Carlo Ferrarese

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.

Mitochondrial DNA haplogroup K is associated with a lower risk of Parkinson's disease in Italians

It has been proposed that European mitochondrial DNA (mtDNA) haplogroups J and K, and their shared 10398G single-nucleotide polymorphism (SNP) in the ND3 gene, are protective from Parkinsons disease (PD). We evaluated the distribution of the different mtDNA haplogroups in a large cohort of 620 Italian patients with adult-onset (>50, <65 years of age) idiopathic PD vs two groups of ethnic-matched controls. Neither the frequencies of haplogroup J nor that of 10398G were significantly different. However, the frequency of haplogroup K was significantly lower in PD. Stratification by sex and age indicated that the difference in the distribution of haplogroup K was more prominent in >50year old males. In spite of the common 10398G SNP, haplogroups J and K belong to widely diverging mitochondrial clades, a consideration that may explain the different results obtained for the two haplogroups in our cohorts. Our study suggests that haplogroup K might confer a lower risk for PD in Italians, corroborating the idea that the mitochondrial oxidative phosphorylation pathway is involved in the susceptibility to idiopathic PD.

Increased cytokine release from peripheral blood cells after acute stroke

Cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α can play pathogenetic or protective roles in stroke. They are increased in the brain after experimental ischemia and in the CSF of patients with stroke. However, their presence in the periphery is still controversial. To determine the source and time-course of cytokines in blood of stroke patients, IL-6 and TNF-α release from blood cells and serum levels were determined in 40 patients on days 1 through 2, 4, 10, 30, and 90 after stroke. Twenty healthy age-matched volunteers were used as controls. IL-6 and TNF-α release from stimulated blood cells was increased in stroke patients, compared to controls. A peak response (+224%) was observed at day 4 for IL-6, while TNF-α release was largely and significantly increased (about three-fold compared to controls) from day 1 to 2 until day 90 after stroke. The increase in IL-6 release was significantly higher in ischemic, compared to hemorragic strokes, at days 1 and 4. Circulating IL-6 was increased at each time point. The ischemic processes in the CNS induces a long-lasting activation of IL-6 and TNF-α production in peripheral blood cells, which are a major source of serum cytokines after stroke.

Effects of Serotonin Transporter Promoter Genotype on Platelet Serotonin Transporter Functionality in Depressed Children and Adolescents

OBJECTIVE To investigate possible associations between serotonin transporter (5-HTT) promoter genotypic variants (l/l, l/s, and s/s) and differential regulation of platelet 5-HTT functionality parameters in a group of drug-naive depressed children and adolescents and healthy controls. METHOD Children and adolescents with major depression (n = 18) defined by DSM-III-R criteria and normal controls (n = 21) were assessed both for platelet serotonin functionality and for genotypic variants on 5-HTT promoter region. Four parameters were considered: (1) serotonin uptake rate (Vmax); (2) serotonin dissociation constant (K(m)); (3) paroxetine binding and density of site (Bmax); and (4) paroxetine dissociation constant (Kd). RESULTS Depressed children had lower Vmax and K(m). Control subjects with l/l genotype had significantly higher Vmax than control subjects with l/s and s/s genotype. Control subjects with l/l genotype also had significantly higher Vmax than their depressed homologs. In contrast, Vmax was not significantly different between depressed and nondepressed subjects who carried the other 2 genotypes. The 5-HTT promoter genotype, diagnoses, or their interaction had no effect on the other serotonin parameters. CONCLUSIONS While showing a significant decrease of Vmax and K(m) in a group of drug-naive depressed children and adolescents, these data suggest that l/l genotype has a substantial effect on the decrease of Vmax during a depressive episode.

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.

Decreased platelet glutamate uptake in patients with amyotrophic lateral sclerosis

Decreased glutamate uptake and a loss of the astrocytic glutamate transporter EAAT2 (GLT-1) have been shown in spinal cord and motor cortex of patients with ALS. Because platelets express the three major glutamate transporter subtypes, including GLT-1, and possess a high-affinity glutamate uptake, the authors investigated glutamate uptake in platelets from patients with ALS and controls. A 43% reduction of high-affinity glutamate uptake rate (p < 0.0001) was observed in patients with ALS compared with normal controls and chronic neurologic disorder patients, suggesting a systemic impairment of glutamate uptake in ALS.

