23 Aug 2019

Mounting evidence suggests midlife hypertension negatively affects late-life cognition and that treating it could help. Three new papers support this idea. In the August 20 Lancet, researchers led by Marcus Richards, Nick Fox, and Jonathan Schott at University College London report that high blood pressure in midlife, starting as early as age 36, predisposes to cerebrovascular damage and brain atrophy in late life. However, they found no association between blood pressure and amyloid load. In the August 13 JAMA, researchers headed by Nick Bryan, University of Pennsylvania, Philadelphia, reported that intensive lowering of blood pressure reduced brain damage five years later. While this treatment also seemed to shrink the brain slightly, the data suggests that aggressive blood-pressure control could reduce small-vessel ischemia that has been associated with Alzheimer’s and related dementias. In the same issue of JAMA Neurology, Rebecca Gottesman and colleagues at Johns Hopkins University in Baltimore, reported that people with chronic hypertension from mid- through late life are at elevated risk for Alzheimer’s disease. Curiously, in those who become hypotensive in their later years, that risk did not decrease, but trended up, supporting the idea that higher blood pressure may be needed for adequate perfusion of the brain as vessels age and stiffen.

Strict blood-pressure control reduced the volume of white-matter intensities seen on MRI.
However, the treatment also shrank brain volume.
Lowering blood pressure too much in late-life increases risk for dementia.

In the UCL study, Christopher Lane and colleagues drew on data from the Medical Research Council’s National Survey of Health and Development. This study has been following 5,362 people from around Britain who were all born in the same week of March 1946. Blood pressure had been assessed five times between the ages of 36 and 69. In Insight 46, an imaging sub-study, brain MRI and amyloid PET scans were done twice, two years apart, in 500 returning participants.

The researchers found that elevated blood pressure at age 53, and a greater increase in blood pressure between the ages of 43 and 53, predicted more white-matter hyperintensities when the people reached their early 70s. Higher diastolic blood pressure at age 43 and a greater increase in DBP between the ages of 36 and 43 also associated with small brain volumes. However, at no time did blood pressure or longitudinal changes predict a positive PET scan for Aβ, or cognitive decline. Alzforum covered these findings from AAIC last year (Aug 2018 conference news).

The PET data suggest that high blood pressure more likely increases risk for dementia through small-vessel disease than through amyloid-related pathways, wrote Lenore Launer, National Institute on Aging, Bethesda, Maryland, in a Lancet editorial. It provides much-needed support for targeting blood pressure to prevent brain disease, she added. “Millions of individuals have unhealthy blood pressure. Immediate attention should be given to efforts to control blood pressure through clinical services and public-health interventions, and to alleviate the barriers to delivery and uptake of these public-health messages,” wrote Launer.

Bryan and colleagues examined data from the SPRINT MIND study, a cognitive sub-study of the larger Systolic Blood Pressure Intervention Trial (SPRINT). The goal of SPRINT was to examine whether lowering systolic blood pressure to 120 mm Hg, even lower than the National Heart, Lung, and Blood Institute (NHLBI)-recommended 140 mm Hg, could protect the cardiovascular system, kidney, and brain. SPRINT MIND researchers had reported that while the more stringent treatment had no effect on the primary outcome of dementia incidence after three years, it lowered the risk of mild cognitive impairment by 19 percent (Aug 2018 conference news; Jan 2019 news). Would the SPRINT blood-pressure regimen also slow cerebral small-vessel disease and brain volume loss?

First author Ilya Nasrallah examined data from a subgroup of 449 SPRINT participants, average age 67, who had undergone baseline and follow-up magnetic resonance imaging. He found that the volume of tissue damage, as judged by white-matter hyperintensities (WMH) on MRI, crept up more slowly in those who maintained systolic blood pressure around 120 mmHg. Over four years, people in the intensive-treatment group had damage to 0.54 cm³ less tissue than did people in the standard treatment group. However, their brain volume had decreased slightly more, by 3.7 cm³. These differences were small but statistically significant, the authors wrote.

“This is an important paper that shows aggressive blood-pressure control may help optimize brain health in later life,” said Charles DeCarli, University of California, Davis, who was not involved in the study. “We really need to strike home this notion that we need to monitor blood pressure and improve our cardiovascular health to keep our brains as healthy as possible.”

