Multiplicity of cerebrospinal fluid functions: New challenges in health and disease

This review integrates eight aspects of cerebrospinal fluid (CSF) circulatory dynamics: formation rate, pressure, flow, volume, turnover rate, composition, recycling and reabsorption. Novel ways to modulate CSF formation emanate from recent analyses of choroid plexus transcription factors (E2F5), ion transporters (NaHCO3 cotransport), transport enzymes (isoforms of carbonic anhydrase), aquaporin 1 regulation, and plasticity of receptors for fluid-regulating neuropeptides. A greater appreciation of CSF pressure (CSFP) is being generated by fresh insights on peptidergic regulatory servomechanisms, the role of dysfunctional ependyma and circumventricular organs in causing congenital hydrocephalus, and the clinical use of algorithms to delineate CSFP waveforms for diagnostic and prognostic utility. Increasing attention focuses on CSF flow: how it impacts cerebral metabolism and hemodynamics, neural stem cell progression in the subventricular zone, and catabolite/peptide clearance from the CNS. The pathophysiological significance of changes in CSF volume is assessed from the respective viewpoints of hemodynamics (choroid plexus blood flow and pulsatility), hydrodynamics (choroidal hypo- and hypersecretion) and neuroendocrine factors (i.e., coordinated regulation by atrial natriuretic peptide, arginine vasopressin and basic fibroblast growth factor). In aging, normal pressure hydrocephalus and Alzheimer's disease, the expanding CSF space reduces the CSF turnover rate, thus compromising the CSF sink action to clear harmful metabolites (e.g., amyloid) from the CNS. Dwindling CSF dynamics greatly harms the interstitial environment of neurons. Accordingly the altered CSF composition in neurodegenerative diseases and senescence, because of adverse effects on neural processes and cognition, needs more effective clinical management. CSF recycling between subarachnoid space, brain and ventricles promotes interstitial fluid (ISF) convection with both trophic and excretory benefits. Finally, CSF reabsorption via multiple pathways (olfactory and spinal arachnoidal bulk flow) is likely complemented by fluid clearance across capillary walls (aquaporin 4) and arachnoid villi when CSFP and fluid retention are markedly elevated. A model is presented that links CSF and ISF homeostasis to coordinated fluxes of water and solutes at both the blood-CSF and blood-brain transport interfaces

Clinical, genetic, and brain imaging predictors of risk for bipolar disorder in high-risk individuals

Introduction: Early detection and intervention in bipolar disorder (BD) might reduce illness severity, slow its progression, and, in specific cases, even ward off the full-blown disorder. Therefore, identifying at-risk individuals and targeting them promptly before the illness onset is of the utmost importance. In the last decades, there has been a significant effort aimed at identifying genetic and molecular factors able to modulate risk and pharmacological outcomes. Areas covered: We performed a narrative review of articles aimed at identifying clinical, genetics, molecular, and brain imaging markers of BD specifically focusing on samples of individuals at high-risk for BD. Special emphasis was put on studies applying an integrative design, e.g. studies combining different markers such as genetic and brain imaging. Expert opinion: Findings from studies in risk individuals are still too sparse to allow drawing definite conclusions. However, the high potentiality of longitudinal studies in individuals considered at risk to develop BD supports the need for more efforts. Future investigations should focus on more homogeneous subpopulations and evaluate the cross-linking between clinical, genetic, and brain morphostructural/functional neuroimaging characteristics as predictors of risk for BD

Ultramicronized palmitoylethanolamide rescues learning and memory impairments in a triple transgenic mouse model of Alzheimer's disease by exerting anti-inflammatory and neuroprotective effects.

In an aging society, Alzheimer's disease (AD) exerts an increasingly serious health and economic burden. Current treatments provide inadequate symptomatic relief as several distinct pathological processes are thought to underlie the decline of cognitive and neural function seen in AD. This suggests that the efficacy of treatment requires a multitargeted approach. In this context, palmitoylethanolamide (PEA) provides a novel potential adjunct therapy that can be incorporated into a multitargeted treatment strategy. We used young (6-month-old) and adult (12-month-old) 3×Tg-AD mice that received ultramicronized PEA (um-PEA) for 3 months via a subcutaneous delivery system. Mice were tested with a range of cognitive and noncognitive tasks, scanned with magnetic resonance imaging/magnetic resonance spectroscopy (MRI/MRS), and neurochemical release was assessed by microdialysis. Potential neuropathological mechanisms were assessed postmortem by western blot, reverse transcription-polymerase chain reaction (RT-PCR), and immunofluorescence. Our data demonstrate that um-PEA improves learning and memory, and ameliorates both the depressive and anhedonia-like phenotype of 3×Tg-AD mice. Moreover, it reduces Aβ formation, the phosphorylation of tau proteins, and promotes neuronal survival in the CA1 subregion of the hippocampus. Finally, um-PEA normalizes astrocytic function, rebalances glutamatergic transmission, and restrains neuroinflammation. The efficacy of um-PEA is particularly potent in younger mice, suggesting its potential as an early treatment. These data demonstrate that um-PEA is a novel and effective promising treatment for AD with the potential to be integrated into a multitargeted treatment strategy in combination with other drugs. Um-PEA is already registered for human use. This, in combination with our data, suggests the potential to rapidly proceed to clinical use

HOW COULD RETINOIDS FIT INTO ALZHEIMER'S THERAPY?

