Further insight into the neurobehavioral pattern of children carrying the 2p16.3 heterozygous deletion involving NRXN1: Report of five new cases

Increasing evidence links heterozygosity for NRXN1 gene deletions to a clinically wide spectrum of neurodevelopmental, psychiatric, and neurological disorders. However, to date, the neurocognitive and social communication features of children carrying this genomic rearrangement have not been assessed in detail. The cognitive and behavioral profiles of five children carrying a heterozygous NRXN1 deletion were investigated through systematic assessment of the cognitive and developmental levels, adaptive profile and presence of behavioral symptoms and autistic features. Furthermore, four transmitting parents were assessed by means of cognitive, psychopathological and parental stress tests. A below‐average cognitive level was documented in all children, and defective adaptive levels were observed in four of them. Three of the five children were diagnosed as having autism spectrum disorder in comorbidity with intellectual disability/global developmental delay, with a major impairment in social communication skills. The remaining two children presented with isolated intellectual disability and an unclassifiable neurodevelopmental disorder, respectively. This study provide data contributing to a more accurate characterization of the neurobehavioral phenotype of individuals carrying heterozygous NRXN1 deletions. This analysis indicates that these structural rearrangements are associated with a variable expression of neuropsychiatric symptoms, and cast some doubts about the incomplete penetrance of the disorder.     

MAOB: a modifier gene in phenylketonuria?

Phenylketonuria (PKU), the most frequent inborn error of metabolism (1/15,000 live births), is an autosomal recessive condition caused by phenylalanine hydroxylase deficiency. Despite early and strict dietary control, some PKU children still exhibit behavioral and cognitive difficulties suggestive of a partly prenatal brain injury. The reported variability between the cognitive and clinical phenotypes within the same family raises the question of modifying genes in PKU. We suggest here that monoamine oxidase type B, MAOB, an enzyme degrading phenylethylamine, a very toxic metabolite of phenylalanine, could act as a modifying gene since a variant enzymatic activity of MAOB in PKU patients with similar phenylalanine levels would result in different phenylethylamine levels and different clinical outcomes. Finally the report of low MAOB, and consequently expectedly high phenylethylamine levels in neonates is consistent with a phenylethylamine-mediated brain injury possibly causing irreversible damages in PKU newborns prior to onset of the low protein diet.     

Neutral amino acids monitoring in phenylketonuric plasma microdialysates using micellar electrokinetic chromatography and laser-induced fluorescence detection

Neutral and non-polar amino acids such as phenylalanine (Phe), valine (Val), tyrosine (Tyr), threonine (Thre) and GABA are hard to resolve by capillary zone electrophoresis (CZE). Their separation is possible by adding a surfactant to the mobile phase. This method is called micellar electrokinetic chromatography (MEKC). We used MEKC with laser-induced fluorescence detection (LIFD) to separate and quantitate these amino acids in plasma microdialysates of patients with phenylketonuria (PKU). This disease is an inborn enzymatic defect with decreased conversion of Phe to Tyr that causes severe neurological damage and mental deterioration, which is diagnosed by measuring plasma Phe and Phe/Tyr ratio. The amino acids tested had linear concentration–signal relation. PKU patients had significantly higher Phe, lower Tyr, 21 times higher Phe/Tyr ratio and decreased values of Val and Thre than controls. These results show that microdialysis of biological fluids coupled with MEKC–LIFD is a convenient technique to measure neutral amino acids in clinical disorders such as PKU.     

Behavioral and Neurochemical Characterization of New Mouse Model of Hyperphenylalaninemia

Hyperphenylalaninemia (HPA) refers to all clinical conditions characterized by increased amounts of phenylalanine (PHE) in blood and other tissues. According to their blood PHE concentrations under a free diet, hyperphenylalaninemic patients are commonly classified into phenotypic subtypes: classical phenylketonuria (PKU) (PHE > 1200 µM/L), mild PKU (PHE 600-1200 µM/L) and persistent HPA (PHE 120-600 µM/L) (normal blood PHE < 120 µM/L). The current treatment for hyperphenylalaninemic patients is aimed to keep blood PHE levels within the safe range of 120-360 µM/L through a PHE-restricted diet, difficult to achieve. If untreated, classical PKU presents variable neurological and mental impairment. However, even mildly elevated blood PHE levels, due to a bad compliance to dietary treatment, produce cognitive deficits involving the prefrontal cortical areas, extremely sensible to PHE-induced disturbances. The development of animal models of different degrees of HPA is a useful tool for identifying the metabolic mechanisms underlying cognitive deficits induced by PHE. In this paper we analyzed the behavioral and biochemical phenotypes of different forms of HPA (control, mild-HPA, mild-PKU and classic-PKU), developed on the base of plasma PHE concentrations. Our results demonstrated that mice with different forms of HPA present different phenotypes, characterized by increasing severity of behavioral symptoms and brain aminergic deficits moving from mild HPA to classical PKU forms. In addition, our data identify preFrontal cortex and amygdala as the most affected brain areas and confirm the highest susceptibility of brain serotonin metabolism to mildly elevated blood PHE.     