In the third paper, Gottesman and colleagues examined the interaction between midlife and late-life hypertension and dementia risk as part of the ongoing Atherosclerosis Risk in Communities (ARIC) cohort. Starting in 1987, 15,792 middle-aged people, average age 54, enrolled in ARIC. Researchers monitored their blood pressure over three more visits until 1998. Then, starting in 2011, 4,761 participants who were dementia-free and now averaging 75 years old returned twice so researchers could take updated blood pressure measurements and administer neuropsychological tests and a functional assessment. People were classified as hypertensive, hypotensive, or normotensive with blood pressures of more than 140/90 mmHg, less than 90/60 mm Hg, or somewhere in between, respectively.

At the final visit, 516 participants were diagnosed with dementia. The 1,030 who had chronic hypertension in both mid- and late life were 1.49 times more likely to develop dementia than those who had normal blood pressure during both periods. However, 389 people who had been hypertensive at enrollment and were then hypotensive at the last two study visits trended toward an enhanced risk of dementia, with a hazard ratio of 1.62 relative to people with normal blood pressure. Having hypertension in midlife and hypotension later raised the risk for mild cognitive impairment by 65 percent. The findings suggest that both hyper- and hypotension in older adults can raise the risk of dementia, but only among people who have high blood pressure in middle age.

“While an opportunity exists for blood pressure modification in the prevention of dementia, earlier, midlife management may be optimal,” wrote Shyam Prabhakaran of Northwestern University in Chicago. “Later blood-pressure–lowering interventions require careful monitoring for the potential cognitive harm associated with late-life hypotension.”—Gwyneth Dickey Zakaib

Comments

- Jurgen Claassen
  Radboud University Nijmegen Medical Center
- Posted: 27 Aug 2019
This is an excellent summary of recent studies that highlight the importance of vascular disease in the etiology and progression of dementia. These, and other recent studies, add to the growing evidence base suggesting that vascular disease is currently the most promising target to reduce the incidence and prevalence of dementia worldwide.

I would like to point out a caveat regarding the last paragraphs of this news article, which suggest that (older) people need high blood pressure to maintain cerebral blood flow. The same goes for the summary statement: "Lowering blood pressure too much in late-life increases risk for dementia."

The common perception that older people need high blood pressure to maintain cerebral perfusion is a myth. As logical as it may sound, it has never been proven in prospective studies. In contrast, cerebral autoregulation, the mechanism that maintains CBF when blood pressure changes, does not become impaired with aging. Even in older people with Alzheimer's disease, cerebral autoregulation functions normally, as we demonstrated recently (de Heus et al., 2018).

Indeed, blood pressure lowering in patients with Alzheimer's, even when they were not hypertensive at baseline, did not lead to lower CBF (de Jong et al., 2019). Not only did CBF remain stable, it also increased by 20 percent in the hippocampus (de Jong et al., 2019). Stable CBF (or an approximate 10 percent increase) with blood pressure lowering in older people with hypertension but without dementia has also been demonstrated by others (see de Jong et al., 2019, for references).

A misinterpretation of the study led by Gottesman is that we interpret the people with hypotension as "overtreatment.” The question is, however, if we have proof that their hypotension is caused by overtreatment of hypertension.

In my clinical experience, I have rarely or never encountered an older patient with a history of hypertension who had a blood pressure as low as <90 systolic solely due to antihypertensive medication. Such values I only encounter when there is also septic shock, or severe fluid loss, or terminal heart failure. We should be careful to interpret observational data as data form intervention studies. There substantial risk of reverse causality, i.e., that the dementia leads to hypotension, or that severe diseases that cause hypotension (e.g. heart failure), also contribute to cause dementia.

As a geriatrician, I welcome and support prudency when it comes to treatment of older patients, but we should not base decisions to forgo or limit antihypertensive treatment on misconceptions.

References:

de Heus RA, de Jong DL, Sanders ML, van Spijker GJ, Oudegeest-Sander MH, Hopman MT, Lawlor BA, Olde Rikkert MG, Claassen JA. Dynamic Regulation of Cerebral Blood Flow in Patients With Alzheimer Disease. Hypertension. 2018 Jul;72(1):139-150. Epub 2018 May 29 PubMed.

de Jong DL, de Heus RA, Rijpma A, Donders R, Olde Rikkert MG, Günther M, Lawlor BA, van Osch MJ, Claassen JA. Effects of Nilvadipine on Cerebral Blood Flow in Patients With Alzheimer Disease. Hypertension. 2019 Aug;74(2):413-420. Epub 2019 Jun 17 PubMed.

