The humble locus coeruleus, a minute speck of tissue nestled deep in the brain stem, has received relatively scant attention in studies of cognitive decline. Now, data published September 9 in Nature Human Behavior add to a recent spate of findings suggesting the structure is important for memory. Martin Dahl and Markus Werkle-Bergner at the Max Planck Institute for Human Development, Berlin, and colleagues correlate age-related neurodegeneration in the frontal part of the locus coeruleus (LC) with worse memory performance. People who maintain a healthy LC into old age do better on cognitive tests, the scientists show. The study makes use of a relatively new MRI technique that images the structure, allowing it to be tracked over time.
- MRI suggests the rostral locus coeruleus degenerates with age.
- This correlated with poorer memory.
- The region is among the first to accumulate phosphorylated tau.
“This paper provides real-time correlations between LC density and memory performance in living subjects,” wrote Scott Counts, Michigan State University, Grand Rapids, to Alzforum. Counts was not involved in the study. “This not only validates and advances the concepts [arising] from clinical pathologic studies, but raises the exciting possibility of a new imaging biomarker tool for cognitive impairment, Alzheimer’s disease, and Lewy body dementias.”
At just 15 mm long and 1–3 mm wide, the cylindrical locus coeruleus serves as the brain’s primary source of the neurotransmitter norepinephrine. Neurons from the front, i.e., rostral, LC project to the hippocampus, while its back, i.e., caudal, region projects to the cerebellum and spinal cord. By releasing norepinephrine, LC neurons modulate attention, learning, memory via long-term potentiation, and depression of synaptic activity, which are important for network plasticity.
The locus coeruleus takes a hit both structurally and functionally in people with Alzheimer’s, Parkinson’s, or dementia with Lewy bodies (Jacobs et al., 2019; Weinshenker 2018). In AD, the LC is one of the earliest regions to accumulate hyperphosphorylated tau (Braak et al., 2011). It’s unclear how toxic tau species affect LC neurons, but some studies suggest that damage to the LC and the resulting loss of norepinephrine speeds up AD pathology (see Dec 2010 Alzforum webinar). This may be related to decline in density of the rostral region with age (for a review, see Manaye et al., 1995). This decline appears to correlate with age-related cognitive impairment, according to postmortem human data (Wilson et al., 2013).
While the LC’s small size and location deep in the brain obscure it to traditional MRI, scientists try to use its natural pigmentation to see it on a scan (Sasaki et al., 2006). Neuromelanin, the dark byproduct of norepinephrine production, builds up in the LC over time, peaking at around age 50 to 60, after which it plateaus or declines. Turbo-spin echo (TSE) MRI takes advantage of neuromelanin’s paramagnetic properties to visualize the structure of the LC.
In the current study, Dahl and colleagues used TSE to correlate the integrity of the LC with memory performance in cognitively healthy participants from the Berlin Aging Study II (Gerstorf et al., 2016). The authors tested 66 people with an average age of 33, and 228 older people, average age 72. Each had a TSE scan and took the Rey Auditory Verbal Learning Test (RAVLT), which asks participants to memorize a list of 15 words and freely recall them in five successive trials.
As expected, the younger volunteers recalled more words than did the older ones, and those with a smaller rostral LC recalled even fewer (see image below). Other memory tasks showed a similar correlation. A denser rostral LC meant people could better recognize faces, remember the locations of pictures on a grid, and memorize pictures of indoor/outdoor scenes. “This indicates a stable link between LC integrity and general memory performance,” Dahl said.
Age Differences. Over five successive trials, the number of recalled words (y-axis) increases for most individuals (thin lines). In general, younger people (left) recall more words than older people (right). Among the latter, those with an LC signal below the median (thick black band) remember fewer words than those with a higher-than-average signal (red). [Courtesy of Dahl et al., 2019.]
The results are in line with recent data implicating neurodegeneration in the LC in age-related cognitive decline (Clewett et al., 2016; Hämmerer et al., 2018). “The study by Dahl et al. shows that it is the rostral part of the LC which is particularly predictive for cognitive decline,” wrote Dorothea Hämmerer, Emrah Düzel, and Matthew Betts of Otto-von-Guericke-University Magdeburg, Germany, to Alzforum.
All three were co-authors on a September 1 consensus statement from the first European Locus Coeruleus Imaging meeting, held in Magdeburg in 2018. The statement discusses how to noninvasively measure locus coeruleus integrity in vivo and use this information for clinical research in neurodegenerative diseases (Betts et al., 2019). Among the challenges is spatial post-processing of imaging data for such a small structure, they told Alzforum. “Together with the advent of other big data samples, including a variety of physiological and imaging data, we are inching our way forward in understanding this enigmatic nucleus in the brainstem,” they wrote.—Gwyneth Dickey Zakaib
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