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.

An updated Italian normative dataset for the Stroop color word test (SCWT).

The Stroop color and word test (SCWT) is widely used to evaluate attention, information processing speed, selective attention, and cognitive flexibility. Normative values for the Italian population are available only for selected age groups, or for the short version of the test. The aim of this study was to provide updated normal values for the full version, balancing groups across gender, age decades, and education. Two kinds of indexes were derived from the performance of 192 normal subjects, divided by decade (from 20 to 90) and level of education (4 levels: 3-5; 6-8; 9-13; >13 years). They were (i) the correct answers achieved for each table in the first 30 s (word items, WI; color items, CI; color word items, CWI) and (ii) the total time required for reading the three tables (word time, WT; color time, CT; color word time, CWT). For each index, the regression model was evaluated using age, education, and gender as independent variables. The normative data were then computed following the equivalent scores method. In the regression model, age and education significantly influenced the performance in each of the 6 indexes, whereas gender had no significant effect. This study confirms the effect of age and education on the main indexes of the Stroop test and provides updated normative data for an Italian healthy population, well balanced across age, education, and gender. It will be useful to Italian researchers studying attentional functions in health and disease.

A normative study of the Italian printed word version of the free and cued selective reminding test.

According to the new research criteria for the diagnosis of Alzheimer's disease, episodic memory impairment, not significantly improved by cueing, is the core neuropsychological marker, even at a pre-dementia stage. The FCSRT assesses verbal learning and memory using semantic cues and is widely used in Europe. Standardization values for the Italian population are available for the colored picture version, but not for the 16-item printed word version. In this study, we present age- and education-adjusted normative data for FCSRT-16 obtained using linear regression techniques and generalized linear model, and critical values for classifying sub-test performance into equivalent scores. Six scores were derived from the performance of 194 normal subjects (MMSE score, range 27-30, mean 29.5 ± 0.5) divided per decade (from 20 to 90), per gender and per level of education (4 levels: 3-5, 6-8, 9-13, >13 years): immediate free recall (IFR), immediate total recall (ITR), recognition phase (RP), delayed free recall (DFR), delayed total recall (DTR), Index of Sensitivity of Cueing (ISC), number of intrusions. This study confirms the effect of age and education, but not of gender on immediate and delayed free and cued recall. The Italian version of the FCSRT-16 can be useful for both clinical and research purposes.

Successful desensitization to natalizumab in a skin test--positive patient: a case report.

Relevant interest has been focused on rapid desensitization for drug hypersensitivity and on its use for reactions to monoclonal antibodies. Natalizumab is a highly effective therapy for multiple sclerosis but its use can be limited by hypersensitivity reactions. Herein we present a case of a 36-year-old male patient with multiple sclerosis who started natalizumab therapy due to rapid neurological deterioration. During the second infusion he developed a reaction involving urticaria, erythema and angioedema. Natalizumab sensitization was demonstrated by a positive result on the intradermal test. The anti-natalizumab IgG neutralizing antibody assay was negative. Lacking any alternative, equally effective treatment, he underwent a rapid intravenous desensitization protocol. Desensitization was successfully repeated eleven times and the patient's neurological conditions improved and remained stable after one year. This case demonstrates that rapid desensitization is a safe and effective procedure in the treatment of natalizumab hypersensitivity.

"Limbic encephalitis with acute onset and Hu antibodies treated with rituximab: Paraneoplastic or non-paraneoplastic disorder?"

