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The Senior Care Pharmacist Jul 2024Parkinson's disease (PD) is a debilitating condition that affects 1.8% of people 65 years of age and older. Patients with PD often require hospitalization and are...
Parkinson's disease (PD) is a debilitating condition that affects 1.8% of people 65 years of age and older. Patients with PD often require hospitalization and are frequently admitted through the emergency department (ED). Notably, their hospital durations tend to be lengthier compared with patients without PD. The primary outcome of this research was to compare the length of stay (LOS) of patients who received carbidopa-levodopa (CL) in the ED with those who did not. Secondary outcomes included 30-day-readmission rates and administration of injectable for agitation. In addition, the percentage of patients receiving CL before and after an information management technology (IMT) alert implementation was compared in a sub-analysis. Patients that received CL during their inpatient stay were identified by a database report in this retrospective study. Patients were excluded if they were not admitted through the ED, younger than 65 years of age, or admitted to the intensive care unit after the ED. There was a total of 266 in the control group and 217 patients in the intervention group. The intervention group had a significantly shorter LOS than the control group (3.29 vs 5.37 days; = 0.002), significantly less frequent 30-day readmissions ( = 0.032), and used fewer injectables for agitation ( = 0.035). The sub-analysis of the IMT alert revealed that prior to the alert's implementation, 28.5% of patients received CL in the ED; whereas post-alert, this percentage increased to 91.4% ( < 0.001). The results of this study found that the group of PD patients who received CL in the ED had shorter LOS, lower 30-day readmissions, and used less injectables for agitation compared with the group that did not receive CL in the ED. This improvement is possibly due to continuity of CL supply considering its short half-life and clinical importance for PD.
Topics: Humans; Carbidopa; Levodopa; Parkinson Disease; Aged; Male; Female; Retrospective Studies; Emergency Service, Hospital; Drug Combinations; Length of Stay; Antiparkinson Agents; Aged, 80 and over; Treatment Outcome; Patient Readmission
PubMed: 38937894
DOI: 10.4140/TCP.n.2024.242 -
BMC Neurology Jun 2024Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and nonmotor system manifestations and psychiatric symptoms. The aim of this...
BACKGROUND
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and nonmotor system manifestations and psychiatric symptoms. The aim of this study was to estimate the age- and sex-specific incidence of PD in Germany using an illness-death model and a corresponding partial differential equation (PDE) based on prevalence and mortality data.
METHODS
Based on a PDE that describes the dynamics in an illness-death model, the age- and sex-specific incidence of PD in Germany was estimated using published prevalence and mortality rates. Prevalence rates were provided by the Central Institute for Statutory Health Insurance (Zi) for the period from 2010 to 2019. Parkinson's related mortality was estimated based on comparable population data from Norway. Bootstrapping was used for incidence estimation (median of 5000 samples) and to obtain 95% confidence intervals to interpret the accuracy of the incidence estimation.
RESULTS
Men had higher incidences of PD than women at all ages. The highest incidences (median of 5000 bootstrap samples) for both groups were estimated for the age of 85 years with an incidence of 538.49 per 100,000 person-years (py) in men and 284.09 per 100,000 py in women, with an increasing width of bootstrapping 95% CIs showing greater uncertainty in the estimation at older ages.
CONCLUSION
The illness-death model and the corresponding PDE, which describes changes in prevalence as a function of mortality and incidence, can be used to estimate the incidence of PD as a chronic disease. As overestimation of incidence is less likely with this method, we found incidence rates of Parkinson's disease that are suitable for further analyses with a lower risk of bias.
Topics: Humans; Parkinson Disease; Male; Germany; Female; Aged; Middle Aged; Incidence; Prevalence; Aged, 80 and over; Adult; Insurance, Health; Young Adult; Adolescent
PubMed: 38937689
DOI: 10.1186/s12883-024-03739-4 -
Nature Reviews. Neuroscience Jun 2024Bradykinesia, or slowness of movement, is a defining feature of Parkinson disease (PD) and a major contributor to the negative effects on quality of life associated with... (Review)
Review
Bradykinesia, or slowness of movement, is a defining feature of Parkinson disease (PD) and a major contributor to the negative effects on quality of life associated with this disorder and related conditions. A dominant pathophysiological model of bradykinesia in PD has existed for approximately 30 years and has been the basis for the development of several therapeutic interventions, but accumulating evidence has made this model increasingly untenable. Although more recent models have been proposed, they also appear to be flawed. In this Perspective, I consider the leading prior models of bradykinesia in PD and argue that a more functionally related model is required, one that considers changes that disrupt the fundamental process of accurate information transmission. In doing so, I review emerging evidence of network level functional connectivity changes, information transfer dysfunction and potential motor code transmission error and present a novel model of bradykinesia in PD that incorporates this evidence. I hope that this model may reconcile inconsistencies in its predecessors and encourage further development of therapeutic interventions.
