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Numerous papers report on connections between creative work and dementing illness, particularly in frontotemporal dementia (FTD), which may combine with motor neuron disease (FTD-MND). However, the emergence of FTD(-MND) patients' de novo artistic activities is rarely reported and underappreciated. Therefore, the present review summarizes relevant case studies' outcomes, capturing creativity's multifaceted nature. Here, we systematically searched for case reports by paying particular attention to the chronological development of individual patients' clinical symptoms, signs, and life events. We synoptically compared the various art domains to the pattern of brain atrophy, the clinical and pathological FTD subtypes. 22 FTD(-MND) patients were identified with creativity occurring either at the same time (41%) or starting after the disease onset (59%); the median lag between the first manifestation of disease and the beginning of creativity was two years. In another five patients, novel artistic activity was developed by a median of 8 years before the start of dementia symptoms. Artistic activity usually evolved over time with a peak in performance, followed by a decline that was further hampered by physical impairment during disease progression. Early on, the themes and objects depicted were often concrete and realistic, but they could become more abstract or symbolic at later stages. Emergent artistic processes may occur early on in the disease process. They appear to be a communication of inner life and may also reflect an attempt of compensation or "self-healing". The relative preservation of primary neocortical areas such as the visual, auditory, or motor cortex may enable the development of artistic activity in the face of degeneration of association cortical areas and subcortical, deeper central nervous system structures. It is crucial to understand the differential loss of function and an individual's creative abilities to implement caregiver-guided, personalized therapeutic strategies such as art therapy. [ABSTRACT FROM AUTHOR]

In this paper a hypothesis that some special signals (“key-signals” excito-amino acids, β-amyloid peptides and α-synuclein) are not only involved in information handling by the neuronal circuits, but also trigger out substantial structural and/or functional changes in the Central Nervous System (CNS) is introduced. This forces the neuronal circuits to move from one stable state towards a new state, but in doing so these signals became potentially dangerous. Several mechanisms are put in action to protect neurons and glial cells from these potentially harmful signals. However, in agreement with the Red Queen Theory of Ageing (Agnati et al. in Acta Physiol Scand 145:301–309, ), it is proposed that during ageing these neuroprotective processes become less effective while, in the meantime, a shortage of brain plasticity occurs together with an increased need of plasticity for repairing the wear and tear of the CNS. The paper presents findings supporting the concept that such key-signals in instances such as ageing may favour neurodegenerative processes in an attempt of maximizing neuronal plasticity. [ABSTRACT FROM AUTHOR]

Recently a revision of the cell theory has been proposed, which has several implications both for physiology and pathology. This revision is founded on adapting the old Julius von Sach’s proposal (1892) of the Energide as the fundamental universal unit of eukaryotic life. This view maintains that, in most instances, the living unit is the symbiotic assemblage of the cell periphery complex organized around the plasma membrane, some peripheral semi-autonomous cytosol organelles (as mitochondria and plastids, which may be or not be present), and of the Energide (formed by the nucleus, microtubules, and other satellite structures). A fundamental aspect is the proposal that the Energide plays a pivotal and organizing role of the entire symbiotic assemblage (see Appendix 1). The present paper discusses how the Energide paradigm implies a revision of the concept of the internal milieu. As a matter of fact, the Energide interacts with the cytoplasm that, in turn, interacts with the interstitial fluid, and hence with the medium that has been, classically, known as the internal milieu. Some implications of this aspect have been also presented with the help of a computational model in a mathematical Appendix 2 to the paper. Finally, relevances of the Energide concept for the information handling in the central nervous system are discussed especially in relation to the inter-Energide exchange of information. [ABSTRACT FROM AUTHOR]

Malignant neoplasms of the central nervous system (CNS) account for about 1.3 % of all tumors and 2.2 % of all cancer-related deaths. CNS tumors consist of heterogeneous group of neoplasms, including different variants of primary brain tumors and metastatic neoplasms. Advanced imaging techniques improved the neuroradiological diagnostic accuracy, although these methods are not specific enough for differentiation of CNS tumors, thus new approaches of patients' diagnosis are critically needed. The best solution for the diagnosis of patients with CNS tumors could be easily available biomarkers, which could be useful for the management of CNS neoplasms. Biomarkers should facilitate the diagnosis, monitor of treatment response and assess the prognosis of patients' survival. Currently, except for rare germ cell tumors, there is a lack of knowledge on biochemical markers for CNS neoplasms. Therefore, in this paper we summarized and referred a number of comprehensive reviews concerning the role of matrix metalloproteinases (MMPs) and their tissue inhibitors in tumor progression, including CNS neoplasms as well as described the general biochemistry of MMPs and their tissue inhibitors. Moreover, we presented the wide variety of previous findings, where authors suggested the significance of selected MMPs and their tissue inhibitors as potential biomarkers of human tumors, including CNS tumors. However, future investigations are needed to be performed before some of these enzymes could finally be used as biomarkers of specific types of CNS neoplasms. [ABSTRACT FROM AUTHOR]