Evidence that DNA damage is associated to phenylalanine blood levels in leukocytes from phenylketonuric patients

Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism, biochemically characterized by the accumulation of Phe and its metabolites in blood and tissues of affected patients. Treatment for PKU consists of a protein restricted diet supplemented with a mixture containing essential amino acids (other than Phe) and micronutrients. In recent years several authors have studied the pathomechanisms of the disease and demonstrated the existence of lipid and protein oxidative damage in PKU patients. In this work we investigated the in vivo and in vitro effects of Phe on DNA damage determined by the alkaline comet assay using silver staining and visual scoring. We found a dose-dependent effect of Phe on DNA damage in leukocytes from normal individuals incubated with different concentrations of Phe. Additionally, by analyzing blood leukocytes from two groups of treated PKU patients based on their blood Phe levels, we verified that the DNA damage index was significantly higher in PKU patients with high Phe blood levels (DI = 68.2 ± 12.3), compared to well-treated patients and the control group (healthy individuals). Furthermore, well-treated PKU patients had greater DNA damage (DI = 44.9 ± 7.6) relatively to controls (DI = 12.7 ± 4.1). Our present in vitro and in vivo findings indicate that DNA damage occurs in peripheral blood from PKU patients and is associated to Phe blood levels.     

Experimental Evidence that Phenylalanine Provokes Oxidative Stress in Hippocampus and Cerebral Cortex of Developing Rats

High levels of phenylalanine (Phe) are the biochemical hallmark of phenylketonuria (PKU), a neurometabolic disorder clinically characterized by severe mental retardation and other brain abnormalities, including cortical atrophy and microcephaly. Considering that the pathomechanisms leading to brain damage and particularly the marked cognitive impairment in this disease are poorly understood, in the present study we investigated the in vitro effect of Phe, at similar concentrations as to those found in brain of PKU patients, on important parameters of oxidative stress in the hippocampus and cerebral cortex of developing rats. We found that Phe induced in vitro lipid peroxidation (increase of TBA-RS values) and protein oxidative damage (sulfhydryl oxidation) in both cerebral structures. Furthermore, these effects were probably mediated by reactive oxygen species, since the lipid oxidative damage was totally prevented by the free radical scavengers α-tocopherol and melatonin, but not by L-NAME, a potent inhibitor of nitric oxide synthase. Accordingly, Phe did not induce nitric oxide synthesis, but significantly decreased the levels of reduced glutathione (GSH), the major brain antioxidant defense, in hippocampus and cerebral cortex supernatants. Phe also reduced the thiol groups of a commercial GSH solution in a cell-free medium. We also found that the major metabolites of Phe catabolism, phenylpyruvate, phenyllactate and phenylacetate also increased TBA-RS levels in cerebral cortex, but to a lesser degree. The data indicate that Phe elicits oxidative stress in the hippocampus, a structure mainly involved with learning/memory, and also in the cerebral cortex, which is severely damaged in PKU patients. It is therefore presumed that this pathomechanism may be involved at least in part in the severe cognitive deficit and in the characteristic cortical atrophy associated with dysmyelination and leukodystrophy observed in this disorder.     

