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Andrea Knight, MD, MSCE

Clinician Investigator

The Hospital of Sick Children (Canada)

Neurosciences and Mental Health Program

https://www.sickkids.ca/en/staff/k/andrea-knight/

Inflammation, brain injury and trajectories of cognitive function in childhood-onset lupus

Approximately 20% of patients with the chronic autoimmune disease systemic lupus erythematosus have childhood-onset, meaning they developed lupus as children. The brain is affected in up to 70% of adolescents with childhood-onset lupus. Systemic lupus erythematosus-induced brain inflammation can cause problems with thinking or cognition which affects school performance, daily activities, and overall quality of life. Past Magnetic Resonance Imaging (MRI) studies showed that the cognition challenges are associated with changes in brain structure. In some patients, these changes persist into adulthood. However, the medical community does not know which adolescents with lupus are most at risk for the structural brain changes.

Dr. Andrea Knight’s goal is to find ways to detect the brain changes early and prevent progression. Healthy adolescents and lupus patients will be invited to participate in a three-year study. At each visit the study participants will complete tests evaluating cognitive function, a brain MRI, and a blood test. Dr. Knight’s research team will look at inflammation markers and brain injury markers in the blood and analyze that information in combination with the MRI and cognitive function tests.

What this study means for people with lupus:

Results of Dr. Knight’s study could provide new means to identify young lupus patients at risk for lupus-associated cognitive changes that may allow healthcare providers to prevent the cognitive impairment progression in childhood-onset lupus early in disease.

Dr. Andrea Knight’s long-term objective is to become a clinician scientist and academic leader in childhood-onset systemic lupus (cSLE) research, with clinical and translational expertise in neuropsychiatric lupus. cSLE is a chronic systemic autoimmune disease with typical onset in adolescence during the formative years of brain development. This critical period may be disrupted by brain inflammation due to lupus, termed neuropsychiatric lupus, manifesting as syndromes such as cognitive dysfunction, seizures, and psychiatric disorders. As many as 60% of patients with cSLE experience cognitive dysfunction, most often within the first year of diagnosis, with potential for long-term cognitive impairment, and adverse clinical and psychosocial outcomes. However, the mechanisms underlying cognitive dysfunction in cSLE are poorly understood, and there is a lack of accurate diagnostic tools and targeted treatments for neuropsychiatric lupus.

There is a critical need to understand the trajectory of cognitive function in cSLE, and its relationship to systemic inflammation, brain injury and structural brain changes. Recent studies suggest that interferons are mediators of inflammation in neuropsychiatric lupus, and that blood markers such as serum neurofilament light may be useful to identify and track brain injury. Additionally, advanced neuroimaging techniques such as structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) provide enhanced characterization of structural brain changes. The main objective of this proposal is to examine trajectories of cognitive function, focusing on executive function, and investigate correlates to systemic interferon-mediated inflammation, brain injury and structural brain changes in adolescents with cSLE. We will study of longitudinal cohort of adolescents with cSLE, comparing to age and sex-matched healthy controls. We will obtain validated measures of cognitive function, along with structural MRI and DTI, and blood markers of interferon-mediated inflammation and brain injury, over 3 time points (baseline, 1 year, 3 years). Aim 1 will determine trajectories of executive function, and correlate these trajectories with changes in frontal brain regions, and baseline demographic/disease characteristics. Aim 2 will investigate the longitudinal relationship between interferon-mediated inflammation and: a) brain injury marker serum neurofilament light, b) structural changes in frontal brain regions, and c) executive function. This research will fill a knowledge gap in the course of executive function and structural brain changes for adolescents with cSLE over time, and identify those most at risk for cognitive impairment. We will gain mechanistic insights into cognitive dysfunction in SLE, and provide new information to guide the prognosis of cognitive dysfunction and neuropsychiatric lupus, as well as development potential intervention strategies for patients with cSLE.

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