Band 4, Heft 2

Recent investigations into the etiology and pathogenesis of Alzheimer’s disease (AD) in the past few years have expanded to include previously unexplored and/or disconnected aspects of AD and related conditions at both the cellular and systemic levels of organization. These include how AD-associated abnormalities affect the cell cycle and neuronal differentiation state and how they recruit signal transduction, membrane trafficking and protein transcytosis mechanisms to produce a neurotoxic syndrome capable of spreading itself throughout the brain. The recent expansion of AD research into intercellular and new aspects of cellular degenerative mechanisms is causing a systemic re-evaluation of AD pathogenesis, including the roles played by well-studied elements, such as the generation of Aβ and tau protein aggregates. It is also changing our view of neurodegenerative diseases as a whole. Here we propose a conceptual framework to account for some of the emerging aspects of the role of tau in AD pathogenesis.

During the past few years, there have been many important contributions to the better understanding of the different types of memory and the putative neural structures that generate them. Moreover, various studies on neurodegenerative diseases in human beings have added useful information about learning and memory formation, and about their loss in patients with these disabling diseases. The development of sophisticated pharmacogenetic tools applied to mouse models, reproducing different types of neurodegenerative disease or, at least, some of their main symptoms, has turned out to be extremely useful for the further development of contemporary neuroscience. In addition, ingenious behavioral and electrophysiological approaches have been developed to study the activity-dependent changes in synaptic strength during learning and memory processes in the best possible way — that is, in the alert behaving animal. Collected data from these numerous studies have enabled us to know more about the role of many different molecular components integrating the synaptic cleft, and to draw some conclusions about the concordance between in vitro and in vivo recorded data, and the generalization of the results to other types of learning and/or brain-related structures. As described here, changes in synaptic strength studied in key neural synapses during learning and memory processes in genetically manipulated mice can represent an interesting and powerful approach to the better understanding of neural processes underlying the acquisition of new motor and cognitive abilities and how they are affected by different human diseases involving the neural tissue.

Astrocytes are the predominant glial cell population in the central nervous system (CNS). Once considered only passive scaffolding elements, astrocytes are now recognised as cells playing essential roles in CNS development and function. They control extracellular water and ion homeostasis, provide substrates for energy metabolism, and regulate neurogenesis, myelination and synaptic transmission. Due to these multiple activities astrocytes have been implicated in almost all brain pathologies, contributing to various aspects of disease initiation, progression and resolution. Evidence is emerging that astrocyte dysfunction can be the direct cause of neurodegeneration, as shown in Alexander’s disease where myelin degeneration is caused by mutations in the gene encoding the astrocyte-specific cytoskeleton protein glial fibrillary acidic protein. Recent studies point to a primary role for astrocytes in the pathogenesis of other genetic leukodystrophies such as megalencephalic leukoencephalopathy with subcortical cysts and vanishing white matter disease. The aim of this review is to summarize current knowledge of the pathophysiological role of astrocytes focusing on their contribution to the development of the above mentioned leukodystrophies and on new perspectives for the treatment of neurological disorders.

Serotonin (5HT) is a biologically active amine with diverse roles in the mammalian organism. Developmental alterations in 5HT homeostasis could lead to exposure of the developing brain to non-optimal serotonin concentrations that may result in developmental and behavioral deficits. In order to explore the molecular basis of the effects of developmental disturbances on 5HT metabolism on adult central 5HT homeostasis, observed in our previous studies, we measured changes in gene expression of the neuronal 5HT-regulating proteins in adult animals after perinatal treatment with the immediate 5HT precursor 5-hydroxytryptophan (5HTP, 25 mg/kg), or monoamine oxidase (MAO) inhibitor tranylcypromine (TCP 2 mg/kg), during the period of the most intensive development of 5HT neurons — from gestational day 12 until postnatal day 21. Adult animals were sacrificed and the relative mRNA levels for tryptophan hydroxylase 2, MAO A, MAO B, receptors 5HT1A and 5HT2A, 5HT transporter (5HTT) and vesicular monoamine transporter (VMAT) were determined in the raphe nuclei region and prefrontal cortex using Real-Time Relative qRT-PCR. In comparison to the saline treated animals, treatment with 5HTP caused mild but significant increase in MAO A and MAO B mRNA abundance. TCP-treated animals, besides an increase in mRNA abundance for both MAO genes, displayed significantly increased 5HTT and VMAT2 mRNA levels and significantly decreased 5HT1A receptor mRNA levels. Our results suggest that perinatal exposure of rats to 5HTP, and especially TCP, induces long-lasting/permanent changes in the expression of 5HT-regulating genes, that presumably underlie 5HT-related neurochemical and behavioral changes in adult animals.

An extremely large number of genes have been associated with autism. The functions of these genes span numerous domains and prove challenging in the search for commonalities underlying the conditions. In this study, we instead looked at characteristics of the genes themselves, specifically in the nature of their transposable element content. Utilizing available sequence databases, we compared occurrence of transposons in autismrisk genes to randomized controls and found that transposable content was significantly greater in our autism group. These results suggest a relationship between transposable element content and autism-risk genes and have implications for the stability of those genomic regions.

Suicide and bipolar disorder (BD) are challenging, complex, and intertwined areas of study in contemporary psychiatry. Indeed, BD is associated with the highest lifetime risk for suicide attempt and completion of all the psychiatric conditions. Given that several clinical risk factors for both suicide and BD have been well noted in the literature, exploring the neurobiological aspects of suicide in BD may provide insights into both preventive measures and future novel treatments. This review synthesizes findings regarding the neurobiological aspects of suicide and, when applicable, their link to BD. Neurochemical findings, genes/epigenetics, and potential molecular targets for current or future treatments are discussed. The role of endophenotypes and related proximal and distal risk factors underlying suicidal behavior are also explored. Lastly, we discuss the manner in which preclinical work on aggression and impulsivity may provide additional insights for the future development of novel treatments.

