!!
UA Clinical Trial to Repurpose #Ketamine for #Parkinson’s Patients
http://uahs.arizona.edu/news/ua-clinical-trial-repurpose-ketamine-parkinsons-patients
Forty percent of patients on levodopa eventually will experience dyskinesia — uncontrollable and involuntary movements of the arms, legs, head or entire body. Severity can range from small, fidget-like motions to larger continuous bursts of movement.
Unless patients stop levodopa treatment altogether, these movements do not go away.
Now, UA researchers will repurpose ketamine, a drug currently used to treat pain and depression, to try to reduce and control these involuntary movements brought on by levodopa.
UA Clinical Trial to Repurpose #Ketamine for #Parkinson’s Patients
http://uahs.arizona.edu/news/ua-clinical-trial-repurpose-ketamine-parkinsons-patients
Forty percent of patients on levodopa eventually will experience dyskinesia — uncontrollable and involuntary movements of the arms, legs, head or entire body. Severity can range from small, fidget-like motions to larger continuous bursts of movement.
Unless patients stop levodopa treatment altogether, these movements do not go away.
Now, UA researchers will repurpose ketamine, a drug currently used to treat pain and depression, to try to reduce and control these involuntary movements brought on by levodopa.
!!
Th17 #Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of #Parkinson’s Disease
https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(18)30297-2?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1934590918302972%3Fshowall%3Dtrue
Increased numbers of T cells are detected in PD postmortem midbrains
•Increased frequencies of IL-17-producing T cells are found in PD patients’ blood
•T cells induce neuronal death in PD revealed by human autologous iPSC-based model
•Neuronal cell death is mediated by IL-17–IL-17R signaling and activation of NFκB
After co-culture with T lymphocytes or the addition of IL-17, PD iPSC-derived MBNs underwent increased neuronal death driven by upregulation of IL-17 receptor (IL-17R) and NFκB activation. Blockage of IL-17 or IL-17R, or the addition of the FDA-approved anti-IL-17 antibody, secukinumab, rescued the neuronal death. Our findings indicate a critical role for IL-17-producing T lymphocytes in sporadic PD
Th17 #Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of #Parkinson’s Disease
https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(18)30297-2?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1934590918302972%3Fshowall%3Dtrue
Increased numbers of T cells are detected in PD postmortem midbrains
•Increased frequencies of IL-17-producing T cells are found in PD patients’ blood
•T cells induce neuronal death in PD revealed by human autologous iPSC-based model
•Neuronal cell death is mediated by IL-17–IL-17R signaling and activation of NFκB
After co-culture with T lymphocytes or the addition of IL-17, PD iPSC-derived MBNs underwent increased neuronal death driven by upregulation of IL-17 receptor (IL-17R) and NFκB activation. Blockage of IL-17 or IL-17R, or the addition of the FDA-approved anti-IL-17 antibody, secukinumab, rescued the neuronal death. Our findings indicate a critical role for IL-17-producing T lymphocytes in sporadic PD
!!
Association of Levels of #Physical Activity With Risk of #Parkinson Disease
A Systematic Review and Meta-analysis
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2703134
Eight prospective studies totaling 544 336 participants included 2192 patients with PD with a median (range) follow-up period of 12 (6.1-22.0) years were identified. A significantly reduced risk of PD was associated with the highest levels of either total physical activity (relative risk, 0.79; 95% CI, 0.68-0.91) or moderate to vigorous physical activity (relative risk, 0.71; 95% CI, 0.58-0.87), with stronger associations among men than among women. In contrast, light physical activity was not associated with PD risk (relative risk, 0.86; 95% CI, 0.60-1.23). The dose-response analysis revealed that for each 10 metabolic equivalent of task–hours/week increase in total or moderate to vigorous physical activity, the risk of PD among men decreased by 10% and 17%, respectively. No linear dose-response association was found between physical activity and PD risk among women.
