The rupture of an intracranial aneurysm is a serious incident, causing subarachnoid hemorrhage associated with high fatality and morbidity rates. Because the demand for radiologic examinations is ...steadily growing, physician fatigue due to an increased workload is a real concern and may lead to mistaken diagnoses of potentially relevant findings. Our aim was to develop a sufficient system for automated detection of intracranial aneurysms.
In a retrospective study, we established a system for the detection of intracranial aneurysms from 3D TOF-MRA data. The system is based on an open-source neural network, originally developed for segmentation of anatomic structures in medical images. Eighty-five datasets of patients with a total of 115 intracranial aneurysms were used to train the system and evaluate its performance. Manual annotation of aneurysms based on radiologic reports and critical revision of image data served as the reference standard. Sensitivity, false-positives per case, and positive predictive value were determined for different pipelines with modified pre- and postprocessing.
The highest overall sensitivity of our system for the detection of intracranial aneurysms was 90% with a sensitivity of 96% for aneurysms with a diameter of 3-7 mm and 100% for aneurysms of >7 mm. The best location-dependent performance was in the posterior circulation. Pre- and postprocessing sufficiently reduced the number of false-positives.
Our system, based on a deep learning convolutional network, can detect intracranial aneurysms with a high sensitivity from 3D TOF-MRA data.
Abstract Introduction Loss of synapses best correlates to cognitive deficits in Alzheimer's disease (AD) in which oligomeric neurotoxic species of amyloid-β appears to contribute synaptic pathology. ...Although a number of clinical pathologic studies have been performed with limited sample size, there are no systematic studies encompassing large samples. Therefore, we performed a meta-analysis study. Methods We identified 417 publications reporting postmortem synapse and synaptic marker loss from AD patients. Two meta-analyses were performed using a single database of subselected publications and calculating the standard mean differences. Results Meta-analysis confirmed synaptic loss in selected brain regions is an early event in AD pathogenesis. The second meta-analysis of 57 synaptic markers revealed that presynaptic makers were affected more than postsynaptic markers. Discussion The present meta-analysis study showed a consistent synaptic loss across brain regions and that molecular machinery including endosomal pathways, vesicular assembly mechanisms, glutamate receptors, and axonal transport are often affected.
Abstract The human norepinephrine transporter (NET) is an established drug target for a wide range of psychiatric disorders. Conventional methods that are used to functionally characterize NET ...inhibitors are based on the use of radiolabeled or fluorescent substrates. These methods are highly informative, but pose limitations to either high-throughput screening (HTS) adaptation or physiologically accurate representation of the endogenous uptake events. Recently, we developed a label-free functional assay based on the activation of G protein-coupled receptors by a transported substrate, termed the TRACT assay. In this study, the TRACT assay technology was applied to NET expressed in a doxycycline-inducible HEK 293 JumpIn cell line. Three endogenous substrates of NET—norepinephrine (NE), dopamine (DA) and epinephrine (EP)—were compared in the characterization of the reference NET inhibitor nisoxetine. The resulting assay, using NE as a substrate, was validated in a manual HTS set-up with a Z′ = 0.55. The inhibitory potencies of several reported NET inhibitors from the TRACT assay showed positive correlation with those from an established fluorescent substrate uptake assay. These findings demonstrate the suitability of the TRACT assay for HTS characterization and screening of NET inhibitors and provide a basis for investigation of other solute carrier transporters with label-free biosensors.
Ageing is a highly complex process marked by a temporal cascade of events, which promote alterations in the normal functioning of an individual organism. The triggers of normal brain ageing are not ...well understood, even less so the factors which initiate and steer the neuronal degeneration, which underpin disorders such as dementia. A wealth of data on how nutrients and diets may support cognitive function and preserve brain health are available, yet the molecular mechanisms underlying their biological action in both normal ageing, age-related cognitive decline, and in the development of neurodegenerative disorders have not been clearly elucidated.
