (Review)
Review
Device-aided therapies (DAT), which include deep brain stimulation and pump-based continuous dopaminergic stimulation with either levodopa or apomorphine, are among the major advances in the clinical management of Parkinson's disease (PD). Although DAT are being increasingly offered earlier in the disease course, their classical indication remains advanced PD. Theoretically, every patient should be offered transition to DAT when faced with refractory motor and nonmotor fluctuations and functional decline. Worldwide clinical reality is far from these ideal, and, therefore, question the "real-world" equal opportunity of access to DAT for PD patients with advanced PD-even within a single health care system. Differences in access to care, referral pattern (timing and frequency), as well as physician biases (unconscious/implicit or conscious/explicit bias), and patients' preferences or health-seeking behaviour are to be considered. Compared to DBS, little information is available concerning infusion therapies, as well as neurologists' and patients' attitudes towards them. This viewpoint aims to be thought-provoking and to assist clinicians in moving through the process of DAT selection, by including in their decision algorithm their own biases, patient perspective, ethical concerns as well as the current unknowns surrounding PD prognosis and DAT-related long-term side effects for a given patient.
Topics: Humans; Parkinson Disease; Antiparkinson Agents; Prognosis; Patient Preference; Uncertainty; Levodopa; Deep Brain Stimulation
PubMed: 37436446
DOI: 10.1007/s00702-023-02668-9 -
MedRxiv : the Preprint Server For... Sep 2023Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD)....
BACKGROUND
Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including and .
OBJECTIVES
To investigate the effects of genetic variants on risk and time to LID.
METHODS
We performed a genome-wide association study (GWAS) and analyses focused on and variants. We also calculated polygenic risk scores including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1,612 PD patients with and 3,175 without LID.
RESULTS
We found that variants were associated with LID risk (OR=1.65, 95% CI=1.21-2.26, p=0.0017) and variants with reduced time to LID onset (HR=1.42, 95% CI=1.09-1.84, p=0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (OR=1.27, 95% CI=1.03-1.56, =0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HR=1.38, 95% CI=1.07-1.79, =0.0128; HR=1.38, 95% CI=1.06-1.78, =0.0147).
CONCLUSIONS
This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care.
PubMed: 37790572
DOI: 10.1101/2023.08.28.23294610 -
BioRxiv : the Preprint Server For... May 2024Striatal Cholinergic Interneurons (CIN) are drivers of L-Dopa induced Dyskinesias (LID). However, what signaling pathways elicit aberrant CIN activity remains unclear....
BACKGROUND
Striatal Cholinergic Interneurons (CIN) are drivers of L-Dopa induced Dyskinesias (LID). However, what signaling pathways elicit aberrant CIN activity remains unclear. CIN express D2 and D5 receptors suggesting repeated activation of these receptors in response to L-Dopa could promote LID. While the role of D5 in this process has recently been probed, little is known about the role of D2.
METHOD
Mice with CIN-specific D2 ablation (D2 KO) underwent unilateral 6-OHDA lesion and chronic L-Dopa dosing, throughout which LID severity was quantified. The effect of D2 KO on histological markers of LID severity and CIN activity were also quantified postmortem.
RESULTS
D2 KO attenuated LID across L-Dopa doses, reduced expression of histological LID marker p-ERK, and prevented L-Dopa-induced increases in CIN activity marker p-rpS6 in the dorsolateral striatum.
CONCLUSION
The activation of D2 specifically on CIN is a key driver of LID.
PubMed: 38765986
DOI: 10.1101/2024.05.10.593604 -
Heliyon Aug 2023Growth hormone stimulation tests (GHST) remain the cornerstone for diagnosing growth hormone deficiency (GHD), yet they can be lengthy and costly. We aimed to examine...
INTRODUCTION
Growth hormone stimulation tests (GHST) remain the cornerstone for diagnosing growth hormone deficiency (GHD), yet they can be lengthy and costly. We aimed to examine whether the combined clonidine and glucagon stimulation test (CGST) and l-dopa and glucagon stimulation test (LDGST) can be shortened without compromising the test's specificity.
MATERIAL AND METHODS
We retrospectively analyzed the baseline characteristics, auxological and laboratory data of children with short stature who had undergone a CGST and an LDGST for GHD. We compared the diagnostic accuracy for the standard test and shortened test, eliminating time points of 0 and 210 min.
