To examine the hypothesis that apathy is a core feature of Parkinson disease (PD) and that apathy can be dissociated from depression.
Eighty patients with PD and 20 patients with dystonia completed ...depression and apathy measures including the Marin Apathy Evaluation Scale (AES), Beck Depression Inventory (BDI), and Centers for Epidemiologic Studies-Depression Scale (CES-D).
There was a significantly higher severity and frequency of apathy in PD (frequency = 51%, 41/80) than in dystonia (frequency = 20%, 4/20). Apathy in the absence of depression was frequent in PD and did not occur in dystonia (PD = 28.8%, dystonia = 0%).
Patients with Parkinson disease (PD) experienced significantly higher frequency and severity of apathy when compared with patients with dystonia. Apathy may be a "core" feature of PD and occurs in the absence of depression.
Summary Background Levodopa is the most effective therapy for Parkinson's disease, but chronic treatment is associated with the development of potentially disabling motor complications. Experimental ...studies suggest that motor complications are due to non-physiological, intermittent administration of the drug, and can be reduced with continuous delivery. We aimed to assess efficacy and safety of levodopa-carbidopa intestinal gel delivered continuously through an intrajejunal percutaneous tube. Methods In our 12-week, randomised, double-blind, double-dummy, double-titration trial, we enrolled adults (aged ≥30 years) with advanced Parkinson's disease and motor complications at 26 centres in Germany, New Zealand, and the USA. Eligible participants had jejunal placement of a percutaneous gastrojejunostomy tube, and were then randomly allocated (1:1) to treatment with immediate-release oral levodopa-carbidopa plus placebo intestinal gel infusion or levodopa-carbidopa intestinal gel infusion plus oral placebo. Randomisation was stratified by site, with a mixed block size of 2 or 4. The primary endpoint was change from baseline to final visit in motor off-time. We assessed change in motor on-time without troublesome dyskinesia as a prespecified key secondary outcome. We assessed efficacy in a full-analysis set of participants with data for baseline and at least one post-baseline assessment, and imputed missing data with the last observation carried forward approach. We assessed safety in randomly allocated patients who underwent the percutaneous gastrojejunostomy procedure. This study is registered with ClinicalTrials.gov , numbers NCT00660387 and NCT0357994. Findings From baseline to 12 weeks in the full-analysis set, mean off-time decreased by 4·04 h (SE 0·65) for 35 patients allocated to the levodopa-carbidopa intestinal gel group compared with a decrease of 2·14 h (0·66) for 31 patients allocated to immediate-release oral levodopa-carbidopa (difference −1·91 h 95% CI −3·05 to −0·76; p=0·0015). Mean on-time without troublesome dyskinesia increased by 4·11 h (SE 0·75) in the intestinal gel group and 2·24 h (0·76) in the immediate-release oral group (difference 1·86 95% CI 0·56 to 3·17; p=0·0059). In the safety analyses 35 (95%) of 37 patients allocated to the levodopa-carbidopa intestinal gel group had adverse events (five 14% serious), as did 34 (100%) of 34 patients allocated to the immediate-release oral levodopa-carbidopa group (seven 21% serious), mainly associated with the percutaneous gastrojejunostomy tube. Interpretation Continuous delivery of levodopa-carbidopa with an intestinal gel offers a promising option for control of advanced Parkinson's disease with motor complications. Benefits noted with intestinal gel delivery were of a greater magnitude than were those obtained with medical therapies to date, and our study is, to our knowledge, the first demonstration of the benefit of continuous levodopa delivery in a double-blind controlled study. Funding AbbVie.
Converging evidence demonstrates that physical activity evokes a brain state characterized by distinctive changes in brain metabolism and cortical function. Human studies have shown that physical ...activity leads to a generalized increase in electroencephalography power across regions and frequencies, and a global increase in brain nonoxidative metabolism of carbohydrate substrates. This nonoxidative consumption of carbohydrate has been hypothesized to include increased de novo synthesis of amino acid neurotransmitters, especially glutamate and GABA. Here, we conducted a series of proton magnetic resonance spectroscopy studies in human volunteers before and after vigorous exercise (≥80% of predicted maximal heart rate). Results showed that the resonance signals of both glutamate and GABA increased significantly in the visual cortex following exercise. We further demonstrated a similar increase in glutamate following exercise in an executive region, the anterior cingulate cortex. The increase in glutamate was similar when using echo times of 30 and 144 ms, indicating that exercise-related T2 relaxation effects across this range of relaxation times did not account for the findings. In addition, we found preliminary evidence that more physical activity during the preceding week predicts higher resting glutamate levels. Overall, the results are consistent with an exercise-induced expansion of the cortical pools of glutamate and GABA, and add to a growing understanding of the distinctive brain state associated with physical activity. A more complete understanding of this brain state may reveal important insights into mechanisms underlying the beneficial effects of physical exercise in neuropsychiatric disorders, neurorehabilitation, aging, and cognition.
