Publications by authors named "Federico Casale"

9 Publications

  • Page 1 of 1

Lifetime sport practice and brain metabolism in Amyotrophic Lateral Sclerosis.

Neuroimage Clin 2020 12;27:102312. Epub 2020 Jun 12.

Institute of Cognitive Sciences and Technologies, C.N.R., Rome, Italy; Department of Nuclear Medicine, Karolinska Hospital, Stockholm, Sweden.

Objective: To evaluate the metabolic correlates of lifetime sport practice in ALS through brain F-FDG-PET.

Methods: 131 patients completed a questionnaire about lifetime exposures, including physical activity related to sports, hobbies and occupations, and underwent brain F-FDG-PET. Exposure to sports was expressed as MET (Metabolic Equivalent of Task). We considered only regular practice (at least 2 h/week, for at least three months). We compared brain metabolism between two groups: subjects who did not report regular sport practice during life (N-group) and patients who did (Y-group). The resulting significant clusters were used in each group as seed regions in an interregional correlation analysis (IRCA) to evaluate the impact of lifetime sport practice on brain networks typically involved by the neurodegenerative process of ALS. Each group was compared to healthy controls (HC, n = 40).

Results: We found a significant, relative cerebellar hypermetabolism in the N-group compared to the Y-group. The metabolism of such cerebellar cluster resulted correlated to more significant and widespread metabolic changes in areas known to be affected by ALS (i.e. frontotemporal regions and corticospinal tracts) in the N-group as compared to the Y-group, despite the same level of disability as expressed by the ALS FRS-R. Such findings resulted independent of age, sex, site of onset (bulbar/spinal), presence/absence of C9ORF72 expansion, cognitive status and physical activity related to hobbies and occupations. When compared to HC, the N-group showed more widespread metabolic changes than the Y-group in cortical regions known to be relatively hypometabolic in ALS patients as compared to HC.

Conclusions: We hypothesize that patients of the N-group might cope better with the neurodegenerative process, since they show more widespread metabolic changes as compared to the Y-group, despite the same level of disability. Nevertheless, further studies are necessary to corroborate this hypothesis.
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http://dx.doi.org/10.1016/j.nicl.2020.102312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334468PMC
June 2020

G-CSF (filgrastim) treatment for amyotrophic lateral sclerosis: protocol for a phase II randomised, double-blind, placebo-controlled, parallel group, multicentre clinical study (STEMALS-II trial).

BMJ Open 2020 03 24;10(3):e034049. Epub 2020 Mar 24.

'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Torino, Piemonte, Italy.

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurological disorder characterised by a selective degeneration of motor neurons (MNs). Stem cell transplantation is considered as a promising strategy in neurological disorders therapy and the possibility of inducing bone marrow cells (BMCs) to circulate in the peripheral blood is suggested to investigate stem cells migration in degenerated ALS nerve tissues where potentially repair MN damage. Granulocyte-colony stimulating factor (G-CSF) is a growth factor which stimulates haematopoietic progenitor cells, mobilises BMCs into injured brain and it is itself a neurotrophic factor for MN. G-CSF safety in humans has been demonstrated and many observations suggest that it may affect neural cells. Therefore, we decided to use G-CSF to mobilise BMCs into the peripheral circulation in patients with ALS, planning a clinical trial to evaluate the effect of G-CSF administration in ALS patients compared with placebo.

Methods And Analysis: STEMALS-II is a phase II multicentre, randomised double-blind, placebo-controlled, parallel group clinical trial on G-CSF (filgrastim) and mannitol in ALS patients. Specifically, we investigate safety, tolerability and efficacy of four repeated courses of intravenous G-CSF and mannitol administered in 76 ALS patients in comparison with placebo (indistinguishable glucose solution 5%). We determine increase of G-CSF levels in serum and cerebrospinal fluid as CD34 cells and leucocyte count after treatment; reduction in ALS Functional Rating Scale-Revised Score, forced vital capacity, Scale for Testing Muscle Strength Score and quality of life; the adverse events/reactions during the treatment; changes in neuroinflammation biomarkers before and after treatment.

