Locus Coeruleus Magnetic Resonance Imaging in Neurological Diseases

Locus coeruleus (LC) is the main noradrenergic nucleus of the brain, and its degeneration is considered to be key in the pathogenesis of neurodegenerative diseases. In the last 15 years,MRI has been used to assess LC in vivo, both in healthy subjects and in patients suffering from neurological disorders. In this review, we summarize the main findings of LC-MRI studies, interpreting them in light of preclinical and histopathological data, and discussing its potential role as diagnostic and experimental tool

Polystyrene microplastics increase microbial release of marine Chromophoric Dissolved Organic Matter in microcosm experiments

About 5 trillion plastic particles are present in our oceans, from the macro to the micro size. Like any other aquatic particulate, plastics and microplastics can create a micro-environment, within which microbial and chemical conditions differ significantly from the surrounding water. Despite the high and increasing abundance of microplastics in the ocean, their influence on the transformation and composition of marine organic matter is largely unknown. Chromophoric dissolved organic matter (CDOM) is the photo-reactive fraction of the marine dissolved organic matter (DOM) pool. Changes in CDOM quality and quantity have impacts on marine microbial dynamics and the underwater light environment. One major source of CDOM is produced by marine bacteria through their alteration of pre-existing DOM substrates. In a series of microcosm experiments in controlled marine conditions, we explored the impact of microplastics on the quality and quantity of microbial CDOM. In the presence of microplastics we observed an increased production of CDOM with changes in its molecular weight, which resulted from either an increased microbial CDOM production or an enhanced transformation of DOM from lower to higher molecular weight CDOM. Our results point to the possibility that marine microplastics act as localized hot spots for microbial activity, with the potential to influence marine carbon dynamic

Regional AT-8 reactive tau species correlate with intracellular Aβ levels in cases of low AD neuropathologic change

The amyloid cascade hypothesis states that Aβ aggregates induce pathological changes in tau, leading to neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the spatio-temporal divide between plaques and NFTs. This has been addressed by the inclusion of soluble Aβ and tau species in the revised amyloid cascade hypothesis. Nevertheless, despite the potential for non-plaque Aβ to contribute to tau pathology, few studies have examined relative correlative strengths between total Aβ, plaque Aβ and intracellular Aβ with tau pathology within a single tissue cohort. Employing frozen and fixed frontal cortex grey and white matter tissue from non-AD controls (Con; n = 39) and Alzheimer’s disease (AD) cases (n = 21), biochemical and immunohistochemical (IHC) measures of Aβ and AT-8 phosphorylated tau were assessed. Biochemical native-state dot blots from crude tissue lysates demonstrated robust correlations between total Aβ and AT-8 tau, when considered as a combined cohort (Con and AD) and when as Con and AD cases, separately. In contrast, no associations between Aβ plaques and AT-8 were reported when using IHC measurements in either Con or AD cases. However, when intracellular Aβ was measured via the Aβ specific antibody MOAB-2, a correlative relationship with AT-8 tau was reported in non-AD controls but not in AD cases. Collectively the data suggests that accumulating intracellular Aβ may influence AT-8 pathology, early in AD-related neuropathological change. Despite the lower levels of phospho-tau and Aβ in controls, the robust correlative relationships observed suggest a physiological association of Aβ production and tau phosphorylation, which may be modified during disease. This study is supportive of a revised amyloid cascade hypothesis and demonstrates regional associative relationships between tau pathology and intracellular Aβ, but not extracellular Aβ plaques

Post-mortem AT-8 reactive tau species correlate with non-plaque Aβ levels in the frontal cortex of non-AD and AD brains

