Nicotinamide Adenine Dinucleotide (NAD+)-Dependent Signaling in Neurological Disorders.

Significance: Nicotinamide adenine dinucleotide (NAD+) participates in redox reactions and NAD+-dependent signaling processes, which couples the enzymatic degradation of NAD+ to posttranslational modifications of proteins or the production of second messengers. Cellular NAD+ levels are dynamically controlled by synthesis and degradation, and dysregulation of this balance has been associated with acute and chronic neuronal dysfunction. Recent Advances: A decline in NAD+ has been observed during normal aging and since aging is the primary risk factor for many neurological disorders, NAD+ metabolism has become a promising therapeutic target and prolific research field in recent years. Critical Issues: In many neurological disorders, either as a primary feature or as consequence of the pathological process, neuronal damage is accompanied by dysregulated mitochondrial homeostasis, oxidative stress, or metabolic reprogramming. Modulating NAD+ availability appears to have a protective effect against such changes observed in acute neuronal damage and age-related neurological disorders. Such beneficial effects could be, at least in part, due to the activation of NAD+-dependent signaling processes. Future Directions: While in many instances the protective effect has been ascribed to the activation of sirtuins, approaches that directly test the role of sirtuins or that target the NAD+ pool in a cell-type-specific manner may be able to provide further mechanistic insight. Likewise, these approaches may afford greater efficacy to strategies aimed at harnessing the therapeutic potential of NAD+-dependent signaling in neurological disorders. Antioxid. Redox Signal. 39, 1150-1166.

Adult Neural Stem Cell Migration Is Impaired in a Mouse Model of Alzheimer's Disease.

Neurogenesis in the adult brain takes place in two neurogenic niches: the ventricular-subventricular zone (V-SVZ) and the subgranular zone. After differentiation, neural precursor cells (neuroblasts) have to move to an adequate position, a process known as neuronal migration. Some studies show that in Alzheimer's disease, the adult neurogenesis is impaired. Our main aim was to investigate some proteins involved both in the physiopathology of Alzheimer's disease and in the neuronal migration process using the APP/PS1 Alzheimer's mouse model. Progenitor migrating cells are accumulated in the V-SVZ of the APP/PS1 mice. Furthermore, we find an increase of Cdh1 levels and a decrease of Cdk5/p35 and cyclin B1, indicating that these cells have an alteration of the cell cycle, which triggers a senescence state. We find less cells in the rostral migratory stream and less mature neurons in the olfactory bulbs from APP/PS1 mice, leading to an impaired odour discriminatory ability compared with WT mice. Alzheimer's disease mice present a deficit in cell migration from V-SVZ due to a senescent phenotype. Therefore, these results can contribute to a new approach of Alzheimer's based on senolytic compounds or pro-neurogenic factors.

Twenty-three-millisecond electron spin coherence of erbium ions in a natural-abundance crystal.

Erbium ions embedded in crystals have unique properties for quantum information processing, because of their optical transition at 1.5 µm and of the large magnetic moment of their effective spin-1/2 electronic ground state. Most applications of erbium require, however, long electron spin coherence times, and this has so far been missing. Here, by selecting a host matrix with a low nuclear-spin density (CaWO4) and by quenching the spectral diffusion due to residual paramagnetic impurities at millikelvin temperatures, we obtain a 23-ms coherence time on the Er3+ electron spin transition. This is the longest Hahn echo electron spin coherence time measured in a material with a natural abundance of nuclear spins and on a magnetically sensitive transition. Our results establish Er3+:CaWO4 as a potential platform for quantum networks.

Detecting spins by their fluorescence with a microwave photon counter.

Quantum emitters respond to resonant illumination by radiating part of the absorbed energy. A component of this radiation field is phase coherent with the driving tone, whereas another component is incoherent and consists of spontaneously emitted photons, forming the fluorescence signal1. Atoms, molecules and colour centres are routinely detected by their fluorescence at optical frequencies, with important applications in quantum technology2,3 and microscopy4-7. By contrast, electron spins are usually detected by the phase-coherent echoes that they emit in response to microwave driving pulses8. The incoherent part of their radiation-a stream of microwave photons spontaneously emitted upon individual spin relaxation events-has not been observed so far because of the low spin radiative decay rate and of the lack of single microwave photon detectors (SMPDs). Here using superconducting quantum devices, we demonstrate the detection of a small ensemble of donor spins in silicon by their fluorescence at microwave frequencies and millikelvin temperatures. We enhance their radiative decay rate by coupling them to a high-quality-factor and small-mode-volume superconducting resonator9, and we connect the device output to a newly developed SMPD10 based on a superconducting qubit. In addition, we show that the SMPD can be used to detect spin echoes and that standard spin characterization measurements (Rabi nutation and spectroscopy) can be achieved with both echo and fluorescence detection. We discuss the potential of SMPD detection as a method for magnetic resonance spectroscopy of small numbers of spins.

