Excitatory neurons are preferentially impaired in early Alzheimer’s disease but the pathways contributing to their relative vulnerability remain largely unknown. Here we report that pathological tau accumulation takes place predominantly in excitatory neurons compared to inhibitory neurons, not only in the entorhinal cortex, a brain region affected in early Alzheimer’s disease, but also in areas affected later by the disease. By analyzing RNA transcripts from single-nucleus RNA datasets, we identified a specific tau homeostasis signature of genes differentially expressed in excitatory compared to inhibitory neurons. One of the genes, BCL2 associated athanogene 3 BAG3 , a facilitator of autophagy, was identified as a hub or master regulator, gene. We verified that reducing BAG3 levels in primary neurons exacerbated pathological tau accumulation whereas overexpression attenuated it. These results support the conclusion that tau homeostasis underlies the cellular and regional vulnerability of excitatory neurons to tau pathology.

Based upon prior research identifying dispositional optimism as a predictor of placebo responding, the present study tested the hypothesis that individuals high in optimism would be more likely to respond to a placebo analgesic. Optimists and pessimists were randomly assigned to a placebo expectation condition or a no expectation condition prior to a cold pressor task. Blood pressure and heart rate were recorded before and during the cold pressor task, and participant ratings of pain and expectations were obtained immediately after the task. Analysis of the expectation manipulation revealed that the placebo instruction was successful in altering participant expectancy during the cold pressor. Supporting the main hypothesis, dispositional optimism was associated with lower pain ratings in the placebo condition but not in the control condition. Because dispositional optimism can alter placebo responding to laboratory pain, future studies should examine the potential role that this individual difference factor may play in patient responsivity to pharmacological and non-pharmacological treatments for clinical pain.

This is the first controlled prospective ITS study to use feedback to reinforce antibiotic policy and reduce CDI. Multicentre ITS or cluster randomized trials of this and other methods need to be undertaken to establish the most effective means of optimizing antibiotic use and reducing CDI.

Dispositional optimism is associated with reduced pain for healthy adults encountering a brief pain stimulus. This relationship is eliminated, however, when individuals are primed with thoughts of health and well-being. The results are interpreted as evidence for the use of differential coping strategies by optimists in response to pain.