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Turkish Neurosurgery Aug 2023Apathy is a newly recognized non-motor symptom and has a high impact on the quality of life in Parkinson's Disease (PD). The effect of subthalamic deep brain stimulation...
AIM
Apathy is a newly recognized non-motor symptom and has a high impact on the quality of life in Parkinson's Disease (PD). The effect of subthalamic deep brain stimulation (STN DBS) on apathy is controversial. This study aimed to investigate the impact of STN DBS on apathy and the possible relationship between apathy, depression, and levodopa equivalent dosage (LED) in PD patients.
MATERIAL AND METHODS
A total of 26 patients have been evaluated via the Unified Parkinson Disease Rating Scale (UPDRS), Beck Depression Inventory (Beck D), and Beck Anxiety Inventory (Beck A), Montreal Cognitive Assessment (MoCA), Parkinson Disease Questionnaire (PDQ-39) just before and 6 months after DBS.
RESULTS
Apathy scores (AES) showed a slight decrease from 54.00±10.30 to 52.69±8.88 without any statistical significance (p= 0.502) after DBS therapy. No correlation was detected between the post-treatment changes in apathy and UPDRS scores, Beck D, Beck A. Although the direction of the correlation between changes in AES scores and LED values was negative, the results did not reach statistical significance.
CONCLUSION
STN DBS therapy does not have a negative effect on apathy in PD Patients. Despite the satisfactory motor improvement, conservative dopaminergic dose reduction after surgery seems to be the main point to prevent apathy increase in PD patients after STN DBS.
PubMed: 38874248
DOI: 10.5137/1019-5149.JTN.43415-23.3 -
Frontiers in Aging Neuroscience 2024Levodopa (L-dopa) therapy is the principal pharmacological treatment for Parkinson's disease (PD). Nevertheless, prolonged use of this drug may result in different...
OBJECTIVE
Levodopa (L-dopa) therapy is the principal pharmacological treatment for Parkinson's disease (PD). Nevertheless, prolonged use of this drug may result in different involuntary movement symptoms caused by the medication, referred to as levodopa-induced dyskinesia (LID). LID is associated with changes in synaptic plasticity of the D1 medium spiny neurons (MSNs) located in the dorsal striatum (dStr). Within the striatum, the amount of Dopamine D3 receptor (D3R) is notably increased in LID, demonstrating colocalization with D1R expression in neurons, and the level of D3R expression is directly related to the intensity of LID. IRL 790, as a D3R antagonist, can ameliorate LID. This study aims to explore if IRL 790 improves LID by regulating the synaptic plasticity of D1+ MSNs in dStr.
METHODS
The electrophysiology and synaptic spine density of D1+ MSNs in dStr were recorded for sham mice, LID mice, and LID mice treated with IRL 790. The regulation of synaptic plasticity in LID D1+ MSNs by IRL 790 was analyzed. Behavioral tests were conducted to confirm the treatment effect of IRL 790 on LID.
RESULTS
In LID D1+ MSNs, there was persistent abnormal LTP, absence of LTD, and an increase in spontaneous excitatory postsynaptic currents (sEPSCs). IRL 790 treatment restored normal LTP, LTD, and sEPSCs. Treatment with IRL 790 also restored the reduced dendritic spine density in D1+ MSNs of LID mice. IRL790 improved dyskinetic manifestations in LID mice.
CONCLUSION
IRL790 ameliorates LID by regulating the synaptic structure and functional plasticity of striatal D1+ MSNs.
PubMed: 38872625
DOI: 10.3389/fnagi.2024.1401991 -
Noro Psikiyatri Arsivi 2024As a neurologist who has followed up countless Parkinson's patients over the last 32 years of my fifty-year career; I denied diagnosing myself with Parkinson's disease... (Review)
Review
As a neurologist who has followed up countless Parkinson's patients over the last 32 years of my fifty-year career; I denied diagnosing myself with Parkinson's disease (PD), although the seldom mild involuntary "twitches" that occurred in the thumb of my right hand over a two-year period, resembled Parkinson's disease tremor. However, when these involuntary contractions became persistent; considering its similarity to characteristic resting tremor in typical PD, the positive effect of dopaminergic medications, the development of levodopa-induced dyskinesias and other non-motor symptoms, it was clear that the PD diagnosis was accurate. This situation naturally caused me anxiety, and for a year and a half, I kept my diagnosis hidden from everyone except a few close relatives. However, with the encouragement of a psychiatrist friend, when I was able to share my condition with my loved ones, I felt a relative reduction in the burden I was carrying and consequently experienced emotional relief. I am still able to carry out my daily activities independently with a rather low dose of medication, and my PD symptoms do not attract noticeable attention.
