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Jacobs HI, Becker JA, Kwong K, Engels-Domínguez N, Prokopiou PC, Papp KV, Properzi M, Hampton OL, d'Oleire Uquillas F, Sanchez JS, Rentz DM, El Fakhri G, Normandin MD, Price JC, Bennett DA, Sperling RA, Johnson KA. In vivo and neuropathology data support locus coeruleus integrity as indicator of Alzheimer's disease pathology and cognitive decline. Sci Transl Med. 2021 Sep 22;13(612):eabj2511. PubMed.
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Medical College of Georgia at Augusta University
The locus coeruleus is the first place where hyperphosphorylated tau aggregates are detected in Alzheimer’s disease, and LC neurons degenerate early in disease progression. Studies in humans that clearly elucidate the interrelationship among LC integrity, tau, Aβ, and age factors are long-awaited. This work is thus highly timely and stimulating.
First, the study clarifies the connection between age and LC integrity, pointing to Aβ and tau pathology as the key modulator of this relationship. In other words, age alone does not sufficiently predict LC integrity; it can only do so in the context of Aβ and tau pathology.
Then the authors show that LC measures are closely associated with the initial AD pathology, following the previously reported topographic patterns. Considering the etiological role of norepinephrine in promoting tau hyperphosphorylation through α2 adrenergic receptor in the presence of Aβ (Zhang et al., 2020), abnormal norepinephrine release resulting from early alterations in LC integrity would affect tau pathology and may underlie the functional interaction between LC integrity and AD pathology.
Finally, the study reveals an association between LC integrity and AD-related memory decline and shows modification of this relationship by cortical tau and Aβ. This early detection of changes in LC integrity provides a promising biomarker for preclinical AD.
Effective therapeutic development targeting the LC-noradrenergic system nevertheless requires a better understanding of the functional outcomes of LC dysfunction in AD, which are more complicated than a simple loss of norepinephrine input to the cortex, especially at the early stage of the disease (Gannon and Wang, 2018). This seminal work with compelling human evidence sets a concrete foundation for pursuing such efforts.
References:
Zhang F, Gannon M, Chen Y, Yan S, Zhang S, Feng W, Tao J, Sha B, Liu Z, Saito T, Saido T, Keene CD, Jiao K, Roberson ED, Xu H, Wang Q. β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade. Sci Transl Med. 2020 Jan 15;12(526) PubMed.
Gannon M, Wang Q. Complex noradrenergic dysfunction in Alzheimer's disease: Low norepinephrine input is not always to blame. Brain Res. 2018 Jan 4; PubMed.
View all comments by Qin WangUniversity of Pisa and IRCCS Neuromed
This manuscript represents a seminal study elucidating the operative subcortical mechanisms at the threshold for susceptibility to neurodegeneration. The multidisciplinary approach strengthens the significance of the data.
This manuscript details the involvement of the brainstem norepinephrine-projecting nucleus Locus Coeruleus, which sends profuse innervation to the cortex, in maintaining the integrity of cognitive functions and neuronal matter. In particular, damage to the LC correlates with the onset of neurofibrillary tangles and amyloid deposits within the forebrain. It is remarkable that the cortical region that is most affected by the loss of LC neurons is the allocortical limbic area, which is known to depend strongly on noradrenergic innervation. Moreover, this cortical area is strongly involved in cognition.
It is difficult at present to know how these findings might translate into clinical practice to predict the risk of developing dementia. Nonetheless, as speculated by the authors, MRIs are now routinely performed in clinical practice and could be extended to quantify the intensity of the LC in the human pons. This might be a routine add-on that would provide substantial significance to these findings as a gateway to assess the risk of dementia at the preclinical stage.
Further studies are required to assess to what extent intragroup variability may bias such a prediction. The value and feasibility of a concomitant PET measurement of tau in the entorhinal cortex needs to be established. The imaging approach should be combined with pathological assessment and neuropsychological scoring. The neuropsychological scoring should possibly be concomitant or follow brain imaging. This is expected to provide more reliable information.
In any case, the manuscript represents a significant advancement in the field of dementia.
View all comments by Francesco FornaiKlinik und Poliklinik für Neurologie
This is a very interesting paper! Doug Feinstein at UIC Chicago and I have been studying effects of locus coeruleus degeneration on AD-related pathology in its projection areas, since the late 1990s, mostly in rodent models of AD.
Here, induced LC degeneration compromised Aβ clearance function (Heneka et al., 2010), but it also massively increased inflammatory signals in rodent models including the generation of interleukin 1β (Heneka et al., 2000, and others).
Given our more recent finding that activation of the NLRP3 inflammasome causes tau hyperphosphorylation and NFT formation in hippocampal neurons via the IL-1 receptor (Ising et al. 2019), the relationship observed here, of decreased LC density and higher tau pathology in the entorhinal cortex, is well explained!
