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Alzheimer's disease (AD) and cerebral small vessel disease (cSVD) are the two main causes of dementia with blood-brain barrier (BBB) breakdown being a common contributor. Recent advances in neuroimaging techniques offer new possibilities to understand how the brain functions in health and disease. This includes methods such as dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) which allows the detection of subtle regional changes in the BBB integrity. The purpose of this work is to provide a review on the recent DCE-MRI findings of subtle BBB leakage focusing on cSVD and AD, including both clinical and pre-clinical studies. Despite being widely used and well-established, we also highlight some of the DCE-MRI challenges and pitfalls faced in the context of dementia inherent to the subtle nature of BBB impairment.

Absence of the astrocyte-specific membrane protein MLC1 is responsible for megalencephalic leukoencephalopathy with subcortical cysts (MLC); this rare type of leukodystrophy is characterized by early-onset macrocephaly and progressive white matter vacuolation that lead to ataxia, spasticity, and cognitive decline. During postnatal development (from P5 to P15 in the mouse), MLC1 forms a membrane complex with GlialCAM (another astrocytic transmembrane protein) at the junctions between perivascular astrocytic processes (PvAPs, which along with blood vessels form the gliovascular unit (GVU)). We analyzed the GVU in the Mlc1 knock-out mouse model of MLC. The absence of MLC1 led to an accumulation of fluid in the brain but did not modify the endothelial organization or the integrity of the blood-brain barrier. From P10 onward, the postnatal acquisition of vascular smooth muscle cell contractility was altered, resulting in a marked reduction in arterial perfusion and neurovascular coupling. These anomalies were correlated with alterations in astrocyte morphology, astrocyte polarity and the structural organization of the PvAP’s perivascular coverage, and poor intraparenchymal circulation of the cerebrospinal fluid (CSF). Hence, MLC1 is required for the postnatal development and organization of PvAPs and controls vessel contractility and intraparenchymal interstitial fluid clearance. Our data suggest that (i) MLC is a developmental disorder of the GVU, and (ii) PvAP and VSMC maturation defects are primary events in the pathogenesis of MLC and therapeutic targets for this disease.