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Sensors (Basel, Switzerland) May 2024Early-morning off periods, causing early-morning akinesia, can lead to significant motor and nonmotor morbidity in levodopa-treated fluctuating Parkinson's disease (PD)...
Early-morning off periods, causing early-morning akinesia, can lead to significant motor and nonmotor morbidity in levodopa-treated fluctuating Parkinson's disease (PD) cases. Despite validated bedside scales in clinical practice, such early-morning off periods may remain undetected unless specific wearable technologies, such as the Parkinson's KinetiGraph™ (PKG) watch, are used. We report five PD cases for whom the PKG detected early-morning off periods that were initially clinically undetected and as such, untreated. These five cases serve as exemplars of this clinical gap in care. Post-PKG assessment, clinicians were alerted and targeted therapies helped abolish the early-morning off periods.
Topics: Humans; Parkinson Disease; Wearable Electronic Devices; Male; Aged; Female; Middle Aged; Levodopa
PubMed: 38793900
DOI: 10.3390/s24103045 -
International Journal of Molecular... May 2024Astrocytes actively participate in neurotransmitter homeostasis by bidirectional communication with neuronal cells, a concept named the tripartite synapse, yet their...
Astrocytes actively participate in neurotransmitter homeostasis by bidirectional communication with neuronal cells, a concept named the tripartite synapse, yet their role in dopamine (DA) homeostasis remains understudied. In the present study, we investigated the kinetic and molecular mechanisms of DA transport in cultured striatal astrocytes of adult rats. Kinetic uptake experiments were performed using radiolabeled [H]-DA, whereas mRNA expression of the dopamine, norepinephrine, organic cation and plasma membrane monoamine transporters (DAT, NET, OCTs and PMAT) and DA receptors D1 and D2 was determined by qPCR. Additionally, astrocyte cultures were subjected to a 24 h treatment with the DA receptor agonist apomorphine, the DA receptor antagonist haloperidol and the DA precursor L-DOPA. [H]-DA uptake exhibited temperature, concentration and sodium dependence, with potent inhibition by desipramine, nortriptyline and decynium-22, suggesting the involvement of multiple transporters. qPCR revealed prominent mRNA expression of the NET, the PMAT and OCT1, alongside lower levels of mRNA for OCT2, OCT3 and the DAT. Notably, apomorphine significantly altered NET, PMAT and D1 mRNA expression, while haloperidol and L-DOPA had a modest impact. Our findings demonstrate that striatal astrocytes aid in DA clearance by multiple transporters, which are influenced by dopaminergic drugs. Our study enhances the understanding of regional DA uptake, paving the way for targeted therapeutic interventions in dopaminergic disorders.
Topics: Animals; Astrocytes; Dopamine; Rats; Corpus Striatum; Haloperidol; Kinetics; Dopamine Plasma Membrane Transport Proteins; Apomorphine; Cells, Cultured; Male; Receptors, Dopamine D1; Biological Transport; Levodopa
PubMed: 38791173
DOI: 10.3390/ijms25105135 -
Journal of the Neurological Sciences Jun 2024Safinamide is an effective adjunctive therapy for wearing-off in Parkinson's disease (PD); however, evidence is lacking in older patients and those in the early stages... (Observational Study)
Observational Study
BACKGROUND
Safinamide is an effective adjunctive therapy for wearing-off in Parkinson's disease (PD); however, evidence is lacking in older patients and those in the early stages of wearing-off. This study evaluated the efficacy and safety of safinamide as adjunctive therapy in patients with PD treated with levodopa monotherapy in clinical practice.
METHODS
This multicentre, open-label observational study was conducted at five sites in Japan. Patients diagnosed with PD and wearing-off initiated safinamide as adjunctive therapy with levodopa monotherapy. Efficacy endpoints were mean changes in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I, III, and IV scores; daily ON-time without dyskinesia using 24-h patient symptom diaries; and 39-item Parkinson's Disease Questionnaire (PDQ-39) scores at 18 weeks of treatment.
RESULTS
In total, 24 patients initiated safinamide (66.7% were aged ≥75 years); the mean duration of wearing-off was 1.2 years. MDS-UPDRS Part III total score, Part IV total score, and PDQ-39 summary index decreased significantly from baseline (mean change -7.0 [p = 0.012], -2.4 [p = 0.007] and - 5.3 [p = 0.012], respectively). There was a non-statistically significant increase of 1.55 h in mean daily ON-time without dyskinesia. Numerical Rating Scale total score for pain (p = 0.015), and scores for OFF-period pain (p = 0.012) and nocturnal pain (p = 0.021) subdomains were significantly improved in the subgroup with pain. Most reported adverse events were classified as mild.
