Association of glial fibrillary acid protein, Alzheimer's disease pathology and cognitive decline.

Increasing evidence shows that neuroinflammation is a possible modulator of tau spread effects on cognitive impairment in Alzheimer's disease. In this context, plasma levels of the glial fibrillary acidic protein (GFAP) have been suggested to have a robust association with Alzheimer's disease pathophysiology. This study aims to assess the correlation between plasma GFAP and Alzheimer's disease pathology, and their synergistic effect on cognitive performance and decline. A cohort of 122 memory clinic subjects with amyloid and tau positron emission tomography, MRI scans, plasma GFAP, and Mini-Mental State Examination (MMSE) was included in the study. A subsample of 94 subjects had a follow-up MMSE score at least one year after baseline. Regional and voxel-based correlations between Alzheimer's disease biomarkers and plasma GFAP were assessed. Mediation analyses were performed to evaluate the effects of plasma GFAP on the association between amyloid and tau PET, and tau PET and cognitive impairment and decline. GFAP was associated with increased tau PET ligand uptake in the lateral temporal and inferior temporal lobes in a strong left-sided pattern independently of age, gender, education, amyloid, and APOE status (ß=0.001, p < 0.01). The annual rate of MMSE change was significantly and independently correlated with both GFAP (ß=0.006, p < 0.01) and global tau SUVR (ß=4.33, p < 0.01), but not with amyloid burden. Partial mediation effects of GFAP were found on the association between amyloid and tau pathology (13.7%), and between tau pathology and cognitive decline (17.4%), but not on global cognition at baseline. Neuroinflammation measured by circulating GFAP is independently associated with tau Alzheimer's disease pathology and with cognitive decline, suggesting neuroinflammation as a potential target for future disease-modifying trials targeting tau pathology. Peretti et al. show that a circulatory marker of neuroinflammation-glial fibrillary acidic protein-is associated with tau pathology in lateral temporal and frontal regions in patients with Alzheimer's disease, independent of amyloid load. Neuroinflammation appears to modulate the association between amyloid and tau biomarkers.

Inflammation and immune system pathways as biological signatures of adolescent depression-the IDEA-RiSCo study.

The biological mechanisms underlying the onset of major depressive disorder (MDD) have predominantly been studied in adult populations from high-income countries, despite the onset of depression typically occurring in adolescence and the majority of the world's adolescents living in low- and middle-income countries (LMIC). Taking advantage of a unique adolescent sample in an LMIC (Brazil), this study aimed to identify biological pathways characterizing the presence and increased risk of depression in adolescence, and sex-specific differences in such biological signatures. We collected blood samples from a risk-stratified cohort of 150 Brazilian adolescents (aged 14-16 years old) comprising 50 adolescents with MDD, 50 adolescents at high risk of developing MDD but without current MDD, and 50 adolescents at low risk of developing MDD and without MDD (25 females and 25 males in each group). We conducted RNA-Seq and pathway analysis on whole blood. Inflammatory-related biological pathways, such as role of hypercytokinemia/hyperchemokinemia in the pathogenesis of influenza (z-score = 3.464, p < 0.001), interferon signaling (z-score = 2.464, p < 0.001), interferon alpha/beta signaling (z-score = 3.873, p < 0.001), and complement signaling (z-score = 2, p = 0.002) were upregulated in adolescents with MDD compared with adolescents without MDD independently from their level of risk. The up-regulation of such inflammation-related pathways was observed in females but not in males. Inflammatory-related pathways involved in the production of cytokines and in interferon and complement signaling were identified as key indicators of adolescent depression, and this effect was present only in females.

Resting state electroencephalographic alpha rhythms are sensitive to Alzheimer's disease mild cognitive impairment progression at a 6-month follow-up.

