Publications by authors named "Maria Puopolo"

53 Publications

The Promotoer, a brain-computer interface-assisted intervention to promote upper limb functional motor recovery after stroke: a study protocol for a randomized controlled trial to test early and long-term efficacy and to identify determinants of response.

BMC Neurol 2020 Jun 27;20(1):254. Epub 2020 Jun 27.

Fondazione Santa Lucia, IRCCS, Rome, Italy.

Background: Stroke is a leading cause of long-term disability. Cost-effective post-stroke rehabilitation programs for upper limb are critically needed. Brain-Computer Interfaces (BCIs) which enable the modulation of Electroencephalography (EEG) sensorimotor rhythms are promising tools to promote post-stroke recovery of upper limb motor function. The "Promotoer" study intends to boost the application of the EEG-based BCIs in clinical practice providing evidence for a short/long-term efficacy in enhancing post-stroke hand functional motor recovery and quantifiable indices of the participants response to a BCI-based intervention. To these aims, a longitudinal study will be performed in which subacute stroke participants will undergo a hand motor imagery (MI) training assisted by the Promotoer system, an EEG-based BCI system fully compliant with rehabilitation requirements.

Methods: This longitudinal 2-arm randomized controlled superiority trial will include 48 first ever, unilateral, subacute stroke participants, randomly assigned to 2 intervention groups: the BCI-assisted hand MI training and a hand MI training not supported by BCI. Both interventions are delivered (3 weekly session; 6 weeks) as add-on regimen to standard intensive rehabilitation. A multidimensional assessment will be performed at: randomization/pre-intervention, 48 h post-intervention, and at 1, 3 and 6 month/s after end of intervention. Primary outcome measure is the Fugl-Meyer Assessment (FMA, upper extremity) at 48 h post-intervention. Secondary outcome measures include: the upper extremity FMA at follow-up, the Modified Ashworth Scale, the Numeric Rating Scale for pain, the Action Research Arm Test, the National Institute of Health Stroke Scale, the Manual Muscle Test, all collected at the different timepoints as well as neurophysiological and neuroimaging measures.

Discussion: We expect the BCI-based rewarding of hand MI practice to promote long-lasting retention of the early induced improvement in hand motor outcome and also, this clinical improvement to be sustained by a long-lasting neuroplasticity changes harnessed by the BCI-based intervention. Furthermore, the longitudinal multidimensional assessment will address the selection of those stroke participants who best benefit of a BCI-assisted therapy, consistently advancing the transfer of BCIs to a best clinical practice.

Trial Registration: Name of registry: BCI-assisted MI Intervention in Subacute Stroke (Promotoer).

Trial Registration Number: NCT04353297 ; registration date on the ClinicalTrial.gov platform: April, 15/2020.
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http://dx.doi.org/10.1186/s12883-020-01826-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320550PMC
June 2020

Spatial Epidemiology of Sporadic Creutzfeldt-Jakob Disease in Apulia, Italy.

Neuroepidemiology 2020 27;54(1):83-90. Epub 2019 Sep 27.

Department of Neuroscience, Istituto Superiore di Sanità, Rome, Italy,

Background: Sporadic Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative disease caused by prions that is randomly distributed in all countries, with an overall yearly mortality rate of about 1-2 cases per million people. On a few occasions, however, sporadic CJD occurred with higher than expected rates, but further investigations failed to recognize any convincing causal link. In Italy, cluster analyses of sporadic CJD cases have not been performed previously.

Objective: To investigate the geographical distribution of sporadic CJD using municipality geographical data of Apulia with the aim of detecting spatial clusters of disease.

Patients And Methods: Patients included in this study were diagnosed as probable or definite sporadic CJD and were residents of the Apulia Region (Italy). Bayesian hierarchical models with spatially structured and unstructured random components were used to describe the spatial pattern of the disease and to assess the extent of heterogeneity among municipalities. The Kulldorff-Nagarwalla scan test and the flexible spatial scan statistic were used for detecting spatial clusters.

Results: Smoothed Bayesian relative risks above the null value were observed in a few adjacent municipalities in the north and middle areas of Apulia. However, both the circular scanning method and the flexible spatial scan statistic identified only a single cluster in the central part of the region.

Conclusion: Geographical analyses and tests for spatial randomness identified a restricted area with an unusually high number of sporadic CJD cases in the Apulia region of Italy. Environmental and genetic risk factors other than mutations in the prion protein gene however, need to be investigated.
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http://dx.doi.org/10.1159/000503234DOI Listing
February 2021

Circulating miR-127-3p as a Potential Biomarker for Differential Diagnosis in Frontotemporal Dementia.

J Alzheimers Dis 2018 ;65(2):455-464

Department of Neuroscience, Istituto Superiore di Sanità, Rome, Italy.

