. Blood Pressure, Brain Volume and White Matter Hyperintensities, and Dementia Risk. JAMA. 2019 Aug 13;322(6):512-513. PubMed.

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  1. 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.

    View all comments by Seth Love
  2. 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:

    . Dynamic Regulation of Cerebral Blood Flow in Patients With Alzheimer Disease. Hypertension. 2018 Jul;72(1):139-150. Epub 2018 May 29 PubMed.

    . 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
  3. 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
  4. 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:

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

    . Association of midlife blood pressure to late-life cognitive decline and brain morphology. Neurology. 1998 Oct;51(4):986-93. PubMed.

    . Blood pressure decrease correlates with tau pathology and memory decline in hypertensive elderly. Neurobiol Aging. 2014 Jan;35(1):64-71. PubMed.

    . Treatment of hypertension in the oldest old: a critical role for frailty?. Hypertension. 2014 Mar;63(3):433-41. Epub 2013 Dec 9 PubMed.

    . 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.

    . 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.

    . 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

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