-
Factors associated with a placebo effect in Parkinson's disease in clinical trials: a meta-analysis.Journal of Neurology Jul 2024Outcomes of clinical trials of treatment in patients with Parkinson's disease (PD) may be influenced by placebo effects. The aim of this study was to determine the...
OBJECTIVES
Outcomes of clinical trials of treatment in patients with Parkinson's disease (PD) may be influenced by placebo effects. The aim of this study was to determine the factors associated with placebo effects in Parkinson's disease (PD) for guidance with design of future clinical trials.
METHODS
Factors associated with placebo effects in PD were examined in a meta-analysis using a random effects model with pooling of placebo effects on the Unified Parkinson's Disease Rating Scale part III (UPDRS III) or Movement Disorder Society sponsored revision of UPDRS III (MDS-UPDRS III). The following prespecified variables were included in the analyses: with or without drug at baseline, with or without a placebo run-in phase, with or without motor fluctuation, published year, number of study sites, placebo administration period, age, sex, disease duration, and daily levodopa dose. Publication bias was assessed by visual inspection of funnel plots and adjusted using the trim-and-fill method.
RESULTS
Thirty-eight articles with a total of 4828 subjects satisfied the inclusion criteria. There was a significant placebo effect using UPDRS III or MDS-UPDRS III (SMD = - 0.25; 95% CI - 0.35 to - 0.14; p < 0.001, I = 92%). Subgroup and/or multivariate meta-regression analyses revealed that placebo effects were associated with advanced PD (p = 0.04), drug exposure at baseline (p < 0.001), placebo administration period (p < 0.001), and disease duration (p < 0.01).
CONCLUSIONS
The results of this study are important as guidance in design of future clinical trials in which the influence of placebo effects is minimized.
PubMed: 38955829
DOI: 10.1007/s00415-024-12529-4 -
Neuropharmacology Jul 2024
Corrigendum to "Neuro-modulatory impact of felodipine against experimentally-induced Parkinson's disease: Possible contribution of PINK1-Parkin mitophagy pathway" [Neuropharmacology 250 (2024), ISSN 0028-3908, 109909].
PubMed: 38955585
DOI: 10.1016/j.neuropharm.2024.110053 -
Ageing Research Reviews Jun 2024Helicobacter pylori, a type of gram-negative bacterium, infects roughly half of the global population. It is strongly associated with gastrointestinal disorders like... (Review)
Review
Helicobacter pylori, a type of gram-negative bacterium, infects roughly half of the global population. It is strongly associated with gastrointestinal disorders like gastric cancer, peptic ulcers, and chronic gastritis. Moreover, numerous studies have linked this bacterium to various extra-gastric conditions, including hematologic, cardiovascular, and neurological issues. Specifically, research has shown that Helicobacter pylori interacts with the brain through the microbiota-gut-brain axis, thereby increasing the risk of neurological disorders. The inflammatory mediators released by Helicobacter pylori-induced chronic gastritis may disrupt the function of the blood-brain barrier by interfering with the transmission or direct action of neurotransmitters. This article examines the correlation between Helicobacter pylori and a range of conditions, such as hyperhomocysteinemia, schizophrenia, Alzheimer's disease, Parkinson's disease, ischemic stroke, multiple sclerosis, migraine, and Guillain-Barré syndrome.
PubMed: 38955263
DOI: 10.1016/j.arr.2024.102399 -
Experimental Gerontology Jun 2024Observational studies have shown that increased serum urate is associated with a lower risk of neurodegenerative diseases (NDs), but the causality remains unclear. We...
OBJECTIVE
Observational studies have shown that increased serum urate is associated with a lower risk of neurodegenerative diseases (NDs), but the causality remains unclear. We employed a two-sample Mendelian randomization (MR) approach to assess the causal relationship between serum urate and four common subtypes of NDs, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS).
METHODS
Serum urate data came from the CKDGen Consortium. GWAS data for PD, AD, ALS, and MS were obtained from four databases in the primary analysis and then acquired statistics from the FinnGen consortium for replication and meta-analysis. Inverse variance weighted (IVW), weighted median (WM), and MR-Egger regression methods were applied in the MR analyses. Pleiotropic effects, heterogeneity, and leave-one-out analyses were evaluated to validate the results.
