See Grinberg and Heinsen (doi:10.1093/brain/awx261) for a scientific commentary on this article. Clinical evidence suggests that aberrant tau accumulation in the locus coeruleus and noradrenergic dysfunction may be a critical early step in Alzheimer’s disease progression. Yet, an accurate preclinical model of these phenotypes that includes early pretangle tau accrual in the locus coeruleus, loss of locus coeruleus innervation and deficits locus coeruleus/norepinephrine modulated behaviours, does not exist, hampering the identification of underlying mechanisms and the development of locus coeruleus-based therapies. Here, a transgenic rat (TgF344-AD) expressing disease-causing mutant amyloid precursor protein (APPsw) and presenilin-1 (PS1ΔE9) was characterized for histological and behavioural signs of locus coeruleus dysfunction reminiscent of mild cognitive impairment/early Alzheimer’s disease. In TgF344-AD rats, hyperphosphorylated tau was detected in the locus coeruleus prior to accrual in the medial entorhinal cortex or hippocampus, and tau pathology in the locus coeruleus was negatively correlated with noradrenergic innervation in the medial entorhinal cortex. Likewise, TgF344-AD rats displayed progressive loss of hippocampal norepinephrine levels and locus coeruleus fibres in the medial entorhinal cortex and dentate gyrus, with no frank noradrenergic cell body loss. Cultured mouse locus coeruleus neurons expressing hyperphosphorylation-prone mutant human tau had shorter neurites than control neurons, but similar cell viability, suggesting a causal link between pretangle tau accrual and altered locus coeruleus fibre morphology. TgF344-AD rats had impaired reversal learning in the Morris water maze compared to their wild-type littermates, which was rescued by chemogenetic locus coeruleus activation via designer receptors exclusively activated by designer drugs (DREADDs). Our results indicate that TgF344-AD rats uniquely meet several key criteria for a suitable model of locus coeruleus pathology and dysfunction early in Alzheimer’s disease progression, and suggest that a substantial window of opportunity for locus coeruleus/ norepinephrine-based therapeutics exists.

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To examine targeted, mechanism-based interventions is the next generation of treatment innovation. Biased threat labeling of ambiguous face emotions (interpretation bias) is a potential behavioral treatment target for anger, aggression, and irritability. Changing biases in face-emotion labeling may improve irritability-related outcomes. Here, we report the first randomized, double-blind placebo-controlled targeted trial of interpretation bias training (IBT) in youths with chronic, severe irritability. Method: Patients with current Disruptive Mood Dysregulation Disorder (DMDD; N ¼ 44) were randomly assigned to complete 4 sessions of active (n ¼ 22) or sham (n ¼ 22) computerized IBT training within a 1-week period. The first and last trainings were completed onsite, and 2 trainings were completed at home. We examined the effects of active IBT on labeling bias, primary outcome measures of irritability, and secondary outcome measures of anxiety, depression, and functional impairment. Follow-up assessments were completed immediately after and 2 weeks after the intervention Q5 .Results: We found that active IBT engaged the behavioral target in the active relative to the sham condition, as shown by a significant shift toward labeling ambiguous faces as happy. However, there was no consistent clinical improvement in active IBT relative to the sham condition either immediately after or 2 weeks after training in either the primary or secondary outcome measure. Conclusion: Although this randomized controlled trial of IBT in youths with DMDD engaged the proposed behavioral target, there was no statistically significant improvement on clinical outcome. Identifying and changing behavioral targets is a first step in novel treatment development; these results have broader implications for targeted-based intervention development. Clinical trial registration information: Psychological Treatments for Youth With Severe Irritability; https://clinicaltrials.gov/; NCT02531893.