Changes of central noradrenaline transporter availability in immunotherapy-naïve multiple sclerosis patients

Abstract

The neurotransmitter noradrenaline (NA) mediates arousal, attention and mood, and exerts antiinflammatory and neuroprotective effects. Alterations of monoamine signalling were reported in multiple sclerosis (MS) and psychiatric illness and may account for the high prevalence of comorbid depression and fatigue in MS patients. We assessed central noradrenaline transporter (NAT) availability using positron emission tomography (PET) and the NAT selective radiotracer S,S-[ 11 c] O-methylreboxetine in immunotherapy-naïve patients with relapsing-remitting MS (RRMS; n = 11) compared to healthy controls (HC; n = 12), and its association to lesion load, time since manifestation, the expanded disability status scale (EDSS), the fatigue scale Würzburger Erschöpfungsinventar bei MS (WEIMuS) and Beck Depression Inventory (BDI). We found NAT availability to be increased in the thalamus, amygdala, putamen and pons/midbrain of MS patients. No relation to clinical or psychometric variables was found. These first data indicate higher NAT availability in subcortical brain regions of immunotherapy-naïve RRMS patients. If these changes of noradrenergic neurotransmission predispose to psychiatric symptoms or associate with disease activity needs to be investigated in longitudinal studies or a larger sample which allows subgroup analyses. Abbreviations [ 11 C]MRB S,S-[ 11 C]O-methylreboxetine BDI Beck depression inventory BMI Body mass index BP ND Binding potential DMT Disease modifying therapy DRKS German clinical trials register DVR Distribution volume ratio EAE Experimental autoimmune encephalitis EDSS Expanded disability status scale FWHM Full-width at half maximum HC Healthy controls

Monoaminergic network abnormalities: a marker for multiple sclerosis-related fatigue and depression

“…Constrained independent component analysis (ICA). (A) Images depict PET atlases for dopamine, serotonin and norepinephrine transporters (colour bar represents normalised image intensity for the ligand binding potential) 14 15 44. (B) Images show the main resting state (RS) functional connectivity (FC) within components obtained by constrained ICA (effects of interest from SPM V.12 ANOVA models, age, sex and scanner adjusted, p<0.05 family-wise error corrected, colour bar reports F contrast values).…”

“…Evidence for direct damage in monoaminergic neurons in MS is hitherto scarce. A single pathological study outlined direct injury to locus coeruleus in eight MS specimens,29 whereas previous PET analyses showed increased noradrenergic transporter expression in the striatum and limbic cortex,14 decreased serotonin transporter expression in the hippocampus and increased serotonin transporter expression in the prefrontal cortex15 in patients with MS. Besides these direct observations, abnormalities of monoaminergic networks were also explored through diffusion or RS fMRI approaches demonstrating more widespread pathological abnormalities, resulting in fronto-limbic-striatum disconnection for the three monoaminergic networks 16–18 30.…”

“…Specifically, the atlases for dopamine and serotonin transporters were publicly available and obtained by averaging [ 18 F]DOPA and [ 11 C]3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile PET images from HCs, respectively 15 26. Conversely, since atlas for norepinephrine was not publicly available, we constructed it based on previously published data for [ 11 C](S,S)-Methylreboxetine brain PET imaging reporting the binding potential values in cortical and subcortical GM areas for 12 HCs (insula: 1.22; hippocampus: 1.03; amygdala: 1.10; nucleus accumbens: 1.16; head of caudate: 1.06; putamen: 1.09; thalamus: 1.42; pons/midbrain: 1.05; locus coeruleus: 1.36; hypothalamus:1.47 14. Image intensity of all atlases was normalised by scaling image values from 0 to 1 for non-zero voxels, by dividing intensity of each voxel for the maximum intensity value.…”

“…As such, abnormalities of monoaminergic networks may have a role in determining fatigue and/or depression occurrence. Previous positron emission tomography (PET) studies demonstrated that patients with MS had increased norepinephrine presynaptic transporter concentrations in the limbic structures,14 decreased serotonin presynaptic transporter concentrations in the limbic and paralimbic structures,15 and increased serotonin presynaptic transporters in the frontal cortex 15. Despite these results, the invasiveness of pathological and PET studies has hampered an extensive analysis of the association between monoaminergic network integrity and fatigue and depression.…”

Exploring the Role of Neurotransmitters in Multiple Sclerosis: An Expanded Review

“…Another study has shown higher NET expression in subcortical brain regions such as thalamus and amygdala in patients with MS. Changes in monoamine signaling reported in MS may contribute to the high prevalence of comorbid depression and fatigue in MS patients. 109 Since the noradrenergic system is significantly involved in neuropsychiatric disorders, targeting NET may be a promising approach to link neuroinflammation with neuropsychiatric symptoms in MS, such as cognitive impairment (Table 4).…”