Tau aggregation begins not in the cortex, but in the brainstem. Does tangle deposition in the locus coeruleus, which often starts in a person’s 30s, presage Alzheimer’s disease? In the September 22 Science Translational Medicine, researchers led by Heidi Jacobs at Massachusetts General Hospital, Boston, suggest as much. In 174 middle-aged and elderly participants, declining health of the LC, as measured by its fading brightness on MRI scans, correlated with cortical Alzheimer’s pathology, poor memory, and recent cognitive decline. Data from two autopsy cohorts strengthened the finding, with tangles in the LC similarly correlating with patchy memory and faltering cognition.
- A dim MRI signal from the locus coeruleus associates with cortical plaques and tangles.
- It also correlates with memory problems and cognitive decline.
- LC signal intensity may be an even earlier indicator of AD than amyloid PET.
Together, the data suggest that the MRI signal intensity in this tiny spot deep inside the brain reflects tangle accumulation, Jacobs noted, and that this is a pathologic process. “LC changes are not merely an age-related phenomenon, but potentially a biomarker of early AD,” she told Alzforum.
Qin Wang at the University of Alabama in Birmingham agreed. “The study clarifies the connection between age and LC integrity,” she wrote, adding, “This work is thus highly timely and stimulating.” Francesco Fornai at the University of Pisa, Italy, also called the work an advance. “The manuscript represents a seminal study elucidating the operative subcortical mechanisms at the threshold for susceptibility to neurodegeneration,” he wrote (full comments below).
Before Plaques? In vivo imaging and postmortem studies clarify the relationships among age (top bar), Alzheimer’s (middle bars), and changes in the locus coeruleus (lower bars). LC MRI signal intensity (top green bar) appears to drop before amyloid PET scans turn positive (gold), and around the time tangles pop up in entorhinal cortex (EC, light gray). The LC loses pigmentation and neurons (lower green) late in disease. [Courtesy of Jacobs et al., Science Translational Medicine/AAAS.]
The locus coeruleus, a blue dot in the brainstem, houses the neurons that make norepinephrine; it is highly connected to other brain regions. These neurons produce the dark pigment neuromelanin and accumulate toxins such as iron, copper, and aggregated tau. At autopsy about half of people who died in their 30s already have neurofibrillary tangles in the LC, well before this pathology develops in the entorhinal cortex or medial temporal lobe. Some postmortem studies correlated LC tangles with cortical tau pathology and cognitive decline, suggesting a connection to AD (Wilson et al., 2013; Ehrenberg et al., 2017; Sep 2019 news). There is no way to measure LC tangle burden in living volunteers to prove this relationship, because the structure is too small to show up on tau PET scans, where spatial resolution is low.
Bright Spot. The locus coeruleus is located deep in the brainstem (gold box, left) and shows up as two bright spots on MRI scans (arrows, right). [Courtesy of Jacobs et al., Science Translational Medicine/AAAS.]
However, the LC does light up on MRI as a bright dot. Jacobs and colleagues examined how this MRI signal varied with age and disease in cross-sectional data from the Harvard Aging Brain Study. Fourteen participants were cognitively healthy and middle-aged, with a median age of 51; 138 were cognitively healthy elderly with a median age of 75; and 22 were cognitively impaired and amyloid-positive, with a median age of 76. All participants underwent amyloid and tau PET as well.
Although some previous studies reported that the LC signal dims with age, Jacobs and colleagues found no age-related difference among cognitively healthy people without amyloid plaques in the brain (Shibata et al., 2006; Liu et al., 2019). On the other hand, in people who did have plaques, the LC signal was dimmer than in age-matched controls. Less LC intensity correlated with a higher amyloid load, as well as with tangles in the entorhinal cortex, medial and lateral temporal lobes, and prefrontal and parietal cortices. It also associated with worse scores on memory tests and the PACC5 cognitive composite (Jun 2014 news). In retrospective cognitive data, people with a weak LC signal were more likely to have declined over the 10 years prior to the scan.
Notably, the relationship between the LC signal and cognitive decline occurred only in the presence of amyloid plaques. This relationship became significant at an amyloid load of nine centiloids, far below the 18 centiloid threshold for a positive PiB PET scan. This finding suggests that a weak LC signal could be an early biomarker of AD.
What could the LC MRI signal represent? The field has been debating this. Some researchers suggest the scan picks up neuromelanin accumulation in these neurons (Priovoulos et al., 2020). Jacobs believes this is not the case. LC neurons lose neuromelanin late in AD, shortly before they die. In 1,524 postmortem brains from the Religious Orders Study and Memory and Aging Project and 2,145 postmortem brains from the National Alzheimer’s Coordinating Center, Jacobs found that pigment loss in the LC associated with advanced Braak stages, suggesting that, unlike the fading MRI signal, it is a late marker.
Instead, the MRI signal may capture a process related to tangle accumulation, Jacobs suggested. What that is remains unclear, but in 160 MAP brains analyzed for LC pathology, tangle density correlated with early memory problems and cognitive decline, just as a low MRI signal did.
Jacobs believes there may be some threshold where tangle accumulation in the LC becomes pathologic and spills over to connected brain regions such as the entorhinal cortex. In ongoing work, she will track LC intensity in younger participants to try to define a cutoff value that might flag early AD.
Other researchers said the findings fit with what is known about tangle spread. Michael Heneka at the German Center for Neurodegenerative Diseases in Bonn has found that LC degeneration boosts inflammation, which in turn can spark tangles (Heneka et al., 2000; Dec 2010 webinar; Nov 2019 news). “Given [this], the observed relationship of decreased LC density and higher tau pathology in the entorhinal cortex is well explained,” Heneka wrote to Alzforum (full comment below).
Tsuneya Ikezu at the Mayo Clinic in Jacksonville, Florida, recently showed that wolframin-1-expressing neurons in the entorhinal cortex may pass aggregated tau to the hippocampus. He said the new work fleshes out the picture (Sep 2021 news). “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,” he wrote (full comment below).
Could LC intensity on MRI scans be used as a biomarker? Some have doubts. “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,” Oskar Hansson at Lund University, Sweden, wrote to Alzforum (comment below). Jacobs noted that the method uses standard 3T scanners and takes roughly three minutes. “It should be easy to implement,” she told Alzforum.—Madolyn Bowman Rogers
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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.