A Federico

Università degli Studi di Siena, Siena, Tuscany, Italy

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Publications (446)1339.27 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused by NOTCH3 mutations. There are no clinical and neuroimaging findings pathognomonic of the disease. The aim of this paper was to provide a description of a group of NOTCH3-negative patients with a phenotype closely resembling that of CADASIL.
    Acta Neurologica Scandinavica 08/2014; · 2.47 Impact Factor
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    ABSTRACT: Neurodegenerative disorders affect almost 30 million individuals leading to disability and death. These disorders are characterized by pathological changes in disease-specific areas of the brain and degeneration of distinct neuron subsets. Despite the differences in clinical manifestations and neuronal vulnerability, the pathological processes appear similar, suggesting common neurodegenerative pathways. Apoptosis seems to play a key role in the progression of several neurologic disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis as demonstrated by studies on animal models and cell lines. On the other hand, research on human brains reported contradictory results. However, many dying neurons have been detected in autoptic brains of patients with neurodegenerative diseases, and these conditions are often associated with significant cell loss accompanied by typical morphological features of apoptosis such as chromatin condensation, DNA fragmentation, and activation of cysteine-proteases called caspases. Cell death and neurodegenerative conditions have been linked to oxidative stress and imbalance between generation of free radicals and antioxidant defenses. Multiple sclerosis, stroke, and neurodegenerative diseases have been associated with reactive oxygen species and nitric oxide. Here we present an overview of the involvement of neuronal apoptosis and oxidative stress in the most important neurodegenerative diseases, mainly focusing the attention on several genetic disorders, discussing the interaction between primary genetic abnormalities and the apoptotic pathways.
    Journal of Alzheimer's disease: JAD 07/2014; · 4.17 Impact Factor
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    ABSTRACT: Adult-onset leukoencephalopathies are clinically and pathologically heterogeneous diseases, characterized by overlapping clinical and neuroradiological features and a difficult diagnostic process. Nevertheless, knowledge of the metabolic and genetic basis of leukoencephalopathies is constantly increasing. This article provides an overview of currently known leukoencephalopathies in adulthood, emphasizing, in addition to the classical forms, their atypical clinical presentations. In particular, we review the clinical spectrum and the molecular pathogenesis of certain adult-onset leukoencephalopathies, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), cerebroretinal microangiopathy with calcifications and cysts (CRMCC), hereditary diffuse leukoencephalopathy with spheroids (HDLS), fragile X-associated tremor/ataxia syndrome (FXTAS), vanishing white matter disease (VWM), autosomal dominant leukodystrophy due to lamin B1 duplication (ADLD), and vascular leukoencephalopathy mapping to chromosome 20q13.
    Journal of Alzheimer's disease: JAD 06/2014; · 4.17 Impact Factor
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    ABSTRACT: Visual sequential search might use a peripheral spatial ranking of the scene to put the next target of the sequence in the correct order. This strategy, indeed, might enhance the discriminative capacity of the human peripheral vision and spare neural resources associated with foveation. However, it is not known how exactly the peripheral vision sustains sequential search and whether the sparing of neural resources has a cost in terms of performance. To elucidate these issues, we compared strategy and performance during an alpha-numeric sequential task where peripheral vision was modulated in three different conditions: normal, blurred, or obscured. If spatial ranking is applied to increase the peripheral discrimination, its use as a strategy in visual sequencing should differ according to the degree of discriminative information that can be obtained from the periphery. Moreover, if this strategy spares neural resources without impairing the performance, its use should be associated with better performance. We found that spatial ranking was applied when peripheral vision was fully available, reducing the number and time of explorative fixations. When the periphery was obscured, explorative fixations were numerous and sparse; when the periphery was blurred, explorative fixations were longer and often located close to the items. Performance was significantly improved by this strategy. Our results demonstrated that spatial ranking is an efficient strategy adopted by the brain in visual sequencing to highlight peripheral detection and discrimination; it reduces the neural cost by avoiding unnecessary foveations, and promotes sequential search by facilitating the onset of a new saccade.
