IL RECETTORE ADENOSINICO A2A COME POSSIBILE BIOMARCATORE NELLA DIAGNOSI DIFFERENZIALE DELLE DEMENZE NELL'ANZIANO.

Although Alzheimer\u2019s disease (AD) might be best designated as a purely degenerative disease in whose pathogenesis amyloid-beta plays a key role, it is acknowledged that in elder patients (>65years) there is an increased likelihood of other neuropathological abnormalities including cerebrovascular lesions. Over the last years, there has been accumulating evidence that the previously held sharp distinction between AD and vascular dementia (VaD) may not be so clear-cut, especially in old age. VaD is the second most common cause of dementia after AD. VaD arises as a consequence of ischemic insults such as hemorrhage and hypoperfusion that trigger neurodegeneration by depriving nerve cells of oxygen and glucose. Such deprivation results in the depletion of nerve cell energy supplies, leading to membrane depolarization, followed by an excessive release of glutamate which activates the N-methyl-D-aspartate receptor (NMDAR). This allows the influx of toxic levels of Ca2+ into nerve cells, which, in turn, activates intracellular calcium-dependent enzymes. The purine ribonucleoside adenosine (Ado) is a naturally occurring metabolite that is ubiquitously distributed throughout the body as a metabolic intermediary. Intra- and extracellular Ado levels rise in response to physiological stimuli and with metabolic/energetic perturbations, inflammatory challenges and tissue injury. The physiological responses to Ado take place as a result of the binding and activation of different transmembrane receptors: the high-affinity A1 and A2A (A2AR) receptors, the low-affinity A2B receptor, or the low-abundance A3 receptor. It has been demonstrated that A2AR is able to prevent amyloid-\uf062-induced synaptotoxicity in animal models and cell cultures. Moreover A2AR has been shown to control NMDA currents and glutamate outflow in the hippocampus. Contrasting data have been reported so far on the beneficial/detrimental effects of A2AR on brain cells. The blockade of A2AR alleviates the long-term burden of brain disorders such as ischemia, epilepsy, Parkinson\u2019s or Alzheimer\u2019s disease. On the other hand, agonists of A2AR can protect the Central Nervous System against several insults, including ischemia and exicitotoxins. In the periphery A2AR contributes to coronary endothelial dilatation in mice, can inhibit endothelial apoptosis and preserves vascular reactivity following hemorrhagic shock in rats. Finally, increasing evidence supports the notion that A2AR is implicated in the downregulation of inflammation. In this study we evaluated the gene and protein expression of A2AR in the peripheral blood mononuclear cells (PBMCs) of patients with VaD, AD, Mild Cognitive Impairment (MCI) and healthy controls in order to investigate its potential role as an easily accessible biomarker in the differential diagnosis of dementia. This study show that A2AR expression is upregulated in the peripheral cells of a-MCI but not AD subjects, supporting an involvement of the Ado system in the early stages of AD. It also shows that A2AR expression is lower in the PBMCs of subjects with VaD than AD, highlighting its possible relevance as a biomarker that may help differentiate two forms of dementia that are often closely associated. From our results it can be concluded that A2AR may play an important but differential role in both types of dementia: its upregulation in the preclinical stages of AD could counterbalance the existing inflammatory state and its downregulation in VaD could reflect the effects of A2AR on the brain vasculature. It can therefore be suggested that A2AR could serve as a biomarker in the differential diagnosis between VaD and AD

Age-Dependent Neuropsychiatric Symptoms in the NF-κB/c-Rel Knockout Mouse Model of Parkinson’s Disease

Non-motor symptoms are frequently observed in Parkinson’s disease (PD) and precede the onset of motor deficits by years. Among them, neuropsychiatric symptoms, including anxiety, depression, and apathy, are increasingly considered as a major challenge for patients with PD and their caregivers. We recently reported that mice lacking the nuclear factor-κB (NF-κB)/c-Rel protein (c-rel–/– mice) develop an age-dependent PD-like pathology and phenotype characterized by the onset of non-motor symptoms, including constipation and hyposmia, starting at 2 months of age, and motor deficits at 18 months. To assess whether c-rel–/– mice also suffer from neuropsychiatric symptoms, in this study we tested different cohorts of wild-type (wt) and c-rel–/– mice at 3, 6, 12, and 18–20 months with different behavioral tests. Mice lacking c-Rel displayed anxiety and depressive-like behavior starting in the premotor phase at 12 months, as indicated by the analysis with the open field (OF) test and the forced swim test with water wheel (FST), respectively. A deficit in the goal-oriented nesting building test was detected at 18–20 months, suggesting apathetic behavior. Taken together, these results indicate that c-rel–/– mice recapitulate the onset and the progression of PD-related neuropsychiatric symptoms. Therefore, this animal model may represent a valuable tool to study the prodromal stage of PD and for testing new therapeutic strategies to alleviate neuropsychiatric symptoms

Protein signature in cerebrospinal fluid and serum of Alzheimer’s disease patients : the case of apolipoprotein A-1 proteoforms