PubMed: 38868853
DOI: 10.29399/npa.28634 -
DOPA-decarboxylase is elevated in CSF, but not plasma, in prodromal and de novo Parkinson's disease.Translational Neurodegeneration Jun 2024
Topics: Parkinson Disease; Humans; Female; Prodromal Symptoms; Male; Middle Aged; Aged; Dopa Decarboxylase; Biomarkers
PubMed: 38863007
DOI: 10.1186/s40035-024-00421-0 -
Proceedings of the National Academy of... Jun 2024In bacteria, attenuation of protein-tyrosine phosphorylation occurs during oxidative stress. The main described mechanism behind this effect is the HO-triggered...
In bacteria, attenuation of protein-tyrosine phosphorylation occurs during oxidative stress. The main described mechanism behind this effect is the HO-triggered conversion of bacterial phospho-tyrosines to protein-bound 3,4-dihydroxyphenylalanine. This disrupts the bacterial tyrosine phosphorylation-based signaling network, which alters the bacterial polysaccharide biosynthesis. Herein, we report an alternative mechanism, in which oxidative stress leads to a direct inhibition of bacterial protein-tyrosine kinases (BY-kinases). We show that DefA, a minor peptide deformylase, inhibits the activity of BY-kinase PtkA when is exposed to oxidative stress. High levels of PtkA activity are known to destabilize pellicle formation, which leads to higher sensitivity to oxidative stress. Interaction with DefA inhibits both PtkA autophosphorylation and phosphorylation of its substrate Ugd, which is involved in exopolysaccharide formation. Inactivation of drastically reduces the capacity of to cope with oxidative stress, but it does not affect the major oxidative stress regulons PerR, OhrR, and Spx, indicating that PtkA inhibition is the main pathway for DefA involvement in this stress response. Structural analysis identified DefA residues Asn95, Tyr150, and Glu152 as essential for interaction with PtkA. Inhibition of PtkA depends also on the presence of a C-terminal α-helix of DefA, which resembles PtkA-interacting motifs from known PtkA activators, TkmA, SalA, and MinD. Loss of either the key interacting residues or the inhibitory helix of DefA abolishes inhibition of PtkA in vitro and impairs postoxidative stress recovery in vivo, confirming the involvement of these structural features in the proposed mechanism.
Topics: Bacillus subtilis; Oxidative Stress; Phosphorylation; Bacterial Proteins; Protein-Tyrosine Kinases; Hydrogen Peroxide; Amidohydrolases
PubMed: 38857388
DOI: 10.1073/pnas.2321890121 -
European Stroke Journal Jun 2024Novel therapeutic approaches are needed in stroke recovery. Whether pharmacological therapies are beneficial for enhancing stroke recovery is unclear. Dopamine is a...
RATIONALE
Novel therapeutic approaches are needed in stroke recovery. Whether pharmacological therapies are beneficial for enhancing stroke recovery is unclear. Dopamine is a neurotransmitter involved in motor learning, reward, and brain plasticity. Its prodrug levodopa is a promising agent for stroke recovery.
AIM AND HYPOTHESIS
To investigate the hypothesis that levodopa, in addition to standardized rehabilitation therapy based on active task training, results in an enhancement of functional recovery in acute ischemic or hemorrhagic stroke patients compared to placebo.
DESIGN
ESTREL (nhancement of troke habilitation with ) is a randomized (ratio 1:1), multicenter, placebo-controlled, double-blind, parallel-group superiority trial.
PARTICIPANTS
610 participants (according to sample size calculation) with a clinically meaningful hemiparesis will be enrolled ⩽7 days after stroke onset. Key eligibility criteria include (i) in-hospital-rehabilitation required, (ii) capability to participate in rehabilitation, (iii) previous independence in daily living.
INTERVENTION
Levodopa 100 mg/carbidopa 25 mg three times daily, administered for 5 weeks in addition to standardized rehabilitation. The study intervention will be initiated within 7 days after stroke onset.
COMPARISON
Matching placebo plus standardized rehabilitation.
