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Several lines of evidence implicate a central role for alpha-synuclein (aSN) in the pathogenesis of Parkinson's disease (PD). Besides rare genetic mutations, post-translational mechanisms, such as oxidative stress-related nitration, may alter the protein properties in terms of propensity to aggregate or be degraded. Our group previously described increased reactive oxygen species (ROS) production within easily accessible peripheral blood mononuclear cells (PBMCs) in PD patients compared to healthy elderly subjects. In the present work, we demonstrated a significant induction of nitrotyrosine (NT)-modifications of aSN within PBMCs derived from individuals with idiopathic PD compared to controls, while aSN protein appeared similarly expressed in the two populations. The amount of NT-modified aSN within PBMCs was positively correlated with intracellular ROS concentration and inversely related to daily dosage of levodopa, making its measurement potentially relevant for disease-intervention studies. Neither aSN expression nor its NT-modifications showed any correlation to specific REP1 genotypes, polymorphic variants within aSN gene promoter whose association to PD susceptibility may occur through the modulation of aSN protein expression. Moreover, although NT-modified aSN has been linked to enhanced propensity to aggregate, we failed to detect an increased presence of insoluble aSN aggregates in PBMCs from PD subjects relative to controls, despite a lack of changes in the ubiquitin-proteasome expression or activity. Nonetheless, a significant activation of the autophagy response was identified within PBMCs from PD individuals, which could represent a protective mechanism against abnormal protein accumulation and may explain the lack of aSN aggregation. We discuss the relevance of these findings with respect to PD pathogenesis and biomarker development.

Oxidative stress, resulting from the imbalance between reactive oxygen species (ROS) formation and antioxidant defenses, plays a major role in the pathogenesis of Parkinson's disease (PD). However, the contribution of levodopa (LD) therapy to oxidative damage is still debated. We investigated oxidative stress in peripheral blood mononuclear cells (PBMCs) from LD-treated PD patients and healthy subjects. Increased ROS production associated with unaltered glutathione reductase activity was detected in PBMC from PD patients. LD daily dosage appeared to be inversely correlated with ROS levels and positively associated with GR activity, suggesting a protective role for LD on PBMCs redox status. Our data support the view of systemic oxidative stress involvement in PD and give further rationale for using PBMCs as an easily accessible ex-vivo dopaminergic model for exploring the biological effects of LD therapy.

Apathy is a salient feature of various neuropsychiatric disorders, from depression to Alzheimer's disease. We formally assess its prevalence in idiopathic Parkinson's disease (PD) together with its clinical, neuropsychological, and morphometric correlates. Thirty patients with PD and 25 normal controls were assessed using an extensive neuropsychological battery and Marin's Apathy Scale; parkinsonian patients also underwent MRI scan, followed by linear measurement of various frontotemporal structures. Approximately 45% of the PD sample showed apathy. For comparison analysis, given the unimodal distribution of the apathy scores, the PD sample was divided into three groups on the basis of the apathy tertiles. All three PD groups had worse cognitive and depression scores than controls, whereas they did not differ in terms of demographic, neurological, general cognitive, or affective features. By contrast, a significant positive association was found between apathy scores and performance on tests of executive function. As regards the morphometric data, we failed to find any specific measure of frontotemporal atrophy correlating with the presence or severity of apathy. Thus, apathy seems to be a frequent and important companion of PD, in many cases probably due to a primary motivational impairment, possibly related to a frontosubcortical dysfunction.

Summary The results of a two-year treatment with α-dihydroergokryptine mesylate (DEK) carried out in 142 (43 male, 99 female; aged 63–83) demented patients (DAV.I.D.E., DAVERIUM ® Italian Dementia Evaluation), are presented here. The study design included a 1-month run in placebo phase, a 1-year in double-blind condition either with a-dihydroergokryptine or placebo, and a further 1-year (open phase) with DEK. For assessing clinical efficacy the Gottfries-Brne-Steen (GBS) rating scale for dementia (primary variable) and the mental deterioration battery (MDB) (secondary variable) were used. Analysis of variance on efficacy variables and summary measures was performed using age and illness duration as covariates. The safety analysis was carried out monitoring vital signs, adverse events and routine laboratory tests. Seventy out of 142 patients were previously treated with DEK and 72 with placebo; 109 patients completed the study, 33 patients dropped out. The patients previously treated with DEK maintained their clinical conditions observed at the end of the double-blind phase; the patients previously treated with placebo improved the motor (GBS score: −33 %), intellectual (−26 %) and emotional (−24 %) functions, and the neuropsychological performances (MDB scores), the difference between the paired samples being significant. Four patients (2.8%) had adverse events, requiring drug suspension in two cases. The results indicate that DEK treatment might slow down the progression of the disease as documented by both functional and neuropsychological parameters. Safety was very good, indicating that the drug is suitable for long-term treatments.

