Blood-brain barrier impairment as an early marker of neurodegeneration in late-onset epilepsy of unknown origin

Purpose: Blood-brain barrier (BBB) plays a crucial role in maintaining brain health, and its dysfunction during the early stages of neurodegeneration may contribute to neuropathological processes. Patients with late-onset epilepsy with unknown etiology (LOEU) can present early signs of neurodegeneration and convert to an overt neurodegenerative disease longitudinally. This study analyzed cerebrospinal-fluid (CSF)/serum albumin ratio (Qalb), as a marker of BBB integrity, and assessed biomarkers of neurodegeneration in patients with LOEU compared to age- and sex-matched controls. Methods: Patients diagnosed with LOEU were compared to a sex- and age-matched control group. All participants underwent a neurological visit, cognitive evaluation to exclude cognitive impairment, and a lumbar puncture for CSF biomarker analysis [β-Amyloid42 (Aβ42); total-Tau (t-Tau); phosphorylated-Tau at threonine 181 (p-Tau181); Qalb]. Lumbar puncture was performed within 2 months after epilepsy diagnosis, and at least 3 weeks after the last seizure. Results: Twenty-eight LOEU patients (53.6 % female, mean age 68.79 ± 7.83 y) and twenty-five controls (52.0 % female, mean age 65.64 ± 8.10 y) were included. LOEU patients showed significantly higher Qalb values (p = 0.003), lower Aβ₄₂ CSF levels (p = 0.030), and higher t-Tau/Aβ₄₂ (p = 0.030) and p-Tau181/Aβ₄₂ ratios (p = 0.030) than controls. Qalb values did not significantly differ between patients with and without pathological AD biomarker profile. Conclusions: LOEU patients show BBB dysfunction and early changes in CSF biomarker ratios pointing to AD pathology. Qalb increase seems to be unrelated to the pathological changes in CSF AD biomarkers. Future studies should be performed to better understand the neuropathological basis of LOEU and the risk for patients to develop a neurodegenerative disorder