• Alzheimer's Disease
• Locus Coeruleus
• Magnetic Resonance Imaging
• Mild Cognitive Impairment

The Locus Coeruleus (LC) is the main noradrenergic nucleus (NA) of the Central Nervous System (CNS). This tiny and tube-shaped nucleus is stretched below and along the floor of the fourth ventricle, in the pons, and it provides the NA innervation for the whole cortical mantle and for virtually all the subcortical structures – with the only exception of basal ganglia. LC is a key part of the Ascending Reticular Activating System (ARAS), promoting wake and being inhibited during sleep. It is also involved in the neuronal networks of attention and orientation as well as those of memory and learning. LC impairment has been associated with several cognitive and behavioral alterations, both in animal models and humans, across all their lifespan.
In Alzheimer's Disease (AD), the most common form of degenerative dementia, the degeneration of the LC is now a well-documented fact. Moreover, recent pathological and radiological data point to structural alteration of the LC as one of the earliest features of the AD course, and experimental studies support a possible pathogenetic role of subsequent NA denervation. In fact, the LC-NA system plays neuroprotective roles through numerous mechanisms, mainly promoting the expression of growth factors, preserving neurovascular unit homeostasis, and regulating glial cell activity. The failure of all these neurobiological pathways has been observed in AD and a possible causal link with LC dysfunction is suspected. In line with this, it could be hypothesized that a higher degree of degeneration of the LC may correspond to more severe AD pathology, and thus a more rapid clinical progression. In other words, individuals with cognitive impairment whose LC-NA system is more markedly disrupted should show a more rapid progression from the prodromal phase of AD (clinically identified as Mild Cognitive Impairment - MCI) to fully developed dementia.
To explore this hypothesis, in the study here reported, a cohort of MCI subjects was submitted to Magnetic Resonance Imaging (MRI), using a specific neuromelanin-sensitive sequence that allowed the in vivo evaluation of LC. They were then followed up for 2.5 years to monitor their clinical evolution. Data analysis showed that MCI subjects with lower LC-MRI signal values had a higher risk of progressing to dementia. Furthermore, MCI subjects who converted to dementia during follow-up showed significantly reduced LC-MRI signal values compared to those who did not convert. These results strongly support the hypothesis mentioned above: loss of LC integrity is associated with faster disease progression.
This study adds to the growing body of evidence supporting the rationale for LC research in AD, not only from a diagnostic/prognostic point of view. Indeed, its early involvement and possible pathogenetic role make the LC-NA system an intriguing target for disease-modifying therapies. Preventing LC degeneration or restoring NA signaling could be just two of the possible strategies to be pursued to halt or - at least - slow the otherwise unstoppable course of AD.