Amyloid peptides (Aβ) can operate as volume transmission (VT) signals since they are continuously released from cells of the central nervous system and diffuse in the extra-cellular space of the brain. They have both regulatory and trophic functions on cellular networks. In agreement with Aβ regulatory actions on glial-neuronal networks, the present paper reports new findings demonstrating that intrastriatal injections of Aβ peptides reduce striatal tyrosine hydroxylase, increase striatal GFAP immunoreactivities and lower pain threshold in experimental rats. Furthermore, it has been demonstrated that exogenous homocysteine (Hcy) binds Aβ(1-40) favouring its β-sheet conformation both in vitro and in vivo and hence the formation of β-fibrils and development of neurotoxicity. Thus, the hypothesis is discussed that Aβ peptides represent crucial VT-signals in the brain and their action is altered by dysmetabolic signals such as high Hcy extra-cellular levels, known to be an important risk factor for Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

Lithium's inhibitory effect on enzymes involved in sulfation process, such as inhibition of 3'(2')-phosphoadenosine 5'-phosphate (PAP) phosphatase, is a possible mechanism of its therapeutic effect for bipolar disorder (BD). 3'-Phosphoadenosine 5'-phosphosulfate (PAPS) is translocated from cytosol to Golgi lumen by PAPS transporter 1 (PAPST1/SLC35B2), where it acts as a sulfa donor. Since SLC35B2 was previously recognized as a molecule that facilitates the release of D-serine, a co-agonist of N-methyl-D-aspartate type glutamate receptor, altered function of SLC35B2 might be associated with the pathophysiology of BD and schizophrenia (SCZ). We performed genetic association analyses of the SLC35B2 gene using Japanese cohorts with 366 BD cases and 370 controls and 2012 SCZ cases and 2170 controls. We then investigated expression of SLC35B2 mRNA in postmortem brains by QPCR using a Caucasian cohort with 33 BD and 34 SCZ cases and 34 controls and by in situ hybridization using a Caucasian cohort with 37 SCZ and 29 controls. We found significant associations between three SNPs (rs575034, rs1875324, and rs3832441) and BD, and significantly reduced SLC35B2 mRNA expression in postmortem dorsolateral prefrontal cortex (DLPFC) of BD. Moreover, we observed normalized SLC35B2 mRNA expression in BD subgroups who were medicated with lithium. While there was a significant association of SLC35B2 with SCZ (SNP rs2233437), its expression was not changed in SCZ. These findings indicate that SLC35B2 might be differentially involved in the pathophysiology of BD and SCZ by influencing the sulfation process and/or glutamate system in the central nervous system. [ABSTRACT FROM AUTHOR]

Cell culture-based blood–brain barrier (BBB) models are useful experimental tools for developing central nervous system drugs. Several endothelial cell sources exist for BBB models, including primary cultured brain endothelial cells and immortalized cell lines. Among them, primary cell-based models are considered suitable for the functional analysis of the BBB; however, little is known about the utility of low-passage brain endothelial cells for this purpose. In this study, we investigated the effect of passage on brain endothelial cells from human, mouse and rat brain tissue as BBB models. We established in vitro BBB models using primary brain endothelial cells (Passage 1–Passage 4) from humans, mice, and rats. To analyze the effect of cell type on BBB function, we evaluated transendothelial electrical resistance (TEER) and performed immunofluorescence staining of tight junction proteins. Among the brain endothelial cell models, TEER was highest in the Passage 1 (P1) cell-based BBB model. There was no adequate increase in TEER in other low-passage cultures (P2–P4). A confluent, non-overlapping, uniform monolayer of cells in all P1 cell-based models was visible on immunostaining of tight junction proteins, whereas it was weak or undetectable in more passaged cultures. Increasing passages cultured of brain endothelial cells did not exhibit restrictive BBB function regardless of the cell source and despite culturing with pericytes and astrocytes. Among the tested culture models, only the lowest cultured cell-based models are suitable for functional analysis of the BBB. [ABSTRACT FROM AUTHOR]

