Guide Biology of Brain Dysfunction: Volume 1

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Illustration Credit: Ben Smith. In summary, experimental studies and human data indicate that oxidative stress and inflammation are critical factors in the alterations in neurovascular and endothelial function produced by hypertension. Furthermore, innate immune cells, the PVM in particular, have emerged as a powerful source of vascular ROS production. The alterations in cerebrovascular structure and function induced by hypertension described in the previous sections predispose the brain to dysfunction and damage, which, in turn, alters cognition.

Chronic hypertension is the major risk factor for ischemic and hemorrhagic stroke, which is associated with a 3- to 6-fold increase in cognitive impairment, especially when multiple strokes are involved multi-infarct dementia. The most common brain lesions associated with hypertension are white matter lesions, especially in the frontal cortex, which appear as areas of hyperintensity on T2-weighted MRI. A population of oligodendrocytes associated specifically with cerebral blood vessels has been identified and oligodendrocyte proliferation and survival requires vascular growth factors.

Indeed, arrested development of oligodendrocyte precursors has been observed human white matter in SVD resulting in faulty remyelination of damaged white matter Figure 4. Figure 4. Potential mechanisms of white matter WM damage by hypertension. Vascular oxidative stress and inflammation disrupt the blood-brain barrier BBB , induce neurovascular unit NVU dysfunction and damage, and impair oligodendrocyte development and function.

The resulting alterations in tissue homeostasis, hypoxia-ischemia, reduced brain clearance, and impaired remyelination lead to WM damage. In summary, oxidative stress, hypoxia-ischemia, inflammation, and BBB dysfunction are critical vascular factors threatening the health of the subcortical white matter. There might be regional differences on the impact of hypertension on white matter, and the white matter of the frontal lobe may be more susceptible. Atrophy, brain damage caused by macroinfarcts and microinfarcts, and hemorrhages are important determinants of cognitive impairment.

Furthermore, infarcts strategically placed in brain regions involved in cognition, for example, hippocampus, medial thalamus, and frontal lobe, can produce cognitive dysfunction, despite relatively small volume of damage, 66 , and the estimated functional impact of microinfarcts is greater than anticipated by the volume of injury. The impact of enlarged perivascular spaces on cognitive impairment of hypertension remains uncertain. The morphological alterations of the perivascular space raise the possibility that perivascular and paravascular clearance systems may be altered and have a role in the white matter damage.

Therefore, direct evidence linking hypertension to brain clearance pathways has not been provided, in humans as in animal models, and additional work is needed in this area. These observations, collectively, suggest that hypertension may lead to cognitive impairment through several pathogenic factors Figure 5. Gray matter loss, loss of connectivity and network efficiency from white matter lesions, reduced perivascular clearance, and neurovascular dysfunction all have the potential to impair brain function, but their relative impact on cognitive processes remain to be established.

Figure 5. Brain lesions produced by hypertension that underlie cognitive impairment. Brain atrophy, microinfarcts, and microbleeds cause neuronal loss and brain dysfunction. In addition, microinfarcts and microbleeds disrupt brain connectivity and reduce network efficiency. Damage to white matter lesions WML also degrades connectivity, especially in thalamo-cortico networks. Alteration in perivascular spaces PVS impairs brain clearance and may promote protein accumulation in brain and vessels, and dysfunction of the neurovascular unit NVU leads to vascular insufficiency and BBB damage.

Potential interactions between different pathogenic mechanisms are indicated by the dashed arrows. CBF indicates cerebral blood flow. A large body of evidence indicates that hypertension is a risk factor for AD—a condition once considered purely a neurodegenerative disease. In the ARIC-PET study, nondemented participants with a greater number of vascular risk factors in middle age, including hypertension, had more elevated brain amyloid in late life, suggesting a possible direct impact of these risk factors on amyloid; hypertension by itself, however, was not significantly associated with elevated amyloid so may not have an independent role.

In addition to the above-cited studies of elevated BP and brain atrophy, 42 midlife BP has also been associated with hippocampal atrophy by MRI, with the strongest associations among untreated hypertensives. At the same time, administration of renin-angiotensin system blockers or AT1R genetic deletion ameliorates amyloid deposition and behavioral dysfunction in APP-overexpressing mice. Endothelial NO prevents tau phosphorylation by inhibiting Cdk5 cyclin-dependent kinase-5 —one of the main kinases phosphorylating tau —and consequently the NO deficit associated with hypertension could promote tau phosphorylation.

