Italian neurologists' perception on cognitive symptoms in major depressive disorder.

The assessment of cognition is an important part of major depressive disorder (MDD) evaluation and a crucial issue is the physicians' perception of cognitive dysfunction in MDD that remains nowadays a little known matter. The present study aims at investigating the understanding of neurologists' perception about cognitive dysfunction in MDD. An on-line survey addressed to 85 Italian neurologists in the period between May and June 2015 was performed. The questionnaire comprised three sections: the first section collecting information on neurologists' socio-demographic profile, the second investigating cognitive symptoms relevance in relation with different aspects and the third one explicitly focusing on cognitive symptoms in MDD. Cognitive symptoms are considered most significant among DSM-5 symptoms to define the presence of a Major Depressive Episode in a MDD, to improve antidepressant therapy adherence, patients' functionality and concurrent neurological condition, once resolved. Furthermore, an incongruity came to light from this survey: the neurologists considered cognitive symptoms a not relevant aspect to choose the antidepressant treatment in comparison with the other DSM-5 symptoms on one side, but they declared the opposite in the third part of the questionnaire focused on cognitive symptoms. Cognitive symptoms appeared to be a relevant aspect in MDD and neurologists have a clear understanding of this issue. Nevertheless, the discrepancy between neurologists' perception on cognitive symptoms and the antidepressant treatment highlights the feeling of an unmet need that could be filled increasing the awareness of existing drugs with pro-cognitive effects.

Comparison of extent of tau pathology in patients with frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration with Pick bodies and early onset Alzheimer's disease.

In order to gain insight into the pathogenesis of frontotemporal lobar degeneration (FTLD), the mean tau load in frontal cortex was compared in 34 patients with frontotemporal dementia linked to chromosome 17 (FTDP-17) with 12 different mutations in the tau gene (MAPT), 11 patients with sporadic FTLD with Pick bodies and 25 patients with early onset Alzheimer's disease (EOAD). Tau load was determined, as percentage of tissue occupied by stained product, by image analysis of immunohistochemically stained sections using the phospho-dependent antibodies AT8, AT100 and AT180. With AT8 and AT180 antibodies, the amount of tau was significantly (P < 0.001 in each instance) less than that in EOAD for both FTDP-17 (8.5% and 10.0% respectively) and sporadic FTLD with Pick bodies (16.1% and 10.0% respectively). With AT100, the amount of tau detected in FTDP-17 was 54% (P < 0.001) of that detected in EOAD, but no tau was detected in sporadic FTLD with Pick bodies using this particular antibody. The amount of insoluble tau deposited within the brain in FTDP-17 did not depend in any systematic way upon where the MAPT mutation was topographically located within the gene, or on the physiological or structural change generated by the mutation, regardless of which anti-tau antibody was used. Not only does the amount of tau deposited in the brain differ between the three disorders, but the pattern of phosphorylation of tau also varies according to disease. These findings raise important questions relating to the role of aggregated tau in neurodegeneration - whether this represents an adaptive response which promotes the survival of neurones, or whether it is a detrimental change that directly, or indirectly, brings about the demize of the affected cell.

The economic burden of stroke in Italy. The EcLIPSE Study: Economic Longitudinal Incidence-based Project for Stroke Evaluation.

Stroke is the second most common cause of death in the world. The aim of this study is to estimate stroke's direct costs and productivity losses in Italy from a societal perspective and to explain cost variability. A prospective observational multicentre cost of illness study was designed. Four hundred and forty-nine consecutive patients admitted because of acute first-ever stroke in 11 Italian hospitals were enrolled. Costs and outcomes were assessed at patients' enrollment, and at 3, 6 and 12 months after discharge. Overall, social costs in the first six months following the attack were euros 11,600 per patient; 53% of this was health care costs, 39% non-health care costs and the remaining 8% productivity losses. Age, level of disability and type of hospital ward were the most significant predictors of six-month social costs. The acute phase counted for more than 50% of total health care costs, leaving the remaining 50% to the post-acute phase, indicating that follow-up should be on the agenda of policy makers also.

Slow wave and rem sleep mechanisms are differently altered in hereditary pick disease associated with the TAU G389R mutation.