When Does Alzheimer's Disease Really Start? The Role of Biomarkers.

(Appeared originally in Int J Mol Sci 2019, 20 5536).

Electroencephalography as a Non-Invasive Biomarker of Alzheimer's Disease: A Forgotten Candidate to Substitute CSF Molecules?

Biomarkers for disease diagnosis and prognosis are crucial in clinical practice. They should be objective and quantifiable and respond to specific therapeutic interventions. Optimal biomarkers should reflect the underlying process (pathological or not), be reproducible, widely available, and allow measurements repeatedly over time. Ideally, biomarkers should also be non-invasive and cost-effective. This review aims to focus on the usefulness and limitations of electroencephalography (EEG) in the search for Alzheimer's disease (AD) biomarkers. The main aim of this article is to review the evolution of the most used biomarkers in AD and the need for new peripheral and, ideally, non-invasive biomarkers. The characteristics of the EEG as a possible source for biomarkers will be revised, highlighting its advantages compared to the molecular markers available so far.

Is Oxidative Stress the Link Between Cerebral Small Vessel Disease, Sleep Disruption, and Oligodendrocyte Dysfunction in the Onset of Alzheimer's Disease?

Oxidative stress is an early occurrence in the development of Alzheimer's disease (AD) and one of its proposed etiologic hypotheses. There is sufficient experimental evidence supporting the theory that impaired antioxidant enzymatic activity and increased formation of reactive oxygen species (ROS) take place in this disease. However, the antioxidant treatments fail to stop its advancement. Its multifactorial condition and the diverse toxicological cascades that can be initiated by ROS could possibly explain this failure. Recently, it has been suggested that cerebral small vessel disease (CSVD) contributes to the onset of AD. Oxidative stress is a central hallmark of CSVD and is depicted as an early causative factor. Moreover, data from various epidemiological and clinicopathological studies have indicated a relationship between CSVD and AD where endothelial cells are a source of oxidative stress. These cells are also closely related to oligodendrocytes, which are, in particular, sensitive to oxidation and lead to myelination being compromised. The sleep/wake cycle is another important control in the proliferation, migration, and differentiation of oligodendrocytes, and sleep loss reduces myelin thickness. Moreover, sleep plays a crucial role in resistance against CSVD, and poor sleep quality increases the silent markers of this vascular disease. Sleep disruption is another early occurrence in AD and is related to an increase in oxidative stress. In this study, the relationship between CSVD, oligodendrocyte dysfunction, and sleep disorders is discussed while focusing on oxidative stress as a common occurrence and its possible role in the onset of AD.

Integrating pheromonal and spatial information in the amygdalo-hippocampal network.

Vomeronasal information is critical in mice for territorial behavior. Consequently, learning the territorial spatial structure should incorporate the vomeronasal signals indicating individual identity into the hippocampal cognitive map. In this work we show in mice that navigating a virtual environment induces synchronic activity, with causality in both directionalities, between the vomeronasal amygdala and the dorsal CA1 of the hippocampus in the theta frequency range. The detection of urine stimuli induces synaptic plasticity in the vomeronasal pathway and the dorsal hippocampus, even in animals with experimentally induced anosmia. In the dorsal hippocampus, this plasticity is associated with the overexpression of pAKT and pGSK3ß. An amygdalo-entorhino-hippocampal circuit likely underlies this effect of pheromonal information on hippocampal learning. This circuit likely constitutes the neural substrate of territorial behavior in mice, and it allows the integration of social and spatial information.

Is Sleep Disruption a Cause or Consequence of Alzheimer's Disease? Reviewing Its Possible Role as a Biomarker.

In recent years, the idea that sleep is critical for cognitive processing has gained strength. Alzheimer's disease (AD) is the most common form of dementia worldwide and presents a high prevalence of sleep disturbances. However, it is difficult to establish causal relations, since a vicious circle emerges between different aspects of the disease. Nowadays, we know that sleep is crucial to consolidate memory and to remove the excess of beta-amyloid and hyperphosphorilated tau accumulated in AD patients' brains. In this review, we discuss how sleep disturbances often precede in years some pathological traits, as well as cognitive decline, in AD. We describe the relevance of sleep to memory consolidation, focusing on changes in sleep patterns in AD in contrast to normal aging. We also analyze whether sleep alterations could be useful biomarkers to predict the risk of developing AD and we compile some sleep-related proposed biomarkers. The relevance of the analysis of the sleep microstructure is highlighted to detect specific oscillatory patterns that could be useful as AD biomarkers.

