Brain Sciences 2019-2020 Best Cover Award

Glioblastoma (GB) are a grade IV aggressive brain tumor with limited treatment options available (chemo- and radiation therapy). The usual lifespan of patients is about 18 months following treatment. To extend the quality of life beyond this boundary, better approaches are necessary, such as targeted gene and drug therapy, use of oncolytic virus, and nutraceuticals. Some of these treatments can reach the GB brain, crossing the blood–brain barrier following systemic injections; however, most of them are failing. To overcome this issue, we and others have used nanoparticles as a vehicle to deliver therapeutics to the brain following systemic injections.

Lemur tyrosine-kinase 2 (LMTK2) is implicated in several physiological and pathological processes. Recent studies have found decreased LMTK2 level in Alzheimer’s disease (AD). However, the relation between LMTK2 and neurofibrillary tangles (NFTs) as the hallmark pathological alteration of AD has not yet been investigated. The main constituent of NFTs is the hyperphosphorylated tau protein. Therefore, we performed LMTK2/phospho-tau fluorescent double-labelling immunohistochemistry in different neuropathological Braak tau stages of AD. We detected a strong negative correlation between the expression of LMTK2 and the extent of NFT pathology. Consequently, it seems that decreased LMTK2 level is not a general feature of AD brains; rather, it is characteristic of the NFT‐affected regions

While EEG alpha desynchronization has been related to orienting of visuospatial attention, its synchronization would index an inhibition of attentional processes. Research has indicated that alpha is also affected by a deficient brain oxygenation (hypoxia). In this study, alpha power during attention alerting, cued and uncued orienting, and control functions in different workload conditions was monitored both in normoxia and hypoxia in healthy students. Independent of oxygenation level, alpha desynchronization was maximal during uncued attentional orienting, whereas hypoxia enhanced alpha synchronization over the right-sided occipitoparietal areas. We interpreted such right-sided modulation as a marker of the suppression of attentional processing induced by hypoxia.

The role of infections in the pathogenesis of autism spectrum disorder (ASD) is still controversial. In this study, we aimed to evaluate markers of infections and immune activation in ASD. Our data do not support an association between infections and ASD; however, a significant number of genes belonging to the prion diseases pathway was found to be modulated in the ASD brain, providing support for the involvement in ASD of common biomolecular pathways related to other neurodegenerative diseases.

We aimed to clarify the effect of the type and number of adverse childhood experiences (ACE) and the timing of adverse experiences on clinical outcomes in 2,675 patients with bipolar disorders. We found that ACE have robust negative effects on clinical outcomes, including earlier age at onset, presence of psychotic episodes, suicide attempts, mixed symptoms, substance misuse comorbidity, and worse life functioning. Specifically, the number of ACE had the most significant effect on clinical outcomes; however, specific ACE, such as physical abuse, had a considerable influence. Moreover, post-childhood adverse experiences had a weaker effect on clinical outcomes than ACE.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system and is considered to be the leading nontraumatic cause of neurological disability in young adults. The Holy Grail for the treatment of MS is to specifically suppress the disease while at the same time allow the immune system to be active against infections and malignancy. This could be achieved by developing immunotherapies designed to specifically suppress immune responses to myelin antigens. This study aims to review different myelin antigen-specific strategies for the prevention/treatment of MS and the challenges they face in being translated to MS patients.

Sleep plays a major role in the neurocognitive development of children, and cognitive impairment is frequent in pediatric cancer, as well as in children who have survived cancer. Pediatric tumors are also often associated with sleep disorders. However, the relationship between sleep disorders, neurodevelopmental disorders, and pediatric cancer is still largely unexplored. Pediatric cancer can be a cause of neurodevelopmental disorders or occur as a comorbid condition in children with neurodevelopmental disorders. In turn, sleep disorders have a particular role in children with cancer and neurodevelopmental disorders. An in-depth knowledge and correct management of sleep disorders can improve the health and quality of life of children with cancer and of their families.

Autistic children present a highly heterogeneous linguistic phenotype involving both expressive and receptive difficulties. The latter, in particular when not associated with expressive deficits, may go unnoticed and may be neglected despite their relevance in everyday life. Grammatical comprehension is the most impaired language domain in autism and is a paramount prognostic marker for developmental trajectories. As grammatical comprehension difficulties tend to persist up to school-age (when generally speech therapy is gradually decreasing) specific interventions on both oral and written receptive skills are mandatory: provision of early support for the acquisition of adequate receptive language skills is crucial for further social development.

