Impaired Glymphatic Function and Pulsation Alterations in a Mouse Model of Vascular Cognitive Impairment

Abstract

Large vessel disease and carotid stenosis are key mechanisms contributing to vascular cognitive impairment (VCI) and dementia. Our previous work, and that of others, using rodent models, demonstrated that bilateral common carotid stenosis (BCAS) leads to cognitive impairment via gradual deterioration of the neuro-glial-vascular unit and accumulation of amyloid-β (Aβ) protein. Since brain-wide drainage pathways (glymphatic) for waste clearance, including Aβ removal, have been implicated in the pathophysiology of VCI via glial mechanisms, we hypothesized that glymphatic function would be impaired in a BCAS model and exacerbated in the presence of Aβ. Male wild-type and Tg-SwDI (model of microvascular amyloid) mice were subjected to BCAS or sham surgery which led to a reduction in cerebral perfusion and impaired spatial learning acquisition and cognitive flexibility. After 3 months survival, glymphatic function was evaluated by cerebrospinal fluid (CSF) fluorescent tracer influx. We demonstrated that BCAS caused a marked regional reduction of CSF tracer influx in the dorsolateral cortex and CA1-DG molecular layer. In parallel to these changes increased reactive astrogliosis was observed post-BCAS. To further investigate the mechanisms that may lead to these changes, we measured the pulsation of cortical vessels. BCAS impaired vascular pulsation in pial arteries in WT and Tg-SwDI mice. Our findings show that BCAS influences VCI and that this is paralleled by impaired glymphatic drainage and reduced vascular pulsation. We propose that these additional targets need to be considered when treating VCI.

Impaired glymphatic system as evidenced by low diffusivity along perivascular spaces is associated with cerebral small vessel disease: a population-based study

“…31 32 Bilateral common carotid artery stenosis in rats, which was thought of as a model of CSVD due to preferentially affect white matter integrity, 33 caused a marked regional reduction in glymphatic transport. 34 In this study, the addition of the DTI-ALPS index to traditional models based on vascular risk factors exhibited better predictive abilities for the presence of CSVD in all eligible residents. Although it may be premature to routinely examine the efficiency of glymphatic system in middle-aged and elderly adults or patients with silent CSVD, to some extent, our findings implied potential predictive value of impaired glymphatic activity for Open access neuroimaging changes of CSVD.…”

The Underlying Role of the Glymphatic System and Meningeal Lymphatic Vessels in Cerebral Small Vessel Disease

“…Bilateral common carotid stenosis (BCAS), by induced chronic cerebral hypoperfusion and white matter lesions, was a typical mouse model of aCSVD and VCI [ 91 ]. BCAS mice showed decreased pulsation of cortical vessels and glymphatic dysfunction by impaired CSF fluorescent tracer influx three months after surgery [ 105 ]. A clinical study investigated glymphatic function by non-invasive DTI-ALPS in patients with CSVD [ 12 ].…”

“FDA-approved carbonic anhydrase inhibitors reduce Amyloid β pathology and improve cognition, by ameliorating cerebrovascular health and glial fitness”

“…In confirmation of this, impaired glymphatic clearance is also present in normal pressure hydrocephalus (NPH) [134], and treatment with low-dose ATZ (125-375mg/day) in this disorder was shown to reverse periventricular white matter hyperintensities [135], suggesting that the protective effects of low doses of ATZ may be uncoupled from its effects on glymphatic clearance in this disorder, as well as in our model. Furthermore, arterial pulsation, which is essential for multiple clearance mechanisms including IPAD [25,136], can also be improved by CAIs [42,54], suggesting that ATZ and MTZ could exert additional positive effects by improving vascular smooth muscle cell tone and function, which is currently the subject of further studies by our group.…”

“…Furthermore, arterial pulsation, which is important for multiple clearance mechanisms including IPAD [26, 136], can also be improved by CAIs [44, 56], suggesting that ATZ and MTZ could exert additional positive effects by improving vascular smooth muscle cell tone and function, which is currently the subject of further studies by our group.…”