Hyperfine spectroscopy in a quantum-limited spectrometer.

We report measurements of electron-spin-echo envelope modulation (ESEEM) performed at millikelvin temperatures in a custom-built high-sensitivity spectrometer based on superconducting micro-resonators. The high quality factor and small mode volume (down to 0.2 pL) of the resonator allow us to probe a small number of spins, down to 5×102. We measure two-pulse ESEEM on two systems: erbium ions coupled to 183W nuclei in a natural-abundance CaWO4 crystal and bismuth donors coupled to residual 29Si nuclei in a silicon substrate that was isotopically enriched in the 28Si isotope. We also measure three- and five-pulse ESEEM for the bismuth donors in silicon. Quantitative agreement is obtained for both the hyperfine coupling strength of proximal nuclei and the nuclear-spin concentration.

When Does Alzheimer's Disease Really Start? The Role of Biomarkers.

While Alzheimer's disease (AD) classical diagnostic criteria rely on clinical data from a stablished symptomatic disease, newer criteria aim to identify the disease in its earlier stages. For that, they incorporated the use of AD's specific biomarkers to reach a diagnosis, including the identification of Aß and tau depositions, glucose hypometabolism, and cerebral atrophy. These biomarkers created a new concept of the disease, in which AD's main pathological processes have already taken place decades before we can clinically diagnose the first symptoms. Therefore, AD is now considered a dynamic disease with a gradual progression, and dementia is its final stage. With that in mind, new models were proposed, considering the orderly increment of biomarkers and the disease as a continuum, or the variable time needed for the disease's progression. In 2011, the National Institute on Aging and the Alzheimer's Association (NIA-AA) created separate diagnostic recommendations for each stage of the disease continuum-preclinical, mild cognitive impairment, and dementia. However, new scientific advances have led them to create a unifying research framework in 2018 that, although not intended for clinical use as of yet, is a step toward shifting the focus from the clinical symptoms to the biological alterations and toward changing the future diagnostic and treatment possibilities. This review aims to discuss the role of biomarkers in the onset of AD.

Obesity as a Risk Factor for Alzheimer's Disease: Implication of Leptin and Glutamate.

Obesity is known to induce leptin and insulin resistance. Leptin is a peptide hormone synthesized in adipose tissue that mainly regulates food intake. It has been shown that insulin stimulates the production of leptin when adipocytes are exposed to glucose to encourage satiety; while leptin, via a negative feedback, decreases the insulin release and enhances tissue sensitivity to it, leading to glucose uptake for energy utilization or storage. Therefore, resistance to insulin is closely related to leptin resistance. Obesity in middle age has also been related to Alzheimer's disease (AD). In recent years, the relation between impaired leptin signaling pathway and the onset of AD has been studied. In all this context the role of the blood brain barrier (BBB) is crucial. Slow excitotoxicity happens in AD due to an excess of the neurotransmitter glutamate. Since leptin has been shown to regulate N-methyl-D-aspartate (NMDA) receptors, we want to review the link between these pathological pathways, and how they are affected by other AD triggering factors and its role in the onset of AD.

Shaped pulses for transient compensation in quantum-limited electron spin resonance spectroscopy.

In high sensitivity inductive electron spin resonance spectroscopy, superconducting microwave resonators with large quality factors are employed. While they enhance the sensitivity, they also distort considerably the shape of the applied rectangular microwave control pulses, which limits the degree of control over the spin ensemble. Here, we employ shaped microwave pulses compensating the signal distortion to drive the spins faster than the resonator bandwidth. This translates into a shorter echo, with enhanced signal-to-noise ratio. The shaped pulses are also useful to minimize the dead-time of our spectrometer, which allows to reduce the wait time between successive drive pulses.

The Effectiveness of Vitamin E Treatment in Alzheimer's Disease.

Vitamin E was proposed as treatment for Alzheimer's disease many years ago. However, the effectiveness of the drug is not clear. Vitamin E is an antioxidant and neuroprotector and it has anti-inflammatory and hypocholesterolemic properties, driving to its importance for brain health. Moreover, the levels of vitamin E in Alzheimer's disease patients are lower than in non-demented controls. Thus, vitamin E could be a good candidate to have beneficial effects against Alzheimer's. However, evidence is consistent with a limited effectiveness of vitamin E in slowing progression of dementia; the information is mixed and inconclusive. The question is why does vitamin E fail to treat Alzheimer's disease? In this paper we review the studies with and without positive results in Alzheimer's disease and we discuss the reasons why vitamin E as treatment sometimes has positive results on cognition but at others, it does not.

Dynamical Coulomb blockade of shot noise.

