AbstractEstablishing spatial correspondence between subject and template images is necessary in neuroimaging research and clinical applications such as brain mapping and stereotactic neurosurgery. In the absence of other quantitative approaches, a point-based set of anatomical fiducials (AFIDs) was recently developed and validated to serve as a quantitative measure of image registration based on salient anatomical features. In this study, we sought to apply the AFIDs protocol to the clinic, specifically focussing on structural magnetic resonance images (MRI) obtained from patients with Parkinson’s Disease (PD). We first confirmed that AFIDs could be placed to millimetric accuracy in the PD dataset with results comparable to those in normal control subjects. With localization error established, we evaluated subject-to-template registration using this framework by aligning the clinical scans to standard template space using a robust open preprocessing workflow for MRI scans. We found that registration errors from this workflow as measured using AFIDs were higher than previously reported suggesting the need for optimization of image processing pipelines for clinical grade datasets. Finally, we examined the utility of using point-to-point distances between AFID points as a morphometric biomarker of PD, finding evidence of reduced distances between AFIDs around the left temporal horn, brainstem and pineal gland in the clinical group, structures that circumscribe regions known to be affected in PD including the substantia nigra. Overall, we provide evidence that AFIDs can be successfully applied in a clinical setting and utilized to provide localized and quantitative measures of registration error. AFIDs provide clinicians and researchers with a common, open framework for quality control and validation of spatial correspondence and the location of anatomical structures, facilitating accurate aggregation of imaging datasets and comparisons between various neurological conditions.