PubMed: 38937655
DOI: 10.1038/s41583-024-00830-0 -
Molecular Neurobiology Jun 2024Cyclin-dependent kinase 5 (CDK5) is a protein kinase involved in neuronal homeostasis and development critical for neuronal survival. Besides, its deregulation is linked...
Cyclin-dependent kinase 5 (CDK5) is a protein kinase involved in neuronal homeostasis and development critical for neuronal survival. Besides, its deregulation is linked to neurodegenerative pathologies such as Alzheimer's and Parkinson's diseases. For that reason, we aimed to generate a deficient CDK5 genetic model in neurons derived from human-induced pluripotent stem cells (hiPSCs) using CRISPR/Cas9 technology. We obtained a heterozygous CDK5 clone for the FN2.1 hiPSC line that retained hiPSC stemness and pluripotent potential. Then, neural stem cells (NSCs) and further neurons were derived from the CDK5 KO FN2.1 hiPSCs, and their phenotype was validated by immunofluorescence staining using antibodies that recognize lineage-specific markers (SOX-1, SOX-2, and NESTIN for NSCs and TUJ-1, MAP-5, and MAP-2 for neurons). We found that the proliferation rate increased in CDK5 KO hiPSC-derived neurons concomitantly with a reduction in NEUN and P35 expression levels. However, the morphometric analysis revealed that CDK5 deficiency caused an increase in the length of the main, primary, and secondary neurites and the neuronal soma area. As a whole, we found that a deficit in CDK5 does not impair hiPSC neuronal differentiation but deregulates proliferation and neurite outgrowth, favoring elongation. The misregulated activity of specific kinases leads to abnormalities such as impaired axonal connectivity in neurodegenerative diseases. Thus, therapeutic approaches aimed at normalizing the activity of kinases, such as CDK5, may help prevent the degeneration of vulnerable neurons.
PubMed: 38937422
DOI: 10.1007/s12035-024-04325-y -
European Spine Journal : Official... Jun 2024Parkinson's Disease (PD) patients represent challenging spinal surgery candidates due to associated frailty and deformity. This study consolidates the literature... (Review)
Review
BACKGROUND
Parkinson's Disease (PD) patients represent challenging spinal surgery candidates due to associated frailty and deformity. This study consolidates the literature concerning spinal surgery outcomes in PD versus non-PD patients, to evaluate if PD predisposes patients to worse post-operative outcomes, so that treatment protocols can be optimised.
METHODS
A systematic review and meta-analysis was conducted of PubMed/Medline, Embase, and Google Scholar databases per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies of interest included comparative (PD versus non-PD) cohorts undergoing spinal instrumented fusions. Post-operative clinical outcomes were collated and compared for significance between cohorts. Further analysis was made on outcomes based on the different surgical procedures performed (Anterior Cervical Discectomy and Fusion (ACDF), Thoracolumbar or Lumbar fusions, Thoracolumbar or Lumbar fusions without Osteoporotic Vertebral Compression fracture (OVCF) patients). All statistical analysis was performed using The R Project for Statistical Computing (version 4.1.2), with a p-value of < 0.05 deemed statistically significant.
RESULTS
In total, 2,323,650 patients were included across 16 studies. Of those, 2,308,949 (99.37%) were patients without PD (non-PD), while 14,701 (0.63%) patients had PD at time of surgery. The collective mean age was 68.23 years (PD: 70.14 years vs non-PD: 64.86 years). Comparatively, there were 844,641 males (PD: 4,574; non-PD: 840,067) and 959,908 females (PD: 3,213; non-PD: 956,695). Overall, there were more post-operative complications in the PD cohort. Specifically, PD patients experienced significantly more surgical site infections (p = 0.01), increased rates of revision surgeries (p = 0.04) and increased venous thromboembolic events (p = 0.02) versus the non-PD cohort. In thoracolumbar/lumbar spinal fusions without OVCF patients, the PD cohort had increased rates of revision surgeries (p < 0.01) in comparison to the non-PD cohort. However, when including OVCF patients in thoracolumbar/lumbar spinal fusions, the PD cohort had significantly higher amounts of postoperative complications (p = 0.01), pneumonia (p = 0.02), and revision surgeries (p < 0.01) when compared to the non-PD cohort.
CONCLUSION
Although more robust prospective studies are needed, the results of this study highlight the need for advanced wound care management in the postoperative period, both in-hospital and in the community, in addition to comprehensive multidisciplinary care from allied health professionals, with potential for the use of Enhanced Recovery After Surgery (ERAS) protocols in PD patients undergoing spinal instrumented fusions.