We observe the suppression of the finite frequency shot noise produced by a voltage biased tunnel junction due to its interaction with a single electromagnetic mode of high impedance. The tunnel junction is embedded in a λ/4 resonator containing a dense SQUID array providing it with a characteristic impedance in the kΩ range and a resonant frequency tunable in the 4-6 GHz range. Such high impedance gives rise to a sizable Coulomb blockade on the tunnel junction ( 30% reduction in the differential conductance) and allows an efficient measurement of the spectral density of the current fluctuations at the resonator frequency. The observed blockade of shot noise is found in agreement with an extension of the dynamical Coulomb blockade theory.

Smart wearable systems: current status and future challenges.

OBJECTIVE: Extensive efforts have been made in both academia and industry in the research and development of smart wearable systems (SWS) for health monitoring (HM). Primarily influenced by skyrocketing healthcare costs and supported by recent technological advances in micro- and nanotechnologies, miniaturisation of sensors, and smart fabrics, the continuous advances in SWS will progressively change the landscape of healthcare by allowing individual management and continuous monitoring of a patient's health status. Consisting of various components and devices, ranging from sensors and actuators to multimedia devices, these systems support complex healthcare applications and enable low-cost wearable, non-invasive alternatives for continuous 24-h monitoring of health, activity, mobility, and mental status, both indoors and outdoors. Our objective has been to examine the current research in wearable to serve as references for researchers and provide perspectives for future research. METHODS: Herein, we review the current research and development of and the challenges facing SWS for HM, focusing on multi-parameter physiological sensor systems and activity and mobility measurement system designs that reliably measure mobility or vital signs and integrate real-time decision support processing for disease prevention, symptom detection, and diagnosis. For this literature review, we have chosen specific selection criteria to include papers in which wearable systems or devices are covered. RESULTS: We describe the state of the art in SWS and provide a survey of recent implementations of wearable health-care systems. We describe current issues, challenges, and prospects of SWS. CONCLUSION: We conclude by identifying the future challenges facing SWS for HM.

Behaviour monitoring of the elderly by trajectories analysis.

This paper presents a way to keep the elderly autonomous in their daily activities. The principle is to monitor their behaviour and more specifically their trajectories of movement in the living area. Two methods have been developed and compared: supervised and unsupervised classification. Some results from data collected in a long-stay setting are shown. They highlight the possibility of determining normal trajectory classes, and by comparison with the usual situation, to trigger alarms when the trajectories are unusual.

Smart homes - current features and future perspectives.

In an ageing world, maintaining good health and independence for as long as possible is essential. Instead of hospitalization or institutionalization, the elderly and disabled can be assisted in their own environment 24h a day with numerous 'smart' devices. The concept of the smart home is a promising and cost-effective way of improving home care for the elderly and the disabled in a non-obtrusive way, allowing greater independence, maintaining good health and preventing social isolation. Smart homes are equipped with sensors, actuators, and/or biomedical monitors. The devices operate in a network connected to a remote centre for data collection and processing. The remote centre diagnoses the ongoing situation and initiates assistance procedures as required. The technology can be extended to wearable and in vivo implantable devices to monitor people 24h a day both inside and outside the house. This review describes a selection of projects in developed countries on smart homes examining the various technologies available. Advantages and disadvantages, as well as the impact on modern society, are discussed. Finally, future perspectives on smart homes as part of a home-based health care network are presented.

PROSAFE-extended, a telemedicine platform to contribute to medical diagnosis.

A single elderly, dependent subject was monitored for a period of three months. Data were collected from 12 sensors in his apartment. We investigated new criteria for diagnosing abnormal events with more reliability. Initial results suggested that six diagnostic functions could be achieved using only presence sensors. These were: immobility detection; the level of agitation; the speed of motion in chosen areas; the distance covered; the time spent in given areas of the apartment; and the activities of getting up, going to bed and going to the toilet. The analysis was based on calculation of thresholds from past behaviour of the user for automatically defined temporal bands. Any variation in these criteria may represent a change in the subject's physical abilities and may thus allow the remote identification of potential risk.

A review of smart homes- present state and future challenges.

In the era of information technology, the elderly and disabled can be monitored with numerous intelligent devices. Sensors can be implanted into their home for continuous mobility assistance and non-obtrusive disease prevention. Modern sensor-embedded houses, or smart houses, cannot only assist people with reduced physical functions but help resolve the social isolation they face. They are capable of providing assistance without limiting or disturbing the resident's daily routine, giving him or her greater comfort, pleasure, and well-being. This article presents an international selection of leading smart home projects, as well as the associated technologies of wearable/implantable monitoring systems and assistive robotics. The latter are often designed as components of the larger smart home environment. The paper will conclude by discussing future challenges of the domain.