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Background: It is desirable to achieve acceptable accuracy for computer aided diagnosis system (CADS) to disclose the dementia-related consequences on the brain. Therefore, assessing and measuring these impacts is fundamental in the diagnosis of dementia. Objective: This study introduces a new CADS for deep learning of magnetic resonance image (MRI) data to identify changes in the brain during Alzheimer’s disease (AD) dementia. Methods: The proposed algorithm employed a decision tree with genetic algorithm rule-based optimization to classify input data which were extracted from MRI. This pipeline is applied to the healthy and AD subjects of the Open Access Series of Imaging Studies (OASIS). Results: Final evaluation of the CADS and its comparison with other systems supported the potential of the proposed model as a novel tool for investigating the progression of AD and its great ability as an innovative computerized help to facilitate the decision-making procedure for the diagnosis of AD. Conclusion: The one-second time response, together with the identified high accurate performance, suggests that this system could be useful in future cognitive and computational neuroscience studies.

Background Cerebral atrophy is a common feature of several neurodegenerative disorders, including Alzheimer's disease (AD). In AD, brain atrophy is associated with loss of gyri and sulci in the temporal and parietal lobes, and in parts of the frontal cortex and cingulate gyrus. Objective The ASCOMALVA trial has assessed, in addition to neuropsychological analysis, whether the addition of the cholinergic precursor choline alphoscerate to treatment with donepezil has an effect on brain volume loss in patients affected by AD associated with cerebrovascular injury. Methods 56 participants to the randomized, placebo-controlled, double-blind ASCOMALVA trial were assigned to donepezil + placebo (D + P) or donepezil + choline alphoscerate (D + CA) treatments and underwent brain magnetic resonance imaging and neuropsychological tests every year for 4 years. An interim analysis of 3-year MRI data was performed by voxel morphometry techniques. Results The D + P group (n = 27) developed atrophy of the gray and white matter with concomitant increase in ventricular space volume. In the D + CA group (n = 29) the gray matter atrophy was less pronounced compared to the D + P group in frontal and temporal lobes, hippocampus, and amygdala. These morphological data are consistent with the results of the neuropsychological tests. Conclusion Our findings indicate that the addition of choline alphoscerate to standard treatment with the cholinesterase inhibitor donepezil counters to some extent the loss in volume occurring in some brain areas of AD patients. The observation of parallel less pronounced decrease in cognitive and functional tests in patients with the same treatment suggests that the morphological changes observed may have functional relevance.

Background: Benzodiazepines are drugs widely used for the treatment of anxiety and insomnia. The present study has analysed the prescriptions of this class of drugs among sailing seafarers, to evaluate the appropriateness of prescribed therapies. Materials and methods: This study assessed the benzodiazepine prescriptions made by Centro Internazionale Radio Medico (CIRM) doctors from 2011 to 2015. A total of 17,844 medical records were examined. Analysis considered the prescriptions of benzodiazepines in monotherapy, or in association with other drugs. Diagnoses of pathologies for which benzodiazepines were prescribed were made according to the ICD-10 classification system proposed by the World Health Organisation. Results: Among medical records analysed, benzodiazepines were prescribed in 765 cases (3.29% of total cases assisted by CIRM). Benzodiazepines were prescribed as a single-drug treatment in 626 (81.83%) cases, whereas in 139 cases they were associated with other classes of drugs. In case of opioids prescribed in association with benzodiazepines, the drug used was codeine. This therapeutic association was prescribed in cases of severe pain. Conclusions: Although the “off label” use of benzodiazepines is not uncommon in medical practice, clear evidence indicates their potential side effects for human health. In this respect, medical professionals should comply with international guidelines on the use of benzodiazepines, both when prescribed as a single drug or in combination with other classes of drugs. These recommendations should be considered seriously in case of limited medical facilities such as on board of sailing ships.

Insulin resistance (IR) is defined as the inability of a known quantity of exogenous or endogenous insulin to increase glucose uptake and utilization. Several mechanisms have been proposed as possible causes underlying the development of IR and the IR syndrome. IR occurs as part of a cluster of cardiovascular-metabolic abnormalities commonly referred to as "The Metabolic Syndrome." This may lead to the development of type 2 diabetes, accelerated atherosclerosis, hypertension, dysmenorrhea, hirsutism, and polycystic ovarian syndrome, depending on the genetic background of the individual developing IR. The aim of this study was to assess, in 123 female and 35 male (mean age, 42 y ± 10.3; range 19-75 y) volunteers) whether IR could be partly related to a dietary sugar intolerance and whether there could be a correlation between the ALCAT intolerance test and a mutation of the TCFTL2 gene (it promotes the trascription of the proglucagone and plays a key role in the development of the Langherans islands). Results evidenced that subjects with an intolerance to sugar, also showed a statistically significant complete or incomplete alteration of the TCFTL2 genetic test. Based upon these findings, our study demonstrated that there is a clinical correlation between the ALCAT food intolerance test and the IR. The positivity to the ALCAT test of one of the sugars tested (fructose, sugar cane, and sugar beet) indicates, in the majority of the subjects, the presence of a mutation of the gene TCF7L2 and could contribute to the prevention and treatment of the IR.

