There is a considerable overlap between Parkinson's Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB). They present a challenge therapeutically, with regard to morbidity and mortality risk. ...In particular, symptoms of psychosis in these conditions augur a considerably increased burden.
To date, there has been a myriad of prospective, retrospective and case studies examining the use of neuroleptics in the treatment of psychotic symptoms in PDD/DLB. Clozapine has the most robust evidence base however its use is limited by agranulocytosis risk and the associated need for frequent blood count monitoring. Quetiapine is more readily used, however, it has a more equivocal evidence base, in terms of efficacy. Other neuroleptics have thus far demonstrated mixed results with increased risk of extrapyramidal worsening. In addition to the atypical agents, the introduction of pimavanserin has provided another treatment option for Parkinson's Disease Psychosis (PDP), decreasing concern for deterioration in motor function. We await further research to confidently demonstrate its efficacy and safety in DLB psychosis. Cholinesterase inhibitors likely have a limited role in treating milder psychosis symptomatology in DLB and perhaps PDD.
After review of the current literature for antipsychotic therapy in both PDD and DLB, we provide a logical framework for addressing psychotic symptoms in each condition.
•Psychosis is patients with Parkinson's and Lewy Body Disease can be a therapeutic challenge.•Pimavanserin, quetiapine and clozapine are relatively safe and have shown some efficacy in treating psychosis.•Other neuroleptics can be very dangerous and should be avoided.
To study the influence of occupational pesticide use on Parkinson's disease (PD) in a population with information on various occupational, residential, and household sources of pesticide exposure.
In ...a population-based case control study in Central California, we used structured interviews to collect occupational history details including pesticide use in jobs, duration of use, product names, and personal protective equipment use from 360 PD cases and 827 controls. We linked reported products to California's pesticide product label database and identified pesticide active ingredients and occupational use by chemical class including fungicides, insecticides, and herbicides. Employing unconditional logistic regression, we estimated odds ratios and 95% confidence intervals for PD and occupational pesticide use.
Ever occupational use of carbamates increased risk of PD by 455%, while organophosphorus (OP) and organochlorine (OC) pesticide use doubled risk. PD risk increased 110–211% with ever occupational use of fungicides, herbicides, and insecticides. Using any pesticide occupationally for >10years doubled the risk of PD compared with no occupational pesticide use. Surprisingly, we estimated higher risks among those reporting use of personal protective equipment (PPE).
Our findings provide additional evidence that occupational pesticide exposures increase PD risk. This was the case even after controlling for other sources of pesticide exposure. Specifically, risk increased with occupational use of carbamates, OPs, and OCs, as well as of fungicides, herbicides, or insecticides. Interestingly, some types of PPE use may not provide adequate protection during pesticide applications.
•Occupational pesticide use increases Parkinson's risk in central California.•Carbamate, organochlorine, and organophosphorus pesticide use increase PD risk.•Home/garden or ambient exposures affected occupational use associations minimally.•Some PPE types may not adequately protect pesticide applicators.
Long-term air pollution (AP) exposure, including diesel exhaust exposure, is increasingly being recognized as a major contributor to the development of neurodegenerative diseases such as Parkinson's ...and Alzheimer's disease. How AP increases the risk of neurodegeneration is not well understood but might include direct neurotoxicity and CNS inflammation. We investigated the impact of diesel exhaust particulate extract (DEPe) exposure on the brain and the mechanisms by which microglia and astroglia might mediate neuronal changes. Zebrafish (ZF) were utilized to determine neuronal toxicity of and microglial response to DEPe and single cell RNA sequencing was employed to study cell type-specific transcriptomic responses within the ZF brain. DEPe exposure induced neuronal injury and microglial activation in vivo. However, preventing the development of microglia did not attenuate DEPe-induced neuron loss, leading us to investigate microglial, astroglial, and neuronal response to DEPe exposure at single-cell resolution. Differentially expressed genes and disease-relevant pathways were identified within glial and neuronal clusters after DEPe exposure. Microglia and astroglia existed in multiple states, some of which appear toxic and others protective to neurons. Neuronal transcriptomic analysis revealed that DEPe exposure reduced expression of autophagy-related genes consistent with direct neurotoxicity. In summary, DEPe exposure was neurotoxic in developing ZF larvae and induced neuroinflammation. The microglial inflammatory response did not contribute to neurotoxicity of DEPe and in fact, some glial clusters upregulated transcriptional pathways that are likely protective. Furthermore, DEPe exposure led to reduced expression of autophagy-related genes in neurons that likely contribute to its toxicity.
