Systolic hypertension-induced neurovascular unit disruption magnifies vascular cognitive impairment in middle-age atherosclerotic LDLr−/−:hApoB+/+ mice

Introduction: The damage in the endothelium and the neurovascular unit appears to play a key role in the pathogenesis of vascular cognitive impairment (VCI). Although there have been many advances in understanding the physiopathology of this disease, several questions remain unanswered. The association with other degenerative diseases and the heterogeneity of its clinical spectrum establish a diagnostic problem, compromising a better comprehension of the pathology and halting the development of effective treatments. The investigation of biomarkers is an important movement to the development of novel explicative models and treatment targets involved in VCI. Methods: We searched MEDLINE considering the original research based on VCI biomarkers in the past 20 years, following prespecified selection criteria, data extraction, and qualitative synthesis. Results: We reviewed 42 articles: 16 investigated plasma markers, 17 analyzed neuropathological markers, 4 studied CSF markers, 4 evaluated neuroimaging markers (ultrasound and MRI), and 1 used peripheral Doppler perfusion imaging. Conclusions: The biomarkers in these studies suggest an intrinsic relationship between endothelial dysfunction and VCI. Nonetheless, there is still a need for identification of a distinctive set of markers that can integrate the clinical approach of VCI, improve diagnostic accuracy, and support the discovery of alternative therapies.

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Therapeutic Potential of Remote Ischemic Conditioning in Vascular Cognitive Impairment

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.706759 ◽

2021 ◽

Vol 15 ◽

Author(s):

Rui Xu ◽

Qianyan He ◽

Yan Wang ◽

Yi Yang ◽

Zhen-Ni Guo

Keyword(s):

Cognitive Impairment ◽

Cognitive Processing ◽

Therapeutic Potential ◽

Recurrent Stroke ◽

Neurovascular Unit ◽

Vascular Cognitive Impairment ◽

Cerebrovascular Diseases ◽

Remote Ischemic Conditioning ◽

Ischemic Conditioning ◽

Social Burden

Vascular cognitive impairment (VCI) is a heterogeneous disease caused by a variety of cerebrovascular diseases. Patients with VCI often present with slower cognitive processing speed and poor executive function, which affects their independence in daily life, thus increasing social burden. Remote ischemic conditioning (RIC) is a non-invasive and efficient intervention that triggers endogenous protective mechanisms to generate neuroprotection. Over the past decades, evidence from basic and clinical research has shown that RIC is promising for the treatment of VCI. To further our understanding of RIC and improve the management of VCI, we summarize the evidence on the therapeutic potential of RIC in relation to the risk factors and pathobiologies of VCI, including reducing the risk of recurrent stroke, decreasing high blood pressure, improving cerebral blood flow, restoring white matter integrity, protecting the neurovascular unit, attenuating oxidative stress, and inhibiting the inflammatory response.

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Decreased parenchymal arteriolar tone uncouples vessel-to-neuronal communication in a mouse model of vascular cognitive impairment

GeroScience ◽

10.1007/s11357-020-00305-x ◽

2021 ◽

Author(s):

Ki Jung Kim ◽

Juan Ramiro Diaz ◽

Jessica L. Presa ◽

P. Robinson Muller ◽

Michael W. Brands ◽

...

Keyword(s):

Cognitive Impairment ◽

Cognitive Decline ◽

Pyramidal Neurons ◽

Ex Vivo ◽

Neurovascular Unit ◽

Vascular Cognitive Impairment ◽

Early Event ◽

Functional Changes ◽

Post Surgery ◽

Arteriolar Tone

AbstractChronic hypoperfusion is a key contributor to cognitive decline and neurodegenerative conditions, but the cellular mechanisms remain ill-defined. Using a multidisciplinary approach, we sought to elucidate chronic hypoperfusion-evoked functional changes at the neurovascular unit. We used bilateral common carotid artery stenosis (BCAS), a well-established model of vascular cognitive impairment, combined with an ex vivo preparation that allows pressurization of parenchymal arterioles in a brain slice. Our results demonstrate that mild (~ 30%), chronic hypoperfusion significantly altered the functional integrity of the cortical neurovascular unit. Although pial cerebral perfusion recovered over time, parenchymal arterioles progressively lost tone, exhibiting significant reductions by day 28 post-surgery. We provide supportive evidence for reduced adenosine 1 receptor-mediated vasoconstriction as a potential mechanism in the adaptive response underlying the reduced baseline tone in parenchymal arterioles. In addition, we show that in response to the neuromodulator adenosine, the action potential frequency of cortical pyramidal neurons was significantly reduced in all groups. However, a significant decrease in adenosine-induced hyperpolarization was observed in BCAS 14 days. At the microvascular level, constriction-induced inhibition of pyramidal neurons was significantly compromised in BCAS mice. Collectively, these results suggest that BCAS uncouples vessel-to-neuron communication—vasculo-neuronal coupling—a potential early event in cognitive decline.

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Extracellular matrix inflammation in vascular cognitive impairment and dementia

Clinical Science ◽

10.1042/cs20160604 ◽

2017 ◽

Vol 131 (6) ◽

pp. 425-437 ◽

Cited By ~ 56

Author(s):

Gary A. Rosenberg

Keyword(s):

Extracellular Matrix ◽

Cognitive Impairment ◽

Blood Vessel ◽

Vascular Disease ◽

Small Vessel Disease ◽

Wide Spectrum ◽

Neurovascular Unit ◽

Vascular Cognitive Impairment ◽

Small Vessel ◽

Chronic Hypertension

Vascular cognitive impairment and dementia (VCID) include a wide spectrum of chronic manifestations of vascular disease related to large vessel strokes and small vessel disease (SVD). Lacunar strokes and white matter (WM) injury are consequences of SVD. The main vascular risk factor for SVD is brain hypoperfusion from cerebral blood vessel narrowing due to chronic hypertension. The hypoperfusion leads to activation and degeneration of astrocytes with the resulting fibrosis of the extracellular matrix (ECM). Elasticity is lost in fibrotic cerebral vessels, reducing the response of stiffened blood vessels in times of increased metabolic need. Intermittent hypoxia/ischaemia activates a molecular injury cascade, producing an incomplete infarction that is most damaging to the deep WM, which is a watershed region for cerebral blood flow. Neuroinflammation caused by hypoxia activates microglia/macrophages to release proteases and free radicals that perpetuate the damage over time to molecules in the ECM and the neurovascular unit (NVU). Matrix metalloproteinases (MMPs) secreted in an attempt to remodel the blood vessel wall have the undesired consequences of opening the blood–brain barrier (BBB) and attacking myelinated fibres. This dual effect of the MMPs causes vasogenic oedema in WM and vascular demyelination, which are the hallmarks of the subcortical ischaemic vascular disease (SIVD), which is the SVD form of VCID also called Binswanger's disease (BD). Unravelling the complex pathophysiology of the WM injury-related inflammation in the small vessel form of VCID could lead to novel therapeutic strategies to reduce damage to the ECM, preventing the progressive damage to the WM.

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