Figure 6. Potential mechanisms underlying the relationship between hypertension and Alzheimer disease AD.

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BBB indicates blood-brain barrier. Adapted from Iadecola et al 8 with permission. These clinical and experimental observations, collectively, suggest that hypertension has the potential to promote AD pathology by acting at different levels. However, it remains unclear whether hypertension is a pathogenic factor in AD, and, conversely, whether the AD pathology associated with hypertension is a contributor to the cognitive dysfunction. Given the strong and consistent associations seen in the epidemiological literature between hypertension and dementia, and given the strong biological plausibility for a link between the two, the inevitable next question is whether treatment of hypertension reduces risk of dementia.

Certainly, this is the major reason why the study of hypertension as a risk factor for dementia is of particular interest: in the absence of other ways to treat or prevent dementia and AD specifically, hypertension is an especially appealing target. Several epidemiological studies have considered the role of antihypertensive medication treatment, although all remain susceptible to some indication bias: individuals who are prescribed and take antihypertensives are different than people who do not, in many ways beyond which can be adjusted statistically.

Thus, clinical trials would be the ideal forum in which to test this question, but given the above reviewed evidence that relationships between hypertension and dementia are the strongest when hypertension is considered in middle age, decades before the development of dementia, and that clinical trials cannot randomize and follow participants for that long duration, some reliance on longer term observational study designs is needed to consider these life span considerations.

These studies also allow consideration of age of treatment or duration of treatment, which can extend beyond the windows allowed by clinical trials. In several observational studies, antihypertensive medication use is associated with less cognitive decline; in the ARIC study, participants taking antihypertensive medications had a year cognitive decline equivalent to a prehypertensive group higher than the normotensives but lower than untreated hypertensives.

In the HAAS study, per additional year of antihypertensive treatment, dementia risk was lower hazard ratio, 0. Although the focus of this review is on hypertension, elevated BP as a risk factor rarely occurs in isolation, and several risk factors co-occurring in the same individuals may further increase accelerated cognitive decline. In the Framingham Heart Study, hypertension was associated with worse decline in the presence of diabetes mellitus compared with its effect in nondiabetics, and in the Framingham Offspring Study, cognitive outcomes were the worst among participants with hypertension and elevated waist-hip ratio.

Similar relationships are seen when consideration is made of any additional risk factor: in participants of the Kaiser HMO Health Maintenance Organization , an increasing number of midlife vascular risk factors was associated with elevated risk of dementia in late life, with a hazard ratio of 1.

A growing body of evidence supports the biological importance of the renin-angiotensin system and points to the potential importance of drugs within this family for dementia prevention in individuals with hypertension. Intervention trials in SHR have shown reduced poststroke cognitive impairment in rodents treated with renin-angiotensin system modifiers specifically candesartan—an AT1R blocker. The optimal treatment regimen to prevent future cognitive impairment or dementia is difficult to ascertain because nearly all antihypertensives have studies supporting their potential benefit.

Again, these are still likely confounded by indication bias, similar to the overall issue of indication bias regarding any antihypertensive use versus none, although to a lesser degree considering one antihypertensive versus another may be influenced by comorbidities or demographic characteristics but are less profoundly impacted by socioeconomic or other factors influencing access to medical care more broadly. Although the body of knowledge relating hypertension to cognitive outcomes, dementia, and AD has expanded tremendously in recent years, several key questions remain.

Answers to some of these questions, listed below, will be critical to gain a better insight into how hypertension impacts cognitive function and to best recommend prevention and management strategies. Hypertension induces alterations in neurovascular function, which are thought to induce brain lesions associated with cognitive impairment Figure 5.

However, it remains to be established whether the neurovascular dysfunction alone is sufficient to induced cognitive impairment. Reduced cerebral perfusion, alterations in brain clearance and BBB, as well as vascular growth factor deficiency have the potential to alter neuronal function in metabolically active brain regions involved in cognitive function, such as the hippocampus, entorinal cortex, and prefrontal cortex.

A better understanding of the natural history of the impact of hypertension on cerebrovascular function, network degradation, and cognition would be needed to address this question, which is relevant to the initiation of antihypertensive therapy. In parallel, a more nuanced understanding of the signaling mechanisms by which the neurovascular dysfunction interferes with neuronal function would also be desirable.