RESULTS
There was no evidence for the effect of serum urate on PD (OR: 1.00, 95 % CI: 0.90-1.11, P = 0.97), AD (OR: 1.02, 95 % CI: 1.00-1.04, P = 0.06), ALS (OR: 1.05, 95 % CI: 0.97-1.13, P = 0.22), and MS (OR: 1.01, 95 % CI: 0.89-1.14, P = 0.90) risk when combined with the FinnGen consortium, neither was any evidence of pleiotropy detected between the instrumental variables (IVs).
CONCLUSION
The MR analysis suggested that serum urate may not be causally associated with a risk of PD, AD, ALS, and MS.
PubMed: 38955238
DOI: 10.1016/j.exger.2024.112503 -
Alzheimer's & Dementia : the Journal of... Jun 2024The recent introduction of seed amplification assays (SAAs) detecting misfolded α-synuclein, a pathology-specific marker for Lewy body disease (LBD), has allowed the in... (Review)
Review
INTRODUCTION
The recent introduction of seed amplification assays (SAAs) detecting misfolded α-synuclein, a pathology-specific marker for Lewy body disease (LBD), has allowed the in vivo identification and phenotypic characterization of patients with co-occurring Alzheimer's disease (AD) and LBD since the early clinical or even preclinical stage.
METHODS
We reviewed studies with an in vivo biomarker-based diagnosis of AD-LBD copathology.
RESULTS
Studies in large cohorts of cognitively impaired individuals have shown that cerebrospinal fluid (CSF) biomarkers detect the coexistence of AD and LB pathology in approximately 20%-25% of them, independently of the primary clinical diagnosis. Compared to those with pure AD, AD-LBD patients showed worse global cognition, especially in attentive/executive and visuospatial functions, and worse motor functions. In cognitively unimpaired individuals, concurrent AD-LBD pathologies predicted longitudinal cognitive progression with faster worsening of global cognition, memory, and attentive/executive functions.
DISCUSSION
Future research studies aiming for a better precision medicine approach should develop SAAs further to reach a quantitative evaluation or staging of each underlying pathology using a single biofluid sample.
HIGHLIGHTS
α-Synuclein seed amplification assays (SAAs) provide a specific marker for Lewy body disease (LBD). SAAs allow for the in vivo identification of co-occurring LBD in patients with Alzheimer's disease (AD). AD-LBD coexist in 20-25% of cognitively impaired elderly individuals, and ∼8% of those asymptomatic. Compared to pure AD, AD-LBD causes a faster worsening of cognitive functions. AD-LBD is associated with worse attentive/executive, memory, visuospatial and motor functions.
PubMed: 38955137
DOI: 10.1002/alz.14039 -
Parkinsonism & Related Disorders Jun 2024Parkinson's disease (PD) presents with a progressive decline in manual dexterity, attributed to dysfunction in the basal ganglia-thalamus-cortex loop, influenced by...
INTRODUCTION
Parkinson's disease (PD) presents with a progressive decline in manual dexterity, attributed to dysfunction in the basal ganglia-thalamus-cortex loop, influenced by dopaminergic deficits in the striatum. Recent research suggests that the motor cortex may play a pivotal role in mediating the relationship between striatal dopamine depletion and motor function in PD. Understanding this connection is crucial for comprehending the origins of manual dexterity impairments in PD. Therefore, our study aimed to explore how motor cortex activation mediates the association between striatal dopamine depletion and manual dexterity in PD.
MATERIALS AND METHODS
We enrolled 26 mildly affected PD patients in their off-medication phase to undergo [F]FDOPA scans for evaluating striatal dopaminergic function. EEG recordings were conducted during bimanual anti-phase finger tapping tasks to evaluate motor cortex activity, specifically focusing on Event-Related Desynchronization in the beta band. Manual dexterity was assessed using the Purdue Pegboard Test. Regression-based mediation analysis was conducted to examine whether motor cortex activation mediates the association between striatal dopamine depletion and manual dexterity in PD.
RESULTS
Mediation analysis revealed a significant direct effect of putamen dopamine depletion on manual dexterity for the affected hand and assembly tasks (performed with two hands), with motor cortex activity mediating this association. In contrast, while caudate nucleus dopamine depletion showed a significant direct effect on manual dexterity, motor cortex mediation on this association was not observed.
