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Bugiani O.,Istituto Neurologico Carlo Besta
Neurological Sciences | Year: 2011

The view that Alzheimer's disease (AD) is a fatal outcome of ageing prevails over the view that it mainly affects people aged 75-95. The former is based on the exponential increase in the incidence of AD with ageing, while the latter on AD prevalence rates. Both views share the idea that neurofibrillary degeneration (NFD) is secondary to the loading of β-protein (Aβ) and its more toxic species in nervous tissue that occurs with ageing in everybody, but is greater in people predisposed to AD. They differ in terms of the complexity attributed to the concept of neuronal vulnerability to Aβ. In the ageing-related hypothesis, it is seen as a phylogenetic characteristic of neurons that predisposes some of them to Aβ-dependent NFD, which spreads from the more vulnerable allocortex to the less vulnerable neocortex and accordingly causes memory decline progressing to dementia. To adapt this to the discontinuity of AD prevalence, it is necessary to see neuronal vulnerability as being modulated by additional ontogenetic factors that make some vulnerable neurons more or less sensitive to Aβ toxicity. This may give the Aβ/NFD relationship enough flexibility to explain the cognitive reserve of the oldest old and the phenotypical variability of AD, in particular why it is that the clinical onset of AD may be characterised by focal signs other than memory loss. Introducing this concept offers a new perspective of AD pathogenesis based on the role played by Aβ and related proteins in nerve cell selection during brain development and adult neurogenesis. © Springer-Verlag 2011.

Bizzi A.,Istituto Neurologico Carlo Besta | Debanne S.M.,Case Western Reserve University | Rowland D.Y.,Case Western Reserve University
Neurology | Year: 2012

Objective: To compare the respective efficiency of CSF tau (quantitative) and CSF 14-3-3 protein (qualitative) in the diagnosis of prion disease. Methods: We made measurements on 420 live subjects, who subsequently underwent a postmortem neuropathology examination, including protein chemistry, immunohistochemistry, and histology. We performed tau by ELISA. We detected 14-3-3 protein by Western blot. Both assays were optimized for maximum efficiency (accuracy). Results: We found tau and 14-3-3 proteins to be closely correlated, but tau had a significantly better ability to predict disease status than 14-3-3 protein. Also, tau distinguished disease status at least as well as when both assays' results are combined in a variety of ways. Importantly, the area under the receiver operating characteristic curve for tau (0.82) was significantly larger than that for 14-3-3 protein (0.68) (p < 0.001). Diagnostic test statistics are provided for the study subjects with 58.3% prevalence, and for a more typical, nonselected, 7.5% prevalence as received by our center. Conclusion: In this study, tau is superior to 14-3-3 protein as a marker in the diagnosis of Creutzfeldt- Jakob disease, and is as efficient singly compared to a variety of combinations with 14-3-3 protein. This is the first study of this magnitude to examine prion disease diagnostic tests in a carefully characterized patient population with detailed statistical evaluation. Copyright © 2012 by AAN Enterprises, Inc.

Winkelmann J.,TU Munich | Winkelmann J.,Helmholtz Center for Environmental Research | Lin L.,Stanford University | Schormair B.,TU Munich | And 19 more authors.
Human Molecular Genetics | Year: 2012

Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT1 as the only gene with mutations found in all five affected individuals. Sanger sequencing confirmed the de novo mutation p.Ala570Val in one family, and showed co-segregation of p.Val606Phe and p.Ala570Val, with the ADCA-DN phenotype, in two other kindreds. An additional ADCA-DN kindred with a p.GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD4+ into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21 and in very close spatial proximity, suggesting distinct phenotypes depending on mutation location within this gene. © The Author 2012. Published by Oxford University Press. All rights reserved.

Moreno-Loshuertos R.,University of Zaragoza | Ferrin G.,University of Zaragoza | Ferrin G.,Hospital Universitario Reina Sofia | Acin-Perez R.,University of Zaragoza | And 7 more authors.
PLoS Genetics | Year: 2011

About half of the mitochondrial DNA (mtDNA) mutations causing diseases in humans occur in tRNA genes. Particularly intriguing are those pathogenic tRNA mutations than can reach homoplasmy and yet show very different penetrance among patients. These mutations are scarce and, in addition to their obvious interest for understanding human pathology, they can be excellent experimental examples to model evolution and fixation of mitochondrial tRNA mutations. To date, the only source of this type of mutations is human patients. We report here the generation and characterization of the first mitochondrial tRNA pathological mutation in mouse cells, an m.3739G>A transition in the mitochondrial mt-Ti gene. This mutation recapitulates the molecular hallmarks of a disease-causing mutation described in humans, an m.4290T>C transition affecting also the human mt-Ti gene. We could determine that the pathogenic molecular mechanism, induced by both the mouse and the human mutations, is a high frequency of abnormal folding of the tRNAIle that cannot be charged with isoleucine. We demonstrate that the cells harboring the mouse or human mutant tRNA have exacerbated mitochondrial biogenesis triggered by an increase in mitochondrial ROS production as a compensatory response. We propose that both the nature of the pathogenic mechanism combined with the existence of a compensatory mechanism can explain the penetrance pattern of this mutation. This particular behavior can allow a scenario for the evolution of mitochondrial tRNAs in which the fixation of two alleles that are individually deleterious can proceed in two steps and not require the simultaneous mutation of both. © 2011 Moreno-Loshuertos et al.

Islam L.,University of Milan | Franzini A.,Istituto Neurologico Carlo Besta | Messina G.,Istituto Neurologico Carlo Besta | Scarone S.,University of Milan | Gambini O.,University of Milan
World Neurosurgery | Year: 2015

BACKGROUND: Obsessive-compulsive disorder (OCD) is a psychiatric condition defined by the presence of obsessions, compulsions, or both. It has a lifetime prevalence of 2%e3% and causes significant impairment in social and work functioning, as well as a reduced quality of life. Treatment includes pharmacotherapy and psychotherapy, but a significant number of patients fail to respond to treatment. Deep brain stimulation has shown to be a safe and effective procedure for severe, chronic, treatment-resistant OCD, and several surgical targets have been proposed for treatment, including the nucleus accumbens, the anterior limb of the internal capsule, the subthalamic nucleus, the globus pallidus, and the bed nucleus of stria terminalis. -OBJECTIVES: To report the first Italian case series of patients who underwent DBS of 2 distinct targets for OCD: Nulceus accumbens and bed nulceus of stria terminalis. METHODS: Four patients underwent DBS of the nulceus accumbens, and 4 patients underwent DBS of the bed nucleus of stria terminalis. -RESULTS: Six patients showed a significant improvement in OCD symptoms. CONCLUSIONS: DBS of these 2 structures is a safe and effective procedure for the treatment of severe, refractory OCD.

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