Diagnosing and monitoring prodromal Alzheimer’s Disease using novel locus ceruleus-based imaging volumetry
Lea Grinberg, Professor
UC San Francisco
Applications for Fall 2024 are closed for this project.
Despite intensive research on AD, effective disease-modifying treatments remain elusive, and novel tools for non-invasively assessing early brains lesions are needed. Our lab confirmed that the brain structures that consistently exhibit the earliest neuropathologic changes in AD, including neuronal loss, are not classically AD-associated cortical regions, but rather are centered in key aminergic brainstem nuclei, including the locus coeruleus (LC) and dorsal raphe. Furthermore, with postmortem tissue, we found that in AD, but not in normally-aging controls, LC showed progressive, AD (Braak) stage-related quantifiable volumetric losses. Namely, LC volume shrinks by an average of 25% before onset of significant neuronal loss at Braak stage 3, which usually coincides with AD-defining clinical symptoms. These findings suggest that longitudinal MRI-based LC volumetry might provide a useful noninvasive tool for screening and monitoring AD progression for clinical studies and therapy trials in patients developing AD.
The overall goal of this project is to develop a histologically validated magnetic resonance imaging (MRI)-based algorithm for assessing longitudinal LC volumetric changes that capture AD-associated neuropathological progression in single subjects, and this goal has widespread potential for application to clinical studies and research into AD.
We will generate templates by a step-wise strategy, using (1) 3D reconstructions of LC from whole postmortem brain tissues, (2) correspondence from 3D LC reconstructions to postmortem in cranio (pre-procurement) 7T MRIs, (3) landmark-based and intensity-based registration techniques that are superior to voxel-based morphometry (VBM) to detect the LC, (4) voxel-wise correspondence between postmortem in cranio 7T and 3T MRIs, and (5) mapping from postmortem to antemortem 3T MRI. Our optimized histological processing and automated reconstruction algorithms accelerate processing to permit scaling up discovery to many subjects in combination.
We hypothesize that MRI-based LC volumetric changes correlate directly with AD stage-related LC histological atrophy and that quantitative LC volumetry will yield a tool to monitor early AD pathology from asymptomatic stages. When effective therapies emerge, early diagnosis will offer the potential to rescue neuronal function and interdict AD progression. MRI-based LC volumetry could be developed for longitudinal screening to help select high-risk candidates for less accessible, more expensive, and invasive studies (e.g. PET scan; CSF assays).
The Specific aims are:
1. Histology-centric: Create histology-based MRI template from postmortem 7T MRI and high-resolution histology in 20 subjects ranging Braak 0-6 in AD progression.
2. MRI-centric: Translate the 7T MRI template into a 3T MRI template using subjects with ante-mortem 3T MR scan, postmortem 3T and 7T MR scans, and postmortem assessment and 3D reconstruction.
3. Precision-centric: Assess extent to which A) longitudinal changes in LC volume detected on serial 3T structural MRIs are associated with changes in hippocampal volume, NbM, cognitive parameters and Aβ PET
Role: The student will assist in this project by working with digitizing histological images, tracing the regions of interest, learning how to do computer-assisted 3D histological reconstructions of the human brain and co-registering histological images to neuroimaging.
Qualifications: Qualifications: - 10+hours/week -in person availability -comfortable with python -detailed-oriented and organized - good team player - quick learner - dependable - knowledge of neuroanatomy, photoshop and passion for neurodegenerative disease research are pluses
Day-to-day supervisor for this project: Tia Lamore
Hours: 9-11 hrs
Off-Campus Research Site: UCSF MISSION BAY CAMPUS 675 Nelson Rising Lane, 94158 San Francisco
Related website: grinberglab.ucsf.edu
Biological & Health Sciences