Investigating the Noradrenergic System in the living human brain with hybrid molecular/functional imaging – INSyst

Investigations of the noradrenergic system function in the brain have mainly been emerged from animal studies so far. Indeed, the lack of suitable imaging tools has hampered its understanding in human. Nevertheless, we now have the means to overcome this long-lasting difficulty as in vivo imaging of the noradrenergic system has recently become feasible with the development of a selective novel PET radiotracer: 11C-Yohimbine (Nahimi et al., 2015). This represents a tremendous and unique opportunity towards the collection of missing data in the living human brain by direct quantification of regional a2-adrenoceptors (a2-ARs) availability. Indeed, a2-ARs play a key role in regulating noradrenergic neurotransmission (Szabadi, 2013) and altered transmission of this neurotransmitter with specific loss of a2-ARs is currently theorized to play a critical role in both the symptoms and the progression of a family of neurodegenerative disorders that includes Parkinson’s disease (PD, Marien et al., 2004). In parallel, growing evidence suggest that aging has an important role in the occurrence of neurodegenerative disorders. So far, healthy aging has been associated with structural, functional and biochemical changes. Noradrenergic mechanisms have also been implicated (Docherty, 2002 for review). However, the in vivo evidence from human research of the role of noradrenaline (NA) is scant and exactly how normal or typical aging affects the locus coeruleus (LC) network, which provides the primary noradrenergic inputs to the cerebral cortex, is still very scarce. Yet, with the rapid growth of aging populations worldwide there is an urgent need to obtain integrated understanding of mechanisms and processes contributing to cognitive and sensorimotor aging. Determining the generality and specificity of this system in vivo in humans also represents an important clinical issue. Indeed, while PD is traditionally considered a hypodopaminergic syndrome, with symptoms resulting predominantly from loss of dopamine-producing neurons in the substantia nigra pars compacta, most of the current disability brought on by patients relates to symptoms that respond poorly to dopaminergic therapy, or even worsen with this therapy. Increasing evidence suggest an important role for extranigral non-dopaminergic mechanisms with particular emphasis on the critical role of the noradrenergic system. For instance, both anti-parkinsonian and neuroprotective properties of the noradrenergic system have been suggested. Yet, the relevance of noradrenaline deficiency was never translated into any major clinical outcome.

Accordingly, the goal of this research proposal is to provide, for the first time in humans, a wider understanding of the role of the LC-NA system both in health and illness through the use of the newly developed radiotracer visualizing a2-ARs combined with a cutting-edge technology, the hybrid PET/MRI scanner. These new non-invasive molecular imaging tools place me in a unique position to elucidate the role of the LC-NA system across the life span and its relevance to the progressive decline of sensory, cognitive, and motor functions observed with time. This will be also the first research to examine how NA modulates both the onset and progression of PD in vivo in humans. The new data obtained in the course of this 4 years’ program will be critical for (i) shedding further light on the hypothetical neuroprotective role of the noradrenergic system, (ii) finding biological screening tools allowing early diagnosis of PD, and (iii) developing novel therapeutic options.