Conclusions and Relevance This analysis revealed an inverse dose-response association between physical activity and PD risk among men; importantly, even moderate exercise was associated with a significant reduction in the risk of PD. Future studies with quantified measurements of physical activity will help identify the precise relative risk estimates for various levels of activity with respect to PD risk
Association of Levels of #Physical Activity With Risk of #Parkinson Disease
A Systematic Review and Meta-analysis
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2703134
Eight prospective studies totaling 544 336 participants included 2192 patients with PD with a median (range) follow-up period of 12 (6.1-22.0) years were identified. A significantly reduced risk of PD was associated with the highest levels of either total physical activity (relative risk, 0.79; 95% CI, 0.68-0.91) or moderate to vigorous physical activity (relative risk, 0.71; 95% CI, 0.58-0.87), with stronger associations among men than among women. In contrast, light physical activity was not associated with PD risk (relative risk, 0.86; 95% CI, 0.60-1.23). The dose-response analysis revealed that for each 10 metabolic equivalent of task–hours/week increase in total or moderate to vigorous physical activity, the risk of PD among men decreased by 10% and 17%, respectively. No linear dose-response association was found between physical activity and PD risk among women.
Conclusions and Relevance This analysis revealed an inverse dose-response association between physical activity and PD risk among men; importantly, even moderate exercise was associated with a significant reduction in the risk of PD. Future studies with quantified measurements of physical activity will help identify the precise relative risk estimates for various levels of activity with respect to PD risk
!!
The vermiform #appendix impacts the risk of developing #Parkinson’s disease
http://stm.sciencemag.org/content/10/465/eaar5280
The pathogenesis of Parkinson’s disease (PD) involves the accumulation of aggregated α-synuclein, which has been suggested to begin in the gastrointestinal tract. Here, we determined the capacity of the appendix to modify PD risk and influence pathogenesis.
In two independent epidemiological datasets, involving more than 1.6 million individuals and over 91 million person-years, we observed that removal of the appendix decades before PD onset was associated with a lower risk for PD, particularly for individuals living in rural areas, and delayed the age of PD onset. We also found that the healthy human appendix contained intraneuronal α-synuclein aggregates and an abundance of PD pathology–associated α-synuclein truncation products that are known to accumulate in Lewy bodies, the pathological hallmark of PD.
Lysates of human appendix tissue induced the rapid cleavage and oligomerization of full-length recombinant α-synuclein. Together, we propose that the normal human appendix contains pathogenic forms of α-synuclein that affect the risk of developing PD.
The vermiform #appendix impacts the risk of developing #Parkinson’s disease
http://stm.sciencemag.org/content/10/465/eaar5280
The pathogenesis of Parkinson’s disease (PD) involves the accumulation of aggregated α-synuclein, which has been suggested to begin in the gastrointestinal tract. Here, we determined the capacity of the appendix to modify PD risk and influence pathogenesis.
In two independent epidemiological datasets, involving more than 1.6 million individuals and over 91 million person-years, we observed that removal of the appendix decades before PD onset was associated with a lower risk for PD, particularly for individuals living in rural areas, and delayed the age of PD onset. We also found that the healthy human appendix contained intraneuronal α-synuclein aggregates and an abundance of PD pathology–associated α-synuclein truncation products that are known to accumulate in Lewy bodies, the pathological hallmark of PD.
Lysates of human appendix tissue induced the rapid cleavage and oligomerization of full-length recombinant α-synuclein. Together, we propose that the normal human appendix contains pathogenic forms of α-synuclein that affect the risk of developing PD.
Science
The vermiform appendix impacts the risk of developing Parkinson’s disease
Misfolded α-synuclein is a pathological hallmark of Parkinson’s disease (PD). Killinger et al . now report that the human appendix contains an abundance of misfolded α-synuclein and that removal of the appendix decreased the risk of developing PD. The appendix…
!!
Characteristics of Waveform Shape in #Parkinson’s Disease Detected with Scalp #Electroencephalography
http://www.eneuro.org/content/early/2019/05/10/ENEURO.0151-19.2019
Neural activity in the beta frequency range (13-30 Hz) is excessively synchronized in Parkinson’s Disease (PD). Previous work using invasive intracranial recordings and non-invasive scalp electroencephalography (EEG) has shown that correlations between beta phase and broad-band gamma amplitude (i.e., phase amplitude coupling) are elevated in PD, perhaps a reflection of this synchrony.