Cognitive dysfunctions are frequent in patients with epilepsy. This comorbidity significantly alters their quality of life and plays an important role in their therapeutic management. Perampanel is a noncompetitive antagonist of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors and is considered a new generation AED (antiepileptic drug) with limited impact on cognitive functions.The aims of this study were to evaluate the efficacy of perampanel as first add-on therapy and its impact on cognitive functions and quality of life in patients with epilepsy followed for 6 months at the Neurology Division of “A. Cardarelli” Hospital in Naples (Italy).

Background Obesity and overweight represent a relevant risk factor for seafarer’s health. The frequency and distribution of overweight and obesity among seafarers working on board of Italian flag ships were studied. Analysis was made on occupational medicine files collected, in the frame of health surveillance inspections, between 2013 and 2016 from Centro Internazionale Radio Medico (CIRM). Methods The data of nationality, age, weight, height, blood glucose and blood pressure values obtained from 1155 seafarers were analyzed. Body mass index (BMI) values were calculated and compared with data reported for the general population of the same nationality of seafarers examined. Results BMI values revealed a tendency to overweight, whereas blood glucose and systolic blood pressure values were in general in the normal range. Approximtely 40% of subjects investigated were overweight, and more than the 10% of them were obese. Underweight was noticeable only in 1.22% of crew members and 0.34% of officers. The 0.52% of subjects investigated was diabetic, and 2.68% were hypertensive. Seafarers, regardless their nationality and rank, showed a greater tendency to overweight and obesity compared with general population of the same ethnicity. Conclusions Due to the occurrence of overweight and obesity among seafarers, campaigns for promoting awareness of the phenomenon and on the danger of these conditions for health should be promoted. Specific initiatives to avoid the assumption of junk food and the organization of adequate spaces, times and programs for physical exercise sessions on board should be offered for keeping seafarers healthier.

Background Apathy is a common symptom in Alzheimer's disease (AD), but no treatment has proven to be effective, although administration of cholinesterase inhibitors has been associated with moderate improvements in the short term. Objective This study has compared apathy scores of patients included in "ASCOMALVA" trial treated for two years with donepezil plus a cholinergic precursor (choline alphoscerate), to those of patients receiving donepezil alone with the purpose of assessing if the availability of a higher amount of acetylcholine by combining precursor loading and inhibition of neurotransmitter breakdown would counter apathy in AD. Methods Apathy was measured at baseline and 3, 6, 9, 12, 18, and 24 months using the apathy subtest of the Neuropsychiatric Inventory in 113 mild-moderate AD patients. Two matched groups were compared: group 1 (56 subjects) treated with donepezil plus choline alphoscerate and group 2 (57 subjects) treated with donepezil alone. Frontal functions were explored by the Frontal Assessment Battery (FAB) at baseline. Results Group 1 subjects showed, as a whole, a lower apathy score after 12 to 24 months. The caregiver distress was descreased after 6 to 24 months. Results were unrelated with cognitive scores measured by the MMSE and ADAS-cog test. Subjects with FAB in the normal range had significantly lower scores. Conclusions The combination of donepezil with choline alphoscerate is more effective than donepezil alone in countering symptoms of apathy in AD. This suggests that the availability in brain of a higher amount of acetylcholine could affect apathy in AD subjects with spared executive functions.

a b s t r a c t Objective: This study has assessed age-related changes of foot morphology for developing appropriate footwear with particular reference to the elderly. Methods: Anatomical parameters such as foot length, circumference and height and ankle length, circum- ference and height were assessed in a sample of males (n = 577) and females (n = 528) divided into three age groups. The groups included young-adult, aged between 20 and 25 years; adult, aged between 35 and 55 years; and old, aged between 65 and 70 years individuals. Results: In terms of gender differences, in young-adult individuals the sex-related morphological dif- ferences observed, are just related to a significantly lower length of foot in females. In adult subjects morphological parameters investigated were significantly lower in females even after normalization for foot length. In old individuals, no differences of the parameters were found after normalization for foot length. Comparative analysis of morphometric data between young-adult and adult individuals revealed that the instep length was smaller in adults. The opposite was observed for the great toe and medial foot arch height. Length of ankle was higher in adult than in young-adult individuals, whereas ankle circum- ference and height were smaller. In old vs adult individuals foot circumference showed the most relevant age-related differences. Conclusions: Feet anatomy presents specific characteristics in different ages of life. The ideal footwear should take into account these characteristics. This is true primarily for the elderly for minimizing the risk of falls or of other problems related to inappropriate footwear.