119 patients were enrolled in a double-blind randomized parallel study versus placebo carried out to assess both the efficacy and tolerability of L-deprenyl (10 mg/day) for treatment of patients with organic mental disorders of the Alzheimer type (DAT). The treatments were given for 3 months, starting after a run-in period of 15 days to evaluate efficacy. A complete neuropsychological battery was administered monthly after the start of treatment whereas tolerability was assessed by checking, recording and classifying all the unfavorable experiences occurring. According to the results, L-deprenyl would seem to be a useful and reliable tool for the treatment of DAT patients in an attempt to improve their cognitive functions and reduce behavioral alterations, without frequent or severe side effects.

In this study we employed an ELISA assay to measure alpha-synuclein protein in lymphomonocytes from 78 PD patients and 78 controls. We correlated protein levels with demographic and clinical characteristics and with the chymotryptic and tryptic activities of the 20S proteasome. Alpha-synuclein levels were not significantly different between patients and controls. In control subjects, alpha-synuclein protein levels increased significantly with age and were significantly higher in men compared to women. Proteasome activity was not significantly different between cases and controls. In control group, the 20S chymotryptic activity tended to decrease significantly with increasing age, though it was not correlated to alpha-synuclein levels. The 20S tryptic activity was not significantly correlated to age, but was inversely correlated to alpha-synuclein levels. Our findings suggest that alpha-synuclein levels in lymphomonocytes are affected by age, gender, and by the 20S proteasome activity in control subjects, but they are not useful as a diagnostic biomarker for PD.

Peripheral-type benzodiazepine receptors were measured in human circulating lymphocytes using 3H-PK 11195 as specific ligand. In a group of outpatients with anxiety disorders a significant decrease of receptor density (– 37%) was found compared with age-matched controls. In these patients long-term diazepam treatment restored binding density to normal levels: the effect persisted after drug withdrawal. Acute i.v. diazepam administration did not change receptor density. The observed receptor changes could reflect a down-regulation phenomenon and indicate that lymphocyte function reflect central nervous events.

The Time and Weight Estimation test (STEP) and the Cognitive Estimation Task (CET) are two recently devised tests for the assessment of cognitive estimation. In the present study, we compared their performance in 30 non-demented idiopathic parkinsonian (PD) patients, also evaluated with the Frontal Assessment Battery (FAB) as an index of executive impairment, with the aim of verifying the putative frontal circuitry of cognitive estimation processes. Six patients (20%) showed a pathological performance on either or both tests. After division of the PD sample into tertiles based on the FAB score, no significant difference was detected by either estimation test. Furthermore, the two questionnaires were unrelated to each other. Thus, deficits of cognitive estimation ability appear to be mild in PD without dementia and do not correlate with executive impairment. Unexpectedly, the CET and the STEP seem to have no unique underlying construct.

Anhedonia is the inability to experience physical or social pleasure. Its physical component is hypothesised to be due to dysfunction of a dopaminergic frontotemporal-subcortical circuit and has never been investigated as a possible affective complication of Parkinson's disease (PD). The aim of this study was to formally assess prevalence and correlates of physical anhedonia in PD patients compared with normal controls. Twenty five people with PD and 25 matched controls were administered a psychometric battery exploring mainly executive functions and mood. Hedonic tone was assessed using Chapman's Physical Anhedonia Scale. PD patients also underwent MRI linear measurement of frontal structures. Anhedonia levels were significantly higher in PD patients with respect to controls, although not extremely elevated; prevalence rate was 40% for parkinsonians, while no anhedonics were found among controls. Clinical, neuropsychological, and quantitative neuroradiological features did not show any significant correlation with physical anhedonia. Physical anhedonia appears to be a relatively frequent, although mild, affective disturbance of PD, independent from neurological, frontal, and depressive aspects.