In the diagnosis of Alzheimer\u2019s disease (AD) total tau (T-tau), tau phosphorylated at threonine 181 (P-tau181), and the 42 amino acid isoform of alpha \u3b2-amyloid (A\u3b2) are well established surrogate CSF markers. However, there is a constant need for new diagnostic markers to identify the disease at a very early stage. The identification of new molecules for AD diagnosis and monitoring in CSF is hampered by several \u201cconfounding\u201d factors including intra- and inter-individual, pre-analytical and analytical variabilities. In an attempt to partially overcome patient\u2019s variability and to determine new molecules significantly dysregulated in CSF, we assessed the proteome profile of low molecular weight protein species in CSF and serum of the same patients. CSFs and sera from 36 ADs, 32 iNPHs (idiopathic normal pressure hydrocephalus) and 12 controls were compared by MALDI profiling (non-parametric statistics, CV0.750). After protein identification by mass spectrometry, the proteoform composition was assessed by 2-D DIGE/MS. Results indicated that CSF of iNPH can be used as control. Serum and CSF of AD patients shows a specific protein profile compared to iNPH samples. A variation (p<0.01) of Apo A-1 levels in AD, together with a specific dysregulation of Apo A-1 proteoforms was observed. The profiling of CSF and serum of the same patients, suggests that the decrement of total Apo A-1 occurs specifically in CSF. Serum and CSF of AD shows a characteristic Apo A-1 proteoform pattern suggesting it as potential marker which can support the clinical workflow adopted for AD diagnosis and progression

The Effects of Resiliency on University Students’ Happiness and Life Effectiveness amid the COVID-19 Pandemic Religious Faith Stands as a Moderator

It is argued that resiliency may contribute to one’s happiness and life effectiveness, while religious faith may strengthen the effects arising from the interchange of those variables. To confirm these assumptions, a study was conducted on a group of students consisting of 506 public and private university students in Sabah, Malaysia, amid the COVID-19 pandemic. Of the participants, 405 (80%) were females, 100 were males (19.8%), and one did not reveal their gender. The mean age was 21.71 (SD = 4.52). The study revealed that resiliency accounted for 6 percent of the variance on happiness and 18 percent of the variance on life effectiveness. However, faith did not show any moderation effects on resiliency as a cause of happiness. In terms of its effect on students’ life efficiency (e.g., time management, emotional control, and social competence), resiliency accounts for 18 percent of the variance on life effectiveness. As to the interaction between resiliency and faith in relation to the quality of life, the study revealed a significant interaction between them, a result that explained an additional 1.6 percent in the variance in life effectiveness. This indicates that strong religious faith could enhance students’ resiliency and contribute to a better life (e.g., managing time, controlling emotion, higher motivation, and competence in social situations), particularly during the pandemic. Therefore, valuing and practicing one’s religious faith, regardless of the religious background, is a powerful tool in boosting students’ flexibility in the face of academic and nonacademic challenges during the COVID-19 pandemic

Increased expression of TREM2 in peripheral cells from mild cognitive impairment patients that progress into Alzheimer&apos;s disease

Background and purpose Neuroinflammation plays a role in the aetiopathogenesis of Alzheimer's disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2), a cell surface receptor of the immunoglobulin superfamily, seems to have protective anti\u2010inflammatory activity in AD. Methods Triggering receptor expressed on myeloid cells 2 expression was analysed in peripheral blood mononuclear cells from healthy subjects (CT) and from patients with either AD or mild cognitive impairment (MCI). MCI patients were re\u2010evaluated at a 2\u2010year follow\u2010up to investigate their progression to AD (MCI\u2010AD) or lack thereof (MCI\u2010MCI). Results Triggering receptor expressed on myeloid cells 2 gene expression was higher in AD than CT patients, but was highest in MCI. At recruitment TREM2 levels were higher in MCI\u2010AD than in MCI\u2010MCI, and in MCI\u2010AD were higher initially than at follow\u2010up. TREM2 displayed a moderate degree of sensitivity and specificity for identifying MCI\u2010AD in all MCI patients. Our data showed higher TREM2 levels in allele \u3b54 of apolipoprotein E (ApoE \u3b54) carriers than non\u2010carriers in MCI and particularly in MCI\u2010AD. Conclusions These data seem to confirm the protective role of TREM2 in the pre\u2010clinical stage of AD. Upregulation of TREM2 in MCI\u2010AD could be a mechanism to counteract the activation of neuroinflammatory processes. It is possible that TREM2 and ApoE \u3b54 interact synergistically in the pre\u2010clinical stage of AD. Therefore, TREM2 may be useful as an early peripheral biomarker for the development of AD

Adenosine Type A2A Receptor in Peripheral Cell from Patients with Alzheimer&apos;s Disease, Vascular Dementia, and Idiopathic Normal Pressure Hydrocephalus : A&#160;New/Old Potential Target