View all comments by Jurgen Claassen

- Seth Love
  University of Bristol
- Posted: 27 Aug 2019
The data from the SPRINT MIND study are very encouraging, but the interpretation may not be quite as straightforward as suggested.

It is certainly possible that the benefits in terms of cognition and MRI changes resulted directly from the aggressive lowering of systolic blood pressure. However, most of the patients were receiving drugs (angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, or calcium channel blockers) that have been shown to cause cerebral arterial vasodilation, which may itself be neuroprotective, by countering the cerebral hypoperfusion that occurs very early in the development of Alzheimer's disease and that is, of course, the principal substrate of vascular dementia.

I suggest that, until the mechanism of therapeutic benefit has been clearly established, the conclusion to draw from the study is that aggressive use of these drugs lowers the risk of mild cognitive impairment and the extent of brain damage. It remains to be determined to what extent the reduction in risk is attributable to the reduction in systemic blood pressure and to what extent it results from direct effects of the drugs on the cerebral vasculature.

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- David Knopman
  Mayo Clinic College of Medicine
- Posted: 27 Aug 2019
As a co-author on the study from the ARIC cohort by Walker et al., I was impressed when I first saw the data, how important midlife hypertension was, particularly in relation to hypertension appearing first in late life, and of course in relation to normotension. The distinction between midlife hypertension followed by late-life hypotension was also an insightful observation. The importance of midlife hypertension is something we have known about for some time, but the unique longitudinal nature of the ARIC study allowed for a very detailed view over a 30-year period of observation.

The SPRINT group’s observations on differences in white-matter hyperintensity burden as a function of intensity of BP lowering was fascinating in that it paralleled the observations from clinical diagnoses as reported in the earlier SPRINT publication by Williamson et al. The observations support the hypothesis that changes in white-matter anatomy, as indexed by MR FLAIR imaging, are in the mechanistic pathway between hypertension and cognition. The only troubling finding in the SPRINT imaging study, however, was that the cognition related to loss of brain volume with the more intensely treated group. To be sure, the volume loss was very small, but the finding is counter to the general belief that preservation of cognition should be associated with less brain-volume loss. There are several explanations as described in the article that cannot be evaluated at this time. Could the reduction in white-matter hyperintensity burden itself be responsible for the brain volume loss? Or could the volume loss represent a deleterious effect of blood pressure lowering? Could the finding be an artifact of differential survival in the more intensely treated group? Is the volume change simply noise and of no consequence in either direction?

View all comments by David Knopman

- Keenan Walker
  National Institute on Aging
- Posted: 29 Aug 2019
The papers highlighted here each underscore the importance of understanding how blood pressure control may be used to reduce dementia risk and improve cognitive outcomes for older adults. In his comment, Dr. Claassen raises important points regarding the interpretation of the results from the recent Atherosclerosis Risk in Communities (ARIC) study published in JAMA, for which I was the lead author. Our finding that individuals with midlife and late-life hypertension were at increased risk for subsequent dementia was expected based on results from previous literature describing the deleterious neurologic effects of chronic hypertension (Power et al., 2013; Swan et al., 1998). Our finding that individuals with a pattern of midlife hypertension followed by late-life hypotension were at increased risk for dementia was more novel, but also not unexpected given what is known from previous studies examining longitudinal blood pressure patterns. For example, one study found that only for adults with a history of hypertension was a decline in blood pressure associated with reduced memory and increased phosphorylated tau in CSF (Glodzik et al., 2014). A similar study found that low diastolic blood pressure in late life was only associated with poorer memory and smaller brain volume among participants with histories of midlife hypertension (Muller et al., 2014).