Are posterior resting-state electroencephalographic (rsEEG) alpha rhythms sensitive to the Alzheimer's disease mild cognitive impairment (ADMCI) progression at a 6-month follow-up? Clinical, cerebrospinal, neuroimaging, and rsEEG datasets in 52 ADMCI and 60 Healthy old seniors (equivalent groups for demographic features) were available from an international archive (www.pdwaves.eu). The ADMCI patients were arbitrarily divided into two groups: REACTIVE and UNREACTIVE, based on the reduction (reactivity) in the posterior rsEEG alpha eLORETA source activities from the eyes-closed to eyes-open condition at ≥ -10% and -10%, respectively. 75% of the ADMCI patients were REACTIVE. Compared to the UNREACTIVE group, the REACTIVE group showed (1) less abnormal posterior rsEEG source activity during the eyes-closed condition and (2) a decrease in that activity at the 6-month follow-up. These effects could not be explained by neuroimaging and neuropsychological biomarkers of AD. Such a biomarker might reflect abnormalities in cortical arousal in quiet wakefulness to be used for clinical studies in ADMCI patients using 6-month follow-ups.

Microstructural alterations in the locus coeruleus-entorhinal cortex pathway in Alzheimer's disease and frontotemporal dementia.

INTRODUCTION: We investigated in vivo the microstructural integrity of the pathway connecting the locus coeruleus to the transentorhinal cortex (LC-TEC) in patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD). METHODS: Diffusion-weighted MRI scans were collected for 21 AD, 20 behavioral variants of FTD (bvFTD), and 20 controls. Fractional anisotropy (FA), mean, axial, and radial diffusivities (MD, AxD, RD) were computed in the LC-TEC pathway using a normative atlas. Atrophy was assessed using cortical thickness and correlated with microstructural measures. RESULTS: We found (i) higher RD in AD than controls; (ii) higher MD, RD, and AxD, and lower FA in bvFTD than controls and AD; and (iii) a negative association between LC-TEC MD, RD, and AxD, and entorhinal cortex (EC) thickness in bvFTD (all p < 0.050). DISCUSSION: LC-TEC microstructural alterations are more pronounced in bvFTD than AD, possibly reflecting neurodegeneration secondary to EC atrophy. Highlights: Microstructural integrity of LC-TEC pathway is understudied in AD and bvFTD.LC-TEC microstructural alterations are present in both AD and bvFTD.Greater LC-TEC microstructural alterations in bvFTD than AD.LC-TEC microstructural alterations in bvFTD are associated to EC neurodegeneration.

Transcriptomic analyses of rats exposed to chronic mild stress: Modulation by chronic treatment with the antipsychotic drug lurasidone.

Exposure to stressful experiences accounts for almost half of the risk for mental disorders. Hence, stress-induced alterations represent a key target for pharmacological interventions aimed at restoring brain function in affected individuals. We have previously demonstrated that lurasidone, a multi-receptor antipsychotic drug approved for the treatment of schizophrenia and bipolar depression, can normalize the functional and molecular impairments induced by stress exposure, representing a valuable tool for the treatment of stress-induced mental illnesses. However, the mechanisms that may contribute to the therapeutic effects of lurasidone are still poorly understood. Here, we performed a transcriptomic analysis on the prefrontal cortex (PFC) of adult male rats exposed to the chronic mild stress (CMS) paradigm and we investigated the impact of chronic lurasidone treatment on such changes. We found that CMS exposure leads to an anhedonic phenotype associated with a down-regulation of different pathways associated to neuronal guidance and synaptic plasticity within the PFC. Interestingly, a significant part of these alterations (around 25%) were counteracted by lurasidone treatment. In summary, we provided new insights on the transcriptional changes relevant for the therapeutic intervention with lurasidone, which may ultimately promote resilience.

Poor reactivity of posterior electroencephalographic alpha rhythms during the eyes open condition in patients with dementia due to Parkinson's disease.