OUTCOMES
The primary outcome is the between-group difference of the Fugl-Meyer-Motor Assessment (FMMA) total score measured 3 months after randomization. Secondary outcomes include patient-reported health and wellbeing (PROMIS 10 and 29), patient-reported assessment of improvement, Rivermead Mobility Index, modified Rankin Scale, National Institutes of Health Stroke Scale (NIHSS), and as measures of harm: mortality, recurrent stroke, and serious adverse events.
CONCLUSION
The ESTREL trial will provide evidence of whether the use of Levodopa in addition to standardized rehabilitation in stroke patients leads to better functional recovery compared to rehabilitation alone.
PubMed: 38853524
DOI: 10.1177/23969873241255867 -
Insights Into Imaging Jun 2024The efficacy of levodopa, the most crucial metric for Parkinson's disease diagnosis and treatment, is traditionally gauged through the levodopa challenge test, which...
BACKGROUND
The efficacy of levodopa, the most crucial metric for Parkinson's disease diagnosis and treatment, is traditionally gauged through the levodopa challenge test, which lacks a predictive model. This study aims to probe the predictive power of T1-weighted MRI, the most accessible modality for levodopa response.
METHODS
This retrospective study used two datasets: from the Parkinson's Progression Markers Initiative (219 records) and the external clinical dataset from Ruijin Hospital (217 records). A novel feature extraction method using MedicalNet, a pre-trained deep learning network, along with three previous approaches was applied. Three machine learning models were trained and tested on the PPMI dataset and included clinical features, imaging features, and their union set, using the area under the curve (AUC) as the metric. The most significant brain regions were visualized. The external clinical dataset was further evaluated using trained models. A paired one-tailed t-test was performed between the two sets; statistical significance was set at p < 0.001.
RESULTS
For 46 test set records (mean age, 62 ± 9 years, 28 men), MedicalNet-extracted features demonstrated a consistent improvement in all three machine learning models (SVM 0.83 ± 0.01 versus 0.73 ± 0.01, XgBoost 0.80 ± 0.04 versus 0.74 ± 0.02, MLP 0.80 ± 0.03 versus 0.70 ± 0.07, p < 0.001). Both feature sets were validated on the clinical dataset using SVM, where MedicalNet features alone achieved an AUC of 0.64 ± 0.03. Key responsible brain regions were visualized.
CONCLUSION
The T1-weighed MRI features were more robust and generalizable than the clinical features in prediction; their combination provided the best results. T1-weighed MRI provided insights on specific regions responsible for levodopa response prediction.
CRITICAL RELEVANCE STATEMENT
This study demonstrated that T1w MRI features extracted by a deep learning model have the potential to predict the levodopa response of PD patients and are more robust than widely used clinical information, which might help in determining treatment strategy.
KEY POINTS
This study investigated the predictive value of T1w features for levodopa response. MedicalNet extractor outperformed all other previously published methods with key region visualization. T1w features are more effective than clinical information in levodopa response prediction.
PubMed: 38853208
DOI: 10.1186/s13244-024-01690-z -
Neurobiology of Disease Aug 2024Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal...
Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal dopamine depletion. In Parkinson's disease therapy, dopamine loss is counteracted by the administration of L-DOPA, which is initially effective in ameliorating motor symptoms, but over time leads to a burdening side effect of uncontrollable jerky movements, termed L-DOPA-induced dyskinesia. To date, no efficient treatment for dyskinesia exists. The dopaminergic and serotonergic systems are intrinsically linked, and in recent years, a role has been established for pre-synaptic 5-HT1a/b receptors in L-DOPA-induced dyskinesia. We hypothesized that post-synaptic serotonin receptors may have a role and investigated the effect of modulation of 5-HT4 receptor on motor symptoms and L-DOPA-induced dyskinesia in the unilateral 6-OHDA mouse model of Parkinson's disease. Administration of RS 67333, a 5-HT4 receptor partial agonist, reduces L-DOPA-induced dyskinesia without altering L-DOPA's pro-kinetic effect. In the dorsolateral striatum, we find 5-HT4 receptor to be predominantly expressed in D2R-containing medium spiny neurons, and its expression is altered by dopamine depletion and L-DOPA treatment. We further show that 5-HT4 receptor agonism not only reduces L-DOPA-induced dyskinesia, but also enhances the activation of the cAMP-PKA pathway in striatopallidal medium spiny neurons. Taken together, our findings suggest that agonism of the post-synaptic serotonin receptor 5-HT4 may be a novel therapeutic approach to reduce L-DOPA-induced dyskinesia.
