J Neurol (2011) 258:795–803 Fig. 4 Hippocampus detection. Hippocampal contours (in red) were pre-detected using a semi- automatic technique prior to submission to the readers for conﬁrmation 799 contours were pre-detected using a semi-automatic tech- nique prior to submission to the readers for conﬁrmation (Fig. 4). For both brain parenchyma and hippocampal masks, 3DT1 data were displayed in a multiplanar reformatted mode so that the readers were able to use the sagittal (native), coronal and transverse orientations when cor- recting the pre-detected masks. The volume of the intracranial cavity was used to nor- malize the different volumetric measurements. The T2* sequence was used for this purpose as it clearly depicts external CSF. Given that the full brain coverage could not be achieved for all patients (24–28 slices of 5 mm were used), the 3DT1 sequence was automatically coregistered to T2* and used to manually complete for potentially missing upper and lower slices, and correct for T2*-related artifacts (Fig. 5). Microbleeds Cerebral microbleeds [17, 18] were deﬁned as punctuate, homogeneous, rounded, hypointense lesions smaller than 5 mm in size, visualised on T2* sequences. They were counted throughout the brain by the readers (Fig. 6). Hypointense lesions in the subarachnoid space were con- sidered likely to represent adjacent pial blood vessels and, therefore, were not included in the analysis. Symmetrical hypointensities in the globi pallidi (likely to represent calciﬁcations or iron deposition) and ﬂow voids from cortical vessels were also disregarded. Cerebral microbleeds were also categorized using the following classiﬁcation: cortical or cortico-subcortical and juxtacortical (\5 mm from cortex) on one hand, or deep and infratentorial (including brainstem, cerebellum, thala- mus, etc.) on the other hand. Brain microstructural tissue changes Diffusion tensor imaging (DTI) is a magnetic reso- nance imaging technique that measures the directionally dependent rate of water self-diffusion in each image voxel. Subcortical white matter ischemic injury causes reduc- tions in the oriented organization of white matter pathways 123