Ethics And Dissemination: The study protocol was approved by the Ethics Committee of Azienda Ospedaliera Universitaria 'Città della Salute e della Scienza', Torino, Italy. Results will be presented during scientific symposia or published in scientific journals.

Trial Registration Number: Eudract 2014-002228-28.
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http://dx.doi.org/10.1136/bmjopen-2019-034049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202695PMC
March 2020

A novel p.Ser108LeufsTer15 SOD1 mutation leading to the formation of a premature stop codon in an apparently sporadic ALS patient: insights into the underlying pathomechanisms.

Neurobiol Aging 2018 12 24;72:189.e11-189.e17. Epub 2018 Aug 24.

ALS Centre, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy; Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, S.C. Neurologia 2 U, Turin, Italy; Neuroscience Institute of Turin (NIT), Turin, Italy; Institute of Cognitive Sciences and Technologies, C.N.R, Rome, Italy.

We report an apparently sporadic amyotrophic lateral sclerosis patient carrying a heterozygous novel frameshift SOD1 mutation (p.Ser108LeufsTer15), predicted to cause a premature protein truncation. RT-PCR analysis of SOD1 mRNA and SDS-PAGE/Western blot analysis of PBMC demonstrated that mRNA from the mutant allele is expressed at levels similar to those of the wild-type allele, but the truncated protein is undetectable also in the insoluble fraction and after proteasome inhibition. Accordingly, the dismutation activity in erythrocytes is halved. Thus, the pathogenic mechanism associated with this mutation might be based on an insufficient activity of SOD1 that would make motor neurons more vulnerable to oxidative injury. However, it cannot be excluded that p.Ser108LeufsTer15 SOD1 is present in the nervous tissue and, being less charged and hence having less repulsive forces than the wild-type protein, may trigger toxic mechanisms as a consequence of its propensity to aggregate.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.08.014DOI Listing
December 2018

Amyotrophic lateral sclerosis and food intake.

Amyotroph Lateral Scler Frontotemporal Degener 2018 05 21;19(3-4):267-274. Epub 2017 Dec 21.

a IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri" , Milano , Italy.

Objective: To verify if specific foods and nutrients could be risk factors or protective factors for amyotrophic lateral sclerosis (ALS).

Methods: Patients with newly diagnosed ALS from three Italian administrative regions were included. For each patient, a healthy control, matched for age (±5 years), sex and administrative region of residence, was selected by a general practitioner. Cases and controls were interviewed by a trained investigator who filled a validated and reproducible food-frequency questionnaire. Daily intake of macronutrients, micronutrients, fatty acids, and total energy were estimated using an Italian food composition database.

Results: Two hundred and twelve cases and 212 controls were included. A risk reduction was found for coffee and tea (odds ratios (OR) = 0.29, 95% CI 0.14-0.60), whole bread (OR = 0.55, 95% CI 0.31-0.99), raw vegetables (OR = 0.25, 95% CI 0.13-0.52) and citrus fruits (OR = 0.49, 95% CI 0.25-0.97). A risk increase was observed for red meat (OR = 2.96, 95% CI 1.46-5.99) and pork and processed meat (OR = 3.87, 95% CI 1.86-8.07). An increased risk was found for total protein (OR = 2.96, 95% CI 1.08-8.10), animal protein (OR = 2.91, 95% CI 1.33-6.38), sodium (OR = 3.96, 95% CI 1.45-10.84), zinc (OR = 2.78, 95% CI 1.01-7.83) and glutamic acid (OR = 3.63, 95% CI 1.08-12.2).

Conclusions: Some foods/nutrients may be risk factors and others protective factors for ALS.
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http://dx.doi.org/10.1080/21678421.2017.1418002DOI Listing
May 2018

Common polymorphisms of chemokine (C-X3-C motif) receptor 1 gene modify amyotrophic lateral sclerosis outcome: A population-based study.