Here, we hypothesized that the reactivity of posterior resting-state electroencephalographic (rsEEG) alpha rhythms during the transition from eyes-closed to -open condition might be lower in patients with Parkinson's disease dementia (PDD) than in patients with Alzheimer's disease dementia (ADD). A Eurasian database provided clinical-demographic-rsEEG datasets in 73 PDD patients, 35 ADD patients, and 25 matched cognitively unimpaired (Healthy) persons. The eLORETA freeware was used to estimate cortical rsEEG sources. Results showed substantial (greater than -10%) reduction (reactivity) in the posterior alpha source activities from the eyes-closed to the eyes-open condition in 88% of the Healthy seniors, 57% of the ADD patients, and only 35% of the PDD patients. In these alpha-reactive participants, there was lower reactivity in the parietal alpha source activities in the PDD group than in the healthy control seniors and the ADD patients. These results suggest that PDD patients show poor reactivity of mechanisms desynchronizing posterior rsEEG alpha rhythms in response to visual inputs. That neurophysiological biomarker may provide an endpoint for (non) pharmacological interventions for improving vigilance regulation in those patients.

Vulnerability and resilience to prenatal stress exposure: behavioral and molecular characterization in adolescent rats.

Exposure to stress can lead to long lasting behavioral and neurobiological consequences, which may enhance the susceptibility for the onset of mental disorders. However, there are significant individual differences in the outcome of stress exposure since only a percentage of exposed individuals may show pathological consequences, whereas others appear to be resilient. In this study, we aimed to characterize the effects of prenatal stress (PNS) exposure in rats at adolescence and to identify subgroup of animals with a differential response to the gestational manipulation. PNS adolescent offspring (regardless of sex) showed impaired emotionality in different pathological domains, such as anhedonia, anxiety, and sociability. However, using cluster analysis of the behavioral data we could identify 70% of PNS-exposed animals as vulnerable (PNS-vul), whereas the remaining 30% were considered resilient (PNS-res). At the molecular level, we found that PNS-res males show a reduced basal activation of the ventral hippocampus whereas other regions, such as amygdala and dorsal hippocampus, show significant PNS-induced changes regardless from vulnerability or resilience. Taken together, our results provide evidence of the variability in the behavioral and neurobiological effects of PNS-exposed offspring at adolescence. While these data may advance our understanding of the association between exposure to stress during gestation and the risk for psychopathology, the investigation of the mechanisms associated to stress vulnerability or resilience may be instrumental to develop novel strategies for therapeutic intervention.

Psychobiological effects of an eHealth psychoeducational intervention to informal caregivers of persons with dementia: a pilot study during the COVID-19 pandemic in Italy.

BACKGROUND: The workload associated with caring for a person with dementia (PwD) could negatively affect informal caregivers' physical and mental health. According to the recent literature, there is a need for studies testing the implementation of affordable and accessible interventions for improving caregivers' well-being. AIMS: This study aimed to explore the feasibility and effectiveness of an 8 week eHealth psychoeducation intervention held during the COVID-19 pandemic in Italy in reducing the psychological burden and neuroendocrine markers of stress in caregivers of PwD. METHODS: Forty-one informal caregivers of PwD completed the eHealth psychoeducation intervention. Self-reported (i.e., caregiver burden, anxiety symptoms, depressive symptoms, and caregiver self-efficacy) and cortisol measurements were collected before and after the intervention. RESULTS: Following the intervention, the caregivers' self-efficacy regarding the ability to respond to disruptive behaviours improved (t = - 2.817, p = 0.007), anxiety and burden levels decreased (state anxiety: t = 3.170, p = 0.003; trait anxiety: t = 2.327, p = 0.025; caregiver burden: t = 2.290, p = 0.027), while depressive symptoms and cortisol levels did not change significantly. Correlation analyses showed that the increase in self-efficacy was positively associated with the improvement of caregiver burden from pre- to post-intervention (r = 0.386, p = 0.014). The intervention had a low rate of dropout (n = 1, due to the patient's death) and high levels of appreciation. DISCUSSION: The positive evidence and participation rate support the feasibility and effectiveness of the proposed eHealth psychoeducational intervention to meet the need for knowledge of disease management and possibly reduce detrimental effects on caregivers' psychological well-being. CONCLUSION: Further placebo-controlled trials are needed to test the generalizability and specificity of our results.

