Exploring cognitive and biological correlates of sleep quality and their potential links with Alzheimer's disease (ALFASleep project): protocol for an observational study.

INTRODUCTION: The growing worldwide prevalence of Alzheimer's disease (AD) and the lack of effective treatments pose a dire medical challenge. Sleep disruption is also prevalent in the ageing population and is increasingly recognised as a risk factor and an early sign of AD. The ALFASleep project aims to characterise sleep with subjective and objective measurements in cognitively unimpaired middle/late middle-aged adults at increased risk of AD who are phenotyped with fluid and neuroimaging AD biomarkers. This will contribute to a better understanding of the pathophysiological mechanisms linking sleep with AD, thereby paving the way for the development of non-invasive biomarkers and preventive strategies targeting sleep. METHODS AND ANALYSIS: We will invite 200 participants enrolled in the ALFA+ (for ALzheimer and FAmilies) prospective observational study to join the ALFASleep study. ALFA+ participants are cognitively unimpaired middle-aged/late middle-aged adults who are followed up every 3 years with a comprehensive set of evaluations including neuropsychological tests, blood and cerebrospinal fluid (CSF) sampling, and MRI and positron emission tomography acquisition. ALFASleep participants will be additionally characterised with actigraphy and CSF-orexin-A measurements, and a subset (n=90) will undergo overnight polysomnography. We will test associations of sleep measurements and CSF-orexin-A with fluid biomarkers of AD and glial activation, neuroimaging outcomes and cognitive performance. In case we found any associations, we will test whether changes in AD and/or glial activation markers mediate the association between sleep and neuroimaging or cognitive outcomes and whether sleep mediates associations between CSF-orexin-A and AD biomarkers. ETHICS AND DISSEMINATION: The ALFASleep study protocol has been approved by the independent Ethics Committee Parc de Salut Mar, Barcelona (2018/8207/I). All participants have signed a written informed consent before their inclusion (approved by the same ethics committee). Study findings will be presented at national and international conferences and submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04932473.

Soundtrack of life: An fMRI study.

Most people have a soundtrack of life, a set of special musical pieces closely linked to certain biographical experiences. Autobiographical memories (AM) and music listening (ML) involve complex mental processes ruled by differentiate brain networks. The aim of the paper was to determine the way both networks interact in linked occurrences. We performed an fMRI experiment on 31 healthy participants (age: 32.4 ± 7.6, 11 men, 4 left-handers). Participants had to recall AMs prompted by music they reported to be associated with personal biographical events (LMM: linked AM-ML events). In the main control task, participants were prompted to recall emotional AMs while listening known tracks from a pool of popular music (UMM: unlinked AM-ML events). We wanted to investigate to what extent LMM network exceeded the overlap of AM and ML networks by contrasting the activation obtained in LMM versus UMM. The contrast LMM>UMM showed the areas (at P < 0.05 FWE corrected at voxel level and cluster size>20): right frontal inferior operculum, frontal middle gyrus, pars triangularis of inferior frontal gyrus, occipital superior gyrus and bilateral basal ganglia (caudate, putamen and pallidum), occipital (middle and inferior), parietal (inferior and superior), precentral and cerebellum (6, 7 L, 8 and vermis 6 and 7). Complementary results were obtained from additional control tasks. Provided part of tLMM>UMM areas might not be related to ML-AM linkage, we assessed LMM brain network by an independent component analysis (ICA) on contrast images. Results from ICA suggest the existence of a cortico-ponto-cerebellar network including left precuneus, bilateral anterior cingulum, parahippocampal gyri, frontal inferior operculum, ventral anterior part of the insula, frontal medial orbital gyri, caudate nuclei, cerebellum 6 and vermis, which might rule the ML-induced retrieval of AM in closely linked AM-ML events. This topography may suggest that the pathway by which ML is linked to AM is attentional and directly related to perceptual processing, involving salience network, instead of the natural way of remembering typically associated with default mode network.

Effects of COVID-19 Home Confinement on Mental Health in Individuals with Increased Risk of Alzheimer's Disease.

We explored the impact of the Spanish COVID-19 strict home confinement on mental health and cognition in non-infected subjects (N = 16, 60-80 years) diagnosed with subjective cognitive decline and APOEɛ3/ɛ4 carriers. Mental health was monitored for 2 months on a daily, weekly, or monthly basis, and compared to pre-confinement values. Emotional distress, anxiety, and depression scores increased to pathological threshold values during and after confinement. Those with lower mood during confinement experienced a decline in their mood after confinement. Cognition did not change. These preliminary results suggest that mental health consequences of corona measures in preclinical stages of Alzheimer's disease should be further evaluated.

The INO80 complex activates the transcription of S-phase genes in a cell cycle-regulated manner.

Chromatin structure is an essential factor in the proper regulation of DNA repair, DNA replication and transcription. The INO80 complex and the SWR complex have been shown to play a fundamental role in transcription regulation through remodeling chromatin at specific genes and loci. Here, we report that the Schizosaccharomyces pombe INO80 complex physically interacts with the mlui-binding factor (MBF) complex. Furthermore, we are able to detect the INO80 complex in MBF-regulated promoters. Binding of INO80 to these genes is cell cycle regulated, with a maximum binding preceding their transcription and accumulation of their mRNAs. In fact, the INO80 complex is required to fully and timely activate the transcription of these genes. We also show that the accumulation of acetylated H2A.Z at the +1 nucleosome is cell cycle regulated. Cells in which H2A.Z acetylation is abolished still have some cell cycle-regulated transcription of MBF-dependent genes, although to a much lesser extent.

Decreased glutathione levels and altered antioxidant defense in an animal model of schizophrenia: long-term effects of perinatal phencyclidine administration.

Perinatal phencyclidine (PCP) administration to rodents represents one of the more compelling animal models of schizophrenia. There is evidence that decreased glutathione (GSH) levels and oxidative stress mediated through free radicals in the central nervous system are involved in the pathophysiology of this disease. Limited data are available on the role of free radicals in neurotoxicity induced by NMDA-receptor antagonists. The aim of this study was to elucidate the long-term effects of perinatal phencyclidine administration on superoxide dismutase (SOD), catalase (CAT), gamma-glutamyl cisteine ligase (gamma-GCL), glutathione peroxidase (GPx), glutathione reductase (GR) and levels of lipid peroxides as well as GSH content. The Wistar rats were treated on the 2nd, 6th, 9th and 12th postnatal (PN) days with either phencyclidine (10mg/kg) or saline and sacrificed on PN70. The activities of antioxidant enzymes and level of lipid peroxides and GSH were determined in dorsolateral frontal cortex (dlFC), hippocampus, thalamus and caudate nucleus. Expression of SOD1 and SOD2 was determined by immunoblot. Region-specific changes of the measured parameters were observed. Decreased content of reduced GSH and altered activities of GR, GPx and SOD were determined in dlFC. In hippocampus, reduced GSH content and decreased activities of GPx and GR were accompanied with increased activity of gamma-GCL and increased level of lipid peroxides. gamma-GCL and GSH content were also decreased in caudate nucleus, while in thalamus major findings are increased levels of lipid peroxides and GR activity and decreased gamma-GCL activity. It can be concluded that perinatal PCP administration produces long-term alteration of antioxidant defense. Further studies are necessary in order to clarify role of redox dysregulation in the pathogenetic mechanism of schizophrenia.