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Olfaction declines with aging and appears to be a prodromal sign of cognitive decline in progressive neurodegenerative diseases. Nevertheless, very little is known about the pathophysiological changes underlying smell loss that may reflect early network dysfunction. A cross-sectional histoanatomical study was conducted on postmortem olfactory nerves of patients with increasing severity of dementia from mild cognitive impairment (MCI) to moderate and severe Alzheimer's disease. The olfactory bulbs and tracts show a prominent and progressive tauopathy in contrast to a weaker amyloid pathology localized to the glomerular region. Topological analysis of Notch signaling components reveals a transient increase in Jagged1 expression in mitral cells of the olfactory bulb of patients with MCI and a gradual decline onwards. Analysis of the olfactory tract reveals an abundance of corpora amylacea, which declines starting from the MCI stage. With the increasing severity of dementia, corpora amylacea are characterized by a gradual shift in cytoskeletal proteins, tau, MAP2 and glial fibrillary acid protein, as well as by a decrease in their Reelin and Jagged1 content. Our research indicates that the olfactory nerve undergoes early and sequential morphological and signaling alterations that correlate with the development of dementia suggesting that this structure may capture and propagate neuronal network imbalances to connected higher brain centers of the entorhinal cortex and hippocampus.

Nursing students represent an important resource both for the patients and for the company organization; however, the impact of their presence on the quality of care is still underestimated.To provide an objective assessment of the quality of care perceived by the patient admitted to hospital departments where internships are held for nursing students.A descriptive observational study was conducted, recruiting a convenience sample made up of patients hospitalized in clinical departments where internships for nursing students of La Fe Hospital in Valencia (ES) are located.75 patients out of 160 hospitalized partecipated to the survey, with a response rate equal to 46.87%. Most patients believe that nurses have careless attitudes towards them (42.9%) even though there is a noticeable emotional support from nurses perceived by patients (90.1%). The degree of relationship and information perceived by patients (96%) suggests that nurses in most cases guaranteed confidentiality and the assistance time employed (70.5%) was perceived as longer than usual, defining a high opinion of patients about the treatment received.The data showed that patients were very keen to be taken into consideration from a social and human point of view and not only from a clinical point of view, so much so that they claimed to perceive a careless attitude from nurses. Despite this, however, the perceived quality of nursing care by the patient was not affected. Regarding the presence of the trainee student, being the latter in the Spanish reality totally flanked by that of the nurse, almost in symbiosis, the degree of attention perceived by the patient in relation to the assistance provided does not vary.Introduzione: Gli studenti infermieri rappresentano una risorsa importante sia per gli assistiti che per l’organizzazione aziendale; tuttavia l’impatto della loro presenza sulla qualità assistenziale è ancora sottostimata. Obiettivo: Fornire una valutazione oggettiva della qualità assistenziale percepita dal paziente ricoverato nei reparti ospedalieri sedi di tirocinio per gli studenti infermieri. Metodo: E' stato condotto uno studio osservazionale descrittivo, arruolando un campione di convenienza composto da pazienti ricoverati nei reparti clinici sede di tirocinio per studenti infermieri dell’Ospedale La Fe di Valencia (ES). Risultati: Hanno partecipato all’indagine n. 75 pazienti sui 160 ricoverati tasso di risposta pari al 46,87%. La maggior parte dei pazienti crede che gli infermieri hanno atteggiamenti poco curanti nei loro confronti (42,9 %) anche se si nota un notevole supporto affettivo da parte degli infermieri percepito dai pazienti (90,1%). Il grado di relazione e informazione percepito dai pazienti (96%) fa intendere che gli infermieri nella maggior parte dei casi garantivano la riservatezza ed il tempo di assistenza impiegato (70,5% ) sia stato percepito come più lungo del solito definendo un’alta opinione dei pazienti circa le cure ricevute. Conclusioni: I dati hanno evidenziato che i pazienti ci tenessero molto a essere presi in considerazione dal punto di vista sociale e umano e non solo da quello clinico, tanto da affermare di percepire un atteggiamento poco curante da parte degli infermieri. Malgrado questo tuttavia la qualità percepita dal paziente dell’assistenza infermieristica non ne ha risentito. Relativamente alla presenza dello studente tirocinante, essendo quest’ultima nella realtà spagnola totalmente affiancata a quella dell’infermiere , quasi in simbiosi, non varia il grado di attenzione percepito dal paziente relativamente all’assistenza erogata.

