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.

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 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.

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.

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.

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.

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.

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

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

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.

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.

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.

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.

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.

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.

Assessment of activity of elderly people using a home monitoring system.

A multisensor home monitoring system has been developed within a telecare project to help elderly people by observing mobility changes indicative of abnormal events. This paper assesses the motor activity and the relationships between activity measures using the system. The motor activity data (in bed, getting up, getting out, visiting the toilets) are analysed from a statistical perspective to assess changes in occurrence, time and duration. Changes in activity data and correlations between in-bed restlessness and getting up variables show interesting trends in the behavior of elderly people and can be used by the system as a predictive tool in abnormal situations. The objective of the telecare project is to build an abnormal event diagnosis system to help elderly people living alone.

Validation of a remote monitoring system for the elderly: application to mobility measurements.

The aim of this paper is to introduce a smart tool for the assessment of the mobility of patient with motor disorders and to evaluate its performance through some initial experiments. These experiments are based on a system which is composed of sensors connected to a Personal Computer (PC) using data acquisition cards and a communication network. The PC includes a data acquisition and processing software. This system has been installed in a patient's housing (a bedroom and a washroom) in a long-stay setting. Pre-established travel and activity (going to bed, getting up, visiting the washroom em leader ) patterns of patient in the housing including their duration have been defined by physicians for the experiments. A volunteer participated in the experiments and the results of his mobility obtained by the data processing software were compared with his real mobility. An agreement was found between the proposed assessment system and the experiments, thereby validating functioning of the whole system. Then, the system has been used to monitor a patient over a period of 39 nights. Again there is a good agreement between the characteristics derived from the system and the findings of the caring staff in charge of the patient's routine night monitoring. Data collected during 24 consecutive hours have been used to identify and characterise the patient's whole day mobility. This study paves the way for a new assessment system of the mobility of patient thus allowing the follow up of patients suffering from dementia and to study their significant mobility changes over time by introducing an indicator of mobility which can be used to assess their motor behavioural disorders.

Assessment of elderly mobility using a remote multisensor monitoring system.

This study was designed to estimate the changes of different activities (going to bed, getting up, visiting washroom) of elderly as an index of mobility. The different values in time and number of the different activities were obtained from 16 elderly suffering from Alzheimer's disease in a hospital for short period observation adding up 4 months of observation data. Significant agreement in different activities (going to bed, getting up, visiting washroom, wandering) among the two measurements by multisensor system and by nursing staff notation was found. As interesting results, the follow up of a patient is shown for 13 consecutive nights. These studies show the potential usefulness of assessment of night activities as an index of mobility, mirror of motor behaviour. Due to minor error, the precise mobility index could not be observed, motor behaviour could simply be evaluated.