Microbiota from Alzheimer's patients induce deficits in cognition and hippocampal neurogenesis.

Alzheimer's disease is a complex neurodegenerative disorder leading to a decline in cognitive function and mental health. Recent research has positioned the gut microbiota as an important susceptibility factor in Alzheimer's disease by showing specific alterations in the gut microbiome composition of Alzheimer's patients and in rodent models. However, it is unknown whether gut microbiota alterations are causal in the manifestation of Alzheimer's symptoms. To understand the involvement of Alzheimer's patient gut microbiota in host physiology and behaviour, we transplanted faecal microbiota from Alzheimer's patients and age-matched healthy controls into microbiota-depleted young adult rats. We found impairments in behaviours reliant on adult hippocampal neurogenesis, an essential process for certain memory functions and mood, resulting from Alzheimer's patient transplants. Notably, the severity of impairments correlated with clinical cognitive scores in donor patients. Discrete changes in the rat caecal and hippocampal metabolome were also evident. As hippocampal neurogenesis cannot be measured in living humans but is modulated by the circulatory systemic environment, we assessed the impact of the Alzheimer's systemic environment on proxy neurogenesis readouts. Serum from Alzheimer's patients decreased neurogenesis in human cells in vitro and were associated with cognitive scores and key microbial genera. Our findings reveal for the first time, that Alzheimer's symptoms can be transferred to a healthy young organism via the gut microbiota, confirming a causal role of gut microbiota in Alzheimer's disease, and highlight hippocampal neurogenesis as a converging central cellular process regulating systemic circulatory and gut-mediated factors in Alzheimer's.

Relationship between default mode network and resting-state electroencephalographic alpha rhythms in cognitively unimpaired seniors and patients with dementia due to Alzheimer's disease.

Here we tested the hypothesis of a relationship between the cortical default mode network (DMN) structural integrity and the resting-state electroencephalographic (rsEEG) rhythms in patients with Alzheimer's disease with dementia (ADD). Clinical and instrumental datasets in 45 ADD patients and 40 normal elderly (Nold) persons originated from the PDWAVES Consortium (www.pdwaves.eu). Individual rsEEG delta, theta, alpha, and fixed beta and gamma bands were considered. Freeware platforms served to derive (1) the (gray matter) volume of the DMN, dorsal attention (DAN), and sensorimotor (SMN) cortical networks and (2) the rsEEG cortical eLORETA source activities. We found a significant positive association between the DMN gray matter volume, the rsEEG alpha source activity estimated in the posterior DMN nodes (parietal and posterior cingulate cortex), and the global cognitive status in the Nold and ADD participants. Compared with the Nold, the ADD group showed lower DMN gray matter, lower rsEEG alpha source activity in those nodes, and lower global cognitive status. This effect was not observed in the DAN and SMN. These results suggest that the DMN structural integrity and the rsEEG alpha source activities in the DMN posterior hubs may be related and predict the global cognitive status in ADD and Nold persons.

Unsupervised [18F]Flortaucipir cutoffs for tau positivity and staging in Alzheimer's disease.

PURPOSE: Several [18F]Flortaucipir cutoffs have been proposed for tau PET positivity (T+) in Alzheimer's disease (AD), but none were data-driven. The aim of this study was to establish and validate unsupervised T+ cutoffs by applying Gaussian mixture models (GMM). METHODS: Amyloid negative (A-) cognitively normal (CN) and amyloid positive (A+) AD-related dementia (ADRD) subjects from ADNI (n=269) were included. ADNI (n=475) and Geneva Memory Clinic (GMC) cohorts (n=98) were used for validation. GMM-based cutoffs were extracted for the temporal meta-ROI, and validated against previously published cutoffs and visual rating. RESULTS: GMM-based cutoffs classified less subjects as T+, mainly in the A- CN (<3.4% vs >28.5%) and A+ CN (<14.5% vs >42.9%) groups and showed higher agreement with visual rating (ICC=0.91 vs ICC<0.62) than published cutoffs. CONCLUSION: We provided reliable data-driven [18F]Flortaucipir cutoffs for in vivo T+ detection in AD. These cutoffs might be useful to select participants in clinical and research studies.