Sleep disturbances are found in the course of most dementing syndromes. We report a longitudinal polysomnographic and 18FDG-PET study in a 38-year-old male with FTDP17 carrying the Tau gene mutation G389R. All-night sleep EEG and wake cerebral glucose metabolism at rest (eyes/ears covered) of the preceding day were studied twice, eight months (Night 1; PET 1) and sixteen months (Night 2; PET 2) after the initial neurological evaluation. The Night 1 study showed sleep fragmentation associated to a short REM latency and a severe reduction of slow wave sleep, with relatively preserved NREM-REM sleep cycles; daytime PET 1 revealed severe cerebral glucose metabolic reductions in frontal and temporal areas, with relative preservation of remaining cortical regions and subcortical structures. On Night 2, the total sleep time was less than 5 hours, delta sleep and REM latency remained shortened and only two sleep cycles could be identified; daytime PET 2 exam revealed a greater cortical metabolic impairment and an involvement of subcortical brain regions as compared to PET 1. Post-mortem neuropathological data showed severe neuronal loss, spongiosis and gliosis that were mostly marked in cortical layers I, II, V and VI. In vivo, neurometabolic and post-mortem neuropathological data are consistent with and indicative of a severe dysfunction of intra- and trans-hemispheric regional connectivity and of cortico-thalamic circuits. These findings suggest that the decreased cortical and subcortical connectivity may have been the main pathophysiological mechanism responsible for delta sleep reduction and the cognitive decline.

Activation of the JNK/p38 pathway occurs in diseases characterized by tau protein pathology and is related to tau phosphorylation but not to apoptosis.

JNK and p38, two members of the MAP kinase family, are strongly induced by various stresses including oxidative stress and have been involved in regulation of apoptosis. As both kinases phosphorylate tau protein in vitro, we have investigated their immunohistochemical localization in a group of neurodegenerative diseases characterized by intracellular deposits of hyperphosphorylated tau. Cases included Alzheimer disease, Pick disease, progressive supranuclear palsy, corticobasal degeneration, Gerstmann-Sträussler-Scheinker disease-Indiana kindred, and frontotemporal dementia with parkinsonism linked to chromosome 17. In all tissue samples, strong immunoreactivity for both MAP kinases was found in the same neuronal or glial cells that contained tau-positive deposits. By double immunohistochemistry, JNK and p38 colocalized with tau in the inclusions. Analysis of apoptosis-related changes (DNA fragmentation, activated caspase-3) showed that the expression of JNK and p38 was unrelated to activation of an apoptotic cascade. Our data indicate that phospho-JNK and phospho-p38 are associated with hyperphosphorylated tau in a variety of abnormal tau inclusions, suggesting that these kinases may play a role in the development of degenerative diseases with tau pathology.

Progress in hereditary tauopathies: a mutation in the Tau gene (G389R) causes a Pick disease-like syndrome.

We describe the clinical and pathologic phenotypes of the G389R mutation in exon 13 of the Tau gene. Progressive aphasia and memory disturbance are the initial signs and begin in the fourth or fifth decade of life, followed by apathy, indifference, hyperphagia, rigidity, pyramidal signs and dementia. Death occurs after two to five years. Magnetic resonance imaging and neuropathologic studies show frontal and temporal atrophy. Pick body-like and axonal filamentous inclusions found in the neocortex and subcortical white matter, respectively, are tau immunoreactive. Immunoblot analysis of sarkosyl-insoluble tau shows two major bands of 60 and 64 kDa that, upon dephosphorylation, resolve into four bands of three- and four-repeat isoforms. Isolated tau filaments are often straight and occasionally twisted. Recombinant mutant tau protein shows a reduced ability to promote microtubule assembly, suggesting that this may be the primary effect of the mutation. The present findings indicate that the G389R mutation in Tau can cause a dementia similar to that in Pick's disease.

Tau gene mutation G389R causes a tauopathy with abundant pick body-like inclusions and axonal deposits.