The COVID-19 pandemic had a relevant health impact in a large part of the planet and there are several studies aimed at understanding its diffusion; however, to date, the problem has not been explored in the correctional setting, with particular concern for the Italian context.To assess and investigate the risk of exposure to COVID-19 in nurses working in the Italian prison system.A multicenter observational descriptive study was conducted, enrolling a convenience sample composed of nurses registered with SIMSPE onlus (Italian Society of Penitentiary Medicine and Health), working in any Italian prison facility at the time of the survey.204 nurses participating in the survey (response rate 49.27%). Most nurses working in prisons (92.65%) were exposed to the risk of Covid-19 virus infection, since they came directly into contact with positive patients (90.69%) and in situations where they were exposed during care procedures in which aerosol was produced by the patient (56.21%). The number of nurses who "always" complied with safety rules for prevention of infection did not differ significantly (p0.05 for each comparison) in situations involving or not involving aerosol exposure.The results highlight the relevance of these issues in the Italian prison context and the need for further investigation. The knowledge of the dimension of this phenomenon, unexplored before this study in this context, represents the first step to be able to identify organizational strategies to manage it effectively or, if possible, to prevent it.La pandemia da Covid 19 ha avuto un impatto sanitario rilevante in gran parte del pianeta e numerosi sono gli studi orientati a comprenderne la diffusione; tuttavia ad oggi il fenomeno non risulta esplorato nell’ambito penitenziario, in particolar modo nel panorama italiano.Valutare e analizzare il rischio di esposizione al COVID-19 negli infermieri operanti nel contesto carcerario italiano. Metodi: E’ stato condotto uno studio multicentrico osservazionale descrittivo, arruolando un campione di convenienza composto da infermieri iscritti alla SIMSPE onlus (Società Italiana di Medicina e Sanità Penitenziara), operanti in qualsiasi struttura carceraria italiana al momento dell’indagine.Hanno partecipato all’indagine 204 infermieri (tasso di risposta 49.27%). La maggior parte degli operatori che lavorano in ambito carcerario (92,65%) sono risultati esposti al rischio di contagio da virus Covid-19 essendo venuti a contatto direttamente con pazienti positivi (90.69%) ed in situazioni in cui sono rimasti esposti durante procedure assistenziali in cui veniva prodotto aerosol da parte dell’assistito (56.21%). Il numero di infermieri che ha rispettato “sempre” le norme di sicurezza per la prevenzione del contagio non differiva significativamente (p0.05 per ogni confronto) nelle situazioni che prevedevano o meno il contatto con aerosol.I risultati evidenziano la rilevanza del problema nel panorama carcerario italiano e la necessità di ulteriori approfondimenti. La conoscenza della dimensione di questo fenomeno, prima di questo studio inesplorato in questo contesto, rappresenta il primo passo per poter individuare strategie organizzative in grado di gestirlo efficacemente o, se possibile, prevenirlo.

Sensory capacities like smell, taste, hearing, vision decline with aging, but increasing evidence show that sensory dysfunctions are one of the early signs diagnosing the conversion from physiological to pathological brain state. Smell loss represents the best characterized sense in clinical practice and is considered as one of the first preclinical signs of Alzheimer’s and Parkinson’s disease, occurring a decade or more before the onset of cognitive and motor symptoms. Despite the numerous scientific reports and the adoption in clinical practice, the etiology of sensory damage as prodromal of dementia remains largely unexplored and more studies are needed to resolve the mechanisms underlying sensory network dysfunction. Although both cognitive and sensory domains are progressively affected, loss of sensory experience in early stages plays a major role in reducing the autonomy of demented people in their daily tasks or even possibly contributing to their cognitive decline. Interestingly, the chemosensory circuitry is devoid of a blood brain barrier, representing a vulnerable port of entry for neurotoxic species that can spread to the brain. Furthermore, the exposure of the olfactory system to the external environment make it more susceptible to mechanical injury and trauma, which can cause degenerative neuroinflammation. In this review, we will summarize several findings about chemosensory impairment signing the conversion from healthy to pathological brain aging and we will try to connect those observations to the promising research linking environmental influences to sporadic dementia. The scientific body of knowledge will support the use of chemosensory diagnostics in the presymptomatic stages of AD and other biomarkers with the scope of finding treatment strategies before the onset of the disease.

