Huntington's disease (HD) is a neurodegenerative disorder characterized by progressive motor, cognitive and psychiatric deficits, associated with predominant loss of striatal neurons and is caused by ...polyglutamine expansion in the huntingtin protein. Mutant huntingtin protein and its fragments are resistant to protein degradation and produce a blockade of the ubiquitin proteasome system (UPS). In HD models, the proteasome inhibitor epoxomicin aggravates protein accumulation and the inductor of autophagy, trehalose, diminishes it. We have investigated the effects of epoxomicin and trehalose in skin fibroblasts of control and HD patients. Untreated HD fibroblasts have increased the levels of ubiquitinized proteins and higher levels of reactive oxygen species (ROS), huntingtin and the autophagy marker LAMP2A. Baseline replication rates were higher in HD than in controls fibroblasts but that was reverted after 12 passages. Epoxomicin increases the activated caspase-3, HSP70, huntingtin, ubiquitinated proteins and ROS levels in both HD and controls. Treatment with trehalose counteracts the increase in ROS, ubiquitinated proteins, huntingtin and activated caspase-3 levels induced by epoxomicin, and also increases the LC3 levels more in HD fibroblast than controls. These results suggest that trehalose could revert protein processing abnormalities in patients with Huntington's Disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Identifying modifiable risk factors for cognitive impairment in the early stages of Parkinson's disease (PD) and estimating their impact on cognitive status may help prevent dementia (PDD) and the ...design of cognitive trials.
Using a standard approach for the assessment of global cognition in PD and controlling for the effects of age, education and disease duration, we explored the associations between cognitive status, comorbidities, metabolic variables and lifestyle variables in 533 PD participants from the COPPADIS study.
Among the overall sample, 21% of participants were classified as PD-MCI (n = 114) and 4% as PDD (n = 26). The prevalence of hypertension, diabetes and dyslipidemia was significantly higher in cognitively impaired patients while no between-group differences were found for smoking, alcohol intake or use of supplementary vitamins. Better cognitive scores were significantly associated with regular physical exercise (p < 0.05) and cognitive stimulation (< 0.01). Cognitive performance was negatively associated with interleukin 2 (Il2) (p < 0.05), Il6 (p < 0.05), iron (p < 0.05), and homocysteine (p < 0.005) levels, and positively associated with vitamin B12 levels (p < 0.005).
We extend previous findings regarding the positive and negative influence of various comorbidities and lifestyle factors on cognitive status in early PD patients, and reinforce the need to identify and treat potentially modifiable variables with the intention of exploring the possible improvement of the global cognitive status of patients with PD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Huntington’s disease (HD) is a neurodegenerative disease for which there is no curative treatment available. Given that the endocannabinoid system is involved in the pathogenesis of HD mouse models, ...stimulation of specific targets within this signaling system has been investigated as a promising therapeutic agent in HD. We conducted a double-blind, randomized, placebo-controlled, cross-over pilot clinical trial with Sativex
®
, a botanical extract with an equimolecular combination of delta-9-tetrahydrocannabinol and cannabidiol. Both Sativex
®
and placebo were dispensed as an oral spray, to be administered up to 12 sprays/day for 12 weeks. The primary objective was safety, assessed by the absence of more severe adverse events (SAE) and no greater deterioration of motor, cognitive, behavioral and functional scales during the phase of active treatment. Secondary objectives were clinical improvement of Unified Huntington Disease Rating Scale scores. Twenty-six patients were randomized and 24 completed the trial. After ruling-out period and sequence effects, safety and tolerability were confirmed. No differences on motor (
p
= 0.286), cognitive (
p
= 0.824), behavioral (
p
= 1.0) and functional (
p
= 0.581) scores were detected during treatment with Sativex
®
as compared to placebo. No significant molecular effects were detected on the biomarker analysis. Sativex
®
is safe and well tolerated in patients with HD, with no SAE or clinical worsening. No significant symptomatic effects were detected at the prescribed dosage and for a 12-week period. Also, no significant molecular changes were observed on the biomarkers. Future study designs should consider higher doses, longer treatment periods and/or alternative cannabinoid combinations.
Clincaltrals.gov identifier: NCT01502046
A good response to levodopa is a key factor to indicate device-aided therapies in people with Parkinson's disease (PwPD). The aim of the present study was to analyze the response to levodopa in PwPD ...with motor fluctuations followed for 4 years.
PwPD with motor fluctuations recruited from January 2016 to November 2017 from the COPPADIS cohort and assessed annually (from baseline to 4-year follow-up) during the OFF and ON states were included in this analysis. At each visit, the Unified Parkinson's Disease Rating Scale – part III (UPDRS-III) was applied during the OFF state (without medication during the last 12 h) and during the ON state. General linear model repeated measures were used to test for changes in the mean UPDRS–III–OFF, UPDRS–III–ON, and ΔUPDRS-III (UPDRS–III–OFF – UPDRS–III–ON) between visits. Levodopa equivalent daily dose (LEDD) was included as covariate.
