Roberto Piolti

Clinical, neuropsychological, and morphometric correlates of apathy in Parkinson's disease

Apathy is a salient feature of various neuropsychiatric disorders, from depression to Alzheimers disease. We formally assess its prevalence in idiopathic Parkinsons 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 Marins 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.

Decreased density of benzodiazepine receptors in lymphocytes of anxious patients: reversal after chronic diazepam treatment

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.

Oxidative stress in peripheral blood mononuclear cells from patients with Parkinson's disease: Negative correlation with levodopa dosage

Oxidative stress, resulting from the imbalance between reactive oxygen species (ROS) formation and antioxidant defenses, plays a major role in the pathogenesis of Parkinsons 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.

Cerebrospinal fluid levels of diazepam‐binding inhibitor in neurodegenerative disorders with dementia

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 Parkinsons disease, 10 with Alzheimers disease, 7 with Huntingtons 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 Alzheimers disease, but decreased in Huntingtons chorea patients. We hypothesize that modifications of CSF DBI levels may be related to a functional or structural alteration of the GABAergic System.

Alpha-synuclein nitration and autophagy response are induced in peripheral blood cells from patients with Parkinson disease.

Several lines of evidence implicate a central role for alpha-synuclein (aSN) in the pathogenesis of Parkinsons 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.

Deep brain stimulation for the treatment of Parkinson's disease: the experience of the Neurosurgical Department in Monza

Abstract. deep brain stimulation is a widely accepted surgical therapy for the symptomatic treatment of advanced parkinsons 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.

Distribution of a putative endogenous modulator of the GABA ergic system in human brain

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.

Different patterns of CSF neurotransmitter metabolism in patients with left or right hemispheric stroke.

ABSTRACT 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‐injuried 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.

Physiologic study of the subthalamic volume.

Abstract 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 sterotactic atlases. Our findings suggest a volume, encompassing the zona incetta, Forels 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.

Cognitve estimation: comparison of two tests in nondemented parkinsonian patients

Abstract.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.