A peripheral signature of Alzheimer's disease featuring microbiota-gut-brain axis markers.

BACKGROUND: Increasing evidence links the gut microbiota (GM) to Alzheimer's disease (AD) but the mechanisms through which gut bacteria influence the brain are still unclear. This study tests the hypothesis that GM and mediators of the microbiota-gut-brain axis (MGBA) are associated with the amyloid cascade in sporadic AD. METHODS: We included 34 patients with cognitive impairment due to AD (CI-AD), 37 patients with cognitive impairment not due to AD (CI-NAD), and 13 cognitively unimpaired persons (CU). We studied the following systems: (1) fecal GM, with 16S rRNA sequencing; (2) a panel of putative MGBA mediators in the blood including immune and endothelial markers as bacterial products (i.e., lipopolysaccharide, LPS), cell adhesion molecules (CAMs) indicative of endothelial dysfunction (VCAM-1, PECAM-1), vascular changes (P-, E-Selectin), and upregulated after infections (NCAM, ICAM-1), as well as pro- (IL1ß, IL6, TNFα, IL18) and anti- (IL10) inflammatory cytokines; (3) the amyloid cascade with amyloid PET, plasma phosphorylated tau (pTau-181, for tau pathology), neurofilament light chain (NfL, for neurodegeneration), and global cognition measured using MMSE and ADAScog. We performed 3-group comparisons of markers in the 3 systems and calculated correlation matrices for the pooled group of CI-AD and CU as well as CI-NAD and CU. Patterns of associations based on Spearman's rho were used to validate the study hypothesis. RESULTS: CI-AD were characterized by (1) higher abundance of Clostridia_UCG-014 and decreased abundance of Moryella and Blautia (p < .04); (2) elevated levels of LPS (p < .03), upregulation of CAMs, Il1ß, IL6, and TNFα, and downregulation of IL10 (p < .05); (3) increased brain amyloid, plasma pTau-181, and NfL (p < 0.004) compared with the other groups. CI-NAD showed (1) higher abundance of [Eubacterium] coprostanoligenes group and Collinsella and decreased abundance of Lachnospiraceae_ND3007_group, [Ruminococcus]_gnavus_group and Oscillibacter (p < .03); (2) upregulation of PECAM-1 and TNFα (p < .03); (4) increased plasma levels of NfL (p < .02) compared with CU. Different GM genera were associated with immune and endothelial markers in both CI-NAD and CI-AD but these mediators were widely related to amyloid cascade markers only in CI-AD. CONCLUSIONS: Specific bacterial genera are associated with immune and endothelial MGBA mediators, and these are associated with amyloid cascade markers in sporadic AD. The physiological mechanisms linking the GM to the amyloid cascade should be further investigated to elucidate their potential therapeutic implications.

Plasma biomarkers for Alzheimer's disease: a field-test in a memory clinic.

