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
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.
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.
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.
Biomarkers in Alzheimer's disease García-Ribas, G; López-Sendón Moreno, J L; García-Caldentey, J
Revista de neurologiá,
04/2014, Letnik:
58, Številka:
7
Journal Article
Recenzirano
The new diagnostic criteria for Alzheimer's disease (AD) include brain imaging and cerebrospinal fluid (CSF) biomarkers, with the aim of increasing the certainty of whether a patient has an ongoing ...AD neuropathologic process or not. Three CSF biomarkers, Aß42, total tau, and phosphorylated tau, reflect the core pathological features of AD. It is already known that these pathological processes of AD starts decades before the first symptoms, so these biomarkers may provide means of early disease detection. At least three stages of AD could be identified: preclinical AD, mild cognitive impairment due to AD, and dementia due to AD. In this review, we aim to summarize the CSF biomarker data available for each of these stages. We also review the actual research on blood-based biomarkers. Recent studies on healthy elderly subjects and on carriers of dominantly inherited AD mutations have also found biomarker changes that allow separate groups in these preclinical stages. These studies may aid for segregate populations in clinical trials and objectively evaluate if there are changes over the pathological processes of AD. Limits to widespread use of CSF biomarkers, apart from the invasive nature of the process itself, is the higher coefficient of variation for the analyses between centres. It requires strict pre-analytical and analytical procedures that may make feasible multi-centre studies and global cut-off points for the different stages of AD.
Background and Purpose. Intravenous thrombolysis using tissue plasminogen activator is safe and probably effective in patients >80 years old. Nevertheless, its safety has not been specifically ...addressed for the oldest old patients (≥85 years old, OO). We assessed the safety and effectiveness of thrombolysis in this group of age. Methods. A prospective registry of patients treated with intravenous thrombolysis. Patients were divided in two groups (<85 years and the OO). Demographic data, stroke aetiology and baseline National Institute Health Stroke Scale (NIHSS) score were recorded. The primary outcome measures were the percentage of symptomatic intracranial haemorrhage (SICH) and functional outcome at 3 months (modified Rankin Scale, mRS). Results. A total of 1,505 patients were registered. 106 patients were OO median 88, range 85–101. Female sex, hypertension, elevated blood pressure at admission, cardioembolic strokes and higher basal NIHSS score were more frequent in the OO. SICH transformation rates were similar (3.1% versus 3.7%, P=1.00). The probability of independence at 3 months (mRS 0–2) was lower in the OO (40.2% versus 58.7%, P=0.001) but not after adjustment for confounding factors (adjusted OR, 0.82; 95% CI, 0.50 to 1.37; P=0.455). Three-month mortality was higher in the OO (28.0% versus 11.5%, P<0.001). Conclusion. Intravenous thrombolysis for stroke in OO patients did not increase the risk of SICH although mortality was higher in this group.
Highlights • Huntington's disease (HD) is associated with the expansion of (CAG) trinucleotide (> 36) at the coding region of the IT 15 gene. • Individuals with 27–35 repeats may present late-onset ...HD. • We present a patient with late onset HD and 29 triplet expansion. • Genetic testing is crucial for proper diagnosis of patients with apparently sporadic senile chorea.
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