Paraneoplastic limbic encephalitis (PLE) associated with Hu antibodies is a rare autoimmune disorder usually characterized by subacute onset of slowly progressive neurocognitive symptoms. Small cell lung carcinoma is the most frequent PLE-associated cancer, which negatively affects the prognosis of the disease. We report on a patient with acute onset of confusional state and disorganized speech. Cerebrospinal fluid analysis and brain MRI temporal lesions corroborated the diagnostic suspects toward infectious or autoimmune encephalitis but testing for onconeural antibodies suggested the alternative diagnosis of PLE, in the absence of cancer (total-body CT and PET were negative). The patient's serum was positive for Hu antibodies, thus leading to a diagnosis of PLE. First-line immunotherapies were ineffective on the neurocognitive symptoms, which improved after rituximab. Six months later, a retropharyngeal peri-jugular mass was histopathologically diagnosed as a metastasis of lung neuroendocrine tumor. Still clinically improved, the patient died from the oncological disease-related complications. Testing for onconeural antibodies should be considered in patients with clinico-radiological features of acute infectious or autoimmune encephalitis.

Effects of age on brain activation during auditory-cued thumb-to-index opposition: A positron emission tomography study.

BACKGROUND AND PURPOSE: Available data indicate a decline in fine finger movements with aging, suggesting changes in central motor processes. Thus far no functional neuroimaging study has assessed the effect of age on activation patterns during finger movement. METHODS: We used high-resolution perfusion positron emission tomography to study 2 groups of 7 healthy right-handed subjects each: a young group (mean age, 24 years) and an old group (mean age, 60 years). The task was a thumb-to-index tapping, auditory-cued at 1. 26 Hz with a metronome, with either the right or the left hand. The control condition was a resting state with the metronome on. RESULTS: Significant differences between old and young subjects were found, suggesting significant overactivation in older subjects affecting the superior frontal cortex (premotor-prefrontal junction) ipsilateral to the moving fingers, as if the execution of this apparently simple motor task was judged more complex by the aged brain. Similar findings in previous perceptual and cognitive paradigms have been interpreted as a compensation process for the neurobiological changes of aging. Analysis of the control condition data in our sample showed, however, that this prefrontal overactivation in the old group was due at least in part to higher resting perfusion in anterior brain areas in the young subjects. CONCLUSIONS: The changes in brain function observed in this study may underlie the subtle decline in fine motor functions known to occur with normal aging. Our findings emphasize the importance of using an age-matched control group in functional imaging studies of motor recovery after stroke.

Dietary influences on the antiparkinsonian response to levodopa.

The ability of dietary factors to modify the response to levodopa was evaluated in six patients with idiopathic Parkinson's disease who manifested fluctuations in motor performance. The single oral administration of a high-protein formula substantially elevated plasma large neutral amino acid levels, and prematurely terminated the antiparkinsonian response to levodopa/carbidopa. In contrast, during oral or intravenous administration of levodopa, the ingestion of diets meeting the recommended daily allowance (RDA) for protein had no significant effect on plasma levodopa or large neutral amino acid levels or variance, nor on parkinsonian scores or variance. The results suggest that while protein intake in excess of the RDA can diminish the antiparkinsonian response to orally administered levodopa/carbidopa in patients with advanced disease, diets adhering to RDA protein guidelines have no clinically appreciable effect.

Levodopa methyl ester treatment of Parkinson's disease.

Intravenously administered levodopa is effective although relatively impractical for the chronic treatment of patients with Parkinson's disease who are disabled by motor fluctuation. In view of its greater solubility, levodopa methyl ester (LDME) was evaluated in seven advanced parkinsonian patients as a potentially more convenient alternative. Compared with oral levodopa, LDME infusions resulted in marked reductions of both plasma levodopa variations and motor response fluctuations in patients with either wearing-off or on-off phenomena. During infusions lasting approximately 1 week, there were no complications except for peripheral vein phlebitis. The results suggest that LDME might be a practical parenteral treatment for those with severe Parkinson's disease. It appears that central venous access or its equivalent will be necessary for its chronic administration.

3-O-methyldopa and motor fluctuations in Parkinson's disease.

High plasma levels of 3-O-methyldopa (OMD) were found in parkinsonian patients chronically treated with levodopa, particularly in those with on-off phenomenon. However, no relation could be established between circulating levels of the levodopa metabolite and the presence of motor response fluctuations at any stage of disease. It appears unlikely that plasma OMD accumulation contributes to the pathogenesis of wearing-off or on-off responses.