    European Journal of Neuroscience 06/2014; · 3.75 Impact Factor
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    ABSTRACT: Transcranial magnetic stimulation (TMS) studies on the pathways to the upper limbs have revealed inconsistent results in patients harboring mutations in SPAST/SPG4 gene, responsible for the commonest form of hereditary spastic paraplegia (HSP). This paper is addressed to study the corticomotor excitability of the pathways to the upper limbs in SPG4 subjects. We assessed the corticomotor excitability of hand muscles in 12 subjects belonging to 7 unrelated SPG4 families and in 12 control subjects by stimulus-response curve [input-output (I-O) curve]. All the parameters of the recruitment curve (threshold, V50, slope and plateau) did not differ significantly from those of the controls. Presence of upper limb hyper-reflexia did not influence the results of I-O curve. Considering the multiplicity of possible genes/loci accounting for pure HSPs, performing TMS analyses could be helpful in differential diagnosis of pure HSPs in the absence of other clinical or neuroimaging tools.
    Neurological Sciences 03/2014; · 1.41 Impact Factor
  • Journal of the neurological sciences 03/2014; · 2.32 Impact Factor
  • Neurological Sciences 03/2014; · 1.41 Impact Factor
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    ABSTRACT: Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is an infantile-onset inherited disease of the brain white matter with a defect in brain ion and water homoeostasis, which leads to an abnormal brain volume regulation. Clinical features of the disease can be variable, but patients typically show early-onset macrocephaly, motor abnormalities, seizures, and almost constant late-onset mild mental deterioration. Brain magnetic resonance imaging (MRI) reveals diffusely abnormal and mildly swollen white matter as well as subcortical cysts in the anterior temporal and frontoparietal regions. We describe here clinical findings and volumetric MRI and (1)H-MR spectroscopic imaging ((1)H-MRSI) data of a 12-year follow-up on a patient with MLC. The patient had only slight clinical worsening during the long follow-up. Volumetric findings showed substantially unchanged cystic volumes and mild brain atrophy rate. In addition, there was no over time increase in the volume of white matter hypointense lesions seen on FLAIR images at baseline, but the degree of hypointensity of these white matter voxels increased over 12 years. Longitudinal (1)H-MRSI examination showed long-term undetectable metabolite signals in the white matter, whereas the metabolic pattern of gray matter voxels remained unchanged over time. Results show that, in MLC, the chronic brain white matter changes resulting from the brain ion, and water homeostasis can be monitored by quantitative MRI modalities. This might be important for assessing treatment effects.
    Neurological Sciences 03/2014; · 1.41 Impact Factor
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    ABSTRACT: White matter hyperintensities (WMH) on MRI are a quantitative marker for sporadic cerebral small vessel disease and are highly heritable. To date, large-scale genetic studies have identified only a single locus influencing WMH burden. This might in part relate to biological heterogeneity of sporadic WMH. The current study searched for genetic modifiers of WMH volume in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a monogenic small vessel disease. We performed a genome-wide association study to identify quantitative trait loci for WMH volume by combining data from 517 CADASIL patients collected through 7 centers across Europe. WMH volumes were centrally analyzed and quantified on fluid attenuated inversion recovery images. Genotyping was performed using the Affymetrix 6.0 platform. Individuals were assigned to 2 distinct genetic clusters (cluster 1 and cluster 2) based on their genetic background. Four hundred sixty-six patients entered the final genome-wide association study analysis. The phenotypic variance of WMH burden in CADASIL explained by all single nucleotide polymorphisms in cluster 1 was 0.85 (SE=0.21), suggesting a substantial genetic contribution. Using cluster 1 as derivation and cluster 2 as a validation sample, a polygenic score was significantly associated with WMH burden (P=0.001) after correction for age, sex, and vascular risk factors. No single nucleotide polymorphism reached genome-wide significance. We found a polygenic score to be associated with WMH volume in CADASIL subjects. Our findings suggest that multiple variants with small effects influence WMH burden in CADASIL. The identification of these variants and the biological pathways involved will provide insights into the pathophysiology of white matter disease in CADASIL and possibly small vessel disease in general.
