Abstract: Altered brain functionality in neurodegenerative diseases, including Par- kinson’s disease (PD) and Alzheimer’s disease (AD), involve com- plex pathological changes and molecular mechanisms which poses a major challenge for development of effective drug treatments. Progressive loss of specifc neuron types and projections are hall- marks of PD and AD and proper histological evaluation of relevant disease models therefore requires highly reliable cell detection and quantification methods. Immunohistochemistry is the prevail- ing method of choice to visualize and quantify histopathological changes in brain tissue sections. Although stereology applied to se- rially sampled sections is considered the gold standard for unbiased three-dimensional (3D) estimation of histomorphometric changes and therapeutic efects in neurodegeneration models, the elaborate sequence of histological processing steps can be time-intensive and limit analyses to a few preselected brain areas. Whereas physical tis- sue sections may provide higher structural resolution for any given 2D plane, the advantage of volume imaging is to facilitate 3D inves- tigation of brain structures and cell populations in the intact brain. In this respect, clinical whole-brain 3D imaging has continued to provide valuable insights in early detection, diagnosis and interpre- tation of PD and AD in humans, yet it has remained challenging to establish in preclinical research and drug discovery.