Durante et al. show that α-synuclein oligomers reduce NMDA receptor-mediated synaptic currents and impair LTP of striatal spiny projection neurons by targeting the GluN2A subunit. Treatment with ...antibodies targeting α-synuclein prevents the synaptic alterations, suggesting that this strategy might counteract synaptic dysfunction in Parkinson's disease.
Abstract
Parkinson's disease is a progressive neurodegenerative disorder characterized by altered striatal dopaminergic signalling that leads to motor and cognitive deficits. Parkinson's disease is also characterized by abnormal presence of soluble toxic forms of α-synuclein that, when clustered into Lewy bodies, represents one of the pathological hallmarks of the disease. However, α-synuclein oligomers might also directly affect synaptic transmission and plasticity in Parkinson's disease models. Accordingly, by combining electrophysiological, optogenetic, immunofluorescence, molecular and behavioural analyses, here we report that α-synuclein reduces N-methyl-d-aspartate (NMDA) receptor-mediated synaptic currents and impairs corticostriatal long-term potentiation of striatal spiny projection neurons, of both direct (D1-positive) and indirect (putative D2-positive) pathways. Intrastriatal injections of α-synuclein produce deficits in visuospatial learning associated with reduced function of GluN2A NMDA receptor subunit indicating that this protein selectively targets this subunit both in vitro and ex vivo. Interestingly, this effect is observed in spiny projection neurons activated by optical stimulation of either cortical or thalamic glutamatergic afferents. We also found that treatment of striatal slices with antibodies targeting α-synuclein prevents the α-synuclein-induced loss of long-term potentiation and the reduced synaptic localization of GluN2A NMDA receptor subunit suggesting that this strategy might counteract synaptic dysfunction occurring in Parkinson's disease.
Abstract
Introduction
Progressive multifocal leukoencephalopathy is a rare but often fatal complication of some multiple sclerosis treatments. Although it has mainly been associated with natalizumab ...treatment, its appearance with other immunosuppressive therapies has also been reported.
Aims
The aim of this case report is to describe the development of progressive multifocal encephalopathy in a patient with relapsing–remitting multiple sclerosis treated with ocrelizumab without previous use of natalizumab.
Conclusions
A summary of the presentation and disease course is provided, presented in the context of the current literature and likely pathophysiology.
When James Parkinson described the classical symptoms of the disease he could hardly foresee the evolution of our understanding over the next two hundred years. Nowadays, Parkinson's disease is ...considered a complex multifactorial disease in which genetic factors, either causative or susceptibility variants, unknown environmental cues, and the potential interaction of both could ultimately trigger the pathology. Noteworthy advances have been made in different fields from the clinical phenotype to the decoding of some potential neuropathological features, among which are the fields of genetics, drug discovery or biomaterials for drug delivery, which, though recent in origin, have evolved swiftly to become the basis of research into the disease today. In this review, we highlight some of the key advances in the field over the past two centuries and discuss the current challenges focusing on exciting new research developments likely to come in the next few years. Also, the importance of pre-motor symptoms and early diagnosis in the search for more effective therapeutic options is discussed.
Background
Cognitive impairment is present in 40–65% of patients with multiple sclerosis (pwMS). Objectively measured cognitive performance often does not match patients' subjective perception of ...their own performance.
Objective
We aimed to compare cognitive performance and subjective perception of cognitive deficits between pwMS and healthy controls (HCs), as well as the accuracy of subjective perception.
Methods
In total, 54 HC and 112 pwMS (relapsing–remitting, RRMS, and progressive PMS) underwent neuropsychological evaluation and completed perceived deficit, fatigue, and anxiety–depression scales. Participants were classified according to their consistency between subjective self-evaluation of cognitive abilities and objective cognitive performance to assess accuracy. Regression models were used to compare cognitive performance between groups and explore factors explaining inaccuracy in the estimation of cognitive performance.
Results
PMS showed greater and more widespread cognitive differences with HC than RRMS. No differences were found between pwMS and HC in the perception of deficit. PMS had higher ratios of overestimators. In explaining inaccuracy, fatigue and cognitive preservation were found to be risk factors for underestimation, whereas physical disability and cognitive impairment were risk factors for overestimation.