Expression of calpastatin, minopontin, NIPSNAP1, rabaptin-5 and neuronatin in the phenylketonuria (PKU) mouse brain: possible role on cognitive defect seen in PKU

Phenylketonuria (PKU) is an inborn error of amino acid metabolism. Phenylalanine hydroxylase (PAH) deficiency results in accumulation of phenylalanine (Phe) in the brain and leads to pathophysiological abnormalities including cognitive defect, if Phe diet is not restricted. Neuronatin and 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) reportedly have role in memory. Therefore, gene expression was examined in the brain of mouse model for PKU. Microarray expression analysis revealed reduced expression of calpastatin, NIPSNAP 1, rabaptin-5 and minopontin genes and overexpression of neuronatin gene in the PKU mouse brain. Altered expression of these genes was further confirmed by one-step real time RT-PCR analysis. Western blot analysis of the mouse brain showed reduced levels of calpastatin and rabaptin-5 and higher amount of neuronatin in PKU compared to the wild type. These observations in the PKU mouse brain suggest that altered expression of these genes resulting in abnormal proteome. These changes in the PKU mouse brain are likely to contribute cognitive impairment seen in the PKU mouse, if documented also in patients with PKU.     

Efectos de un programa de intervención neuropsicológica basado en mindfulness sobre la enfermedad de Alzheimer: ensayo clínico aleatorizado a doble ciego

Introduction

The purpose of this research was to assess effects of a mindfulness based neuropsychological intervention on the clinical course of Alzheimer's disease.

Material and method

A two year randomized and double blind clinical trial was conducted on 127 probable Alzheimer's disease patients, according to NINCDS-ADRDA scale. Patients were grouped into three experimental groups (cognitive stimulation, progressive muscular relaxation, and mindfulness) plus a control group. All participants were receiving donepezil. Cognitive skills were assessed with CAMCOG and MMSE, functional area with RDRS-2, and NPI was used for psychopathology screening. Three treatment sessions per week were carried out for two years, and follow up measurements were taken every six months.

Results

The global cognitive function, functionality and behavioral disorders measurements indicated that patients from the experimental group based on mindfulness were stable during the two years, while patients from the control group, as well as the other experimental groups, showed a mild but significant worsening of their mental capacities.

Conclusion

The mindfulness based neuropsychological program showed better cognitive and functional stability, as well as significant improvement in the psychopathological condition of mild to moderate Alzheimer’ patients. These results support the idea that a mindfulness based intervention can produce a clinically relevant improvement in the treatment of dementia. More research is needed to confirm these data.     

A randomized, placebo-controlled, double-blind trial of supplemental docosahexaenoic acid on cognitive processing speed and executive function in females of reproductive age with phenylketonuria: A pilot study

Low blood docosahexaenoic acid (DHA) is reported in patients with phenylketonuria (PKU); however, the functional implications in adolescents and adults are unknown. This pilot study investigated the effect of supplemental DHA on cognitive performance in 33 females with PKU ages 12–47 years. Participants were randomly assigned to receive DHA (10 mg/kg/day) or placebo for 4.5 months. Performance on cognitive processing speed and executive functioning tasks was evaluated at baseline and follow up. Intention-to-treat and per protocol analyses were performed. At follow up, biomarkers of DHA status were significantly higher in the DHA-supplemented group. Performance on the cognitive tasks and reported treatment-related adverse events did not differ. While no evidence of cognitive effect was seen, a larger sample size is needed to be conclusive, which may not be feasible in this population. Supplementation was a safe and effective way to increase biomarkers of DHA status (www.clinicaltrials.gov; Identifier: NCT00892554).     

Effects of L-phenylalanine on acetylcholinesterase and Na+,K+-ATPase activities in suckling rat frontal cortex, hippocampus and hypothalamus

The effect of different L-phenylalanine (Phe) concentrations (0.12-12.1 mM) on acetylcholinesterase (AChE), (Na+,K+)-ATPase and Mg2+-ATPase activities was evaluated in homogenates of suckling rat frontal cortex, hippocampus and hypothalamus. Phe, at high concentrations, reduced AChE activity in frontal cortex and hippocampus by 18%-20%. On the contrary, the enzyme activity was unaltered in the hypothalamus. Na+,K+-ATPase was stimulated by high levels of the amino acid, both in the frontal cortex and the hypothalamus by 60%, whereas it was inhibited in the hippocampus by 40%. Mg2+-ATPase was not influenced by Phe. It is suggested that: a) In the frontal cortex, the improper acetylcholine (ACh) release, due to AChE inhibition by Phe, combined with the stimulation of Na+,K+-ATPase, possibly explain tremor and the hyperkinetic behaviour in patients with classical phenylketonuria (PKU). b) In the hippocampus, inhibition of AChE by Phe could lead to problems in memory, while Na+,K+-ATPase inhibition by Phe may induce metabolic disorders and electrical instability of the synaptosomal membrane. c) In the hypothalamus, the behavioral problems in PKU "off diet" may be related to noradrenaline (NA) levels, which are probably correlated with the modulated Na+,K+-ATPase by Phe.     