deep brain stimulation is a widely accepted surgical therapy for the symptomatic treatment of advanced parkinson's disease; high frequency chronic stimulation of the subthalamic nucleus proved its efficacy to control the major motor symptoms. In the neurosurgical department of Monza we treated 72 parkinsonian patients (November 1998–January 2003). One year follow-up results are: decrease of tremor 90%, hypertonous 56%, bradykinesia 70%, voice impairment amelioration 30%, mean total daily L-dopa intake reduced 58%. Freezing and balance did not ameliorate, some voice impairment and psychic derangement have been observed. Major surgical complications were: haemorrage (1 case – transient hemiparesis), infections (2 cases), pulmonary embolisation (1 case). To optimise the surgical results, careful clinical and instrumental selection of the patients are mandatory before surgery.

Defects in mitochondrial enzymes have been found not only in substantia nigra, but also in platelets from Parkinson's Disease (PD) patients, suggesting a systemic impairment of energy metabolism. Since platelets present an energy-dependent glutamate uptake similar to that described in central nervous system, glutamate uptake was determined in platelets from 34PD patients and 21 age-related normal controls, as Na+-dependent [3H]glutamate influx; glutamate level was also analyzed by reverse-phase HPLC. A 50% reduction of glutamate uptake (p < 0.001) was observed in idiopathic PD patients, respect to controls and secondary parkinsonian syndromes. The decrease correlated with the severity of PD, measured by the UPDRS (r = -0.54; P < 0.05). Glutamate level was increased in platelets of PD patients, but was not correlated to the uptake decrease. Both phoenomena may be explained by the modifications of mitochondrial enzymes described in platelets, which could be used as a peripheral model of glutamatergic function in PD

Although patients with brain lesions of neurosurgical interest may sometimes present with a cognitive profile very similar to a primary dementia, they usually have a history and/or a neurologic examination which alert the clinician. The occurrence of mass lesions with purely isolated cognitive deterioration has been mainly reported for locations at the level of the frontal lobes. A potentially positive prognosis is advocated in these cases, in terms of even complete reversibility of the mental impairment when surgical removal is feasible and successful. We report two rare cases of posterior intraventricular meningiomas presenting with isolated cognitive and behavioural changes consistent with a frontal type dementia; the outcome was favourable in one patient, whereas the second one suffered from massive intracerebral bleeding during the neurosurgical removal and required prolonged hospitalization and subsequent intensive neurorehabilitative efforts. By comparing our cases with previously published decision-rules regarding neuroimaging in dementia, we suggest that criteria should be enlarged, especially those regarding the age of the subject and the time elapsed from the first signs of the cognitive deterioration.

Over-stimulation of glutamate receptors and oxidative stress are two possible mechanisms that cooperate to selective degeneration of dopaminergic cells in Parkinson’s Disease (PD)1,2,3. Defects in mitochondrial enzymes, which make dopaminergic cells more susceptible to oxidative stress, have been found not only in substantia nigra of PD patients4, but also in their peripheral tissues5and blood platelets6,7,8,9. Recent studies also indicated that impaired mitochondrial function in platelets of PD patients is a characteristic of the disease and is not a consequence of pharmacological treatment10.

We present 2 cases of Listeria monocytogenes rhombencephalitis (L-RE), both affecting previously healthy adult men. Each of them developed a diphasic syndrome first characterized by fever, nausea and headache, followed, in a second phase, by severe brain stem dysfunction at the level of the pons, with meningism, multiple cranial nerve palsies, ataxia, and, in one case, seizures. The early examination of the cerebrospinal fluid (CSF) demonstrated the presence of Gram-positive bacilli whose typical characteristics were compatible with those of Listeria, allowing for immediate administration of a specific therapy. Neuroimaging techniques (either CT or MRI) did not provide any evidence of brain stem involvement, and they did not positively contribute to the diagnostic process. The immediate use of a specific antibiotic therapy led to a favourable clinical outcome for both patients.

In a pilot study, proglumide, a cholecystokinin receptor antagonist, was administered to 8 patients affected from Huntington's chorea under long-term haloperidol treatment. The effectiveness of haloperidol on chronic symptomatology was reduced by the concomitant administration of proglumide; the latter drug, when administered alone, did not modify the severity of chorea compared to placebo. Possible explanations of these results are discussed, stressing the modulatory role of CCK not only on the dopaminergic, but also on the GABAergic system.