Conclusion
PwMS have metacognitive knowledge impairments. This study provides new information about metacognition, data on the prevalence of impairments over a relatively large sample of PwMS, and new insights into factors explaining it. Anosognosia, related to cognitive impairment, may be present in pwMS. Fatigue is a key factor in underestimating cognition.
Abstract Carbon-11 labeled dihydrotetrabenazine (11 C-DTBZ) binds to the vesicular monoamine transporter 2 and has been used to assess nigro-striatal integrity in animal models and patients with ...Parkinson's disease. Here, we applied11 C-DTBZ positron emission tomography (PET) to obtain longitudinally in-vivo assessment of striatal dopaminergic loss in the classic unilateral and in a novel bilateral 6-hydroxydopamine (6-OHDA) lesion rat model. Forty-four Sprague–Dawley rats were divided into 3 sub-groups: 1. 6-OHDA-induced unilateral lesion in the medial forebrain bundle, 2. bilateral lesion by injection of 6-OHDA in the third ventricle, and 3. vehicle injection in either site.11 C-DTBZ PET studies were investigated in the same animals successively at baseline, 1, 3 and 6 weeks after lesion using an anatomically standardized volumes-of-interest approach. Additionally, 12 rats had PET and Magnetic Resonance Imaging to construct a new11 C-DTBZ PET template. Behavior was characterized by rotational, catalepsy and limb-use asymmetry tests and dopaminergic striatal denervation was validated post-mortem by immunostaining of the dopamine transporter (DAT).11 C-DTBZ PET showed a significant decrease of striatal binding (SB) values one week after the unilateral lesion. At this point, there was a 60% reduction in SB in the affected hemisphere compared with baseline values in 6-OHDA unilaterally lesioned animals. A 46% symmetric reduction over baseline SB values was found in bilaterally lesioned rats at the first week after lesion. SB values remained constant in unilaterally lesioned rats whereas animals with bilateral lesions showed a modest (22%) increase in binding values at the 3rd and 6th weeks post-lesion. The degree of striatal dopaminergic denervation was corroborated histologically by DAT immunostaining. Statistical analysis revealed a high correlation between11 C-DTBZ PET SB and striatal DAT immunostaining values (r = 0.95, p < 0.001). The data presented here indicate that11 C-DTBZ PET may be used to ascertain changes occurring in-vivo throughout the evolution of nigro-striatal dopaminergic neurodegeneration, mainly in the unilateral 6-OHDA lesion rat.
Cognitive impairment is common in multiple sclerosis (MS). Unfortunately, the synaptic and molecular mechanisms underlying MS-associated cognitive dysfunction are largely unknown. We explored the ...presence and the underlying mechanism of cognitive and synaptic hippocampal dysfunction during the remission phase of experimental MS. Experiments were performed in a chronic-relapsing experimental autoimmune encephalomyelitis (EAE) model of MS, after the resolution of motor deficits. Immunohistochemistry and patch-clamp recordings were performed in the CA1 hippocampal area. The hole-board was utilized as cognitive/behavioural test. In the remission phase of experimental MS, hippocampal microglial cells showed signs of activation, CA1 hippocampal synapses presented an impaired long-term potentiation (LTP) and an alteration of spatial tests became evident. The activation of hippocampal microglia mediated synaptic and cognitive/behavioural alterations during EAE. Specifically, LTP blockade was found to be caused by the reactive oxygen species (ROS)-producing enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. We suggest that in the remission phase of experimental MS microglia remains activated, causing synaptic dysfunctions mediated by NADPH oxidase. Inhibition of microglial activation and NADPH oxidase may represent a promising strategy to prevent neuroplasticity impairment associated with active neuro-inflammation, with the aim to improve cognition and counteract MS disease progression.
Oxygen is a neonatal health hazard that should be avoided in clinical practice. In this review, an international team of neonatologists and nurses assessed oxygen saturation (SpO2) targeting in ...preterm infants and evaluated the potential weaknesses of randomised clinical trials.
Conclusion
SpO2 of 85–89% can increase mortality and 91–95% can cause hyperoxia and ill effects. Neither of these ranges can be recommended, and wider intermediate targets, such as 87–94% or 88–94%, may be safer.
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