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Carelli V.,IRCCS Institute of Neurological science of Bologna | Carelli V.,University of Bologna | Chan D.C.,California Institute of Technology
Neuron | Year: 2014

Because of their high-energy metabolism, neurons are strictly dependent on mitochondria, which generate cellular ATP through oxidative phosphorylation. The mitochondrial genome encodes for critical components of the oxidative phosphorylation pathway machinery, and therefore, mutations in mitochondrial DNA (mtDNA) cause energy production defects that frequently have severe neurological manifestations. Here, we review the principles of mitochondrial genetics and focus on prototypical mitochondrial diseases to illustrate how primary defects in mtDNA or secondary defects in mtDNA due to nuclear genome mutations can cause prominent neurological and multisystem features. In addition, we discuss the pathophysiological mechanisms underlying mitochondrial diseases, the cellular mechanisms that protect mitochondrial integrity, and the prospects for therapy. The nervous system relies on mitochondrial metabolism to drive energy-consuming processes. Carelli and Chan illustrate how defects in mitochondrial DNA lead to neurological dysfunction and discuss how research in mitochondrial biology can unravel pathogenic mechanisms and translate into therapy. © 2014 Elsevier Inc. Source

Burte F.,Northumbria University | Carelli V.,IRCCS Institute of Neurological science of Bologna | Chinnery P.F.,Northumbria University | Yu-Wai-Man P.,Northumbria University
Nature Reviews Neurology | Year: 2015

Mitochondria form a highly interconnected tubular network throughout the cell via a dynamic process, with mitochondrial segments fusing and breaking apart continuously. Strong evidence has emerged to implicate disturbed mitochondrial fusion and fission as central pathological components underpinning a number of childhood and adult-onset neurodegenerative disorders. Several proteins that regulate the morphology of the mitochondrial network have been identified, the most widely studied of which are optic atrophy 1 and mitofusin 2. Pathogenic mutations that disrupt these two pro-fusion proteins cause autosomal dominant optic atrophy and axonal Charcot-Marie-Tooth disease type 2A, respectively. These disorders predominantly affect specialized neurons that require precise shuttling of mitochondria over long axonal distances. Considerable insight has also been gained by carefully dissecting the deleterious consequences of imbalances in mitochondrial fusion and fission on respiratory chain function, mitochondrial quality control (mitophagy), and programmed cell death. Interestingly, these cellular processes are also implicated in more-common complex neurodegenerative disorders, such as Alzheimer disease and Parkinson disease, indicating a common pathological thread and a close relationship with mitochondrial structure, function and localization. Understanding how these fundamental processes become disrupted will prove crucial to the development of therapies for the growing number of neurodegenerative disorders linked to disturbed mitochondrial dynamics. © 2015 Macmillan Publishers Limited. All rights reserved. Source

Makovac E.,Neuroimaging Laboratory | Garfinkel S.N.,University of Sussex | Bassi A.,IRCCS Santa Lucia Foundation | Basile B.,Neuroimaging Laboratory | And 12 more authors.
Neuropsychopharmacology | Year: 2015

Autonomic nervous system activity is an important component of human emotion. Mental processes influence bodily physiology, which in turn feeds back to influence thoughts and feelings. Afferent cardiovascular signals from arterial baroreceptors in the carotid sinuses are processed within the brain and contribute to this two-way communication with the body. These carotid baroreceptors can be stimulated non-invasively by externally applying focal negative pressure bilaterally to the neck. In an experiment combining functional neuroimaging (fMRI) with carotid stimulation in healthy participants, we tested the hypothesis that manipulating afferent cardiovascular signals alters the central processing of emotional information (fearful and neutral facial expressions). Carotid stimulation, compared with sham stimulation, broadly attenuated activity across cortical and brainstem regions. Modulation of emotional processing was apparent as a significant expression-by-stimulation interaction within left amygdala, where responses during appraisal of fearful faces were selectively reduced by carotid stimulation. Moreover, activity reductions within insula, amygdala, and hippocampus correlated with the degree of stimulation-evoked change in the explicit emotional ratings of fearful faces. Across participants, individual differences in autonomic state (heart rate variability, a proxy measure of autonomic balance toward parasympathetic activity) predicted the extent to which carotid stimulation influenced neural (amygdala) responses during appraisal and subjective rating of fearful faces. Together our results provide mechanistic insight into the visceral component of emotion by identifying the neural substrates mediating cardiovascular influences on the processing of fear signals, potentially implicating central baroreflex mechanisms for anxiolytic treatment targets. © 2015 American College of Neuropsychopharmacology. Source

Beghi E.,Mario Negri Institute for Pharmacological Research | Giussani G.,Mario Negri Institute for Pharmacological Research | Grosso S.,University of Siena | Iudice A.,University of Pisa | And 7 more authors.
Epilepsia | Year: 2013