The amyloid cascade hypothesis states that Aβ and its aggregates induce pathological changes in tau, leading to formation of neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the temporo-spatial divide between plaques and NFTs. This has been addressed by the inclusion of soluble species of Aβ and tau in the revised amyloid cascade hypothesis, however, the demonstration of a correlative relationship between Aβ and tau burden in post-mortem human tissue has remained elusive. Employing frozen and fixed frontal cortex grey and associated white matter tissue from non-AD controls (Con; n=39) and Alzheimer’s diseases (AD) cases (n=21), biochemical and immunohistochemical measures of Aβ and AT-8 phosphorylated tau were assessed. Native-state dot-blot from crude tissue lysates demonstrated robust correlations between intraregional Aβ and AT-8 tau, such increases in Aβ immunoreactivity conferred increases in AT-8 immunoreactivity, both when considered across the entire cohort as well as separately in Con and AD cases. In contrast, no such association between Aβ plaques and AT-8 were reported when using immunohistochemical measurements. However, when using the non-amyloid precursor protein cross reactive MOAB-2, antibody to measure intracellular Aβ within a subset of cases, a similar correlative relationship with AT-8 tau as that observed in biochemical analysis was observed. Collectively our data suggests that accumulating intracellular Aβ may influence AT-8 pathology. Despite the markedly lower levels of phospho-tau in non-AD controls correlative relationships between AT-8 phospho-tau and Aβ as measured in both biochemical and immunohistochemical assays were more robust in non-AD controls, suggesting a physiological association of Aβ production and tau phosphorylation, at least within the frontal cortex. Such interactions between regional Aβ load and phospho-tau load may become modified with disease potentially, as a consequence of interregional tau seed propagation, and thus may diminish the linear relationship observed between Aβ and phospho-tau in non-AD controls. This study provides evidence supportive of the revised amyloid cascade hypothesis, and demonstrates an associative relationship between AT-8 tau pathology and intracellular Aβ but not extracellular Aβ plaques

beta-Secretase1 biological markers for Alzheimer's disease : state-of-art of validation and qualification

beta -Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodily fluids, are promising candidate biological markers for guidance in clinical trials investigating BACE1 inhibitors to halt or delay the dysregulation of the amyloid-beta pathway in Alzheimer's disease (AD). A robust body of evidence demonstrates an association between cerebrospinal fluid/blood BACE1 biomarkers and core pathophysiological mechanisms of AD, such as brain protein misfolding and aggregration, neurodegeneration, and synaptic dysfunction.In pharmacological trials, BACE1 candidate biomarkers may be applied to a wide set of contexts of use (CoU), including proof of mechanism, dose-finding, response and toxicity dose estimation. For clinical CoU, BACE1 biomarkers show good performance for prognosis and disease prediction.The roadmap toward validation and qualification of BACE1 biomarkers requires standardized pre-analytical and analytical protocols to reduce inter-site variance that may have contributed to inconsistent results.BACE1 biomarker-drug co-development programs, including biomarker-guided outcomes and endpoints, may support the identification of sub-populations with a higher probability to benefit from BACE1 inhibitors with a reduced risk of adverse effects, in line with the evolving precision medicine paradigm

Pharmacokinetic Interactions of Clinical Interest Between Direct Oral Anticoagulants and Antiepileptic Drugs

Direct oral anticoagulants (DOACs), namely apixaban, dabigatran, edoxaban, and rivaroxaban are being increasingly prescribed among the general population, as they are considered to be associated to lower bleeding risk than classical anticoagulants, and do not require coagulation monitoring. Likewise, DOACs are increasingly concomitantly prescribed in patients with epilepsy taking, therefore, antiepileptic drugs (AEDs), above all among the elderly. As a result, potential interactions may cause an increased risk of DOAC-related bleeding or a reduced antithrombotic efficacy. The objective of the present review is to describe the pharmacokinetic interactions between AEDs and DOACs of clinical relevance. We observed that there are only few clinical reports in which such interactions have been described in patients. More data are available on the pharmacokinetics of both drugs classes which allow speculating on their potential interactions. Older AEDs, acting on cytochrome P450 isoenzymes, and especially on CYP3A4, such as phenobarbital, phenytoin, and carbamazepine are more likely to significantly reduce the anticoagulant effect of DOACs (especially rivaroxaban, apixaban, and edoxaban). Newer AEDs not affecting significantly CYP or P-gp, such as lamotrigine, or pregabalin are not likely to affect DOACs efficacy. Zonisamide and lacosamide, which do not affect significantly CYP activity in vitro, might have a quite safe profile, even though their effects on P-gp are not well-known, yet. Levetiracetam exerts only a potential effect on P-gp activity, and thus it might be safe, as well. In conclusion, there are only few case reports and limited evidence on interactions between DOACs and AEDs in patients. However, the overall evidence suggests that the interaction between these drug classes might be of high clinical relevance and therefore further studies in larger patients' cohorts are warranted for the future in order to better clarify their pharmacokinetic and define the most appropriate clinical behavior