CONCLUSION
Safinamide improved motor and non-motor symptoms and quality of life-related measures in older patients with PD in the early stages of wearing-off without new safety concerns.
STUDY REGISTRATION
University Hospital Medical Information Network in Japan; study ID: UMIN000044341.
Topics: Humans; Parkinson Disease; Male; Benzylamines; Female; Aged; Levodopa; Alanine; Japan; Antiparkinson Agents; Middle Aged; Treatment Outcome; Drug Therapy, Combination; Aged, 80 and over; Severity of Illness Index; East Asian People
PubMed: 38788287
DOI: 10.1016/j.jns.2024.123051 -
Journal of Alzheimer's Disease : JAD 2024The recent Alva et al. Phase 3b study on pimavanserin use in older adults with neurodegenerative diseases (NDDs), specifically including Alzheimer's disease, vascular...
The recent Alva et al. Phase 3b study on pimavanserin use in older adults with neurodegenerative diseases (NDDs), specifically including Alzheimer's disease, vascular dementia, Parkinson's disease (with or without dementia), frontotemporal dementia, and dementia with Lewy bodies, provides important new data on its safety for managing neuropsychiatric symptoms in this population. This commentary on the study further examines the findings within the broader context of antipsychotic therapy as it has evolved from chlorpromazine to pimavanserin in a continuous search for greater safety. Comparing pimavanserin's safety and efficacy profile with historical data and regulatory milestones provides a nuanced perspective for clinicians regarding the significance of the drug's known advantages over prior antipsychotic treatments. More research is needed to determine the full potential of pimavanserin to improve neuropsychiatric symptoms in older adults with NDDs.
Topics: Humans; Piperidines; Urea; Antipsychotic Agents; Neurodegenerative Diseases; Dementia; Aged; Clinical Trials, Phase III as Topic
PubMed: 38788080
DOI: 10.3233/JAD-240274 -
Neurosurgical Review May 2024Parkinson's disease (PD) presents as a complex neurodegenerative disorder characterized by motor and non-motor symptoms, resulting from dopaminergic neuron degeneration....
Parkinson's disease (PD) presents as a complex neurodegenerative disorder characterized by motor and non-motor symptoms, resulting from dopaminergic neuron degeneration. Current treatment strategies primarily aim to alleviate symptoms through pharmacotherapy and supportive therapies. However, emerging research explores novel therapeutic avenues, including the repurposing of drugs like lixisenatide, a GLP-1 receptor agonist initially developed for type 2 diabetes. This correspondence summarizes a phase 2 clinical trial investigating lixisenatide's efficacy in early PD, demonstrating a potential for mitigating motor disability progression. Findings reveal a marginal improvement or stabilization in motor function among lixisenatide-treated individuals compared to placebo, emphasizing its therapeutic promise. Nonetheless, the emergence of gastrointestinal adverse events underscores the need for careful monitoring and management. Further extensive trials are warranted to delineate lixisenatide's efficacy and safety profile, fostering collaborative efforts towards precision treatments in PD.
Topics: Humans; Parkinson Disease; Peptides; Treatment Outcome; Antiparkinson Agents; Glucagon-Like Peptide-2 Receptor
PubMed: 38787469
DOI: 10.1007/s10143-024-02475-0 -
Experimental Neurology Aug 2024Gamma oscillations have been frequently observed in levodopa-induced dyskinesia (LID), manifest as broadband (60-120 Hz) and narrowband (80-110 Hz) gamma activity in...