Exonic and intronic mutations in Tau cause familial neurodegenerative syndromes characterized by frontotemporal dementia and dysfunction of multiple cortical and subcortical circuits. Here we describe a G389R mutation in exon 13 of Tau. When 38 years old, the proband presented with progressive aphasia and memory disturbance, followed by apathy, indifference, and hyperphagia. Repeated magnetic resonance imaging showed the dramatic progression of cerebral atrophy. Positron emission tomography revealed marked glucose hypometabolism that was most severe in left frontal, temporal, and parietal cortical regions. Rigidity, pyramidal signs and profound dementia progressed until death at 43 years of age. A paternal uncle, who had died at 43 years of age, had presented with similar symptoms. The proband's brain showed numerous tau-immunoreactive Pick body-like inclusions in the neocortex and the fascia dentata of the hippocampus. In addition, large numbers of tau-positive filamentous inclusions were present in axons in the frontal, temporal, and parietal lobes. Immunoblot analysis of sarkosyl-insoluble tau showed 2 major bands of 60 and 64 kDa. Upon dephosphorylation, these bands resolved into 4 bands consisting of three- and four-repeat tau isoforms. Most isolated tau filaments were straight and resembled filaments found in Alzheimer disease and some frontotemporal dementias with tau mutations. A smaller number of twisted filaments was also observed. Biochemically, recombinant tau proteins with the G389R mutation showed a reduced ability to promote microtubule assembly, suggesting that this may be the primary effect of the mutation. Taken together, the present findings indicate that the G389R mutation in Tau can cause a dementing condition that closely resembles Pick's disease.

Allopurinol as add-on therapy in refractory epilepsy: a double-blind placebo-controlled randomized study.

The antiepileptic effect of allopurinol was assessed in a double-blind, randomized, placebo-controlled, cross-over trial in 84 patients with epileptic seizures refractory to standard antiepileptic drugs (AEDs). During a retrospective baseline period, patients experienced at least four seizures of any type per month. The effects of allopurinol and matching placebo were examined for 4-month periods. Allopurinol dosage was 150 mg daily for children weighing < 20 kg and 300 mg daily for other patients. Efficacy analysis based on the Wilcoxon rank-sum test was conducted for the 80 patients who completed the study. No significant period effect or treatment-period interaction was noted. Allopurinol significantly reduced total seizures (p = 0.005), and secondarily generalized seizures (p = 0.0015). Median seizure reduction for total seizures was 10.5 and 27.9% for secondarily generalized seizures. Subjective preferences by clinicians evaluated blindly significantly favored allopurinol. No significant change occurred in the plasma concentration of concomitant AEDs between treatment periods, but serum urate decreased by 32% during allopurinol treatment. No clinically relevant side effects or changes in routine laboratory clinical chemistry or hematology were ascribed to allopurinol.

Effects of frontal lesions on a selective attention task.

We set out to test the hypothesis that patients with frontal damage are specifically disabled in carrying out tasks requiring a high level of controlled attention. A group of patients with frontal lesions and another group of patients with retrorolandic lesions were tested for selective attention on a computerized task designed to produce a conflict situation between automatic and controlled processes. Frontal patients proved to be significantly more prone to errors of commission (false alarms) than retrorolandic patients.

Alterations of ornithine decarboxylase gene during the progression of rat liver carcinogenesis.

Liver nodules and carcinomas, developing in F344 rats initiated with diethylnitrosamine, exhibit high ornithine decarboxylase (ODC) activity and DNA synthesis. ODC-related RNAs of 1.8, 2.1 and 2.6 kb are produced by normal rat liver. Early preneoplastic nodules, developing 10 weeks after initiation, showed overproduction of 1.8 and 2.1 kb RNAs, while the 2.6 kb RNA was barely detectable. Rises in the 1.8, 2.1 and 2.6 kb RNAs occur in late nodules (30 weeks after initiation) and in carcinomas. The comparison of different tissues for relative increase in ODC activity, RNA levels and DNA synthesis showed that these parameters behaved in the same way: highest increases occurred in early nodules and carcinomas. These observations suggest that overexpression of ODC gene and alterations in regulatory mechanisms of ODC gene expression may be implicated in the progression of preneoplastic lesions to malignancy. Southern blot analysis of PstI DNA digests revealed the presence of ODC gene rearrangement in two carcinomas and in one late nodule. However, the role of this phenomenon in the progression of preneoplastic lesions is unclear, due to the possibility that ODC pseudogenes are involved instead of or in addition to ODC gene.

