Transcranial Doppler ultrasonography in neurogeriatric disorders.
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Aged↗
Biomedical subjects
L Fernández-Novoa
Publications and source records attributed to L Fernández-Novoa.
Brain electrical activity in neurogerontology and psychogeriatric disorders.
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Aged↗
Effects of neurotoxic lesions in the posterior hypothalamic region on psychomotor activity and learning.
Histamine (HA) acts as a neurotransmitter and/or neuromodulator in mammalian brain. Central HA has been found to be involved in the regulation of behavioral, cognitive, neurovegetative, neuroendocrine and neuroimmune functions. In this study we have evaluated psychomotor activity (PMA) and passive avoidance behavior (PAB) in rats with bilateral neurotoxic lesions in the posterior hypothalamic region (PHR) (L), where histaminergic neurons are located, and in sham-operated rats (S), two weeks after neurosurgery. In an open-field paradigm, lesioned rats showed higher PMA scores than sham-operated animals. However, L rats exhibited a significant decrease in PMA on consecutive days (motor habituation) similar to that found in S rats. In a maze paradigm, in which the animals had to learn to stay on a neutral platform in order to avoid a 1.5 mA electric footshock during 10 trails, no significant differences were observed between L and S rats on the task performance. According to the present results, it seems that bilateral neurotoxic lesions in the PHR induced hyperactivity with no apparent effects on PAB, suggesting that neuronal HA might be involved, directly and/or by influencing arousal/alertness-mediated mechanisms, in the regulation of PMA processes.
Analysis of Variance↗
Effects of neurotoxic lesions in histaminergic neurons on brain tumor necrosis factor levels.
Histamine (HA) is a biogenic amine involved in the regulation of neurovegetative, cognitive, neuroendocrine and neuroimmune functions in the central nervous system (CNS). A bidirectional interaction between the CNS and the neuroimmune system has been demonstrated in recent years. However, data concerning brain HA-cytokine interactions are scarce. In this study we have evaluated tumor necrosis factor-alpha (TNF-alpha) levels in the posterior hypothalamic region (PHR) and hippocampus (HP) of rats with: (a) bilateral ibotenic acid neurotoxic lesions in histaminergic neurons located in the PHR (I); (b) saline injections in the PHR (S); and (c) sham operation (C), two weeks after neurosurgery. The bilateral disruption of PHR HA neurons with ibotenic acid decreased TNF-alpha levels in the PHR with respect to sham-operated (C), but not saline-injected (S), rats. In contrast, hippocampal TNF-alpha concentrations were higher in lesioned rats (I) than in C and S animals. Our results indicate that the neurotoxic destruction of HA neurons decreases TNF-alpha synthesis in the hypothalamus while enhancing TNF-alpha production in the hippocampus, suggesting that neuronal HA might be involved in the regulation of the brain TNF-alpha system.
Animals↗
Brain interleukin-1 beta in Alzheimer's disease and vascular dementia.
Recent investigations indicate that a neuroimmune reaction, associated with inflammatory mechanisms, can contribute in Alzheimer's disease (AD) to cell damage and neurodegeneration. Activation of microglial cells, expression of immunohistochemical markers of brain immune function, the presence of complement proteins in brain tissue and changes in cytokine production have been reported in AD. We have studied the concentration of interleukin-1 beta (IL-1 beta) in different regions of the central nervous system (CNS) in post-mortem samples from patients with AD or vascular dementia (VD) and in age-matched control subjects (CS). IL-1 beta levels were significantly higher in AD than in VD or CS in the frontal cortex, parietal cortex, temporal cortex, hypothalamus, thalamus and hippocampus. The highest increases in IL-1 beta levels were observed in the frontal cortex (CS = 0.75 +/- 0.045; AD = 2.47 +/- 0.12, p < 0.001; VD = 1.52 +/- 0.078 pg/mg, p < 0.001) and hippocampus (CS = 0.71 +/- 0.042; AD = 2.63 +/- 0.19, p < 0.001; VD = 1.21 +/- 0.23 pg/mg, p < 0.01). No significant changes were detected in the occipital cortex and cerebellum in either AD or VD. These results clearly demonstrate that demented patients show a generalized increment of IL-1 beta production in the CNS, with maximum response in those brain regions where AD neuropathology is most prominent. This overall increase in cytokine production might represent an early event in the activation of a neuroimmune cascade leading to cell death and neurodegeneration in brain regions where a primary cause (e.g., genetic, toxic, vascular) facilitates the induction of resting microglia for firing brain immune function.
