Brain : a journal of neurology
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Multiple avenues of research including epidemiology, molecular genetics and cell biology have identified links between Parkinson's disease and type 2 diabetes mellitus. Several recent discoveries have highlighted common cellular pathways that potentially relate neurodegenerative processes with abnormal mitochondrial function and abnormal glucose metabolism. This includes converging evidence identifying that peroxisome proliferator activated receptor gamma coactivator 1-α, a key regulator of enzymes involved in mitochondrial respiration and insulin resistance, is potentially pivotal in the pathogenesis of neurodegeneration in Parkinson's disease. ⋯ In parallel with these advances, there are already randomized trials evaluating several established treatments for insulin resistance (pioglitazone and exenatide) as possible disease modifying drugs in Parkinson's disease, with only preliminary insights regarding their mechanisms of action in neurodegeneration, which may be effective in both disease processes through an action on mitochondrial function. Furthermore, parallels are also emerging between these same pathways and neurodegeneration associated with Alzheimer's disease and Huntington's disease. Our aim is to highlight this converging evidence and stimulate further hypothesis-testing studies specifically with reference to the potential development of novel neuroprotective agents in Parkinson's disease.
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Carriers of mutations in the glucocerebrosidase gene (GBA) are at increased risk of developing Parkinson's disease. The frequency of GBA mutations in unselected Parkinson's disease populations has not been established. Furthermore, no previous studies have investigated the influence of GBA mutations on the natural history of Parkinson's disease using prospective follow-up. ⋯ To our knowledge, this is the first time a genetic locus has been shown to influence motor progression in Parkinson's disease. If confirmed in further studies, this may indicate that GBA mutation status could be used as a prognostic marker in Parkinson's disease. Elucidation of the molecular mechanisms that underlie this effect will further our understanding of the pathogenesis of the disease and may in turn suggest novel therapeutic strategies.
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Polymicrogyria and lissencephaly are causally heterogeneous disorders of cortical brain development, with distinct neuropathological and neuroimaging patterns. They can be associated with additional structural cerebral anomalies, and recurrent phenotypic patterns have led to identification of recognizable syndromes. The lissencephalies are usually single-gene disorders affecting neuronal migration during cerebral cortical development. ⋯ One of the patients with a TUBB2B mutation had a lissencephalic phenotype, similar to that previously associated with a TUBA1A mutation. The remainder had a polymicrogyria-like cortical dysplasia, but the grey matter malformation was not typical of that seen in 'classical' polymicrogyria. We propose that the cortical malformations associated with these genes represent a recognizable tubulinopathy-associated spectrum that ranges from lissencephalic to polymicrogyric cortical dysplasias, suggesting shared pathogenic mechanisms in terms of microtubular function and interaction with microtubule-associated proteins.
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Incidence of intracerebral haemorrhage over the past three decades is reported as stable. This disappointing finding is questionable and suggests that any reduction in intracerebral haemorrhage incidence associated with improvements in primary prevention, namely, better control of blood pressure, might have been offset by an increase in cases of intracerebral haemorrhage owing to other factors, including the use of antithrombotic drugs in the ageing population. Therefore, we aimed to analyse trends in intracerebral haemorrhage incidence from 1985 to 2008 in the population-based registry of Dijon, France, taking into consideration the intracerebral haemorrhage location, the effect of age and the changes in the distribution of risk factors and premorbid treatments. ⋯ This result was attributed to a 2-fold increase in lobar intracerebral haemorrhage in the elderly, concomitantly with an observed rise in the premorbid use of antithrombotics at this age, whatever the intracerebral haemorrhage location considered. In conclusion, intracerebral haemorrhage profiles have changed in the past 20 years, suggesting that some bleeding-prone vasculopathies in the elderly are more likely to bleed when antithrombotic drugs are used, as illustrated by the rise in the incidence of lobar intracerebral haemorrhage in the elderly, in which cerebral amyloid angiopathy may be strongly implicated. Future research should focus on the impact and management of antithrombotics in patients with intracerebral haemorrhage, which may differ according to the underlying vessel disease.