Protease-activated receptor 1 (PAR1) is a cell surface receptor, which belongs to a family of G protein-coupled receptors and signals in response to multiple extracellular proteases. PAR1 is widely distributed in mammalian cells and tissues, including human glial cells. Within this context, PAR1 may participate to various activities promoted by glial cells. In fact, glia does not represent merely a glue in the nervous system but affects significantly various neuronal functions and activities being also significantly involved in the pathophysiology of various nervous system disorders. In this review, we summarize the current understanding of PAR1 expression and functions within glial cells both in the central and peripheral nervous system. [ABSTRACT FROM AUTHOR]

Klotho is a humoral factor with pleiotropic effects. Most notably, Klotho deficiency is associated with a phenotype comprising organ manifestations accompanying aging including atherosclerosis and cognitive impairment. Research on the role of Klotho in affective disorder is scarce, which is surprising in light of the fact that depression is associated with accelerated cellular aging as well as aging-related phenotypes and comorbidity observed in Klotho deficiency. Soluble α-Klotho (sKlotho) serum levels in patients with a major depressive episode and either undergoing electroconvulsive therapy (n = 16) or a monotherapy with an antidepressant (n = 37) were investigated. We measured the sKlotho serum levels in those patients before and after treatment and compared the baseline levels with those of age-matched healthy controls (n = 39). No group differences were found between the baseline sKlotho levels of patients and controls (573.5 pg/ml vs. 563.8 pg/ml; p = 0.80) and between pre- and post-treatment in the patients with depression (563.8 pg/ml vs. 561.8 pg/ml; p = 0.15), when treated either with electroconvulsive therapy or antidepressant. The major limitation of our study might be that peripheral material such as serum might not reliably reflect processes in the central nervous system. In sum, this first study on peripheral sKlotho levels in a clinical sample cannot confirm a global Klotho dysregulation in depression as it has been already suggested by others. Nonetheless, further preclinical and clinical studies on the involvement of Klotho in affective disorders should be carried out. [ABSTRACT FROM AUTHOR]

The pioneering work of Arvid Carlsson has laid the foundation for a number of innovative therapies for severe central nervous system (CNS) diseases. He was awarded the Nobel Price for the discovery of the crucial role of dopamine (DA) as a neurotransmitter in the CNS, thereby forming the basis for the symptomatic therapy of Parkinson's disease (PD) with l-DOPA and subsequently dopaminergic drugs. Parenteral apomorphine has a short lasting effect in PD, bromocriptine can be administered orally and has a long-lasting effects but is poorly tolerated. Lisuride on the other hand has a high affinity to DA receptors and can be administered orally, parenterally or via the transdermal route of administration. Last but not least Carlsson developed the concepts of presynaptic effects of DA agonists as well as DA partial agonism potentially innovative mechanisms for treatment of PD and schizophrenia. [ABSTRACT FROM AUTHOR]

The current view on the organization of the central nervous system (CNS) is basically anchored to the paradigm describing the brain as formed by networks of neurons interconnected by synapses. Synaptic contacts are a fundamental characteristic for describing CNS operations, but increasing evidence accumulated in the last 30 years pointed to a refinement of this view. A possible overcoming of the classical 'neuroscience paradigm' will be here outlined, based on the following hypotheses: (1) the basic morpho-functional unit in the brain is a compartment of tissue (functional module) where different resident cells (not only neurons) work as an integrated unit; (2) in these complex networks, a spectrum of intercellular communication processes is exploited, that can be classified according to a dichotomous criterion: wiring transmission (occurring through physically delimited channels) and volume transmission (exploiting diffusion in the extracellular space); (3) the connections between cells can themselves be described as a network, leading to an information processing occurring at different levels from cell network down to molecular level; (4) recent evidence of the existence of specialized structures (microvesicles and tunneling nanotubes) for intercellular exchange of materials, could allow a further type of polymorphism of the CNS networks based on at least transient changes in cell phenotype. When compared to the classical paradigm, the proposed scheme of cellular organization could allow a strong increase of the degrees of freedom available to the whole system and then of its plasticity. Furthermore, long range coordination and correlation can be more easily accommodated within this framework. [ABSTRACT FROM AUTHOR]

In the mammalian central nervous system (CNS), coupling of neurons by gap junctions (electrical synapses) increases during early postnatal development, then decreases, but increases in the mature CNS following neuronal injury, such as ischemia, traumatic brain injury and epilepsy. Glutamate-dependent neuronal death also occurs in the CNS during development and neuronal injury, i.e., at the time when neuronal gap junction coupling is increased. Here, we review our recent studies on regulation of neuronal gap junction coupling by glutamate in developing and injured neurons and on the role of gap junctions in neuronal cell death. A modified model of the mechanisms of glutamate-dependent neuronal death is discussed, which includes neuronal gap junction coupling as a critical part of these mechanisms. [ABSTRACT FROM AUTHOR]

