Esther Blessing, MD, PhD

My laboratory is interested in how the temperature of the brain affects the molecular processing of proteins whose misfolding leads to neurodegenerative disease. We are especially interested in how disturbance in the diurnal pattern of core body and brain temperature change over the sleep-wake cycle interacts with tau protein processing, which is sensitive to small changes in temperature. Our first in human, first in mouse research in collaboration with the Planel Lab at the University of Laval, showed that core body temperature (Tc) rhythm correlated with diurnal rhythms in plasma and CSF tau protein levels, emphasizing the importance of measuring Tc when interpreting their levels as biomarkers https://www.jci.org/articles/view/182931/pdf. This work also showed that diurnal core body and brain temperature rhythm was found to causally drive diurnal variation in extracellular tau levels in mouse via temperature-dependent of molecular pathways underlying tau secretion and phosphorylation—these results suggest patterns observed in human may partially result from causal effects of temperature upon tau processing.

Interestingly, in Alzheimer’s Disease and other tauopathies, hyperphosphorylated tau aggregates first form in brainstem and hypothalamus thermoregulatory neurons, including the parabrachial nucleus, lateral hypothalamic orexin neurons and preoptic area, among others. It is likely that in vivo associations between tau pathology and Tc disturbance may derive from bidirectional effects, resulting from both tauopathy induced thermoregulatory neuron dysfunction leading to Tc rhythm disturbance, as well as this in turn disrupting temperature-dependent tau processing. Indeed, our first in human study showed that Tc alterations in cognitively normal older adults were associated with tau tracer uptake in early Braak stage areas seen in PET MR neuroimaging https://pubmed.ncbi.nlm.nih.gov/35550158. We are pursuing both arms of this bi-directional mechanism. We are collaborating with the Grinberg lab at UCSF, who study early tau pathology in neuromodulatory subcortical system neurons, to examine whether Tc rhythm disturbance pre-mortem correlates with tau pathology in these thermoregulatory neurons post-mortem.

Our work also expands to understand how factors associated with disturbance of the diurnal body temperature pattern, including aging, sleep disorder, inactivity, and genetic factors may lead to increased risk for neurodegenerative disease. In our collaboration with the Fortea Lab at the University of St Pau, Barcelona, we are studying how Tc disturbance in Down Syndrome may increase risk for earlier development of Alzheimer’s Disease. We are also evaluating how thermal interventions like sauna, sleeping cool, and pharmacological interventions that alter body temperature impact neurodegenerative processes.

In a second avenue of research, my laboratory runs clinical trials testing the efficacy of cannabidiol for the treatment of stress related disorders including post-traumatic stress disorder and social anxiety disorder, in collaboration with Dr. Naomi Simon. These studies include precision medicine prediction of treatment response and drug target engagement based upon genomic, transcriptomic and neural circuit (MR imaging) biomarkers and neuropsychological assessments.