Transcranial magnetic stimulation (TMS) is a neurostimulation and neuromodulation technique that has provided over two decades of data in focal, non-invasive brain stimulation based on the principles of electromagnetic induction. Its minimal risk, excellent tolerability and increasingly sophisticated ability to interrogate neurophysiology and plasticity make it an enviable technology for use in pediatric research with future extension into therapeutic trials. While adult trials show promise in using TMS as a novel, non-invasive, non-pharmacologic diagnostic and therapeutic tool in a variety of nervous system disorders, its use in children is only just emerging. TMS represents an exciting advancement to better understand and improve outcomes from disorders of the developing brain.

Amyloid β1–42 (Aβ1–42), total tau (t-tau), and phosphorylated tau (p-tau) are the main cerebrospinal fluid (CSF) biomarkers for early diagnosis of Alzheimer’s disease (AD). Detection of AD is critically important in view of the growing number of potential new drugs that may influence the course of the disease in its early phases. However, cut-off levels for these CSF biomarkers have not yet been established. Variability in absolute concentrations of AD biomarkers is high among studies and significant differences were noticed even within the same datasets. Variability in biomarkers levels in these assays may be due to many aspects of operating procedures. Standardization of pre-analytical and analytical procedures in collection, treatment, and storage of CSF samples is crucial because differences in sample handling can drastically influence results. Multicenter studies showed that usage of ELISA kits from different manufacturers also affects outcome. So far only very few studies tested the efficiency of ELISA kits produced by different vendors. In this study, the performance of Innogenetics (Gent, Belgium) and Invitrogen (Camarillo, CA, USA) ELISA kits for t-tau and Aβ1–42 was tested. Passing-Bablok analysis showed significant differences between Invitrogen and Innogenetics ELISA methods, making it impossible to use them interchangeably.

Much evidence indicates that gene-by-environment interactions (GxE) play a role in alcohol misuse. It has been proposed that interactions between serotonin and stress confer vulnerability for alcohol misuse. The present review examined studies of the interaction between the serotonin transporter linked polymorphic region (5-HTTLPR) genotype and stressful life events and alcohol-related phenotypes, in rhesus monkeys and humans. Ten studies were found that had investigated the interaction of 5-HTTLPR and various measures of stress and alcohol use or misuse, two studies of rhesus monkeys, and eight of humans. The results are contradictory. Important differences were reported in study samples, experimental designs, measures used to assess environmental variables, definitions and measurements of alcohol-related phenotypes, and in the statistical analyses. These differences may explain the contradictory results. Guidelines for future studies are suggested. Results are discussed in light of findings from molecular, non-human animal, and clinical studies. The review highlights the need for future studies examining associations of interactions between the serotonin transporter gene and environmental factors and alcohol misuse, especially in samples followed over time.

Non-epileptic seizures (NES) are episodes that appear as epileptic seizures, but are not caused by epileptic discharges in the brain. The inclusion of NES in the differential diagnosis of epileptic seizures is important, as an accurate diagnosis is required for the administration of appropriate treatment. NES in the differential diagnosis may be classified as (1) physiologic or pathophysiologic NES, e.g. syncope, sleep disturbances, motor symptoms, migraine attacks, etc., and (2) psychogenic NES (PNES), e.g. affective disorders with anxiety or panic, dissociative disorders (somatoform or conversion) as well as depression or posttraumatic stress disorder (PTSD). PNES is the condition most frequently misdiagnosed as epilepsy. We report NES as experienced in our epilepsy monitoring unit (EMU) for adults in the neurology department of a university hospital in Norway. Our main emphasis is on PNES, highlighting the diagnostic procedures, currently recommended treatment options, and follow-up. A team approach with video-EEG monitoring and clinical observation by trained nurses, epileptologists and other personnel is preferred in the diagnosis and treatment of PNES. Evaluations are performed by a neuropsychologist and trained social worker. The EMU closely cooperates with cardiologists and sleep center specialists. They can also refer patients to psychosomatic medicine specialists. Components of the differential diagnosis addressed are syncope, motor symptoms, sleep disorders, migraine and other paroxysmal neurological symptoms.

It is known that the brain can compensate for deficits induced by acquired and developmental lesions through functional reorganization of the remaining parenchyma. Arteriovenous malformations (AVM) usually appear prenatally before a functional regional organization of the brain is fully established and patients generally do not present with motor deficits even when the AVM is located in the primary motor area indicating the redistribution of functions in cortical areas that are not pathologically altered. Here we present reorganization of the motor cortex in a patient with a large AVM involving most of the left parietal lobe and the paramedian part of the left precentral gyrus that is responsible for controlling the muscles of the lower limbs. Functional MRI showed that movements of both the right and left feet activated only the primary motor cortex in the right hemisphere, while there was no activation in the left motor cortex. This suggests that complete ipsilateral control over the movements of the right foot had been established in this patient. A reconstruction of the corticospinal tract using diffusion tensor imaging showed a near-complete absence of corticospinal fibers from the part of the left precentral gyrus affected by the AVM. From this clinical presentation it can be concluded that full compensation of motor deficits had occurred by redistributing function to the corresponding motor area of the contralateral