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Hypertension-induced cognitive impairment: from pathophysiology to public health

Nature Reviews Nephrology volume 17, pages 639–654 (2021)Cite this article

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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.

Key points

  • Hypertension is associated with ageing and significantly increases the risk of vascular cognitive impairment and Alzheimer’s disease.

  • In older individuals, hypertension leads to maladaptation of the cerebral circulation, resulting in dysregulation of cerebral blood flow, microvascular rarefaction, blood–brain barrier disruption, oxidative stress and impaired neurovascular coupling.

  • Hypertension causes pathological alterations in cerebral microvessels that damage microvascular structure, network architecture and function, and contribute to the genesis of cerebral microhaemorrhages, lacunar infarcts and white matter injury; these factors are associated with cognitive decline.

  • Potential mechanisms by which hypertension could exacerbate the progression of Alzheimer’s disease include increased oxidative microvascular damage, brain inflammation and blood–brain barrier disruption, as well as impaired glymphatic (also known as glial-lymphatic) clearance of amyloid-β.

  • Use of pharmaceutical and/or lifestyle interventions that reduce blood pressure in combination with treatments that promote microvascular health could potentially prevent or delay cognitive decline in patients with hypertension.

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Fig. 1: Age-related autoregulatory dysfunction exacerbates hypertension-induced cerebromicrovascular injury.
Fig. 2: Hypertension-induced small vessel disease and its radiological manifestations.
Fig. 3: Hypertension-induced blood–brain barrier disruption.
Fig. 4: Hypertension-induced cerebral microhaemorrhages.
Fig. 5: Hypertension and ageing exert synergistic negative effects on cerebromicrovascular network maintenance.
Fig. 6: Hypertension and ageing lead to impairment of endothelium-dependent neurovascular coupling and functional hyperaemia.
Fig. 7: Hypertension exacerbates Alzheimer’s disease pathologies.

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Acknowledgements

The authors’ work was supported by grants from the American Heart Association, the Oklahoma Center for the Advancement of Science and Technology, the Presbyterian Health Foundation and the Department of Veterans Affairs (award Number CX000340).

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Authors and Affiliations

  1. Vascular Cognitive Impairment and Neurodegeneration Program, Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Zoltan Ungvari, Peter Toth, Stefano Tarantini & Anna Csiszar

  2. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary

    Zoltan Ungvari, Peter Toth & Stefano Tarantini

  3. Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Zoltan Ungvari & Stefano Tarantini

  4. Department of Neurosurgery, Medical School, University of Pecs, Pecs, Hungary

    Peter Toth

  5. Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Calin I. Prodan

  6. Veterans Affairs Medical Center, Oklahoma City, OK, USA

    Calin I. Prodan

  7. Department of Neurology, Division of Stroke and Neurocritical Care, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Farzaneh Sorond

  8. Heart and Vascular Center, Semmelweis University, Budapest, Hungary

    Bela Merkely

  9. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Institute of Clinical Experimental Research, Semmelweis University, Budapest, Hungary

    Anna Csiszar

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  1. Zoltan Ungvari
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Glossary

Lacunar infarcts

Small infarcts (2–20 mm in diameter) in the deep cerebral white matter, basal ganglia, or pons that are presumed to result from the occlusion of a single small perforating artery supplying the subcortical areas of the brain.

White matter lesions

Areas of abnormal myelination in the brain that are best visualized as hyperintensities on T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI sequences.

Abstract reasoning

A cognitive domain that is closely related to fluid intelligence. The ability to quickly reason with information to solve new, unfamiliar problems, independent of any prior knowledge.

Executive function

A set of mental skills that include working memory, flexible thinking and self-control.

Digit Symbol Substitution Test

A paper-and-pencil cognitive test that requires matching of symbols to numbers.

Mini-Mental State Examination

(MMSE). A test of cognitive function that is widely used for elderly people. The MMSE includes tests of orientation, attention, memory, language and visuo-spatial skills.

Lipohyalinosis

Cerebral small vessel disease affecting the small arteries and arterioles in the brain. Lipohyalinosis is characterized by vessel wall thickening and a resultant reduction in luminal diameter.

Lacunes

Small subcortical infarcts (<15 mm in diameter) in the territory of the deep penetrating arteries. These lesions may present with specific lacunar syndromes or they may be asymptomatic.

Gliosis

An inflammatory process leading to scars in the central nervous system that involves the production of a dense fibrous network of neuroglia in areas of damage.

Astrocytic endfeet

Processes that physically connect the astrocyte cell body to the outside of capillary walls.

Pathogen-associated molecular patterns

Small molecular motifs that are recognized by Toll-like receptors. PAMPS activate innate immune responses that protect the host from infection.

Transverse aortic coarctation

Narrowing of the transverse aortic arch.

Neuropil

A dense network of interwoven nerve fibres and their branches and synapses together with glial filaments.

Senolytics

A class of small molecules that selectively induce death of senescent cells. Senolytics are being developed with the aim of delaying, preventing, alleviating or reversing age-related diseases and improving human health.

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Ungvari, Z., Toth, P., Tarantini, S. et al. Hypertension-induced cognitive impairment: from pathophysiology to public health. Nat Rev Nephrol 17, 639–654 (2021). https://doi.org/10.1038/s41581-021-00430-6

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