An avatar-based system for identifying individuals likely to develop dementia

This paper presents work on developing an automatic dementia screening test based on patients’ ability to interact and communicate — a highly cognitively demanding process where early signs of dementia can often be detected. Such a test would help general practitioners, with no specialist knowledge, make better diagnostic decisions as current tests lack specificity and sensitivity. We investigate the feasibility of basing the test on conversations between a ‘talking head’ (avatar) and a patient and we present a system for analysing such conversations for signs of dementia in the patient’s speech and language. Previously we proposed a semi-automatic system that transcribed conversations between patients and neurologists and extracted conversation analysis style features in order to differentiate between patients with progressive neurodegenerative dementia (ND) and functional memory disorders (FMD). Determining who talks when in the conversations was performed manually. In this study, we investigate a fully automatic system including speaker diarisation, and the use of additional acoustic and lexical features. Initial results from a pilot study are presented which shows that the avatar conversations can successfully classify ND/FMD with around 91% accuracy, which is in line with previous results for conversations that were led by a neurologist

Toward the Automation of Diagnostic Conversation Analysis in Patients with Memory Complaints.

BACKGROUND: The early diagnosis of dementia is of great clinical and social importance. A recent study using the qualitative methodology of conversation analysis (CA) demonstrated that language and communication problems are evident during interactions between patients and neurologists, and that interactional observations can be used to differentiate between cognitive difficulties due to neurodegenerative disorders (ND) or functional memory disorders (FMD). OBJECTIVE: This study explores whether the differential diagnostic analysis of doctor-patient interactions in a memory clinic can be automated. METHODS: Verbatim transcripts of conversations between neurologists and patients initially presenting with memory problems to a specialist clinic were produced manually (15 with FMD, and 15 with ND). A range of automatically detectable features focusing on acoustic, lexical, semantic, and visual information contained in the transcripts were defined aiming to replicate the diagnostic qualitative observations. The features were used to train a set of five machine learning classifiers to distinguish between ND and FMD. RESULTS: The mean rate of correct classification between ND and FMD was 93% ranging from 97% by the Perceptron classifier to 90% by the Random Forest classifier.Using only the ten best features, the mean correct classification score increased to 95%. CONCLUSION: This pilot study provides proof-of-principle that a machine learning approach to analyzing transcripts of interactions between neurologists and patients describing memory problems can distinguish people with neurodegenerative dementia from people with FMD

The Vasopressin Receptor 2 Mutant R137L Linked to the Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) Signals through an Alternative Pathway that Increases AQP2 Membrane Targeting Independently of S256 Phosphorylation

NSIAD is a rare X-linked condition, caused by activating mutations in the AVPR2 gene coding for the vasopressin V2 receptor (V2R) associated with hyponatremia, despite undetectable plasma vasopressin levels. We have recently provided in vitro evidence that, compared to V2R-wt, expression of activating V2R mutations R137L, R137C and F229V cause a constitutive redistribution of the AQP2 water channel to the plasma membrane, higher basal water permeability and significantly higher basal levels of p256-AQP2 in the F229V mutant but not in R137L or R137C. In this study, V2R mutations were expressed in collecting duct principal cells and the associated signalling was dissected. V2R-R137L and R137C mutants had significantly higher basal pT269-AQP2 levels -independently of S256 and PKA-which were reduced to control by treatment with Rho kinase (ROCK) inhibitor. Interestingly, ROCK activity was found significantly higher in V2R-R137L along with activation of the Gα12/13-Rho-ROCK pathway. Of note, inhibition of ROCK reduced the basal elevated osmotic water permeability to control. To conclude, our data demonstrate for the first time that the gain-of-function mutation of the V2R, R137L causing NSIAD, signals through an alternative PKA-independent pathway that increases AQP2 membrane targeting through ROCK-induced phosphorylation at S/T269 independently of S256 of AQP2

Liquid state properties from first principles DFT calculations: Static properties

In order to test the Vibration-Transit (V-T) theory of liquid dynamics, ab initio density functional theory (DFT) calculations of thermodynamic properties of Na and Cu are performed and compared with experimental data. The calculations are done for the crystal at T = 0 and T_m, and for the liquid at T_m. The key theoretical quantities for crystal and liquid are the structural potential and the dynamical matrix, both as function of volume. The theoretical equations are presented, as well as details of the DFT computations. The properties compared with experiment are the equilibrium volume, the isothermal bulk modulus, the internal energy and the entropy. The agreement of theory with experiment is uniformly good. Our primary conclusion is that the application of DFT to V-T theory is feasible, and the resulting liquid calculations achieve the same level of accuracy as does ab initio lattice dynamics for crystals. Moreover, given the well established reliability of DFT, the present results provide a significant confirmation of V-T theory itself.Comment: 9 pages, 3 figures, 5 tables, edited to more closely match published versio