The Time and Weight Estimation test (STEP) and the Cognitive Estimation Task (CET) are two recently devised tests for the assessment of cognitive estimation. In the present study, we compared their performance in 30 non-demented idiopathic parkinsonian (PD) patients, also evaluated with the Frontal Assessment Battery (FAB) as an index of executive impairment, with the aim of verifying the putative frontal circuitry of cognitive estimation processes. Six patients (20%) showed a pathological performance on either or both tests. After division of the PD sample into tertiles based on the FAB score, no significant difference was detected by either estimation test. Furthermore, the two questionnaires were unrelated to each other. Thus, deficits of cognitive estimation ability appear to be mild in PD without dementia and do not correlate with executive impairment. Unexpectedly, the CET and the STEP seem to have no unique underlying construct.

Genetic risk factors seem to play a role in sporadic Parkinson's disease (PD), maybe triggering oxidative stress and excitotoxicity within substantia nigra. However, genetic factors act at systemic level: reduced activity of mitochondrial enzymes and decreased glutamate uptake have been shown in platelets from PD patients. In this study we investigated glutamate uptake in platelets from 38 sporadic PD patients, 13 patients with parkinsonian syndromes and 28 controls and assessed polymorphisms of alpha -synuclein and ApoE genes. A 48% reduction of glutamate uptake (p

Deep brain stimulation (DBS) obtains good control of advanced PD symptoms. Chronic stimulation of Stn may alleviate rigidity, dyskinesia and tremor. Anatomical and functional intraoperative mapping are mandatory to obtain careful target localisation. Per-operative macrostimulation was carried out in 22 patients undergoing bilateral DBS in Stn; a volume 6 mm above to 4 mm below Stn was explored. Positive, collateral and adverse effects were recorded every 2 mm. Results obtained during acute stimulation were correlated to anatomical data from stereotactic atlases. Our findings suggest a volume, encompassing the zona incerta, Forel's fields and the lowermost part of anterior thalamus, functionally homogeneous to Stn. In fact, the stimulation of this volume obtains reduction of PD symptoms comparable to Stn.

The efficacy and safety of alpidem, a new anxiolytic imidazopyridine, were compared with those of placebo in anxious elderly patients (65-80 years) by means of a randomized, double-blind, parallel group study. Following a 7-day "placebo run-in," 40 anxious patients were randomized to receive either alpidem or placebo. Daily doses ranging from 75 to 150 mg (25-50 mg t.i.d.) were administered for 3 weeks. Hamilton Rating Scale for Anxiety (HRSA), State Trait Anxiety Inventory (STAI-X1), Visual Analogue Scale (VAS), and Clinical Global Impression (CGI) were used on days 0, 3, 7, 14, and 21 for assessing efficacy. Psychomotor and mnesic performances were evaluated at the same time by means of the Digit Symbol Substitution Test (DSST), the Grunberger's test for fine motor coordination, and the Hawie's test for immediate memory. Possible adverse events were also recorded during the five visits. The anxiolytic efficacy of alpidem was significantly (p < 0.01) superior to that of placebo in all the rating scales adopted. The anxiolytic action was clearly evident from day 7. For most of the patients the active dose was 25 mg t.i.d. No relevant adverse effects were observed in both groups. No impairment of psychomotor and mnesic performances could be observed in the alpidem group. Alpidem is a new interesting anxiolytic drug for anxious elderly patients because it appears remarkably safe and, at effective doses, it does not impair psychomotor performances and cognitive functions.

A multicenter study has been conducted to determine the interobserver reproducibility of four of the most frequently used rating scales for Parkinson's disease: the Columbia University Rating Scale (CURS) and the Webster Rating Scale (WRS), both for assessing clinical signs; the Northwestern University Disability Scale (NUDS); and the Hoehn and Y ahr staging. Four resident neurologists, inexperienced in the use of the four scales, independently examined 48 parkinsonian patients. The extent to which their assessments agreed was determined by calculating the Cohen k index after the scores had been recodified. The physicians' scores agreed substantially for the CURS and the Hoehn and Y ahr scale, while those for the NUDS and the WRS agreed only moderately. Analysis of individual item scores within the scales suggests improvements that would offer greater interobserver consistency.

