Background: The Apolipoprotein E4 (ApoE4) genotype is strongly associated with Alzheimer’s disease (AD), although the presence of the ApoE4 allele alone is not sufficient to explain AD. The pathophysiology of amnestic mild cognitive impairment (aMCI) remains unclear. This study aims to examine associations between peripheral blood biomarkers coupled with ApoE4 and episodic and semantic memory. Methods: The CERAD battery was completed and various biomarkers were assayed in 60 subjects with aMCI, 60 with AD and 62 healthy controls. Results: Deficits in semantic and episodic memory were significantly predicted by anion gap and bicarbonate, albumin and glucose coupled with Apo E4. Furthermore, these peripheral biomarkers interacted with ApoE to predict greater memory impairments. Conclusions: Peripheral blood biomarkers may interact with pathways related to ApoE4 to predict greater semantic and episodic memory impairments, thus contributing to the pathophysiology of aMCI and AD. Our data suggest that the transition from aMCI to AD could at least in some cases be associated with significant interactions between ApoE4 and those peripheral blood biomarkers.

Autism Spectrum Disorders (ASD) are neurodevelopmental disturbances affecting social skills, whose incidence worldwide is dramatically increasing. Together with the rise of ASD prevalence, several immune conditions are following the same trend, including Atopic Dermatitis (AD), with a possible clinical relationship with ASD. To date, their pathogenesis is still unknown, but several studies highlighted the relevance of gene-environment interactions to the onset of both disorders. Among potential contributing factors, microRNAs (miRNAs), small molecules capable of controlling gene expression and targeting mRNA transcripts, might represent one of the major circulating link, unraveling the connections between neurodevelopmental and immune conditions. We conducted a systematic literature review, under the PRISMA guidelines, trying to define the panel of common miRNAs involved in both ASD and AD. The review retrieved articles published until December 13, 2018, in PubMed, ScienceDirect, PsycARTICLES and Google Scholar. We found a handful works dealing with miRNAs in ASD and AD, with the most overlapping dysregulated miRNAs being miR-146 and miR-155. Two possible compounds are abnormally regulated in both ASD and AD subjects, possibly cross-contributing to the interactions between the two disorders, setting the basis to investigate more precisely the possible link between ASD and AD from another, not just clinical, perspective.

Increased gut permeability (leaky gut) with increased translocation of Gram-negative bacteria plays a role in the gut-brain axis through effects on systemic immune-inflammatory processes. Deficit schizophrenia is characterized by an immune-inflammatory response combined with a deficit in natural IgM antibodies to oxidative specific epitopes (OSEs), which are a first line defense against bacterial infections. This study measured plasma IgA/IgM responses to 5 Gram-negative bacteria in association with IgM responses to malondialdehyde (MDA) and azelaic acid in 80 schizophrenia patients (40 with the deficit syndrome and 40 without) and in 38 healthy controls.Deficit schizophrenia was characterized by significantly increased IgA responses to Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii and Klebsiella pneumoniae as compared with non-deficit schizophrenia. The presence of deficit schizophrenia was highly predicted by increased IgA responses to Pseudomonas putida and IgM responses to all 5 Gram-negative bacteria and lowered natural IgM to MDA and azelaic acid with a bootstrap area under the ROC curve of 0.960 (2000 random curves). A large proportion of the variance (41.5%) in the PANSS negative score was explained by the regression on IgA responses to K. pneumoniae and IgM responses to the 5 enterobacteria coupled with lowered IgM antibodies to azelaic acid. There were significant associations between IgA levels to Gram-negative bacteria and Mini Mental State Examination, Boston naming test, Verbal Fluency and Word List Memory test scores.These findings provide further evidence that deficit schizophrenia is a distinct phenotype of schizophrenia, which is characterized by an increased impact of Gram-negative commensal bacteria coupled with a deficit in natural IgM, pointing to aberrations in B1 cells. It is concluded that increased bacterial translocation and deficits in the compensatory immune-regulatory system (CIRS) may drive negative symptoms and neurocognitive impairments, which are hallmarks of deficit schizophrenia.