PubMed: 38937352
DOI: 10.1007/s00586-024-08307-5 -
The Journal of Pharmacology and... Jun 2024Through its pathological and genetic association to Parkinson's Disease (PD), α-synuclein (α-syn) remains a favorable therapeutic target that is being investigated...
Through its pathological and genetic association to Parkinson's Disease (PD), α-synuclein (α-syn) remains a favorable therapeutic target that is being investigated using various modalities, including many passive immunotherapy approaches clinically targeting different forms of α-syn and epitopes. Whereas published studies from some immunotherapy trials have demonstrated engagement in plasma, none have shown direct drug-antigen interactions in the disease-relevant compartment, the central nervous system (CNS). Cinpanemab (BIIB054) selectively targets pathological aggregated α-syn with low affinity binding to monomeric forms. The avidity-driven binding, low drug concentration, and the very low α-syn levels plus its heterogeneous nature in cerebrospinal fluid (CSF) made it not possible to measure drug-target interactions by conventional assays. Here we overcame these challenges by using zero-length crosslinking to stabilize the BIIB054-α-syn complexes and then quantified the crosslinked complexes using a Meso Scale Discovery (MSD) electrochemiluminescence assay. CSF samples from healthy volunteers (HV, n=46) and individuals with PD (PD, n=18) from study 228HV101 (Phase I clinical trial of BIIB054), demonstrated dose- and time- dependent binding of cinpanemab to α-syn with measurable complexes detected at doses {greater than or equal to}15 mg/kg. Complex formation displayed a direct positive correlation to drug concentration (Spearman rank correlation = 0.8295 (HV), 0.8032 (PD) p < 0.0001 (HV, PD)). The observed binding of cinpanemab to α-syn in CSF is consistent with its low intrinsic affinity for α-syn monomer and provides evidence that the drug is behaving with expected binding dynamics in the central nervous system compartment. A zero-length cross-linking method with MSD detection was developed to enable quantification of cinpanemab-α-syn complexes in Phase 1 clinical CSF samples by preventing signal loss caused by their rapid dissociation. Observed dose- and time-dependent binding were consistent with cinpanemab's affinity for α-syn and provided confidence that the drug had engaged its target at the desired site of action. This is the first demonstration of α-syn binding by an antibody in clinical samples from the CNS.
PubMed: 38936981
DOI: 10.1124/jpet.124.002199 -
The European Journal of Neuroscience Jun 2024Activation of metabotropic glutamate 2 (mGlu) receptors is a potential novel therapeutic approach for the treatment of parkinsonism. Thus, when administered as...
Activation of metabotropic glutamate 2 (mGlu) receptors is a potential novel therapeutic approach for the treatment of parkinsonism. Thus, when administered as monotherapy or as adjunct to a low dose of L-3,4-dihydroxyphenylalanine (L-DOPA), the mGlu positive allosteric modulator (PAM) LY-487,379 alleviated parkinsonism in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primates. Here, we sought to investigate the effect of biphenyl-indanone A (BINA), a highly selective mGlu PAM whose chemical scaffold is unrelated to LY-487,379, to determine if a structurally different mGlu PAM would also confer anti-parkinsonian benefit. In monotherapy experiments, MPTP-lesioned marmosets were injected with either vehicle, L-DOPA/benserazide (15/3.75 mg/kg, positive control) or BINA (0.1, 1, 10 mg/kg). In adjunct to a low L-DOPA dose experiments, MPTP-lesioned marmosets were injected with L-DOPA/benserazide (7.5/1.875 mg/kg) in combination with vehicle or BINA (0.1, 1, 10 mg/kg). Parkinsonism, dyskinesia and psychosis-like behaviours (PLBs) were then quantified. When administered alone, BINA 1 and 10 mg/kg decreased parkinsonism severity by ~22% (p < 0.01) and ~47% (p < 0.001), when compared with vehicle, which was comparable with the global effect of a high L-DOPA dose. When administered in combination with a low L-DOPA dose, BINA 1 and 10 mg/kg decreased global parkinsonism by ~38% (p < 0.001) and ~53% (p < 0.001). BINA 10 mg/kg decreased global dyskinesia by ~94% (p < 0.01) and global PLBs by ~92% (p < 0.01). Our results provide additional evidence that mGlu positive allosteric modulation elicits anti-parkinsonian effects. That this benefit is not related to a particular chemical scaffold suggests that it may be a class effect rather than the effect of a specific molecule.
PubMed: 38936819
DOI: 10.1111/ejn.16454 -
Free Radical Biology & Medicine Jun 2024Disturbance in iron homeostasis has been described in Parkinson's disease (PD), in which iron regulatory protein 2 (IRP2) plays a crucial role. IRP2 deletion resulted in...