Sixty-three patients (63.94 ± 8.42 years old; 68.3% males) were included. Mean disease duration was 7.81 ± 3.64 years. From baseline to 4-year follow-up visit, a significant increase in both the UPDRS–III–OFF (from 27.98 ± 9.58 to 31.75 ± 12.39; p = 0.003) and the UPDRS–III–ON (from 15.92 ± 7.93 to 18.84 ± 8.17; p = 0.006) was observed despite the significant increase in the LEDD (from 896.35 ± 355.65 to 1085.51 ± 488.29; p = 0.003). However, no significant differences were detected between visits in the ΔUPDRS-III.
In this cohort of PwPD with motor fluctuations, the response to levodopa did not weaken after a 4-year follow-up.
•A good response to levodopa is a key factor to indicate device-aided or on-demand therapies in Parkinson's disease.•Response to levodopa did not weaken after a 4-year follow-up in 63 fluctuators PD patients.•On and off scores worsen at the expense of axial symptoms and in parallel with conservation of the levodopa response.•There were no differences by motor phenotype.
Background and Objective
Caregiver burden in Parkinson's disease (PD) has been studied in many cross‐sectional studies but poorly in longitudinal ones. The aim of the present study was to analyze the ...change in burden, strain, mood, and quality of life (QoL) after a 2‐year follow‐up in a cohort of caregivers of patients with PD and also to identify predictors of these changes.
Patients and Methods
PD patients and their caregivers who were recruited from January/2016 to November/2017 from 35 centers of Spain from the COPPADIS cohort were included in the study. They were evaluated again at 2‐year follow‐up. Caregivers completed the Zarit Caregiver Burden Inventory (ZCBI), Caregiver Strain Index (CSI), Beck Depression Inventory‐II (BDI‐II), and EUROHIS‐QOL 8‐item index (EUROHIS‐QOL8) at baseline (V0) and at 2‐year follow‐up (V2). General linear model repeated measure and lineal regression models were applied.
Results
Significant changes, indicating an impairment, were detected on the total score of the ZCBI (p < 0.0001), CSI (p < 0.0001), BDI‐II (p = 0.024), and EUROHIS‐QOL8 (p = 0.002) in 192 PD caregivers (58.82 ± 11.71 years old; 69.3% were females). Mood impairment (BDI‐II; β = 0.652; p < 0.0001) in patients from V0 to V2 was the strongest factor associated with caregiver's mood impairment after the 2‐year follow‐up. Caregiver's mood impairment was the strongest factor associated with an increase from V0 to V2 on the total score of the ZCBI (β = 0.416; p < 0.0001), CSI (β = 0.277; p = 0.001), and EUROHIS‐QOL (β = 0.397; p = 0.002).
Conclusion
Burden, strain, mood, and QoL were impaired in caregivers of PD patients after a 2‐year follow‐up. Mood changes in both the patient and the caregiver are key aspects related to caregiver burden increase.
Key points
The present study is, to date, the largest prospective longitudinal study conducted for analyzing how burden, strain, mood, and quality of life change (QoL) in the principal caregiver of a patient with Parkinson's disease (PD).
After 2 years of follow‐up, the status of the principal caregiver of a patient with PD worsens as a whole with an increase in burden and stress and a worsening in mood and QoL.
Mood changes in the patient and in the caregiver as well are key aspects related to increase in caregiver burden.
These findings suggest that it could be essential to detect depressive symptoms both in the patient and in the caregiver too.
Background
Detection of suicidal ideation (SI) is key for trying to prevent suicide. The aim of this study was to analyze the frequency of SI and related factors in Spanish people with Parkinson's ...Disease (PwPD) and to compare them with a control group.
Methods
PD patients and controls recruited from the Spanish cohort COPPADIS from January 2016 to November 2017 were included. Two visits were conducted: V0 (baseline); V2 (2‐year ± 1 month follow‐up). SI was defined as a score ≥1 on item nine of the Beck Depression Inventory‐II (BDI‐II). Regression analyses were conducted to identify factors related to SI.
Results
At baseline, 693 PwPD (60.2% males; 62.59 ± 8.91 years old) and 207 controls (49.8% males; 60.99 ± 8.32 years old) were included. No differences between PwPD and controls were detected in SI frequency at either V0 (5.1% 35/693 vs. 4.3% 9/207; p = 0.421) or at V2 (5.1% 26/508 vs. 4.8% 6/125; p = 0.549). Major depression (MD) and a worse quality of life were associated with SI at both visits in PwPD: V0 (MD, OR = 5.63; p = 0.003; PDQ‐39, OR = 1.06; p = 0.021); V2 (MD, OR = 4.75; p = 0.027; EUROHIS‐QOL8, OR = 0.22; p = 0.006). A greater increase in the BDI‐II total score from V0 to V2 was the only factor predicting SI at V2 (OR = 1.21; p = 0.002) along with an increase in the total number of non‐antiparkinsonian drugs (OR = 1.39; p = 0.041).
Conclusion
The frequency of SI (5%) in PwPD was similar to in controls. Depression, a worse quality of life, and a greater comorbidity were related to SI.
Key points
This study detected suicidal ideation in about 5% of people with Parkinson's disease (PwPD) and was not more frequent than in controls.
Independent factors associated with suicidal ideation were major depression, a worse quality of life, and an increase in mood impairment or comorbidity over time.
These findings suggest the importance of detecting depressive symptoms in PwPD and evaluation for suicide thoughts, especially in those PwPD with major depression.
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