CONCLUSION
Our study confirms the association between striatum dopamine depletion and impaired manual dexterity in PD, with motor cortex activity mediating this relationship.
PubMed: 38955097
DOI: 10.1016/j.parkreldis.2024.107049 -
ACS Sensors Jul 2024Brain organoids are being recognized as valuable tools for drug evaluation in neurodegenerative diseases due to their similarity to the human brain's structure and...
Brain organoids are being recognized as valuable tools for drug evaluation in neurodegenerative diseases due to their similarity to the human brain's structure and function. However, a critical challenge is the lack of selective and sensitive electrochemical sensing platforms to detect the response of brain organoids, particularly changes in the neurotransmitter concentration upon drug treatment. This study introduces a 3D concave electrode patterned with a mesoporous Au nanodot for the detection of electrochemical signals of dopamine in response to drugs in brain organoids for the first time. The mesoporous Au nanodot-patterned film was fabricated using laser interference lithography and electrochemical deposition. Then, the film was attached to a polymer-based 3D concave mold to obtain a 3D concave electrode. Midbrain organoids generated from Parkinson's disease (PD) patient-derived iPSCs with gene mutations (named as PD midbrain organoid) or normal midbrain organoids were positioned on the developed 3D concave electrode. The 3D concave electrode showed a 1.4 times higher electrochemical signal of dopamine compared to the bare gold electrode. And the dopamine secreted from normal midbrain organoids or PD midbrain organoids on the 3D concave electrode could be detected electrochemically. After the treatment of PD midbrain organoids with levodopa, the drug for PD, the increase in dopamine level was detected due to the activation of dopaminergic neurons by the drug. The results suggest the potential of the proposed 3D concave electrode combined with brain organoids as a useful tool for assessing drug efficacy. This sensing system can be applied to a variety of organoids for a comprehensive drug evaluation.
PubMed: 38954790
DOI: 10.1021/acssensors.4c00476 -
Brain : a Journal of Neurology Jul 2024The ability to initiate volitional action is fundamental to human behaviour. Loss of dopaminergic neurons in Parkinson's disease is associated with impaired action...
The ability to initiate volitional action is fundamental to human behaviour. Loss of dopaminergic neurons in Parkinson's disease is associated with impaired action initiation, also termed akinesia. Both dopamine and subthalamic deep brain stimulation (DBS) can alleviate akinesia, but the underlying mechanisms are unknown. An important question is whether dopamine and DBS facilitate de novo build-up of neural dynamics for motor execution or accelerate existing cortical movement initiation signals through shared modulatory circuit effects. Answering these questions can provide the foundation for new closed-loop neurotherapies with adaptive DBS, but the objectification of neural processing delays prior to performance of volitional action remains a significant challenge. To overcome this challenge, we studied readiness potentials and trained brain signal decoders on invasive neurophysiology signals in 25 DBS patients (12 female) with Parkinson's disease during performance of self-initiated movements. Combined sensorimotor cortex electrocorticography (ECoG) and subthalamic local field potential (LFP) recordings were performed OFF therapy (N = 22), ON dopaminergic medication (N = 18) and ON subthalamic deep brain stimulation (N = 8). This allowed us to compare their therapeutic effects on neural latencies between the earliest cortical representation of movement intention as decoded by linear discriminant analysis classifiers and onset of muscle activation recorded with electromyography (EMG). In the hypodopaminergic OFF state, we observed long latencies between motor intention and motor execution for readiness potentials and machine learning classifications. Both, dopamine and DBS significantly shortened these latencies, hinting towards a shared therapeutic mechanism for alleviation of akinesia. To investigate this further, we analysed directional cortico-subthalamic oscillatory communication with multivariate granger causality. Strikingly, we found that both therapies independently shifted cortico-subthalamic oscillatory information flow from antikinetic beta (13-35 Hz) to prokinetic theta (4-10 Hz) rhythms, which was correlated with latencies in motor execution. Our study reveals a shared brain network modulation pattern of dopamine and DBS that may underlie the acceleration of neural dynamics for augmentation of movement initiation in Parkinson's disease. Instead of producing or increasing preparatory brain signals, both therapies modulate oscillatory communication. These insights provide a link between the pathophysiology of akinesia and its' therapeutic alleviation with oscillatory network changes in other non-motor and motor domains, e.g. related to hyperkinesia or effort and reward perception. In the future, our study may inspire the development of clinical brain computer interfaces based on brain signal decoders to provide temporally precise support for action initiation in patients with brain disorders.
