Many aspects of cognition and behaviour are regulated by noradrenergic projections to the forebrain originating from the locus coeruleus, acting through alpha and beta adrenoreceptors. Loss of these projections is common in neurodegenerative diseases and contributes to their cognitive and behavioural deficits. We review the evidence for a noradrenergic modulation of cognition in its contribution to Alzheimer’s disease, Parkinson’s disease and other cognitive disorders. We discuss the advances in human imaging and computational methods that quantify the locus coeruleus and its function in humans, and highlight the potential for new noradrenergic treatment strategies.

Background: Synaptic loss is a prominent and early feature of many neurodegenerative diseases.Objectives: We tested the hypothesis that synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) (Richardson’s syndrome) and amyloid‐negative corticobasal syndrome (CBS).Methods: Forty‐four participants (15 CBS, 14 PSP, and 15 age‐/sex‐/education‐matched controls) underwent PET with the radioligand [¹¹C]UCB‐J, which binds to synaptic vesicle glycoprotein 2A, a marker of synaptic density; participants also had 3 Tesla MRI and clinical and neuropsychological assessment.Results: Nine CBS patients had negative amyloid biomarkers determined by [¹¹C]PiB PET and hence were deemed likely to have corticobasal degeneration (CBD). Patients with PSP‐Richardson’s syndrome and amyloid‐negative CBS were impaired in executive, memory, and visuospatial tasks. [¹¹C]UCB‐J binding was reduced across frontal, temporal, parietal, and occipital lobes, cingulate, hippocampus, insula, amygdala, and subcortical structures in both PSP and CBD patients compared to controls (P < 0.01), with median reductions up to 50%, consistent with postmortem data. Reductions of 20% to 30% were widespread even in areas of the brain with minimal atrophy. There was a negative correlation between global [¹¹C]UCB‐J binding and the PSP and CBD rating scales (R = –0.61, P < 0.002; R = –0.72, P < 0.001, respectively) and a positive correlation with the revised Addenbrooke’s Cognitive Examination (R = 0.52; P = 0.01).Conclusions: We confirm severe synaptic loss in PSP and CBD in proportion to disease severity, providing critical insight into the pathophysiology of primary degenerative tauopathies. [¹¹C]UCB‐J may facilitate treatment strategies for disease‐modification, synaptic maintenance, or restoration. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Apathy is a debilitating feature of many neuropsychiatric diseases, that is typically described as a reduction of goal-directed behaviour. Despite its prevalence and prognostic importance, the mechanisms underlying apathy remain controversial. Degeneration of the locus coeruleus-noradrenaline system is known to contribute to motivational deficits, including apathy. In healthy people, noradrenaline has been implicated in signalling the uncertainty of expectations about the environment. We proposed that noradrenergic deficits contribute to apathy by modulating the relative weighting of prior beliefs about action outcomes. We tested this hypothesis in the clinical context of Parkinson’s disease, given its associations with apathy and noradrenergic dysfunction. Participants with mild-to-moderate Parkinson’s disease (N = 17) completed a randomised double-blind, placebo-controlled, crossover study with 40 mg of the noradrenaline reuptake inhibitor atomoxetine. Prior weighting was inferred from psychophysical analysis of performance in an effort-based visuomotor task, and was confirmed as negatively correlated with apathy. Locus coeruleus integrity was assessed in vivo using magnetisation transfer imaging at ultra-high field 7T. The effect of atomoxetine depended on locus coeruleus integrity: participants with a more degenerate locus coeruleus showed a greater increase in prior weighting on atomoxetine versus placebo. The results indicate a contribution of the noradrenergic system to apathy and potential benefit from noradrenergic treatment of people with Parkinson’s disease, subject to stratification according to locus coeruleus integrity. More broadly, these results reconcile emerging predictive processing accounts of the role of noradrenaline in goal-directed behaviour with the clinical symptom of apathy and its potential pharmacological treatment.