Gamma oscillations have been frequently observed in levodopa-induced dyskinesia (LID), manifest as broadband (60-120 Hz) and narrowband (80-110 Hz) gamma activity in cortico-striatal projection. We investigated the electrophysiological mechanisms and correlation of gamma oscillations with dyskinesia severity, while assessing the administration of fenobam, a selective metabotropic glutamate receptor 5 (mGluR5) antagonist, in regulating dyskinesia-associated gamma activity. We conducted simultaneous electrophysiological recordings in Striatum (Str) and primary motor cortex (M1), together with Abnormal Involuntary Movement Scale scoring (AIMs). Phase-amplitude coupling (PAC), power, coherence, and Granger causality analyses were conducted for electrophysiological data. The findings demonstrated increased beta oscillations with directionality from M1 to Str in parkinsonian state. During on-state dyskinesia, elevated broadband gamma activity was modulated by the phase of theta activity in Str, while M1 → Str gamma causality mediated narrowband gamma oscillations in Str. Striatal gamma power (both periodic and aperiodic power), periodic power, peak frequency, and PAC at 80 min (corresponding to the peak dyskinesia) after repeated levodopa injections across recording days (day 30, 33, 36, 39, and 42) increased progressively, correlating with total AIMs. Additionally, a time-dependent parabolic trend of PAC, peak frequency and gamma power was observed after levodopa injection on day 42 from 20 to 120 min, which also correlated with corresponding AIMs. Fenobam effectively alleviates dyskinesia, suppresses enhanced gamma oscillations in the M1-Str directionality, and reduces PAC in Str. The temporal characteristics of gamma oscillations provide parameters for classifying LID severity. Antagonizing striatal mGluR5, a promising therapeutic target for dyskinesia, exerts its effects by modulating gamma activity.
Topics: Animals; Gamma Rhythm; Rats; Male; Dyskinesia, Drug-Induced; Corpus Striatum; Rats, Sprague-Dawley; Levodopa; Motor Cortex; Imidazoles
PubMed: 38782350
DOI: 10.1016/j.expneurol.2024.114833 -
European Journal of Endocrinology Jun 2024Unravel the potential mechanism(s) of the on- and off-target actions of dopamine agonist therapy in both human prolactinoma tumors and neighboring stromal and immune...
OBJECTIVE
Unravel the potential mechanism(s) of the on- and off-target actions of dopamine agonist therapy in both human prolactinoma tumors and neighboring stromal and immune cells.
DESIGN AND METHODS
Five surgically resected prolactinomas (PRLomas) from 3 cabergoline (CBG)-treated patients and 2 treatment-naive patients were analyzed by using single-cell RNA sequencing (scRNA-seq) to compare the cellular composition and transcriptional landscape.
RESULTS
Six major cell populations, namely tumor (88.2%), immune (5.6%), stromal (4.9%), progenitor cells (0.6%), proliferating cells (0.4%), and erythrocytes (0.2%), were observed. Tumor cells from CBG-treated patients expressed lower levels of genes that regulated hormone secretion, such as SCG2, VGF, TIMP1, NNAT, and CALD1, consistent with the inhibitory effects of CBG on hormone processing and secretion. Interestingly, we also observed an increased number of CD8+ T cells in the CBG-treated tissues. These cytotoxic CD8+ T cells expressed killing granule components such as perforin and the granzymes GZMB, GNLY, and KLRD1 as well as the inflammatory cytokine CCL5. Immune cell activation of these CD8+ T cells was further analyzed in a compartment-specific manner, and increased CD25 (IL2R) expression was noted in the CD8+ T cells from the CBG-treated samples. Additionally, and confirming prior reports, we noted a higher stromal cell population in the CBG-treated samples.
CONCLUSIONS
Our scRNA-seq studies revealed key differences in the transcriptomic features of CBG-treated and CBG-untreated PRLomas in both tumor and microenvironment cellular constituents, and for the first time, describe the previously unknown activation of CD8+ T cells following CBG treatment, which may play a role in the tumoricidal actions of CBG.
Topics: Humans; Cabergoline; Prolactinoma; Male; Female; Pituitary Neoplasms; Adult; Middle Aged; Fibrosis; Prolactin; Dopamine Agonists; CD8-Positive T-Lymphocytes; Stromal Cells; Young Adult; Tumor Microenvironment
PubMed: 38781434
DOI: 10.1093/ejendo/lvae055 -
Current Opinion in Neurology Aug 2024to review recent progress in the development and use of continuous levodopa therapies in Parkinson disease (PD). (Review)
Review
PURPOSE OF REVIEW
to review recent progress in the development and use of continuous levodopa therapies in Parkinson disease (PD).
RECENT FINDINGS
Levodopa/Carbidopa intestinal gel (LCIG) is a continuous levodopa therapy which is widely used in the United States, Europe and other countries and is effective at reducing 'off' time. Recent work has shown that LCIG can be useful in managing dyskinesias and can improve nonmotor symptoms and quality of life. Several studies have shown good long-term effectiveness of LCIG. Recent data support the cost-effectiveness of this treatment strategy. Subcutaneous (SC) delivery of levodopa is a newer strategy that avoids the need for a surgically placed gastric tube. Two different products enabling SC delivery of levodopa are in development: ND0612 and foslevodopa/foscarbidopa. Both have recently been shown to reduce 'off' time in randomized, double-blind trials. Adverse effects of SC levodopa are primarily related to skin reactions at the infusion site.