Aged↗
CDP-choline-induced blood histamine changes in Alzheimer's disease.
Histamine (HA) is a known neurotransmitter with a wide spectrum of biological actions at the central and peripheral levels. Recently, it has been found that HA is involved in the regulation of immune cell function, acting as an immunomodulator. A hyperactivation in the histaminergic system has been demonstrated in Alzheimer's disease (AD), including increased levels of HA in brain, serum, and cerebrospinal fluid of AD patients. In addition, changes in phospholipid metabolism and neuroimmune function have been reported in AD. CDP-choline (cytidine-5-diphosphate-choline) participates in the phospholipid metabolism pathway incorporating free choline into phosphatidyl-choline and choline plasmalogens in several tissues, including the central nervous system. In this study we have measured the concentration of HA in blood from patients with early-onset AD (EOAD) and late-onset AD (LOAD) under treatment with CDP-choline (1000 mg p.o. x30 days). HA was measured by high performance liquid chromatography (HPLC) with fluorometric detection. CDP-choline reduced the basal levels of blood HA in both EOAD and LOAD by 2-fold. The reduction in blood HA content was observed 2 h after CDP-choline administration and gradually progressed for 30 days of treatment. These results confirm the potential immunogenic effects of CDP-choline and also that an excess of HA might influence some etiopathogenic events in AD.
Administration, Oral↗
Effect of CDP-choline on cognition and immune function in Alzheimer's disease and multi-infarct dementia.
The cholinergic dysfunction present in Alzheimer's disease (AD) might be due to a specific vulnerability of cholinergic neurons linked to neurotrophic imbalance, neuroimmune impairment, and/or direct effects of beta-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 beta-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-1 beta 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.
Aged↗
Serum histamine in Alzheimer's disease and multi-infarct dementia.
Recent data indicate that a neuroimmune reaction might be responsible in part for neuronal death and cognitive deterioration in senile dementia. The potential involvement of brain histamine (HA) and interleukin-1 (IL-1) in this process has been previously documented. We have studied the concentration of serum HA in patients with Alzheimer's disease (AD) or multi-infarct dementia (MID) and in age-matched control subjects. Serum HA levels were significantly higher in AD (10.935 +/- 5.692 nM) and MID (8.521 +/- 3.44 nM) than in controls (5.533 +/- 2.567 nM) and correlated with mental performance as evaluated with the Mini-Mental State Examination (MMSE) (r = +0.493, p < 0.009). No correlation was found with cardiovascular parameters, cerebrovascular risk factors or age. Hyperactivation of the histaminergic system in AD at central and peripheral levels might reflect a neuroimmune reaction to brain tissue damage, a neurotrophic response, and/or a reactive process to regulate the IL-1 induced amyloid precursor protein (APP) overproduction.
Adult↗
Blood levels of histamine, IL-1 beta, and TNF-alpha in patients with mild to moderate Alzheimer disease.