Given the heterogeneous nature of frontotemporal dementia (FTD), sensitive biomarkers are greatly needed for the accurate diagnosis of this neurodegenerative disorder. Circulating miRNAs have been reported as promising biomarkers for neurodegenerative disorders and processes affecting the central nervous system, especially in aging. The objective of the study was to evaluate if some circulating miRNAs linked with apoptosis (miR-29b-3p, miR-34a-5p, miR-16-5p, miR-17-5p, miR-107, miR-19b-3p, let-7b-5p, miR-26b-5p, and 127-3p) were able to distinguish between FTD patients and healthy controls. For this study, we enrolled 127 subjects, including 54 patients with FTD, 20 patients with Alzheimer's disease (AD), and 53 healthy controls. The qRT-PCR analysis showed a downregulation of miR-127-3p in FTD compared to controls, while the levels of other miRNAs remained unchanged. Then, miR-127-3p expression was also analyzed in AD patients, finding a different expression between two patient groups. A receiver operating characteristic curve was then created for miR-127-3p to discriminate FTD versus AD (AUC: 0.8986), and versus healthy controls (AUC: 0.8057). In conclusion, miR-127-3p could help to diagnose FTD and to distinguish it from AD.
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http://dx.doi.org/10.3233/JAD-180364DOI Listing
August 2019

Age at onset of genetic (E200K) and sporadic Creutzfeldt-Jakob diseases is modulated by the gene.

J Neurol Neurosurg Psychiatry 2018 12 21;89(12):1243-1249. Epub 2018 Jul 21.

Department of Neuroscience, Istituto Superiore di Sanità, Roma, Italy

Objectives: The Glu to Lys change at codon 200 (E200K) of the gene is the most frequent mutation associated to genetic Creutzfeldt-Jakob disease (CJD) and the only one responsible for geographical clusters. Patients carrying this mutation develop disease at different ages and show variable clinical phenotypes that are not affected by the methione/valine polymorphism at codon 129 of the gene suggesting the influence of other factors. The objective of this study is to look for genes other than that might be responsible of this variability.

Methods: We searched for other genes by performing genome-wide analyses (GWA) on 19 patients with genetic CJD and 18 healthy subjects carrying the E200K mutation of and belonging to the Calabrian cluster in Italy. We then validate this result in 32 patients with E200K CJD from non-cluster areas and 259 patients with sporadic CJD referred to the Italian CJD national registry.

Results And Conclusions: We identified two single nucleotide polymorphisms on the  gene locus as candidate disease modifiers in patients with E200K CJD of the cluster area and confirmed this finding in 32 patients with E200K CJD from non-cluster areas and 259 patients with sporadic CJD. Our results indicate that the  gene modulates the onset of disease in patients with E200K genetic and sporadic CJD. This finding improves our understanding on the pathogenesis of CJD, suggests new targets for developing novel therapeutic strategies and might be useful for the stratification of patients in future preventive treatment trials.
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http://dx.doi.org/10.1136/jnnp-2018-318756DOI Listing
December 2018

Bilateral Patterns of Repetitive Movements in 6- to 12-Month-Old Infants with Autism Spectrum Disorders.

Front Psychol 2017 11;8:1168. Epub 2017 Jul 11.

Department of Developmental Neuroscience, IRCCS Stella Maris FoundationPisa, Italy.

Some patterns of repetitive movements and their frequency have been proved to distinguish infants with Autism Spectrum Disorders (ASD) from infants with Typical Development (TD) and Developmental Delay (DD) from 12 months of life on. The purpose of this study is to investigate if a specific repertoire of repetitive movements is present earlier in life, and if their higher rate and duration could differentiate infants with ASD from infants with DD and TD aged between 6 and 12 months. We conducted a retrospective analysis of video-clips taken from home videos to compare the frequency and the duration of Repetitive Movement Episodes (RMEs) in a sample of 30 children equally distributed among the three groups. Significantly higher total scores in bilateral RMEs with arms, hands, fingers, and lower limbs were found to distinguish ASD infants from both DD and TD infants, with a satisfactory diagnostic efficiency. No significant difference was found between the distributions of unilateral RMEs between ASD and DD/TD. Results indicate the presence at this age of an ASD-specific pattern of bilateral repetitive movements. We hypothesize a continuum between this pattern and the lack of variability in finalized and communicative movements and gestures observed in children with ASD during the second year of life.
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http://dx.doi.org/10.3389/fpsyg.2017.01168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504227PMC
July 2017

Prion Strain Characterization of a Novel Subtype of Creutzfeldt-Jakob Disease.

J Virol 2017 06 12;91(11). Epub 2017 May 12.

Department of Neurosciences, Istituto Superiore di Sanità, Rome, Italy

In 2007, we reported a patient with an atypical form of Creutzfeldt-Jakob disease (CJD) heterozygous for methionine-valine (MV) at codon 129 who showed a novel pathological prion protein (PrP) conformation with an atypical glycoform (AG) profile and intraneuronal PrP deposition. In the present study, we further characterize the conformational properties of this pathological prion protein (PrP MV), showing that PrP MV is composed of multiple conformers with biochemical properties distinct from those of PrP type 1 and type 2 of MV sporadic CJD (sCJD). Experimental transmission of CJD-MV to bank voles and gene-targeted transgenic mice carrying the human prion protein gene (TgHu mice) showed unique transmission rates, survival times, neuropathological changes, PrP deposition patterns, and PrP glycotypes that are distinct from those of sCJD-MV1 and sCJD-MV2. These biochemical and experimental data suggest the presence of a novel prion strain in CJD-MV Sporadic Creutzfeldt-Jakob disease is caused by the misfolding of the cellular prion protein, which assumes two different major conformations (type 1 and type 2) and, together with the methionine/valine polymorphic codon 129 of the prion protein gene, contribute to the occurrence of distinct clinical-pathological phenotypes. Inoculation in laboratory rodents of brain tissues from the six possible combinations of pathological prion protein types with codon 129 genotypes results in the identification of 3 or 4 strains of prions. We report on the identification of a novel strain of Creutzfeldt-Jakob disease isolated from a patient who carried an abnormally glycosylated pathological prion protein. This novel strain has unique biochemical characteristics, does not transmit to humanized transgenic mice, and shows exclusive transmission properties in bank voles. The identification of a novel human prion strain improves our understanding of the pathogenesis of the disease and of possible mechanisms of prion transmission.
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http://dx.doi.org/10.1128/JVI.02390-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432879PMC
June 2017

Follicular Volume Predicts Oocyte Maturity: A Prospective Cohort Study Using Three-Dimensional Ultrasound and SonoAVC.