BACKGROUND: The key Alzheimer's disease (AD) biomarkers are traditionally measured with techniques/exams that are either expensive (amyloid-positron emission tomography (PET) and tau-PET), invasive (cerebrospinal fluid Aß42 and p-tau181), or poorly specific (atrophy on MRI and hypometabolism on fluorodeoxyglucose-PET). Recently developed plasma biomarkers could significantly enhance the efficiency of the diagnostic pathway in memory clinics and improve patient care. This study aimed to: (1) confirm the correlations between plasma and traditional AD biomarkers, (2) assess the diagnostic accuracy of plasma biomarkers as compared with traditional biomarkers, and (3) estimate the proportion of traditional exams potentially saved thanks to the use of plasma biomarkers. METHODS: Participants were 200 patients with plasma biomarkers and at least one traditional biomarker collected within 12 months. RESULTS: Overall, plasma biomarkers significantly correlated with biomarkers assessed through traditional techniques: up to r=0.50 (p<0.001) among amyloid, r=0.43 (p=0.002) among tau, and r=-0.23 (p=0.001) among neurodegeneration biomarkers. Moreover, plasma biomarkers showed high accuracy in discriminating the biomarker status (normal or abnormal) determined by using traditional biomarkers: up to area under the curve (AUC)=0.87 for amyloid, AUC=0.82 for tau, and AUC=0.63 for neurodegeneration status. The use of plasma as a gateway to traditional biomarkers using cohort-specific thresholds (with 95% sensitivity and 95% specificity) could save up to 49% of amyloid, 38% of tau, and 16% of neurodegeneration biomarkers. CONCLUSION: The implementation of plasma biomarkers could save a remarkable proportion of more expensive traditional exams, making the diagnostic workup more cost-effective and improving patient care.

What a Single Electroencephalographic (EEG) Channel Can Tell us About Alzheimer's Disease Patients With Mild Cognitive Impairment.

Abnormalities in cortical sources of resting-state eyes closed electroencephalographic (rsEEG) rhythms recorded by hospital settings (10-20 montage) with 19 scalp electrodes characterized Alzheimer's disease (AD) from preclinical to dementia stages. An intriguing rsEEG application is the monitoring and evaluation of AD progression in large populations with few electrodes in low-cost devices. Here we evaluated whether the above-mentioned abnormalities can be observed from fewer scalp electrodes in patients with mild cognitive impairment due to AD (ADMCI). Clinical and rsEEG data acquired in hospital settings (10-20 montage) from 75 ADMCI participants and 70 age-, education-, and sex-matched normal elderly controls (Nold) were available in an Italian-Turkish archive (PDWAVES Consortium; www.pdwaves.eu). Standard spectral fast fourier transform (FFT) analysis of rsEEG data for individual delta, theta, and alpha frequency bands was computed from 6 monopolar scalp electrodes to derive bipolar C3-P3, C4-P4, P3-O1, and P4-O2 markers. The ADMCI group showed increased delta and decreased alpha power density at the C3-P3, C4-P4, P3-O1, and P4-O2 bipolar channels compared to the Nold group. Increased theta power density for ADMCI patients was observed only at the C3-P3 bipolar channel. Best classification accuracy between the ADMCI and Nold individuals reached 81% (area under the receiver operating characteristic curve) using Alpha2/Theta power density computed at the C3-P3 bipolar channel. Standard rsEEG power density computed from six posterior bipolar channels characterized ADMCI status. These results may pave the way toward diffuse clinical applications in health monitoring of dementia using low-cost EEG systems with a strict number of electrodes in lower- and middle-income countries.

What a single electroencephalographic (EEG) channel can tell us about patients with dementia due to Alzheimer's disease.

Abnormalities in cortical sources of resting-state eyes-closed electroencephalographic (rsEEG) rhythms recorded by hospital settings (10-20 electrode montage) with 19 scalp electrodes provide useful markers of neurophysiological dysfunctions in the vigilance regulation in patients with Alzheimer's disease dementia (ADD). Here we tested whether these markers may be effective from a few scalp electrodes towards the use of low-cost recording devices. Clinical and rsEEG data acquired in hospital settings (10-20 electrode montage) from 88 ADD participants and 68 age-, education-, and sex-matched normal elderly controls (Nold) were available in an international Eurasian database. Standard spectral FFT analysis of rsEEG data for individual delta, theta, and alpha frequency bands was from C3-P3, C4-P4, P3-O1, and P4-O2 bipolar channels. As compared to the Nold group, the ADD group showed increased delta, theta, low-frequency alpha power density and decreased high-frequency alpha power density at all those bipolar channels. The highest classification accuracy between the ADD and Nold individuals reached 90 % (area under the receiver operating characteristic curve) using Alpha2/Theta power density computed at the C3-P3 bipolar channel. Standard rsEEG power density computed from a few posterior bipolar channels successfully classified Nold and ADD individuals, thus encouraging a massive prescreening of neurophysiological mechanisms underpinning the vigilance dysregulation in underserved old seniors.

