State-of-the-art imaging of neuromodulatory subcortical systems in aging and Alzheimer's disease: Challenges and opportunities

Abstract

Primary prevention trials have shifted their focus to the earliest stages of Alzheimer's disease (AD). Autopsy data indicates that the neuromodulatory subcortical systems' (NSS) nuclei are specifically vulnerable to initial tau pathology, indicating that these nuclei hold great promise for early detection of AD in the context of the aging brain. The increasing availability of new imaging methods, ultra-high field scanners, new radioligands, and routine deep brain stimulation implants has led to a growing number of NSS neuroimaging studies on aging and neurodegeneration. Here, we review findings of current state-of-the-art imaging studies assessing the structure, function, and molecular changes of these nuclei during aging and AD. Furthermore, we identify the challenges associated with these imaging methods, important pathophysiologic gaps to fill for the AD NSS neuroimaging field, and provide future directions to improve our assessment, understanding, and clinical use of in vivo imaging of the NSS.

Keywords: (Functional) magnetic resonance imaging; Alzheimer’s Disease; Brain aging; Diffusion-weighted imaging; Electrophysiology; Neuroimaging; Neuromodulators; Positron emission tomography.

Figure 1.. Location of the NSS and their most important projections and interactions.

NSS modulate a wide range of cognitive functions and behaviors, as illustrated by their widespread projections to (sub)cortical structures. Blue: the noradrenergic LC, green: the serotonergic DRN, orange: the dopaminergic VTA, pink: the orexinergic LH, yellow: the cholinergic NbM. For simplification purposes, visualization has been limited to main projections and interactions between the NSS. Abbreviations: DRN, dorsal raphe nucleus; LC, locus coeruleus; LH, lateral hypothalamus; NbM, nucleus basalis of Meynert; NSS, neuromodulatory subcortical systems; VTA, ventral tegmental area.

Figure 2.. Imaging method comparison pertaining to NSS imaging.

Current neuroimaging tools differ greatly in spatial and temporal resolution, as well as in their invasiveness and the type of measurements taken. Legend: , invasive; , radioactive; , structural only; , indirect measure of neuronal activity; δ θ α β γ, EEG bands. Abbreviations: APs, action potentials; BOLD, blood oxygen dependent level; DBS, deep brain stimulation; DWI, diffusion-weighted imaging; EEG, electroencephalogram; fMRI, functional magnetic resonance imaging; MEG, magnetoencephalogram; MRI, magnetic resonance imaging; PET, positron emission tomography; sEEG, stereoencephalography.

Figure 3.. Multiplanar visualization of the spatial discrepancies among several published atlases of the LC and the VTA.

Differences in the data acquisition approach (e.g., in vivo vs. post-mortem, 3T vs. 7T), in the characteristics of the investigated population (e.g., lifespan vs. specific age range; healthy controls vs. patients), and/or in the image processing methods (e.g., registration/normalization pipeline) may lead to significant discrepancies in the location and spatial coverage of a generated atlas for a given NSS. Top: LC atlases retrieved from Keren et al. (2009) (green), Betts et al. (2017) (orange), Liu et al. (2019) (blue), and Ye et al. (2021) (yellow). Bottom: VTA atlases retrieved from Pauli et al. (2018) (green), Trutti et al. (2021) (orange), and Edlow et al. (2012) (blue). All atlases are superimposed on the MNI152 template in MRIcroGL software (https://www.nitrc.org/projects/mricrogl). Abbreviations: LC, locus coeruleus; VTA, ventral tegmental area.