Parkinson disease (PD) treatment options have conventionally focused on dopamine replacement and provision of symptomatic relief. Current treatments cause undesirable adverse effects, and a large ...unmet clinical need remains for treatments that offer disease modification and that address symptoms resistant to levodopa. Advances in high-throughput drug screening methods for small molecules, developments in disease modelling and improvements in analytical technologies have collectively contributed to the emergence of novel compounds, repurposed drugs and new technologies. In this Review, we focus on disease-modifying and symptomatic therapies under development for PD. We review cellular therapies and repurposed drugs, such as nilotinib, inosine, isradipine, iron chelators and anti-inflammatories, and discuss how their success in preclinical models has paved the way for clinical trials. We provide an update on immunotherapies and vaccines. In addition, we review non-pharmacological interventions targeting motor symptoms, including gene therapy, adaptive deep brain stimulation (DBS) and optogenetically inspired DBS. Given the many clinical phenotypes of PD, individualization of therapy and precision of treatment are likely to become important in the future.
Parkinson's disease is a chronic neurodegenerative disease characterized by the accumulation of misfolded alpha-synuclein protein (Lewy bodies) in dopaminergic neurons of the
and other related ...circuitry, which contribute to the development of both motor (bradykinesia, tremors, stiffness, abnormal gait) and non-motor symptoms (gastrointestinal issues, urinogenital complications, olfaction dysfunction, cognitive impairment). Despite tremendous progress in the field, the exact pathways and mechanisms responsible for the initiation and progression of this disease remain unclear. However, recent research suggests a potential relationship between the commensal gut bacteria and the brain capable of influencing neurodevelopment, brain function and health. This bidirectional communication is often referred to as the microbiome-gut-brain axis. Accumulating evidence suggests that the onset of non-motor symptoms, such as gastrointestinal manifestations, often precede the onset of motor symptoms and disease diagnosis, lending support to the potential role that the microbiome-gut-brain axis might play in the underlying pathological mechanisms of Parkinson's disease. This review will provide an overview of and critically discuss the current knowledge of the relationship between the gut microbiota and Parkinson's disease. We will discuss the role of α-synuclein in non-motor disease pathology, proposed pathways constituting the connection between the gut microbiome and the brain, existing evidence related to pre- and probiotic interventions. Finally, we will highlight the potential opportunity for the development of novel preventative measures and therapeutic options that could target the microbiome-gut-brain axis in the context of Parkinson's disease.
•2020 marks 60 years since dopamine deficiency was discovered.•Most therapies for Parkinson’s disease (PD) are largely focused on providing symptomatic relief rather than disease ...modification.•Antibody therapies, vaccines and immune mediated approaches specifically target abnormal protein aggregates and are emerging as promising therapeutic approaches.•Active and passive immunotherapies aimed at clearing α-syn pathology are well tolerated.•It is critical to develop biomarkers alongside, which will help diagnose and track disease progression and aid in the development of PD therapies.
Current treatment options for Parkinson’s disease (PD) typically aim to replace dopamine, and hence only provide symptomatic relief. However, in the long run, this approach alone loses its efficacy as it is associated with debilitating side effects. Hence there is an unmet clinical need for addressing levodopa resistant symptoms, and an urgency to develop therapies that can halt or prevent the course of PD. The premise that α-syn can transmit from cell-to-cell in a prion like manner has opened up the possibility for the use of immunotherapy in PD. There is evidence for inflammation in PD as is evidenced by microglial activation, as well as the involvement of the peripheral immune system in PD, and peripheral inflammation can exacerbate dopaminergic degeneration as seen in animal models of the disease. However, mechanisms that link the immune system with PD are not clear, and the sequence of immune responses with respect to PD are still unknown. Nevertheless, our present knowledge offers avenues for the development of immune-based therapies for PD. In order to successfully employ such strategies, we must comprehend the state of the peripheral immune system during the course of PD. This review describes the developments in the field of both active and passive immunotherapies in the treatment of PD, and highlights the crucial need for future research for clarifying the role of inflammation and immunity in this debilitating disease.