The main purpose of this study was to facilitate the delivery of kynurenic acid (KYNA) across the blood-brain barrier (BBB) by applying micelles as nanoscale containers. Non-ionic amphiphilic molecules were used for preparation of spherical micelles for delivery of kynurenic acid in aqueous solution in physiological condition. It was established that Triton X 100 and Lutensol AP 20 non-ionic surfactants are able to produce stable nanocontainers for delivery of kynurenic acid molecules. The incorporation of KYNA molecules was investigated by dynamic light scattering and the size of micelles were calculated between 5 and 10 nm in 150 mM NaCl and pH 7.5-7.6 solutions. Encapsulated kynurenic acid showed a significantly higher blood-brain barrier permeability compared with non-encapsulated kynurenic acid. The in vivo experiments showed that the encapsulated kynurenic acid is able to display effects within the central nervous system, even after its peripheral administration. [ABSTRACT FROM AUTHOR]

Encephalopathy associated with septic shock as well as psychiatric disorders can be caused by the central nervous formation of reactive oxygen species (ROS) associated with inflammation. The systemic application of lipopolysaccharide (LPS, 100 μg/kg i.p.) also serves as a model for major depression and results in enhanced inflammatory processes. which are characterized by the stimulation of microglia or macrophages that then impair normal brain function. The aim of the present study was to analyze the effect of peripherally applied LPS on the central nervous formation of ROS and IL-6 in wild-type mice and in mice lacking the NADPH oxidase Nox2 subunit gp91phox. Microdialysis was performed in the striatum of the mice. Central nervous ROS were detected by electron spin resonance spectroscopy using 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine (CMH) as reactant, which was infused via a microdialysis probe. IL-6 was measured in microdialysis samples by an immunoassay. Finally, blood samples were taken by heart puncture to detect IL-6 in plasma. In the wild-type mice, LPS significantly increased the ROS formation in the striatum of wild-type mice and resulted in a significantly enhanced IL-6 production. In the mice lacking the NADPH oxidase Nox2 subunit gp91phox, LPS did not enhance ROS formation, while central IL-6 was significantly increased. IL-6 plasma values were enhanced in both types of mice. In conclusion, the gp91phox-containing NADPH oxidase complex is involved in the central nervous ROS formation after peripheral LPS stimulation and might be a pharmacological target in patients with septic shock. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) carboxyterminally truncated amyloid-beta (Aβ) peptides, Aβ1-42 and tau protein were evaluated in 30 patients with frontotemporal lobe degenerations (FTLD), 30 Alzheimer’s disease (AD) patients and 30 non-demented disease controls (NDC) by Aβ-SDS-PAGE/immunoblot as well as commercial ELISAs for Aβ1-42 and total tau. FTLD displayed a significant drop of Aβ1-37 (p = 2.7 × 10−4), Aβ1-38 (p = 4.2 × 10−5) and Aβ1-42 (p = 3.3 × 10−4). Aβ1-42 was selectively decreased in AD (p = 8.5 × 10−10). Decreased Aβ1-38 enabled contrasts of beyond 85% to distinguish FTLD from AD and NDC patients, alone or in combination. Accordingly, low CSF Aβ1-37 and Aβ1-38 represent a biomarker candidate for FTLD and may reflect disease-specific changes of APP metabolism. Further validation should be carried out on dementias other than AD, diagnostically relevant control groups without dementia and without any evident affection of the central nervous system and subgroups of FTLD. Moreover, independent methods of measurement should be applied to CSF Aβ1-38. [ABSTRACT FROM AUTHOR]

Role of excitatory amino acids, glutamate, aspartate, and inhibitory amino acids, gamma aminobutyric acid (GABA) and glycine in brain damage caused by heat stress was examined in a rat model. Subjection of rats to 4 h heat stress at 38°C in a biological oxygen demand (BOD) incubator resulted in a marked increase in glutamate and aspartate in some brain regions, whereas a significant decline in GABA and glycine was observed in several brain areas. Profound behavioural alterations and impairment of motor and cognitive functions were seen at this time. Breakdown of the blood–brain barrier (BBB), reduction in regional cerebral blood flow (CBF), edema formation and cell injuries are prominent in several parts of the brain. Pretreatment with multiple opioid receptor antagonist, naloxone (10 mg/kg, i.p.) significantly restored the heat stress induced decline in GABA and glycine and thwarted the elevation of glutamate and aspartate in various brain areas. The motor or cognitive deficits were also attenuated. A significant reduction in BBB permeability, cerebral blood flow abnormalities, edema formation and cell injuries was evident. These novel observations suggest that (i) glutamate, aspartate, GABA and glycine are involved in the pathophysiology of heat stress, and (ii) a balance between excitatory and inhibitory amino acids in brain is crucial in hyperthermia induced brain injuries or repair. [ABSTRACT FROM AUTHOR]

