GLP‐1 receptor agonists for Parkinson's disease Mulvaney, Caroline A; Mulvaney, Caroline A; Duarte, Gonçalo S ...
Cochrane database of systematic reviews,
07/2020, Letnik:
2020, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Background
Parkinson's disease (PD) is a progressive disorder characterised by both motor and non‐motor problems. Glucagon‐like peptide‐1 (GLP‐1) receptor agonists, licensed for treatment of type 2 ...diabetes, work by stimulating GLP‐1 receptors in the pancreas, which triggers the release of insulin. GLP‐1 receptors have been found in the brain. Insulin signalling in the brain plays a key role in neuronal metabolism and repair and in synaptic efficacy, but insulin signalling is desensitised in the brain of people with PD. Researchers are exploring the neuroprotective effects of GLP‐1 receptor agonists in neurodegenerative disorders such as PD.
Objectives
To evaluate the effectiveness and safety of GLP‐1 receptor agonists for Parkinson's disease.
Search methods
We searched the Cochrane Movement Disorders Group trials register; the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; and Ovid MEDLINE and Embase. We also searched clinical trials registries, and we handsearched conference s. The most recent search was run on 25 June 2020.
Selection criteria
We included randomised controlled trials (RCTs) of adults with PD that compared GLP‐1 receptor agonists with conventional PD treatment, placebo, or no treatment.
Data collection and analysis
Two review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We rated the quality of evidence using GRADE. We resolved discrepancies between the two data extractors by consultation with a third review author.
Main results
Through our searches, we retrieved 99 unique records, of which two met our inclusion criteria. One double‐blind study of exenatide versus placebo randomised 62 participants, who self‐administered exenatide or placebo for 48 weeks and were followed up at 60 weeks after a 12‐week washout. One single‐blind study of exenatide versus no additional treatment randomised 45 participants; participants in the intervention group self‐administered exenatide for 12 months, and all participants were followed up at 14 months and 24 months following absence of exenatide for 2 months and 12 months, respectively. These trials had low risk of bias, except risk of performance bias was high for Aviles‐Olmos 2013.
Exenatide versus placebo
Primary outcomes
We found low‐certainty evidence suggesting that exenatide improves motor impairment as assessed by the Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) Part III in the off‐medication state (mean difference (MD) ‐3.10, 95% confidence interval (CI) ‐6.11 to ‐0.09). The difference in scores was slightly greater when scores were adjusted for baseline severity of the condition (as reported by study authors) (MD ‐3.5, 95% CI ‐6.7 to ‐0.3), exceeding the minimum clinically important difference (MCID).
We found low‐certainty evidence suggesting that exenatide has little or no effect on health‐related quality of life (HRQoL) as assessed by the Parkinson's Disease Questionnaire (PDQ)‐39 Summary Index (SI) (MD ‐1.80, 95% CI ‐6.95 to 3.35), the EuroQol scale measuring health status in five dimensions (EQ5D) (MD 0.07, 95% CI ‐0.03 to 0.16), or the EQ5D visual analogue scale (VAS) (MD 5.00, 95% CI ‐3.42 to 13.42). Eight serious adverse events (SAEs) were recorded, but all were considered unrelated to the intervention. Low‐certainty evidence suggests that exenatide has little or no effect on weight loss (risk ratio (RR) 1.25, 95% CI 0.89 to 1.76).
Exenatide versus no treatment
Primary outcomes at 14 months
We found very low‐certainty evidence suggesting that exenatide improves motor impairment as assessed by MDS‐UPDRS Part III off medication (MD ‐4.50, 95% CI ‐8.64 to ‐0.36), exceeding the MCID. We are uncertain whether exenatide improves HRQoL as assessed by the PDQ‐39 SI (MD 3.50, 95% CI ‐2.75 to 9.75; very low‐quality evidence). We found very low‐certainty evidence suggesting that exenatide has little or no effect on the number of SAEs (RR 1.60, 95% 0.40 to 6.32). We found very low‐certainty evidence suggesting that exenatide may lead to weight loss (MD ‐2.40 kg, 95% CI ‐4.56 to ‐0.24).
Primary outcomes at 24 months
We found evidence as reported by study authors to suggest that exenatide improves motor impairment as measured by MDS‐UPDRS Part III off medication (MD 5.6 points, 95% CI 2.2 to 9.0). Exenatide may not improve HRQoL as assessed by the PDQ‐39 SI (P = 0.682) and may not result in weight loss (MD 0.1 kg, 95% CI 3.0 to 2.8).
