Tommaso Piccoli

Causes and place of death in Italian patients with amyotrophic lateral sclerosis

Spataro R, Lo Re M, Piccoli T, Piccoli F, La BellaV. Causes and place of death in Italian patients with amyotrophic lateral sclerosis.
Acta Neurol Scand: 122: 217–223.
© 2010 The Authors Journal compilation

A Case Study of Primary Progressive Aphasia: Improvement on Verbs After rTMS Treatment

This case-report shows that high frequency repetitive Transcranial Magnetic Stimulation (hf-rTMS), applied to the left prefrontal cortex, may improve the linguistic skills in Primary Progressive Aphasia (PPA). The patients performance was evaluated on a battery of language production and memory span tasks, before and after two hf-rTMS treatments and one SHAM treatment. We observed a significant and lasting improvement of the patients performance on verb production following the application of hf-rTMS versus Baseline and SHAM conditions. This finding suggests that hf-rTMS may directly strengthen the neural connections within an area of metabolic dysfunction and encourages the use of rTMS as an alternative therapeutic tool for neurodegenerative forms of aphasia.

The default mode network and the working memory network are not anti-correlated during all phases of a working memory task

Introduction The default mode network and the working memory network are known to be anti-correlated during sustained cognitive processing, in a load-dependent manner. We hypothesized that functional connectivity among nodes of the two networks could be dynamically modulated by task phases across time. Methods To address the dynamic links between default mode network and the working memory network, we used a delayed visuo-spatial working memory paradigm, which allowed us to separate three different phases of working memory (encoding, maintenance, and retrieval), and analyzed the functional connectivity during each phase within and between the default mode network and the working memory network networks. Results We found that the two networks are anti-correlated only during the maintenance phase of working memory, i.e. when attention is focused on a memorized stimulus in the absence of external input. Conversely, during the encoding and retrieval phases, when the external stimulation is present, the default mode network is positively coupled with the working memory network, suggesting the existence of a dynamically switching of functional connectivity between “task-positive” and “task-negative” brain networks. Conclusions Our results demonstrate that the well-established dichotomy of the human brain (anti-correlated networks during rest and balanced activation-deactivation during cognition) has a more nuanced organization than previously thought and engages in different patterns of correlation and anti-correlation during specific sub-phases of a cognitive task. This nuanced organization reinforces the hypothesis of a direct involvement of the default mode network in cognitive functions, as represented by a dynamic rather than static interaction with specific task-positive networks, such as the working memory network.

Elevated cerebrospinal fluid and plasma homocysteine levels in ALS

Background:  High cerebrospinal fluid (CSF) and plasma levels of homocysteine (HC) have been reported in certain neurodegenerative disorders, such as Alzheimer’s, Parkinson’s diseases and, recently, amyotrophic lateral sclerosis (ALS).

The serum level of free testosterone is reduced in amyotrophic lateral sclerosis

Sporadic amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting upper and lower motoneurons. There is an approximately 2:1 higher incidence of ALS in men compared to women, and this has raised the hypothesis of an involvement of sex hormones in the etiopathogenesis of the disorder. In this work, the serum levels of dehydroepiandrosterone sulphate (DHEAS), 17-betaestradiol, free and total testosterone were measured in 35 patients with defined or probable ALS, according to the El-Escorial/WFN revisited criteria, and compared to those obtained from 57 disease controls, matched for age and gender to the ALS group. We found no differences between ALS cases and disease controls in the serum levels of DHEAS, 17-betaestradiol and total testosterone. Conversely, free testosterone was significantly decreased in the ALS group. Given that testosterone crosses the blood-brain barrier only as unbound form, we suggest a possible involvement of this sex hormone in the pathophysiology of this severe motor neuron disease.

Distributed analysis of simultaneous EEG-fMRI time-series: modeling and interpretation issues

Functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) represent brain activity in terms of a reliable anatomical localization and a detailed temporal evolution of neural signals. Simultaneous EEG-fMRI recordings offer the possibility to greatly enrich the significance and the interpretation of the single modality results because the same neural processes are observed from the same brain at the same time. Nonetheless, the different physical nature of the measured signals by the two techniques renders the coupling not always straightforward, especially in cognitive experiments where spatially localized and distributed effects coexist and evolve temporally at different temporal scales. The purpose of this article is to illustrate the combination of simultaneously recorded EEG and fMRI signals exploiting the principles of EEG distributed source modeling. We define a common source space for fMRI and EEG signal projection and gather a conceptually unique framework for the spatial and temporal comparative analysis. We illustrate this framework in a graded-load working-memory simultaneous EEG-fMRI experiment based on the n-back task where sustained load-dependent changes in the blood-oxygenation-level-dependent (BOLD) signals during continuous item memorization co-occur with parametric changes in the EEG theta power induced at each single item. In line with previous studies, we demonstrate on two single-subject cases how the presented approach is capable of colocalizing in midline frontal regions two phenomena simultaneously observed at different temporal scales, such as the sustained negative changes in BOLD activity and the parametric EEG theta synchronization. We discuss the presented approach in relation to modeling and interpretation issues typically arising in simultaneous EEG-fMRI studies.