Muscle Nerve 2018 02 25;57(2):212-216. Epub 2017 Apr 25.

"Rita Levi Montalcini" Department of Neuroscience, Neurology II, ALS Center, University of Torino, Via Cherasco 15, I-10126, Torino, Italy.

Introduction: In the brain, the chemokine (C-X3-C motif) receptor 1 (1CX3CR1) gene is expressed only by microglia, where it acts as a key mediator of the neuron-microglia interactions. We assessed whether the 2 common polymorphisms of the CX3CR1 gene (V249I and T280M) modify amyotrophic lateral sclerosis (ALS) phenotype.

Methods: The study included 755 ALS patients diagnosed in Piemonte between 2007 and 2012 and 369 age-matched and sex-matched controls, all genotyped with the same chips.

Results: Neither of the variants was associated with an increased risk of ALS. Patients with the V249I V/V genotype had a 6-month-shorter survival than those with I/I or V/I genotypes (dominant model, P = 0.018). The T280M genotype showed a significant difference among the 3 genotypes (additive model, P = 0.036). Cox multivariable analysis confirmed these findings.

Discussion: We found that common variants of the CX3CR1 gene influence ALS survival. Our data provide further evidence for the role of neuroinflammation in ALS. Muscle Nerve 57: 212-216, 2018.
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http://dx.doi.org/10.1002/mus.25653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912184PMC
February 2018

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.

Nat Genet 2016 09 25;48(9):1043-8. Epub 2016 Jul 25.

Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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http://dx.doi.org/10.1038/ng.3622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556360PMC
September 2016

NADPH oxidase (NOX2) activity is a modifier of survival in ALS.

J Neurol 2014 Nov 2;261(11):2178-83. Epub 2014 Sep 2.

"Rita Levi Montalcini" Department of Neuroscience, ALS Centre, University of Torino, Via Cherasco 15, 10126, Turin, Italy,

NADPH-oxidases (NOX) catalyze the formation of reactive oxygen species (ROS), which play a role in the development of neurological diseases, particularly those generated by the phagocytic isoform NOX2. Increased ROS has been observed in the amyotrophic lateral sclerosis (ALS) SOD1 transgenic mouse, and in this preclinical model the inactivation of NOX2 decreases ROS production and extends survival. Our aim was to evaluate NOX2 activity measuring neutrophil oxidative burst in a cohort of 83 ALS patients, and age- and gender-matched healthy controls. Oxidative burst was measured directly in fresh blood using Phagoburst™ assay by flow cytometry. Mean fluorescence intensity (MFI), emitted in response to different stimuli, leads to produce ROS and corresponds to the percentage of oxidizing cells and their enzymatic activity (GeoMean). No difference was found between the MFI values in cases and controls. NOX2 activity was independent from gender and age, and in patients was not related to disease duration, site of onset (bulbar vs. spinal), or ALSFRS-R score. However, patients with a NOX2 activity lower than the median value showed a 1-year increase of survival from onset (p = 0.011). The effect of NOX2 was independent from other known prognostic factors. These findings are in keeping with the observations in the mouse model of ALS, and demonstrate the strong role of NOX2 in modifying progression in ALS patients. A proper modulation of NOX2 activity might hold therapeutic potential for ALS.
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http://dx.doi.org/10.1007/s00415-014-7470-0DOI Listing
November 2014

Pharmacokinetics of cyclosporine in recipients of marginal versus standard liver transplants.

Pharmacol Res 2006 Oct 30;54(4):287-92. Epub 2006 Jun 30.

Department of Anatomy, Pharmacology and Forensic Medicine, Section of Pharmacology and Experimental Therapeutics, University of Turin, Via P Giuria 13, Turin, Italy.

