Vascular mechanisms of cognitive impairment: roles of hypertension and subsequent small vessel disease under sympathetic influences

Abstract

M ild cognitive impairment (MCI) and vascular cognitive impairment are clinically important in the development of Alzheimer disease (AD) 1 and Binswanger disease/vascular dementia. 2,3 The vascular mechanisms of MCI/vascular cognitive impairment, as well as AD with vascular factors, are likely chronic cerebral ischemia due to both hypertensive lipohyalinotic small artery disease and arteriolar-capillary fibrohyalinosis with subsequent dysfunction of the blood-brain barrier. 4,5 These may ultimately cause multiple lacunes in the basal ganglia and the white matter, as well as white matter rarefaction by alteration in the glia and axons. 4 Sympathetic nerve terminals exist not only in the innermost part of the adventitia, but also in the outer layer of the tunica media in human cerebral arteries. 6 Furthermore, the density of sympathetic terminals in cerebral arterial walls makes up over 30% of the total nerve terminals. 7 These may have roles in the development of angionecrosis/medial necrosis under excessive neurogenic control to smooth muscle layers by repeated arterial constrictions, while maintaining autoregulation of perfusion pressure under persistent hypertension. Thus, earthenware pipe-like subpial medial necrosis and medullary arteriolosclerosis accompanying diffuse white matter lesions in vascular cognitive impairment/Binswanger disease brains appear. 8,9 Moreover, blood-brain barrier alters with aging and even in some normal brain structures such as the olfactory bulb, hippocampus and periventricular areas, 10-12 and bloodbrain barrier dysfunctions with the development of capillary collagenosis have been revealed not only in Binswanger disease brains, 13,14 but also spontaneously hypertensive rats and a rat model of chronic cerebral hypoperfusion. 15,16 Recently, it has been shown that the intra-cranial capillary diameter is regulated by pericyte contraction under noradrenergic and purinergic neurotransmitter influences. 17 All the above findings suggest that a failure in autonomic control of cerebral circulation and damage in blood-brain barrier under untreated hypertension have significant roles in the pathogenesis of MCI/vascular cognitive impairment.The relationship, however, between hypertension and cognitive impairment has long been debated and still remains controversial. The majority of studies suggest that elevated blood pressure (BP) is associated with cognitive decline. 18 Longitudinal studies examining midlife hypertension have reported BP as a risk factor for dementia, suggesting its association with late-life atherosclerosis and vascular mechanisms of dementia. The Honolulu-Asia Aging Study-which tracked 2505 men, ages ranging from 71 to 93 years old, who were dementia-free over a mean of 5.1 years-demonstrated that dementia was significantly associated with high systolic BP, but not with pulse pressure. 19 Hypertension may be expected to predispose patients to the development of small vessel diseases, such as silent lacunar infarcts or white matter lesions, leading to cognitive impairmen...

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“…Elevated blood pressure often results in generalized vascular disease (45), stroke (46) and dementia (47), and thus, it is a major risk factor for death. Moreover, the individual tendency to exhibit abnormally enhanced responses to stressors predicts the development of later hypertension (48).…”

MRI features of Binswanger's disease predict prognosis and associated pathology

“…Thus, a longitudinal epidemiological cohort study is required to attempts to clarify the true clinical profile and outcome of cerebral small vessel diseases. In subcortical VaD/BD patients, concomitant chronic kidney disease, systemic vascular disease, cardiac insufficiency, and a hypercoagulation state may further accelerate their poor prognosis 8,26,31,32…”

“…These structures are primarily involved in lacunes, branch atheromatous diseases, hippocampal sclerosis, and fiber bundle lesions related to these structures. Macro-pathological involvements in these structures and micro-cellular pathologies because of hypertensive small vessel diseases and chronic hypoperfusion (including microinfarcts, perivascular space pathologies, axonal damage, and immune-inflammatory responses) are essential for estimating pathological diagnosis scores 8,17,18,26…”

Combined Effects of Cognitive Impairment and Hypertension on Total Mortality in Elderly People: The Kangwha Cohort Study

“…In this regard, demonstrated by Skoog [35] , changes in cerebral white matter, or leukoaraiosis, can also occur resulting from prolonged high BP. In addition, prospective studies examining midlife hypertension have reported that hypertension is a significant risk factor for cognitive impairment, hence it could be associated with late-life atherosclerosis and vascular mechanisms of cognitive impairment [34,36] . All the above findings suggest that vascular changes which are caused by hypertension can develop cognitive impairment [15,31,35] .…”

“…Hypertension may develop small vessel diseases such as silent lacunar infarcts or white matter lesions; those subsequently cause cognitive impairment [34] . In this regard, demonstrated by Skoog [35] , changes in cerebral white matter, or leukoaraiosis, can also occur resulting from prolonged high BP.…”