Gulf War veterans suffer from a chronic multi-symptom disorder called Gulf War Illness (GWI) that has been associated with central nervous system (CNS) dysfunction. Symptoms of GWI overlap with other chronic conditions, including irritable bowel syndrome (IBS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). To differentiate these disorders, we examined blood-based CNS autoantibody biomarkers among the illnesses. We found that veterans with GWI had much higher levels of autoantibodies to 9 out of 10 CNS proteins in their blood showing that GWI is a distinct disorder with more CNS involvement than ME/CFS or IBS.

Children with fragile X syndrome (FXS) exhibit deficits in a variety of cognitive processes within the executive function domain. As working memory (WM) is known to support a wide range of cognitive, learning and adaptive functions, WM computer-based training programs have the potential to benefit people with FXS and other forms of intellectual and developmental disability (IDD). However, research on the effectiveness of WM training has been mixed. The current study is a follow-up “deep dive” into the data collected during a randomized controlled trial of Cogmed (Stockholm, Sweden) WM training in children with FXS.

Pathological inclusions known as neurofibrilary tangles, composed of the microtubule associated protein tau (tau), are a typical pathological hallmark in Alzheimer’s and other neurodegenerative disorders. Tau pathology seems to spread between neurons as disease progresses, but the precise mechanisms underlying pathology spreading are still unclear. Nevertheless, pharmacological modulation of tau aggregation and spreading between neurons is a promising strategy for therapeutic intervention.

Alzheimer’s disease is a complex, multifaceted neurodegenerative disorder. There is increasing evidence that a key signalling system in the brain—Wnt signalling—becomes dysregulated as part of the disease process, and this may lead to loss of synapses, altered microglial function and potentially an impaired blood–brain barrier. Deeper understanding of this dysregulation may reveal opportunities for therapeutic intervention through normalisation of specific components of the Wnt signalling process.

Like humans, some rodents will drink to excess, and a tendency to binge drink is in part inherited. The cover image shows inbred High Drinking in the Dark mice. These mice have been bred for their willingness to drink alcohol to the point of intoxication, and offer insight into the genetic contributors to risk. The paper explores their motivation to drink in binge-like fashion and reports their apparent failure to stop drinking once intoxication has occurred. The animals offer a partial model for one of the most troubling features of alcohol use disorders.

Measuring gait and postural control provides valuable information about neurological conditions. Using quantifiable measures of gait and postural control, we can evaluate subtle impairments as well as providing a standardised approach for clinical use. Research supports the use of gait and postural control outcomes for risk prediction, disease phenotyping, to enhance diagnostic algorithms and track disease progression. In turn, this allows optimised therapeutic interventions and clinical management. This review highlights the efforts made in Parkinson’s disease, ataxia and dementia. It also envisions future directions for quantitative gait and postural control assessment in the management of neurological disorders with technological advancements and the evolution of data analytics.

Alcohol use disorder (AUD) is a chronic relapsing brain disease with a lifetime prevalence of ~29%. AUD has devastating consequences for the affected individual and their families. In addition, the financial burden to society is enormous. While previous work has found that AUD has a high rate of heritability, DNA variants identified by genetic studies only explain a small amount of this heritability. Beeler et al. tested the hypothesis that alcohol-induced epigenetic changes contribute to the effects of alcohol across generations. Using an inbred mouse model, Beeler et al. demonstrated that paternal preconception voluntary alcohol drinking altered various behaviors and alcohol consumption in adult offspring. This study adds to a growing literature that one’s alcohol drinking behavior is impacted by ancestral alcohol exposure. Images used under license from Shutterstock.com.

Borderline Personality Disorder (BPD) has been the subject of extensive research, particularly its symptom of impulsivity, which is considered a key component of neurobehavioral models of BPD and often leads to severe negative consequences for the person. Impulsivity and the measurements used to assess it have greatly evolved over time. Recently, the study of inhibition processes with behavioral tasks has highlighted some cognitive and affective deficits in this population. However, the literature presents important inconsistencies which raise questions about the potential role played by personality processes such as the self-concept. We investigated this question via a systematic review and our results lead us to propose a new theoretical model which integrates inhibition processes and the self-concept in order to explain the occurrence of borderline impulsive behavior.

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by a wide range of intellectual ability, autism and to various degrees of behavior and social difficulties. Over the past decades, significant advancements have been made in characterizing the molecular and cellular underpinnings of FXS, leading to a better diagnosis. Further, extensive research and preclinical studies have been conducted to develop molecular signatures for target drug development and pharmacologic treatments. However, the lack of feasible biomarkers limits our ability to monitor disease severity and to evaluate the clinical benefit of pharmaceutical interventions. This review highlights the efforts made in establishing potential molecular biomarkers in FXS by using in vivo and in vitro models and the promising stories of the ones that have proven their worth in current human clinical trials.