Surface ictal electroencephalographic patterns in frontal vs temporal lobe epilepsy.

The effectiveness of long term EEG monitoring in the localization of the epileptic focus was studied in 37 patients with temporal lobe epilepsy comprising 190 recorded seizures, in 19 frontal lobe epileptic patients with 172 recorded seizures and in 12 additional patients which were classified as fronto-temporal. In the temporal lobe group, 49/190 seizures began focally (26%) and 20/190 seizures exhibited a regional onset (10%). In the frontal lobe group, only 21 out of 172 seizures (12%) had a focal ictal onset. 41/172 seizures began regionally (24%). In the fronto-temporal group, 31/55 seizures disclosed a focal EEG onset (57%). This study demonstrates that there is a two-fold increase in seizures beginning focally in the temporal lobe epilepsy group versus the frontal lobe group.

[Antiphospholipid antibodies and cerebral ischemia]. / Anticorpi antifosfolipidi ed ischemia cerebrale.

Lupus anticoagulants (LAs) and anticardiolipin antibodies (ACAs) are acquired circulating immunoglobulins that cross-react with anionic and neural phospholipids. These factors may display anticoagulant properties in vitro by interfering with phospholipid-dependent coagulation tests. These antibodies are usually not associated with a bleeding tendency. In fact, paradoxically to their name, since the initial recognition they have been related to systemic and cerebral thromboembolisms, despite their in vitro "anticoagulant" properties. We report the clinical and laboratory findings in 4 LAs and ACAs positive patients with brain ischemia.

Predictive performance of pharmacokinetic methods for phenytoin dosing: a multi-center evaluation in 282 patients with epilepsy.

A retrospective study was conducted in 282 patients with epilepsy to assess the predictive performance of pharmacokinetic methods for individualizing dosage of phenytoin. Two population-based dosing methods (population clearance method and bayesian feedback method) and one individual-based method (the so-called linearized Michaelis-Menten method) were evaluated, when applicable, for single-point and/or 2-point dose predictions of phenytoin. In single-point predictions, we found a generally low percentage of dose calculations falling inside the +/- 10% range (48.9% and 51.1% for the population clearance and the bayesian methods, respectively). In 2-point predictions, the bayesian method was 'accurate' (dose within the +/- 10% range) in approximately 54.3% or 55.0% of cases (depending on the particular method of implementation adopted). An even worse percentage of 'accurate' dose predictions (38.3%) was obtained by using the linearized Michaelis-Menten method. Our data do not confirm results from previous studies indicating a generally good performance of pharmacokinetic methods for predicting phenytoin dosage.

[Relational models and psychopathology of epileptics in a group-psychotherapy perspective (author's transl)]. / Note per una psicopatologia relazionale dei pazienti epilettici e prospettive psicoterapeutiche in gruppo

Epileptic patients show a large range of psychopathologic manifestations, both from a qualitative point of view (even with an exact reference to the nature and the site of lesion) and from a quantitative point of view (from the so-called characterial attitude to the psychotic developments). Perhaps all these alterations of psychiatric interest have a common denominator because, after all, they arise from the sum of two essential moments: the experience of the critical event on the one hand, and the interactive network between the patient and those who are present to his critical manifestations on the other. In particular this complex relational psychopathology needs several therapeutic interventions which are to be complementary and concordant so that they may give satisfactory results of psychosocial reinsertion. We think that the model of intervention to be preferred for its effectiveness is that drawn from group-psychotherapy tecniques: the model in which "psychoanalysis meets sociology (Foulkes) seems to be particularly specific to this problem because it concerns the microsocial and investigates (and, by means of the conduction, it resolves) distorted ways of communication and conflictual dynamic interactions. We followed some epileptics in the group-community of the neurological department of a general hospital (of course with other mental, not epileptic, patients). These preliminary studies lead us to point out the theoretical reasons and the practical justifications of such possible management of the psychological manifestations of epileptic patients.