This review aims to summarise the current state of knowledge of vulnerabilities that predispose towards dysfunctional brain ageing, highlight potential protective mechanisms, and discuss dietary interventions that may be used as therapies. A special focus of this paper is on the impact of nutrition on neuroprotection and the underlying molecular mechanisms, and this focus reflects the discussions held during the 2nd workshop 'Nutrition for the Ageing Brain: Functional Aspects and Mechanisms' in Copenhagen in June 2016. The present review is the most recent in a series produced by the Nutrition and Mental Performance Task Force under the auspice of the International Life Sciences Institute Europe (ILSI Europe).
Coupling studies of cognitive ageing with studies investigating the effect of nutrition and dietary interventions as strategies targeting specific mechanisms, such as neurogenesis, protein clearance, inflammation, and non-coding and microRNAs is of high value. Future research on the impact of nutrition on cognitive ageing will need to adopt a longitudinal approach and multimodal nutritional interventions will likely need to be imposed in early-life to observe significant impact in older age.
Solute carriers (SLCs) are relatively underexplored compared to other prominent protein families such as kinases and G protein-coupled receptors. However, proteins from the SLC family play an ...essential role in various diseases. One such SLC is the high-affinity norepinephrine transporter (NET/SLC6A2). In contrast to most other SLCs, the NET has been relatively well studied. However, the chemical space of known ligands has a low chemical diversity, making it challenging to identify chemically novel ligands. Here, a computational screening pipeline was developed to find new NET inhibitors. The approach increases the chemical space to model for NETs using the chemical space of related proteins that were selected utilizing similarity networks. Prior proteochemometric models added data from related proteins, but here we use a data-driven approach to select the optimal proteins to add to the modeled data set. After optimizing the data set, the proteochemometric model was optimized using stepwise feature selection. The final model was created using a two-step approach combining several proteochemometric machine learning models through stacking. This model was applied to the extensive virtual compound database of Enamine, from which the top predicted 22,000 of the 600 million virtual compounds were clustered to end up with 46 chemically diverse candidates. A subselection of 32 candidates was synthesized and subsequently tested using an impedance-based assay. There were five hit compounds identified (hit rate 16%) with sub-micromolar inhibitory potencies toward NET, which are promising for follow-up experimental research. This study demonstrates a data-driven approach to diversify known chemical space to identify novel ligands and is to our knowledge the first to select this set based on the sequence similarity of related targets.
Accumulating evidence shows nutritional factors influence the risk of developing Alzheimer's disease (AD) and its rate of clinical progression. Dietary and lifestyle guidelines to help adults reduce ...their risk have been developed. However, the clinical dementia picture remains complex, and further evidence is required to demonstrate that modifying nutritional status can protect the brain and prevent, delay, or reduce pathophysiological consequences of AD. Moreover, there is a pressing need for further research because of the global epidemic of overweight and obesity combined with longer life expectancy of the general population and generally observed decreases in body weight with aging and AD. A new research approach is needed, incorporating more sophisticated models to account for complex scenarios influencing the relationship between nutritional status and AD. Systematic research should identify and address evidence gaps. Integrating longitudinal epidemiological data with biomarkers of disease, including brain imaging technology, and randomized controlled interventions may provide greater insights into progressive and subtle neurological changes associated with dietary factors in individuals at risk for or living with AD. In addition, greater understanding of mechanisms involved in nutritional influences on AD risk and progression, such as oxidative stress and loss of neuronal membrane integrity, will better inform possible interventional strategies. There is consensus among the authors that nutritional deficits, and even states of excess, are associated with AD, but more work is needed to determine cause and effect. Appropriately designed diets or nutritional interventions may play a role, but additional research is needed on their clinical-cognitive effectiveness.
Abstract Introduction Synaptic membrane formation depends on nutrients that fuel metabolic pathways for the synthesis of constituent phospholipids. Consequently, insufficient availability of such ...nutrients may restrict membrane formation and contribute to synaptic dysfunction in Alzheimer's disease (AD). We assessed whether blood and cerebrospinal fluid (CSF) concentrations of nutrients related to phospholipid synthesis differ among patients with AD, mild cognitive impairment (MCI), and control subjects. Methods Concentrations of uridine, choline, folate, homocysteine, and other related metabolites were analyzed in paired blood and CSF samples from subjects selected from the Amsterdam Dementia Cohort with AD ( n = 150; age, 66 ± 7 years; 37% female), MCI ( n = 148; age, 66 ± 8 years; 37% female), and control subjects ( n = 148; age, 59 ± 8 years; 38% female). Results Age- and gender-adjusted analysis of variance revealed different concentrations of circulating uridine, choline, and folate and CSF uridine, folate, and homocysteine (all P < .05) among the three diagnostic groups. Post hoc pairwise comparison showed that subjects with AD had lower CSF uridine, plasma choline and higher CSF homocysteine concentrations, whereas subjects with MCI had lower plasma and CSF uridine, serum and CSF folate, and higher CSF homocysteine concentrations compared with control subjects (all P < .05), with differences ranging from −11 to +22%. Discussion AD and MCI patients have lower levels of nutrients involved in phospholipid synthesis. The current observations warrant exploration of the application of nutritional strategies in the early stages of AD.