Retinoids are a class of natural and synthetic molecules structurally and/or functionally related to all-trans-retinoic acid (ATRA), a metabolite of Vitamin A (retinol). The retinoid system controls the expression of hundreds of genes, including transcription factors, enzymes, structural proteins, cell surface receptors, neurotransmitters, hormones and growth factors, hence modulating cell proliferation, differentiation, morphogenesis and immunity. The retinoid-associated signaling plays a critical role in neurodevelopment and remains active in the adult central nervous system, thus assuming high relevance in the context of neurodegeneration. The ability of retinoids to exert antioxidant effects, decrease β-amyloid (Aβ) accumulation, improve neurotransmission, suppress neuroinflammation and promote neural regeneration is discussed. Although retinoids with their pleiotropic activity are revealing a promising approach for the management of Alzheimer's disease (AD), timing as well as appropriate dosage and safety still remain a challenge. In particular, assuming that the end-stage lesions (senile plaques and neurofibrillary tangles) are an adaptive response to oxidative stress underlying AD, late administration of retinoids could paradoxically suppress a protective mechanism by inhibiting Aβ deposits

Depression and coronary heart disease: Clinical characteristics, pathogenetic links and treatment issues

It is widely accepted that depression increases the risk of coronary heart disease (CHD) in healthy people while, in individuals with an existing heart disease, depression is a predictor of recurrent cardiac events and death. It seems that new-onset depression after an acute coronary syndrome (ACS) and not recurrent depression may worsen the cardiovascular outcome, and it has been suggested, although not conclusively proved, that depressive somatic symptoms, could be more cardiotoxic than depressive cognitive symptoms. Both psychosocial (low social support, less adherence to treatment recommendations, physical inactivity) and biological mechanisms (autonomic nervous system dysregulation, platelet and endothelial dysfunctions, inflammation, and neuroendocrine abnormalities) have been hypothesized to explain the link between depression and the increased risk of CHD or adverse cardiovascular prognosis. Randomized controlled clinical trials seem to suggest that depression in CHD patients is poor responsive to both pharmacological and psychotherapeutic treatments. Nevertheless, these trials provide also a robust evidence that CHD depressed patients non responder to antidepressant treatments are at greater risk of adverse cardiac event than patients with successfully treated depression. Therefore, it is advisable that psychiatrists, cardiologists and general practitioners coordinate their efforts in managing depression in CHD patients. © 2012 Schattauer GmbH

S100B induces tau protein hyperphosphorylation via Dickopff-1 up-regulation and disrupts the Wnt pathway in human neural stem cells

Previous studies suggest that levels of the astrocyte-derived S100B protein, such as those occurring in brain extra-cellular spaces consequent to persistent astroglial activation, may have a pathogenetic role in Alzheimer's disease (AD). Although S100B was reported to promote beta amyloid precursor protein overexpression, no clear mechanistic relationship between S100B and formation of neurofibrillary tangles (NFTs) is established. This in vitro study has been aimed at investigating whether S100B is able to disrupt Wnt pathway and lead to tau protein hyperphosphorylation. Utilizing Western blot, electrophoretic mobility shift assay, supershift and reverse transcriptase-polymerase chain reaction techniques, it has been demonstrated that micromolar S100B concentrations stimulate c-Jun N-terminal kinase (JNK) phosphorylation through the receptor for advanced glycation ending products, and subsequently activate nuclear AP-1/cJun transcription, in cultured human neural stem cells. In addition, as revealed by Western blot, small interfering RNA and immunofluorescence analysis, S100B-induced JNK activation increased expression of Dickopff-1 that, in turn, promoted glycogen synthase kinase 3beta phosphorylation and beta-catenin degradation, causing canonical Wnt pathway disruption and tau protein hyperphosphorylation. These findings propose a previously unrecognized link between S100B and tau hyperphosphorylation, suggesting S100B can contribute to NFT formation in AD and in all other conditions in which neuroinflammation may have a crucial role

S100B induces tau protein hyperphosphorylation via Dickopff-1 up-regulation and disrupts the Wnt pathway in human neural stem cells.

Previous studies suggest that levels of the astrocyte-derived S100B protein, such as those occurring in brain extra-cellular spaces consequent to persistent astroglial activation, may have a pathogenetic role in Alzheimer's disease (AD). Although S100B was reported to promote beta amyloid precursor protein overexpression, no clear mechanistic relationship between S100B and formation of neurofibrillary tangles (NFTs) is established. This in vitro study has been aimed at investigating whether S100B is able to disrupt Wnt pathway and lead to tau protein hyperphosphorylation. Utilizing Western blot, electrophoretic mobility shift assay, supershift and reverse transcriptase-polymerase chain reaction techniques, it has been demonstrated that micromolar S100B concentrations stimulate c-Jun N-terminal kinase (JNK) phosphorylation through the receptor for advanced glycation ending products, and subsequently activate nuclear AP-1/cJun transcription, in cultured human neural stem cells. In addition, as revealed by Western blot, small interfering RNA and immunofluorescence analysis, S100B-induced JNK activation increased expression of Dickopff-1 that, in turn, promoted glycogen synthase kinase 3 beta phosphorylation and beta-catenin degradation, causing canonical Wnt pathway disruption and tau protein hyperphosphorylation. These findings propose a previously unrecognized link between S100B and tau hyperphosphorylation, suggesting S100B can contribute to NFT formation in AD and in all other conditions in which neuroinflammation may have a crucial role