In the field of transplants, the practice of using marginal donor livers has become widely accepted, yielding good clinical results. This study investigated and compared the pharmacokinetics of cyclosporine in marginal and standard liver transplant recipients. Twenty-four de novo liver transplant patients, 12 with marginal and 12 with standard (normal) grafts, were treated with a microemulsion formulation of cyclosporine (capsules 100 mg) as immunosuppressive therapy. Blood concentration profiles were measured, and pharmacokinetic calculations performed at days 3 and 10 after transplantation. Different sampling strategies to predict drug exposure (AUC(0-12 h)) were compared, and the best limited-sampling strategies to monitor the desired blood levels were determined. Marginal and standard patients showed a significant difference in blood concentration and pharmacokinetic profiles of cyclosporine at the day 10 post-transplantation. Blood concentration at 4h (C(4 h)) was the single best timepoint to estimate AUC(0-12 h) in marginal liver transplant (r(2)=0.700), while C(2h) was confirmed to be the optimal choice with standard graft (r2=0.720). Two blood samples at 2 and 6 h significantly improved the prediction model in both groups (r2=0.920). Our data suggest that patients receiving a marginal liver transplant present a different pharmacokinetic profile of cyclosporine from those receiving standard graft, which should be taken into account in dosing the patient to avoid subtherapeutic blood concentrations or toxic effects.
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http://dx.doi.org/10.1016/j.phrs.2006.06.004DOI Listing
October 2006

Plasma concentrations of 5-fluorouracil and its metabolites in colon cancer patients.

Pharmacol Res 2004 Aug;50(2):173-9

Department of Anatomy, Pharmacology and Forensic Medicine, University of Torino, Via P. Giuria 13, Torino 10125, Italy.

5-Fluorouracil (5-FU) is a common anticancer agent used in the treatment of solid tumours, with a reported variability in the pharmacokinetic profile and inter-patient differences in efficacy and toxicity. Since 5-FU is intracellularly metabolised to active cytotoxic fluoronucleotides, some authors suggested it would be useful to determine the plasma levels of its main metabolites 5-fluoro-5,6-dihydrouracil (5-FUH2), 5-fluorouridine (5-FUrd) and 5-fluoro-2'-deoxyuridine (5-FdUrd), in order to better characterise population pharmacokinetics-pharmacodynamics (PK-PD) of this drug. We developed and validated an HPLC method to simultaneously determine plasma concentrations of 5-FU and the three main metabolites, and we analysed the plasma concentration-time curves of the first dose of 18 colon cancer patients treated with folinic acid and 5-FU 400 mg m(-2) by intra-venous bolus injection as adjuvant chemotherapy. Non-compartmental PK analysis has been applied to 5-FU and 5-FUH2 concentrations, estimating the following parameters (median values): Cmax 55.44 and 6.23 microg ml(-1), respectively, AUC(0-2 h) 11.59 and 5.94 hx microg ml(-1), CLTB 30.64 and 51.81 lh(-1) m(-2), 5-FUH2/5-FU AUC ratio 0.47 (range 0.29-1.12). We verified the patient covariables which could influence the inter-patient variability in the area under the time-concentration curves, and we observed that age, sex, weight, body surface area, cycle of therapy, toxicity development and 5-FUrd or 5-FdUrd detectability did not have statistical influence on 5-FUH2/5-FU AUC ratio. In eight subjects, we compared the PK data of the first and the fifth day of dose administration, and we found stable 5-FU values, but the 5-FUH2 disposition decreased with lower AUC(0-2 h) (7.90 hx microg ml(-1) versus 5.99 hx microg ml(-1)) and, particularly, Cmax (8.38 microg ml(-1) versus 5.50 microg ml(-1)) at day 5. This fact, evident in almost every patient, could suggest a possible reduction in the catabolic pathway of 5-FU leading to 5-FUH2, with a possible increase of the therapeutic pathway. For this reason, we tried to detect 5-FUrd and 5-FdUrd and, in fact, in our patients these metabolites were detected only in few samples, but most of them at day 5. In conclusion, our study confirms the relevance of pharmacokinetic analysis of 5-FU main metabolites and especially 5-FUH2, to better understand the metabolism and to improve the therapeutic efficacy.
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http://dx.doi.org/10.1016/j.phrs.2004.01.006DOI Listing
August 2004