Brianne Kent (PhD)

Sleep and Circadian Rhythms in Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common cause of dementia. AD is clinically heterogeneous, with numerous risk factors that affect its clinical and neuropathologic course. The hallmark neuropathology of AD is the accumulation of extracellular deposits of amyloid beta (Aβ) and intraneuronal accumulation of hyperphosphorylated tau, which lead to neuronal cell death, brain atrophy, and severe cognitive impairment.

Sleep abnormalities have long been known to be a feature of neurodegenerative disorders and in some cases are considered a core manifestation of the disease. Sleep has been shown to directly regulate the rate of Aβ production and clearance from the brain, and evidence suggests that sleep disruption may be a direct critical pathway by which Aβ disrupts hippocampal-dependent memory consolidation (Mander et al., 2015). Thus, improving sleep may directly support mnemonic processes and reduce the accumulation of Aβ, which is considered the pathogenic driver of AD.

Patients with AD also exhibit disruptions of daily (circadian) rhythms, but it is unclear whether this reflects a primary disorder of internal circadian timekeeping and whether disruption contributes to symptoms and progression. Circadian biology examines daily 24-hour (‘circa-diem’) rhythms that govern many aspects of physiology, behaviour and metabolism, including sleep-wake cycle, rest-activity patterns, cognitive function, mood, and many hormonal rhythms and metabolic processes. Changes in circadian rhythms may be a strong, reliable, and measurable indicator of the earliest signs of AD. Correction of circadian misalignment, including promotion of more stable and robust rhythms in cognition, sleep-wake, and metabolism, holds promise as an inexpensive and noninvasive method for slowing disease progression and improving quality of life for patients and their families.

To learn more, here is our recent review Kent et al., 2020.

Translational Neuroscience and Touchscreen Cognitive Testing

A huge challenge in developing treatments for Alzheimer’s disease is moving discoveries from fundamental, preclinical research into the clinical domain. This is referred to as the “translational gap.” One goal of my research is to shrink the translational gap by designing preclinical research that is directly informed by clinical research, and vice versa. My research utilizes the heightened control enabled by studying animal models to evaluate the cognitive processes most vulnerable to sleep and circadian rhythm disruption and then translate the insight gained from the rodent models to evaluate the same processes in humans. Touchscreen cognitive tests have been developed to increase the similarity between rodent and human testing, enabling greater control, precision, and translational potential.

Touchscreen testing in rodents enables the assessment of targeted cognitive domains comparable to test batteries used in humans, such as the Cambridge Neuropsychological Test Automated Battery (CANTAB), with the goal of having greater relevance to human health and disease. Touchscreen cognitive testing has numerous advantages compared to traditional tests of learning and memory. First, a battery approach can be taken, running a variety of operant tasks using the same testing chamber, which helps control for potential confounds (e.g., types of stimuli, rewards, apparatus). Second, the semi-automated approach enables several behavioural measures to be assessed simultaneously (e.g., accuracy, reaction time, activity counts, omission rates) and minimizes experimenter contact with animals during testing. Third, the precision and control enabled by the tasks, allows us to assess specific aspects of cognition and functions in targeted brain regions. Finally, touchscreen testing is ideal to combine with neurotechnology such as electrophysiology, chemogenetics, and optogenetics. Thus, touchscreen testing in rodents is highly translatable to humans and enables the mapping of complex behaviour onto specific aspects of neurobiology with the highest level of precision and control.