L. Fernández-Novoa

Blood levels of histamine, IL-1β, and TNF-α in patients with mild to moderate alzheimer disease

In this study, we have evaluated the levels of blood histamine, serum interleukin-1 beta (IL-1β), and plasma tumor necrosis factor-alpha (TNF-α) in 20 patients with mild to moderate Alzheimer disease (AD; 13 early onset and 7 late-onset AD subjects) and in 20 agematched control subjects (C). AD patients showed higher concentrations of histamine (AD=452.9±237.9 pmol/mL; C=275.3±151.5 pmol/mL;p<0.05) and IL-1β (AD=211.2±31.1 pg/mL; C=183.4±24.4 pg/mL;p<0.01), and lower values of TNF-α (AD=3.59±2.02 pg/mL; C=9.47±2.64 pg/mL;p<0.001) than elderly controls. Increased levels of histamine and decreased levels of TNF-α were observed in both early onset AD (EOAD) and late-onset AD (LOAD) patients, but only EOAD subjects had elevated serum IL-1β values compared with age-matched controls. Age negatively correlated with histamine (r=−0.57;p<0.05) and positively with IL-1β levels (r=0.48;p<0.05) in healthy subjects, but not in AD, whereas a positive correlation between TNF-α scores and age was only found in AD patients (r=0.46;p<0.05). Furthermore, histamine and TNF-α values correlated negatively in AD (r=−0.50,p<0.05). In addition, cognitive impairment increased in patients with lower TNF-α and higher histamine and IL-1β levels, as indicated by the correlations between mental performance scores and histamine (r=−0.37, ns), IL-1β (r=−0.33, ns) and TNF-α levels (r=0.42,p<0.05). Finally, histamine concentrations decreased as depression scores increased in AD (r=−0.63,p<0.01). These data suggest a dysfunction in cytokine and histamine regulation in AD, probably indicating changes associated with inflammatory processes.

Histamine function in brain disorders

The neurotransmitter histamine (HA) has been implicated in the regulation of numerous and important activities of the central nervous system as arousal, cognition, circadian rhythms and neuroendocrine regulation. The data presented here indicate the participation of the histaminergic system in central nervous system disorders, such as Alzheimers disease and schizophrenia. We also present experimental data on histamine in an animal model of neurodegeneration and the cytotoxic effects of histamine on cultured rat endothelial cells. More studies are needed to investigate the role of the histaminergic system in central nervous system disorders. Peripheral cellular studies in health and disease, molecular studies on receptors and in vivo pharmacological studies may help us to better understand the function of the histaminergic system in health and disease.

Resting-State Network Disruption and APOE Genotype in Alzheimer's Disease: A lagged Functional Connectivity Study

Background The apolipoprotein E epsilon 4 (APOE-4) is associated with a genetic vulnerability to Alzheimers disease (AD) and with AD-related abnormalities in cortical rhythms. However, it is unclear whether APOE-4 is linked to a specific pattern of intrinsic functional disintegration of the brain after the development of the disease or during its different stages. This study aimed at identifying spatial patterns and effects of APOE genotype on resting-state oscillations and functional connectivity in patients with AD, using a physiological connectivity index called “lagged phase synchronization”. Methodology/Principal Findings Resting EEG was recorded during awake, eyes-closed state in 125 patients with AD and 60 elderly controls. Source current density and functional connectivity were determined using eLORETA. Patients with AD exhibited reduced parieto-occipital alpha oscillations compared with controls, and those carrying the APOE-4 allele had reduced alpha activity in the left inferior parietal and temporo-occipital cortex relative to noncarriers. There was a decreased alpha2 connectivity pattern in AD, involving the left temporal and bilateral parietal cortex. Several brain regions exhibited increased lagged phase synchronization in low frequencies, specifically in the theta band, across and within hemispheres, where temporal lobe connections were particularly compromised. Areas with abnormal theta connectivity correlated with cognitive scores. In patients with early AD, we found an APOE-4-related decrease in interhemispheric alpha connectivity in frontal and parieto-temporal regions. Conclusions/Significance In addition to regional cortical dysfunction, as indicated by abnormal alpha oscillations, there are patterns of functional network disruption affecting theta and alpha bands in AD that associate with the level of cognitive disturbance or with the APOE genotype. These functional patterns of nonlinear connectivity may potentially represent neurophysiological or phenotypic markers of AD, and aid in early detection of the disorder.