We investigated CSF levels of diazepam-binding inhibitor (DBI), a recently discovered neuropeptide that allosterically modulates GABAergic transmission, in various neurodegenerative disorders with dementia (28 patients with Parkinson's disease, 10 with Alzheimer's disease, 7 with Huntington's chorea). We applied a battery of neuropsychological tests to determine the degree of dementia and to exclude the presence of mood alterations. CSF DBI levels were elevated in parkinsonian subjects with dementia and in patients with Alzheimer's disease, but decreased in Huntington's chorea patients. We hypothesize that modifications of CSF DBI levels may be related to a functional or structural alteration of the GABAergic System.

We have characterized the specific binding of [3H]-phorbol-12,13-dibutyrate in the white and gray matter of normal human brain and in cerebral tumors as an index of the availability of protein kinase C enzyme molecules. White matter has less than 50% phorbol-ester-binding capacity in comparison to gray matter. The binding is lower in tumors of glial origin when compared with normal white matter. Tumors of nonglial origin such as neurinoma and meningioma have a lower binding capacity than glial tumors. Metastatic tissues have the lowest binding capacity. The analysis of binding parameters in tumors and in the corresponding normal peritumoral tissues confirms the decreased binding capacity of neoplastic tissues in comparison to tissues not undergoing malignant transformation. These data suggest that brain glial tumors have a low availability of protein kinase C enzyme molecules and point to the potential involvement of this system in malignant transformation of human brain cells.

Proglumide, a cholecystokinin antagonist, did not improve Parkinson's disease in a preliminary drug treatment trial.

The anxiolytic activity of alpidem (150 mg/day) and its effects on psychomotor performances were compared with placebo in 60 outpatients. The trial was a double-blind, parallel group, and the two treatments were administered orally in three divided doses for 3 weeks. Eighteen male and 42 female patients (mean age, 39.6 years) suffering from generalized anxiety or adjustment disorder with anxious mood of at least 1-month duration entered the trial at the end of a 1-week placebo run-in period designed to exclude early placebo responders. Efficacy was assessed with the Hamilton rating scale for anxiety (HRSA), the state-trait anxiety inventory (STAI x 1: anxiety as state), a visual analogue scale (VAS), and clinical global impression (CGI). Psychomotor performance was assessed by the digit symbol substitution test (DSST). Alpidem was significantly more effective than placebo in decreasing the severity of anxiety, both in the physician's judgment [total HRSA (p = 0.007), psychic symptoms (p = 0.0040), somatic symptoms (p = 0.0002)] and in the patients' evaluation [STAI x 1 (p = 0.0001) and VAS (p = 0.0003)]. Psychomotor performance was improved by both treatments; there was no difference between results with alpidem and placebo at the DSST (p = 0.2801), but the improvement was almost twofold on alpidem. Side effects were negligible with both treatments and the efficacy index, obtained from the CGI, was significantly better with alpidem than with placebo after day 7 (at least p less than 0.03).

In human and animal brain microvessels beta-adrenergic receptors have been identified which are suggested to subserve the regulation of capillary function in both physiological and pathological conditions. Brain tumors are supplied by vessels that differ from those supplying normal cerebral tissue in various structural and functional parameters. In order to study the characteristics of brain tumor microcirculation, we have investigated the presence of beta-adrenergic receptors in capillaries isolated from different types of neoplasms using the specific radioligand 125I-iodocyanopindolol (ICYP). The microvessels were isolated and prepared by albumin flotation and glass bead filtration from normal and pathological tissues. No ICYP-specific binding was detected in the microvessels of tumors of glial origin, while capillaries obtained from meningiomas and neurinomas showed, like the normal brain, a specific binding of the radioligand. The data indicate that the regulation of capillary function in glial tumors differs from that of normal cerebral tissue and extraparenchymal tumors, thus indicating an impaired control of the vascular permeability.