Dysphagia is the main cause of aspiration pneumonia and death in Parkinson disease (PD) with no established restorative behavioral treatment to date. Reduced swallow safety may be related to ...decreased elevation and excursion of the hyolaryngeal complex. Increased submental muscle force generation has been associated with expiratory muscle strength training (EMST) and subsequent increases in hyolaryngeal complex movement provide a strong rationale for its use as a dysphagia treatment. The current study's objective was to test the treatment outcome of a 4-week device-driven EMST program on swallow safety and define the physiologic mechanisms through measures of swallow timing and hyoid displacement.
This was a randomized, blinded, sham-controlled EMST trial performed at an academic center. Sixty participants with PD completed EMST, 4 weeks, 5 days per week, for 20 minutes per day, using a calibrated or sham, handheld device. Measures of swallow function including judgments of swallow safety (penetration-aspiration PA scale scores), swallow timing, and hyoid movement were made from videofluoroscopic images.
No pretreatment group differences existed. The active treatment (EMST) group demonstrated improved swallow safety compared to the sham group as evidenced by improved PA scores. The EMST group demonstrated improvement of hyolaryngeal function during swallowing, findings not evident for the sham group.
EMST may be a restorative treatment for dysphagia in those with PD. The mechanism may be explained by improved hyolaryngeal complex movement.
This intervention study provides Class I evidence that swallow safety as defined by PA score improved post EMST.
Objective: To study the safety and efficacy of a cholinesterase inhibitor, donepezil hydrochloride, for the treatment of dementia in Parkinson’s disease (PD). Methods: This was a randomised double ...blind, placebo controlled, crossover study in 22 subjects with PD and dementia. Participants were randomised to receive either donepezil followed by identical placebo, or placebo followed by donepezil. Donepezil was administered at 5–10 mg/day. Treatment periods were 10 weeks with a washout period of 6 weeks between the two periods. The primary outcome measure was the Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAScog). Results: Donepezil was well tolerated and most adverse events were mild. There was no worsening of PD symptoms as measured by the total or motor sections of the Unified Parkinson’s Disease Rating Scale. There was a 1.9 point trend toward better scores on the ADAScog on treatment compared with placebo that was not statistically significant. The secondary cognitive measures showed a statistically significant 2 point benefit on the Mini Mental Status Examination and no change on the Mattis Dementia Rating Scale (MDRS). The Clinical Global Impression of Change (CGI) showed a significant 0.37 point improvement on donepezil. No improvement was observed on the MDRS or the Brief Psychiatric Rating Scale. Carryover between treatment periods was observed but was not statistically significant. Conclusions: Donepezil was well tolerated and did not worsen PD. There may be a modest benefit on aspects of cognitive function. The possible clinical benefit measured by CGI was reflected in only one of the cognitive scales used in this study.
Pre-treatments are often applied in anaerobic digestion in order to improve the performance of the process: increased methane yield and rate. Physical pretreatments are the most commonly used for ...anaerobic digestion of agricultural waste. The main purpose of this work was to evaluate the effects of different lab-scale mechanical pretreatments on cattle manure. Three mechanical pre-treatments were sequentially applied to cattle manure: shredding, mixing and blending. An original set of analytical procedures was performed before and after mechanical pretreatments, in order to assess physical, chemical and biological properties of the feedstock. Thus, shredding and mixing pre-treatments were not significantly efficient in terms of methane production yield and rate. In contrast, methane production rate increased with blending treatment, and methane yield was slightly improved as well. An increase of soluble chemical oxygen demand (COD) was also reported with blending pretreatment. The reduction of particle size was mainly between 31.5 and 4 mm for all pretreatments and it led to an increase of water retention capacity of the cattle manure. Therefore, mechanical pre-treatments do not only affect the biochemical characteristics of agricultural waste. It also influences its structure and reactivity. In this context, blending pretreatment showed as the most performant pretreatment among the evaluated pretreatments with an increase of 18% on methane rate and a higher COD solubilisation.
Graphic Abstract
Abstract
While Parkinson's disease (PD)-related neurodegeneration is associated with structural changes in the brain, conventional magnetic resonance imaging (MRI) has proven less effective for ...clinical diagnosis due to its inability to reliably identify subtle changes early in the disease course. In this study, we aimed to develop a structural MRI-based biomarker to predict the rate of progression of motor symptoms in the early stages of PD. The study included 88 patients with PD and 120 healthy controls from the Parkinson's Progression Markers Initiative database; MRI at baseline and motor symptom scores assessed using the MDS-UPDRS-III at two time points (baseline and 48 months) were selected. Group-level volumetric analyses at baseline were not associated with the decline in motor functioning. Then, we developed a patient-specific multivariate gray matter volumetric distance and demonstrated that it could significantly predict changes in motor symptom scores (
P
< 0.05). Further, we classified patients as relatively slower and faster progressors with 89% accuracy using a support vector machine classifier. Thus, we identified a promising structural MRI-based biomarker for predicting the rate of progression of motor symptoms and classifying patients based on motor symptom severity.