Worldwide, at least 2.8 million people die each year as a result of being overweight or obese. Obesity leads to metabolic syndrome, a pathological condition characterized by adverse metabolic effects on blood pressure, cholesterol, triglycerides and insulin resistance. Population- based investigations have suggested that obesity and metabolic syndrome may be associated with poorer cognitive performance.A structured search of bibliographic source (PubMed) was undertaken. The following terms "inflammation and obesity and brain", "cholinergic system and obesity", "cholinergic system and metabolic syndrome", "Cognitive impairment and obesity" and "metabolic syndrome and brain" were used as search strings.Over 200 papers, mainly published in the past 10 years were analysed. The major results regarded keyword "metabolic syndrome and brain" followed by, "Cognitive impairment and obesity", "inflammation and obesity and brain", "cholinergic system and obesity" and "cholinergic system and metabolic syndrome". Most papers were pre-clinical but, in general, they were inhomogeneous. Therefore, the results were cited according their contribution to clarify the molecular involvement of obesity and/or metabolic syndrome in cholinergic impairment.This review focuses on the correlation between brain cholinergic system alterations and high-fat diet, describing the involvement of cholinergic system in inflammatory processes related to metabolic syndrome and obesity, which may lead to cognitive decline. Metabolic syndrome has been suggested as a risk factor for cerebrovascular diseases and has been associated with cognitive impairment in different functional brain domains. Preclinical and clinical studies have identified the cholinergic system as a specific target of metabolic syndrome and obesity. The modifications of cholinergic neurotransmission and its involvement in neuro-inflammation may be related to cognitive impairment that affects obese patients.

Background Behavioral and psychological symptoms of dementia (BPSD) are a group of psychological reactions, psychiatric symptoms, and behaviors commonly found in Alzheimer's disease (AD). Four clusters of BPSD have been described: mood disorders (depression, anxiety, and apathy), psychotic symptoms (delusions and hallucinations), aberrant motor behaviors (pacing, wandering, and other purposeless behaviors), and inappropriate behaviors (agitation, disinhibition, and euphoria). Most of them are attributed to acetylcholine deficiency. Objective To evaluate if a higher amount of acetylcholine obtained by associating donepezil and choline alphoscerate might have a favorable effect on BPSD. Methods BPSD were measured at baseline and after 24 months in 113 mild/moderate AD patients, included in the double-blind randomized trial ASCOMALVA, by the Neuropsychiatric Inventory (NPI). Two matched groups were compared: group A treated with donepezil (10 mg/day) plus choline alphoscerate (1200 mg/day), and group B treated with donepezil (10 mg/day) plus placebo. Results Data of NPI revealed a significant decrease of BPSD severity and distress of the caregiver in patients of group A compared with group B. Mood disorders (depression, anxiety and apathy) were significantly decreased in subjects treated with donepezil and choline alphoscerate, while their severity and frequency was increased in the other group. Conclusions Patients treated with donepezil plus choline alphoscerate showed a lower level of behavioral disturbances than subjects treated with donepezil only, suggesting that the association can have beneficial effects.

Background: In their working activity, seafarers are exposed to high levels of stress that should be accuratelyinvestigated, measured, followed up and, if possible, countered. This is also required by regulations recently entered into force such as the Maritime Labour Convention 2006, recommending to consider special physiological or psychological problems created by the shipboard environment. The choice of the tools for this evaluation is challenging, and a common basic standard usable in a large scale should be identified. Aim: The aim of this study was to evaluate: 1) the suitability of the Psychological General Well-Being Index (PGWBI) questionnaire conducted on board for assessing stress in the sailing seafarers, 2) The presenceof stress in seafarers of different categories (deck officers, engine officers, deck crew, engine crew, chiefstewards/catering staff) monitored by the PGWBI. Materials and methods: 162 male seafarers on board of 7 tankers belonging to the same shipping companywere evaluated through the PGWB questionnaire. Analysis of variance (ANOVA) was used to analyse thedifferences in the scores of the questionnaire. Results: Engine officers exhibited significantly higher anxiety levels than the deck or engine crew, andshowed lower satisfaction than the deck crew. Deck and engine officers revealed higher self-control levelsthan the engine crew. Chief stewards/catering staff showed lower vitality levels than the deck crew. Conclusions: Deck or engine officers should achieve a greater self-control than the crew and this is documentedby the present study. Our findings support the view that management responsibility is more often associated with higher levels of stress. In our opinion, the PGWB questionnaire is a reasonable compromise forobtaining a global evaluation of psychological conditions, including stress of seafarers. It should be therefore considered as a large scale tool for assessing the well-being and eventual stress levels of sailing seafarers.