Oxidative stress in patients with phenylketonuria

Phenylketonuria (PKU) is an autossomal recessive disease caused by phenylalanine-4-hydroxylase deficiency, which is a liver-specific enzyme that catalyzes the hydroxylation of l-phenylalanine (Phe) to l-tyrosine (Tyr). The deficiency of this enzyme leads to the accumulation of Phe in the tissues and plasma of patients. The clinical characterization of this disease is mental retardation and other neurological features. The mechanisms of brain damage are poorly understood. Oxidative stress is observed in some inborn errors of intermediary metabolism owing to the accumulation of toxic metabolites leading to excessive free radical production and may be a result of restricted diets on the antioxidant status. In the present study we evaluated various oxidative stress parameters, namely thiobarbituric acid-reactive species (TBA-RS) and total antioxidant reactivity (TAR) in the plasma of PKU patients. The activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were also measured in erythrocytes from these patients. It was observed that phenylketonuric patients present a significant increase of plasma TBA-RS measurement, indicating a stimulation of lipoperoxidation, as well as a decrease of plasma TAR, reflecting a deficient capacity to rapidly handle an increase of reactive species. The results also showed a decrease of erythrocyte GSH-Px activity. Therefore, it is presumed that oxidative stress is involved in the pathophysiology of the tissue damage found in PKU.     

Persistent cognitive and motor deficits after successful antimalarial treatment in murine cerebral malaria

Human cerebral malaria causes neurological and behavioral deficits which persist long after resolution of infection and clearance of parasites with antimalarial drugs. Previously, we demonstrated that during active infection, mice with cerebral malaria demonstrated negative behavioral outcomes. Here we used a chloroquine treatment model of cerebral malaria to determine whether these abnormal outcomes would be persistent in the mouse model. C57BL/6 mice were infected with Plasmodium berghei ANKA, and treated for ten days. After cessation of chloroquine, a comprehensive assessment of cognitive and motor function demonstrated persistence of abnormal behavioral outcomes, 10 days after successful eradication of parasites. Furthermore, these deficits were still evident forty days after cessation of chloroquine, indicating persistence long after successful treatment, a hallmark feature of human cerebral malaria. Thus, cognitive tests similar to those used in these mouse studies could facilitate the development of adjunctive therapies that can ameliorate adverse neurological outcomes in human cerebral malaria.     

Evidence that l-Carnitine and Selenium Supplementation Reduces Oxidative Stress in Phenylketonuric Patients

It is well established that the involvement of reactive species in the pathophysiology of several neurological diseases, including phenylketonuria (PKU), a metabolic genetic disorder biochemically characterized by elevated levels of phenylalanine (Phe). In previous studies, we verified that PKU patients (treated with a protein-restricted diet supplemented with a special formula not containing L-carnitine and selenium) presented high lipid and protein oxidative damage as well as a reduction of antioxidants when compared to the healthy individuals. Our goal in the present study was to evaluate the effect of Phe-restricted diet supplemented with L-carnitine and selenium, two well-known antioxidant compounds, on oxidative damage in PKU patients. We investigated various oxidative stress parameters in blood of 18 treated PKU patients before and after 6 months of supplementation with a special formula containing L-carnitine and selenium. It was verified that treatment with L-carnitine and selenium was capable of reverting the lipid peroxidation, measured by thiobarbituric acid-reactive species, and the protein oxidative damage, measured by sulfhydryl oxidation, to the levels of controls. Additionally, the reduced activity of glutathione peroxidase was normalized by the antioxidant supplementation. It was also verified a significant inverse correlation between lipid peroxidation and L-carnitine blood levels as well as a significant positive correlation between glutathione peroxidase activity and blood selenium concentration. In conclusion, our results suggest that supplementation of L-carnitine and selenium is important for PKU patients since it could help to correct the oxidative stress process which possibly contributes, at least in part, to the neurological symptoms found in phenylketonuric patients.     

Large Neutral Amino Acid Supplementation Exerts Its Effect through Three Synergistic Mechanisms: Proof of Principle in Phenylketonuria Mice

Background

Phenylketonuria (PKU) was the first disorder in which severe neurocognitive dysfunction could be prevented by dietary treatment. However, despite this effect, neuropsychological outcome in PKU still remains suboptimal and the phenylalanine-restricted diet is very demanding. To improve neuropsychological outcome and relieve the dietary restrictions for PKU patients, supplementation of large neutral amino acids (LNAA) is suggested as alternative treatment strategy that might correct all brain biochemical disturbances caused by high blood phenylalanine, and thereby improve neurocognitive functioning.

