Hypertension-Induced Cognitive Impairment: from Pathophysiology to Public Health
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REVIEWS Hypertension-induced cognitive impairment: from pathophysiology to public health Zoltan Ungvari1,2,3, Peter Toth1,2,4, Stefano Tarantini1,2,3, Calin I. Prodan 5,6, Farzaneh Sorond 7, Bela Merkely8 and Anna Csiszar1,9 ✉ Abstract | Hypertension affects two-thirds of people aged >60 years and significantly increases the risk of both vascular cognitive impairment and Alzheimer’s disease. Hypertension compromises the structural and functional integrity of the cerebral microcirculation, promoting microvascular rarefaction, cerebromicrovascular endothelial dysfunction and neurovascular uncoupling, which impair cerebral blood supply. In addition, hypertension disrupts the blood–brain barrier, promoting neuroinflammation and exacerbation of amyloid pathologies. Ageing is characterized by multifaceted homeostatic dysfunction and impaired cellular stress resilience, which exacerbate the deleterious cerebromicrovascular effects of hypertension. Neuroradiological markers of hypertension-induced cerebral small vessel disease include white matter hyperintensities, lacunar infarcts and microhaemorrhages, all of which are associated with cognitive decline. Use of pharmaceutical and lifestyle interventions that reduce blood pressure, in combination with treatments that promote microvascular health, have the potential to prevent or delay the pathogenesis of vascular cognitive impairment and Alzheimer’s disease in patients with hypertension. Vascular cognitive impairment (VCI) and Alzheimer’s mechanisms, including regulation of cerebral blood disease (AD) are major obstacles to healthy ageing and flow and microvascular pressure. Third, ageing is asso- the principal causes of chronic disability and decreased ciated with impaired cellular stress resilience, which quality of life among elderly people in the industrialized exacerbates cellular and molecular damage resulting world. The prevalence of AD and VCI is projected to from hypertension-induced haemodynamic and oxi- quadruple in the next 50 years owing to rapid ageing dative stress. Fourth, several key cellular and molecu- of the populations of Europe, Japan and the USA. The lar mechanisms, including oxidative stress, endothelial economic impact of dementia has been estimated at US dysfunction, inflammatory processes and blood–brain $200 billion per year in the USA1 and US $600 billion per barrier (BBB) dysfunction, are common to vascular year worldwide2, including market costs associated with ageing and hypertension-induced vascular dysfunction nursing home care and the economic burden of unpaid and end organ damage. Hypertension-induced vascular care-givers. The maintenance of cognitive health and pathologies can therefore be considered to be the result prevention of dementia among older adults is a critical of accelerated vascular ageing. Chronic hypertension can scientific and public health priority. also promote the development of atherosclerotic plaques Among the potential targets for improvement of in larger cerebral arteries9, which may adversely impact cognitive health among older adults, arterial hyper- cerebral blood flow and lead to ischaemic strokes that tension is one of the most prevalent and potentially contribute to cognitive decline in the elderly3. modifiable pathologies. Hypertension, especially in Here, we review the synergistic deleterious effects of older adults, substantially increases the risk of VCI3 elevated blood pressure and old age on the structural and exacerbates the pathogenesis of AD4–8. The inter- and functional integrity of the cerebral microcircu- actions of hypertension and ageing and the contribu- lation and cognitive function. We discuss the role of ✉e-mail: anna-csiszar@ tions of hypertension to cognitive dysfunction in older advanced age in cerebrovascular maladaptation to hyper- ouhsc.edu individuals are multifaceted. First, hypertension itself tension and the resulting exacerbation of microvascular https://doi.org/10.1038/ is a disease of ageing. Second, ageing is associated with pathologies. We then focus on microvascular contribu- s41581-021-00430-6 the generalized impairment of several homeostatic tions to exacerbated hypertension-induced cognitive NATURE REVIEWS | NEPHROLOGY VOLUME 17 | OCTOBER 2021 | 639 0123456789();: REVIEWS 14 Key points cognition . Subsequently, many prospective longitudinal studies have demonstrated a causal relationship between • Hypertension is associated with ageing and significantly increases the risk of vascular blood pressure and the incidence of VCI and AD15. cognitive impairment and Alzheimer’s disease. The Honolulu-Asia Aging Study5 demonstrated an • In older individuals, hypertension leads to maladaptation of the cerebral