Enrichment of CD56dimKIR+CD57+ highly cytotoxic NK cells in tumor infiltrated lymph nodes of melanoma patients

An important checkpoint in the progression of melanoma is the metastasis to lymph nodes. Here, to investigate the role of lymph node NK cells in disease progression, we analyze frequency, phenotype and functions of NK cells from tumor-infiltrated (TILN) and tumor-free ipsilateral lymph nodes (TFLN) of the same patients. We show an expansion of CD56dimCD57dimCD69+CCR7+KIR+ NK cells in TILN. TILN NK cells display robust cytotoxic activity against autologous melanoma cells. In the blood of metastatic melanoma patients the frequency of NK cells expressing the receptors for CXCL8 receptor is increased compared to healthy subjects, and blood NK cells also express the receptors for CCL2 and IL6. These factors are produced in high amount in TILN and in vitro switch the phenotype of blood NK cells from healthy donors to the phenotype associated with TILN. Our data suggest that the microenvironment of TILN generates and/or recruits a particularly effective NK cell subset

A MSFD complementary approach for the assessment of pressures, knowledge and data gaps in Southern European Seas : the PERSEUS experience

PERSEUS project aims to identify the most relevant pressures exerted on the ecosystems of the Southern European Seas (SES), highlighting knowledge and data gaps that endanger the achievement of SES Good Environmental Status (GES) as mandated by the Marine Strategy Framework Directive (MSFD). A complementary approach has been adopted, by a meta-analysis of existing literature on pressure/impact/knowledge gaps summarized in tables related to the MSFD descriptors, discriminating open waters from coastal areas. A comparative assessment of the Initial Assessments (IAs) for five SES countries has been also independently performed. The comparison between meta-analysis results and IAs shows similarities for coastal areas only. Major knowledge gaps have been detected for the biodiversity, marine food web, marine litter and underwater noise descriptors. The meta-analysis also allowed the identification of additional research themes targeting research topics that are requested to the achievement of GES. 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license.peer-reviewe

Studio in vivo del nucleo noradrenergico Locus Coeruleus in pazienti con decadimento cognitivo lieve, demenza di Alzheimer e in soggetti sani

