In Vivo High-Resolution 7 Tesla MRI Shows Early and Diffuse Cortical Alterations in CADASIL Franc ¸ois De Guio 1,2 , Sonia Reyes 3 , Alexandre Vignaud 4 , Marco Duering 5 , Stefan Ropele 6 , Edouard Duchesnay 4 , Hugues Chabriat 1,2,3 , Eric Jouvent 1,2,3 * 1 Univ Paris Diderot, Sorbonne Paris Cite ´, UMR-S 1161 INSERM, Paris, France, 2 DHU NeuroVasc Sorbonne Paris Cite ´, Paris, France, 3 AP-HP, Lariboisie `re Hosp, Department of Neurology, Paris, France, 4 UNIRS, Neurospin, CEA, Gif-sur-Yvette, France, 5 Institute for Stroke and Dementia Research, Klinikum der Universita ¨t Mu ¨ nchen, Ludwig- Maximilians-University, Munich, Germany, 6 Department of Neurology, Medical University of Graz, Graz, Austria Abstract Background and Purpose: Recent data suggest that early symptoms may be related to cortex alterations in CADASIL (Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), a monogenic model of cerebral small vessel disease (SVD). The aim of this study was to investigate cortical alterations using both high-resolution T2* acquisitions obtained with 7 Tesla MRI and structural T1 images with 3 Tesla MRI in CADASIL patients with no or only mild symptomatology (modified Rankin’s scale #1 and Mini Mental State Examination (MMSE) $24). Methods: Complete reconstructions of the cortex using 7 Tesla T2* acquisitions with 0.7 mm isotropic resolution were obtained in 11 patients (52.1613.2 years, 36% male) and 24 controls (54.8611.0 years, 42% male). Seven Tesla T2* within the cortex and cortical thickness and morphology obtained from 3 Tesla images were compared between CADASIL and control subjects using general linear models. Results: MMSE, brain volume, cortical thickness and global sulcal morphology did not differ between groups. By contrast, T2* measured by 7 Tesla MRI was significantly increased in frontal, parietal, occipital and cingulate cortices in patients after correction for multiple testing. These changes were not related to white matter lesions, lacunes or microhemorrhages in patients having no brain atrophy compared to controls. Conclusions: Seven Tesla MRI, by contrast to state of the art post-processing of 3 Tesla acquisitions, shows diffuse T2* alterations within the cortical mantle in CADASIL whose origin remains to be determined. Citation: De Guio F, Reyes S, Vignaud A, Duering M, Ropele S, et al. (2014) In Vivo High-Resolution 7 Tesla MRI Shows Early and Diffuse Cortical Alterations in CADASIL. PLoS ONE 9(8): e106311. doi:10.1371/journal.pone.0106311 Editor: Stephen D. Ginsberg, Nathan Kline Institute and New York University School of Medicine, United States of America Received March 19, 2014; Accepted July 24, 2014; Published August 28, 2014 Copyright: ß 2014 De Guio et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that, for approved reasons, some access restrictions apply to the data underlying the findings. Our IT politic prohibits permanent data deposition due to size reasons (more than 50 Go). Data requests may be addressed to a researcher from the UMR-S 1161 team (Franc ¸ois De Guio, Hugues Chabriat, Eric Jouvent). Funding: This work was founded by a FP6 European Research Area Net (ERA-NET) NEURON grant (01 EW1207), with the support of the French CADASIL association, the PLAGNIOL foundation and the NRJ foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: eric.jouvent@lrb.aphp.fr Introduction Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary cerebral small vessel disease (SVD) caused by mutations of the NOTCH3 gene [1]. It is now widely recognized as a unique model for the study of more prevalent forms of SVD related to aging and hypertension [2]. The pathophysiology of SVD is thought to be mainly of subcortical origin, hence the term ‘‘subcortical ischemic vascular dementia’’ [3], but during the last decade the cerebral cortex was shown to be a key player in both sporadic forms of SVD and in CADASIL [4–8]. In a recent longitudinal study in CADASIL, processing speed slowing, but not global cognitive worsening nor increased disability was related to alteration of sulcal morphology, suggesting that early cognitive changes may be more specifically related to sulcal morphology than to other MRI markers [9]. The observed modifications of sulcal morphology could however be linked to underlying white matter structure changes [10] or to actual cortex involvement. The latter hypothesis could involve focal intra- cortical small-sized lesions [4], cortical demyelination [11] or increased iron content due to secondary degeneration, as reported previously in deep nuclei in CADASIL [12], all of which may translate in alterations of T2* measured using 7 Tesla MRI within the cortical mantle [13]. The aim of the present study was to investigate the cortex morphology using state of the art post-processing of 3 Tesla 3D T1 acquisitions together with its structure using high-resolution T2* 7 Tesla acquisitions in CADASIL patients at the early stage of the disease, with no or only mild symptomatology (modified Rankin’s scale #1 and MMSE $24), by comparison to age and sex matched controls. PLOS ONE | www.plosone.org 1 August 2014 | Volume 9 | Issue 8 | e106311