Here we show, using scalp electroencephalography (EEG), that the nonsinusoidal shape of beta (13-30 Hz) oscillations over sensorimotor cortex distinguishes PD patients on and off medication and patients off medication from controls. This change in waveform shape may reflect hypersynchronous input, possibly originating from basal ganglia. Thus, waveform shape is a putative non-invasive electrophysiology biomarker of PD state with potential utility for assessing treatments, monitoring disease, or diagnosis. This signature can be detected with a safe, affordable, and available method (i.e. EEG).
Characteristics of Waveform Shape in #Parkinson’s Disease Detected with Scalp #Electroencephalography
http://www.eneuro.org/content/early/2019/05/10/ENEURO.0151-19.2019
Neural activity in the beta frequency range (13-30 Hz) is excessively synchronized in Parkinson’s Disease (PD). Previous work using invasive intracranial recordings and non-invasive scalp electroencephalography (EEG) has shown that correlations between beta phase and broad-band gamma amplitude (i.e., phase amplitude coupling) are elevated in PD, perhaps a reflection of this synchrony.
Here we show, using scalp electroencephalography (EEG), that the nonsinusoidal shape of beta (13-30 Hz) oscillations over sensorimotor cortex distinguishes PD patients on and off medication and patients off medication from controls. This change in waveform shape may reflect hypersynchronous input, possibly originating from basal ganglia. Thus, waveform shape is a putative non-invasive electrophysiology biomarker of PD state with potential utility for assessing treatments, monitoring disease, or diagnosis. This signature can be detected with a safe, affordable, and available method (i.e. EEG).
eNeuro
Characteristics of Waveform Shape in Parkinson’s Disease Detected with Scalp Electroencephalography
Neural activity in the beta frequency range (13-30 Hz) is excessively synchronized in Parkinson’s Disease (PD). Previous work using invasive intracranial recordings and non-invasive scalp electroencephalography (EEG) has shown that correlations between beta…
!!
#Bipolar disorder and risk of #Parkinson disease
A nationwide longitudinal study
https://n.neurology.org/content/early/2019/05/22/WNL.0000000000007649
Patients with BD had a higher incidence of PD (0.7% vs 0.1%, p < 0.001) during the follow-up period than the controls. A Cox regression analysis with adjustments for demographic data and medical comorbid conditions revealed that patients with BD were more likely to develop PD (hazard ratio HR 6.78, 95% confidence interval CI 5.74–8.02) than the control group. Sensitivity analyses after exclusion of the first year (HR 5.82, 95% CI 4.89–6.93) or first 3 years (HR 4.42; 95% CI 3.63–5.37) of observation showed consistent findings. Moreover, a high frequency of psychiatric admission for manic/mixed and depressive episodes was associated with an increased risk of developing PD.
Conclusion Patients with BD had a higher incidence of PD during the follow-up period than the control group. Manic/mixed and depressive episodes were associated with an elevated likelihood of developing PD. Further studies are necessary to investigate the underlying pathophysiology between BD and PD.
#Bipolar disorder and risk of #Parkinson disease
A nationwide longitudinal study
https://n.neurology.org/content/early/2019/05/22/WNL.0000000000007649
Patients with BD had a higher incidence of PD (0.7% vs 0.1%, p < 0.001) during the follow-up period than the controls. A Cox regression analysis with adjustments for demographic data and medical comorbid conditions revealed that patients with BD were more likely to develop PD (hazard ratio HR 6.78, 95% confidence interval CI 5.74–8.02) than the control group. Sensitivity analyses after exclusion of the first year (HR 5.82, 95% CI 4.89–6.93) or first 3 years (HR 4.42; 95% CI 3.63–5.37) of observation showed consistent findings. Moreover, a high frequency of psychiatric admission for manic/mixed and depressive episodes was associated with an increased risk of developing PD.