Authors' conclusions
Low‐ or very low‐certainty evidence suggests that exenatide may improve motor impairment for people with PD. The difference in motor impairment observed between groups may persist for some time following cessation of exenatide. This raises the possibility that exenatide may have a disease‐modifying effect. SAEs were unlikely to be related to treatment. The effectiveness of exenatide for improving HRQoL, non‐motor outcomes, ADLs, and psychological outcomes is unclear. Ongoing studies are assessing other GLP‐1 receptor agonists.
We present a numerical routine (oscode) with a C++ and Python interface for the efficient solution of one-dimensional, second-order, ordinary differential equations with rapidly oscillating ...solutions. The method is based on a Runge-Kutta-like stepping procedure that makes use of the Wentzel-Kramers-Brillouin approximation to skip regions of integration where the characteristic frequency varies slowly. In regions where this is not the case, the method is able to switch to a made-to-measure Runge-Kutta integrator that minimizes the total number of function evaluations. We demonstrate the effectiveness of the method with example solutions of the Airy equation and an equation exhibiting a burst of oscillations, discussing the error properties of the method in detail. We then show the method applied to physical systems. First, the one-dimensional, time-independent Schrödinger equation is solved as part of a shooting method to search for the energy eigenvalues for a potential with quartic anharmonicity. Then, the method is used to solve the Mukhanov-Sasaki equation describing the evolution of cosmological perturbations, and the primordial power spectrum of the perturbations is computed in different cosmological scenarios. We compare the performance of our solver in calculating a primordial power spectrum of scalar perturbations to that of bingo, an efficient code specifically designed for such applications, and find that our method performs better.
We discuss the challenges of motivating, constructing, and quantizing a canonically normalized inflationary perturbation in spatially curved universes. We show that this has historically proved ...challenging due to the interaction of nonadiabaticity with spatial curvature. We construct a novel curvature perturbation that is canonically normalized in the sense of its equation of motion and is unique up to a single scalar parameter. With this construction it becomes possible to set initial conditions invariant under canonical transformations, overcoming known ambiguities in the literature. This corrected quantization has potentially observational consequences via modifications to the primordial power spectrum at large angular scales, as well as theoretical implications for quantization procedures in curved cosmologies filled with a scalar field. Published by the American Physical Society 2024
The Chandeleur Islands, Louisiana (USA), were among the first coastal locations in the northern Gulf of Mexico (GoM) threatened by exposure to Deepwater Horizon oil. Shoreline oiling data and surface ...oil trajectories (aerial and satellite imagery) showed oil passing through seagrass beds on the shallow back barrier shelf west of the islands repeatedly between May and early July 2010. Aerial photos in May 2010 revealed a heterogeneous distribution of surface oil crossing the shelf, and MC252 exposure was confirmed in sediments and seagrass tissue during field assessments. We observed 5 seagrasses growing at densities comparable to other northern GoM communities. Ruppia maritima and Halodule wrightii were the most common, followed by Thalassia testudinum. Syringodium filiforme and Halophila engelmannii were rarely encountered. The subtidal and intertidal seascape on the shelf was a mosaic of seagrass patches distributed in varying sizes among unvegetated and sparsely vegetated areas at water depths and in sediment types known to support seagrasses. To quantitatively assess the seagrass response following exposure, sophisticated change detection methodologies were applied to aerial photography acquired in October 2010, 2011, and 2012 in a subsample of 5 locations on the shelf where Deepwater Horizon oil exposure was confirmed. The analysis conservatively estimated a seagrass loss of 104.22 acres (42.18 ha) at these locations. Unexpectedly, the whole back barrier shelf experienced a net gain of 228 acres (92.27 ha) of seagrass between 2010 and 2011, representing a pause in the long-standing trend in seagrass declines in the Chandeleurs and indicating that oil exposure did not result in a shelf-wide catastrophe for seagrasses. Predictions for the impending disappearance of this seagrass resource in the near future may need to be reconsidered.
It has been widely accepted that 5HT neurones promote anxiety, in humans as well as in animal models. This could be termed the "classic" hypothesis and it has led to a determined search for drugs ...which reduce 5HT function, especially agents which have selective actions at 5HT receptor subtypes. However, these novel agents tend to have weak and/or variable effects in animal models and more detailed examination of their actions suggests that not all findings are accounted for by the classic hypothesis. There appear to be circumstances in which increased 5HT activity can reduce anxious behaviour. There is increasing evidence for multiple anxiety mechanisms, which may be able to explain differential patterns of drug effects within and between models. Animal models of anxiety may also detect non-anxiety factors: effects on cognition or on impulsivity could be reflected in some models. This could be important in the light of recent evidence that 5HT-selective reuptake inhibitors are effective in impulsivity disorders. The classic hypothesis of 5HT function in anxiety may be only one part of an increasingly complex story. Unravelling the rest of this story is likely to lead to new insights in our understanding of anxiety and related disorders.