Premessa: la malattia di Alzheimer (AD) è la più comune forma di demenza neurodegenerativa non vascolare. Per quanto numerosi elementi dei processi patogenetici e fisiopatologici che la caratterizzano siano stati individuati, il quadro complessivo non è ancora del tutto chiaro, e ciò limita, almeno in parte, la progettazione di trattamenti che possano prevenire lo sviluppo dell’AD in soggetti a rischio. Il coinvolgimento del nucleo pontino noradrenergico Locus Coeruleus (LC) nell’AD è noto sin dagli anni ’60 del XX secolo, ma solo recentemente la compromissione di tale nucleo è stata ipotizzata da vari ricercatori essere centrale fin dalle fasi precoci della patogenesi dell’AD. Tale ipotesi noradrenergica ha potenziali importanti implicazioni dal punto di vista fisiopatologico, diagnostico, e, in prospettiva, terapeutico. Obiettivi: valutare parametri ascrivibili al LC in vivo nella popolazione sana e in soggetti con declino cognitivo AD-legato. Metodi: il LC è stato studiato utilizzando un software di analisi semiautomatico applicato a sequenze specifiche T1-pesate acquisite con RMN 3 Tesla (LC-RMN), sfruttando il segnale neuromelanina-dipendente, su una popolazione divisa in tre gruppi (soggetti di controllo sani, pazienti con Mild Cognitive Impairment – MCI – e pazienti con AD) e valutata con test neuropsicologici formali. I risultati sono poi stati analizzati statisticamente, per mettere in luce differenze significative e correlazioni. Risultati: nel gruppo dei controlli, si è rivelata una correlazione, modesta ma presente, tra i parametri LC-RMN e l’invecchiamento. Inoltre sono state riscontrate differenze significative di volume del nucleo e intensità di segnale nei pazienti AD rispetto ai soggetti sani. Conclusioni: l’analisi semiautomatica di LC-RMN si è mostrata essere un potenziale utile metodo d’indagine del LC in vivo e ha prodotto risultati promettenti, che consentono di ipotizzarne un futuro utilizzo come utile parametro diagnostico. Tali risultati, inoltre, consentono speculazioni sul ruolo fisiopatologico del LC nella patogenesi dell’AD e sulle potenziali implicazioni terapeutiche di tale coinvolgimento, in linea con quanto riportato nella letteratura attuale

Locus Coeruleus Magnetic Resonance Imaging in Alzheimer's Disease

The Locus Coeruleus (LC) is the main noradrenergic nucleus (NA) of the Central Nervous System (CNS). This tiny and tube-shaped nucleus is stretched below and along the floor of the fourth ventricle, in the pons, and it provides the NA innervation for the whole cortical mantle and for virtually all the subcortical structures – with the only exception of basal ganglia. LC is a key part of the Ascending Reticular Activating System (ARAS), promoting wake and being inhibited during sleep. It is also involved in the neuronal networks of attention and orientation as well as those of memory and learning. LC impairment has been associated with several cognitive and behavioral alterations, both in animal models and humans, across all their lifespan. In Alzheimer's Disease (AD), the most common form of degenerative dementia, the degeneration of the LC is now a well-documented fact. Moreover, recent pathological and radiological data point to structural alteration of the LC as one of the earliest features of the AD course, and experimental studies support a possible pathogenetic role of subsequent NA denervation. In fact, the LC-NA system plays neuroprotective roles through numerous mechanisms, mainly promoting the expression of growth factors, preserving neurovascular unit homeostasis, and regulating glial cell activity. The failure of all these neurobiological pathways has been observed in AD and a possible causal link with LC dysfunction is suspected. In line with this, it could be hypothesized that a higher degree of degeneration of the LC may correspond to more severe AD pathology, and thus a more rapid clinical progression. In other words, individuals with cognitive impairment whose LC-NA system is more markedly disrupted should show a more rapid progression from the prodromal phase of AD (clinically identified as Mild Cognitive Impairment - MCI) to fully developed dementia. To explore this hypothesis, in the study here reported, a cohort of MCI subjects was submitted to Magnetic Resonance Imaging (MRI), using a specific neuromelanin-sensitive sequence that allowed the in vivo evaluation of LC. They were then followed up for 2.5 years to monitor their clinical evolution. Data analysis showed that MCI subjects with lower LC-MRI signal values had a higher risk of progressing to dementia. Furthermore, MCI subjects who converted to dementia during follow-up showed significantly reduced LC-MRI signal values compared to those who did not convert. These results strongly support the hypothesis mentioned above: loss of LC integrity is associated with faster disease progression. This study adds to the growing body of evidence supporting the rationale for LC research in AD, not only from a diagnostic/prognostic point of view. Indeed, its early involvement and possible pathogenetic role make the LC-NA system an intriguing target for disease-modifying therapies. Preventing LC degeneration or restoring NA signaling could be just two of the possible strategies to be pursued to halt or - at least - slow the otherwise unstoppable course of AD