The aim of the COGNIDAGE study was to examine the association between 25(OH)D and cognitive status in a group of elderly patients with vitamin D deficiency and high burden of comorbidities attending Geriatric Outpatient Clinics.We studied the relationship between 25(OH)D and cognitive functions taking into account comorbidities and cognitive functions assessed by MMSE (Mini Mental State Examination), CDT (Clock Drawing Test) and CIRS (Cumulative Illness Rating Scale), in 132 consecutive elderly patients with low levels of 25(OH)D (10 ng/ml) compatible with the condition of vitamin deficiency. The association among 25(OH)D levels, MMSE score, CDT score and CIRS scores were analyzed using Pearson correlation. All the elderly patients received an adequate vitamin D supplementation and were reassessed after 6 months.At baseline, mean MMSE and CIRS scores were: 21.8+5.56 and 2.96 +1.63 respectively. Mean CDT score was 3,66+-2.05. No associations were found between 25(OH)D levels and global cognitive function. A significant relationship was observed between the total CIRS score and 25(OH)D levels (r=0.305; p=0.000) as well as between total CIRS score and MMSE (r=-0.375; p=0.000). After 6 months, 83.9 % had 25(OH)D levels20 ng/ml. Mean MMSE and CDT scores were 22.20+-5.76 and 3.90+-2.06 respectively. There was no significant correlation among 25(OH)D, MMSE and CDT scores while a significant correlation was found between 25(OH)D and CIRS- severity score (r=0.275; p=0.001) and between MMSE and total CIRS scores (r=-0.247; p=0.005 for CIRS-comorbidities; r=-0.184; p=0.04 for CIRS-severity). A post hoc evaluation on two subgroups of elderly patients (the first with vitamin D deficiency without cognitive impairment, the second with vitamin D deficiency and dementia) showed a statistically significant difference (p=0.00001) regarding the CIRS-comorbidities scores.In our cohort of elderly patients with a high burden of comorbidities, 25(OH)D low levels (10 ng/ml) are not associated with MMSE and CDT scores. There is no statistically difference among the levels of 25(OH)D and MMSE and CDT scores after 6 months. The strong correlation we found regarding CIRS-comorbidities in the two sub-groups suggests that vitamin D deficiency may play a role in promoting cognitive impairment only with comorbidities.

Nicardipine is a dihydropyridine-type Ca(2+) channel blocker (CCB) with strong antihypertensive activity and with a peculiar cerebrovascular profile. This paper has reviewed the main controlled clinical studies on nicardipine in pathologies associated with cerebrovascular impairment. Subarachnoid haemorrhage (SAH) is managed with CCBs to prevent vasospasm and improve clinical outcomes. Nimodipine is the CCB licensed for this indication. Former studies did not demonstrate an advantage of nicardipine versus nimodipine in SAH. A more recent approach administering the drug intra-arterially or using implants of nicardipine prolonged-release showed a decreased incidence of vasospasm, delayed ischemic deficits and improved clinical outcome after severe SAH. Nicardipine is recommended for elevated blood pressure after acute ischemic stroke or intracerebral haemorrhage and is effective in prevention of stroke. More recent investigations were focused on the treatment of cognitive deterioration of vascular origin. In this setting nicardipine has been investigated in more than 6000 patients, with improvement of cognitive deterioration in more than 60% of patients treated. The anti-hypertensive activity of nicardipine, its safety and effectiveness in cognitive domain, suggests re-considering this drug in the treatment of cognitive impairment of vascular origin and for reducing the risk of recurrent stroke in patients at high risk of it.

Control of blood pressure protects against the development of cerebrovascular lesions, stroke, and vascular dementia (VaD). Cerebrovascular disease is increasingly recognized as a cause of cognitive impairment and dementia primarily in the elderly. Nicardipine is a dihydropyridine-type calcium channel blocker (CCB) with a peculiar cerebrovascular profile developed approximately 30 years ago. This study has reviewed the main controlled clinical studies investigating the use of nicardipine in pathologies associated with cerebrovascular injury, such as subarachnoid haemorrhage (SAH), acute stroke, and VaD. SAH is a main cerebrovascular indication of CCBs. In this indication, CCBs prevent vasospasm and improve clinical outcomes. Nimodipine represents the CCB more investigated in this indication. Former studies did not demonstrate a clear advantage of nicardipine versus nimodipine in SAH. A more recent approach using implants of nicardipine prolonged-release showed a decreased incidence of vasospasm, delayed ischemic deficits, and improved clinical outcome after severe SAH. Controlled trials have shown the effectiveness of the drug in preventing stroke. Increasing evidence suggests some benefit of some CCBs in VaD or mixed degenerative and vascular dementia. In this setting, nicardipine has been investigated in approximately 6,000 patients, with an improvement of cognitive deterioration in more than 60% of patients treated. The pronounced anti-hypertensive activity of nicardipine and its safety and effectiveness in cognitive domain suggest its reconsideration in the treatment of cognitive impairment of vascular origin as well as for reducing the risk of recurrent stroke in patients at high risk of it.

Lovastatin is a lipid-lowering agent indicated for primary hypercholesterolemia. This study has assessed single-dosing pharmacokinetics of lovastatin and of its main metabolite, lovastatin beta-hydroxyacid, and has compared the pharmacokinetics of two formulations of lovastatin, a test lovastatin generic (LVSG), and a reference (mevinacor 40 MSD) preparation. The pharmacokinetics and bioequivalence of the two formulations of lovastatin were evaluated by a two-way cross-over randomized double blinded study, in 36 healthy volunteers after a single oral dose of 2 x 40 mg per subject. On plasma samples, collected at given intervals of time (0-24h), lovastatin and its main active metabolite were assayed by high pressure liquid chromatography with positive turbo ion spray ionization tandem mass spectrometry detection. The pharmacokinetic parameters, area under the curve total (AUC(t)) and to infinity (AUC(inf)), peak plasma concentration (C(max)), time to attain peak (t(max)), and elimination half-life (t(1/2)) were determined and analyzed statistically. Only minor differences in the pharmacokinetics of lovastatin and lovastatin hydroxyacid between LVSG and mevinacor were found. Analysis of variance (ANOVA) did not show any significant difference between the two formulations, and 90% confidence intervals fell within the acceptable range for bioequivalence. The tolerability profile was good and comparable for the two formulations of lovastatin. Our study, which was performed with the largest number of subjects compared with those published in literature, indicates the bioequivalence of LVSG and mevinacor tablets. The high inter-subject variability of parameters investigated indicate the need of appropriate sample size in pharmacokinetics studies with lovastatin.