Childhood trauma is a common and potent risk factor for developing major depressive disorder in adulthood, associated with earlier onset, more chronic or recurrent symptoms, and greater probability ...of having comorbidities. Some studies indicate that evidence-based pharmacotherapies and psychotherapies for adult depression might be less efficacious in patients with a history of childhood trauma than patients without childhood trauma, but findings are inconsistent. Therefore, we examined whether individuals with major depressive disorder, including chronic forms of depression, and a reported history of childhood trauma, had more severe depressive symptoms before treatment, had more unfavourable treatment outcomes following active treatments, and were less likely to benefit from active treatments relative to a control condition, compared with individuals with depression without childhood trauma.
We did a comprehensive meta-analysis (PROSPERO CRD42020220139). Study selection combined the search of bibliographical databases (PubMed, PsycINFO, and Embase) from Nov 21, 2013, to March 16, 2020, and full-text randomised clinical trials (RCTs) identified from several sources (1966 up to 2016-19) to identify articles in English. RCTs and open trials comparing the efficacy or effectiveness of evidence-based pharmacotherapy, psychotherapy, or combination intervention for adult patients with depressive disorders and the presence or absence of childhood trauma were included. Two independent researchers extracted study characteristics. Group data for effect-size calculations were requested from study authors. The primary outcome was depression severity change from baseline to the end of the acute treatment phase, expressed as standardised effect size (Hedges' g). Meta-analyses were done using random-effects models.
From 10 505 publications, 54 trials met the inclusion criteria, of which 29 (20 RCTs and nine open trials) contributed data of a maximum of 6830 participants (age range 18-85 years, male and female individuals and specific ethnicity data unavailable). More than half (4268 62% of 6830) of patients with major depressive disorder reported a history of childhood trauma. Despite having more severe depression at baseline (g=0·202, 95% CI 0·145 to 0·258, I
=0%), patients with childhood trauma benefitted from active treatment similarly to patients without childhood trauma history (treatment effect difference between groups g=0·016, -0·094 to 0·125, I
=44·3%), with no significant difference in active treatment effects (vs control condition) between individuals with and without childhood trauma (childhood trauma g=0·605, 0·294 to 0·916, I
=58·0%; no childhood trauma g=0·178, -0·195 to 0·552, I
=67·5%; between-group difference p=0·051), and similar dropout rates (risk ratio 1·063, 0·945 to 1·195, I
=0%). Findings did not significantly differ by childhood trauma type, study design, depression diagnosis, assessment method of childhood trauma, study quality, year, or treatment type or length, but differed by country (North American studies showed larger treatment effects for patients with childhood trauma; false discovery rate corrected p=0·0080). Most studies had a moderate to high risk of bias (21 72% of 29), but the sensitivity analysis in low-bias studies yielded similar findings to when all studies were included.
Contrary to previous studies, we found evidence that the symptoms of patients with major depressive disorder and childhood trauma significantly improve after pharmacological and psychotherapeutic treatments, notwithstanding their higher severity of depressive symptoms. Evidence-based psychotherapy and pharmacotherapy should be offered to patients with major depressive disorder regardless of childhood trauma status.
None.
Sensitivity forecasts inform the design of experiments and the direction of theoretical efforts. To arrive at representative results, Bayesian forecasts should marginalize their conclusions over ...uncertain parameters and noise realizations rather than picking fiducial values. However, this is typically computationally infeasible with current methods for forecasts of an experiment's ability to distinguish between competing models. We thus propose a novel simulation-based methodology capable of providing expedient and rigorous Bayesian model comparison forecasts without relying on restrictive assumptions.
Terahertz pulsed imaging is a spectroscopic imaging modality using pulses of electromagnetic radiation (100 GHz–10 THz), and there has been recent interest in studying biomedical specimens. It is ...usual to display parametric images derived from the measured pulses. In this work, classification was achieved by applying multispectral clustering techniques to sets of parametric images. It was hypothesised that adequate information for clustering was carried in a small number of parametric images, providing these were weighted by complementary physical properties. Materials prepared for histopathological examination were chosen because their condition remained stable during long imaging periods and because their dehydrated state led to greater penetration of the radiation. Two specimens were examined in this pilot study, one of basal cell carcinoma and one of melanoma. Unsupervised ISODATA classification using three selected parametric terahertz pulsed images was compared qualitatively with
k-means classification using the shape of the whole time series, and with conventional stained microscope slides. There was good qualitative agreement between the classifications. Classifications were consistent with the morphological appearances expected, but further work is required to determine if tumour discrimination is possible. The results have implications for the future development of the technique as the need for only a small number of features could lead to considerably reduced acquisition times.
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