Is CBF insufficiency the major factor? Or, are there other aspects of cerebrovascular biology, such as trophic support by endothelial factors or perivascular clearance, also at play? As summarized above, the benefits of antihypertensive therapy are likely to be the greatest when initiated in midlife, and continued over decades, although preliminary results from the SPRINT-MIND trial suggest that benefits may still be possible with a shorter duration of antihypertensive therapy.

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In this regard, it would be important to assess whether the appearance of brain lesions diminishes the impact of hypertensive therapy on cognitive health. Although difficult to study in clinical trials, further consideration will need to be made of optimal age and duration of antihypertensive therapy, and correlation with cardiovascular and structural-functional imaging biomarkers, to best prevent cognitive decline, MCI, and dementia. Individuals with more vascular risk factors appear especially vulnerable to hypertension, with worse outcomes among individuals with several vascular risk factors.

This suggests that individuals with other known risk factors, such as diabetes mellitus, may need better screening of BP with a lower threshold for initiation of antihypertensive therapy. This is consistent with the management of vascular risk factors because they relate to other cardiovascular outcomes.

Beyond vascular risk, there may be genetic susceptibilities, such as has been seen with the APOE data, leading to greater risk and, therefore, greater potential benefit from antihypertensive therapy, in individuals with a known risk allele or even of a particular race or sex. Focused trials with enrollment of these higher risk groups could identify a subgroup in whom prevention might be especially effective.

Although ongoing studies are directly addressing the potential benefit of particular antihypertensives, at least on surrogate end points, at the time of this manuscript preparation, no convincing data point to a clinical difference with the use of particular antihypertensive medications. This question—whether any antihypertensive is as effective as the next—will be critical as evidence is translated into practice.

Furthermore, it is possible that the same recommended therapeutics may not be ideal for all individuals. Race-based differences in therapeutic effect for distinct antihypertensives have been noted for other cardiovascular outcomes, and similar differences by race, or other demographic or genetic factors, may be found for reduction of adverse cognitive outcomes. Biomarkers or surrogate end points are valuable in studying long-term relationships as seen between hypertension and dementia because they allow for earlier assessment of therapeutic effect, both for research purposes, as well as clinically, to evaluate benefits of treatment.

Ongoing studies and consortia, including MarkVCID Mark Vascular Contributions to Cognitive Impairment and Dementia , are evaluating biomarkers for the vascular contribution to cognitive impairment and dementia, which likely would be candidates for the specific effect of hypertension on the brain as well, and may include serum, CSF, or imaging markers to examine the contribution from AD pathology.

As discussed in a previous section, there is biological plausibility that hypertension and other vascular risk factors may promote AD pathology and vice versa. However, the clinical-pathological evidence remains contradictory. The recent development and validation of amyloid and tau PET imaging provides the opportunity to examine in vivo the reciprocal interaction between markers of AD and hypertensive neuropathology and their relative contribution to cognitive impairment.

These findings would have important implications for targeting treatments to the relevant pathology responsible for the cognitive deficits in a particular individual. These are a few of the outstanding questions that remain to be addressed. Answering these questions will require engaging both the preclinical and clinical scientific communities in a concerted effort to advance the understanding of how hypertension affects brain function leading to cognitive impairment.

Thus, epidemiological, biomarker, and clinical-pathological studies should be closely related to basic science efforts to unravel mechanisms and provide new targets to be tested in clinical trials. Such cooperation will be essential for the development of new diagnostic tools and treatment strategies for one of the most devastating health challenges of our times.

Iadecola , RNS C. Iadecola , KAG R. Gottesman , and RAG R. Gottesman is Associate Editor for the journal Neurology. Home Circulation Research Vol. View PDF. Tools Add to favorites Download citations Track citations Permissions. Jump to. Rebecca F. Gottesman Rebecca F. Gottesman Departments of Neurology R. Epidemiology R. Abstract Hypertension has emerged as a leading cause of age-related cognitive impairment. Download figure Download PowerPoint. Email coi med. References 1. Global burden of hypertension and systolic blood pressure of at least to mm Hg, Spieth W. Cardiovascular health status, age, and psychological performance.

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Frith, C. The social brain?

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Individuals with rage disorder have smaller volumes in brain areas linked to emotion. Call Us At Additional authors include Daniel A.