In 30 ischemic stroke patients, divided into 2 groups depending on the side of their hemispheric cerebral lesion, the authors evaluated the levels of CSF homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA). The changes of these metabolites in CSF samples collected 3, 14 and 25 days after stroke have been correlated to the clinical course. In both groups, which were similar in respect to the localization of the infarcted area and to the volume of the lesion, the levels of HVA and 5-HIAA increased in the first 2-3 days and gradually declined to normal values in the following 3 weeks, in parallel with the regression of neurological deficits. The increase of HVA and 5-HIAA was statistically significant only in left hemisphere-injured patients. A linear regression analysis between the clinical score values and the CSF levels of the two metabolites at different time-points of observation revealed a significant correlation only for the HVA in the left-lesioned patients.

Benzodiazepines can regulate neoplastic growth and immune response through specific peripheral benzodiazepine receptors. We investigated the presence of peripheral and classic central benzodiazepine receptors as well as diazepam-binding inhibitor, an endogenous ligand of both types of receptors, in different human cerebral tumors. Peripheral benzodiazepine receptors were present in all the tumor types studied, whereas central benzodiazepine receptors and diazepam-binding inhibitor were detectable in astrocytomas and glioblastomas and undetectable in meningiomas, neurinomas, and metastases. The role of diazepam-binding inhibitor and of the different benzodiazepine receptors in neoplastic cells is still to be defined.

The properties of [3H]-gamma-aminobutyric acid [( 3H]GABA) binding were studied in biopsied specimens from normal human brain and from 18 cases of human brain gliomas, made up of 6 astrocytomas, 6 glioblastomas, 3 oligodendrogliomas, and 3 medulloblastomas. In fresh membranes obtained from normal gray and white matter one population of Na+-dependent GABA receptors was observed, while in the frozen Triton X-100-treated membranes two distinct populations of Na+-independent binding sites were detected. Specific GABA binding sites in brain gliomas were shown only in frozen Triton X-100-treated membranes. As in normal tissue, these receptors are Na+-independent and bind [3H]GABA with two distinct affinity components. The biochemical profiles of [3H]GABA binding to membranes obtained from different tumors of glial origin are quite similar and cannot be related to the degree of malignancy of the neoplasia.

Diazepam binding inhibitor (DBI) is a novel neuropeptide purified from rat, cow, and human brain that allosterically modulates GABA ergic transmission by binding to benzodiazepine (BDZ)-recognition sites. Using a specific radioimmunoassay for human DBI, we investigated the distribution of this peptide in different brain areas. We characterized with high-pressure liquid chromatography the DBI immunoreactivity in brain tissue obtained by biopsy and autopsy; we detected one molecular species of DBI in both instances. The regional distribution of DBI in the human brain is similar to that observed in rat brain: high concentrations in cortical and limbic areas, cerebellum, and brainstem, and low concentrations in the basal ganglia. These data suggest a modulatory role for DBI in human brain.

The anxiolytic activity of alpidem (150 mg/day) and its effects on psychomotor performances were compared with placebo in 60 outpatients. The trial was a double-blind, parallel group, and the two treatments were administered orally in three divided doses for 3 weeks. Eighteen male and 42 female patients (mean age, 39.6 years) suffering from generalized anxiety or adjustment disorder with anxious mood of at least 1-month duration entered the trial at the end of a 1-week placebo run-in period designed to exclude early placebo responders. Efficacy was assessed with the Hamilton rating scale for anxiety (HRSA), the state-trait anxiety inventory (STAI x 1: anxiety as state), a visual analogue scale (VAS), and clinical global impression (CGI). Psychomotor performance was assessed by the digit symbol substitution test (DSST). Alpidem was significantly more effective than placebo in decreasing the severity of anxiety, both in the physician's judgment [total HRSA (p = 0.007), psychic symptoms (p = 0.0040), somatic symptoms (p = 0.0002)] and in the patients' evaluation [STAI x 1 (p = 0.0001) and VAS (p = 0.0003)]. Psychomotor performance was improved by both treatments; there was no difference between results with alpidem and placebo at the DSST (p = 0.2801), but the improvement was almost twofold on alpidem. Side effects were negligible with both treatments and the efficacy index, obtained from the CGI, was significantly better with alpidem than with placebo after day 7 (at least p less than 0.03).

Transdihydrolisuride is an ergot derivative with mixed agonist and antagonist effects on central dopamine receptors. We gave the drug orally (1 mg daily) to 10 patients with Huntington's disease. In seven patients, the chorea improved with no adverse effects during the study.