A new study has identified a distinct inflammatory signature in people with tuberous sclerosis complex (TSC), pointing to several blood-based biomarkers—including glial fibrillary acidic protein (GFAP)—that could help predict active epilepsy and guide future therapeutic strategies. The findings offer one of the clearest connections to date between neuroinflammation and epileptogenesis in TSC.
Tuberous sclerosis complex (TSC) is a genetic disorder that affects multiple body systems, characterized by the sustained activation of the mechanistic target of rapamycin (mTOR) pathway. This activation leads to various clinical manifestations, with epilepsy and renal angiomyolipoma being significant causes of illness in people with TSC. The mTOR pathway is also known to play a crucial role in inflammation, which can influence the clinical symptoms of TSC. Given the lack of reliable biomarkers to monitor and predict the progression and treatment response for epilepsy in individuals with TSC, this study aimed to identify accessible biomarkers and potential new therapeutic targets by characterizing the relationship between markers of neuroglial activation/injury, peripheral inflammation, and active epilepsy in people with TSC.The researchers utilized blood samples from the TSC Alliance Biosample Repository and from the Centre hospitalier de l’Université de Montréal.
Key Findings on Inflammation Markers
- Elevated GFAP Levels: The study found that individuals with TSC, particularly those with active epilepsy, exhibit elevated levels of GFAP in their blood. GFAP can be a marker of astrocyte activation, cells in the brain which generally support a healthy brain but can release pro-inflammatory mediators. Elevated GFAP levels were observed in people with TSC having either TSC1 or TSC2 mutations and were significantly higher in those with active epilepsy compared to those without epilepsy for all genotypes (TSC1, TSC2, no mutation identified). This suggests that TSC-related mTOR hyperactivity is linked to astrocyte activation, and that brain inflammation may contribute to the development of epilepsy (epileptogenesis) in TSC.
- Pro-inflammatory Molecules: TSC is associated with increased serum levels of pro-inflammatory molecules such as interleukin 1β (IL-1β), CXCL8, and epidermal growth factor (EGF) compared to healthy controls and non-TSC-related epilepsy controls.
- Distinct Inflammatory Profile in Active Epilepsy: Active epilepsy in individuals with TSC is linked to a specific inflammatory profile, including elevated levels of pro-inflammatory cytokines IL-17A, IL-17C, and tumor necrosis factor α (TNF-α). These markers were not significantly related to recent seizure activity or treatment with mTOR inhibitors. This suggests that the pro-epileptogenic environment, rather than the seizures themselves, likely drives the increased levels of pro-inflammatory markers.
- Impact of mTOR Inhibition: Inflammatory markers associated with TSC status and active epilepsy were not related to mTOR inhibitor treatment.
Potential Biomarkers and Therapeutic Targets
The study highlights that GFAP levels in the peripheral blood serve as an accessible marker to distinguish people with TSC from healthy individuals and, more importantly, to differentiate individuals with TSC with active epilepsy from those without. A combination of GFAP, IL-1β, and EGF showed a high predictive accuracy in distinguishing TSC from healthy controls. For distinguishing individuals with TSC with active epilepsy from those without, GFAP alone showed high predictive accuracy. These findings suggest that key inflammatory mediators could contribute to epileptogenesis and represent novel biomarkers and therapeutic targets in TSC.
In conclusion, this research identifies a distinct pro-inflammatory profile in individuals with TSC, especially those with active epilepsy. Markers like GFAP, IL-1β, CXCL8, IL-17A, IL-17C, and TNF-α are elevated in the peripheral blood, indicating significant astrocyte activation and inflammation. These findings offer promising avenues for developing new biomarkers for epilepsy in TSC and suggest potential therapeutic targets beyond current treatments.
Lead author: Catherine Larochelle, MD PhD, Clinical Associate Professor, Department of Neuroscience, Université de Montréal, Montréal, Québec, Canada, and Mark Keezer, MD PhD, Clinical Associate Professor, Department of Neuroscience, Université de Montréal, Montréal, Québec, Canada
Help the TSC Alliance accelerate TSC research by donating to the 50 Forward Fund!