Schizophrenia is characterized by an interrelated activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory reflex system (CIRS), which downregulates the IRS. Deficit schizophrenia is characterized by a deficit in natural regulatory autoimmune responses to tryptophan catabolites. The presence and correlates of IgM isotype antibodies to oxidative specific epitopes (OSEs), nitroso (NO) and nitro (NO₂) adducts in schizophrenia remain unknown.This study measured IgM antibodies to malondialdehyde (MDA), azelaic acid, phosphatidylinositol, oleic acid, NO-tryptophan, NO-albumin, NO-cysteinyl and NO₂-tyrosine in a sample of 80 schizophrenia patients, divided into those with and those without deficit schizophrenia, and 38 healthy controls.Deficit schizophrenia was characterized by significantly lower IgM antibody levels to all OSEs as compared with non-deficit schizophrenia and controls. Lowered IgM antibodies to MDA coupled with increased IgM levels to NO-cysteinyl and NO₂-tyrosine strongly predict deficit schizophrenia versus non-deficit schizophrenia with an area under the ROC curve of 0.913. A large part of the variance (21.2 – 42.2 %) in the negative symptoms of schizophrenia and excitation is explained by IgM antibody titers to MDA (inversely) and NO-cysteinyl and/or NO₂-tyrosine (both positively). Lower IgM antibodies to MDA are significantly associated with impairments in episodic memory including direct and delayed recall.These findings further indicate that deficit schizophrenia is a distinct phenotype of schizophrenia, which is characterized by lower natural IgM antibody levels to OSEs and relative increments in nitrosylation and nitration of proteins. It is concluded that deficits in lowered IgM responses to MDA and azelaic acid (part of the CIRS) attenuate the negative immune-regulatory feedback on the primary immune response and that this process may drive negative symptoms and impairments in episodic memory and thus deficit schizophrenia.

Ongoing debates regarding the virtues and challenges of implementing open science for brain imaging research mirror those of the larger scientific community. The present commentary acknowledges the merits of arguments on both sides, as well as the underlying realities that have forced so many to feel the need to resist the implementation of an ideal. Potential sources of top-down reform are discussed, along with the factors that threaten to slow their progress. The potential roles of generational change and the individual are discussed, and a starter list of actionable steps that any researcher can take, big or small, is provided.

Even though Alzheimer’s disease (AD) is of significant interest to the scientific community, its pathogenesis is very complicated and not well-understood. A great deal of progress has been made in AD research recently and with the advent of these new insights more therapeutic benefits may be identified that could help patients around the world. Much of the research in AD thus far has been very neuron-oriented; however, recent studies suggest that glial cells, i.e., microglia, astrocytes, oligodendrocytes, and oligodendrocyte progenitor cells (NG2 glia), are linked to the pathogenesis of AD and may offer several potential therapeutic targets against AD. In addition to a number of other functions, glial cells are responsible for maintaining homeostasis (i.e., concentration of ions, neurotransmitters, etc.) within the central nervous system (CNS) and are crucial to the structural integrity of neurons. This review explores the: (i) role of glial cells in AD pathogenesis; (ii) complex functionalities of the components involved; and (iii) potential therapeutic targets that could eventually lead to a better quality of life for AD patients

One of the most commonly known chronic neurodegenerative disorders, Alzheimer’s disease (AD), manifests the common type of dementia in 60–80% of cases. From a clinical standpoint, a patent cognitive decline and a severe change in personality, as caused by a loss of neurons, is~usually evident in AD with about 50 million people affected in 2016. The disease progression in patients is distinguished by a gradual plummet in cognitive functions, eliciting symptoms such as memory loss, and eventually requiring full-time medical care. From a histopathological standpoint, the~defining characteristics are intracellular aggregations of hyper-phosphorylated tau protein, known as neurofibrillary tangles (NFT), and depositions of amyloid β-peptides (Aβ) in the brain. The~abnormal phosphorylation of tau protein is attributed to a wide gamut of neurological disorders known as tauopathies. In addition to the hyperphosphorylated tau lesions, neuroinflammatory processes could occur in a sustained manner through astro-glial activation, resulting in the disease progression. Recent findings have suggested a strong interplay between the mechanism of Tau phosphorylation, disruption of microtubules, and synaptic loss and pathology of AD. The mechanisms underlying these interactions along with their respective consequences in Tau pathology are still ill-defined. Thus, in this review: (1) we highlight the interplays existing between Tau pathology and AD; and (2) take a closer look into its role while identifying some promising therapeutic advances including state of the art imaging~techniques.

