HAI Book 2025 - Flipbook - Page 594
Van Egroo, Maxime
138
Concomitant neurodegeneration of the lateral hypothalamus and
locus coeruleus is associated with early Alzheimer9s disease-related
pathophysiological and cognitive processes
Maxime Van Egroo1,2,3, Marion Baillet2,3, J. Alex Becker3,4, Julie C. Price2,3, Michael J.
Properzi3,5, Kathryn V. Papp3,6, Dorene M. Rentz3,6, Reisa A. Sperling2,3,5,6, Keith A. Johnson3,4,5,6,
Heidi I.L. Jacobs1,2,3
1
Faculty of Health, Medicine and Life Sciences, Mental Health and Neuroscience Research Institute, Alzheimer Center
Limburg, Maastricht University, Maastricht, NL
2
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital,
Boston, MA, US
3
Harvard Medical School, Boston, MA, US
4
Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA, US
5
Department of Neurology, Massachusetts General Hospital, Boston, MA, US
6
Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Boston,
MA, US
Background: The brainstem locus coeruleus (LC) and the lateral hypothalamus (LH) are densely interconnected
neuromodulatory subcortical regions that display selective vulnerability to the earliest accumulation of tau
pathology in Alzheimer9s disease (AD). Recent advances in neuroimaging methods now allow us to quantify the
structural integrity of these small brain regions in vivo. Here, we investigated the co-occurrence of
neurodegeneration in the LC and LH, and their combined effect on early AD-related pathophysiological and
cognitive processes in older individuals.
Methods. 175 participants from the Harvard Aging Brain Study underwent structural MRI including dedicated LC
imaging, Flortaucipir (FTP)-PET scan, and longitudinal cognitive evaluations (Figure 1). Bilateral volumes of
hypothalamic subunits, including the LH, were obtained using FastSurfer-HypVINN segmentation. LC integrity
was derived from 5 connected voxels with hyperintense signal, using the pons as a reference region. Thickness of
the entorhinal cortex was extracted with FreeSurfer. In addition, entorhinal FTP-PET values were computed and
corrected for partial-volume effects. Finally, we used longitudinal Preclinical Alzheimer9s Cognitive Composite 5
(PACC5) scores, anchored on the structural LC MRI visit, to assess cognitive decline.
Results. Multiple linear regression models adjusted for age, sex, education, and APOE genotype revealed that
lower LC MRI signal intensity was specifically linked to smaller LH volumes (p=0.03; Figure 2). In addition,
interaction models indicated that lower LC MRI signal intensity combined with smaller LH volume were associated
with lower entorhinal thickness (p=0.002) and elevated entorhinal FTP-PET values (p=0.04). Linear mixed-effects
models further showed that decline in PACC5 was steepest in individuals with both lower LC MRI signal intensity
and smaller LH volume (p=0.002; Figure 3).
Conclusion. These findings emphasize the importance of considering alterations among multiple subcortical
regions collectively to improve early detection of at-risk individuals. Future analyses will integrate additional
neuromodulatory subcortical systems such as the cholinergic basal forebrain.
HAI2025 - 594