Alzheimer's Disease with Epileptiform EEG Activity: Abnormal Cortical Sources of Resting State Delta Rhythms in Patients with Amnesic Mild Cognitive Impairment.

BACKGROUND: Patients with amnesic mild cognitive impairment due to Alzheimer's disease (ADMCI) typically show a "slowing" of cortical resting-state eyes-closed electroencephalographic (rsEEG) rhythms. Some of them also show subclinical, non-convulsive, and epileptiform EEG activity (EEA) with an unclear relationship with that "slowing." OBJECTIVE: Here we tested the hypothesis that the "slowing" of rsEEG rhythms is related to EEA in ADMCI patients. METHODS: Clinical and instrumental datasets in 62 ADMCI patients and 38 normal elderly (Nold) subjects were available in a national archive. No participant had received a clinical diagnosis of epilepsy. The eLORETA freeware estimated rsEEG cortical sources. The area under the receiver operating characteristic curve (AUROCC) indexed the accuracy of eLORETA solutions in the classification between ADMCI-EEA and ADMCI-noEEA individuals. RESULTS: EEA was observed in 15% (N = 8) of the ADMCI patients. The ADMCI-EEA group showed: 1) more abnormal Aß42 levels in the cerebrospinal fluid as compared to the ADMCI-noEEA group and 2) higher temporal and occipital delta (<4 Hz) rsEEG source activities as compared to the ADMCI-noEEA and Nold groups. Those source activities showed moderate accuracy (AUROCC = 0.70-0.75) in the discrimination between ADMCI-noEEA versus ADMCI-EEA individuals. CONCLUSION: It can be speculated that in ADMCI-EEA patients, AD-related amyloid neuropathology may be related to an over-excitation in neurophysiological low-frequency (delta) oscillatory mechanisms underpinning cortical arousal and quiet vigilance.

Reactivity of posterior cortical electroencephalographic alpha rhythms during eyes opening in cognitively intact older adults and patients with dementia due to Alzheimer's and Lewy body diseases.

Please modify the Abstract as follows:Here we tested if the reactivity of posterior resting-state electroencephalographic (rsEEG) alpha rhythms from the eye-closed to the eyes-open condition may differ in patients with dementia due to Lewy Bodies (DLB) and Alzheimer's disease (ADD) as a functional probe of the dominant neural synchronization mechanisms regulating the vigilance in posterior visual systems.We used clinical, demographical, and rsEEG datasets in 28 older adults (Healthy), 42 DLB, and 48 ADD participants. The eLORETA freeware was used to estimate cortical rsEEG sources.Results showed a substantial (> -10%) reduction in the posterior alpha activities during the eyes-open condition in 24 Healthy, 26 ADD, and 22 DLB subjects. There were lower reductions in the posterior alpha activities in the ADD and DLB groups than in the Healthy group. That reduction in the occipital region was lower in the DLB than in the ADD group.These results suggest that DLB patients may suffer from a greater alteration in the neural synchronization mechanisms regulating vigilance in occipital cortical systems compared to ADD patients.

Resting State Alpha Electroencephalographic Rhythms Are Affected by Sex in Cognitively Unimpaired Seniors and Patients with Alzheimer's Disease and Amnesic Mild Cognitive Impairment: A Retrospective and Exploratory Study.