Although the current guidelines for the clinical diagnosis of multiple system atrophy (MSA) do not require structural or functional brain imaging, investigations utilizing positron emission tomography (PET) have been helpful diagnostically in differentiating between MSA and primary autonomic failure; idiopathic Parkinson’s disease; and sporadic olivopontocerebellar atrophy. These investigations have demonstrated different patterns of cerebral glucose utilization and of nigrostriatal projection abnormalities among these disorders and between the cerebellar and parkinsonian forms of MSA. Most of the studies have focused upon patients with well-established disease and none have examined the utility of PET imaging in early stage patients with follow-up of clinical course and autopsy verification to ensure accuracy of diagnosis and to determine the sensitivity and specificity of PET techniques for diagnosis. Recent PET studies have revealed denervation of myocardial post-ganglionic sympathetic neurons in some MSA patients, indicating that this disorder can affect the peripheral autonomic as well as the central nervous system. Investigations utilizing ligands to quantify central nervous system dopaminergic and cholinergic terminals have begun to provide insight into the neurochemical disorders that may underlie two of the sleep disturbances common in MSA, rapid eye movement sleep behavior disorder and obstructive sleep apnea. [ABSTRACT FROM AUTHOR]

Involvement of the α1-adrenoceptor subtypes in early and late phases of formalin pain was investigated by quantitative in vitro autoradiography in the spinal cord and brain structures of CD-1 mice. Total α1-adrenoceptors binding (including all α1-adrenoceptor subtypes) was assessed with [3H]prazosin; α1B-adrenoceptor was assessed with [3H]prazosin in the presence of 10 nM WB4101 to mask remaining α1-adrenoceptor subtypes. Early after formalin injection the α1-adrenoceptors (mainly α1B receptor) binding was reduced in the contralateral hind limb area of the somatosensory cortex and in the secondary motor cortex. A reduction occurred also in the ipsilateral laminae I–III of the spinal cord (both α1B- and non-α1B-adrenoceptors). Lately an increase of α1-adrenoceptors binding (mostly subtypes other than α1B) appeared in discrete amygdaloid and thalamic nuclei. These results provide the first description of changes at the level of central α1-adrenoceptors’ binding during the formalin-induced pain in mice. Their distribution suggests that they may have a functional meaning. [ABSTRACT FROM AUTHOR]

Summary. Previous studies using BOLD fMRI to examine age-related changes in cortical activation used tasks that relied on peripheral systems to activate the brain. They were unable to distinguish between alterations due to age-related changes in the periphery and actual changes in cortical physiology. Transcranial magnetic stimulation (TMS), which allows direct, noninvasive stimulation of cortical neurons, was interleaved with BOLD fMRI to study 6 young and 5 old subjects. Three different tasks were compared: direct stimulation by TMS, indirect active stimulation produced by a motor task, and indirect passive stimulation produced by hearing the TMS coil discharge. Direct neuronal stimulation by TMS produced similar fMRI signal increases in both groups, suggesting that cortical physiology itself may not necessarily decline with age. [ABSTRACT FROM AUTHOR]

Summary. Cerebral dysfunction without corresponding structural pathology has been reported in brain imaging studies of violent offenders. Biochemical markers in the CSF reflect various types of CNS pathology, such as blood-brain barrier dysfunction (CSF/S albumin ratio), infectious or inflammatory processes (IgG and IgM indices), neuronal or axonal degeneration (CSF-tau protein) and synaptic de- or regeneration (CSF-growth associated protein-43 (GAP-43)). We compared these CSF markers in 19 non-psychotic perpetrators of severe violent crimes undergoing pretrial forensic psychiatric investigation and 19 age- and sex-matched controls. Index subjects had significantly higher albumin ratios (p = 0.002), indicating abnormal vascular permeability as part of the complex CNS dysfunction previously reported in violent offenders. Axis I disorders, including substance abuse or current medication, did not explain this finding. Since Ig-indices, CSF-tau protein or CSF-GAP-43 were not increased, there was no support for inflammation or neuronal/synaptic degeneration as etiological factors to CNS dysfunction in this category of subjects. [ABSTRACT FROM AUTHOR]