Disturbance in iron homeostasis has been described in Parkinson's disease (PD), in which iron regulatory protein 2 (IRP2) plays a crucial role. IRP2 deletion resulted in the misregulation of iron metabolism and subsequent neurodegeneration. However, growing evidence showed that the levels of IRP2 were increased in the substantial nigra (SN) in MPTP-induced PD mice. To further clarify the role of increased IRP2 in PD, we developed IRP2-overexpressed mice by microinjecting AAV-Ireb2 in the SN. These mice showed decreased motor ability, abnormal gait and anxiety. Iron deposits induced by increased TFR1 and dopaminergic neuronal loss were observed in the SN. When these mice were treated with MPTP, exacerbated dyskinesia and dopaminergic neuronal loss were observed. In addition, TP53 was post-transcriptionally upregulated by IRP2 binding to the iron regulated element (IRE) in its 3' untranslated region. This resulted in increased lipid peroxidation levels and induced ferroptosis through the SLC7A11-ALOX12 pathway, which was independent of GPX4. This study revealed that IRP2 homeostasis in the SN was critical for PD progression and clarified the molecular mechanism of ferroptosis caused by IRP2.
PubMed: 38936518
DOI: 10.1016/j.freeradbiomed.2024.06.020 -
Neuroscience Jun 2024The mammalian brain's complete dependence on oxygen for ATP production makes it highly susceptible to hypoxia, at high altitudes or in clinical scenarios including... (Review)
Review
The mammalian brain's complete dependence on oxygen for ATP production makes it highly susceptible to hypoxia, at high altitudes or in clinical scenarios including anemia or pulmonary disease. Hypoxia plays a crucial role in the development of various brain disorders, such as Alzheimer's, Parkinson's, and other age-related neurodegenerative diseases. On the other hand, a decrease in environmental oxygen levels, such as prolonged stays at high elevations, may have beneficial impacts on the process of ageing and the likelihood of death. Additionally, the utilization of controlled hypoxia exposure could potentially serve as a therapeutic approach for age-related brain diseases. Recent findings indicate that the involvement of HIF-1α and the NLRP3 inflammasome is of significant importance in the development of Alzheimer's disease. HIF-1α serves as a pivotal controller of various cellular reactions to oxygen deprivation, exerting influence on a multitude of physiological mechanisms such as energy metabolism and inflammatory responses. The NLRP3 plays a crucial role in the innate immune system by coordinating the initiation of inflammatory reactions through the assembly of the inflammasome complex. This review examines the information pertaining to the contrasting effects of hypoxia on the brain, highlighting both its positive and deleterious effects and molecular pathways that are involved in mediating these different effects. This study explores potential strategies for therapeutic intervention that focus on restoring cellular balance and reducing neuroinflammation, which are critical aspects in addressing this severe neurodegenerative condition and addresses crucial inquiries that warrant further future investigations.
PubMed: 38936458
DOI: 10.1016/j.neuroscience.2024.06.021 -
Ageing Research Reviews Jun 2024Parkinson's disease (PD) is estimated to impact up to 1% of the global population aged 60 years and older. Among the non-motor manifestations of idiopathic PD, radicular... (Review)
Review
Parkinson's disease (PD) is estimated to impact up to 1% of the global population aged 60 years and older. Among the non-motor manifestations of idiopathic PD, radicular neuropathic pain emerges as a noteworthy concern due to its potential for debility in affected individuals. In, this systematic review and meta-analysis we aimed to evaluate the prevalence of radicular neuropathic pain and thus provide evidence of how this painful symptom affects the lives of patients with idiopathic PD. We registered the research protocol for this study in PROSPERO (CRD42022327220). We searched the Embase, Scopus, and PubMed platforms for studies on PD and neuropathic pain until April 2023. The search yielded 36 articles considered to have a low risk of bias. The prevalence of radicular neuropathic pain in patients with PD was 12.7%, without a difference when we consider the duration of diagnosis (cut-off < 7 years) or levodopa dosage (cut-off <600mg/dL). Moreover, there was no variation in the prevalence of radicular neuropathic pain regarding a Hoehn and Yahr stage cut-off of <2.5 or >2.5. Of note, a limited number of patients received pain treatment (21.5%). We also found that the source of publication bias is the use of the Ford criteria (FC), suggesting that this type of diagnostic criteria may contribute to an underdiagnosis of radicular neuropathic pain in patients with PD. This study underlines the necessity for a more discerning and comprehensive approach to the diagnosis and management of radicular neuropathic pain in patients with idiopathic PD.
PubMed: 38936433
DOI: 10.1016/j.arr.2024.102374