Effect of CDP-Choline on Cognition and Immune Function in Alzheimer's Disease and Multi-Infarct Dementiaa

The cholinergic dysfunction present in Alzheimers disease (AD) might be due to a specific vulnerability of cholinergic neurons linked to neurotrophic imbalance, neuroimmune impairment, and/or direct effects of β‐amyloid deposition and NFT formation in ACh neurons. The presence of abnormal epitopes exposed on neuronal membranes may contribute to the activation of resting microglia initiating a neuroimmune cascade leading to cell destruction. According to this hypothesis, a multifactorial treatment in AD should produce: 1) inhibition of β‐amyloid and NFT formation; 2) restoration of neuronal membrane integrity; and 3) control of neuroimmune auto‐aggression. Since interleukin‐1 (IL‐1) is an APP gene promoter showing a progressive increase in body fluids in parallel with mental deterioration in AD patients, we have studied the effects of CDP‐choline on cognition, several biological parameters, and IL‐1β production in AD and multi‐infarct dementia (MID) in order to elucidate whether this compound alone or in combination with other drugs is able to restore immune function and improve mental performance in senile dementia.

A novel mutation in the predicted TM2 domain of the presenilin 2 gene in a Spanish patient with late-onset Alzheimer's disease.

ABSTRACTMutations in the presenilin-2 (PS-2) gene are less frequent than mutations in the PS-1 gene. All mutations described in the PS-1 gene were found in early-onset Alzheimers disease (AD) patients. At present, there are two missense mutations described for the PS-2 gene in some AD pedigrees. We have therefore analyzed transmembrane 2 (TM2) and TM5 domains of the PS-2 gene in AD patients and in a group of age-matched healthy controls. In a patient who was clinically diagnosed as having late-onset AD, we found a novel missense mutation consisting of a G- 1 A substitution on exon 5 of the PS-2 gene, which results in a Val to Ile substitution at codon 148 within the predicted TM2 domain of the PS-2 protein. This is the third mutation described in the PS-2 gene and the first presenilin mutation detected in a Spanish AD patient. Both, the N141I mutation and the V148I mutation described here are located within the predicted TM2 domain and both were found in late-onset AD kindreds, whereas the mutation within the predicted TM5 domain was found in an early-onset AD pedigree. Carriers of mutations within TM2 of PS-1 have a mean age at onset of 40 years, while the other mutations in PS-1 occur in families with a mean age at onset of 47 years. In summary, we report here the first mutation in a presenilin gene in a Spanish AD case, which is the third mutation detected for the PS-2 gene.

Phenotypic profiles and functional genomics in Alzheimer's disease and in dementia with a vascular component

Abstract Alzheimers disease (AD) and dementia with vascular component (DVC) are the most prevalent forms of dementia. Both clinical entities share many similarities, but they differ in major phenotypic and genotypic profiles as revealed by structural and functional genomics studies. Comparative phenotypic studies have identified significant differences in 25% of more than 100 parametric variables, including anthropometry, cardiovascular function, aortic atherosclerosis, brain atrophy, blood pressure, blood biochemistry, hematology, thyroid function, folate and vitamin B12 levels, brain hemodynamics and lymphocyte markers. The phenotypic profile of patients with DVC differs from that of AD patients in the following: anthropometric values (weight, height); cardiovascular function (ECG, heart rate); blood pressure; lipid metabolism (HDL–CHO, TGs); uric acid metabolism; peripheral calcium homeostasis; liver function (GOT, GPT, GGT); alkaline phosphatase; lactate dehydrogenase; red and white blood cells; regional brain atrophy (left temporal region, inter-hippocampal distance); and left anterior blood flow velocity. Functional genomics studies incorporating APOE-related changes in biological markers extended the difference between AD and DVC up to 57%. Brain perfusion studies show a severe brain hypoperfusion in dementia associated with enlarged age-dependent arterial perfusion times. Structural genomics studies with AD-related genes, including APP, MAPT, APOE, PS1, PS2, A2M, ACE, AGT, cFOS and PRNP genes, demonstrate different genetic profiles in AD and DVC, with an absolute genetic variation rate ranging from 30% to 80%, depending upon genes and genetic clusters. Single gene analysis identifies relative genetic variations ranging from 0% to 5%. The relative polymorphic variation in genetic clusters integrated by two, three or four genes associated with AD ranges from 1% to 3%. The main phenotypic differences between AD and DVC are genotype-dependent, especially in AD, probably indicating that different genomic factors are determinant for the expression of dementia symptoms which might be accelerated or induced by environmental and/or cerebrovascular factors.