SUMMARY
Continuous levodopa therapies can be used to treat Parkinson disease motor fluctuations that cannot be managed with standard oral therapies. They may also improve nonmotor symptoms, and improve overall quality of life in patients with advanced PD.
Topics: Humans; Levodopa; Parkinson Disease; Antiparkinson Agents; Carbidopa; Drug Combinations; Infusions, Subcutaneous
PubMed: 38780079
DOI: 10.1097/WCO.0000000000001277 -
Food Chemistry Sep 2024Herein, a novel surface enhanced Raman spectroscopy (SERS) aptasensor was developed for amantadine (AMD) detection, based on magnetite nanoparticles coated with...
Herein, a novel surface enhanced Raman spectroscopy (SERS) aptasensor was developed for amantadine (AMD) detection, based on magnetite nanoparticles coated with polyethylenimine, silver nanoclusters and aptamers (FeO@PEI@AgNC-apt) as the capture probe and complementary DNA-modified gold nanorods (AuNRs@4-MPBA@Ag-c-DNA containing 4-mercaptophenylboric acid molecules) as the reporter probe. In the presence of AMD, the AMD and the reporter probe competed for the aptamer on the surface of the capture probe, resulting in the reporter probe detaching from the capture probe leading to a decrease in intensity of the SERS signal at 1067 cm for 4-MPBA. Under optimal conditions, a good linear relationship was established between the SERS intensity at 1067 cm and the logarithm of the AMD concentration over the range 10-10 mg L, with a LOD of 0.50 × 10 mg L. The AMD levels in spiked samples were evaluated using the SERS aptasensor, with good recoveries ranging from 90.57% to 113.49% being obtained.
Topics: Gold; Silver; Spectrum Analysis, Raman; Nanotubes; Aptamers, Nucleotide; Food Contamination; Amantadine; Limit of Detection; Biosensing Techniques; Metal Nanoparticles
PubMed: 38776796
DOI: 10.1016/j.foodchem.2024.139665 -
European Journal of Endocrinology Jun 2024The aim of this study is to compare the response to first-line medical treatment in treatment-naive acromegaly patients with pure growth hormone (GH)-secreting pituitary...
OBJECTIVE
The aim of this study is to compare the response to first-line medical treatment in treatment-naive acromegaly patients with pure growth hormone (GH)-secreting pituitary adenoma (GH-PA) and those with GH and prolactin cosecreting PA (GH&PRL-PA).
DESIGN
This is a retrospective multicentric study of acromegaly patients followed from 2003 to 2023 in 33 tertiary Spanish hospitals with at least 6 months of first-line medical treatment.
METHODS
Baseline characteristics, first-line medical treatment strategies, and outcomes were analyzed. We employed a multiple logistic regression full model to estimate the impact of some baseline characteristics on disease control after each treatment modality.
RESULTS
Of the 144 patients included, 72.9% had a GH-PA, and 27.1% had a GH&PRL-PA. Patients with GH&PRL-PA were younger (43.9 ± 15.0 vs 51.9 ± 12.7 years, P < .01) and harboring more frequently macroadenomas (89.7% vs 72.1%, P = .03). First-generation somatostatin receptor ligand (fgSRL) as monotherapy was given to 106 (73.6%) and a combination treatment with fgSRL and cabergoline in the remaining 38 (26.4%). Patients with GH&PRL-PA received more frequently a combination therapy (56.4% vs 15.2%, P < .01). After 6 months of treatment, in the group of patients under fgSRL as monotherapy, those patients with GH&PRL-PA had worse control compared to GH-PAs (29.4% vs 55.1%, P = .04). However, these differences in the rate of disease control between both groups disappeared when both received combination treatment with fgSRL and cabergoline.
CONCLUSION
In GH&PRL-PA, the biochemical control achieved with fgSRL as monotherapy is substantially worse than in patients harboring GH-PA, supporting the inclusion of cabergoline as first-line medical treatment in combination with fgSRLs in these subgroups of patients.
Topics: Humans; Acromegaly; Female; Male; Middle Aged; Retrospective Studies; Adult; Cabergoline; Treatment Outcome; Prolactin; Growth Hormone-Secreting Pituitary Adenoma; Human Growth Hormone; Adenoma; Aged; Drug Therapy, Combination; Somatostatin; Pituitary Neoplasms; Spain
PubMed: 38771697
DOI: 10.1093/ejendo/lvae053