Recent studies have indicated that several anti-hypertensive drugs may delay the development and progression of Alzheimer’s disease (AD). However, the relationships among AD, hypertension, and oxidative stress remain to be elucidated. In the present study, we aimed to determine whether treatment with resveratrol reduces reactive oxygen species (ROS) generation in the brain, thereby reducing cognitive impairment in rats with angiotensin II (Ang-II)-induced early AD. Male WKY rats with Ang-II-induced AD were treated with losartan or resveratrol for 2 weeks. Our results revealed that treatment with resveratrol (10 mg/kg/day) decreased blood pressure, increased levels of brain-derived neurotrophic factor (BDNF) in the hippocampus, and decreased ROS production in the nucleus tractus solitarius (NTS) in the Ang-II groups. In addition, inhibition of Tau^T231 phosphorylation in the hippocampus using resveratrol significantly abolished Ang-II-induced expression of Ab precursors, active caspase 3, and glycogen synthase kinase 3b (GSK-3b)^Y216 while increasing Akt^S473 phosphorylation. Notably, resveratrol reversed impairments in hippocampal-dependent contextual memory induced by deleting NADPH oxidase and NOX2. Overall, our results suggest that resveratrol exerts neuroprotective effects against memory impairment and hippocampal damage in a rat model of early stage AD by reducing oxidative stress. These novel findings indicate that resveratrol may represent a pharmacological option for patients with hypertension at a risk of AD during old age.

1) Background: We analyzed, by PET-SCAN, how growth hormone (GH) could act on the brain of an older woman, not GH-deficient, which was beginning to show some cognitive deficiencies and presented an ApoE genotype 4/3; 2) Methods: After performing a first psychometric study (TAVEC verbal learning test), the metabolic activity of brain structures related to knowledge, memory, and behavior was analyzed using 18-F Fluorodeoxyglucose PET-SCAN. The patient was then treated with GH (0.4 mg/day) for three weeks and on the last day under this treatment, a new PET-SCAN was performed. One month after beginning treatment with GH, a new TAVEC test was performed; 3) Results: GH administration normalized the cognitive deficits observed in the first psychometric test and increased significantly (P < 0.025) the metabolic activity in practically all brain cortical areas, specifically in the left hippocampus and left amygdala, although not in the left parahippocampus; and 4) Conclusions: This is the first study in which the positive effects of GH on cerebral metabolism have been visualized in a human patient. Our data confirm the positive effects of this hormone on cognition, memory and behavior in patients affected by mild cognitive impairments.

There is increasing evidence and recognition that Lyme borreliosis, and other associated tick-borne diseases (LB/TBD) cause mental symptoms. Data was drawn from databases, search engines and clinical experience to review current information on LB/TBD. LB/TBD infections cause immune and metabolic effects that result in a gradually developing spectrum of neuropsychiatric symptoms, usually presenting with significant comorbidity and may include developmental disorders, autism spectrum disorders, schizoaffective disorders, bipolar disorder, depression, anxiety disorders (panic disorder, social anxiety disorder, generalized anxiety disorder, posttraumatic stress disorder, intrusive symptoms), eating disorders, decreased libido, sleep disorders, addiction, opioid addiction, cognitive impairments, dementia, seizure disorders, suicide, violence, anhedonia, depersonalization, dissociative episodes, derealization and other impairments. Screening assessment followed by a comprehensive psychiatric clinical exam relevant to patient’s complaints and findings with a thorough history, mental status exam, review of systems, neurological exam, physical exam, a knowledgeable interpretation of laboratory findings, pattern recognition and clinical judgment facilitate diagnosis. Psychotropics and antibiotics may help improve functioning and prevent further disease progression. Awareness of the association between LB/TBD and neuropsychiatric impairments and studies of their prevalence in neuropsychiatric conditions can improve understanding of the causes of mental illness and violence and result in more effective prevention, diagnosis and treatment.