Topics: Animals; Dyskinesia, Drug-Induced; Levodopa; Oxidopamine; Mice; Male; Mice, Inbred C57BL; Serotonin 5-HT4 Receptor Agonists; Antiparkinson Agents; Corpus Striatum; Receptors, Serotonin, 5-HT4; Parkinsonian Disorders; Pyridines; Neurons; Piperidines; Pyrimidines
PubMed: 38852753
DOI: 10.1016/j.nbd.2024.106559 -
NPJ Parkinson's Disease Jun 2024The effects of subthalamic nucleus deep brain stimulation (STN-DBS) on anxiety in Parkinson's disease (PD) are understudied. We identified clinical predictors of STN-DBS...
The effects of subthalamic nucleus deep brain stimulation (STN-DBS) on anxiety in Parkinson's disease (PD) are understudied. We identified clinical predictors of STN-DBS effects on anxiety in this study. In this prospective, open-label, multicentre study, we assessed patients with anxiety undergoing STN-DBS for PD preoperatively and at 6-month follow-up postoperatively. We assessed the Hospital Anxiety and Depression Scale (HADS-anxiety and depression subscales), Unified PD Rating Scale-motor examination, Scales for Outcomes in PD-motor (SCOPA-M)-activities of daily living (ADL) and -motor complications, Non-Motor Symptom Scale (NMSS), PDQuestionnaire-8 (PDQ-8), and levodopa-equivalent daily dose. We tested changes at follow-up with Wilcoxon signed-rank test and corrected for multiple comparisons (Bonferroni method). We identified patients with a clinically relevant anxiety improvement of anxiety based on a designated threshold of ½ standard deviation of baseline HADS-anxiety. Moreover, we investigated predictors of HADS-anxiety changes with correlations and linear regressions. We included 50 patients with clinically relevant baseline anxiety (i.e., HADS-anxiety ≥ 8) aged 63.1 years ± 8.3 with 10.4 years ± 4.5 PD duration. HADS-anxiety improved significantly at 6-month follow-up as 80% of our cohort experienced clinically relevant anxiety improvement. In predictor analyses, worse baseline SCOPA-ADL and NMSS-urinary domain were associated with greater HADS-anxiety improvements. HADS-anxiety and PDQ-8 changes correlated moderately. Worse preoperative ADL and urinary symptoms predicted favourable postoperative anxiety outcome, which in turn was directly proportionate to greater QoL improvement. This study highlights the importance of detailed anxiety assessments alongside other non-motor and motor symptoms when advising and monitoring patients undergoing STN-DBS for PD.
PubMed: 38851717
DOI: 10.1038/s41531-024-00701-6 -
Parkinson's Disease 2024Patients with Parkinson's disease (PD) experience significantly reduced quality of life when PD is complicated with Pisa syndrome (PS). PS is a postural abnormality...
Patients with Parkinson's disease (PD) experience significantly reduced quality of life when PD is complicated with Pisa syndrome (PS). PS is a postural abnormality associated with a lateral bending of the trunk, causing the patient to lean to one side. Microsaccades during fixation are transmitted to the visual cortex, and this gaze movement may be impaired in PD. We aimed to detect presymptomatic signs of PS. We enrolled 50 patients with PD without dementia and investigated the visual systems in patients with concurrent PD and PS based on a Romberg ratio of<1.0. Gaze analysis, pupil diameter, stabilization tests, neuropsychological tests, and cerebral perfusion scintigraphy were reviewed and statistically analyzed. Two years later, we divided the patients into three groups as follows: PISA++ (patients who had PS at enrollment), PISA-+ (patients without PS that developed PS during the 2-year period), and PISA-- (patients without PS that did not develop PS during the 2-year period). The PISA-+ group exhibited a significantly higher daily levodopa dose and longer fixations, as well as lower position discrimination, Wechsler Adult Intelligence Scale-Third Edition blocking, and blood flow in the left supramarginal and orbital gyri than that in the PISA-- group. The PISA++ group showed a significantly longer fixation time and lower Mini-Mental State Examination score, Romberg ratio of area, amplitude, velocity of microsaccades, and blood flow in the left precuneus and cuneus than that in the PISA-+ group. Before the onset of PS, hypoperfusion occurred in the correlative visual cortex and the position discrimination test. Patients with PS have reduced saccades and slow microsaccades.
PubMed: 38846136
DOI: 10.1155/2024/5550362