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Barcelona, Spain

Elder G.A.,Neurology Service | Elder G.A.,Mount Sinai School of Medicine | Stone J.R.,University of Virginia | Ahlers S.T.,Naval Medical Research Center
Frontiers in Neurology | Year: 2014

High-pressure blast waves can cause extensive CNS injury in human beings. However, in combat settings, such as Iraq and Afghanistan, lower level exposures associated with mild traumatic brain injury (mTBI) or subclinical exposure have been much more common. Yet controversy exists concerning what traits can be attributed to low-level blast, in large part due to the difficulty of distinguishing blast-related mTBI from post-traumatic stress disorder (PTSD). We describe how TBI is defined in human beings and the problems posed in using current definitions to recognize blast-related mTBI. We next consider the problem of applying definitions of human mTBI to animal models, in particular that TBI severity in human beings is defined in relation to alteration of consciousness at the time of injury, which typically cannot be assessed in animals. However, based on outcome assessments, a condition of "low-level" blast exposure can be defined in animals that likely approximates human mTBI or subclinical exposure. We review blast injury modeling in animals noting that inconsistencies in experimental approach have contributed to uncertainty over the effects of low-level blast. Yet, animal studies show that low-level blast pressure waves are transmitted to the brain. In brain, low-level blast exposures cause behavioral, biochemical, pathological, and physiological effects on the nervous system including the induction of PTSD-related behavioral traits in the absence of a psychological stressor. We review the relationship of blast exposure to chronic neurodegenerative diseases noting the paradoxical lowering of Abeta by blast, which along with other observations suggest that blast-related TBI is pathophysiologically distinct from non-blast TBI. Human neuroimaging studies show that blast-related mTBI is associated with a variety of chronic effects that are unlikely to be explained by co-morbid PTSD. We conclude that abundant evidence supports low-level blast as having long-term effects on the nervous system. © 2014 Elder, Stone and Ahlers.

Benavente L.,Hospital Universitario Central Asturias | Moris G.,Neurology Service
European Journal of Neurology | Year: 2011

Background and purpose: The study is aimed to report neurologic manifestations in a population of patients with inflammatory bowel disease in order to address its clinical characteristics.Methods: We conducted a retrospective study based on a computer-guided search, of patients with Crohn's disease or ulcerative colitis diagnosed at three hospitals in Spain spanning from 2000 through 2008. Patients were classified into different clinical groups based on the type of neurologic involvement. Only patients without iatrogenic complications, vitamin deficiencies, or known cerebrovascular risk factors were included.Results: We identified and reviewed the records of eighty-four inflammatory bowel disease patients with neurologic symptoms: thirteen patients with ulcerative colitis and twelve patients with Crohn's disease associated with neurologic complications were identified. Their ages ranged from 17 to 74 years. There was a slight predominance of women. Only four of them have another extra-intestinal manifestation. Most of the patients developed neurologic manifestations coincidental or after digestive symptoms appeared. Demyelinating disease was the most frequent manifestation observed (8 patients). Cerebrovascular, peripheral nerve, and epilepsy disorders were diagnosed in 6, 5, and 3 patients, respectively. One patient with myoclonus, one with amyotrophic lateral sclerosis, and one with sensorineural hearing loss were found.Conclusions: Although an incidence could not be obtained, this population of patients with inflammatory bowel disease have a low frequency of severe neurologic disorders. Neurologic diseases, such as cerebrovascular disease, demyelinating disease, and peripheral neuropathy, could be associated with Crohn's disease and ulcerative colitis. © 2010 The Author(s). European Journal of Neurology © 2010 EFNS.

Salat D.,Neurology Service | Noyce A.J.,University College London | Schrag A.,University College London | Tolosa E.,University of Barcelona
The Lancet Neurology | Year: 2016

Neurodegeneration in Parkinson's disease starts years before a clinical diagnosis can be reliably made. The prediagnostic phase of the disease offers a window of opportunity in which disease-modifying therapies-ie, those aimed at delaying or preventing the progression to overt disease and its many complications-could be most beneficial, but no such therapies are available at present. The unravelling of the mechanisms of neurodegeneration from the earliest stages, however, could lead to the development of new interventions whose therapeutic potential will need to be assessed in adequately designed clinical trials. Advances in the understanding of this prediagnostic phase of Parkinson's disease (for which the clinical diagnostic and prognostic markers used in more advanced disease stages are not applicable) will lead to the identification of biomarkers of neurodegeneration and its progression. These biomarkers will, in turn, help to identify the optimum population to be included and the most appropriate outcomes to be assessed in trials of disease-modifying drugs. Potential risks to minimally symptomatic participants, some of whom might not progress to manifest Parkinson's disease, and individuals who do not wish to know their mutation carrier status, could pose specific ethical dilemmas in the design of these trials. © 2016 Elsevier Ltd.

Handforth A.,Neurology Service
Cerebellum | Year: 2016

In this review, we hope to stimulate interest in animal models as opportunities to understand tremor mechanisms within the cerebellar system. We begin by considering the harmaline model of essential tremor (ET), which has ET-like anatomy and pharmacology. Harmaline induces the inferior olive (IO) to burst fire rhythmically, recruiting rhythmic activity in Purkinje cells (PCs) and deep cerebellar nuclei (DCN). This model has fostered the IO hypothesis of ET, which postulates that factors that promote excess IO, and hence PC complex spike synchrony, also promote tremor. In contrast, the PC hypothesis postulates that partial PC cell loss underlies tremor of ET. We describe models in which chronic partial PC loss is associated with tremor, such as the Weaver mouse, and others with PC loss that do not show tremor, such as the Purkinje cell degeneration mouse. We postulate that partial PC loss with tremor is associated with terminal axonal sprouting. We then discuss tremor that occurs with large lesions of the cerebellum in primates. This tremor has variable frequency and is an ataxic tremor not related to ET. Another tremor type that is not likely related to ET is tremor in mice with mutations that cause prolonged synaptic GABA action. This tremor is probably due to mistiming within cerebellar circuitry. In the final section, we catalog tremor models involving neurotransmitter and ion channel perturbations. Some appear to be related to the IO hypothesis of ET, while in others tremor may be ataxic or due to mistiming. In summary, we offer a tentative framework for classifying animal action tremor, such that various models may be considered potentially relevant to ET, subscribing to IO or PC hypotheses, or not likely relevant, as with mistiming or ataxic tremor. Considerable further research is needed to elucidate the mechanisms of tremor in animal models. © 2015, Springer Science+Business Media New York (outside the USA).

Wang M.M.,Neurology Service | Wang M.M.,University of Michigan
International Journal of Biochemistry and Cell Biology | Year: 2011

Originally discovered nearly a century ago, the Notch signaling pathway is critical for virtually all developmental programs and modulates an astounding variety of pathogenic processes. The DSL (Delta, Serrate, LAG-2 family) proteins have long been considered canonical activators of the core Notch pathway. More recently, a wide and expanding network of non-canonical extracellular factors has also been shown to modulate Notch signaling, conferring newly appreciated complexity to this evolutionarily conserved signal transduction system. Here, I review current concepts in Notch signaling, with a focus on work from the last decade elucidating novel extracellular proteins that up- or down-regulate signal potency. © 2011 Elsevier Ltd. All rights reserved.

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