Reprod Sci 2016 12 29;23(12):1639-1643. Epub 2016 Sep 29.

Centro de Asistencia a la Reproducción Humana de Canarias, La Laguna, Tenerife, Spain

The aim of this study was to investigate whether the automatic measurement of follicular volume by three-dimensional (3D) ultrasound can predict the number of mature oocytes retrieved. A prospective cohort study including 47 women undergoing in vitro fertilization was conducted in a private fertility center. Follicular growth was monitored both manually and automatically using 3D scanning with SonoAVC on the day of human chorionic gonadotropin (hCG) administration. Regression analysis showed that under a standard protocol for hCG administration, the count of mature oocytes is well predicted by a multivariate model including the counts of follicles in the volume classes 2.00 to 5.00 cm, 1.50 to 1.99 cm, 1.00 to 1.49 cm, and 0.60 to 0.99 cm In conclusion, this study shows that follicular volume as measured by SonoAVC on the day of hCG administration can be useful to predict oocyte maturity. Specifically, larger follicles and smaller size follicles (class 0.60-0.99 cm) contribute to the mature oocyte count. This finding warrants the design of clinical trials to establish new criteria for hCG administration based on follicular volume.
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http://dx.doi.org/10.1177/1933719116671003DOI Listing
December 2016

Reduced miR-659-3p Levels Correlate with Progranulin Increase in Hypoxic Conditions: Implications for Frontotemporal Dementia.

Front Mol Neurosci 2016 3;9:31. Epub 2016 May 3.

Laboratory of RNA Biology and Biotechnology, Centre for Integrative Biology, University of Trento Trento, Italy.

Progranulin (PGRN) is a secreted protein expressed ubiquitously throughout the body, including the brain, where it localizes in neurons and is activated microglia. Loss-of-function mutations in the GRN gene are an important cause of familial frontotemporal lobar degeneration (FTLD). PGRN has a neurotrophic and anti-inflammatory activity, and it is neuroprotective in several injury conditions, such as oxygen or glucose deprivation, oxidative injury, and hypoxic stress. Indeed, we have previously demonstrated that hypoxia induces the up-regulation of GRN transcripts. Several studies have shown microRNAs (miRNAs) involvement in hypoxia. Moreover, in FTLD patients with a genetic variant of GRN (rs5848), the reinforcement of miR-659-3p binding site has been suggested to be a risk factor. Here, we report that miR-659-3p interacts directly with GRN 3'UTR as shown by luciferase assay in HeLa cells and ELISA and Western Blot analysis in HeLa and Kelly cells. Moreover, we demonstrate the physical binding between GRN mRNA and miR-659-3p employing a miRNA capture-affinity technology in SK-N-BE and Kelly cells. In order to study miRNAs involvement in hypoxia-mediated up-regulation of GRN, we evaluated miR-659-3p levels in SK-N-BE cells after 24 h of hypoxic treatment, finding them inversely correlated to GRN transcripts. Furthermore, we analyzed an animal model of asphyxia, finding that GRN mRNA levels increased at post-natal day (pnd) 1 and pnd 4 in rat cortices subjected to asphyxia in comparison to control rats and miR-659-3p decreased at pnd 4 just when GRN reached the highest levels. Our results demonstrate the interaction between miR-659-3p and GRN transcript and the involvement of miR-659-3p in GRN up-regulation mediated by hypoxic/ischemic insults.
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http://dx.doi.org/10.3389/fnmol.2016.00031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853935PMC
May 2016

Difference in Visual Social Predispositions Between Newborns at Low- and High-risk for Autism.

Sci Rep 2016 05 20;6:26395. Epub 2016 May 20.

CIMeC, Center for Mind/Brain Sciences, University of Trento, 38068, Italy.

Some key behavioural traits of Autism Spectrum Disorders (ASD) have been hypothesized to be due to impairments in the early activation of subcortical orienting mechanisms, which in typical development bias newborns to orient to relevant social visual stimuli. A challenge to testing this hypothesis is that autism is usually not diagnosed until a child is at least 3 years old. Here, we circumvented this difficulty by studying for the very first time, the predispositions to pay attention to social stimuli in newborns with a high familial risk of autism. Results showed that visual preferences to social stimuli strikingly differed between high-risk and low-risk newborns. Significant predictors for high-risk newborns were obtained and an accurate biomarker was identified. The results revealed early behavioural characteristics of newborns with familial risk for ASD, allowing for a prospective approach to the emergence of autism in early infancy.
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http://dx.doi.org/10.1038/srep26395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873740PMC
May 2016

Expression Levels of the Oxidative Stress Response Gene ALDH3A2 in Granulosa-Lutein Cells Are Related to Female Age and Infertility Diagnosis.

Reprod Sci 2016 May 8;23(5):604-9. Epub 2015 Oct 8.