In the present study, including 66 schizophrenic patients and 73 healthy controls, the effect of atypical antipsychotic treatment over a period of 14 weeks on psychotic symptoms and plasma levels of ...glutamate and monoaminergic metabolites was investigated.
Treatment induced a modest reduction of psychotic symptoms in 42% of the patients (response criterion: Brief Psychiatric Rating Scale BPRS decrease ≥40%). Poor response was associated with severity of psychopathology, age and duration of disease.
Glutamate at baseline was significantly higher in patients as compared to controls (
p<0.01). During treatment, a significant further increase of glutamate, not related to response, was observed. Glutamate levels correlated significantly with negative symptom scores at baseline and weeks 3, 6 and 14 (
p<0.05).
At baseline, serotonin (5-HT) in plasma and 5-HT in platelets were significantly lower in the poor responders as compared to controls (
p<0.05) and increased significantly during treatment (
p<0.05). In the responders, treatment coincided with a decrease of 5-HT parameters.
No differences in plasma levels of HVA, 5-HIAA and their ratio were observed between controls and response groups.
The results of this study suggest an effect of atypical antipsychotics on glutamatergic neurotransmission and an association between lower pretreatment peripheral 5-HT parameters and response.
Objective The aim of the study was to explore the effect of a medical food intervention, developed to improve synaptic formation and function, on magnetoencephalography (MEG), as a proxy of ...macroscopic effects of synaptic changes, in patients with mild Alzheimer’s disease (AD). Methods In an exploratory 24-weeks, double blind, randomised controlled sub-study of the Souvenir II study, differences between the active ( n = 22) and control ( n = 27) drug-naïve mild AD patients were computed for frequency analysis, functional connectivity and functional brain network measures in source space MEG. Results The groups were significantly different with respect to baseline mini-mental state examination (MMSE) (active: 23.8 ± 2.3 (mean ± SD); control 25.3 ± 2.6). No consistent statistically significant intervention effects were found on the MEG measures. Conclusions In the current subsample of mild AD patients we could not detect an intervention effect of the medical food on MEG measures as opposed to EEG that has been used in a larger sample and revealed beneficial intervention effects on functional connectivity and brain network organisation in mild AD. Key message Further research is needed with substantially larger sample sizes and better balanced study groups to further assess the role of MEG in intervention trials in AD.
Reconstruction of nasal skin defects can be challenging due to limited skin laxity and underlying cartilage and, therefore, often require a complex repair. The aim of this review is to systematically ...analyze the literature on nasal skin reconstructions with specific detail to flap reconstructions.
A systematic literature review of nasal skin reconstruction was performed and focused on flap reconstructions. Flap reconstructions were stratified based on defect size, nasal subunit, and reconstruction type. Complication rates (CRs) and patient outcomes were also assessed.
A total of 176 articles (11,370 patients) met the inclusion criteria. Of these, 59 articles showed various flap techniques. For defects ≤1.5 cm, every subunit had four to six options except the alar rim, which showed one option. Rotation-advancement flaps were mostly used for the nasal tip and sidewall, whereas bilobed flaps were used more for the ala and dorsum. Defects >1.5 cm were most commonly reconstructed with the forehead flap. The mean CR of flap reconstructions was 13.8%. Only 8 of the 176 articles (4.5%) reported patient satisfaction using a standardized questionnaire.
This review shows various flap reconstruction options with their corresponding CR that will help guide the surgeon in choosing reconstructive options for different nasal skin defects.
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