Stereotaxy is based on the precise image-guided spatial localization of targets within the human brain. Even with the recent advances in MRI technology, histological examination renders different (and complementary) information of the nervous tissue. Although several maps have been selected as a basis for correlating imaging results with the anatomical locations of sub-cortical structures, technical limitations interfere in a point-to-point correlation between imaging and anatomy due to the lack of precise correction for post-mortem tissue deformations caused by tissue fixation and processing. We present an alternative method to parcellate human brain cytoarchitectural regions, minimizing deformations caused by post-mortem and tissue-processing artifacts and enhancing segmentation by means of modified high thickness histological techniques and registration with MRI of the same specimen and into MNI space (ICBM152). A three-dimensional (3D) histological atlas of the human thalamus, basal ganglia, and basal forebrain cholinergic system is displayed. Structure's segmentations were performed in high-resolution dark-field and light-field microscopy. Bidimensional non-linear registration of the histological slices was followed by 3D registration with in situ MRI of the same subject. Manual and automated registration procedures were adopted and compared. To evaluate the quality of the registration procedures, Dice similarity coefficient and normalized weighted spectral distance were calculated and the results indicate good overlap between registered volumes and a small shape difference between them in both manual and automated registration methods. High thickness high-resolution histological slices in combination with registration to in situ MRI of the same subject provide an effective alternative method to study nuclear boundaries in the human brain, enhancing segmentation and demanding less resources and time for tissue processing than traditional methods.

Histopathological studies in Alzheimer's disease (AD) suggest severe and region-specific neurodegeneration of the basal forebrain cholinergic system (BFCS). Here, we studied the between-center reliability and diagnostic accuracy of MRI-based BFCS volumetry in a large multicenter data set, including participants with prodromal (n = 41) or clinically manifest AD (n = 134) and 148 cognitively healthy controls. Atrophy was determined using voxel-based and region-of-interest based analyses of high-dimensionally normalized MRI scans using a newly created map of the BFCS based on postmortem in cranio MRI and histology. The AD group showed significant volume reductions of all subregions of the BFCS, which were most pronounced in the posterior nucleus basalis Meynert (NbM). The mild cognitive impairment-AD group showed pronounced volume reductions in the posterior NbM, but preserved volumes of anterior-medial regions. Diagnostic accuracy of posterior NbM volume was superior to hippocampus volume in both groups, despite higher multicenter variability of the BFCS measurements. The data of our study suggest that BFCS morphometry may provide an emerging biomarker in AD.