Conclusion Patients with BD had a higher incidence of PD during the follow-up period than the control group. Manic/mixed and depressive episodes were associated with an elevated likelihood of developing PD. Further studies are necessary to investigate the underlying pathophysiology between BD and PD.
Neurology
Bipolar disorder and risk of Parkinson disease
Objective To evaluate the risk of Parkinson disease (PD) among patients with bipolar disorder (BD).
Methods Using the Taiwan National Health Insurance Research Database, we examined 56,340 patients with BD and 225,360 age- and sex-matched controls between…
Methods Using the Taiwan National Health Insurance Research Database, we examined 56,340 patients with BD and 225,360 age- and sex-matched controls between…
!!
Intestinal #infection triggers #Parkinson’s disease-like symptoms in Pink1−/− mice
https://www.nature.com/articles/s41586-019-1405-y
Parkinson’s disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles1,2. An early-onset form of Parkinson’s disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes
..Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with L-DOPA.
These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson’s disease, which highlights the relevance of the gut–brain axis in the disease
Intestinal #infection triggers #Parkinson’s disease-like symptoms in Pink1−/− mice
https://www.nature.com/articles/s41586-019-1405-y
Parkinson’s disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles1,2. An early-onset form of Parkinson’s disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes
..Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with L-DOPA.
These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson’s disease, which highlights the relevance of the gut–brain axis in the disease
Nature
Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1 [−/−] mice
Nature - In mice lacking PINK1, bacterial infection in the intestine results in mitochondrial antigen presentation and generation of CD8+ T cells, and infected mice develop motor impairments,...
Risk of Developing #Parkinson Disease in #Bipolar Disorder
A Systematic Review and Meta-analysis
..Seven studies were eligible for inclusion and included 4 374 211 participants overall. A previous diagnosis of BD increased the likelihood of a subsequent diagnosis of idiopathic PD (odds ratio, 3.35; 95% CI, 2.00-5.60; I2 = 92%). A sensitivity analysis was performed by removing the studies that had a high risk of bias and also showed an increased risk of PD in people with BD (odds ratio, 3.21; 95% CI, 1.89-5.45; I2 = 94%). Preplanned subgroup analyses according to study design and diagnostic certainty failed to show a significant effect.
Conclusions and Relevance This review suggests that patients with BD have a significantly increased risk of developing PD compared with the general population. Subgroup analyses suggested a possible overestimation in the magnitude of the associations. These findings highlight the probability that BD may be associated with a later development of PD and the importance of the differential diagnosis of parkinsonism features in people with BD.
A Systematic Review and Meta-analysis
..Seven studies were eligible for inclusion and included 4 374 211 participants overall. A previous diagnosis of BD increased the likelihood of a subsequent diagnosis of idiopathic PD (odds ratio, 3.35; 95% CI, 2.00-5.60; I2 = 92%). A sensitivity analysis was performed by removing the studies that had a high risk of bias and also showed an increased risk of PD in people with BD (odds ratio, 3.21; 95% CI, 1.89-5.45; I2 = 94%). Preplanned subgroup analyses according to study design and diagnostic certainty failed to show a significant effect.
Conclusions and Relevance This review suggests that patients with BD have a significantly increased risk of developing PD compared with the general population. Subgroup analyses suggested a possible overestimation in the magnitude of the associations. These findings highlight the probability that BD may be associated with a later development of PD and the importance of the differential diagnosis of parkinsonism features in people with BD.
!!
Probiotic Bacillus subtilis Protects against α-Synuclein Aggregation in C. elegans
Recent discoveries have implicated the gut #microbiome in the progression and severity of #Parkinson’s disease; however, how gut bacteria affect such neurodegenerative disorders remains unclear. Here, we report that the Bacillus subtilis probiotic strain PXN21 inhibits α-synuclein aggregation and clears preformed aggregates in an established Caenorhabditis elegans model of synucleinopathy. This protection is seen in young and aging animals and is partly mediated by DAF-16. Multiple B. subtilis strains trigger the protective effect via both spores and vegetative cells, partly due to a biofilm formation in the gut of the worms and the release of bacterial metabolites.