Laboratorio de Biología del Desarrollo, UD de Bioquímica y Biología Molecular, Universidad de la Laguna, La Laguna, Spain CIBICAN, Universidad de La Laguna, La Laguna, Spain.

Oxidative stress (OS) plays an important role in all physiological processes. The effect of OS on cellular processes is modulated by the ability of the cell to express genes implicated in the reversal of lipid, protein, and DNA injury. Aldehyde dehydrogenase 3, member A2 (ALDH3A2) is a ubiquitous enzyme involved in lipid detoxification. The objective of this study was to investigate the expression ofALDH3A2in human granulosa-lutein (GL) cells of women undergoing in vitro fertilization (IVF) and its relationship with age, infertility diagnosis, and IVF outcome variables. Relative expression levels ofALDH3A2were determined by quantitative reverse transcription-polymerase chain reaction. To investigate the effect of age onALDH3A2expression, 72 women between 18 and 44 years of age with no ovarian factor (NOF) were analyzed. To evaluate the effect of infertility diagnosis onALDH3A2expression, the following groups were analyzed: 22 oocyte donors (ODs), 24 women >40 years old (yo) with tubal or male factor and no ovarian pathology, 18 poor responders (PRs), 19 cases with endometriosis (EM), and 18 patients with polycystic ovarian syndrome (PCOS). In NOF,ALDH3A2expression correlated positively with age and with the doses of follicle-stimulating hormone and luteinizing hormone administered and negatively with the number of total and mature oocytes. When different groups were analyzed,ALDH3A2expression levels were higher in patients >40 yo and in PR compared to OD. On the contrary, EM and PCOS levels were lower than expected for age. These data suggest that GL cellALDH3A2expression levels correlate with age, cause of infertility, and ovarian response to stimulation.
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http://dx.doi.org/10.1177/1933719115607996DOI Listing
May 2016

Immune and Epstein-Barr virus gene expression in cerebrospinal fluid and peripheral blood mononuclear cells from patients with relapsing-remitting multiple sclerosis.

J Neuroinflammation 2015 Jul 14;12:132. Epub 2015 Jul 14.

Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.

Background: Gene expression analyses in paired cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMC) from patients with multiple sclerosis (MS) are restrained by the low RNA amounts from CSF cells and low expression levels of certain genes. Here, we applied a Taqman-based pre-amplification real-time reverse-transcription polymerase chain reaction (RT-PCR) (PreAmp RT-PCR) to cDNA from CSF cells and PBMC of MS patients and analyzed multiple genes related to immune system function and genes expressed by Epstein-Barr virus (EBV), a herpesvirus showing strong association with MS. Using this enhanced RT-PCR method, we aimed at the following: (1) identifying gene signatures potentially useful for patient stratification, (2) understanding whether EBV infection is perturbed in CSF and/or blood, and (3) finding a link between immune and EBV infection status.

Methods: Thirty-one therapy-free patients with relapsing-remitting MS were included in the study. Paired CSF cells and PBMC were collected and expression of 41 immune-related cellular genes and 7 EBV genes associated with latent or lytic viral infection were determined by PreAmp RT-PCR. Clinical, radiological, CSF, and gene expression data were analyzed using univariate and multivariate (cluster analysis, factor analysis) statistical approaches.

Results: Several immune-related genes were differentially expressed between CSF cells and PBMC from the whole MS cohort. By univariate analysis, no or only minor differences in gene expression were found associated with sex, clinical, or radiological condition. Cluster analysis on CSF gene expression data grouped patients into three clusters; clusters 1 and 2 differed by expression of genes that are related mainly to innate immunity, irrespective of sex and disease characteristics. By factor analysis, two factors grouping genes involved in antiviral immunity and immune regulation, respectively, accurately discriminated cluster 1 and cluster 2 patients. Despite the use of an enhanced RT-PCR method, EBV transcripts were detected in a minority of patients (5 of 31), with evidence of viral latency activation in CSF cells or PBMC and of lytic infection in one patient with active disease only.

Conclusions: Analysis of multiple cellular and EBV genes in paired CSF cell and PBMC samples using PreAmp RT-PCR may yield new information on the complex interplay between biological processes underlying MS and help in biomarker identification.
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http://dx.doi.org/10.1186/s12974-015-0353-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501166PMC
July 2015

Development of a pilot project on data sharing among partners of the Italian Hub of Population Biobanks (HIBP): association between lipid profile and socio-demographic variables.

Biopreserv Biobank 2014 Aug 30;12(4):225-33. Epub 2014 Jul 30.

1 Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità , Rome, Italy .

The Italian Hub of Population Biobanks (HIBP) includes both ongoing and completed studies that are heterogeneous in both their purpose and in the specimens collected. The heterogeneity in starting conditions makes sharing study data very difficult because of technical, ethical, and collection rights issues that hamper collaboration and synergy. With the aim of overcoming these difficulties and establishing the "proof-of-concept" that sharing studies is achievable among Italian collections, a data-sharing pilot project has been agreed to by HIBP members. Participants agreed to the general methodology and signed a shared Data Transfer Agreement. The biobanks involved were: EURAC (Micros study), CIG (GEHA project), CNESPS (FINE, MATISS, MONICA, OEC1998, ITR (Italian Twin Register), and IPREA studies, and MOLIBANK (Moli-Sani project). Biobank data were uploaded into a common database using a dedicated informatics infrastructure. Demographic data, and anthropometric and hematochemical parameters were shared for each record. Each biobank uploaded into the common database a dataset with a minimum of 1000 subjects, for a total of 5071 records. After a harmonization process, the final dataset included 3882 records. Subjects were grouped into three main geographic areas of Italy (North, Center, and South) and separate analyses were performed for men and women. The 3882 records were analyzed through multivariate logistic regression analysis. Results were expressed as odds ratios with 95% confidence interval. Results show several geographical differences in the lipidemic pattern, mostly regarding cholesterol-HDL, which represents a strong basis for further, deeper sample-based studies. This HIBP pilot study aimed to prove the feasibility of such collaborations and it provides a methodological prototype for future studies based on the participation in the partnership of well-established quality collections.
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http://dx.doi.org/10.1089/bio.2014.0001DOI Listing
August 2014

