Serum glial fibrillary acidic protein is sensitive to acute but not chronic tissue damage in cerebral small vessel disease

In this prospective observational study, we could demonstrate that sGFAP quantified by the ultrasensitive SIMOA technique in the first days after stroke symptom onset is increased in patients with RSSI compared to age- and sex-matched controls with comparable WMH severity. While sGFAP further correlated with the size of the RSSI, this marker was not associated with chronic CSVD features or the occurrence of incident cerebrovascular lesions during a follow-up period of 15 months. These findings indicate that serum GFAP is a sensitive marker for acute tissue damage even in small subcortical brain infarction but not related to chronic brain damage from CSVD as evidenced by MRI.

Our work provides novel information as GFAP has not yet been investigated in sporadic CSVD and lacunar stroke (with its neuroimaging correlate RSSI) as the most destructive phenotype of CSVD. There exists only one prior report on the role of sGFAP in CADASIL patients [7]. In this work, sGFAP levels were increased in 63 Taiwanese CADASIL patients compared to 17 controls. In line with our findings, sGFAP was not associated with the severity of WMH and lacunes, but in contrast to our work, sGFAP was higher in patients with cerebral microbleeds, and predicted incident intracerebral hemorrhage over 3 years of follow-up. In this context, it is important to note that a direct comparison between genetic and sporadic CSVD is limited due to various pathophysiological differences. Moreover, the two study cohorts also differed regarding clinical presentations. All our patients had a sudden cerebrovascular event (lacunar stroke with MRI-confirmed RSSI), while the CADASIL patients represented a rather heterogenous group with prior ischemic or hemorrhagic strokes or even without a history of stroke, and they had more extensive CSVD with more lacunes and especially microbleeds on brain MRI. Given these methodological constraints, the Taiwanese study [7] also remained unresolved whether sGFAP is already increased in the acute phase of CSVD-related stroke, as blood sampling for sGFAP measurement was performed more than one year after stroke symptom onset. Furthermore, prior studies on serum sGFAP in stroke mostly used conventional ELISA techniques (as opposed to the ultrasensitive SIMOA assay applied in our work), analyzed more heterogenous cohorts of acute ischemic stroke patients with more severe strokes and mainly concentrated on the differentiation between ischemic and hemorrhagic stroke subtypes, thereby consistently showing higher GFAP levels in patients with acute intracerebral hemorrhage [2,3,4,5,6,7, 15, 16]. Moreover, none of these studies accounted for concomitant chronic cerebrovascular lesions or lesion progression on follow-up MRI scans and they also did not provide serial sGFAP measurement available for the analysis of temporal dynamics of this biomarker after the acute event. While we found a positive correlation of sGFAP with axial RSSI diameter, suggesting that sGFAP levels increase with the size of ischemic infarction, neither baseline nor follow-up GFAP levels were related to clinical stroke severity (according to the NIHSS) or functional neurological outcome (rated by the mRS). These findings contrast the results from an earlier study in Chinese stroke patients [6], reporting that sGFAP levels measured one day after stroke symptom onset were increased in patients with higher NIHSS scores and associated with worse functional neurological outcome at 1 year. However, we acknowledge that the range of NIHSS and mRS in our cohort might have been too small to detect such a potential effect in our work.

Because of the dedicated design of our study, we also were able to investigate the temporal dynamics of sGFAP levels in RSSI. Interestingly, there was no correlation of sGFAP levels with the time from symptom onset to baseline blood sampling within 13 days, even after adjusting for age, sex and RSSI size. This observation indicates that sGFAP is a sensitive acute marker for small ischemic infarcts that is rapidly released into the blood. Blood brain barrier dysfunction and alterations of the glymphatic system—two mechanisms which have been implicated in the pathophysiology of CSVD—might accelerate GFAP drainage into the blood and might contribute to its rapid detection in the serum of RSSI patients [17, 18].