This study has investigated, under controlled conditions, peripheral mononuclear cells (PMNC) subset redistribution in a human experimental stress model consisting of cycloergometer activity in healthy male volunteers exposed to a stressful stimulus. After stressful stimuli, leucocyte subpopulations undergo a stereotyped redistribution peculiar for each PMNC cytotype. PMNC subpopulations involved to a greater extent were natural killer (NK) cells and lymphocytes T "memory" cells. The post-stress period was characterized by a decrease of the NK subpopulation. Our findings confirm the view of a sensible functional reduction of immunocompetence in stress conditions. This brings to the opening, even if for a short time, an "immunological window." This window remains open throughout the time of the stimulus, probably representing the basis of the progressive reduction of the competency of immune system. Catecholamines support the acute effects of stress influencing the anatomical redistribution of lymphocyte subpopulation and intermediating acute effects on PMNC. Cortisol, acting for longer time, contributes to create and maintain both the neutrocytosis and lymphopenia in the post-stress period following lymphocytosis.

The present work has used controlled conditions to study how physical activity and stress affect oxidant and anti-oxidant systems in a human model. Stress test consisting of one hour exercise at a cycloergometer with intensity over the 75% of the maximal cardiac frequency was followed by non-significant changes of malonyldialdehyde, assayed as a marker of lipid peroxidation, and by an increase of erythrocyte catalase and plasma and erythrocyte glutathione peroxidase after the test. These findings suggest that antioxidant response is broadly versatile and adaptable, and that physical activity may prevent extended cellular damage with consequent flogosis. Hence, controlled physical exercise may contribute to protect target organs, including cardiovascular systems, against oxidative stress.

Amlodipine, marketed primarily as a besylate salt, is a calcium channel blocker used for treating essential hypertension. Amlodipine maleate is another salt that is considered, in terms of pharmacokinetics and pharmacodynamics, similar to amlodipine besylate. This open, randomized, two-period crossover trial has investigated in 24 healthy volunteers over a 144 h period the bioequivalence of amlodipine maleate tablets 10 mg versus amlodipine besylate tablets (Norvasc 10 mg). Plasma amlodipine concentrations were assessed by ultra performance liquid chromatography interfaced with a double quadrupole mass spectrometer. The area under the curve total (AUC(t)) and the area under the curve to infinity (AUC(inf)) values, peak plasma concentration (C(max)), and time to attain peak (t(max)) were not statistically different between the two drugs. AUC(t) and AUC(inf) values were higher (p < 0.05) in females than in males. The tolerability profile was comparable for the two salts of amlodipine. These findings indicate that amlodipine maleate and besylate are bioequivalent and were well tolerated, which suggests that the plasma kinetics of amlodipine depend on the properties of the molecule itself. Hence, the two salts investigated could be used interchangeably in clinical practice.

Cholinesterase inhibitors (ChE-Is) are used for symptomatic treatment of mild-to-moderate Alzheimer's disease (AD), but long-term effects of these compounds are mild and not always obvious. Preclinical studies have shown that combination of ChE-Is and the cholinergic precursor choline alphoscerate increases brain acetylcholine levels more effectively than single compounds alone. ASCOMALVA (Effect of association between a ChE-I and choline alphoscerate on cognitive deficits in AD associated with cerebrovascular injury) is a double-blind trial investigating if the ChE-I donepezil and choline alphoscerate in combination are more effective that donepezil alone. The trial has recruited AD patients suffering from ischemic brain damage documented by neuroimaging and has completed 2 years of observation in 113 patients of the 210 planned. Patients were randomly allotted to an active treatment group (donepezil + choline alphoscerate) or to a reference group (donepezil + placebo). Cognitive functions were assessed by the Mini-Mental State Evaluation and Alzheimer's Disease Assessment Scale Cognitive subscale. Daily activity was evaluated by the basic and instrumental activities of daily living tests. Behavioral symptoms were assessed by the Neuropsychiatric Inventory. Over the 24-month observation period, patients of the reference group showed a moderate time-dependent worsening in all the parameters investigated. Treatment with donepezil plus choline alphoscerate significantly slowed changes of the different items analyzed. These findings suggest that the combination of choline alphoscerate with a ChE-I may prolong/increase the effectiveness of cholinergic therapies in AD with concomitant ischemic cerebrovascular injury.