Assessment of prion reduction filters in decreasing infectivity of ultracentrifuged 263K scrapie-infected brain homogenates in "spiked" human blood and red blood cells.

Transfusion 2014 Apr 5;54(4):990-5. Epub 2013 Aug 5.

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.

Background: The safety of red blood cells (RBCs) is of concern because of the occurrence of four transfusion-transmitted variant Creutzfeldt-Jakob disease (vCJD) cases in the United Kingdom. The absence of validated screening tests requires the use of procedures to remove prions from blood to minimize the risk of transmission. These procedures must be validated using infectious prions in a form that is as close as possible to one in blood.

Study Design And Methods: Units of human whole blood (WB) and RBCs were spiked with high-speed supernatants of 263K scrapie-infected hamster brain homogenates. Spiked samples were leukoreduced and then passed through prion-removing filters (Pall Corporation). In another experiment, RBCs from 263K scrapie-infected hamsters were treated as above, and residual infectivity was measured by bioassay.

Results: The overall removal of infectivity by the filters from prion-spiked WB and RBCs was approximately two orders of magnitude. No infectivity was detected in filtered hamster RBCs endogenously infected with scrapie.

Conclusion: The use of prion-removing filters may help to reduce the risk of transfusion-transmitted vCJD. To avoid overestimation of prion removal efficiency in validation studies, it may be more appropriate to use supernates from ultracentrifugation of scrapie-infected hamster brain homogenate rather than the current standard brain homogenates.
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http://dx.doi.org/10.1111/trf.12369DOI Listing
April 2014

Age at Death of Creutzfeldt-Jakob disease in subsequent family generation carrying the E200K mutation of the prion protein gene.

PLoS One 2013 2;8(4):e60376. Epub 2013 Apr 2.

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.

Background: The E200K mutation of the prion protein gene (PRNP) is the most frequent amino acid substitution in genetic Creutzfeldt-Jakob disease and is the only one responsible for the appearance of clustered cases in the world. In the Israel and Slovakian clusters, age of disease onset was reduced in successive generations but the absence of a clear molecular basis raised the possibility that this event was an observational bias. The aim of the present study was to investigate possible selection biases or confounding factors related to anticipation in E200K CJD patients belonging to a cluster in Southern Italy.

Methods: Clinical and demographical data of 41 parent-offspring pairs from 19 pedigrees of the Italian cluster of E200K patients were collected. Age at death of parents was compared with age at death of E200K CJD offspring. Subgroup analyses were performed for controlling possible selection biases, confounding factors, or both.

Results: The mean age at death/last follow-up of the parent generation was 71.4 years while that of CJD offspring was 59.3 years with an estimated anticipation of 12.1 years. When the same analysis was performed including only parents with CJD or carrying the E200K mutation (n = 26), the difference between offspring and parents increased to 14.8 years.

Conclusions: These results show that early age at death occurs in offspring of families carrying the E200K PRNP mutation and that this event is not linked to observational biases. Although molecular or environmental bases for this occurrence remain unsettled, this information is important for improving the accuracy of information to give to mutated carriers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060376PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3614945PMC
September 2013

Effects of chronic caffeine intake in a mouse model of amyotrophic lateral sclerosis.

J Neurosci Res 2013 Apr 30;91(4):585-92. Epub 2013 Jan 30.

Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.

Caffeine is a nonselective adenosine receptor antagonist; chronic consumption has proved protective toward neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. The present study was designed to determine whether caffeine intake affected survival and/or motor performance in a transgenic model of amyotrophic lateral sclerosis (ALS). SOD1(G93A) mice received caffeine through drinking water from 70 days of age until death. Body weight, motor performance and survival were evaluated. Furthermore, the expression of adenosine A(2A) receptors (A(2A) Rs), glial glutamate transporter (GLT1), and glial fibrillar acidic protein (GFAP) were evaluated by Western blotting. The results showed that caffeine intake significantly shortened the survival of SOD1(G93A) mice (log rank test, P = 0.01) and induced a nonsignificant advancing of disease onset. The expression of A(2A) R, GLT1, and GFAP was altered in the spinal cords of ALS mice, but caffeine did not influence their expression in either wild-type or SOD1(G93) mice. These data indicate that adenosine receptors may play an important role in ALS.
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http://dx.doi.org/10.1002/jnr.23185DOI Listing
April 2013

Isoprostanes in clinically isolated syndrome and early multiple sclerosis as biomarkers of tissue damage and predictors of clinical course.

Mult Scler 2013 Apr 23;19(4):411-7. Epub 2012 Aug 23.

Department of Neurology and Psychiatry, Sapienza University, Rome, Italy.

