Search

Abstract Background Index measures for health-related quality of life (HRQoL) quantify the desirability (utility) of a certain health state. The commonly used generic index measure, e.g. EuroQol: EQ-5D, may underestimate relevant areas of specific diseases, resulting in lower validity. Disease-specific index measures on the other hand combine disease-specificity and quantification of perceived quality on several health domains of a certain disease into one single figure. These instruments have been developed for several diseases, but a dementia-specific HRQoL index instrument was not yet available. Facing the increasing individual and societal burden of dementia, specific HRQoL values with metric characteristics are especially useful because they will provide vital information for health outcome research and economic evaluations. Aims of the study To develop and validate the prototype of a dementia-specific HRQoL index measure: Dementia Quality of life Instrument (DQI), as the first step towards valuation of the dementia health state. Methods For development of the DQI we created a conceptual framework based on a review of the literature, qualitative interviews with people with dementia and their carers, expert opinion and team discussion. To assess validity we undertook a survey under 241 dementia professionals. Measurements consisted of ranking (1–5) and rating (1–10) of 5 dementia-specific DQI domains (memory, orientation, independence, social activities and mood) and simultaneously rating of 9 DQI-derived health states on a visual analogue scale (VAS). We also performed a cross-sectional study in a large sample of people with very mild to moderate dementia and their caregivers (N = 145) to assess feasibility and concurrent validity. In addition, caregivers valued 10 DQI and 10 EQ-5D + C derived health states of the patient simultaneously on the same VAS. Setting: outpatient clinics, nursing homes and patient residences. Results All professionals judged the selected DQI domains to be relevant. Differences in ranking and rating behaviors were small. Mood was ranked (≥3.3) and rated (≥8.2) as most, orientation as least important (rank ≤2.6, value 7.5) health domain for dementia. For the validation part of this study the completion rates for all domains were above 98% for patients and 100% for caregivers on patients. A priori hypothesized DQI versus QOL-AD correlations that were significant in both patients and caregivers were: memory/memory, orientation/memory, independence/physical health, social activities/energy and mood/mood. Patient/caregiver inter-rater agreement was low (K Conclusions Professionals judged all domains as relevant. The DQI prototype proved valid and feasible for patients and caregivers and is appropriate for very mild to moderate dementia. The differences in concurrent correlations with generic health status instruments imply that the dementia-specific DQI health domains indeed provide different information. The finding that patient HRQoL measured with the DQI was lower supports this notion. The new DQI shows comparable psychometric properties to the best available dementia-specific (QOL-AD) and generic (EQ-5D + C) measures. Further research is needed to generate values in the general population for each of the possible DQI states and to derive an algorithm that converts the 5 separate DQI domain scores into one single DQI Index score. Introducing the DQI Index will advance dementia-related HRQoL measurement by overcoming the shortcomings of generic and non-index instruments. This will allow more unequivocal interpretation of subjective dementia HRQoL states in dementia research.

The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease. Herein, we report on the identification of a series of orally bioavailable, small-molecule MC4R antagonists using a focused hit identification effort and the optimization of these antagonists to provide clinical candidate 23 . Introduction of a spirocyclic conformational constraint allowed for simultaneous optimization of MC4R potency and ADME attributes while avoiding the production of hERG active metabolites observed in early series leads. Compound 23 is a potent and selective MC4R antagonist with robust efficacy in an aged rat model of cachexia and has progressed into clinical trials.

The valence of memories is malleable because of their intrinsic reconstructive property. This property of memory has been used clinically to treat maladaptive behaviours. However, the neuronal mechanisms and brain circuits that enable the switching of the valence of memories remain largely unknown. Here we investigated these mechanisms by applying the recently developed memory engram cell- manipulation technique. We labelled with channelrhodopsin-2 (ChR2) a population of cells in either the dorsal dentate gyrus (DG) of the hippocampus or the basolateral complex of the amygdala (BLA) that were specifically activated during contextual fear or reward conditioning. Both groups of fear-conditioned mice displayed aversive light-dependent responses in an optogenetic place avoidance test, whereas both DG- and BLA-labelled mice that underwent reward conditioning exhibited an appetitive response in an optogenetic place preference test. Next, in an attempt to reverse the valence of memory within a subject, mice whose DG or BLA engram had initially been labelled by contextual fear or reward conditioning were subjected to a second conditioning of the opposite valence while their original DG or BLA engram was reactivated by blue light. Subsequent optogenetic place avoidance and preference tests revealed that although the DG-engram group displayed a response indicating a switch of the memory valence, the BLA-engram group did not. This switch was also evident at the cellular level by a change in functional connectivity between DG engram-bearing cells and BLA engram-bearing cells. Thus, we found that in the DG, the neurons carrying the memory engram of a given neutral context have plasticity such that the valence of a conditioned response evoked by their reactivation can be reversed by re-associating this contextual memory engram with a new unconditioned stimulus of an opposite valence. Our present work provides new insight into the functional neural circuits underlying the malleability of emotional memory.