Hypertension and small vessel disease: A dangerous association for cognitive impairment over time

In the current issue of the Journal, Pavlovic et al1 reported data that showed further proof of the involvement of arterial hypertension as a risk factor for cognitive impairment in patients with asymptomatic cerebral small vessel disease (SVD). Findings of their study were based on a cohort of 424 patients diagnosed with SVD by magnetic resonance imaging (MRI), followed prospectively for approximately four years, and classified into two groups according to the presence or absence of hypertension at baseline. Development of vascular cognitive impairment at follow‐up was more frequent in hypertensive patients compared with the non‐hypertensive group, and the difference was statistically significant (HR 1.60, 95% CI: 1.16 to 2.21, P = 0.004). Therefore, it appears that hypertension and SVD is a dangerous combination putting patients at increased risk for cognitive decline.

There is solid and robust evidence of the role of hypertension as a major risk factor for cardiovascular disease as well as for cognitive impairment, vascular dementia, and Alzheimer's disease.2 Hypertension accelerates the evolution of atherosclerosis and contributes to increased cardiovascular morbidity and mortality. Also, it has been shown that patients with hypertension are at higher risk for lacunar stroke, atherothrombotic infarcts, primary intracerebral hemorrhage, and stroke recurrence.3, 4 On the other hand, blood pressure variability (expressed as average day and night time values, day‐to‐day, or visit‐to‐visit variability) is associated with increased risk of cardiovascular events in patients with hypertension, irrespective of the baseline risk of cardiovascular events.5 High blood pressure variability has a detrimental effect on stroke prognosis,6 showing an independent and linear association with the development of neurologic deterioration in the acute stage of ischemic stroke.7 An increased 24‐hour blood pressure variability may contribute to hypertension‐related cerebral damage and unfavorable neurologic outcome in stroke patients.8 Interestingly, long‐term fluctuation of blood pressure is associated with cerebrovascular disease in the form of white matter hyperintensities (WMHs) and infarction in a linear fashion, which places individuals at an increased rate of cognitive decline, particularly among individuals with mild cognitive impairment or dementia.9 White matter is particularly susceptible to blood pressure variability or inconsistent perfusion,10 and the presence of WMHs is associated with the risk of progressing from normal to mild cognitive impairment.11

The mechanisms underlying hypertension‐related cognitive decline have not been fully elucidated. Hypertension‐associated pathologic changes in the brain and its vasculature, including vascular remodeling, impaired cerebral autoregulation, cerebral microbleeds, white matter lesions, unrecognized lacunar infarcts, and Alzheimer‐like changes such as amyloid angiopathy and cerebral atrophy have been postulated.12, 13 A process involving endothelial activation and disruption of the blood‐brain barrier integrity might play an early role in the pathogenic pathways of cognitive impairment in patients with hypertension.14 Also, hypertension may promote a preexisting subclinical Alzheimer's disease and could cause neurobiological alterations resulting in neuropathological damage. Finally, age and risk factors may act together to cause cerebral vascular degeneration, mitochondrial disruption, reduced glucose oxidation, and reduced ATP synthesis, all of which result in neuronal death and dementia.15 Prompt diagnosis of elevated blood pressure, monitoring of blood pressure variability, and adequate antihypertensive treatment is a rational basis for a more effective therapeutic strategy to achieve optimal brain perfusion, thus reducing the occurrence of a mild stage of cognitive impairment preceding dementia. In this respect, clinicians should be aware of the early diagnosis and treatment of high blood pressure in an attempt to preserve cognitive performance or delay cognitive decline.

On the other hand, cognitive impairment of vascular origin caused by cerebral small vessel disease (CSVD) has been well documented. CSVD is a highly prevalent condition associated with diffuse ischemic damage and cognitive dysfunction, particularly in executive function and attention. In patients with a first‐ever lacunar stroke, mild neuropsychological abnormalities are found in up to 57% of patients, especially in atypical lacunar syndrome and pure motor hemiparesis subtypes.16 Factors contributing to an increased risk of cognitive impairment include some symptomatic lacunar infarcts, some silent lacunes, the presence and extension of leukoaraiosis, microbleeds, brain atrophy, and the recurrence of stroke.16, 17, 18 Interruption of prefrontal‐subcortical loops by the lacunar infarction and leukoaraiosis results in neuropsychological impairment in CSVD.19 Progression of leukoaraiosis has been associated with cognitive decline; however, an association between the presence of periventricular WMHs at baseline and cognitive decline has not been established.20

Pavlovic et al1 conducted a pioneer longitudinal study assessing the impact of the combined presence of hypertension and asymptomatic CSVD on the development of vascular cognitive impairment. The Kaplan‐Meier survival analysis showed a higher proportion of patients with hypertension progressing from normal cognitive status to cognitive decline over time compared to those without hypertension. Although the authors recognized that imaging confounders for vascular cognitive impairment, such as brain atrophy or microbleeds, were not analyzed, other limitations should be addressed. It is stated that MRI evidence of CSVD was an entry criterion, but what constitutes such evidence is not described. Also, diagnosis of vascular dementia and criteria for “cognitive impairment no dementia” was based on the NINDS‐AIREN criteria, which were analyzed jointly as vascular cognitive impairment (the main outcome of the study). However, it is unknown whether the diagnosis of vascular dementia was based on possible, probable, or definitive NINDS‐AIREN criteria. Moreover, different studies have raised questions regarding the complexity of the radiological criteria of the NINDS‐AIREN criteria, the suboptimal reproducibility, and the poor interobserver agreement, which may compromise their appropriateness for routine diagnosis.21, 22 The concept of “cognitive impairment no dementia” is also confusing. In our opinion, these aspects merit clarification.

Despite these observations, in CSVD patients, the presence of hypertension as a comorbid disease is a risk factor for cognitive impairment over time. These findings are clinically relevant and should alert clinicians to maintain strict blood pressure control in patients with CSVD.

CONFLICT OF INTEREST

None to be declared.