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London, United Kingdom 2013 4 Small vessel stroke and white matter disease 15:00 - 15:10 Functional MRI with verbal memory task in patients with moderate to severe leukoaraio-sis and mild cognitive impairment: preliminary results and clinical implications A. Chiti1, G. Gialdini2, M. Gennaro3, E. Terni4, N. Giannini5, M. Cosottini6, I. Pesaresi7, P. Cecchi8, G. Tognoni9, G. Orlandi10, U. Bonuccelli11, D. Inzitari12 on behalf of the VMCI-Tuscany Study Group Neurological Clinic, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, ITALY1,Neurological Clinic, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, ITALY2, Neurological Clinic, Department of Clinical and Experimen-tal Medicine, University of Pisa, Pisa, ITALY3, Neurological Clinic, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, ITALY4, Neurological Clinic, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, ITALY5, Unit of Neuroradiol-ogy, Azienda Ospedaliero-Universitaria Pisana, Pisa, ITALY6, Unit of Neuroradiology, Azienda Ospedaliero-Universitaria Pisana, Pisa, ITALY7, Unit of Neuroradiology, Azienda Ospedalie-ro- Universitaria Pisana, Pisa, ITALY8, Neurological Clinic, Department of Clinical and Experi-mental Medicine, University of Pisa, Pisa, ITALY9, Neurological Clinic, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, ITALY10, Neurological Clinic, Department of Clinical and Experimental Medicine, Uni-versity of Pisa, Pisa, ITALY11, Department of Neurological and Psychiatric Sciences, Universi-ty of Florence, Florence, ITALY12 Background: Moderate to severe leukoaraiosis is a predictor of transition to dementia in pa-tients with mild cognitive impairment (MCI). In such patients, not only executive, but also memory functions can be impaired. Cortical activation during memory tasks has never been evaluated. Methods: 9 patients with moderate to severe leukoaraiosis (modified Fazekas Scale Score 2-3, respectively) and MCI (vascular MCI, V-MCI group; mean age 74 years, range 67- 79) underwent a specific fMRI protocol at high-field strenght (3 Tesla), in addition to conven-tional morphological imaging. fMRI experiments explored verbal memory and were designed according to previously described experiences (1). fMRI was also performed in 9 MCI patients without moderate to severe leukoaraiosis (non vascular MCI, NV-MCI group; mean age 74 years, range 70-84) and in 9 cognitively normal elderly (NE; mean age 71 years, range 65-75). Results: NE exhibited a prominent activation in left emisphere (inferior and middle frontal gy-rus, angular gyrus, inferior parietal gyrus) and bilateral cuneus. Compared to NE, MCI group showed a similar pattern, with the additional activation of right angular gyrus (Z > 2.3; p < 0.05. FIGURE 1). V-MCI group showed a greatly reduced involvement of areas activated in NE, with concomitant activation of large areas in right emisphere (angular gyrus, superior tem-poral gyrus and inferior parietal gyrus. Z > 2.3; p < 0.05. FIGURE 2). Conclusion: In compari-son to NE and even to NV-MCI, V-MCI patients may be associated with an extremely modified functional network underlying memory impairment and extensively involving the right emi-sphere, probably as an attempt of compensation. Further refinement of such patterns and accu-rate follow-up could help to determine which cases are at high risk of transition to dementia, prompting early therapy. References: 1. Daselaar SM, Rombouts SARB, Veltman DJ, Raaijmakers JGW, Lazeron RHC, Jonker C. NeuroImage 2001; 13: 1113–1120. Cerebrovasc Dis 2013; 35 (suppl 3)1-854 39 3 Small vessel stroke and white matter disease 14:50 - 15:00 Rare genetic variants in genes of NO metabolism in lacunar stroke patients. C.M.J. Loos1, J. Staals2, H.J.M. Smeets3, R.J. van Oostenbrugge4 Department of Neurology and Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center., Maastricht, THE NETHERLANDS1,Department of Neurology and Cardiovascular Research Institute Maastricht (CARIM), Maastricht Universi-ty Medical Center., Maastricht, THE NETHERLANDS2, Department of Clinical Genomics, and Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center., Maastricht, THE NETHERLANDS3, Department of Neurology and Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center., Maastricht, THE NETH-ERLANDS4 Background - In normal vascular physiology, nitric oxide (NO) plays a key role in regulating the function of vascular endothelium. Endothelial dysfunction is thought to play an important role in the pathogenesis of cerebral small vessel disease (cSVD). As evidence suggests that genetic factors contribute to the pathogenesis of cSVD, we tested for rare genetic variants in 4 major genes regulating NO metabolism in highly selected, well-phenotyped patients with cSVD. Methods - We selected 32 first-ever lacunar stroke patients < 70 years with a positive first-de-gree family history of stroke and with extensive white matter lesions on brain MRI. We directly sequenced exons and intronic flanking regions of NOS3, GCH1, DDAH2 and NOX4 genes and recorded all rare variants (minor allele frequency < 1 %) and predicted their possible pathogen-ic effect on splicing and/or protein function by using different software-based bioinformatical tools. Results - We detected 21 rare variants scattered over the NOS3, GCH1, DDAH2 and NOX4 genes. Four of these rare variants (2999 G/A in NOS 3 and 291 G/T, 909 C/G and 938 C/T in NOX4) were likely pathogenic and were found in 25% of our population. Furthermore, 2 of these rare, likely pathogenic variants (909 C/G and 938 C/T) and one rare intronic variant (847- 40T/C) in NOX 4 co-occurred and were each detected in the same 6 of our 32 (19 %) lacunar stroke patients. Conclusion - We identified rare variants in genes regulating vascular NO metabolism. Of these, two likely pathogenic variants in the NOX4 gene were found in a substantial portion of our pa-tients. Therefore it seems that dysfunction of the NOX 4 protein could play an important role in endothelial dysfunction in cSVD. Further research to explore the biological mechanism un-derlying these rare variants and to determine the exact role of NOX 4 in cSVD seems warrant-ed.


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