Objective. This review has evaluated the effectiveness of pharmacological treatment of apathy in patients with Alzheimer’s disease (AD).Methods. A systematic literature search was conducted on published clinical trials assessing the effects of pharmacological treatment on apathy in AD over the last 10 years.Results. Fourteen studies considered of good quality were included in the analysis (4 randomized controlled trials, 9 open-label studies, and 1 retrospective analysis). Cholinesterase inhibitors were investigated in 9 studies, monoaminergic compounds such as methylphenidate and modafinil in two trials and one trial, respectively, andGinkgo biloba(EGb 761 extract) and citalopram in one study each. Cholinesterase inhibitors did not show statistical significant effect in 1 RCT study but were associated to improvement in 3 open-label studies. Methylphenidate elicited a small but significant activity accompanied by relevant side effects such as high blood pressure, cough, and osteoarticular pain. EGb 761 was well tolerated and countered apathy. Other treatments induced modest improvements or were ineffective.Conclusions. Apathy treatment remains a challenge and there is no evident advantage of any specific pharmacotherapy tested so far. The development of controlled studies according to updated guidelines for the diagnosis of apathy in patients with AD is desirable.

Background Neuropathology of Alzheimer's disease (AD) demonstrates that the common occurrence of vascular lesions and vascular factors is suggested to contribute significantly to the clinical progression of the disease. This study has assessed the presence of vascular brain lesions and risk factors in subjects with diagnosis of AD and their influence on the disease course both in Late Onset Dementia (LOD) and in Early Onset Dementia (EOD). Methods MRI scans of 374 LOD and of 67 EOD patients were evaluated for the presence of vascular associated lesions and rated according to the age-related white matter changes (ARWMC) scale as “pure degenerative”, “mixed” and “vascular” cases of dementia. Vascular risk factors burden (hypertension, diabetes, dyslipidemia, myocardial infarction) and disease progression were also assessed. Results 44% of LOD cases and 46% of EOD were classified as “mixed dementia cases”. The vascular risk factors burden showed an increase from the pure degenerative to the pure vascular forms. Disease progression, calculated in two years using the Mini Mental State Evaluation (MMSE), Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scores, did not reveal differences among the three different classes of dementias. Conclusions Vascular lesions are found in the majority of LOD cases and in about one half of EOD. This observation is consistent with the hypothesis of a synergistic effect of the degenerative and vascular factors on the development of cognitive dysfunction. The linear increase of the vascular burden supports the idea of a continuum spectrum between the pure degenerative and the pure vascular forms of adult-onset dementia disorders.

Background Cholinesterase inhibitors (ChE-Is) are among the drugs more largely used for the treatment of mild-to-moderate symptoms of Alzheimer's disease (AD), but beneficial long-term effects of these compounds on the cognitive, functional, and behavioural symptoms of the disease are small and not always apparent in practice. Preclinical investigations have suggested that association between ChE-Is and the cholinergic precursor choline alphoscerate enhances cholinergic neurotransmission more effectively than single compounds alone. The ongoing clinical trial on the “Effect of association between a ChE-I and choline alphoscerate on cognitive deficits in Alzheimer's disease associated with cerebrovascular injury” (ASCOMALVA) was designed to assess if association of the ChE-I donepezil with choline alphoscerate has a more favourable clinical profile than monotherapy with donepezil alone. Methods ASCOMALVA is a double-blind multicentre trial that has completed the first 12 months of observation of 91 patients of the 210 planned. Patients were aged between 56 and 91 years (mean 75 ± 10 years) and were included in the protocol with a MMSE score between 15 and 24. Patients with AD diagnosed according to the DSM IV criteria suffer from ischemic brain damage documented by neuroimaging (MRI and CT scan), with a score ≥ 2 in at least one subfield of the New Rating Scale for Age-Related White Matter Changes (ARWMC). Patients were randomly allotted to an active treatment group (donepezil + choline alphoscerate) or to a reference treatment group (donepezil + placebo) and were examined after 3, 6, 9 and 12 months of treatment. Results Cognitive functions, patient's daily activities and behavioural symptoms were assessed by the Mini‐Mental State Evaluation (MMSE), Alzheimer's Disease Assessment Scale Cognitive subscale (ADAS-cog), Basic Activities of Daily Living (BADL), Instrumental Activities of Daily Living (IADL) and Neuropsychiatric Inventory (NPI), of severity and of caregiver distress measures (NPI-F and NPI-D). Patients of the reference group (donepezil + placebo) showed along the course of the 12 months of observation, a slight time-dependent worsening of MMSE, ADAS-cog, IADL and NPI-D scores and no changes in the BADL and NPI-F scores. Donepezil plus choline alphoscerate improved compared to donepezil alone the different items analysed except the BADL. Conclusions The first results of the ASCOMALVA trial suggest that association of choline alphoscerate to the standard treatment with a ChE-I may represent an option to prolong beneficial effects of cholinergic therapies in AD with concomitant ischemic cerebrovascular injury.

Aim: We evaluated variations in behavior of arylsulphatase A activity (an enzyme that catabolizes sulphatides) and of sulphatide concentration in the placenta, cord and membranes of healthy gravidas at term pregnancy, following spontaneous birth. Methods: We extracted and biochemically determined arylsulphatase A and sulphatide concentration in placenta, cord and membranes (far from and close to internal uterine os) in 14 patients. Results: Activity of arylsulphatase A decreased in the cord, in membranes far from the internal uterine os, in membranes close to the internal uterine os and in the placenta. Sulphatide concentration was minimal in the cord and maximal in placenta, with intermediate values in the membranes. No correlation was found between arylsulphatase A activity and sulphatide concentration, nor among arylsulphatase A activities, nor among sulphatide concentrations among the different tissues. It seems that multiparity may increase and the duration of active labor may decrease arylsulphatase A activity in membranes far from the internal uterine os, while active labor duration does not appear to have any implication on sulphatide concentration in membranes close to the internal uterine os. Conclusions: Arylsulphatase A activities and sulphatide concentrations in fetal adnexa show significant differences.

