25th Annual Computational Neuroscience Meeting: CNS-2016

Abstracts of the 25th Annual Computational Neuroscience Meeting: CNS-2016 Seogwipo City, Jeju-do, South Korea. 2–7 July 201

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

Stroke Assessment With Diffusional Kurtosis Imaging

BACKGROUND AND PURPOSE: Despite being the gold standard technique for stroke assessment, conventional diffusion magnetic resonance imaging (dMRI) provides only partial information about tissue microstructure. Diffusional kurtosis imaging (DKI) is an advanced dMRI method that yields, in addition to conventional diffusion information, the diffusional kurtosis (K), which may help improve characterization of tissue microstructure. In particular, this additional information permits the description of white matter (WM) in terms of WM-specific diffusion metrics (WMM). The goal of this study is to elucidate possible biophysical mechanisms underlying ischemia using these new WMM. METHODS: We performed a retrospective review of clinical and DKI data of forty-four acute/subacute ischemic stroke patients. Patients with a history of brain neoplasm or intracranial hemorrhages were excluded from this study. ROI analysis was performed to measure percent change of diffusion metrics in ischemic WM lesions compared to the contralateral hemisphere. RESULTS: K maps exhibit distinct ischemic lesion heterogeneity that is not apparent on apparent diffusion coefficient (ADC) maps. K metrics also have significantly higher absolute percent change than complementary conventional diffusion metrics. Our WMM reveal an increase in axonal density and a larger decrease in the intra-axonal (D(a)) compared to extra-axonal (D(e)) diffusion microenvironment of the ischemic WM lesion. CONCLUSIONS: The well-known decrease in the ADC of WM following ischemia is found to be mainly driven by a significant drop in D(a). Our results suggest that ischemia preferentially alters intra-axonal environment, consistent with a proposed mechanism of focal enlargement of axons known as axonal swelling or beading

Novel pharmacological targets for the treatment of Parkinson's disease

Dopamine deficiency, caused by the degeneration of nigrostriatal dopaminergic neurons, is the cause of the major clinical motor symptoms of Parkinson's disease. These symptoms can be treated successfully with a range of drugs that include levodopa, inhibitors of the enzymatic breakdown of levodopa and dopamine agonists delivered by oral, subcutaneous, transcutaneous, intravenous or intra-duodenal routes. However, Parkinson's disease involves degeneration of non-dopaminergic neurons and the treatment of the resulting predominantly non-motor features remains a challenge. This review describes the important recent advances that underlie the development of novel dopaminergic and non-dopaminergic drugs for Parkinson's disease, and also for the motor complications that arise from the use of existing therapies