Biology subjects

Arkadir, D.

Publications and source records attributed to Arkadir, D..

5 recordsLinked to original sources

bioRxiv2025

The Quest for a Universal Parkinson's Transcriptomics Signature is Derailed by Inherent Variability between Patients

ObjectiveTo systematically evaluate the reproducibility and clinical utility of published blood mRNA-based gene signatures for classifying PD from healthy controls, and to uncover the pitfalls that limit their performances. MethodsWe validated the classification performance of 13 gene signatures unique for PD (published 2015-2025) using the Parkinsons Progression Markers Initiative (PPMI) database. We further validated classification performance on data collected in a prospective clinical trial where demographic and clinical parameters were minimized and environmental confounders were strictly controlled. Sources of gene expression variability were studied by mean pairwise distance analysis. ResultsGene overlap between signatures was low (11/411, 2.7%) but statistically significant (P<0.001) and enriched with genes involved in lipid metabolism. The majority (10/13) of these signatures retained statistical significance when tested on the PPMI dataset, but their classification performance was modest (median AUC 59.7%), substantially lower than originally reported. Classification performance improved when comparing GBA1-associated PD to controls (median AUC 65.4%, P=0.006). A prospective trial (16 PD patients, 14 controls) with rigorous environmental standardization did not improve classification accuracy. Inter-individual expression variability is the dominant limiting factor in classifier performance. Variability was not impacted by long-term levodopa therapy. InterpretationWhile blood transcriptomic signatures unique to PD are reproducible and may elucidate PD pathophysiology, their broad clinical utility remains severely limited by inherent inter-individual variability. Future research should prioritize biomarkers of divergence rather than the pursuit of a universal PD signature.

bioinformatics↗

bioRxiv2024

Multiparametric quantitative MRI uncovers putamen microstructural changes in Parkinson's Disease

Parkinsons disease (PD) is a progressive neurodegenerative disorder dominated by motor and non-motor dysfunction. Despite extensive research, the in vivo characterization of PD-related microstructural brain changes remains an ongoing challenge, limiting advancements in diagnostic and therapeutic strategies. The putamen, a critical structure within the basal ganglia, plays a key role in regulating movement and is profoundly affected in early PD-related neurodegeneration. In this study, we collected multiparametric quantitative MRI (qMRI) brain data of PD patients and healthy controls, to investigate microstructural alterations in the putamen in PD. We utilized a gradient analysis technique to analyze the spatial variations of various qMRI parameters, including relaxation rates (R1, R2, R2*), water fraction (WF), susceptibility, magnetization transfer saturation (MTsat), and diffusion metrics (MD, FA). Our findings reveal significant spatial gradients and interhemispheric asymmetries in these biophysical properties along the anterior-posterior axis of the putamen. Notably, PD patients exhibited increased water fraction and altered transverse relaxation rate R2*, particularly in the posterior putamen, correlated with motor symptom laterality. These microstructural changes suggest underlying tissue atrophy or neuroinflammatory processes associated with PD. The study underscores the importance of the posterior putamen as a focal point for PD pathology and highlights the potential of localized gradient analysis in detecting subtle yet clinically significant brain changes. The new qMRI dataset provides valuable insights into PD pathology, potentially aiding in the development of more precise diagnostic tools and targeted therapies.

neuroscience↗

bioRxiv2023

Non-linear input-output relationships in the subthalamic nucleus of Parkinson's patients

Both local field potentials (LFP) and spiking (SPK) activity in the subthalamic nucleus (STN) are related to Parkinsons disease (PD) symptoms; however, their relationship is poorly understood. We explore it by separating STN signals of 146 PD patients (308 trajectories, >25,000 recording sites) into aperiodic and periodic components and whitening these signals using their corresponding aperiodic parameters. The LFP aperiodic exponents resemble Brown noise ( = 2.20 {+/-} 0.40) and are significantly higher than SPK aperiodic exponents ( = 0.11 {+/-} 0.22, White noise). The periodic oscillations of LFP are overwhelmingly distributed in the high beta frequency domain while those of SPK are in both low and high beta domains. Beta oscillation center frequencies were downshifted in SPK relative to simultaneously recorded LFP. This demonstrates that the STN synaptic input (LFP) undergoes significant modifications when transformed into STN output (SPK) of PD patients, and may explain the critical role of STN in PD physiology and STN-Deep-Brain-Stimulation therapeutic efficacy.

neuroscience↗

bioRxiv2019

Opposing patterns of abnormal D1 and D2 receptor dependent cortico-striatal plasticity explain increased risk taking in patients with DYT1 dystonia

Patients with dystonia caused by the mutated TOR1A gene exhibit a risk neutral behaviour compared to controls who are risk averse in the same reinforcement learning task. We hypothesised this increased risk taking could be reproduced by a reinforcement learning model which included biologically realistic striatal plasticity learning rules. We aimed to test whether a specific combination of cortico-striatal plasticity abnormalities at D1 and D2 receptors could explain the abnormal behaviour. We found a model of cortico-striatal plasticity could generate simulated behaviour indistinguishable from patients only when both D1 and D2 plasticity was abnormally increased in opposite directions: specifically when D1 synaptic potentiation and D2 depotentiation were both increased. This result is consistent with previous observations in rodent models of cortico-striatal plasticity at D1 receptors, but contrasts with the pattern reported in vitro for D2 synapses. This suggests that additional factors in patients who manifest motor symptoms may lead to divergent effects on D2 synaptic plasticity that are not apparent in rodent models of this disease.

neuroscience↗

bioRxiv2018

Human Subthalamic Nucleus Selectively Decreases its Response to the Go-Signal in a Motor Inhibition Context

To better understand the mechanism of movement facilitation and inhibition in the subthalamic nucleus (STN), we recorded subthalamic multiunit activity intra-operatively while parkinsonian patients (n=43 patients, 173 sites) performed increasingly complex oddball paradigms: auditory ( None-Go, n=7, 28), simple movement ( All-Go, n=7, 26) and movement inhibition ( Go-NoGo, n=29, 119) tasks. To enable physiological sampling of the different subthalamic nucleus domains in both hemispheres, each patient performed one of the oddball paradigms several times.\n\nThe human STN responded mainly to movement-involving tasks: movement execution at the motor STN and movement planning at the limbic-associative STN. In the limbic-associative STN, responses to the inhibitory cue (deviant tone) in the movement inhibition task were not significantly different from the simple movement task. However, responses to the go cue (frequent tone) were significantly reduced. The reduction was mainly in the negative component of the evoked response amplitude. Successful movement inhibition was correlated with higher baseline activity before the inhibitory cue.\n\nWe suggest that the STN adapts to movement inhibition context by selectively decreasing the amplitude of neuronal activity. Thus, the STN enables movement inhibition not by increasing responses to the inhibitory cue but by reducing responses to the release cue. The negative component of the evoked response probably facilitates movement and a higher baseline activity enables successful inhibition of movement. These discharge modulations were found in the ventromedial, non-motor domain of the STN and therefore suggest a significant role of the associative-limbic domains in movement planning and in global movement regulation.

neuroscience↗