Mutation analysis of the SPG4 gene in Italian patients with pure and complicated forms of spastic paraplegia

Mutations in the SPG4 gene are the most common causes of hereditary spastic paraplegia (HSP) accounting for up to 40% of autosomal dominant (AD) forms and 12-18% of sporadic cases. The phenotype associated with HSP due to mutations in the SPG4 gene tends to be pure. There is increasing evidence, however, of patients with complicated forms of spastic paraplegia in which SPG4 mutations were identified. A cohort of 38 unrelated Italian patients with spastic paraplegia, of which 24 had a clear dominant inheritance and 14 were apparently sporadic, were screened for mutations in the SPG4 gene. We identified 11 different mutations, six of which were novel (p.Glu143GlyfsX8, p.Tyr415X, p.Asp548Asn, c.1656_1664delinsTGACCT, c.1688-3C>G and c.*2G>T) and two exon deletions previously reported. The overall rate of SPG4 gene mutation in our patients was 36.8% (14/38); in AD-HSP we observed a mutation frequency of 45.8% (11/24), in sporadic cases the frequency was 21.4% (3/14). Furthermore, we found a mutational rate of 22.2% (2/9) and 41.4% (12/29) in the complicated and pure forms, respectively. The results underlie the importance of genetic testing in all affected individuals.

Bilateral Transcranial Magnetic stimulation of the Prefrontal cortex reduces cocaine intake: a Pilot study

Background Chronic cocaine consumption is associated with a decrease in mesolimbic dopamine transmission that maintains drug intake. transcranial magnetic stimulation (TMS) is gaining reliability, a useful therapeutic tool in drug addiction, since it can modulate cortico-limbic activity resulting in reduction of drug craving. Aims In the present study, we investigated the therapeutic effect of bilateral TMS of prefrontal cortex (PFC) in reducing cocaine intake, in a sample of treatment-seeking patients with current cocaine use disorder (DSM-V). Methods Ten cocaine addicts (DSM-V) were randomly assigned to the active or sham stimulation protocol in a double-blind experimental design. Twelve repetitive TMS (rTMS) sessions were administered three times a week for 4 weeks at 100% of motor threshold, over bilateral PFC. Cocaine intake (ng/mg) was assessed by hair analysis at baseline (before treatment, T0), after 1 month (end of treatment, T1), 3 (T2), and 6 (T3) months later. All subjects received psychological support weekly. Results The two-way ANOVA for repeated measures did not show a significant effect of the interaction between time and treatment (F4,32 = 0.35; p = 0.87). Despite that result indicated no difference in the effect of the two conditions (active vs. sham) along time, a decreasing trend in cocaine consumption in active TMS group (F3,23 = 3.42; p = 0.04) vs. sham (F3,15 = 1.88; p = 0.20) was observed when we performed exploratory analysis with time as factor. Indeed, Post hoc comparisons showed a significant reduction in the amount of cocaine detected from the onset to 3 months later (T0–T2; p = 0.02) and to the end of treatment (T0–T3; p = 0.01) in addicts from the active group. Conclusion Bilateral rTMS of PFC at 10 Hz did not show a significant effect on cocaine intake compared to sham. However, a long-term reduction on cocaine intake in active TMS-treated patients was observed when we considered the time as factor. Further studies are required to confirm these encouraging but preliminary findings, in order to consolidate rTMS as a valid tool to treat cocaine addiction.

Cerebrospinal fluid tau protein is not a biological marker in amyotrophic lateral sclerosis

Background:  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder leading to progressive motor neuron cell death. Etiopathogenesis is still imperfectly known and much effort have been undertaken to find a biological marker that could help in the early diagnosis and in the monitoring of disease progression. Cerebrospinal fluid (CSF) concentrations of tau, an axonal microtubule‐associated protein, have been measured in ALS with levels found increased in some studies and unchanged in others.

Haptoglobin interacts with Apolipoprotein e and beta-amyloid and influences their crosstalk

Beta-amyloid accumulation in brain is a driving force for Alzheimers disease pathogenesis. Apolipoprotein E (ApoE) represents a critical player in beta-amyloid homeostasis, but its role in disease progression is controversial. We previously reported that the acute-phase protein haptoglobin binds ApoE and impairs its function in cholesterol homeostasis. The major aims of this study were to characterize the binding of haptoglobin to beta-amyloid, and to evaluate whether haptoglobin affects ApoE binding to beta-amyloid. Haptoglobin is here reported to form a complex with beta-amyloid as shown by immunoblotting experiments with purified proteins, or by its immunoprecipitation in brain tissues from patients with Alzheimers disease. The interaction between ApoE and beta-amyloid was previously shown to be crucial for limiting beta-amyloid neurotoxicity and for promoting its clearance. We demonstrate that haptoglobin, rather than impairing ApoE binding to beta-amyloid, promotes to a different extent the formation of the complex between beta-amyloid and ApoE2 or ApoE3 or ApoE4. Our data suggest that haptoglobin and ApoE functions in brain should be evaluated taking into account their mutual interaction with beta-amyloid. Hence, the risk of developing Alzheimers disease might not only be linked to the different ApoE isoforms, but also rely on the level of critical ligands, such as haptoglobin.