Locus coeruleus integrity is related to tau burden and memory loss in autosomal-dominant Alzheimer’s disease

Abstract

Abnormally phosphorylated tau, an indicator of Alzheimer’s disease, begins to accumulate in the first decades of life in the locus coeruleus (LC), the primary source of cortical norepinephrine. Ensuing dysfunction in noradrenergic neuromodulation is hypothesized to contribute to Alzheimer’s progression. However, research into the role of the LC has been impeded by a lack of effective ways of assessing it in vivo. Advances in high-resolution brainstem magnetic resonance imaging (MRI) hold potential to investigate the association of locus coeruleus integrity and Alzheimer’s-related neuropathological markers in vivo.Leveraging a meta-analytical approach, we first synthesized LC localizations and dimensions across previously published studies to improve the reliability and validity of MR-based locus coeruleus detection. Next, we applied this refined volume of interest to determine whether MR-indexed LC integrity can serve as a marker for noradrenergic degeneration in early-onset Alzheimer’s disease. Eighteen participants (34.7±10.1 years; 9♀) with or known to be at-risk for mutations in genes associated with autosomal-dominant Alzheimer’s disease (ADAD) were investigated. Genotyping confirmed mutations in seven participants (PSEN1, n = 6; APP, n = 1), of which four were symptomatic. Participants underwent 3T-MRI, flortaucipir positron emission tomography (PET), and cognitive testing. LC MRI intensity, a non-invasive proxy for neuronal density, was semi-automatically extracted from high-resolution brainstem scans across the rostrocaudal extent of the nucleus.Relative to healthy controls, symptomatic participants showed lower LC intensity. This effect was pronounced in rostral segments of the nucleus that project to the mediotemporal lobe and other memory-relevant areas. Among carriers of ADAD-causing mutations, closer proximity to the mutation-specific median age of dementia diagnosis was associated with lower LC intensity. Leveraging a multivariate statistical approach, we revealed a pattern of LC-related tau pathology in occipito-temporo-parietal brain regions. Finally, higher locus intensity was closely linked to memory performance across a variety of neuropsychological tests.Our finding of diminished MR-indexed LC integrity in autosomal-dominant Alzheimer’s disease suggest a role of the noradrenergic system in this neurodegenerative disease.

Examining the Role of the Noradrenergic Locus Coeruleus for 2 Predicting Attention and Brain Maintenance in Healthy Old Age 3 and Disease: An MRI Structural Study for the Alzheimer’s Disease 4 Neuroimaging Initiative

“…The new "omni-comprehensive" LC mask included the six LC MNI atlases previously published: 1) Keren [84] without encroaching the Median Raphe (MR) and the Dorsal Raphe (DR) defined by Beliveau et al (2015) [85] and the cerebellar white matter. Additionally, the new created LC "omni-comprehensive" mask included the LC meta-mask developed by Dahl et al (2021) [57], but with a larger and symmetrical rostro-caudal extent as to avoid induced lateralization biases in the analyses. Indeed, as pointed out by Betts et al [83], the LC asymmetries reported in certain MRI studies could be caused by MRI biases of how radiofrequencies are transmitted and received in the scanner.…”

Examining the Role of the Noradrenergic Locus Coeruleus for 2 Predicting Attention and Brain Maintenance in Healthy Old Age 3 and Disease: An MRI Structural Study for the Alzheimer’s Disease 4 Neuroimaging Initiative

“…The new "omni-comprehensive" LC mask included the six LC MNI atlases previously published: 1) Keren [85] and the cerebellar white matter. Additionally, the new created LC "omni-comprehensive" mask included the LC meta-mask developed by Dahl et al (2021) [57], but with a larger and symmetrical rostro-caudal extent as to avoid induced lateralization biases in the analyses. Indeed, as pointed out by Betts et al [83], the LC asymmetries reported in certain MRI studies could be caused by MRI biases of how radiofrequencies are transmitted and received in the scanner.…”

“…To this end, we adopted a neuroimaging voxel-based morphometry (VBM) approach utilizing 3T T1-weighted structural MRI scans from 686 subjects [n=395 (HC), n=156 (MCI), and 135 (AD)] provided by Alzheimer's Disease Neuroimaging Initiative -ADNI (ADNI2 and ADNI3 phases) [49,50]. Structural volumetric analyses on 3T T1-weighted MRIs with this methodology have been already carried out by several studies showing accurate reliability investigating the integrity of the Brainstem [51,52,53,54], the LC also in the ADNI [55,56,57,58] and the other neuromodulators' seeds such as the Raphe Nuclei [59,60,61,62], the Ventral Tegmental Area (VTA) [63,64,65,66] and the Nucleus Basalis of Meynert (NBM) [67,68,69,70,71,72,73,74]. The main objectives of this study were threefold.…”

“…On the right portion of the figure are shown 3D reconstructions (displayed in the MNI152 space) of the results in comparison with previously published LC atlases and masks. a) average LC result; b) average LC result is shown in the LC "omni-comprehensive" mask; c) Keren et al (2009) [81, 179]; d) Tona et al (2017) [82]; e) Betts et al (2017) [83]; f) Dahl et al (2019) [32]; g) Liu et al (2019) [183]; h) Rong Ye et al (2020) [84]; i) LC meta-mask by Dahl et al (2021)[57]. The last column on the right shows the regions of the LC mask negatively related with TMT-A performances for the three groups considered separately (p<0.01): HC n=395 (no results), MCI n=156 and AD n=135.…”

Examining the Role of the Noradrenergic Locus Coeruleus for Predicting Attention and Brain Maintenance in Healthy Old Age, Mild Cognitive Impairment and Alzheimer’s Disease: An MRI Structural Study On the Adni Cohort

“…To this end, we adopted a neuroimaging voxel-based morphometry (VBM) approach utilizing 3T T1-weighted structural MRI scans from 686 subjects [n=395 (HC), n=156 (MCI), and 135 (AD)] provided by Alzheimer Disease Neuroimaging Initiative -ADNI (ADNI2 and ADNI3 phases) [49,50]. Structural volumetric analyses on 3T T1-weighted MRIs with this methodology have been already carried out by several studies showing accurate reliability investigating the Brainstem [51,52,53,54], the LC also in the ADNI [55,56,57,58] and the other neuromodulators' seeds such as the Raphe Nuclei [59,60,61,62], the Ventral Tegmental Area [63,64,65,66] and the Nucleus Basalis of Meynert [67,68,69,70,71,72,73,74]. The main objectives of this study were threefold.…”