Histamine and Immune Biomarkers in CNS Disorders

Neuroimmune dysregulation is a common phenomenon in different forms of central nervous system (CNS) disorders. Cross-links between central and peripheral immune mechanisms appear to be disrupted as reflected by a series of immune markers (CD3, CD4, CD7, HLA-DR, CD25, CD28, and CD56) which show variability in brain disorders such as anxiety, depression, psychosis, stroke, Alzheimers disease, Parkinsons disease, attention-deficit hyperactivity disorder, migraine, epilepsy, vascular dementia, mental retardation, cerebrovascular encephalopathy, multiple sclerosis, brain tumors, cranial nerve neuropathies, mental retardation, and posttraumatic brain injury. Histamine (HA) is a pleiotropic monoamine involved in several neurophysiological functions, neuroimmune regulation, and CNS pathogenesis. Changes in brain HA show an age- and sex-related pattern, and alterations in brain HA levels are present in different CNS regions of patients with Alzheimers disease (AD). Brain HA in neuronal and nonneuronal compartments plays a dual role (neurotrophic versus neurotoxic) in a tissue-specific manner. Pathogenic mechanisms associated with neuroimmune dysregulation in AD involve HA, interleukin-1β, and TNF-α, whose aberrant expression contributes to neuroinflammation as an aggravating factor for neurodegeneration and premature neuronal death.

Neuroprotective role of S12024 against neurodegeneration in the rat dentate gyrus

We assessed the neuroprotective capabilities of S12024 (R,S 1-methyl 8-(2-morpholinylmethoxy)-1,2,3,4-tetrahydroquinoleine methane sulphonate) in a model of neuronal degeneration in the dentate gyrus of the rat hippocampus. Specific degeneration of a large part of neurons in the lateral blade of the gyrus dentatus occurred after small intrahippocampal injections of water with or without amyloid-beta 1-28 fragment. S12024 reduced the number of animals with neuronal loss in the hippocampus, diminished the extent of the lesion, and reversed deficits of passive avoidance learning acquisition in animals with deposits of amyloid-beta 1-28. These results suggest that S12024 has neuroprotective effects on hippocampal cells and that the neurodegeneration by fluid injection combined with deposit of amyloid-beta 1-28 may be used to assay the neuroprotective activity of pharmacological compounds.

In vitro regulation of rat derived microglia.

The cell culture approach to the study of the nervous system attempts to reduce cellular complexity to various extents and to characterize the influences of extrinsic molecules on the cell population under study. To date, the main source of culture model systems to explore CNS function and dysfunction is fetal brain material from experimental animals, typically rodents. We have developed primary microglial cell cultures and focused on the concentration-dependent effects of different amino acids and growth promoting additives on microglial morphology and function. We used Basal Medium Eagle (BME) with 1g/L of glucose instead of Dulbeccos modified Eagle medium (DMEM) as serum-free condition, since BME does not contain L-Glycine (Gly) and L-Serine (Ser), and investigated the effects of these two amino acids on microglial morphology and functions by adding various concentrations of the amino acids to BME and different concentrations of ascorbic acid (10–75 μg/ml), hydrocortisone (1–7.5 nM) and DL-α-tocopherol (0.01–0.5 μg/ml) as growth promoters. Under Gly/Ser-free, serum-free condition, and growth promoters-free conditions, the majority of rat microglial cells displayed round morphology, whereas in the presence of 5 μM Gly and 25 μM Ser, which correspond to the concentrations of Gly and Ser in the cerebrospinal fluid, they extended multiple branched processes and formed clusters of rough endoplasmic reticulum. Ascorbic acid (25 μg/ml), 2.5 nM hydrocortisone and 0.05 μg/ml of DL-α-tocopherol elicited the highest level of microglial activation as measured by an increased expression of MHC class-I and MHC class-II antigens. Neuron culture experiments using the conditioned medium obtained from the different microglial culture conditions indicate neurotoxic and neurotrophic effects depending on the concentrations of amino acids as well as on the concentration of the growth promoters. These findings suggest that resting ramified microglial cells with neurotrophic activity can be induced with the combination of BME medium and small amounts of extracellular matrix growth promoters.

Short term food supplementation effects of a fish derived extract on the immunological status of pregnant rats and their sucking pups

There is emerging evidence that PUFAs influence immune functions by controlling the normal inflammatory process and may do so by serving as a signal modulator that regulates specific enzymatic activities typically elevated during inflammation at the inflammation site. In the present study, the effect of 12 weeks food supplementation with E-SAR 94010, a marine fish extract, before and during pregnancy and lactation in Sprague-Dawley rats and their offspring was investigated. Triglyceride plasma levels of pups and their mothers was lower in the treated groups than in the control group. No significant differences in the atherogenic index (total cholesterol-HDLcholesterol/HDLcholesterol) were observed. Studies on the lymphocyte cell marker suggest a clear immune activation as measured by the increased levels of CD25, CD28, CD54, CD62 and CD56 on lymphocytes derived from both E-SAR treated mothers and newborns. Therefore the present results indicate that E-SAR-94010 dietary supplementation can be responsible for an increased level of immune surveillance.