Huntington's disease: effect of cysteamine, a somatostatin-depleting agent.

Somatostatin levels in the basal ganglia are elevated in Huntington's disease. A controlled therapeutic trial of the somatostatin-depleting agent, cysteamine, was therefore conducted in five patients, including one with the rigid-akinetic form. Maximum tolerated dosage for 2 weeks produced no consistent change in extrapyramidal or dementia scores. Somatostatin concentrations were not significantly altered in plasma or CSF. Growth hormone levels, on the other hand, more than doubled, suggesting a functionally significant decrease in central somatostatin levels.

Absence of hemispheric dominance for mental rotation ability: a transcranial Doppler study.

Mean blood flow velocity (MFV) of the middle cerebral arteries was monitored in 19 healthy, adult, right-handed subjects during the resting phase and the execution of a series of neuropsychological tests: two right/left discrimination tasks, two mental rotation paradigms (the Ratcliff's test and a cube comparison test) and a phonemic fluency task, which was utilised as an internal control. In the group as a whole, the Ratcliff's test was associated with a significant bilateral increase in MFV versus both the resting state (right: p < .000001, left: p < .000001) and right/left discrimination tasks (task 1: right: p = .003, left: p = .005; task 2: right: p = .001, left: p = .001). The cube comparison in turn produced a significant increase in MFV versus both the baseline conditions (right: p < .000001, left: p < .000001) and the Ratcliff's test (right: p = .01, left: p = .002). As expected, the fluency task was associated with a significant asymmetric increase in cerebral perfusion (left > right: p = .0001). Increasing task difficulty (right/left discrimination < Ratcliffs test < cube comparison) was paralleled by a roughly proportional rise in MFV values (right: r = .424, p < .01; left: r = .331, p = .01). In conclusion, we were able to demonstrate that (1) in addition to the amount of MFV variation due to right/left discrimination (when required), mental rotation per se causes a bihemispheric activation irrespective of the experimental paradigm; (2) the MFV variation is proportional to the difficulty of the tasks.

Exercise and the antiparkinsonian response to levodopa.

The contribution of acute physical exercise to the motor fluctuations occurring in advanced Parkinson's disease was studied in four patients using a standard treadmill protocol. With a constant optimal-dose intravenous levodopa infusion, no changes in plasma drug levels or antiparkinsonian response were observed during or for 60 min following a 35-min exercise period, during which the work load increased from minimal to vigorous. Although an effect of exercise on levodopa absorption from the gastrointestinal tract cannot be excluded, there seems to be no basis on which to implicate acute physical activity, at levels ordinarily experienced by parkinsonian patients, in the pathogenesis of the fluctuations in motor performance.

Agomelatine but not melatonin improves fatigue perception: a longitudinal proof-of-concept study.

Chronic Fatigue Syndrome (CFS) represents a disabling condition characterized by persistent mental and physical fatigue, bodily discomfort and cognitive difficulties. To date the neural bases of CFS are poorly understood; however, mono-aminergic abnormalities, sleep-wake cycle changes and prefrontal dysfunctions are all thought to play a role in the development and maintenance of this condition. Here we explored in a group of 62 CFS subjects the impact on fatigue levels of agomelatine, an antidepressant with agonist activity at melatonin receptors (MT1 and MT2) and antagonist activity at serotoninergic 2C receptors (5HT2C). To tease out the relative effects of MT-agonism and 5HT2C antagonism on fatigue, we compared agomelatine 50mg u.i.d. with sustained release melatonin 10mg u.i.d. in the first 12-week-long phase of the study, and then switched all melatonin-treated subjects to agomelatine in the second 12-week-long phase of the study. Agomelatine treatment, but not melatonin, was associated with a significant reduction of perceived fatigue and an increase in perceived quality of life. Moreover the switch from melatonin to agomelatine was associated with a reduction of fatigue levels. Agomelatine was well tolerated by all enrolled subjects. Our data, albeit preliminary, suggest that agomelatine treatment could represent a novel useful approach to the clinical care of subjects with CFS.