    Stroke 02/2014; · 6.16 Impact Factor
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    ABSTRACT: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant disorder characterized by white matter neurodegeneration, progressive cognitive decline, and motor symptoms. Histologically, it is characterized by axonal swellings ("spheroids"). To date, over 20 different mutations affecting the tyrosine kinase domain of the protein have been identified in the colony stimulating factor 1 receptor (CSF1R) gene. Our goal is to describe three unrelated Italian patients affected by HDLS and carrying new CSF1R mutations, thus expanding the mutational spectrum and phenotypic presentation. CSF1R gene analysis was performed in 15 patients (age range 25-83 years) with undefined leukoencephalopathy and progressive cognitive decline. In three patients (two males and one female, aged 58, 37, and 48 years, respectively), new heterozygous missense mutations affecting the protein tyrosine kinase domain of the CSF1R gene were detected. In all of these patients, behavioural and cognitive changes were preceded by an ischemic stroke-like episode. A positive family history was present in only one case.
    Journal of Neurology 02/2014; · 3.58 Impact Factor
  • Andrea Mignarri, Antonio Federico
    Neurological Sciences 02/2014; · 1.41 Impact Factor
  • Journal of Neurology 02/2014; · 3.58 Impact Factor
  • D Marino, A Federico
    Neurological Sciences 02/2014; · 1.41 Impact Factor
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    ABSTRACT: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary nonhypertensive cause of recurrent lacunar stroke and cognitive decline associated with alopecia, spondylosis deformans, and lumbago.(1) The disease has been linked to mutations in the HTRA1 gene, encoding for serine protease HTRA1, loss of which causes dysregulation of transforming growth factor-β signaling.(2.)
    Neurology 02/2014; · 8.25 Impact Factor
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    ABSTRACT: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder characterized by a heterogeneous presentation and a broad spectrum of clinical manifestations. Since early diagnosis and replacement therapy with chenodeoxycholic acid can prevent clinical deterioration, our aim was to develop a diagnostic tool to identify and treat CTX patients at an initial stage of the disease. We devised a suspicion index, composed of weighted scores assigned to indicators such as family history characteristics and common systemic and neurological features, on the basis of a pooled analysis of selected international CTX series. The indicators were classified as very strong (score 100), strong (50) or moderate (25). The suspicion index was then applied retrospectively to our CTX population. Early systemic signs such as cataract, diarrhea and neonatal cholestatic jaundice were considered strong indicators, together with neurological features such as intellectual impairment, psychiatric disturbances, ataxia, spastic paraparesis and dentate nuclei abnormalities at MRI. Tendon xanthomas were regarded as very strong indicators, as was an affected sibling. A total score ≥ 100 warranted serum cholestanol assessment. Elevated cholestanol or a total score ≥ 200, with one very strong or four strong indicators, warranted CYP27A1 gene analysis. In our patients, age at diagnosis was 35.5 ± 11.8 years (mean ± standard deviation), whereas with the diagnostic tool it became 10.6 ± 9.8 years (p < 0.01). Our suspicion index provides a simple and inexpensive diagnostic tool allowing diagnosis and treatment of CTX before neurological disability occurs.
    Journal of Inherited Metabolic Disease 01/2014; · 4.07 Impact Factor
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    ABSTRACT: The 3243A>G mutation of mtDNA usually is associated with MELAS syndrome. Here we report a patient with the 3243A>G mutation presenting only recurrent muscle fatigue and elevated levels of serum creatine kinase (CK). The mother of the proband was referred to us for type 2 diabetes mellitus, muscle pain and sensorineural hearing loss. The percentage of mutation load in different tissues was similar in both subjects, except in the urinary epithelium. The mutation load in the son's urinary epithelial cells (UEC) was consistently higher (nearly 50%) than in his muscle (nearly 20%). We conclude that a correlation between the proportion of the UEC mutation load and the severity of the disease was lacking in this pedigree. The use of UEC as the tissue of choice in the noninvasive diagnosis of the 3243A>G mutation offers a very attractive alternative to muscle biopsy. Finally, our data expand the clinical spectrum of the 3243A>G mutation.