Objective. The aim of this work was to assess the effects of hexavalent chromium [Cr(VI)] on shoe, leather, and hide industry workers, based on the assumption that Cr(VI) can behave as an environmental immunological “stressor.” Methods. The immunological patterns of 84 male subjects were studied in relation to Cr(VI) hematic and urinary levels. Cr(VI) was measured through atomic absorption. Lymphocyte subsets, mitogen-mediated lymphocyte-proliferation, cytokine levels, and natural killer (NK) cytotoxic activity were also assayed. Results. The urinary levels of the total amount of Cr(VI) were significantly higher in a subgroup of exposed subjects (group B) than in the control or in the lower exposed (group A). In group B, Cr(VI) caused a decrease in the density of glucocorticoid receptors (GR) on peripheral blood mononuclear cells (PBMC) and a increase of IL-6. Cr(VI) did not modify NK-mediated cytotoxicity, the plasmatic levels of inflammatory cytokines and related soluble receptors, and prostaglandin levels, while it tended to increase lymphocyte sensitivity to mitogens and the production of immunomodulant cytokines (IFN-γ, IL-4, and IL-2). The experimental addition of Cr(VI) to the in vitro lymphocyte culture determined a significant inhibition of phagocytosis percentage, index, and killing percentage. These effects were neutralized by exogenous IFN-γ. Conclusion. Cr(VI) could represent an environmental immunological stressor whose effects can be evaluated through laboratory surveys. The lymphocyte mitogen-induced proliferation, GR receptor on PBMC, and IL-6 plasma levels may represent a discriminating element between Cr(VI)-induced stress and other kinds of stress. © 2008 Wiley Periodicals, Inc. Environ Toxicol, 2009.

Nimodipine is a 1,4-dihydropyridine-derivative Ca(2+)-channel blocker developed approximately 30 years ago. It is highly lipophilic, crosses the blood-brain barrier, and reaches brain and cerebrospinal fluid. Early treatment with nimodipine reduces the severity of neurological deficits resulting from vasospasm in subarachnoid haemorrhage (SAH) patients. In SAH, nimodipine reduced spasm-related deficits of all severities, but no spasm-unrelated deficits. This paper has reviewed preclinical studies on the influence of nimodipine in various animal models of cerebral ischemia, with particular attention toward investigations published in the last 10 years. These studies further support the main indication of nimodipine, by clarifying some mechanisms of the anti-ischemic activity of the compound. Papers reporting a possible role of nimodipine in epileptogenesis were also examined. Clinical studies on nimodipine were grouped into subarachnoid hemorrhage, acute ischemic stroke, cerebral ischemia without stroke, dementia disorders, and migraine. Clinical investigations have shown that the drug improves neurological outcome by reducing the incidence and severity of ischemic deficits in patients with SAH from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition. No relevant effects of treatment with nimodipine were reported for acute ischemic stroke, cerebral ischemia without stroke, and migraine, except than for cluster headache. The less pronounced cardiovascular effects of nimodipine compared to other dihydropyridine-type Ca(2+)-channel blockers probably accounts for its use out of label for treating patients affected by chronic cerebral ischemia and vascular cognitive impairment. However, the blood pressure-lowering effects of nimodipine should not be minimized, as clinical studies have documented lowering blood pressure in small groups of patients, including cases of withdrawn due to pronounced hypotension induced by nimodipine administration. In the area of vascular cognitive impairment, short-term benefits of nimodipine do not justify its use as a long-term anti-dementia drug, and benefits obtained in elderly patients affected by subcortical vascular dementia require to be confirmed by other groups and in larger scale trials. In conclusion, nimodipine is a safe drug with an important place in pharmacotherapy and with the main documentation for reduction in the severity of neurological deficits resulting from vasospasm in SAH patients.

This study was designed to evaluate in healthy volunteers plasma and cellular (in erythrocytes) of three formulations of alpha-lipoic acid (ALA) available in Italy with different rates of absorption, two with a claimed high absorption rate (Byodinoral 600 QR, Tiocronal 600 HR) and one with a claimed prolonged absorption rate (Tiobec 600 retard). These formulations were compared with the registered ethic formulation of the compound (Thioctacid 600 mg HR), available in Germany. Area under the curve from time 0 to last measured time (AUC(t)), peak plasma concentration (C(max)) of ALA, and time (T(max) ) at which C(max) was observed were the plasma kinetic parameters measured. Concentration of ALA at different sampling times was the only parameter assessed for erythrocytes. The AUC(t) values were similar for the four formulations of ALA tested. C(max) was significantly higher for Byodinoral 600 QR, Tiocronal 600 HR compared to Thioctacid 600 mg HR or Tiobec 600 retard, whereas T(max) value was significantly shorter for Byodinoral 600 QR in the order by Tiocronal 600 HR, Thioctacid 600 mg HR, and Tiobec 600 retard. ALA concentrations that accumulated in erytrocytes after the administration of the different formulations of the antioxidant are directly proportional to the plasma levels of each formulation. Because antioxidant capabilities of ALA depend on the glutathione regeneration the compound induces in cells, the most rationale approach for eliciting antioxidant activity at the cellular level is probably in the use of a formulation allowing the compound to reach its target at highest concentrations and in the shortest time.

