# Time-Domain Near-Infrared Spectroscopy in Subjects with Asymptomatic Cerebral Small Vessel Disease
## 4 Discussion  
The present study is the first attempt to assess oxygenation of microcirculation of cerebral outer layers by means of TD-NIRS in subjects with asymptomatic CSVD. Considering that CSVD is a structural and functional disorder of brain microcirculation, techniques that investigate the microcirculation might provide complementary information about early changes in asymptomatic CSVD. Some of the limitations of previous NIRS techniques have been overcome by TD-NIRS and FD-NIRS, which can better discriminate the extracerebral contribution to the signal and provide absolute and reproducible concentration of hemoglobin species and StO\({}_{2}\). TD-NIRS investigates the oxygenation of microcirculation of cerebral outer layers that is functionally and anatomically connected to the microcirculation of subcortical and deep white matter on the arterial and venous side. Indeed, subcortical and deep white matter regions receive arterial blood through medullary arteries coming from leptomeningal spaces [21] and the venous drainage of subcortical white matter is directed to cortical pai veins [22]. While the radiological signs of CSVD are mainly located in deep and periventricular regions, it might be conceivable that the microcirculatory impairment or consequences are global. Therefore, the study of oxygenation of cerebral outer layers with TD-NIRS might indirectly reflect the presence of radiological signs of CSVD. According to our explorative data, cerebral oximetry with TD-NIRS was able to detect significantly lower cerebral StO\({}_{2}\) in a cohort of subjects with incidental radiological signs of asymptomatic CSVD located in periventricular and deep white matter regions compared to individuals without white matter hyperintensities. We also observed that StO\({}_{2}\) did not differ between subjects without WMHs and with WMHs only in periventricular regions. This could be due to the more limited extension of CSVD or to an intrinsic limitation of TD-NIRS to detect signals from the deeper arterial and venous blood systems supply of periventricular regions. Previous NIRS studies have shown that StO\({}_{2}\) is a highly reproducible parameter with a fairly restricted coefficient of variation among subjects [10; 11]. Previous TD-NIRS data suggested that HbR, HbO, HbT and, to a lesser extent, StO\({}_{2}\) values reduce with increasing age [10]. In our cohort, as expected, subjects with noWMHs were younger than individuals with pvWMHs and d+pvWMHs. However, in multiple linear regression analysis including age as independent variable, StO\({}_{2}\) remained statistically significantly associated with increasing extension of WMHs. Figure 2: ROC curve sensitivity and specificity of StO\({}_{2}\) in predicting d+pvWMHs. In this exploratory study, we assessed subjects with only minor signs of CSVD without functional impact. Although incidental radiological signs of CSVD have a high prevalence in healthy subjects, it remains to determine what proportion of asymptomatic CSVD will progress into cognitive impairment, dementia or stroke. Some population studies have shown progression of WMHs and of cognitive decline not only in subjects with confluent alterations, but also in individuals with punctate lesions [23; 24]. Longitudinal studies might contribute to identify subjects at high probability of becoming symptomatic to whom possibly offer future treatment strategies at an early asymptomatic phase of the disease. Our preliminary data suggest that minor, asymptomatic radiological CSVD might be associated with low \(\text{StO}_{2}\) values, that might represent a sign of dysfunction of cerebral microcirculation. We acknowledge that this study has a number of limitations among which the very small sample size, the gender unbalance between d+pvWMHs and the other groups and the retrospective nature of the study, which can reduce the general validity of findings. Therefore, these preliminary results need to be confirmed in a larger cohort of subjects along with longitudinal test of cognitive functions and brain MRI imaging.