    Journal of the neurological sciences 01/2014; · 2.32 Impact Factor
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    Giacomo Veneri, Antonio Federico, Alessandra Rufa
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    ABSTRACT: Attention allows us to selectively process the vast amount of information with which we are confronted, prioritizing some aspects of information and ignoring others by focusing on a certain location or aspect of the visual scene. Selective attention is guided by two cognitive mechanisms: saliency of the image (bottom up) and endogenous mechanisms (top down). These two mechanisms interact to direct attention and plan eye movements; then, the movement profile is sent to the motor system, which must constantly update the command needed to produce the desired eye movement. A new approach is described here to study how the eye motor control could influence this selection mechanism in clinical behavior: two groups of patients (SCA2 and late onset cerebellar ataxia LOCA) with well-known problems of motor control were studied; patients performed a cognitively demanding task; the results were compared to a stochastic model based on Monte Carlo simulations and a group of healthy subjects. The analytical procedure evaluated some energy functions for understanding the process. The implemented model suggested that patients performed an optimal visual search, reducing intrinsic noise sources. Our findings theorize a strict correlation between the "optimal motor system" and the "optimal stimulus encoders."
    BioMed research international. 01/2014; 2014:162423.
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    ABSTRACT: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder characterized by ataxia, spastic paraparesis, polyneuropathy, and evidence of superior cerebellar vermis atrophy at magnetic resonance imaging (MRI). Reports of atypical presentations and additional clinical or MRI findings have been recently published, but psychiatric disturbances have never been associated with ARSACS. We describe four ARSACS patients manifesting severe psychiatric symptoms including psychosis, panic disorder, and depression during the course of the disease. Our case reports further expand the ARSACS phenotype and add clinical data in favor of the hypothesized relationship between cerebellar dysfunction and psychiatric disorders.
    Neurological Sciences 12/2013; · 1.41 Impact Factor
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    ABSTRACT: Most of causative mutations of the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are missense point mutations either creating or deleting one cysteine residue, inherited in a heterozygous state. Only few homozygous patients are reported to date and some of them showed phenotypic peculiarities. We here describe a CADASIL family in which a member showed homozygous mutation and compare its clinical profile with five subjects throughout three generation of the pedigree, carrying the same mutation in heterozygosity. The index patient was a 44-year-old Italian man, born from consanguineous parents (first cousins). Symptoms started at 23 years and progressing with recurrent ischemic stroke episode. Diffuse leukoencephalopathy and a severe cognitive impairment were evident, GOMs were detected in skin specimens and a homozygous p.Cys183Ser mutation of the NOTCH3 gene was found. Among the other five heterozygous relatives for the same mutation, both parents developed stroke in advanced age and all the others were clinically asymptomatic. We discuss these findings in relationship to previous data from the literature in CADASIL and in other dominant neurological disorders.
    Neurological Sciences 11/2013; · 1.41 Impact Factor

Publication Stats

4k Citations
1,339.27 Total Impact Points


  • 1980–2014
    • Università degli Studi di Siena
      • Department of Medicine, Surgery and Neuroscience
      Siena, Tuscany, Italy
  • 2004–2013
    • Azienda Ospedaliera Universitaria Senese
      Siena, Tuscany, Italy
    • University of Florence
      • Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino
      Florence, Tuscany, Italy
    • IRCCS Fondazione Istituto Neurologico Nazionale C. Mondino
      Ticinum, Lombardy, Italy
  • 2010–2011
    • Centro Neurolesi Bonino Pulejo, Messina
      Messina, Sicily, Italy
  • 2009
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2008–2009
    • Ospedale Pediatrico Bambino Gesù
      Roma, Latium, Italy
    • University of Rome Tor Vergata
      Roma, Latium, Italy
    • University of Naples Federico II
      • Department of Molecular Medicine and Medical Biotechnology
      Napoli, Campania, Italy
  • 2007
    • Oasi Città Aperta
      Troina, Sicily, Italy
    • Università degli Studi di Bari Aldo Moro
      Bari, Apulia, Italy
  • 2006
    • Università degli Studi di Messina
      • Dipartimento di Neuroscienze
      Messina, Sicily, Italy
  • 2003
    • University of Ferrara
      Ferrare, Emilia-Romagna, Italy
  • 2002
    • Oxford University Hospitals NHS Trust
      • Department of Clinical Neurology
      Oxford, England, United Kingdom
  • 2000
    • University of Pavia
      Ticinum, Lombardy, Italy
  • 1999
    • Sapienza University of Rome
      Roma, Latium, Italy
  • 1992
    • Istituto delle Scienze Neurologiche, Ospedale Bellaria
      Bolonia, Emilia-Romagna, Italy
  • 1979–1985
    • Università degli Studi di Napoli L'Orientale
      Napoli, Campania, Italy