Objectives
Deep brain stimulation (DBS) is used for a variety of movement disorders, including Parkinson's disease. There are several theories regarding the biology and mechanisms of action of DBS. ...Previously, we observed an up‐regulation of neural progenitor cell proliferation in post‐mortem tissue suggesting that DBS can influence cellular plasticity in regions beyond the site of stimulation. We wanted to support these observations and investigate the relationship if any, between DBS, neural progenitor cells, and microglia.
Methods
We used naïve rats in this study for DBS electrode implantation, stimulation, and microlesions. We used immunohistochemistry techniques for labeling microglial and progenitor cells, and fluorescence microscopy for viewing and quantification of labeled cells.
Results
We present data that demonstrates a reciprocal relationship of microglia and neural precursor cells in the presence of acute high frequency stimulation. In our hands, stimulated animals demonstrate significantly lower numbers of activated microglia (p = 0.026) when compared to microlesion and sham animals. The subthalamic region surrounding the DBS stimulating electrode reveals a significant increase in the number of neural precursor cells expressing cell cycle markers, plasticity and precursor cell markers (Ki67; p = 0.0013, MCM2; p = 0.0002).
Interpretation
We conclude that in this animal model, acute DBS results in modest local progenitor cell proliferation and influenced the total number of activated microglia. This could be of clinical significance in patients with PD, as it is thought to progress via neuroinflammatory processes involving microglia, cytokines, and the complement system. Further studies are required to comprehend the behavior of microglia in different activation states and their ability to regulate adult neurogenesis under physiologic and pathologic conditions.
Brain banking occupies a central role for the advancement of the study of human neurodegenerative and neuropsychiatric diseases. The smooth functioning and effectiveness of a brain bank is largely a ...multidisciplinary effort and requires the cooperation and participation of several players including neurologists, neuropathologists, and research coordinators to guarantee that donated tissue is properly processed and archived. If properly run, brain banks can ultimately lay the foundation for new brain research and pioneer the discovery of new therapies for a variety of neurological diseases.
Parkinson's Disease (PD) is one of the most common neurodegenerative diseases. PD has recently received more attention by researchers in the midst of the COVID-19 pandemic.
Yet to be researched is ...the effect of the COVID-19 vaccines on PD patients. Several PD patients are still hesitant to the vaccine due to this unaddressed fear. The purpose of this study is to address this gap.
Surveys were administered to PD patients 50 years and older at UF Fixel Institute who received at least one dose of the COVID-19 vaccine. Survey questions included patients' severity of PD symptoms before and after the vaccine and extent of worsening PD symptoms post-vaccination. After three weeks of collecting responses, the data was analyzed.
34 respondents were eligible for data consideration because they fell within the age range being studied. A total of 14 respondents out of 34 (41%, p=0. 0001) reported that their PD symptoms worsened after the COVID-19 vaccine to some extent.
There was strong evidence of worsening of PD symptoms post COVID-19 vaccination, however it was mostly mild and limited to a couple of days. The worsening had statistically significant moderate positive correlation with vaccine hesitancy and post-vaccine general side effects. A possible causative mechanism of PD symptom worsening using existing scientific knowledge would be stress and anxiety associated with vaccine hesitancy and the extent of post-vaccine general side effects (fever, chills, pain), likely via simulating a mild systemic infection/inflammation the latter already established causes of PD symptom worsening.
Background:
Previous studies have found gait and balance abnormalities in patients with cervical dystonia. However, the characteristics of gait and balance in cervical dystonia with head tremors have ...not been ascertained. A midline constant head tremor when walking would likely render gait and balance more difficult. The pathophysiology of dystonia has also been increasingly linked with cerebellar function abnormality, commonly implicated in gait and balance disorders.
Methods:
We examined the gait and balance characteristics of cervical dystonia presenting with head tremors. We used the timed up-and-go (TUG) walk test, 10 m walk test, Berg Balance Scale (BBS), and Gait and Freezing questionnaire. We then assessed the gait on an instrumented walkway system to capture spatiotemporal measures such as speed, cadence, step time, step length, stride width, swing%, stance%, single support%, double support%, and gait variability index (GVI). We also assessed whether the gait in dystonic tremor (DT) differed from essential tremor (ET) and orthostatic tremor (OT), as these tremor disorders share the cerebello-thalamo-cortical pathway as the common pathological pathway.