White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia.

Despite numerous studies that attempt to develop reliable animal models which reflecting the primary processes underlying neurodegeneration, very few have been widely accepted. Here, we propose a new procedure adapted from the well-known ex vivo brain slice technique, which offers a closer in vivo-like scenario than in vitro preparations, for investigating the early events triggering cell degeneration, as observed in Alzheimer's disease (AD). This variation consists of simple and easily reproducible steps, which enable preservation of the anatomical cytoarchitecture of the selected brain region and its local functionality in a physiological milieu. Different anatomical areas can be obtained from the same brain, providing the opportunity to perform multiple experiments with the treatments in question in a site-, dose-, and time-dependent manner. Potential limitations which could affect the outcomes related to this methodology are related to the conservation of the tissue, i.e., the maintenance of its anatomical integrity during the slicing and incubation steps and the section thickness, which can influence the biochemical and immunohistochemical analysis. This approach can be employed for different purposes, such as exploring molecular mechanisms involved in physiological or pathological conditions, drug screening, or dose-response assays. Finally, this protocol could also reduce the number of animals employed in behavioral studies. The application reported here has been recently described and tested for the first time on ex vivo rat brain slices containing the basal forebrain (BF), which is one of the cerebral regions primarily affected in AD. Specifically, it has been demonstrated that the administration of a toxic peptide derived from the C-terminus of acetylcholinesterase (AChE) could prompt an AD-like profile, triggering, along the antero-posterior axis of the BF, a differential expression of proteins altered in AD, such as the alpha7 nicotinic receptor (α7-nAChR), phosphorylated Tau (p-Tau), and amyloid beta (Aβ).

Despite numerous studies that attempt to develop reliable animal models which reflecting the primary processes underlying neurodegeneration, very few have been widely accepted. Here, we propose a new procedure adapted from the well-known ex vivo brain slice technique, which offers a closer in vivo-like scenario than in vitro preparations, for investigating the early events triggering cell degeneration, as observed in Alzheimer's disease (AD). This variation consists of simple and easily reproducible steps, which enable preservation of the anatomical cytoarchitecture of the selected brain region and its local functionality in a physiological milieu. Different anatomical areas can be obtained from the same brain, providing the opportunity to perform multiple experiments with the treatments in question in a site-, dose-, and time-dependent manner. Potential limitations which could affect the outcomes related to this methodology are related to the conservation of the tissue, i.e., the maintenance of its anatomical integrity during the slicing and incubation steps and the section thickness, which can influence the biochemical and immunohistochemical analysis. This approach can be employed for different purposes, such as exploring molecular mechanisms involved in physiological or pathological conditions, drug screening, or dose-response assays. Finally, this protocol could also reduce the number of animals employed in behavioral studies. The application reported here has been recently described and tested for the first time on ex vivo rat brain slices containing the basal forebrain (BF), which is one of the cerebral regions primarily affected in AD. Specifically, it has been demonstrated that the administration of a toxic peptide derived from the C-terminus of acetylcholinesterase (AChE) could prompt an AD-like profile, triggering, along the antero-posterior axis of the BF, a differential expression of proteins altered in AD, such as the alpha7 nicotinic receptor (α7-nAChR), phosphorylated Tau (p-Tau), and amyloid beta (Aβ).

