Small vessel disease, neurovascular regulation and cognitive impairment: post-mortem studies reveal a complex relationship, still poorly understood

Abstract

The contribution of vascular disease to cognitive impairment is under-recognized and the pathogenesis is poorly understood. This information gap has multiple causes, including a lack of post-mortem validation of clinical diagnoses of vascular cognitive impairment (VCI) or vascular dementia (VaD), the exclusion of cases with concomitant neurodegenerative disease when diagnosing VCI/VaD, and a lack of standardization of neuropathological assessment protocols for vascular disease. Other contributors include a focus on end-stage destructive lesions to the exclusion of more subtle types of diffuse brain injury, on structural abnormalities of arteries and arterioles to the exclusion of non-structural abnormalities and capillary damage, and the use of post-mortem sampling strategies that are biased towards the identification of neurodegenerative pathologies. Recent studies have demonstrated the value of detailed neuropathology in characterizing vascular contributions to cognitive impairment (e.g. in diabetes), and highlight the importance of diffuse white matter changes, capillary damage and vasoregulatory abnormalities in VCI/VaD. The use of standardized, evidence-based post-mortem assessment protocols and the inclusion of biochemical as well as morphological methods in neuropathological studies should improve the accuracy of determination of the contribution of vascular disease to cognitive impairment and clarify the relative contribution of different pathogenic processes to the tissue damage.

Cystatin C promotes cognitive dysfunction in rats with cerebral microbleeds by inhibiting the ERK/synapsin Ia/Ib pathway

“…CMB may play a role in development of cerebrovascular diseases and neurodegenerative diseases. Its detection rate in Alzheimer's disease is twice that in the same age control group (38). In electrophysiology, LTP is a synaptic plasticity mechanism underlying learning and memory (39)(40).…”

A short communication about vascular dementia

“…About the pathogenesis on the cerebral tissue level, multiple process contributes for VCI/VaD development. The relation between Cerebrovascular Diseases (CVD) and VCI in VaD, as its pathogenesis, is not well understood, Love and Miners (2017).…”

“…In this way, when the VCI cases are evaluated, the disease of small vases appears to be the most frequent cause, which can be subdivided in two mean classes that have in common the stenosis of the arteriole. However, it is not known if the cause of this narrowing of the vascular lumen is related directly with the pericytes activity, which are important to maintain the blood brain barrier and for the regulation of the perfusion and vascular linkage in capillary level, Love and Miners (2017).…”

Nanotherapy for Alzheimer's disease and vascular dementia: Targeting senile endothelium

“…If the NVC signaling cascade is impaired and cerebrovascular tone pathologically altered, local blood flow is compromised and neuronal dysfunction ensues. Cerebral blood flow is known to be disturbed both in neurodegenerative diseases (Alzheimer's disease and vascular dementia) and in a range of their risk factors (e.g., hypertension, stroke, and diabetes) (Arvanitakis et al 2016;Bogush et al 2017;Eskildsen et al 2017;Kelleher and Soiza 2013;Longden et al 2016;Love and Miners 2017;McInerney et al 2017;Nielsen et al 2017;Perrotta et al 2016;Sheen and Sheu 2016;Sudduth et al 2017). Moreover, brain imaging (via MRI) of human subjects (n=143) yielded results showing brain iron deposits significantly associated with general cognitive ability in old age and with age-related cognitive decline (Penke et al 2012).…”

“…In summary, endothelial cells are the main component of the blood-brain barrier (BBB), which is seriously disrupted in various neurological pathologies --including many neurodegenerative disorders (Kelleher and Soiza 2013;Tenreiro et al 2016;Yoon et al 2017). Hence, vascular-targeted therapies become plausible for the prevention and treatment of common dementias (Beishon et al 2017;Dichgans and Leys 2017;Kelleher and Soiza 2013;Love and Miners 2017;Velagapudi et al 2017;. In respect to vascular tone, vasodilators (nitric oxide, acetylcholine) are repressed while vasoconstrictor (endothelin-1) is enhanced, thus contributing to endothelial dysfunction in Alzheimer's disease (Lourenco et al 2017;Tenreiro et al 2016).…”