As the European population gets older, the incidence of neurological disorders increases with significant impact on social costs. Despite differences in disease etiology, several brain disorders in the elderly (e.g., Alzheimer's disease, vascular dementia, normal pressure hydrocephalus) share dementia as a common clinical feature. The current treatment for the majority of these diseases is merely symptomatic and does not modify the course of the illness. Symptoms of normal pressure hydrocephalus are the only ones that can be modified if they are recognized in time and treated appropriately. Therefore, an important clinical strategy may be disclosed by pathogenic pathways that can be modified and to find drugs that can slow down or even arrest disease progression. Possibly a way to answer this question could be by re-examining all the molecules which have so far succeeded in improving many aspects of cognitive deterioration in some neurodegenerative conditions, that were not considered because of controversial opinions. The main purpose of this summary is to further substantiate the hypothesis that the pathway of adenosine type A2A receptor could be used as a potential target to develop new/old therapeutic strategies

Phenotypic variability associated with the C9ORF72 hexanucleotide repeat expansion : a sporadic case of frontotemporal lobar degeneration with prodromal hyposmia and predominant semantic deficits

We describe a sporadic case of frontotemporal lobar degeneration, associated with the C9ORF72 mutation, with prominent behavioral changes and semantic deficits. Predominant deficits in naming, vocabulary, word comprehension, and face and object recognition emerged on neuropsychological assessment. Amnesia, behavioral changes, and isolated psychotic symptoms were also present. Hyposmia was an unspecific prodromal sign. Brain imaging showed basofrontal and temporopolar hypometabolism bilaterally, and predominantly left-sided atrophy. Levels of cerebrospinal fluid biomarkers (amyloid-\u3b2, tau and p-tau) were normal. This description further confirms the heterogeneous presentation of the C9ORF72 mutation

Different Aaenosine A2A receptor expression in peripheral cells from elderly patients with vascular dementia and Alzheimer&apos;s disease

The line between vascular dementia (VaD) and Alzheimer's disease (AD) is often blurred. In this study we investigated whether adenosine A2A receptor (A2AR) expression can be used to differentiate between VaD and AD. We evaluated the expression of this receptor in the peripheral blood mononuclear cells of patients with VaD, mild cognitive impairment, AD, and controls. We found statistically significant lower levels of A2AR mRNA in VaD compared to AD subjects. These data suggest that A2AR expression may help in the differential diagnosis between VaD and AD

Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with T2 to T4, N0 and N1 breast cancer

Abstract Background Histological status of axillary lymph nodes is an important prognostic factor in patients receiving surgery for breast cancer (BC). Sentinel lymph node (SLN) biopsy (B) has rapidly replaced axillary lymph node dissection (ALND), and is now the standard of care for axillary staging in patients with clinically node-negative (N0) operable BC. The aim of this study is to compare pretreatment lymphoscintigraphy with a post primary systemic treatment (PST) scan in order to reduce the false-negative rates for SLNB. Methods In this single-institution study we considered 170 consecutive T2-4 N0-1 M0 BC patients treated with anthracycline-based PST. At the time of incisional biopsy, we performed sentinel lymphatic mapping. After PST, all patients repeated lymphoscintigraphy with the same methodology. During definitive surgery we performed further sentinel lymphatic mapping, SLNB and ALND. Results The SLN was removed in 158/170 patients giving an identification rate of 92.9% (95% confidence interval (CI) = 88.0–96.3%) and a false-negative rate of 14.0% (95% CI = 6.3–25.8%). SLNB revealed a sensitivity of 86.0% (95% CI = 74.2–93.7%), an accuracy of 94.9% (95% CI = 90.3–97.8%) and a negative predictive value of 92.7% (95% CI = 86.1–96.8%). Conclusion Identification rate, sensitivity and accuracy are in accordance with other studies on SLNB after PST, even after clinically negative node conversion following PST. This study confirms that diagnostic biopsy and neoadjuvant chemotherapy maintain breast lymphatic drainage unaltered

Epigenetic Regulation of Fatty Acid Amide Hydrolase in Alzheimer Disease

OBJECTIVE: Alzheimer disease (AD) is a progressive, degenerative and irreversible neurological disorder with few therapies available. In search for new potential targets, increasing evidence suggests a role for the endocannabinoid system (ECS) in the regulation of neurodegenerative processes. METHODS: We have studied the gene expression status and the epigenetic regulation of ECS components in peripheral blood mononuclear cells (PBMCs) of subjects with late-onset AD (LOAD) and age-matched controls (CT). RESULTS: We found an increase in fatty acid amide hydrolase (faah) gene expression in LOAD subjects (2.30 ± 0.48) when compared to CT (1.00 ± 0.14; *p<0.05) and no changes in the mRNA levels of any other gene of ECS elements. Consistently, we also observed in LOAD subjects an increase in FAAH protein levels (CT: 0.75 ± 0.04; LOAD: 1.11 ± 0.15; *p<0.05) and activity (pmol/min per mg protein CT: 103.80 ± 8.73; LOAD: 125.10 ± 4.00; *p<0.05), as well as a reduction in DNA methylation at faah gene promoter (CT: 55.90 ± 4.60%; LOAD: 41.20 ± 4.90%; *p<0.05). CONCLUSIONS: Present findings suggest the involvement of FAAH in the pathogenesis of AD, highlighting the importance of epigenetic mechanisms in enzyme regulation; they also point to FAAH as a new potential biomarker for AD in easily accessible peripheral cells