Objective

As a proof-of-principle, this study aimed to investigate all hypothesized biochemical treatment objectives of LNAA supplementation (normalizing brain phenylalanine, non-phenylalanine LNAA, and monoaminergic neurotransmitter concentrations) in PKU mice.

Methods

C57Bl/6 Pah-enu2 (PKU) mice and wild-type mice received a LNAA supplemented diet, an isonitrogenic/isocaloric high-protein control diet, or normal chow. After six weeks of dietary treatment, blood and brain amino acid and monoaminergic neurotransmitter concentrations were assessed.

Results

In PKU mice, the investigated LNAA supplementation regimen significantly reduced blood and brain phenylalanine concentrations by 33% and 26%, respectively, compared to normal chow (p<0.01), while alleviating brain deficiencies of some but not all supplemented LNAA. Moreover, LNAA supplementation in PKU mice significantly increased brain serotonin and norepinephrine concentrations from 35% to 71% and from 57% to 86% of wild-type concentrations (p<0.01), respectively, but not brain dopamine concentrations (p = 0.307).

Conclusions

This study shows that LNAA supplementation without dietary phenylalanine restriction in PKU mice improves brain biochemistry through all three hypothesized biochemical mechanisms. Thereby, these data provide proof-of-concept for LNAA supplementation as a valuable alternative dietary treatment strategy in PKU. Based on these results, LNAA treatment should be further optimized for clinical application with regard to the composition and dose of the LNAA supplement, taking into account all three working mechanisms of LNAA treatment.     

Altered brain protein expression profiles are associated with molecular neurological dysfunction in the PKU mouse model

Phenylketonuria (PKU), if not detected and treated in newborns, causes severe neurological dysfunction and cognitive and behavioral deficiencies. Despite the biochemical characterization of PKU, the molecular mechanisms underlying PKU‐associated brain dysfunction remain poorly understood. The aim of this study was to gain insights into the pathogenesis of this neurological damage by analyzing protein expression profiles in brain tissue of Black and Tan BRachyury‐PahEnu2 mice (a mouse model of PKU). We compared the cerebral protein expression of homozygous PKU mice with that of their heterozygous counterparts using two‐dimensional difference gel electrophoresis analysis, and identified 21 differentially expressed proteins, four of which were over‐expressed and 17 under‐expressed. An in silico bioinformatic approach indicated that protein under‐expression was related to neuronal differentiation and dendritic growth, and to such neurological disorders as progressive motor neuropathy and movement disorders. Moreover, functional annotation analyses showed that some identified proteins were involved in oxidative metabolism. To further investigate the proteins involved in the neurological damage, we validated two of the proteins that were most strikingly under‐expressed, namely, Syn2 and Dpysl2, which are involved in synaptic function and neurotransmission. We found that Glu2/3 and NR1 receptor subunits were over‐expressed in PKU mouse brain. Our results indicate that differential expression of these proteins may be associated with the processes underlying PKU brain dysfunction, namely, decreased synaptic plasticity and impaired neurotransmission.

     

Mutations in the regulatory domain of phenylalanine hydroxylase and response to tetrahydrobiopterin

Tetrahydrobiopterin (BH4) is a co-factor that enhances the activity of other enzymes, and this co-factor level is found to be affected in phenylketonuria (PKU), an amino acid metabolism disorder. The present study was aimed at understanding the effect of BH4 on mutations in the regulatory domain of phenylalanine hydroxylase (PAH). Among 14 patients, 5 patients were classical PKU, 3 were atypical PKU, and 6 were mild PKU. All of these patients had at least one mutation in the regulatory domain. Patients were given 10 mg/kg BH4, and the response of blood phenylalanine (Phe) levels was monitored following treatment. The level of blood Phe decreased after BH4 treatment in all of the patients. These studies suggest that mutations in the regulatory domain also responded to BH4 even if the patient had classical PKU.     