1) This study describes the good evolution of a 6-year-old girl genetically diagnosed with Rett syndrome (RTT), after having been treated with IGF-1, MT (MT), blackcurrant extracts (BC), and rehabilitation during 6 months. 2) The patient stopped her normal development from the first year of age. The patient showed low weight and height and met the main criteria for typical RTT. Curiously, there was pubic hair (Tanner II), very high plasma testosterone, despite low gonadotropins. No adrenal enzymatic deficits existed, and ultrasound abdominal studies were normal. Treatment consisted in IGF-1 (0.04 mg/kg/day, 5/week, sc) during 3-months and then 15-days resting, MT (50 mg/day, orally, uninterruptedly) and neurorehabilitation. The new blood tests were absolutely normal and the pubic hair disappeared. Then, a new treatment with IGF-1, MT, and BC started for another 3 months. After it, pubic Tanner stage increased to III, without a known cause. 3) The treatment followed led to clear improvements in most of the initial impairments, perhaps because of the effect of IGF-I, the antioxidant effects of MT and BC, and the increase in cyclic-glycine-proline (cGP) after BC administration. 4) A continuous treatment with IGF-1, MT and BC may recover most of the neurologic disabilities that occur in RTT.

Studies reported adverse behavioral development including internalizing and externalizing problems in association with prenatal exposure to bisphenol A (BPA) and phthalates, however, findings were not sufficient due to using different assessment tools and child ages among studies. This study aimed to examine associations between maternal serum levels of BPA and phthalate metabolites and behavioral problems at preschool age. The Strengths and Difficulties Questionnaire (SDQ) was used to assess behavioral problems at 5 years of age. BPA and phthalate metabolite levels in the 1^st trimester maternal serum was determined by LC-MS/MS for 458 children. Variables used for adjustment were parental ages, maternal cotinine levels, family income during pregnancy, child sex, birth order and age at SDQ completed. The median concentrations of BPA, MnBP, MiBP, MEHP and MECPP were 0.062, 26.0, 7.0, 1.40, and 0.20 ng/ml, respectively. BPA level was associated with increased hyperactivity/inattention risk among girls (OR=1.66, 95% CI: 0.95-2.90) and∑DBP_m (MnBP + MiBP) level was associated with decreased total difficulties risk overall and among girls (OR=0.48, 95% CI: 0.20-1.13, OR=0.24, 95% CI: 0.06-1.03, respectively) without significance. MECPP level was associated with increase conduct problems risk (OR=2.78, 95% CI: 1.36-5.68). Our analyses found no significant association between BPA or summation of phthalate metabolite levels and any of the behavioral problems at 5 years of age, however, suggested possible association between MECPP levels and increased risk of conduct problems.

Objective: to evaluate the effects of excitatory repetitive transcranial magnetic stimulation (rTMS) of the international 10-20 system P3 point (intraparietal sulcus region) in chronic patients with a frontal lesion and parietal sparing due to stroke on the impaired upper (UL) and lower limb (LL) as measured by Fugl-Meyer Assessment (FMA). Methods: three patients (C1: 49.83/2.75, C2: 53.17/3.83, C3: 63.33/3.08 years-old at stroke/ years post-stroke, respectively) received two weeks (five days/ week) of rTMS at 10 Hz of P3. A patient was treated in similar conditions with a sham coil (S1: 56.58/4.33). No complimentary therapy was delivered during the study. Patients were evaluated before, after- and two months post-treatment (A1, A2 and A3, respectively). Results: we found increased scores for LL in motor function subsection for C1 and C3 and in sensory function for C2 by A2 that remained at A3. We also found an increased score for UL motor function for C2 and C3, but the score decreased by A3 for C2. C3 score for UL range of motion increased by A3 compared to A1 and A2. Conclusion: In a variable way, P3 excitatory rTMS increased FMA scores in different upper and lower limb subsections of our three treated patients.

Autism spectrum disorder (ASD) refers to the diverse range of neurodevelopmental disorders accompanying impairments in social interaction, difficulties in communication, and stereotyped or repetitive behaviors. Unlike the older term, autism, the newer term, ASD, better reflects the broad range of autistic symptoms and denotes a single diagnostic category of autism accompanied by numerous conditions. The pineal hormone melatonin is a well-known neuroprotectant and circadian entrainer. This hormone crosses the placenta and enters the fetal circulation, then conveys photoperiodic information to the fetus during pregnancy. These actions enable normal sleep patterns and circadian rhythms, followed by normal neurodevelopment. Melatonin also reduces oxidative stress, which is harmful to the central nervous system. Therefore, melatonin acts as a neuroprotectant and circadian entrainer, and may reduce the risk of neurodevelopmental disorders such as ASD.