There are several potential explanations for why sizable late-life drops in blood pressure may be associated with increased dementia risk in individuals who were previously hypertensive. As mentioned, neurodegenerative changes, even when subclinical, may lead to drops in blood pressure. Several studies have demonstrated declines in blood pressure in individuals who subsequently (or concomitantly) develop dementia (e.g., Qiu et al., 2004). In our recent study, we attempted to reduce the likelihood that incipient dementia explained the drop in late-life blood pressure by (1) separating the period of longitudinal-blood-pressure measurement from the period of dementia surveillance and by (2) demonstrating in a sensitivity analysis that the findings were similar when analyses were restricted to participants who were cognitively normal at the time of the final blood-pressure measurement (before initiation of the dementia-surveillance period). Given that the Alzheimer’s pathology and neurodegenerative processes are known to emerge one to two decades before the onset of clinical symptoms, it is likely that the dementia pathogenesis was well underway at the time late-life hypotension was determined in individuals who subsequently developed dementia in our study. Therefore, it is possible that subclinical neurodegenerative changes (the risk of which is increased by midlife hypertension) may have caused late-life declines in blood pressure, at least for a subset of our participants.

Whether antihypertensive medication overuse may have been a cause of late-life hypotension is unknown. However, we note that the vast majority (96 percent) of participants in our study with a pattern of midlife hypertension and late-life hypotension were using antihypertensive medication during late life. Other possible causes of late-life hypotension include cardiovascular disease, such as heart failure, physical frailty or a general decline in health, and autonomic dysfunction. Future work is needed to understand the determinants of late-life declines in blood pressure in those who go on to develop dementia. It is also worth noting that most participants who met criteria for late-life hypotension did so because they had a diastolic blood pressure below 60 mm Hg. Consistent with Dr. Claassen’s clinical observation, only a small subset of participants met systolic criteria for late-life hypotension (< 90 mm Hg). Late-life declines in diastolic blood pressure may have resulted from increased arterial stiffening, which itself has been associated with dementia-related outcomes in older adults (Nation et al., 2015).

It remains possible that late-life hypotension itself plays a mechanistic role in increasing dementia risk. Some have posited that a reduction in systemic blood pressure during late life in individuals who were previously hypertensive may lead to lower cerebral blood flow (CBF). The data put forth by de Heus et al., (2018), which suggests that this may not be the case, is highly informative and relevant to the interpretation of the results from the ARIC study. Continued efforts to understand the neurobiological changes associated with chronic hypertension and late-life blood-pressure declines will be important for improving our knowledge of how specific blood-pressure trajectories may contribute to dementia risk.

References:

Power A. Stroke in dialysis and chronic kidney disease. Blood Purif. 2013;36(3-4):179-83. Epub 2013 Dec 20 PubMed.

Swan GE, DeCarli C, Miller BL, Reed T, Wolf PA, Jack LM, Carmelli D. Association of midlife blood pressure to late-life cognitive decline and brain morphology. Neurology. 1998 Oct;51(4):986-93. PubMed.

Glodzik L, Rusinek H, Pirraglia E, McHugh P, Tsui W, Williams S, Cummings M, Li Y, Rich K, Randall C, Mosconi L, Osorio R, Murray J, Zetterberg H, Blennow K, de Leon M. Blood pressure decrease correlates with tau pathology and memory decline in hypertensive elderly. Neurobiol Aging. 2014 Jan;35(1):64-71. PubMed.

Muller M, Smulders YM, de Leeuw PW, Stehouwer CD. Treatment of hypertension in the oldest old: a critical role for frailty?. Hypertension. 2014 Mar;63(3):433-41. Epub 2013 Dec 9 PubMed.

Qiu C, von Strauss E, Winblad B, Fratiglioni L. Decline in blood pressure over time and risk of dementia: a longitudinal study from the Kungsholmen project. Stroke. 2004 Aug;35(8):1810-5. PubMed.

Nation DA, Edmonds EC, Bangen KJ, Delano-Wood L, Scanlon BK, Han SD, Edland SD, Salmon DP, Galasko DR, Bondi MW, Alzheimer’s Disease Neuroimaging Initiative Investigators. Pulse pressure in relation to tau-mediated neurodegeneration, cerebral amyloidosis, and progression to dementia in very old adults. JAMA Neurol. 2015 May;72(5):546-53. PubMed.

de Heus RA, de Jong DL, Sanders ML, van Spijker GJ, Oudegeest-Sander MH, Hopman MT, Lawlor BA, Olde Rikkert MG, Claassen JA. Dynamic Regulation of Cerebral Blood Flow in Patients With Alzheimer Disease. Hypertension. 2018 Jul;72(1):139-150. Epub 2018 May 29 PubMed.

View all comments by Keenan Walker