Background: Isoprostanes (IsoP) are sensitive biomarkers of oxidative stress. Their cerebrospinal-fluid (CSF) level is increased in several neurological conditions, including multiple sclerosis (MS). In particular, in relapsing-remitting MS, IsoP have been proposed as an index of neurodegenerative processes. The mechanisms leading to neuroaxonal damage in MS are not fully understood but oxidative mechanisms play a substantial role. Although axonal loss is present in MS patients since their first clinical symptoms, IsoP levels at this early stage have not been evaluated yet.

Objectives: The objectives of this study were (a) to assess IsoP levels in CSF of patients with a first clinical attack suggestive of MS; (b) to correlate IsoP levels with magnetic resonance imaging (MRI) measures of brain damage and (c) to assess IsoP value in predicting disease clinical evolution.

Methods: Thirty-nine patients with a first clinical attack suggestive of MS underwent neurological examination, lumbar puncture with IsoP levels quantification and conventional/spectroscopic-MRI. Patients were followed up for 24 months.

Results: CSF IsoP levels were higher in patients than controls (mean ± standard deviation (SD) 123.4 ± 185.8 vs 4.5 ± 2.9 pg/ml; p<0.0001) and inversely correlated to normalized brain volume (p=0.04) and N-acetylaspartate/choline (NAA/Cho) (p=0.01). The risk of experiencing clinical relapses differed according to IsoP level: subjects with levels higher than 95 pg/ml (a cut-off value resulting from ROC analysis) were more likely to relapse than patients with levels equal or lower than 95 pg/ml (59% vs 27% respectively; p=0.03).

Conclusions: CSF IsoP might be useful biomarkers of tissue damage in MS with a predictive value of disease course.
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http://dx.doi.org/10.1177/1352458512457721DOI Listing
April 2013

Increased levels of acute-phase inflammatory proteins in plasma of patients with sporadic CJD.

Neurology 2012 Sep 1;79(10):1012-8. Epub 2012 Aug 1.

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.

Objective: Screening plasma samples from patients with sporadic Creutzfeldt-Jakob disease (CJD) to discover diagnostic biomarkers.

Methods: Plasma samples were collected from 17 patients with sporadic CJD, 17 patients with Alzheimer disease (AD), and 20 healthy subjects. A 2-phase screening was carried out using quantitative protein mass spectrometry. The putative sporadic CJD biomarkers were then validated independently by immunoturbidimetry.

Results: Mass spectrometry uncovered 7 candidate sporadic CJD protein biomarkers, all belonging to the acute-phase response. Highly significant increases of these markers in patients with sporadic CJD, compared with healthy subjects and patients with AD, was confirmed by immunoturbidimetry.

Conclusions: The increase in plasma levels of a related set of acute-phase reactants in patients with sporadic CJD is a novel finding that suggests new pathogenetic hypotheses. The possible value of this set of proteins as biomarkers in the diagnosis of sporadic CJD or for blood/tissue donor screening remains to be further explored and validated in larger studies.
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http://dx.doi.org/10.1212/WNL.0b013e318265a55dDOI Listing
September 2012

Assessing prion infectivity of human urine in sporadic Creutzfeldt-Jakob disease.

Emerg Infect Dis 2012 Jan;18(1):21-8

Case Western Reserve University, Cleveland,Ohio, USA.

Prion diseases are neurodegenerative conditions associated with a misfolded and infectious protein, scrapie prion protein (PrP(Sc)). PrP(Sc) propagate prion diseases within and between species and thus pose risks to public health. Prion infectivity or PrP(Sc) presence has been demonstrated in urine of experimentally infected animals, but there are no recent studies of urine from patients with Creutzfeldt-Jakob disease (CJD). We performed bioassays in transgenic mice expressing human PrP to assess prion infectivity in urine from patients affected by a common subtype of sporadic CJD, sCJDMM1. We tested raw urine and 100-fold concentrated and dialyzed urine and assessed the sensitivity of the bioassay along with the effect of concentration and dialysis on prion infectivity. Intracerebral inoculation of transgenic mice with urine from 3 sCJDMM1 patients failed to demonstrate prion disease transmission, indicating that prion infectivity in urine from sCJDMM1 patients is either not present or is <0.38 infectious units/mL.
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http://dx.doi.org/10.3201/eid1801.110589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310101PMC
January 2012

Comparison of nanofiltration efficacy in reducing infectivity of centrifuged versus ultracentrifuged 263K scrapie-infected brain homogenates in "spiked" albumin solutions.

Transfusion 2012 May 14;52(5):953-62. Epub 2011 Nov 14.

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, Italy.

Background: The safety of plasma-derived products is of concern for possible transmission of variant Creutzfeldt-Jakob disease. The absence of validated screening tests requires the use of procedures to remove or inactivate prions during the manufacture of plasma-derived products to minimize the risk of transmission. These procedures need proper validation studies based on spiking human plasma or intermediate fractions of plasma fractionation with prions in a form as close as possible to that present in blood.

Study Design And Methods: Human albumin was spiked with low-speed or high-speed supernatants of 263K scrapie-infected hamster brain homogenates. Spiked albumin was then passed through a cascade of filters from 100 nm down to 20 to 15 nm. Residual infectivity was measured by bioassay.

Results: The overall removal of infectivity spiked into albumin through serial nanofiltration steps was 4 to 5 logs using low-speed supernatant and 2 to 3 logs with high-speed supernatant.