In the present retrospective and exploratory study, we tested the hypothesis that sex may affect cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms recorded in normal elderly (Nold) seniors and patients with Alzheimer's disease and mild cognitive impairment (ADMCI). Datasets in 69 ADMCI and 57 Nold individuals were taken from an international archive. The rsEEG rhythms were investigated at individual delta, theta, and alpha frequency bands and fixed beta (14-30 Hz) and gamma (30-40 Hz) bands. Each group was stratified into matched females and males. The sex factor affected the magnitude of rsEEG source activities in the Nold seniors. Compared with the males, the females were characterized by greater alpha source activities in all cortical regions. Similarly, the parietal, temporal, and occipital alpha source activities were greater in the ADMCI-females than the males. Notably, the present sex effects did not depend on core genetic (APOE4), neuropathological (Aß42/phospho-tau ratio in the cerebrospinal fluid), structural neurodegenerative and cerebrovascular (MRI) variables characterizing sporadic AD-related processes in ADMCI seniors. These results suggest the sex factor may significantly affect neurophysiological brain neural oscillatory synchronization mechanisms underpinning the generation of dominant rsEEG alpha rhythms to regulate cortical arousal during quiet vigilance.

Exploring the role of immune pathways in the risk and development of depression in adolescence: Research protocol of the IDEA-FLAME study.

Extensive research suggests a role for the innate immune system in the pathogenesis of depression, but most of the studies are conducted in adult populations, in high-income countries and mainly focus on the study of inflammatory proteins alone, which provides only a limited understanding of the immune pathways involved in the development of depression. The IDEA-FLAME study aims to identify immune phenotypes underlying increased risk of developing depression in adolescence in a middle-income country. To this end, we will perform deep-immunophenotyping of peripheral blood mononuclear cells and RNA genome-wide gene expression analyses in a longitudinal cohort of Brazilian adolescents stratified for depression risk. The project will involve the 3-year follow-up of an already recruited cohort of 150 Brazilian adolescents selected for risk/presence of depression on the basis of a composite risk score we developed using sociodemographic characteristics (50 adolescents with low-risk and 50 with high-risk of developing depression, and 50 adolescents with a current major depressive disorder). We will 1) test whether the risk group classification at baseline is associated with differences in immune cell frequency, phenotype and functional status, 2) test whether baseline immune markers (cytokines and immune cell markers) are associated with severity of depression at 3-year follow-up, and 3) identify changes in gene expression of immune pathways over the 3-year follow-up in adolescents with increased risk and presence of depression. Because of the exploratory nature of the study, the findings would need to be replicated in a separate and larger sample. Ultimately, this research will contribute to elucidating key immune therapeutic targets and inform the development of interventions to prevent onset of depression among adolescents.

The Complex Molecular Picture of Gut and Oral Microbiota-Brain-Depression System: What We Know and What We Need to Know.

Major depressive disorder (MDD) is a complex mental disorder where the neurochemical, neuroendocrine, immune, and metabolic systems are impaired. The microbiota-gut-brain axis is a bidirectional network where the central and enteric nervous systems are linked through the same endocrine, immune, neural, and metabolic routes dysregulated in MDD. Thus, gut-brain axis abnormalities in MDD patients may, at least in part, account for the symptomatic features associated with MDD. Recent investigations have suggested that the oral microbiome also plays a key role in this complex molecular picture of relationships. As on one hand there is a lot of what we know and on the other hand little of what we still need to know, we structured this review focusing, in the first place, on putting all pieces of this complex puzzle together, underlying the endocrine, immune, oxidative stress, neural, microbial neurotransmitters, and metabolites molecular interactions and systems lying at the base of gut microbiota (GM)-brain-depression interphase. Then, we focused on promising but still under-explored areas of research strictly linked to the GM and potentially involved in MDD development: (i) the interconnection of GM with oral microbiome that can influence the neuroinflammation-related processes and (ii) gut phageome (bacteria-infecting viruses). As conclusions and future directions, we discussed potentiality but also pitfalls, roadblocks, and the gaps to be bridged in this exciting field of research. By the development of a broader knowledge of the biology associated with MDD, with the inclusion of the gut/oral microbiome, we can accelerate the growth toward a better global health based on precision medicine.