Background Notch1 signaling is a cellular cascade with a fundamental role from brain development to adult brain function. Reduction in Notch1 affects synaptic plasticity, memory and olfaction. On the other hand, Notch1 overactivation after brain injury is detrimental for neuronal survival. Some familial Alzheimer’s disease (FAD) mutations in Presenilins can affect Notch1 processing/activation. Others report that Notch1 is overexpressed in sporadic Alzheimer’s disease (AD). These works indicate that imbalances in Notch1 may be implicated in AD pathophysiology. In this study, we addressed whether Notch1 alteration can be considered a hallmark of AD. Results Immunohistochemical analysis of Notch1 on cortical and hippocampal tissue from post-mortem patients indicates an accumulation of Notch1 in plaque-like structures in the brain parenchyma of subjects with sporadic AD. Further analysis shows that displaced Notch1 is associated with fibrillary tangles/plaques. Biochemical validation confirms an accumulation of Notch1 in cytosolic brain fractions. This increase in protein is not accompanied with a raise in the Notch1 targets Hes1 and Hey1. Examination of the cerebrospinal fluid (CSF) indicates that the full length and truncations of the Notch1 protein are reduced in AD patients hinting at an accumulation in the brain parenchyma. Conclusions Our research indicates that Notch1 is significantly displaced and accumulated in fibrillary structures in the susceptible hippocampal and cortical regions of sporadic AD patients. The dominant deposition of Notch1 in the brain parenchyma and its general signal reduction in neurons is consistent in all the AD patients analyzed and suggests that Notch1 may potentially be considered a novel hallmark of AD. Electronic supplementary material The online version of this article (doi:10.1186/s40478-016-0327-2) contains supplementary material, which is available to authorized users.

Notch signaling plays a crucial role in adult brain function such as synaptic plasticity, memory and olfaction. Several reports suggest an involvement of this pathway in neurodegenerative dementia. Yet, to date, the mechanism underlying Notch activity in mature neurons remains unresolved. In this work, we investigate how Notch regulates synaptic potentiation and contributes to the establishment of memory in mice. We observe that Notch1 is a postsynaptic receptor with functional interactions with the Reelin receptor, apolipoprotein E receptor 2 (ApoER2) and the ionotropic receptor, N-methyl-D-aspartate receptor (NMDAR). Targeted loss of Notch1 in the hippocampal CA fields affects Reelin signaling by influencing Dab1 expression and impairs the synaptic potentiation achieved through Reelin stimulation. Further analysis indicates that loss of Notch1 affects the expression and composition of the NMDAR but not AMPAR. Glutamatergic signaling is further compromised through downregulation of CamKII and its secondary and tertiary messengers resulting in reduced cAMP response element-binding (CREB) signaling. Our results identify Notch1 as an important regulator of mechanisms involved in synaptic plasticity and memory formation. These findings emphasize the possible involvement of this signaling receptor in dementia. Highlights In this paper, we propose a mechanism for Notch1-dependent plasticity that likely underlies the function of Notch1 in memory formation: Notch1 interacts with another important developmental pathway, the Reelin cascade. Notch1 regulates both NMDAR expression and composition. Notch1 influences a cascade of cellular events culminating in CREB activation.

Olfaction is highly conserved among species and is required for reproduction and survival. In humans, olfaction is also one of the senses that is affected with aging and is a strong predictor of neurodegenerative diseases. Thus, olfaction testing is used as a non-invasive diagnostic method to detect neurological deficits early on. In order to understand the mechanisms underlying olfactory network susceptibility, olfactory research in rodents has gained momentum in the past decade. Here, we present a very simple, time efficient and reproducible olfactory testing method of innate odor perception and sensitivity in mice without the need of any prior food or water restriction. The tests are performed in a familiar environment to the mice, require only the scents and a 2 min session of odorant exposure. The analysis is performed, post-hoc, using computer-assisted commands on ImageJ and can be, therefore, carried out from start to end by one researcher. This protocol does not require any special hardware or setup and is indicated for any laboratory interested in testing olfactory perception and sensitivity.

Genomic studies suggest an association of circadian clock genes with bipolar disorder (BD) and lithium response in humans. Therefore, we tested mice mutant in various clock genes before and after lithium treatment in the forced swim test (FST), a rodent behavioral test used for evaluation of depressive-like states. We find that expression of circadian clock components, including Per2, Cry1 and Rev-erbα, is affected by lithium treatment, and thus, these clock components may contribute to the beneficial effects of lithium therapy. In particular, we observed that Cry1 is important at specific times of the day to transmit lithium-mediated effects. Interestingly, the pathways involving Per2 and Cry1, which regulate the behavior in the FST and the response to lithium, are distinct as evidenced by the phosphorylation of GSK3β after lithium treatment and the modulation of dopamine levels in the striatum. Furthermore, we observed the co-existence of depressive and mania-like symptoms in Cry1 knock-out mice, which resembles the so-called mixed state seen in BD patients. Taken together our results strengthen the concept that a defective circadian timing system may impact directly or indirectly on mood-related behaviors.