The Italian League Against Epilepsy has issued evidence-based guidelines to help practicing physicians in their decision to stop or withhold antiepileptic drugs (AEDs) in patients achieving a prolonged period of seizure freedom. Six adult and two child neurologists, divided into four pairs, critically appraised 128 published reports and provided graded recommendations answering 15 key questions: length of the seizure-free period after treatment initiation, difference in seizure-free periods in children and adults, electroencephalography (EEG) pattern at the time of discontinuation, etiology of epilepsy, seizure type(s), patient's age and sex, family history of epilepsy, history of febrile seizures, epilepsy syndrome, seizure frequency before entering remission, duration of active epilepsy, tapering period, number and type of AEDs taken at time of discontinuation, combination of risk factors for recurrence, and length of patient monitoring after treatment discontinuation. Based on the available data, the following recommendations can be outlined: (1) antiepileptic treatment might be discontinued after a minimum period of 2 years of seizure freedom; shorter seizure-free periods are associated to a higher risk of relapse; (2) in children, AED discontinuation could be considered after less than two seizurefree years because of a marginally higher risk of relapse for early withdrawal; (3) factors, such as abnormal EEG (including epileptiform abnormalities) at the time of treatment discontinuation, a documented etiology of seizures (including mental retardation, perinatal insults, and abnormal neurologic examination), partial seizures, or an older age at disease onset, enhance the risk of relapse; however, patients should not be encouraged to withhold treatment unless a combination of two or more of these factors is present; (4) female sex, family history of epilepsy, history of febrile seizures, disease length/severity, and number and type of drugs taken should not influence the decision to stop treatment; (5) epilepsy syndrome should be always included in the decision process; (6) slow (at least 6 months) AED discontinuation should be encouraged; in any case the duration of the tapering period should be tailored to the patient's needs and preference; and (7) patient discontinuing treatment should be followed for no <2 years. As a general habit, the decision to stop treatment should be discussed and shared with each patient, taking into account social and personal complications of a seizure relapse and the medical complications of chronic AED treatment. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy. Source

Michelucci R.,IRCCS Institute of Neurological science of Bologna | Pasini E.,IRCCS Institute of Neurological science of Bologna | Meletti S.,University of Modena and Reggio Emilia | Fallica E.,University of Ferrara | And 8 more authors.
Epilepsia | Year: 2013

Purpose: To present new information on the semiology and short-term evolution of seizures associated with primary brain tumors (PBTs) in a prospective study. Methods: This study is a section of the PERNO study - Project of Emilia Romagna Region on Neuro-Oncology, the main aim of which is to collect prospectively all cases of PBTs occurring in the Emilia-Romagna region, northeast Italy (3,983, 346 population) from January 2009 to December 2011, to allow epidemiologic, clinical, and biomolecular studies.The epilepsy section of the PERNO study included all the patients who experienced seizures, either as first symptom of the tumor or appearing during the course of the disease. Each patient was interviewed by the referring neurologist with a specific interest in epilepsy. The patients who entered the study were followed up with visits on a quarterly basis. Key Findings: We collected 100 cases with full clinical, neuroradiologic, and pathologic data. The majority (79%) had high grade PBTs (glioblastoma in 50 cases), whereas the remaining patients had low-grade gliomas, mostly localized in the frontal (60%), temporal (38%), and parietal (28%) lobes. Seizures were the first symptom of the tumor in 72 cases. Overall, the initial seizures were tonic-clonic (48%) (without clear initial focal signs in more than half of the patients), focal motor (26%), complex partial (10%), and somatosensitive (8%). The majority of cases (60%) had isolated seizures or a low seizure frequency at the onset of the disease, whereas a high seizure frequency or status epilepticus was observed in 18% and 12% of cases, respectively. Ninety-two patients underwent surgical removal of the tumor, which was either radical (38%) or partial (53%). Seven patients underwent only cerebral biopsy. In the 72 patients in whom seizures were the first symptom, the mean time to the surgical treatment was 174 days, with a significant difference between high grade (95 days) and low grade (481 days) gliomas. At the time of our first observation, the majority of patients (69%) had already undergone surgical removal, with a mean follow-up of 3 months after the procedure. Overall, 39 patients (56%) were seizure free after tumor removal. The good outcome did not depend on presurgical seizure frequency or tumor type, although there was a trend for better results with low-grade PBTs. Significance: These data provide evidence that seizures are strictly linked to the tumoral lesion: They are the initial symptom of the tumor, reflect the tumor location and type, are usually resistant to antiepileptic treatment, and may disappear after the treatment of the lesion.Wiley Periodicals, Inc. © 2013 International League Against Epilepsy. Source

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