We identify several host metabolic pathways differentially regulated in response to probiotic exposure, including sphingolipid metabolism. We further demonstrate functional roles of the sphingolipid metabolism genes lagr-1, asm-3, and sptl-3 in the anti-aggregation effect. Our findings provide a basis for exploring the disease-modifying potential of B. subtilis as a dietary supplement.
https://bit.ly/2Gm0uMk
Probiotic Bacillus subtilis Protects against α-Synuclein Aggregation in C. elegans
Recent discoveries have implicated the gut #microbiome in the progression and severity of #Parkinson’s disease; however, how gut bacteria affect such neurodegenerative disorders remains unclear. Here, we report that the Bacillus subtilis probiotic strain PXN21 inhibits α-synuclein aggregation and clears preformed aggregates in an established Caenorhabditis elegans model of synucleinopathy. This protection is seen in young and aging animals and is partly mediated by DAF-16. Multiple B. subtilis strains trigger the protective effect via both spores and vegetative cells, partly due to a biofilm formation in the gut of the worms and the release of bacterial metabolites.
We identify several host metabolic pathways differentially regulated in response to probiotic exposure, including sphingolipid metabolism. We further demonstrate functional roles of the sphingolipid metabolism genes lagr-1, asm-3, and sptl-3 in the anti-aggregation effect. Our findings provide a basis for exploring the disease-modifying potential of B. subtilis as a dietary supplement.
https://bit.ly/2Gm0uMk
!!
Body #mass index, #diabetes, and the risk of #Parkinson's disease
..A total of 33,443 individuals were diagnosed with PD during the follow‐up period (7.3 years). An increased risk of PD incidence was observed in the underweight group versus the normal group (adjusted hazard ratio: 1.28; 95% confidence interval: 1.21–1.36), whereas a decreased risk of PD incidence was observed (adjusted hazard ratio: 0.88; 95% confidence interval: 0.88–0.93) in the obese group and (adjusted hazard ratio: 0.77; 95% confidence interval: 0.72–0.82) in the severely obese group. This association consistently persisted after stratification by diabetes mellitus status, with the steepest downward slope for PD risk present with increasing body mass index in patients with severe diabetes mellitus (i.e., long duration or complication).
Conclusions
Being underweight and diabetes mellitus were associated with an increased risk of PD incidence, and effect of being underweight was more prominent in those with diabetes mellitus, with a dose‐response relationship existing according to diabetes mellitus status. Further research is warranted to understand the clinical implications of the significant interaction between being underweight and diabetes mellitus status in the development of PD
https://bit.ly/2VcuRxz
Body #mass index, #diabetes, and the risk of #Parkinson's disease
..A total of 33,443 individuals were diagnosed with PD during the follow‐up period (7.3 years). An increased risk of PD incidence was observed in the underweight group versus the normal group (adjusted hazard ratio: 1.28; 95% confidence interval: 1.21–1.36), whereas a decreased risk of PD incidence was observed (adjusted hazard ratio: 0.88; 95% confidence interval: 0.88–0.93) in the obese group and (adjusted hazard ratio: 0.77; 95% confidence interval: 0.72–0.82) in the severely obese group. This association consistently persisted after stratification by diabetes mellitus status, with the steepest downward slope for PD risk present with increasing body mass index in patients with severe diabetes mellitus (i.e., long duration or complication).
Conclusions
Being underweight and diabetes mellitus were associated with an increased risk of PD incidence, and effect of being underweight was more prominent in those with diabetes mellitus, with a dose‐response relationship existing according to diabetes mellitus status. Further research is warranted to understand the clinical implications of the significant interaction between being underweight and diabetes mellitus status in the development of PD
https://bit.ly/2VcuRxz
Wiley Online Library
Body mass index, diabetes, and the risk of Parkinson's disease
Background
There are conflicting findings in the literature regarding the association of body mass index and incidence of PD.
Objectives
This study aimed to investigate the association of body mas...
There are conflicting findings in the literature regarding the association of body mass index and incidence of PD.
Objectives
This study aimed to investigate the association of body mas...