Data augmentation using generative networks to identify dementia

Data limitation is one of the most common issues in training machine learning classifiers for medical applications. Due to ethical concerns and data privacy, the number of people that can be recruited to such experiments is generally smaller than the number of participants contributing to non-healthcare datasets. Recent research showed that generative models can be used as an effective approach for data augmentation, which can ultimately help to train more robust classifiers sparse data domains. A number of studies proved that this data augmentation technique works for image and audio data sets. In this paper, we investigate the application of a similar approach to different types of speech and audio-based features extracted from interactions recorded with our automatic dementia detection system. Using two generative models we show how the generated synthesized samples can improve the performance of a DNN based classifier. The variational autoencoder increased the F-score of a four-way classifier distinguishing the typical patient groups seen in memory clinics from 58% to around 74%, a 16% improvement

Olive Leaf Extract (OLE) impaired vasopressin-induced aquaporin-2 trafficking through the activation of the calcium-sensing receptor

Vasopressin (AVP) increases water permeability in the renal collecting duct through the regulation of aquaporin-2 (AQP2) trafficking. Several disorders, including hypertension and inappropriate antidiuretic hormone secretion (SIADH), are associated with abnormalities in water homeostasis. It has been shown that certain phytocompounds are beneficial to human health. Here, the effects of the Olive Leaf Extract (OLE) have been evaluated using in vitro and in vivo models. Confocal studies showed that OLE prevents the vasopressin induced AQP2 translocation to the plasma membrane in MCD4 cells and rat kidneys. Incubation with OLE decreases the AVP-dependent increase of the osmotic water permeability coefficient (Pf). To elucidate the possible effectors of OLE, intracellular calcium was evaluated. OLE increases the intracellular calcium through the activation of the Calcium Sensing Receptor (CaSR). NPS2143, a selective CaSR inhibitor, abolished the inhibitory effect of OLE on AVP-dependent water permeability. In vivo experiments revealed that treatment with OLE increases the expression of the CaSR mRNA and decreases AQP2 mRNA paralleled by an increase of the AQP2-targeting miRNA-137. Together, these findings suggest that OLE antagonizes vasopressin action through stimulation of the CaSR indicating that this extract may be beneficial to attenuate disorders characterized by abnormal CaSR signaling and affecting renal water reabsorption

In vivo treatment with calcilytic of CaSR knock-in mice ameliorates renal phenotype reversing downregulation of the vasopressin-AQP2 pathway

Abstract: High concentrations of urinary calcium counteract vasopressin action via the activation of the Calcium-Sensing Receptor (CaSR) expressed in the luminal membrane of the collecting duct cells, which impairs the trafficking of aquaporin-2 (AQP2). In line with these findings, we provide evidence that, with respect to wild-type mice, CaSR knock-in (KI) mice mimicking autosomal dominant hypocalcaemia, display a significant decrease in the total content of AQP2 associated with significantly higher levels of AQP2 phosphorylation at Ser261, a phosphorylation site involved in AQP2 degradation. Interestingly, KI mice also had significantly higher levels of phosphorylated p38MAPK, a downstream effector of CaSR and known to phosphorylate AQP2 at Ser261. Moreover, ATF1 phosphorylated at Ser63, a transcription factor downstream of p38MAPK, was significantly higher in KI. In addition, KI mice had significantly higher levels of AQP2-targeting miRNA137 consistent with a post-transcriptional downregulation of AQP2. In vivo treatment of KI mice with the calcilytic JTT-305, a CaSR antagonist, increased AQP2 expression and reduced AQP2-targeting miRNA137 levels in KI mice. Together, these results provide direct evidence for a critical role of CaSR in impairing both short-term vasopressin response by increasing AQP2-pS261, as well as AQP2 abundance, via the p38MAPK-ATF1-miR137 pathway. (Figure presented.). Key points: Calcium-Sensing Receptor (CaSR) activating mutations are the main cause of autosomal dominant hypocalcaemia (ADH) characterized by inappropriate renal calcium excretion leading to hypocalcaemia and hypercalciuria. Current treatments of ADH patients with parathyroid hormone, although improving hypocalcaemia, do not improve hypercalciuria or nephrocalcinosis. In vivo treatment with calcilytic JTT-305/MK-5442 ameliorates most of the ADH phenotypes of the CaSR knock-in mice including hypercalciuria or nephrocalcinosis and reverses the downregulation of the vasopressin-sensitive aquaporin-2 (AQP2) expression, providing direct evidence for a critical role of CaSR in impairing vasopressin response. The beneficial effect of calcilytic in reducing the risk of renal calcification may occur in a parathyroid hormone-independent action through vasopressin-dependent inhibition of cAMP synthesis in the thick ascending limb and in the collecting duct. The amelioration of most of the abnormalities in calcium metabolism including hypercalciuria, renal calcification, and AQP2-mediated osmotic water reabsorption makes calcilytic a good candidate as a novel therapeutic agent for ADH

Investigating Dementia via a multicompartmental poroelastic model of parenchymal tissue

In this paper, a workflow within the VPH-DARE@IT Clinical Research Platform is presented. This is used to model the biomechanical behaviour of perfused brain tissue. This workflow features a 3D multicompartmental poroelastic framework, patient-specific brain anatomy representations and continuous waveforms of internal carotid and vertebral arteries, which are used as a means of personalizing the boundary conditions that feed the arterial compartment of the in-house poroelastic solver. Results are shown comparing CSF/ISF clearance and accumulation in two males of similar age, both are non-smokers, however one is more active and is diagnosed with MCI and experiences less sleep