The Inventory Déjà Vu Experiences Assessment (IDEA) is the only screening instrument proposed to evaluate Déjà vu (DV) experience. Here we intended to validate the Italian version of IDEA (I-IDEA) and at the same time to investigate the incidence and subjective qualities of DV phenomenon in Italian healthy adult individuals on basis of an Italian multicentre observational study. In this study we report normative data on the I-IDEA, collected on a sample of 542 Italian healthy subjects aging between 18 to 70 years (average age 40, range 18-70) with a formal educational from 1-19 years. From September 2013 to March 2016 were recruited 542 healthy volunteers from ten outpatient neurological clinics in ItalyAll participants (i.e family members of neurological patients enrolled, medicine’s student, physicians) had no neurological or psychiatric illness and they gave informed consent to participate in the study. All subjects enrolled had self-administered the questionnaire and they are able to complete I-IDEA test without any support. In total 396 (73%) of the 542 healthy controls had DV phenomenon. The frequency of DV was inversely related to age as well as to derealisation, jamais vu, precognitive dreams, depersonalization, paranormal activity, remembering dreams, travel frequency and daydreams (all P<0.012). The Italian version of IDEA maintains good properties in Italian version, thus confirming that this instrument is reliable for detecting and characterising the DV phenomenon.

Recent methodological advances have enabled researchers to track the network structure of the human brain over time. Together, these studies provide novel insights into effective brain function, highlighting the importance of the systems-level perspective in understanding the manner in which the human brain organizes its activity to facilitate behavior. Here, we review a range of recent fMRI and electrophysiological studies that have mapped the relationship between inter-regional communication and network structure across a diverse range of brain states. In doing so, we identify both behavioral and biological axes that may underlie the tendency for network reconfiguration. We conclude our review by providing suggestions for future research endeavors that may help to refine our understanding of the functioning of the human brain.

Fragile X syndrome (FXS) is the most frequent monogenic form of autism spectrum disorder (ASD). Autistic FXS is caused by loss of the fmr1 gene product, the fragile X mental retardation protein (FMRP), triggering physiological and behavioral abnormalities. It is correlated with clock components for behavioral circadian rhythm. Mutation of this gene causes the disturbances in sleep patterns and circadian behavior commonly observed in patients with autistic FXS, accompanied by frequent dysregulation of melatonin synthesis and melatonin-dependent signaling. These changes impair vigilance, learning and memory, and are also linked to autistic behavior including the abnormal anxiety response. However, although several possible causes, symptoms, and clinical features of ASD have been investigated, the correlation between an altered circadian rhythm and autistic FXS has not been extensively studied. Recent works have highlighted the impact of melatonin on the nervous, immune, and metabolic systems. Even though utilization of melatonin for sleep disorder in ASD has been considered in clinical research, further studies should be aimed at its neuroprotective role in ASD during developmental period. In this review, we focus on the regulatory circuits involved in melatonin dysregulation and circadian system disruption in those with autistic FXS. Additionally, we discuss the neuroprotective effect of melatonin intervention. This may improve neuroplasticity and physical capability. We also review the underlying molecular mechanisms, and suggest that melatonin may be a useful novel treatment for autistic FXS, countering the adverse effects of circadian variation.

An increased risk of multiple sclerosis (MS) had been found when individuals had consumed large amounts of processed meat and sausages at young age (Lauer, 2014). Furthermore it was found in many studies that MS patients had acquired a number of common childhood infections at higher ages than controls. Therefore, MS patients from an epidemiological long-term investigation in Germany and different hospital controls, were evaluated for a statistical interaction of these two factors. 324 MS patients and 242 hospital controls were inquired. The study focussed on age 0 - 16. Subjects were tested for additive interaction by multiple linear regression analysis (Knol et al., 2007). There was an additive interaction of the age at any common childhood infection with the consumption of scalded sausages (regression estimate = 0.1370; standard error = 0.0603; p = 0.0239). In contrast, no such interaction could be shown for: animal fats; smoked meat (e.g. ham and bacon); and cold - smoked German salami. Thus there was a synergy of the intake of scalded sausages (e.g. frankfurters, bolognas, etc.) and age at common childhood infections, for the later risk of MS.