RESULTS
We reviewed 830 charts (8.17 ± 2.92 years old; 56.27% males), with 431 (57.0%) children in the CGST group, and 38 (51.35%) in the LDGST group who tested negative for GHD. The peak and maximum GH levels occurred at the 60-min time point for both the CGST and LDGST. Eliminating the 0-min time point was the only time that did not affect the specificity of the CGST, with a false-positive rate of 2 (2.99%), specificity of 0.99 (0.99-0.99), and p value of 0.25. Eliminating the 0- and 210-min time points did not affect the specificity of the LDGST, with a false-positive rate of 2 (5.26%), specificity of 0.95 (0.95-0.95), and p value of 0.24.
CONCLUSIONS
We concluded that 0-min time point could be eliminated without compromising the combined GHST diagnostic value, thus resulting in cost reduction. Larger studies are needed for the combined LDGST to explore whether the 30- and 210-min time points could be eliminated, thus resulting in cost and time savings.
PubMed: 37560690
DOI: 10.1016/j.heliyon.2023.e18713 -
Molecular Brain Apr 2024Dopamine plays important roles in cognitive function and inflammation and therefore is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's...
Dopamine plays important roles in cognitive function and inflammation and therefore is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Drugs that increase or maintain dopamine levels in the brain could be a therapeutic strategy for AD. However, the effects of dopamine and its precursor levodopa (L-DOPA) on Aβ/tau pathology in vivo and the underlying molecular mechanisms have not been studied in detail. Here, we investigated whether L-DOPA treatment alters neuroinflammation, Aβ pathology, and tau phosphorylation in 5xFAD mice, a model of AD. We found that L-DOPA administration significantly reduced microgliosis and astrogliosis in 5xFAD mice. In addition, L-DOPA treatment significantly decreased Aβ plaque number by upregulating NEP and ADAM17 levels in 5xFAD mice. However, L-DOPA-treated 5xFAD mice did not exhibit changes in tau hyperphosphorylation or tau kinase levels. These data suggest that L-DOPA alleviates neuroinflammatory responses and Aβ pathology but not tau pathology in this mouse model of AD.
Topics: Animals; Levodopa; Alzheimer Disease; Disease Models, Animal; ADAM17 Protein; Amyloid beta-Peptides; tau Proteins; Neuroinflammatory Diseases; Phosphorylation; Mice, Transgenic; Plaque, Amyloid; Mice; Brain
PubMed: 38685105
DOI: 10.1186/s13041-024-01092-8 -
Frontiers in Aging Neuroscience 2023The spatiotemporal gait changes in advanced Parkinson's disease (PD) remain a treatment challenge and have variable responses to L-dopa and subthalamic deep brain...
OBJECTIVE
The spatiotemporal gait changes in advanced Parkinson's disease (PD) remain a treatment challenge and have variable responses to L-dopa and subthalamic deep brain stimulation (STN-DBS). The purpose of this study was to determine whether low-frequency STN-DBS (LFS; 60 Hz) elicits a differential response to high-frequency STN-DBS (HFS; 180 Hz) in spatiotemporal gait kinematics.
METHODS
Advanced PD subjects with chronic STN-DBS were evaluated in both the OFF and ON medication states with LFS and HFS stimulation. Randomization of electrode contact pairs and frequency conditions was conducted. Instrumented Stand and Walk assessments were carried out for every stimulation/medication condition. LM-ANOVA was employed for analysis.
RESULTS
Twenty-two PD subjects participated in the study, with a mean age (SD) of 63.9 years. Significant interactions between frequency (both LFS and HFS) and electrode contact pairs (particularly ventrally located contacts) were observed for both spatial (foot elevation, toe-off angle, stride length) and temporal (foot speed, stance, single limb support (SLS) and foot swing) gait parameters. A synergistic effect was also demonstrated with L-dopa and both HFS and LFS for right SLS, left stance, left foot swing, right toe-off angle, and left arm range of motion. HFS produced significant improvement in trunk and lumbar range of motion compared to LFS.
CONCLUSION
The study provides evidence of synergism of L-dopa and STN-DBS on lower limb spatial and temporal measures in advanced PD. HFS and LFS STN-DBS produced equivalent effects among all other tested lower limb gait features. HFS produced significant trunk and lumbar kinematic improvements.
PubMed: 37842127
DOI: 10.3389/fnagi.2023.1206533