Several articles suggest that DNA methylation levels in blood relate to Parkinson's disease (PD) but there is a need for a large-scale study that involves suitable population based controls. The ...purposes of the study were: (1) to study whether PD status is associated with DNA methylation levels in blood/saliva; (2) to study whether observed associations relate to blood cell types; and (3) to characterize genome-wide significant markers ("CpGs") and clusters of CpGs (co-methylation modules) in terms of biological pathways.
In a population-based case control study of PD, we studied blood samples from 335 PD cases and 237 controls and saliva samples from another 128 cases and 131 controls. DNA methylation data were generated from over 486,000 CpGs using the Illumina Infinium array. We identified modules of CpGs (clusters) using weighted correlation network analysis (WGCNA).
Our cross-sectional analysis of blood identified 82 genome-wide significant CpGs (including cg02489202 in LARS2 p = 8.3 × 10
and cg04772575 in ABCB9 p = 4.3 × 10
). Three out of six PD related co-methylation modules in blood were significantly enriched with immune system related genes. Our analysis of saliva identified five significant CpGs. PD-related CpGs are located near genes that relate to mitochondrial function, neuronal projection, cytoskeleton organization, systemic immune response, and iron handling.
This study demonstrates that: (1) PD status has a profound association with DNA methylation levels in blood and saliva; and (2) the most significant PD-related changes reflect changes in blood cell composition. Overall, this study highlights the role of the immune system in PD etiology but future research will need to address the causal structure of these relationships.
In this randomized trial of deep-brain stimulation targeted to either the globus pallidus interna or the subthalamic nucleus in patients with advanced Parkinson's disease, the patients assigned to ...pallidal stimulation and those assigned to subthalamic stimulation had a similar improvement in motor function.
In this trial of deep-brain stimulation targeted to either the globus pallidus interna or the subthalamic nucleus in patients with advanced Parkinson's disease, the patients assigned to pallidal stimulation and those assigned to subthalamic stimulation had a similar improvement in motor function.
Randomized studies have shown that treatment with deep-brain stimulation, which involves the surgical implantation of a device that sends electrical impulses to specific parts of the brain, is superior to medical therapy for improving motor function and quality of life for patients with advanced Parkinson's disease.
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The globus pallidus interna and the subthalamic nucleus are both accepted targets for deep-brain stimulation. The subthalamic nucleus is used more commonly as the target, despite the lack of evidence showing that neurostimulation of this target provides a better outcome. Our multicenter, randomized, blinded trial, called the Veterans Affairs Cooperative Studies Program (CSP) . . .
Objectives There is a general consensus that pesticides are involved in the aetiology of Parkinson's disease (PD), although associations between specific pesticides and the risk of developing PD have ...not been well studied. This study examines the risk of developing PD associated with specific organophosphate (OP) pesticides and their mechanisms of toxicity. Methods This case–control study uses a geographic information system-based exposure assessment tool to estimate ambient exposure to 36 commonly used OPs from 1974 to 1999. All selected OPs were analysed individually and also in groups formed according to their presumed mechanisms of toxicity. Results The study included 357 incident PD cases and 752 population controls living in the Central Valley of California. Ambient exposure to each OP evaluated separately increased the risk of developing PD. However, most participants were exposed to combinations of OPs rather than a single pesticide. Risk estimates for OPs grouped according to different presumed functionalities and toxicities were similar and did not allow us to distinguish between them. However, we observed exposure-response patterns with exposure to an increasing number of OPs. Conclusions This study adds strong evidence that OPs are implicated in the aetiology of idiopathic PD. However, studies of OPs at low doses reflective of real-world ambient exposure are needed to determine the mechanisms of neurotoxicity.
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