Many people with lupus experience cognitive impairment (CI), often referred to as “brain fog,” which can significantly affect their daily lives. Despite its prevalence, there are currently no reliable biomarkers to diagnose neuropsychiatric systemic lupus erythematosus (SLE) or its brain-related symptoms. This has created an urgent need for tools to identify CI early and enable the development of effective treatments. With previous LRA funding, Dr. Touma made significant progress by not only recommending a computerized test for CI called the Automated Neuropsychologic Assessment Metrics (ANAM) but also by discovering two promising blood biomarkers — S100A8/A9 and MMP-9 — that appear to be linked to cognitive function in lupus patients. When cognitive function worsens, the levels of these markers increase; when cognitive function improves, the levels decrease. While these findings are exciting, these potential diagnostic tools need to be validated in different groups of lupus patients to confirm their reliability as indicators of CI.

Dr. Touma will test whether these biomarkers (S100A8/A9 and MMP-9) can differentiate between lupus patients with and without CI in a different group of individuals from various clinics. He will also track the levels of the biomarkers over time, measuring them at baseline and again at one and two years. Throughout the study, participants will complete cognitive assessments using the ANAM test and report on various factors like brain fog, anxiety, depression, and overall quality of life. If these biomarkers are validated, they could not only serve as diagnostic tools but may also point to the underlying causes of CI in lupus.

What this means for people with lupus

Dr. Touma’s findings could represent a major step forward in understanding and diagnosing CI in lupus. Validating these blood biomarkers could lead to earlier detection and, ultimately, new treatments for brain fog, improving the quality of life for people with lupus.

Patients with SLE often report Cognitive Impairment (CI), which is one of the most common manifestations of neuropsychiatric SLE with a prevalence of 38%.

In 2020, we received the Lupus Research Alliance Lupus Innovation, titled Modeling CI in Patients with SLE. This award allowed us to: 1) validate the Automated Neuropsychologic Assessment Metrics (ANAM) for the screening and diagnosis of CI; 2) develop different approaches to interpret ANAM’s results; 3) establish CI subtypes; and 4) identify new serum biomarkers associated with CI.

Recently, we have demonstrated the association of serum S100A8/A9 and MMP-9 (Matrix Metalloproteinase) with CI – S100A8/A9 and MMP-9 were significantly higher in patients with CI (p=0.006 and p=0.036, respectively) cross-sectionally. More recently, we have confirmed that changes in S100A8/A9 levels correspond with changes in cognitive status over one year, suggesting a possible role for S100A8/A9 in the development of CI. MMP-9 positively correlated with S100A8/A9 at baseline and follow up visits suggesting that MMP-9 may contribute, to some extent, to the mechanisms by which S100A8/A9 influences cognitive decline in SLE patients. These results are significant but need to be validated externally in different cohorts to confirm its accuracy.

Based on this, we proposed two broader hypotheses:

1) Serum S100A8/A9, MMP-9 are analytes that can be used to differentiate SLE-CI from SLE non-CI patients [diagnostic serum biomarker panel for SLE CI]

2) Serum S100A8/A9, MMP-9, themselves and/or their biological pathways play a role in the development of CI in SLE and are targets for drug development [viable therapeutic tool]

The main objectives of the project are: 1-External validity study to assess the ability of these serum analytes to differentiate between SLE patients with and without CI. 2-Internal and external validity study on the utility of these serum analytes to change overtime in association with cognitive status.

For objective 1, 125 patients will be recruited from each centre at the Washington University in St Louis and at the Feinstein Institutes for Medical Research [cross-sectional analysis].

For objective 2, we will measure the analytes in the serum sample size available on all patient-visits at available at the Toronto Lupus Clinic and we will continue to collect data to achieve a total of 200 patients at each landmark. We will also collect samples at baseline and follow up visits at year 1 and 2 at both US centres listed above.

At each visit, patients will complete the ANAM and data will be collected on demographics, clinical and patient-reported outcomes, and serum (which will be analysed at the Toronto Lupus Clinic).

For the first milestone, we need to validate externally the association of serum S100A8/A9 and MMP-9 (with CI). This is essential to move forward to the second milestone where we anticipate to demonstrate that S100A8/A9 levels change when cognitive status changes.