Glutamate uptake is decreased in platelets from Alzheimer's disease patients

Because excitotoxicity may be involved in neurodegeneration in Alzheimers disease, we investigated possible modifications of platelet glutamate uptake in AD patients. High‐affinity glutamate uptake was studied in platelets from 35 Alzheimers disease patients, 10 multi‐infarct dementia patients, and 35 age‐matched normal controls; it was decreased by 40% in platelets from Alzheimers disease patients compared with controls and with multi‐infarct dementia patients. Platelet glutamate uptake could be used as peripheral marker of glutamatergic involvement and as adjunctive diagnostic tool in Alzheimers disease patients. Ann Neurol 2000;47:641–643

Benzodiazepine receptors and diazepam binding inhibitor: A possible link between stress, anxiety and the immune system

This review summarizes the evidence available on the involvement in stress of different classes of benzodiazepine receptors and their putative endogenous ligand, diazepam binding inhibitor (DBI), with particular reference to their role in modifications of the immune response. The presented data from in vitro, experimental, and clinical studies suggest that benzodiazepine receptors and DBI play a major role in regulating steroid production in both the adrenals and central nervous system, and may be involved in the activation of the hypothalamic-pituitary-adrenal axis in stress response.

Systemic thrombolysis in patients with acute ischemic stroke and Internal Carotid ARtery Occlusion: the ICARO study

Background and Purpose— The beneficial effect of intravenous thrombolytic therapy in patients with acute ischemic stroke attributable to internal carotid artery (ICA) occlusion remains unclear. The aim of this study was to evaluate the efficacy and safety of intravenous recombinant tissue-type plasminogen activator in these patients. Methods— ICARO was a case-control multicenter study on prospectively collected data. Patients with acute ischemic stroke and ICA occlusion treated with intravenous recombinant tissue-type plasminogen activator within 4.5 hours from symptom onset (cases) were compared to matched patients with acute stroke and ICA occlusion not treated with recombinant tissue-type plasminogen activator (controls). Cases and controls were matched for age, gender, and stroke severity. The efficacy outcome was disability at 90 days assessed by the modified Rankin Scale, dichotomized as favorable (score of 0–2) or unfavorable (score of 3–6). Safety outcomes were death and any intracranial bleeding. Results— Included in the analysis were 253 cases and 253 controls. Seventy-three cases (28.9%) had a favorable outcome as compared with 52 controls (20.6%; adjusted odds ratio (OR), 1.80; 95% confidence interval [CI], 1.03–3.15; P=0.037). A total of 104 patients died, 65 cases (25.7%) and 39 controls (15.4%; adjusted OR, 2.28; 95% CI, 1.36–3.22; P=0.001). There were more fatal bleedings (2.8% versus 0.4%; OR, 7.17; 95% CI, 0.87–58.71; P=0.068) in the cases than in the controls. Conclusions— In patients with stroke attributable to ICA occlusion, thrombolytic therapy results in a significant reduction in the proportion of patients dependent in activities of daily living. Increases in death and any intracranial bleeding were the trade-offs for this clinical benefit.

Anti-Aβ autoantibodies in the CSF of a patient with CAA-related inflammation: A case report

A 68-year-old man presented with a 4-month history of progressive memory loss and mood disorders. Neurologic examination revealed severe impairment of attention and verbal skills, without motor and sensory deficits. His medical history included mild arterial hypertension, idiopathic partial epilepsy, and obsessive compulsive disorder. Brain MRI showed the presence of bilateral, asymmetric, swollen white matter lesions in the cerebral hemispheres, hyperintense in T2-weighted images, that partially involved the left frontal cortex (figure). On diffusion-weighted sequences, the white matter abnormalities were consistent with vasogenic edema. No pathologic contrast enhancement was present. Figure MRI of cerebral amyloid angiopathy–related inflammation (CAA-ri) and levels of anti-Aβ 1-40 and 1-42 autoantibodies in the CSF Axial fluid-attenuated inversion recovery brain MRI shows bilateral hyperintense lesions of the subcortical white matter (A), which are reduced after 20 days of steroid treatment (B). Axial T2*-weighted gradient-echo MRI (C) obtained 33 days later shows further reduction of white matter lesions and multiple, scattered, hypointense cortical lesions due to microhemorrhages (arrows). (D) Reibers graph. X- and y-axes show, respectively, albumin (QAlb) and immunoglobulin G quotient (QIgG), obtained by the ratio between the level of the protein in the CSF from the first lumbar puncture and in the plasma. The QAlb indicates the permeability of the blood–brain barrier (BBB) to water-soluble molecules. The QIgG (total IgG including specific anti-Aβ autoantibodies) plotted into the graph discriminates between intrathecal production of IgG and …