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Background: Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have emerged as biomarkers for cerebral small vessel disease (SVD). We investigated their role in a hereditary SVD model, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S)., Methods: NfL and GFAP levels of 17 pre-symptomatic, 22 symptomatic RVCL-S mutation carriers and 69 controls were measured using a Simoa assay. We assessed the association of serum and cerebrospinal fluid (CSF) levels of NfL and GFAP with RVCL-S symptomatology and neuropsychological functioning., Results: Serum and CSF NfL levels were higher in symptomatic RVCL-S compared to controls ≥ 45 years (33.5 pg/mL vs. 9.2 pg/mL, p < 0.01; 8.5*10 2  pg/mL vs. 3.9*10 2  pg/mL, p < 0.01, respectively). Serum NfL levels were higher in symptomatic RVCL-S than pre-symptomatic carriers (33.5 pg/mL vs. 5.9 pg/mL, p = 0.02). Pre-symptomatic RVCL-S carriers had increased CSF NfL levels compared to controls < 45 years (5.2*10 2  pg/mL vs. 1.9*10 2  pg/mL, p < 0.01). No differences were found in GFAP levels across groups, but in RVCL-S carriers higher serum levels of both NfL and GFAP were linked to poorer global cognitive functioning (β[95%CI] = - 2.86 [- 5.58 to - 0.13], p = 0.04 and β[95%CI] =  - 6.85 [- 11.54 to - 2.15], p = 0.01, respectively) and prolonged psychomotor test times (β[95%CI] = 6.71 [0.78-12.65], p = 0.03 and β[95%CI] = 13.84 [3.09-24.60], p = 0.01)., Discussion: Higher levels of serum NfL and GFAP are associated with worse cognitive functioning in RVCL-S carriers and may serve as marker for disease progression. CSF NfL levels may serve as early marker as pre-symptomatic RVCL-S patients already show differences compared to young controls., (© 2024. The Author(s).)

Background: The brain and retina share many neuronal and vasculature characteristics. We investigated the retinal microvasculature in patients with a monogenic vasculopathy using optical coherence tomography angiography (OCTA). OCT-A is a novel precise non-invasive imaging method that may provide biomarkers suitable for diagnosis and follow-up of small vessel diseases., Methods: In this exploratory cross-sectional study, eleven RVCL-S patients and eleven age-matched healthy control participants were included. The size of the foveal avascular zone (FAZ) and the vascular density of the superficial capillary networks in the retina were measured by OCT-A., Results: The symptomatic and presymptomatic patients showed significantly lower vascular density values than controls in the foveal region [median (IQR) 18.2% (15.8-18.6) vs. 24.4% (21.5-26.8) ( p < 0.001), 29.8% (29.6-30.8) vs. 33.2% (32.0-33.6) ( p = 0.002), respectively]. The FAZ was significantly larger in the symptomatic RVCL-S patients than in the control group [13,416 square pixels [7,529-22,860] vs. 1,405 square pixels [1,344-2,470] ( p < 0.001)]. No significant difference was identified in measurements of FAZ comparing presymptomatic and controls., Conclusion: Our findings with OCT-A demonstrated that RVCL-S causes an increase in the size of the FAZ in symptomatic RVCL-S patients compared to healthy participants. Moreover, there is a decrease in vessel density in the superficial capillary networks in both symptomatic and presymptomatic patients. In the future, newly developed precise objective instruments such as OCT (-A) may provide important tools in determining disease activity for follow up of common small vessel diseases., Competing Interests: Author IB reports independent research support from the international retinal research foundation (IRRF) and Dutch Heart foundation. Author IN reports independent research support by the IRRF and Stichting Dioraphte. Author GT reports grants or consultancy support from Novartis, Lilly, Teva, Allergan, and independent support from Netherlands Organization for Health Research and Development (NWO, and ZonMW), NIH, European Community, Dutch Heart Foundation, and Dutch Brain Foundation, IRRF and Stichting Dioraphte. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Al-Nofal, de Boer, Agirman, Wilms, Zamanipoor Najafabadi, Terwindt and Notting.)

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare, underrecognized, systemic small vessel disease caused by heterozygous C-terminal truncating TREX1 mutations. The disease is characterized by vascular retinopathy, focal neurological complaints, cognitive decline and a wide range of systemic manifestations, including Raynaud's phenomenon, anemia and liver and kidney disease. Eventually, RVCL-S leads to premature death. The underlying pathological finding in RVCL-S is a nonatherosclerotic, amyloid-negative angiopathy involving small arteries and capillaries. However, the exact mechanisms by which the truncated TREX1 protein causes angiopathy remains unknown. Timely recognition of this disease is important to slow down and treat complications of the disorder, but also to prevent unnecessary (invasive) diagnostic or therapeutic procedures. As we move forward, translational research combining basic science advances and clinical findings as well as studies focusing on natural history following RVCL-S patients at different disease stages, will be critical to help elucidate RVCL-S pathophysiology. These studies will also provide the tools to identify appropriate biomarkers and therapeutic agent options for RVCL-S patients., (© 2022 The Authors. Published by Elsevier B.V.)