Conclusion: These findings confirm the utility of nanofiltration in removing infectivity from plasma (or other products) spiked with scrapie brain homogenate supernatants. However, efficiency is diminished using supernatants that have been ultracentrifuged to reduce aggregated forms of the infectious agent. Thus, filtration removal data based on experiments using "standard" low-speed centrifugation supernatants might overestimate the amount of prion removal in plasma or urine-derived therapeutic products.
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http://dx.doi.org/10.1111/j.1537-2995.2011.03425.xDOI Listing
May 2012

Is growth-discordance in twins a substantial risk factor in adverse neonatal outcomes?

Twin Res Hum Genet 2011 Oct;14(5):463-7

Division of Neonatology Catholic University of Sacred Heart, Rome, Italy.

To evaluate whether growth discordance is an independent risk factor in the neonatal outcome of the smaller twin, all medical records of twin pregnancies delivered between 26 and 41 weeks during a 5-year period (January 2004-December 2008) were reviewed. Among the 49 selected twins, weight discordance was 15-20% in 7 infants, 21-30% in 16 infants, 31-40% in 16 infants and > 40% in 10 infants. No significant differences between the four groups were found with regards to obstetric complications and neonatal disease. Occurrence of birthweight below the 10th percentile and rate of admission to the neonatal intensive care unit significantly increased as intra-pair birthweight difference increased (p = .03). The > 40% discordant group had a significantly lower gestational age (p = .03), lower birthweight (p = .007) and a significantly higher mortality rate (4/10 versus 3/39 p = .04) in comparison with the other discordant groups. Multiple logistic regression analysis showed that birthweight was the single independent and consistent factor associated with elevated risks of mortality. For every 250 g increase in birthweight, the risk for mortality decreased by about 84% [RR 0.16(CI 0.00-0.70)]. Gestational age was the most reliable predictor for major neonatal complications. For every 1-week increase in gestational age a significant decreased risk for all outcomes was found. Discordance alone should not be considered as a predictor for adverse neonatal outcome. Neonatal outcome in discordant twins appears to be related to gestational age and birthweight rather than to the degree of discordance.
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http://dx.doi.org/10.1375/twin.14.5.463DOI Listing
October 2011

Need to improve clinical trials in rare neurodegenerative disorders.

Ann Ist Super Sanita 2011 ;47(1):55-9

Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Rome, Italy.

Rare neurodegenerative diseases are fatal and no therapy is available to cure or slow down the progression of disease. We report possibly weaknesses in the management of clinical studies in these diseases, ranging from poor preclinical studies, difficulties in the recruitment of patients, delay in the onset of treatment because of lack in early disease-specific biomarkers, and suboptimal design of Phase II clinical trials. The adoption of innovative statistical approaches in early Phase II trials might improve the screening of drugs in rare neurodegenerative disorders, but this implicates efforts from clinical researchers, statisticians, and regulatory people to the development of new strategies that should maintain rigorous scientific integrity together with a more ethical approach to human experimentations.
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http://dx.doi.org/10.4415/ANN_11_01_12DOI Listing
July 2011

Transmission of sporadic Creutzfeldt-Jakob disease by blood transfusion: risk factor or possible biases.

Transfusion 2011 Jul 7;51(7):1556-66. Epub 2011 Jan 7.

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.

Background: The occurrence of transfusion transmissions of variant Creutzfeldt-Jakob disease (CJD) cases has reawakened attention to the possible similar risk posed by other forms of CJD.

Study Design And Methods: CJD with a definite or probable diagnosis (sporadic CJD, n = 741; genetic CJD, n = 175) and no-CJD patients with definite alternative diagnosis (n = 482) with available blood transfusion history were included in the study. The risk of exposure to blood transfusion occurring more than 10 years before disease onset and for some possible confounding factors was evaluated by calculating crude odds ratios (ORs). Variables with significant ORs in univariate analyses were included in multivariate logistic regression analyses.

Results: In the univariate model, blood transfusion occurring more than 10 years before clinical onset is 4.1-fold more frequent in sporadic CJD than in other neurologic disorders. This significance is lost when the 10-year lag time was not considered. Multivariate analyses show that the risk of developing sporadic CJD after transfusion increases (OR, 5.05) after adjusting for possible confounding factors. Analysis conducted on patients with genetic CJD did not reveal any significant risk factor associated with transfusion.

Conclusion: This is the first case-control study showing a significant risk of transfusion occurring more than 10 years before clinical onset in sporadic CJD patients. It remains questionable whether the significance of these data is biologically plausible or the consequence of biases in the design of the study, but they counterbalance previous epidemiologic negative reports that might have overestimated the assessment of blood safety in sporadic CJD.
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http://dx.doi.org/10.1111/j.1537-2995.2010.03004.xDOI Listing
July 2011

PrPTSE in muscle-associated lymphatic tissue during the preclinical stage of mice infected orally with bovine spongiform encephalopathy.

J Gen Virol 2009 Oct 17;90(Pt 10):2563-2568. Epub 2009 Jun 17.

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.