In the last 15 years, increasing numbers of individuals have self-referred to research laboratories in the belief that they experience severe everyday difficulties with face recognition. The current study assessed 165 adults who believe they experience DP, and 38% of the sample were impaired on at least two of the tests outlined above. While statistical dissociations between face perception and face memory were only observed in four cases, a further 25% of the sample displayed dissociations between impaired famous face recognition and intact short-term unfamiliar face memory and face perception. We discuss whether this pattern of findings reflects (a) limitations within dominant diagnostic tests and protocols, (b) a less severe form of DP, or (c) a currently unrecognized but prevalent form of the condition that affects long-term face memory, familiar face recognition or semantic processing.

Immune dysfunction is often reported in autism spectrum disorders (ASD), however, the extent and type of inflammation has been reported with mixed and sometimes contradictory findings. One common component that may help to explain these different inflammatory profiles is deficits in immune regulation. We and others have previously found reductions in regulatory T cells (Tregs) and associated cytokines. Tregs, though they make up a small percentage of the body’s lymphocytes, provide the necessary signals required to control immune responses and bring the immune system back to homeostasis. In the current study we describe reduced plasma interluekin-35, a novel immunoregulatory cytokine produced primarily by Tregs, in children with ASD and discuss how deficits in immune regulation may contribute to etiology and aberrant behaviors associated with ASD.

Alzheimer's disease is a neurological disorder characterized by brain cell death, memory loss and cognitive decline. The porpouse of this work was to study the transcriptional profile in cells of neuroblastoma differentiated with retinoic acid, exposed to Aβ1-42 and subsequently treated with α-tocopherol. The results of the transcriptomic analysis showed that the treatment of α-tocopherol upregulated the genes involved in processing the APP through the non-amyloidogenic pathway. Furthermore, α-tocopherol modulated the expression of genes involved in autophagy by degrading the autophagosomes. In addition, α-tocopherol downregulated some cell cycle markers, such as cyclins and cyclin-dependent kinases and markers of DNA replication. Immunohistochemistry has shown that treatment with α-tocopherol was also able to reduce oxidative stress.

The possibility to detect the earliest clinical manifestations of Alzheimer’s disease, in order to proceed to a biomarker based diagnosis even before the stage of mild cognitive impairment (MCI), represents a major goal, since it would offer the opportunity to have a timely access disease-modifying drugs. In a recent systematic review and meta-analysis, it has been shown that individuals with subtle cognitive decline (“pre-MCI”) with AD biomarker positivity - pre-MCI due to AD - have a high risk of progression to MCI or dementia, similar to what observed for MCI due to AD (Parnetti et al., 2019). In this review, we further focus on this issue, giving more details about neuropsychological profile, its association with biomarkers and neuropathological picture.

Autism spectrum disorder (ASD) is a complex neuropsychiatric disorder characterized by deficits in social interactions, communication, language and in a limited repertoire of activities and interests. Genetic, epigenetic and environmental factors contribute to the onset of ASD. This work aims to provide an overview of the animal models of ASD and the role of the different miRNAs involved in this disorder. The results of this study showed that miRNA-125b, miRNA-132, miRNA-146a, miRNA-146b, miRNA-137, miRNA-134, miRNA-358 134-5p, miRNA-138-5p, miRNA-34a, miRNA-181c and miRNA-30d regulate the expression of several genes directly involved in ASD. On the basis of these observations, researchers have identified miRNAs as important biomarkers to discover new targets for ASD treatment.

Very limited knowledge exists regarding risk factors of insomnia among African-American older adults who live in economically disadvantaged areas. This study investigated measured insomnia, in addition to demographic factors, financial difficulty, number of chronic diseases, self-rated health, pain intensity, and depression among 398 African-American older adults in one of the most economically disadvantaged areas of Los Angeles. Financial difficulty, pain, chronic disease and depression were associated with higher odds of clinical insomnia. Insomnia does not occur in a vacuum and accompanies other social and health needs. African-American older adults who live in economically disadvantaged areas require comprehensive care packages that simultaneously address insomnia, financial needs, mental health, and physical health.

Clinical data suggest that deafferentation-related disinhibition tends to occur primarily in the aged brain. Therefore, aging-related disinhibition may, in part, be related to the high metabolic demands of inhibitory neurons relative to their excitatory counterparts. These findings suggest that both deafferentation-related maladaptive plastic changes and aging-related metabolic factors combine to produce changes in central auditory function. Here, we explore the arguments that downregulation of inhibition may be due to homeostatic responses to diminished afferent input vs. metabolic vulnerability of inhibitory neurons in the aged brain. Understanding the relative importance of these mechanisms will be critical for the development of treatments for the underlying causes of aging-related central disinhibition.