It would have been super interesting to analyze microglial activation by PET in this context; I am sure such studies will follow.
References:
Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-Kurutz D, Walter J, Kirchhoff F, Hanisch UK, Kummer MP. Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):6058-63. PubMed.
Heneka MT, Klockgether T, Feinstein DL. Peroxisome proliferator-activated receptor-gamma ligands reduce neuronal inducible nitric oxide synthase expression and cell death in vivo. J Neurosci. 2000 Sep 15;20(18):6862-7. PubMed.
Ising C, Venegas C, Zhang S, Scheiblich H, Schmidt SV, Vieira-Saecker A, Schwartz S, Albasset S, McManus RM, Tejera D, Griep A, Santarelli F, Brosseron F, Opitz S, Stunden J, Merten M, Kayed R, Golenbock DT, Blum D, Latz E, Buée L, Heneka MT. NLRP3 inflammasome activation drives tau pathology. Nature. 2019 Nov;575(7784):669-673. Epub 2019 Nov 20 PubMed.
View all comments by Michael HenekaMayo Clinic Florida
It is very intriguing to see the strong association of locus coeruleus integrity with memory impairment via tau accumulation in the entorhinal cortex. This may enhance the diagnostic accuracy of AD in combination with tau and Aβ PET imaging.
The synaptic connection between the locus coeruleus and trans-entorhinal cortex is documented using human brain tissues and neuroimaging (Sun et al., 2020), but it has not been shown in mouse brain.
Wolframin-1-expressing neurons in the entorhinal cortex are mainly pyramidal cells and may receive tau from the locus coeruleus via trans-entorhinal cortical region, which may explain the age-dependent tau spread (Sep 2021 news).
References:
Sun W, Tang Y, Qiao Y, Ge X, Mather M, Ringman JM, Shi Y, for Alzheimer's Disease Neuroimaging Initiative. A probabilistic atlas of locus coeruleus pathways to transentorhinal cortex for connectome imaging in Alzheimer's disease. Neuroimage. 2020 Dec;223:117301. Epub 2020 Aug 28 PubMed.
View all comments by Tsuneya IkezuLund University
The paper is impressive, including two neuropathology cohorts and a cohort with advanced in vivo imaging. The results are congruent with the hypothesis that the LC starts to degenerate early in AD, and then continues to deteriorate with disease progression.
It will be very exciting to see future longitudinal studies comparing changes in LC imaging with changes in cortical thickness, tau-PET, and cognition over time.
However, I am uncertain if LC imaging can be used reliably in clinical trials or practice, because the method is technically quite challenging and might result in high test/retest variability due to, e.g., motion artifacts and variations in which voxels are labelled as being part of LC.
View all comments by Oskar HanssonUniversity of Pittsburgh
In this interesting paper, Jacobs and colleagues reported in 3,669 NACC/ROSMAP postmortem brains and 221 HABS participants studied with PET scans that locus coeruleus changes were associated with tau accumulation and cognitive decline in AD. Where previous postmortem studies have linked LC changes with AD, Jacobs' work provides compelling new evidence that LC integrity is associated with AD pathophysiology in living patients. More specifically, their work suggests that LC abnormality measured with a non-invasive MRI technique may be used as an indicator of forthcoming disease progression.
I look forward to seeing what else LC measures can accomplish by increasing their sensitivity when/if the group uses their 7T MRI scanner for quantification. The authors found an association between locus coeruleus and tau accumulation in Braak stages, and previous experimental studies suggest that locus coeruleus lesions potentiate AD mainly through inflammation pathways (Giorgi et al., 2019). Therefore, the authors' results also suggest that it would be interesting to test whether locus coeruleus integrity modulates the association between inflammation and tau propagation in Braak stages reported recently by our group (Pascoal et al., 2021).
In summary, I think this is a very important study that raises new questions and possibilities for future research.
References:
Giorgi FS, Saccaro LF, Galgani A, Busceti CL, Biagioni F, Frati A, Fornai F. The role of Locus Coeruleus in neuroinflammation occurring in Alzheimer's disease. Brain Res Bull. 2019 Nov;153:47-58. Epub 2019 Aug 13 PubMed.
Pascoal TA, Benedet AL, Ashton NJ, Kang MS, Therriault J, Chamoun M, Savard M, Lussier FZ, Tissot C, Karikari TK, Ottoy J, Mathotaarachchi S, Stevenson J, Massarweh G, Schöll M, de Leon MJ, Soucy JP, Edison P, Blennow K, Zetterberg H, Gauthier S, Rosa-Neto P. Microglial activation and tau propagate jointly across Braak stages. Nat Med. 2021 Sep;27(9):1592-1599. Epub 2021 Aug 26 PubMed. Correction.
View all comments by Tharick PascoalMake a Comment
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