Results:
50 participants comprising DT (20 patients), ET (15 patients), and OT (15 patients) were enrolled. While the gait abnormalities were subclinical, 11/20 DT patients (55%) walked at a slower speed on the TUG, 11/20 (55%) had reduced scores on the BBS, 9/20 (45%) had increased step time, 4/20 (20%) had reduced step length, 4/20 (20%) had wider stride width, 9/20 (45%) spent greater time during double support and 8/20 (40%) patients had an abnormal GVI. Comparisons of DT with healthy control data revealed a slower gait velocity (
p
= 0.001) and a reduced step length (
p
= 0.001). Compared to DT, the ET group revealed a reduced cadence (
p
= 0.04) and the OT group revealed an increased TUG time (
p
= 0.03), reduced BBS scores (
p
= 0.02), reduced step length (
p
= 0.02), reduced cadence (
p
= 0.03), reduced GVI (
p
= 0.01), and increased double support phase (
p
= 0.045).
Conclusion:
DT is accompanied by multiple abnormalities affecting gait and balance, albeit subclinical and less pronounced than ET and OT, possibly related to more effective compensatory mechanisms. Nevertheless, these abnormalities indicate that rehabilitative measures warrant consideration when managing in clinical settings.
The gut brain axis (GBA), a bidirectional communication pathway has often been linked to health and disease, and gut microbiota (GM), a key component of this pathway shown to be altered in ...Parkinson's disease (PD), are suggested to contribute to the pathogenesis of PD. There are few studies that report the impact of oral medication therapy on GM, however, there are even fewer studies that discuss the impact of other treatments such as device assisted therapies (DAT) including deep brain stimulation (DBS), levodopa-carbidopa intestinal gel infusion (LCIG) and photobiomodulation (PBM) and how these might impact GM. Here, we review the literature and summarize findings of the potential contributions of GM to the heterogenous clinical response to pharmaceutical therapies among individuals with PD. We also discuss the potential interactions between the GM and DATs such as DBS and LCIG and present evidence for alterations in GM in response to DATs. Given the complexity and highly individual nature of the GM of patients with PD and the potential influence that other external factors such as diet, lifestyle, medications, stage of the disease and other comorbidities, further investigations into the response of GM to therapies are worthy of future study in prospective, controlled trials as well as medication naïve individuals. Such detailed studies will help us further comprehend the relationship between GM in PD patients, and will help investigate the potential of targeting GM associated changes as a treatment avenue for PD.
Based on the clonal evolution model and the assumption that the vast majority of tumor cells are able to propagate and drive tumor growth, the goal of cancer treatment has traditionally been to kill ...all cancerous cells. This theory has been challenged recently by the cancer stem cell (CSC) hypothesis, that a rare population of tumor cells, with stem cell characteristics, is responsible for tumor growth, resistance, and recurrence. Evidence for putative CSCs has been described in blood, breast, lung, prostate, colon, liver, pancreas, and brain. This new hypothesis would propose that indiscriminate killing of cancer cells would not be as effective as selective targeting of the cells that are driving long-term growth (ie, the CSCs) and that treatment failure is often the result of CSCs escaping traditional therapies.The CSC hypothesis has gained a great deal of attention because of the identification of a new target that may be responsible for poor outcomes of many aggressive cancers, including malignant glioma. As attractive as this hypothesis sounds, especially when applied to tumors that respond poorly to current treatments, we will argue in this article that the proposal of a stemlike cell that initiates and drives solid tissue cancer growth and is responsible for therapeutic failure is far from proven. We will present the point of view that for most advanced solid tissue cancers such as glioblastoma multiforme, targeting a putative rare CSC population will have little effect on patient outcomes. This review will cover problems with the CSC hypothesis, including applicability of the hierarchical model, inconsistencies with xenotransplantation data, and nonspecificity of CSC markers.
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