The factorial structure of the mini mental state examination (MMSE) in Alzheimer's disease.

Our aim was to evaluate the factorial structure of the mini mental state examination (MMSE) in Alzheimer's disease (AD). Five hundred and twenty-four consecutive outpatients at their first diagnostic work-up (age 78.02+/-6.07 years, education 6.62+/-3.48 years, mean MMSE score 20.23+/-4.89) (+/-S.D.) with probable AD (based on DSM-IV and NINCDS-ADRDA criteria) were enrolled in a multicenter, cross-sectional, regional-based study. For the purpose of the present study, the 11 subtests composing the MMSE and the global MMSE score (ranging from 10 to 29, included) were considered. Factor analysis with Varimax rotation method identified two factors that explained about the 85% of total variance. The first factor explained the 65% of variance and mainly included temporal orientation, delayed recall, attention/concentration, and constructional praxia. The second factor explained the 20% of variance and included reading a sentence, writing a sentence, naming, verbal repetition and immediate memory. The first factor was a reliable index of cognitive deterioration along the MMSE score interval between 29 and 10, whereas the second factor was not a suitable marker in this range. The two-factor structure of the MMSE in AD is shown in a large series of patients. The first factor expresses the ability to use new information and is related with working memory. The second factor is related with a more consolidated knowledge, namely verbal abilities, and is essentially useless in mild to moderate AD.

[Cerebrospinal fluid levels of leucine enkephalin and methionine enkephalin in patients with altered behavior]. / Studio dei livelli liquorali della leucinencefalina e della metioninencefalina in pazienti con alterazioni comportamentali.

CSF endorphins levels have been measured in neuropsychiatric patients, in relation to controls. The results we obtained don't allow us to suggest any specific pathophysiological role to endorphins; their levels seemed to be modified in relation to a generic stress-response.

Selective D-1 dopamine receptor agonist treatment of Parkinson's disease.

Preclinical evidence suggests that the D-1 dopamine receptor contributes to the generation of behaviors used as models for human extrapyramidal disorders. To evaluate the potential of D-1 receptor stimulation in neurologic disease, SKF 38393, a selective D-1 dopamine receptor agonist, was administered to seven patients with idiopathic Parkinson's disease in a double-blind, placebo controlled study. SKF 38393 was found to be rapidly absorbed when administered orally, and to occur in micromolar concentrations in spinal fluid. No change in scores of parkinsonian severity were noted when SKF 38393 was administered alone, or when the drug was combined with intravenous levodopa. The results support the view that the pathophysiology of Parkinson's disease may relate exclusively to the D-2 subclass of dopamine receptors.

Levodopa pharmacokinetic mechanisms and motor fluctuations in Parkinson's disease.

The contribution of the peripheral and central pharmacokinetic mechanisms of levodopa to the pathogenesis of the motor fluctuations that complicate its long-term administration was studied in 28 parkinsonian patients. The rate of levodopa clearance from the general circulation, its plasma half-life, and apparent volume of distribution were indistinguishable between patients with the on-off or the wearing-off phenomenon and those with a stable response to levodopa or those who had not been previously treated with levodopa. Peripheral pharmacokinetic factors are thus unlikely to account for the development of these response fluctuations. Conversely, the efficacy half-time of levodopa differed markedly among the four response groups studied and may provide a quantitative index of central mechanisms that favor the development of the wearing-off and on-off phenomena. Although symptom duration was the best predictor of the severity of untreated parkinsonism, levodopa dose correlated best with response half-time. The wearing-off phenomenon may primarily reflect the loss of buffering capacity caused by degeneration of the dopamine neurons, while the development of the on-off phenomenon appears to require additional postsynaptic changes, possibly at the receptor level.