Experimental hyperphenylalaninemia provokes oxidative stress in rat brain

Tissue accumulation of L-phenylalanine (Phe) is the biochemical hallmark of human phenylketonuria (PKU), an inherited metabolic disorder clinically characterized by mental retardation and other neurological features. The mechanisms of brain damage observed in this disorder are poorly understood. In the present study we investigated some oxidative stress parameters in the brain of rats with experimental hyperphenylalaninemia. Chemiluminescence, total radical-trapping antioxidant potential (TRAP), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities were measured in the brain of the animals. We observed that chemiluminescence is increased and TRAP is reduced in the brain of hyperphenylalaninemic rats. Similar data were obtained in the in vitro experiments using Phe at various concentrations. CAT activity was significantly inhibited by Phe in vitro and in vivo, whereas GSH-Px activity was reduced in vivo but not in vitro and SOD activity was not altered by any treatment. The results indicate that oxidative stress may be involved in the neuropathology of PKU. However, further studies are necessary to confirm and extend our findings to the human condition and also to determine whether an antioxidant therapy may be of benefit to these patients.     

Cytoskeleton of human mononuclear cells as a possible peripheral marker for phenylalanine neurotoxicity in PKU

In this work we tested human mononuclear cells as a peripheral marker to study neurotoxicity of phenylalanine (Phe). Slices of cerebral cortex of rats or human mononuclear cells were incubated with different concentrations of Phe and/or Ala in the presence of ³²P-orthophosphate, the cytoskeletal fraction was extracted, and the radioactivity incorporated into intermediate filament proteins was measured. Our results show that 2 mM Phe as well as 1 mM Ala are effective in increasing the ³²P in vitro incorporation into IFs in both tissues. When cerebral cortex slices or mononuclear cells were incubated with different concentrations of Phe and/or Ala, the effects on the ³²P in vitro incorporation into IF proteins was compatible with an antagonistic mechanism of action of the two amino acids on the enzymes of the phosphorylating system. In addition, these blood cells may be a possible peripheral marker to study neurotoxicity of Phe in patients with PKU.     

Functional Implications of an Early Exposure to General Anesthesia: Are We Changing the Behavior of Our Children?

There is a rapidly growing body of animal and clinical evidence suggesting that the exposure to anesthetics and sedatives during the critical stages of brain development results in long-lasting (perhaps permanent) impairment in cognitive development in a variety of mammalian species. With improved understanding of the mechanisms responsible for behavioral outcomes of anesthesia-induced developmental neurotoxicity, there is hope for development of protective strategies that will enable safe use of anesthesia in the youngest members of our society. Here, I review presently available evidence regarding anesthesia-induced neurocognitive and social behavioral impairments and possible strategies for preventing them. I also review limited and somewhat controversial evidence that examines the effects of nociception and surgical stimulation on anesthesia-­induced developmental neurotoxicity.     

Neurocognitive Function in Acromegaly after Surgical Resection of GH-Secreting Adenoma versus Na?ve Acromegaly

Patients with active untreated acromegaly show mild to moderate neurocognitive disorders that are associated to chronic exposure to growth hormone (GH) and insulin-like growth factor (IGF-I) hypersecretion. However, it is unknown whether these disorders improve after controlling GH/IGF-I hypersecretion. The aim of this study was to compare neurocognitive functions of patients who successfully underwent GH-secreting adenoma transsphenoidal surgery (cured patients) with patients with naive acromegaly. In addition, we wanted to determine the impact of different clinical and biochemical variables on neurocognitive status in patients with active disease and after long-term cure. A battery of six standardized neuropsychological tests assessed attention, memory and executive functioning. In addition, a quantitative electroencephalography with Low-Resolution Electromagnetic Tomography (LORETA) solution was performed to obtain information about the neurophysiological state of the patients. Neurocognitive data was compared to that of a healthy control group. Multiple linear regression analysis was also conducted using clinical and hormonal parameters to obtain a set of independent predictors of neurocognitive state before and after cure. Both groups of patients scored significantly poorer than the healthy controls on memory tests, especially those assessing visual and verbal recall. Patients with cured acromegaly did not obtain better cognitive measures than naïve patients. Furthermore memory deficits were associated with decreased beta activity in left medial temporal cortex in both groups of patients. Regression analysis showed longer duration of untreated acromegaly was associated with more severe neurocognitive complications, regardless of the diagnostic group, whereas GH levels at the time of assessment was related to neurocognitive outcome only in naïve patients. Longer duration of post-operative biochemical remission of acromegaly was associated with better neurocognitive state. Overall, this data suggests that the effects of chronic exposure to GH/IGF-I hypersecretion could have long-term effects on brain functions.