An open-label, randomized, crossover single-dose study, using two periods and two sequences with a washout period of seven days was conducted to assess the comparative bioavailability of thioctic (alpha-lipoic) acid (ALA) 600 mg formulation and that of a reference formulation. Blood samples were collected up to +6 h post dosing, the plasma was separated, and thioctic acid concentrations were determined by high-performance liquid chromatographic method with single mass spectrometry detection (HPLC-MS) and a lower limit of quantification of 190.1 ng/ml. Mean values of the individual C(max) were 1338.6 +/- 751.8 ng/ml and 1215.8 +/- 560.5 ng/ml for the test and reference preparations, respectively. Mean +/- standard deviation (SD) total area under the curve up to the last measurable concentration (AUC(t)) was 3510.9 +/- 1088.6 ng x h/ml for the test formulation and 3563.5 +/- 1374.1 ng x h/ml for the reference formulation. Mean +/- SD total area under the curve (AUC(inf)) was 6925.6 +/- 4045.8 ng x h/ml for the test formulation and 7797.1 +/- 5963.1 ng x h/ml for the reference preparation. Terminal elimination half-life was 5.68 +/- 5.05 h for the test and 6.11 +/- 6.15 h for the reference formulations. Time of maximum concentration (t(max)) was 1.24 +/- 1.23 h for the test and 2.05 +/- 1.21 h for the reference formulations. Ninety percent confidence intervals were comprised within the bioequivalence acceptance criteria (80-125%) for all of the parameters analyzed except t(max). The comparison between males and females showed no significant difference for the two drug treatment.

Inhibition of endogenous acetylcholine degradation through cholinesterase inhibitors represents a milestone in symptomatic treatment of cognitive symptoms in mild to moderate stages of Alzheimer's disease. Cholinesterase inhibitors are also under investigation for treating cognitive dysfunction of cerebrovascular origin, but to date they do not have specific indication for vascular dementia or vascular cognitive impairment. This paper reviews the main clinical studies assessing the activity of cholinergic precursors in the treatment of adult-onset dementia disorders of vascular origin. The first cholinergic precursor used phosphatidylcholine (lecithin) did not show any clear clinical benefit on symptoms of dementia disorders. The same is not true for other phospholipids involved in choline biosynthetic pathways such as cytidine 5'-diphosphocholine (CDP-choline) and choline alphoscerate for which a modest improvement of cognitive dysfunction in dementia of neurodegenerative and vascular origin is documented. Positive results obtained with selected cholinergic precursors cannot be generalized due to the small numbers of patients studied in appropriate clinical trials. However, they probably would justify reconsideration of the most promising molecules in larger carefully controlled studies.

Objective To evaluate arylsulphatase A activity and sulphatide concentrations in decidua of women at 41 and 42 weeks of gestation. Study design Enzyme activity and sulphatide concentrations were determined by biochemical procedures on samples of women at 41 and 42 weeks of gestation; thin-layer chromatography was also prepared to separate and visualize sulphatides and other lipid fractions. Results The spectrophotometric values of arylsulphatase A showed very low values at 41 weeks, which reduced to a half at 42 weeks of gestation, while values of sulphatide concentrations increased in 42 weeks. Conclusions The behavior of two parameters examined could be due to the amount of placental estriol reduction, because of sudden placental aging.

Cholinergic precursors have represented the first approach to counter cognitive impairment occurring in adultonset dementia disorders. These compounds were early leaved because their clinical efficacy was not clearly demonstrated. This is probably not true for some choline-containing phospholipids including choline alphoscerate. Choline alphoscerate increases the release of acetylcholine in rat hippocampus, facilitates learning and memory in experimental animals, improves brain transduction mechanisms and decreases age-dependent structural changes occurring in rat brain areas involved in learning and memory. The compound exerts neuroprotective effects in models of altered cholinergic neurotransmission and of brain vascular injury. In clinical studies choline alphoscerate improved memory and attention impairment, as well as affective and somatic symptoms in dementia disorders. An ongoing trial indicates that association between the acetylcholinesterase inhibitor donepezil and choline alphoscerate is accompanied by an improvement in several cognitive tests superior to that induced by donepezil alone. It is suggested that this association may represent a therapeutic option to prolong beneficial effects of cholinergic therapies in Alzheimer’s disease patients with concomitant ischemic cerebrovascular disorders. In summary, choline alphoscerate has significant effects on cognitive function with a good safety profile and tolerability. Although limited both in terms of size of the samples investigated and of the length of treatment, preclinical and clinical results presented suggest that cognitive enhancing capabilities of choline alphoscerate merit of being further investigated in appropriate trials.