PubMed: 38954651
DOI: 10.1093/brain/awae219 -
Drugs - Real World Outcomes Jul 2024Opicapone is a third-generation catechol-O-methyl-transferase inhibitor currently used for the treatment of motor fluctuations in Parkinson's disease. Its benefit and...
BACKGROUND
Opicapone is a third-generation catechol-O-methyl-transferase inhibitor currently used for the treatment of motor fluctuations in Parkinson's disease. Its benefit and safety have been established by clinical trials; however, data about its use in a real-life context, and particularly in an Italian population of patients with Parkinson's disease, are missing.
OBJECTIVES
We aimed to gather data about the real-life tolerability/safety of opicapone when used for the treatment of Parkinson's disease-related motor fluctuations.
METHODS
We enrolled 152 consecutive patients with Parkinson's disease and followed them for 2 years after opicapone introduction. We obtained baseline clinical and demographical information, including disease duration, stage, phenotype, as well as axial and non-motor symptoms. We collected the reasons for any treatment interruption and adverse events emerging after opicapone introduction.
RESULTS
Eighty-nine (58%) patients reported adverse events and 46 (30%) patients discontinued the treatment. Adverse events occurred less frequently in "earlier" patients accordingly to the disease course and L-Dopa treatment pathway; a motor fluctuation duration ≥12 months and Hoehn and Yahr scale score ≥2.5 were the main predictors of therapy withdrawal.
CONCLUSIONS
This study confirms the good tolerability/safety profile of opicapone in a real-life setting and provides country-specific data for Italian patients with Parkinson's disease.
PubMed: 38954191
DOI: 10.1007/s40801-024-00442-1 -
European Journal of Nuclear Medicine... Jul 2024There is an unmet need for compounds to detect fibrillar forms of alpha-synuclein (αSyn) and 4-repeat tau, which are critical in many neurodegenerative diseases. Here,...
PURPOSE
There is an unmet need for compounds to detect fibrillar forms of alpha-synuclein (αSyn) and 4-repeat tau, which are critical in many neurodegenerative diseases. Here, we aim to develop an efficient surface plasmon resonance (SPR)-based assay to facilitate the characterization of small molecules that can bind these fibrils.
METHODS
SPR measurements were conducted to characterize the binding properties of fluorescent ligands/compounds toward recombinant amyloid-beta (Aβ), K18-tau, full-length 2N4R-tau and αSyn fibrils. In silico modeling was performed to examine the binding pockets of ligands on αSyn fibrils. Immunofluorescence staining of postmortem brain tissue slices from Parkinson's disease patients and mouse models was performed with fluorescence ligands and specific antibodies.
RESULTS
We optimized the protocol for the immobilization of Aβ, K18-tau, full-length 2N4R-tau and αSyn fibrils in a controlled aggregation state on SPR-sensor chips and for assessing their binding to ligands. The SPR results from the analysis of binding kinetics suggested the presence of at least two binding sites for all fibrils, including luminescent conjugated oligothiophenes, benzothiazole derivatives, nonfluorescent methylene blue and lansoprazole. In silico modeling studies for αSyn (6H6B) revealed four binding sites with a preference for one site on the surface. Immunofluorescence staining validated the detection of pS129-αSyn positivity in the brains of Parkinson's disease patients and αSyn preformed-fibril injected mice, 6E10-positive Aβ in arcAβ mice, and AT-8/AT-100-positivity in pR5 mice.
CONCLUSION
SPR measurements of small molecules binding to Aβ, K18/full-length 2N4R-tau and αSyn fibrils suggested the existence of multiple binding sites. This approach may provide efficient characterization of compounds for neurodegenerative disease-relevant proteinopathies.
PubMed: 38953933
DOI: 10.1007/s00259-024-06806-7