In this study, we have evaluated the levels of blood histamine, serum interleukin-1 beta (IL-1 beta), and plasma tumor necrosis factor-alpha (TNF-alpha) in 20 patients with mild to moderate Alzheimer disease (AD; 13 early onset and 7 late-onset AD subjects) and in 20 age-matched 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-1 beta (AD = 211.2 +/- 31.1 pg/mL; C = 183.4 +/- 24.4 pg/mL; p < 0.01), and lower values of TNF-alpha (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-alpha were observed in both early onset AD (EOAD) and late-onset AD (LOAD) patients, but only EOAD subjects had elevated serum IL-1 beta values compared with age-matched controls. Age negatively correlated with histamine (r = -0.57; p < 0.05) and positively with IL-1 beta levels (r = 0.48; p < 0.05) in healthy subjects, but not in AD, whereas a positive correlation between TNF-alpha scores and age was only found in AD patients (r = 0.46; p < 0.05). Furthermore, histamine and TNF-alpha values correlated negatively in AD (r = -0.50, p < 0.05). In addition, cognitive impairment increased in patients with lower TNF-alpha and higher histamine and IL-1 beta levels, as indicated by the correlations between mental performance scores and histamine (r = -0.37, ns), IL-1 beta (r = -0.33, ns) and TNF-alpha 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.
Age of Onset↗
Genomics and phenotypic profiles in dementia: implications for pharmacological treatment.
Constitutive genomics are probably determinant for the onset of dementia in conjunction with cerebrovascular and environmental factors. Furthermore, pharmacogenomic studies predict that the therapeutic response in Alzheimer's disease (AD) is genotype-specific, and that the expression of genes involved in the regulation of drug metabolism can influence efficacy and safety issues in pharmacotherapy. AD and dementia with a vascular component (DVC = VD + MXD) are the most prevalent forms of dementia. These 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, folic acid and vitamin B(12) levels, brain hemodynamics and lymphocyte markers. The phenotypic profile of patients with DVC differs from that of AD patients in the following: (a) anthropometric values, (b) cardiovascular function, (c) blood pressure, (d) lipid metabolism, (e) uric acid levels, (f) peripheral calcium levels, (g) liver function (GOT, GPT, GGT), (h) alkaline phosphatase, (i) lactate dehydrogenase, (j) red and white blood cells, (k) regional brain atrophy (left temporal region, inter-hippocampal distance) and (l) brain blood flow velocity. Functional genomics studies incorporating APOE-related changes in biological markers extended the difference between AD and DVC up to 57%. 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 2, 3 or 4 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 essential for the expression of dementia symptoms that might be accelerated or induced by environmental and/or cerebrovascular factors.
Age Distribution↗
Serum tumor necrosis factor (TNF) in Alzheimer's disease and multi-infarct dementia.
Changes in neuroimmune parameters and cytokine production have been reported in patients with Alzheimer's disease, including increased levels of interleukin-1 (IL-1) and histamine in brain tissue, cerebrospinal fluid and serum. Specific neuroimmune reactions may be responsible in part for astrogliosis and neuronal death in particular circumstances. Since IL-1 and tumor necrosis factor (TNF) tend to act synergistically in physiological conditions and in some pathological processes, we have studied the concentration of TNF-alpha in patients with Alzheimer's disease (AD) or multi-infarct dementia (MID) and in age-matched control subjects (CS) in order to evaluate possible changes in the levels of this cytokine with potential influence on the pathogenesis of AD. Serum TNF-alpha levels were significantly lower in AD (2.5 +/- 1.25 pg/ml, p < 0.01) and MID (1.64 +/- 1.17 pg/ml, p < 0.001) than in CS (10.66 +/- 8.92 pg/ml). A negative correlation between serum TNF-alpha levels and age in AD was found (r = -0.645, p < 0.01); however, no significant correlations were detected between serum TNF-alpha levels and mental performance, cerebrovascular risk, heart rate and blood pressure in either AD or MID. In conclusion, there is a marked reduction in the concentration of serum TNF-alpha in both AD and MID which seems to be poorly related to cognitive dysfunction and/or neurovascular damage, probably reflecting an endogenous immune dysregulation and/or an inhibitory reactive process in demented patients.
Adult↗