While our findings potentially indicate that sGFAP stays elevated for at least about 2 weeks after RSSI onset (given the lack of change with time from acute symptoms to sampling), our work additionally demonstrated that sGFAP levels return to the levels observed in controls at 3 months after stroke and that they remain at this level 15 months after the stroke incident. This suggests that a rise in sGFAP reflects acute astro-glial damage rather than ongoing injury and/or activation. As a matter of fact, our study cannot serve to define the exact timepoint when sGFAP levels peaked or started to decrease, because this would necessitate high frequency blood sampling in narrow time intervals. In this context, a recent review [2] identified that there is a clear knowledge gap regarding longitudinal dynamics of sGFAP in (sub)acute neurological conditions. In a small study on 34 patients with traumatic brain injury, sGFAP levels were highest on day 1 but still elevated at 90 days after the acute event [19]. This difference compared to our findings can be attributed to the more severe global and diffuse cerebral damage and blood barrier disruption in cerebral trauma.

Although follow-up sGFAP levels were associated with WMH severity as well as presence of lacunes and microbleeds in univariable analysis, these relationships were no longer present after adjusting for the important covariates age, sex and arterial hypertension. The missing association of sGFAP values and chronic CSVD neuroimaging features in our control participants points into the same direction.

In a substantial number of patients, CSVD has a progressive disease course with the occurrence of new cerebrovascular lesions which often occur without obvious clinical symptoms but—as they accumulate—associate with cognitive impairment and dementia, gait disturbance, depression and an increased rate of recurrent stroke, brain hemorrhage and mortality [20,21,22]. Because frequent follow-up MRI scans to capture progressive CSVD are not feasible, a blood-derived biomarker for this purpose would be highly desired. Unfortunately, our results argue against such a potential role for GFAP, at least over a follow-up period of 15 months. Notably, we cannot rule out that GFAP might have the potential to indicate microscopic damage that remains undetected by conventional MRI sequences. Such an association has been described in patients with mild traumatic brain injury [23] and should be a target for future studies on CSVD (e.g., using diffusion tensor imaging or other techniques to capture ultastructural tissue damage which can precede obvious lesion detectable by routine brain MRI.

Considering the given limitations, our findings do not suggest that sGFAP may serve as a tool to identify (clinically silent) CSVD progression. On the other hand, there might have been too few events and the time period might have been too long to capture the (acute) occurrence of new cerebrovascular lesions with increased GFAP levels. We do not know the exact timepoint when the clinically silent lesions occurred in our patients, and therefore, tissue destruction together with GFAP levels might have already stabilized at time of blood sampling.

Notably, serum neurofilament light that has also been investigated in a subgroup of the present study cohort in an earlier work [8], was not only elevated in the acute phase of RSSI but also correlated with WMH severity and progressive CSVD on follow-up brain MRI. Therefore, the neuroaxonal biomarker neurofilament light seems to be more sensitive for ongoing (clinically silent) active CSVD compared to sGFAP, which—if confirmed in further independent cohorts—might have the potential to serve as an acute marker even for small subcortical ischemic brain infarcts.

Major strengths of our study include the application of the ultrasensitive SIMOA technique for sGFAP assessment and the availability of longitudinal GFAP measurements. To minimize the impact of concomitant neurodegenerative processes which could have affected sGFAP levels [2, 24], we used an age limit above 75 years and an mRS score of > 1 as exclusion criteria in this study (enabling analysis of sGFAP in more “pure” CSVD). However, we acknowledge that our cohort might not represent the entire spectrum of patients with lacunar stroke.

Another limitation of this study comes from the fact that it was not primarily designed to study the role of GFAP as a biomarker. This explains our focus on patients with an RSSI and the different sampling intervals. The sample size of the present study was moderate and consistent measurements of GFAP were missing in a few patients. In this context, we were not able to identify factors that could explain the wide range of sGFAP levels in our cohort.

On the other hand, the availability of longitudinal information on GFAP levels and the comprehensive and standardized MRI follow-up scans at predefined timepoints allowing for exact identification of neuroimaging markers of CSVD and their progress over time represent major strengths of the present work.

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