Objective: Synaptic loss is an early feature of neurodegenerative disease models, and is severe in post mortem clinical studies, including frontotemporal dementia. Positron emission tomography (PET) with radiotracers that bind to synaptic vesicle glycoprotein 2A enables quantification of synaptic density in vivo. This study used [¹¹C]UCB‐J PET in participants with behavioral variant frontotemporal dementia (bvFTD), testing the hypothesis that synaptic loss is severe and related to clinical severity.Methods: Eleven participants with clinically probable bvFTD and 25 age‐ and sex‐matched healthy controls were included. Participants underwent dynamic [¹¹C]UCB‐J PET, structural magnetic resonance imaging, and a neuropsychological battery, including the revised Addenbrooke Cognitive Examination, and INECO frontal screening. General linear models compared [¹¹C]UCB‐J binding potential maps and gray matter volume between groups, and assessed associations between synaptic density and clinical severity in patients. Analyses were also performed using partial volume corrected [¹¹C]UCB‐J binding potential from regions of interest (ROIs).Results: Patients with bvFTD showed severe synaptic loss compared to controls. [¹¹C]UCB‐J binding was reduced bilaterally in medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insular cortex, and medial temporal lobe. Synaptic loss in the frontal and cingulate regions correlated significantly with cognitive impairments. Synaptic loss was more severe than atrophy. Results from ROI‐based analyses mirrored the voxelwise results.Interpretation: In accordance with preclinical models, and human postmortem evidence, there is widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to severity. [¹¹C]UCB‐J PET could support translational studies and experimental medicine strategies for new disease‐modifying treatments for neurodegeneration. ANN NEUROL 2023;93:142–154

Synaptic loss is an early and clinically relevant feature of many neurodegenerative diseases. Here we assess three adults at risk of frontotemporal dementia from C9orf72 mutation, using [¹¹C]UCB‐J PET to quantify synaptic density in comparison with 19 healthy controls and one symptomatic patient with behavioural variant frontotemporal dementia. The three pre‐symptomatic C9orf72 carriers showed reduced synaptic density in the thalamus compared to controls, and there was an additional extensive synaptic loss in frontotemporal regions of the symptomatic patient. [¹¹C]UCB‐J PET may facilitate early, pre‐symptomatic assessment, monitoring of disease progression and evaluation of new preventive treatment strategies for frontotemporal dementia.

The relationship between in vivo synaptic density and molecular pathology in primary tauopathies is key to understanding the impact of tauopathy on functional decline and in informing new early therapeutic strategies. In this cross-sectional observational study, we determine the in vivo relationship between synaptic density and molecular pathology in the primary tauopathies of progressive supranuclear palsy and corticobasal degeneration as a function of disease severity. Twenty-three patients with progressive supranuclear palsy and 12 patients with corticobasal syndrome were recruited from a tertiary referral centre. Nineteen education-, sex- and gender-matched control participants were recruited from the National Institute for Health Research ‘Join Dementia Research’ platform. Cerebral synaptic density and molecular pathology, in all participants, were estimated using PET imaging with the radioligands ¹¹C-UCB-J and ¹⁸F-AV-1451, respectively. Patients with corticobasal syndrome also underwent amyloid PET imaging with ¹¹C-PiB to exclude those with likely Alzheimer’s pathology—we refer to the amyloid-negative cohort as having corticobasal degeneration, although we acknowledge other underlying pathologies exist. Disease severity was assessed with the progressive supranuclear palsy rating scale; regional non-displaceable binding potentials of ¹¹C-UCB-J and ¹⁸F-AV-1451 were estimated in regions of interest from the Hammersmith Atlas, excluding those with known off-target binding for ¹⁸F-AV-1451. As an exploratory analysis, we also investigated the relationship between molecular pathology in cortical brain regions and synaptic density in subcortical areas. Across brain regions, there was a positive correlation between ¹¹C-UCB-J and ¹⁸F-AV-1451 non-displaceable binding potentials (β = 0.4, t = 3.6, P = 0.001), independent of age or time between PET scans. However, this correlation became less positive as a function of disease severity in patients (β = −0.02, t = −2.9, P = 0.007, R = −0.41). Between regions, cortical ¹⁸F-AV-1451 binding was negatively correlated with synaptic density in subcortical areas (caudate nucleus, putamen). Brain regions with higher synaptic density are associated with a higher ¹⁸F-AV-1451 binding in progressive supranuclear palsy/corticobasal degeneration, but this association diminishes with disease severity. Moreover, higher cortical ¹⁸F-AV-1451 binding correlates with lower subcortical synaptic density. Longitudinal imaging is required to confirm the mediation of synaptic loss by molecular pathology. However, the effect of disease severity suggests a biphasic relationship between synaptic density and molecular pathology with synapse-rich regions vulnerable to accrual of pathological aggregates, followed by a loss of synapses in response to the molecular pathology. Given the importance of synaptic function for cognition and action, our study elucidates the pathophysiology of primary tauopathies and may inform the design of future clinical trials.