This study was the first to quantitatively image BBB leakage in lung cancer patients who had not yet developed brain metastases and found that aLC exhibited higher levels of BBB leakage in some brain regions and correlated with cognitive impairment in patients. These findings provide a critical step in determining the role of BBBD in the pathogenesis of brain metastases from lung cancer and highlight the BBB as a potential diagnostic and predictive target.
BMs cause severe, uncontrollable symptoms and reduce quality of life, such as paralysis, increased intracranial pressure, or seizures, and the incidence of BM has shown an upward trend in the last decade, but there has been little progress in treatment options and poor outcomes(Soffietti et al., 2017). Therefore, it is important to be able to detect early BM in patients with lung cancer who are more prone to develop BM and to provide enhanced adjuvant therapy for them. In this study, BBB leakage examination was performed in patients who had not yet developed visible brain metastases, and increased leakage was found in patients with progressive disease. This suggests an increased risk of brain metastasis.
The development of BM involves a series of interrelated steps, starting with the invasion of cancer cells into the intravascular and/or lymphatic system. Due to the lack of a lymphatic system in the central nervous system (CNS), the only possible way for cancer cells to reach the brain is through blood circulation. The circulating tumor cells (CTCs) may circulate into the brain's microcirculation and adapt to the brain's microenvironment, resulting in the formation of micro-metastases, which eventually form visible tumors through "metastatic colonization"(Hanahan & Weinberg, 2011; Paduch, 2016). However, metastatic cells that invade the CNS parenchyma must pass through the BBB. During this process, changes occur in the cerebral vascular endothelium(Bart et al., 2000), including impaired tight junction structures and increased perivascular gaps(Liebner et al., 2000). In addition, windows corresponding to the surrounding vascular system can be found in these vessels, and the number and activity of cytosolic vesicles are increased(Shibata, 1989). Therefore, these vessels may reflect those of the tumor tissue rather than those of the CNS endothelium. As a result of these structural alterations leading to increased BBB leakiness, plasma leaks into the extracellular space outside the vasculature(Nduom et al., 2013). And our findings coincide with this process.
DCE-MRI allows the leakage of the extracellular gap within each voxel to be assessed by pharmacokinetic parameters (Ktrans), detecting leakage of the BBB in response to the destruction of the BBB. Ktrans is defined as the volume transfer constant between the plasma and the extracellular space outside the blood vessel, and it is often used as a synonym for permeability(Tofts & Kermode, 1991). DCE-MRI has been widely used in neuro-oncology imaging(Bar-Klein et al., 2017; Kamintsky et al., 2020; Lublinsky et al., 2019; Rüber et al., 2018; Serlin et al., 2019). However, measuring leakage from a relatively intact BBB is not common. And the leakage of BBB we need to measure may be microleakage, so the patlak model is used to calculate Ktrans because it is more accurate in measuring microleakage(Barnes et al., 2016; Heye et al., 2016; Patlak et al., 1983).
Our findings confirm that, compared to the HCs, LCs have higher levels of BBB leakage, especially more pronounced in aLCs. It suggests that as LC progress, more and higher leakage of the BBB may occur in brain areas and the brain BBB integrity suffers disruption. And these changes indicate changes in the cerebral vascular endothelium in these brain regions, damage to tight junction structures and increased perivascular gaps(Soffietti et al., 2017). This signals the possibility of micro-metastasis, or a shift from BBB to BTB, as BTB is often considered “leakier” than BBB. Therefore, without further clinical intervention, visible BM may develop. Early detection of increased BBB leakage and enhanced clinical intervention are important to prevent the development of BMs.
Cognitive impairment in cancer patients has been of concern and increases the risk of developing dementia(Heck et al., 2008; Lovelace et al., 2019). Functional impairment of visuospatial/executive and delayed recall was found in patients with advanced lung cancer, and the decrease was more obvious with the progression of the disease. It is suggested that the development of lung cancer will impair cognitive function, giving priority to visuospatial/executive and delayed recall, but the specific mechanism is unclear. Our study also found that with the progression of lung cancer, BBB leakage increased in more brain areas, and the more obvious the damage to visuospatial/executive and delayed recall. It is suggested that the impairment of BBB may be one of the causes of cognitive impairment. So, in the treatment of lung cancer, it is necessary to consider the cognitive impairment of patients, avoid inappropriate treatment, aggravate the cognitive impairment of patients, and reduce the quality of life.
The advantages of this study include no recruitment bias, and the time between clinical evaluation and neuroimaging regimens is close, usually, after clinical evaluation, an MRI examination is completed within 1 day. However, the sample size of our cohort is small, and our imaging scheme requires a gadolinium-based contrast agent, which may cause potential damage to the kidney. BBB imaging without contrast agents may have more extensive applicability.