Intracranial functional haemodynamic relationships in patients with cerebral small vessel disease

Background: Cerebral small vessel disease (SVD) is a major cause of stroke and dementia. The underlying cerebrovascular dysfunction is poorly understood. We investigated cerebrovascular reactivity, blood flow, vascular and cerebrospinal fluid (CSF) pulsatility, and their independent relationship to SVD features, in patients with minor ischaemic stroke and MRI evidence of SVD. Methods: We recruited patients with minor ischaemic stroke and assessed CVR using Blood Oxygen Level Dependent (BOLD) MRI during a hypercapnic challenge, cerebral blood flow, vascular and CSF pulsatility using phase contrast MRI, and structural MR brain imaging to quantify white matter hyperintensities (WMH) and perivascular spaces (PVS). We quantified CVR in seven white matter and six subcortical grey matter regions, measured blood flow in carotid and vertebral arteries, intracranial venous sinuses, internal jugular veins and CSF flow at the aqueduct and foramen magnum. We used multiple regression to identify SVD features, blood flow and pulsatility parameters associated with CVR, controlling for patient characteristics.Results: In 53 of 60 patients with complete data (age 68.0+/-8.8, 74% male, 75% hypertensive), CVR in grey and white matter decreased with increasing blood pressure (BP, respectively -0.001%/mmHg, p=0.01 and -0.006%/mmHg, p=0.01, per mmHg increase in BP). After controlling for age, gender and systolic BP, white matter CVR decreased with increasing WMH volume (-0.01%/mmHg per log10 increase in WMH volume, p=0.02) and basal ganglia PVS (-0.01%/mmHg per point increase in PVS score, p=0.02). White matter CVR decreased with increasing venous pulsatility (superior sagittal sinus -0.03%/mmHg, p=0.02, per unit increase in pulsatility index) but not with cerebral blood flow (p=0.58). Lower foramen magnum CSF stroke volume was associated with worse white matter CVR (0.04%/mmHg per ml increase in stroke volume, p=0.04) and increased basal ganglia PVS. Conclusions: Contemporaneous assessment of CVR, intracranial vascular and CSF pulsatility demonstrates important interrelationships of these vascular functions in humans. Decreased CVR, increased venous pulsatility and reduced foramen magnum CSF stroke volume suggests that dynamic vascular dysfunctions underpin PVS dysfunction and WMH development. Improved understanding of microvascular dysfunction and CSF dynamics offers new intervention targets to reduce SVD lesion development and their impact on cognitive dysfunction and stroke.