circulation, association between mid-life blood pressure and VCI resulting in dysregulation of cerebral blood flow, microvascular rarefaction, and AD in old age. Among participants who were never blood–brain barrier disruption, oxidative stress and impaired neurovascular coupling. treated for hypertension, higher blood pressure was • Hypertension causes pathological alterations in cerebral microvessels that damage associated with a significantly increased risk of demen- microvascular structure, network architecture and function, and contribute to the tia owing to VCI or AD (odds ratio (OR) 3.8 for DBP genesis of cerebral microhaemorrhages, lacunar infarcts and white matter injury; these factors are associated with cognitive decline. 90–94 mmHg, and 4.3 for DBP ≥95 mmHg compared with DBP 80–89 mmHg)5. Compared with normotensive indi- • Potential mechanisms by which hypertension could exacerbate the progression of Alzheimer’s disease include increased oxidative microvascular damage, brain viduals, patients with hypertension (SBP ≥160 mmHg) 5 inflammation and blood–brain barrier disruption, as well as impaired glymphatic had a 4.8-fold higher risk of dementia . In a retrospec- (also known as glial-lymphatic) clearance of amyloid-β. tive cohort study in Northern California, USA, the pres- • Use of pharmaceutical and/or lifestyle interventions that reduce blood pressure in ence of hypertension at midlife substantially increased 16 combination with treatments that promote microvascular health could potentially the risk of late-life dementia . Similar results were prevent or delay cognitive decline in patients with hypertension. obtained in a prospective, population-based study in east- ern Finland, which showed that hypertension in midlife increases the risk of AD in later life17. The prospective Lacunar infarcts impairment in ageing, including small vessel disease, Adult Health Study in Japan confirmed the association Small infarcts (2–20 mm in capillary rarefaction and BBB disruption, neurovascu- between mid-life hypertension and VCI in old age. In the diameter) in the deep cerebral lar dysfunction and the pathogenesis of cerebral micro- US ARIC study, midlife hypertension was associated with white matter, basal ganglia, haemorrhages, lacunar infarcts and white matter lesions increased cognitive decline during 20 years of follow-up18. or pons that are presumed to result from the occlusion of a (also known as leukoaraiosis), as well as the role of The Swedish Gothenburg H-70 study showed that single small perforating artery hypertension in the pathogenesis of AD in older adults. participants who developed dementia at age 79–85 years supplying the subcortical areas had significantly higher SBP (mean 178 vs 164 mmHg) of the brain. Epidemiology and higher DBP (mean 101 vs 92 mmHg) at age 70 than Hypertension (defined as systolic blood pressure those who did not develop dementia19. Another Swedish White matter lesions Areas of abnormal myelination (SBP) ≥140 mmHg or diastolic blood pressure (DBP) study showed that older adults with SBP >180 mmHg are 10 20 in the brain that are best ≥90 mmHg ) affects 1 billion individuals worldwide, at a significantly increased risk of AD . A US prospective visualized as hyperintensities and the prevalence significantly increases with age11. cohort study demonstrated that high SBP (≥160 mmHg) on T2-weighted and In the USA, the estimated prevalence of hypertension was associated with an increased risk of dementia among fluid-attenuated inversion 21 recovery (FLAIR) MRI is 76% among adults aged 65−74 years and 82% among young elderly people (aged 64–75 years) . Studies in 12 22 23 sequences. adults aged ≥75 years . Despite increasing aware- Japan and the USA reported that hypertension is an ness of the deleterious effects of hypertension, rates of independent risk factor for vascular dementia in indi- Abstract reasoning blood pressure control remain suboptimal. In the past viduals aged ≥65 years. In addition, hypertension was A cognitive domain that decade, only ~50% of adult US patients with hyperten- a risk factor for mild cognitive impairment in elderly is closely related to fluid 11 intelligence. The ability to sion achieved adequate blood pressure control . The participants (mean age 75 years) in a US longitudinal 24 quickly reason with information deleterious effects of high blood pressure on cognitive population study . to solve new, unfamiliar function were recognized at the end of the nineteenth The cognitive domains that are negatively affected problems, independent century13, and studies in the 1960s and 1970s provided by hypertension include abstract reasoning and/or of any prior knowledge. evidence that hypertension impairs various domains of executive function, memory and mental processing speed3. A study that used the Digit Symbol Substitution