Patients with Parkinson's disease chronically treated with levodopa commonly have delayed or unpredictable onset of its benefits after oral intake. In this study, we assessed the safety and efficacy ...of CVT-301, a self-administered levodopa oral inhalation powder, for the treatment of patients with Parkinson's disease during off periods.
In this randomised, double-blind, placebo-controlled, phase 3 trial, patients were recruited at 65 sites in Canada, Poland, Spain, and the USA. Eligible participants were patients with Parkinson's disease aged 30–85 years, who had daily off periods of 2 h or longer and showed an improvement of 25% or greater in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score from off to on state after use of an oral levodopa plus a dopa-decarboxylase inhibitor combination. Patients were assigned (1:1:1) with a computer-generated randomisation code, in fixed blocks of six, to either CVT-301 60 mg, CVT-301 84 mg, or placebo. Spirometry results and modified Hoehn and Yahr disease stage at screening were used for stratification of treatment groups. Patients, the sponsor, and site personnel were masked to treatment assignment. Each study dose consisted of two capsules administered with an inhaler. Patients were instructed to use the study drug as needed for off periods, and could self-administer up to five doses per day. The primary endpoint was the change in UPDRS motor score from predose to 30 min postdose, assessed at week 12 during an in-clinic off period, in the CVT-301 84 mg group compared with the placebo group. Analysis was by intention to treat. Safety was assessed in all patients who received at least one dose of experimental treatment. This trial is registered with ClinicalTrials.gov, number NCT02240030.
Between Dec 4, 2014, and Aug 26, 2016, 351 patients were enrolled and randomly assigned to receive CVT-301 60 mg (115 patients), CVT-301 84 mg (120 patients), or placebo (116 patients). Of these, 339 received the assigned study treatment (CVT-301 60 mg, n=113; CVT-301 84 mg, n=114; placebo, n=112) and 290 completed the study (CVT-301 60 mg, n=96; CVT-301 84 mg, n=97; placebo, n=97). The least-squares mean difference in UPDRS motor score change from predose to 30 min postdose was −5·91 (SE 1·50, 95% CI −8·86 to −2·96) for the placebo group and −9·83 (1·51; −12·79 to −6·87) for the CVT-301 84 mg group (between-group difference −3·92 –6·84 to −1·00; p=0·0088). Treatments were safe and well tolerated. Severe adverse events were reported by 2 (2%) of 112 patients in the placebo group, 7 (6%) of 113 in the CVT-301 60 mg group, and 5 (4%) of 114 in the CVT-301 84 mg group, with no severe adverse event occurring in more than one patient in any treatment group. 11 (3%) of 339 patients had 19 serious adverse events (three 3% of 112 patients in placebo, six 5% of 113 in CVT-301 60 mg, and two 2% of 114 in CVT-301 84 mg). Of these, hypotension and atrial fibrillation were assessed by investigators to be possibly related to the study drug.
CVT-301 can improve UPDRS motor scores of patients with Parkinson's disease during in-clinic off periods, with few severe or serious adverse events. The long-term safety and efficacy of CVT-301 need to be investigated in future studies.
Acorda Therapeutics.
Saving freshwater from salts Cañedo-Argüelles, M.; Hawkins, C. P.; Kefford, B. J. ...
Science (American Association for the Advancement of Science),
02/2016, Letnik:
351, Številka:
6276
Journal Article
Recenzirano
Ion-specific standards are needed to protect biodiversity
Many human activities—like agriculture and resource extraction—are increasing the total concentration of dissolved inorganic salts (i.e., ...salinity) in freshwaters. Increasing salinity can have adverse effects on human health (
1
); increase the costs of water treatment for human consumption; and damage infrastructure e.g., amounting to $700 million per year in the Border Rivers catchment, Australia (
2
). It can also reduce freshwater biodiversity (
3
); alter ecosystem functions (
4
); and affect economic well-being by altering ecosystem goods and services (e.g., fisheries collapse). Yet water-quality legislation and regulations that target salinity typically focus on drinking water and irrigation water, which does not automatically protect biodiversity. For example, specific electrical conductivities (a proxy for salinity) of 2 mS/cm can be acceptable for drinking and irrigation but could extirpate many freshwater insect species (
3
). We argue that salinity standards for specific ions and ion mixtures, not just for total salinity, should be developed and legally enforced to protect freshwater life and ecosystem services. We identify barriers to setting such standards and recommend management guidelines.
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