The involvement of muscles in the pathogenesis of transmissible spongiform encephalopathies (TSEs) is irregular and unpredictable. We show that the TSE-specific protein (PrP(TSE)) is present in muscles of mice fed with a mouse-adapted strain of bovine spongiform encephalopathy as early as 100 days post-infection, corresponding to about one-third of the incubation period. The proportion of mice with PrP(TSE)-positive muscles and the number of muscles involved increased as infection progressed, but never attained more than a limited distribution, even at the clinical stage of disease. The appearance of PrP(TSE) in muscles during the preclinical stage of disease was probably due to the haematogenous/lymphatic spread of infectivity from the gastrointestinal tract to lymphatic tissues associated with muscles, whereas in symptomatic animals, the presence of PrP(TSE) in the nervous system, in neuromuscular junctions and in muscle fibres suggests a centrifugal spread from the central nervous system, as already observed in other TSE models.
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http://dx.doi.org/10.1099/vir.0.010801-0DOI Listing
October 2009

Efficacy of phthalocyanine tetrasulfonate against mouse-adapted human prion strains.

Arch Virol 2009 21;154(6):1005-7. Epub 2009 May 21.

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.

In vitro and in vivo studies have shown that phthalocyanine tetrasulfonate (PcTS), a cyclic tetrapyrrole compound, is an efficient antiscrapie drug. To investigate the spectrum of PcTS against prion diseases, we tested the effect of PcTS on two mouse-adapted human strains. We also tested PcTS in rodents infected with two scrapie strains (139A and 263K). PcTS treatment significantly prolonged mean survival times of all infected animals. These results show that PcTS is effective on different prion strains, confirming its potential use for prion therapy.
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http://dx.doi.org/10.1007/s00705-009-0394-9DOI Listing
June 2009

Oral pravastatin prolongs survival time of scrapie-infected mice.

J Gen Virol 2009 Jul 12;90(Pt 7):1775-1780. Epub 2009 Mar 12.

Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.

Statins are potent inhibitors of HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase in the cholesterol-biosynthesis pathway. They are either lipophilic (e.g. simvastatin) or hydrophilic [e.g. pravastatin (PRV)] compounds, considered mainly for long-term treatment of hypercholesterolaemic individuals. Beneficial effects of statins are not related exclusively to their lipid-lowering action; they also possess cholesterol-independent, pleiotropic effects (e.g. anti-inflammatory and antioxidant). Recent studies revealed that simvastatin treatment increased survival significantly in scrapie-infected mice. Although PRV treatment results in measurable drug levels in the mouse brain, the anti-prion effect of this compound has not been investigated. Therefore, we aimed to test the potential therapeutic action of PRV in a murine scrapie model. Our study showed that high-dose and long-term oral PRV treatment prolonged survival times of strain 139A scrapie-infected mice significantly (194 versus 177 days) in the absence of any obvious toxicity, suggesting that protective effects of statins may be independent of absolute solvent or water solubility of the drug.
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http://dx.doi.org/10.1099/vir.0.009936-0DOI Listing
July 2009

Survival in Alzheimer's disease is shorter in women carrying heterozygosity at codon 129 of the PRNP gene and no APOE epsilon 4 allele.

Dement Geriatr Cogn Disord 2008 7;25(4):354-8. Epub 2008 Mar 7.

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.

We assessed the role of the APOE genotype and prion protein polymorphism at codon 129 in predicting the clinical duration of 92 neuropathologically confirmed sporadic Alzheimer's disease patients. Analyses of survival showed that the absence of the APOE epsilon 4 allele in heterozygous codon 129 PRNP carriers is a negative predictor of survival. When this subgroup of patients was stratified by sex, the effect of APOE was observed in women, but not in men.
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http://dx.doi.org/10.1159/000119730DOI Listing
June 2008

Plasma levels of 15-F(2t)-isoprostane in newborn infants are affected by mode of delivery.

Clin Biochem 2007 Dec 21;40(18):1420-2. Epub 2007 Sep 21.

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena, 299-00161 Rome, Italy.

Objective: To investigate how the mode of delivery affects the level oxidative stress in newborns.

Design And Methods: 15-F(2t)-isoprostane, as index of oxidative stress, was measured in umbilical cord plasma samples from 37 infants born after vaginal delivery or caesarian section, using specific immuno-affinity extraction and immunoassay.

Results: 15-F(2t)-isoprostane levels were higher in infants born after vaginal delivery (n=18) compared to those delivered by elective caesarian section (n=19).

Conclusions: 15-F(2t)-isoprostane is a sensitive biomarker of fetal oxidative stress during labor.
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http://dx.doi.org/10.1016/j.clinbiochem.2007.09.004DOI Listing
December 2007

Attention and memory in the preclinical stage of dementia.

J Geriatr Psychiatry Neurol 2007 Jun;20(2):67-75

Memory Clinic, Centre for the Medicine of the Ageing, Catholic University, Rome, Italy.

The aim of this study was to investigate whether attention may be specifically impaired in Alzheimer's disease from the early stages of the disease. Subgroups of patients with different types of mild cognitive impairment were selected according to standard criteria. Patients and controls were given tasks exploring various subcomponents of attention and executive functions. Only subgroups of mild cognitive impairment characterized by memory disorders obtained lower scores than controls on attention and executive tasks. On the basis of the scores obtained on the Clinical Dementia Rating at the 1-year follow-up, patients were redistributed into 2 groups: those who developed and those who did not develop dementia. Patients who presented evolution to dementia already had, at baseline, lower scores than patients who did not evolve on tasks exploring attention and executive functions. The results suggest that not only memory disorders but also attention/executive deficits may characterize dementia at the onset.
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http://dx.doi.org/10.1177/0891988706297469DOI Listing
June 2007