Notch signalling plays an important role in synaptic plasticity, learning and memory functions in both Drosophila and rodents. In this paper, we report that this feature is not restricted to hippocampal networks but also involves the olfactory bulb (OB). Odour discrimination and olfactory learning in rodents are essential for survival. Notch1 expression is enriched in mitral cells of the mouse OB. These principal neurons are responsive to specific input odorants and relay the signal to the olfactory cortex. Olfactory stimulation activates a subset of mitral cells, which show an increase in Notch activity. In Notch1cKOKln mice, the loss of Notch1 in mitral cells affects the magnitude of the neuronal response to olfactory stimuli. In addition, Notch1cKOKln mice display reduced olfactory aversion to propionic acid as compared to wildtype controls. This indicates, for the first time, that Notch1 is involved in olfactory processing and may contribute to olfactory behaviour.

Notch signaling is an evolutionarily conserved pathway, which is fundamental for neuronal development and specification. In the last decade, increasing evidence has pointed out an important role of this pathway beyond embryonic development, indicating that Notch also displays a critical function in the mature brain of vertebrates and invertebrates. This pathway appears to be involved in neural progenitor regulation, neuronal connectivity, synaptic plasticity and learning/memory. In addition, Notch appears to be aberrantly regulated in neurodegenerative diseases, including Alzheimer's disease and ischemic injury. The molecular mechanisms by which Notch displays these functions in the mature brain are not fully understood, but are currently the subject of intense research. In this review, we will discuss old and novel Notch targets and molecular mediators that contribute to Notch function in the mature brain and will summarize recent findings that explore the two facets of Notch signaling in brain physiology and pathology.

Neurological disorders such as Alzheimer's disease stroke and epilepsy are currently marred by the lack of effective treatments to prevent neuronal death. Erroneous cell cycle reentry (CCR) is hypothesized to have a causative role in neurodegeneration. We show that forcing S phase reentry in cultured hippocampal neurons is sufficient to induce neurodegeneration. We found that kainic acid treatment in vivo induces erroneous CCR and neuronal death through a Notch dependent mechanism. Ablating Notch signaling in neurons provides neuroprotection against kainic acid induced neuronal death. We further show that kainic acid treatment activates Notch signaling which increases the bioavailability of CyclinD1 through Akt/GSK3ß pathway leading to aberrant CCR via activation of CyclinD1 Rb E2F1 axis. In addition pharmacological blockade of this pathway at critical steps is sufficient to confer resistance to kainic acid induced neurotoxicity in mice. Taken together our results demonstrate that excitotoxicity leads to neuronal death in a Notch dependent manner through erroneous CCR.Cell Death and Differentiation advance online publication 27 March 2015; doi:10.1038/cdd.2015.23.

Notch1 signaling is a cellular cascade with a fundamental role from brain development to adult brain function. Reduction in Notch1 affects synaptic plasticity, memory and olfaction. On the other hand, Notch1 overactivation after brain injury is detrimental for neuronal survival. Some familial Alzheimer's disease (FAD) mutations in Presenilins can affect Notch1 processing/activation. Others report that Notch1 is overexpressed in sporadic Alzheimer's disease (AD). These works indicate that imbalances in Notch1 may be implicated in AD pathophysiology. In this study, we addressed whether Notch1 alteration can be considered a hallmark of AD.Immunohistochemical analysis of Notch1 on cortical and hippocampal tissue from post-mortem patients indicates an accumulation of Notch1 in plaque-like structures in the brain parenchyma of subjects with sporadic AD. Further analysis shows that displaced Notch1 is associated with fibrillary tangles/plaques. Biochemical validation confirms an accumulation of Notch1 in cytosolic brain fractions. This increase in protein is not accompanied with a raise in the Notch1 targets Hes1 and Hey1. Examination of the cerebrospinal fluid (CSF) indicates that the full length and truncations of the Notch1 protein are reduced in AD patients hinting at an accumulation in the brain parenchyma.Our research indicates that Notch1 is significantly displaced and accumulated in fibrillary structures in the susceptible hippocampal and cortical regions of sporadic AD patients. The dominant deposition of Notch1 in the brain parenchyma and its general signal reduction in neurons is consistent in all the AD patients analyzed and suggests that Notch1 may potentially be considered a novel hallmark of AD.