Effect of Intensive Blood Pressure Control on Subtypes of Mild Cognitive Impairment and Risk of Progression From SPRINT Study

Sarah A. Gaussoin MS; Nicholas M. Pajewski PhD; Gordon Chelune PhD; Maryjo L. Cleveland MD; Michael G. Crowe PhD; Lenore J. Launer PhD; Alan J. Lerner MD; Jennifer Martindale-Adams EdD; Linda O. Nichols PhD; Paula K. Ogrocki PhD; Bonnie C. Sachs PhD; Kaycee M. Sink MD; Mark A. Supiano MD; Virginia G. Wadley PhD; Valerie M. Wilson MD; Clinton B. Wright MD; Jeff D. Williamson MD; David M. Reboussin PhD; Stephen R. Rapp PhD

Disclosures

J Am Geriatr Soc. 2022;70(5):1384-1393. 

In This Article

Discussion

Hypertension is a well-established risk factor for cognitive impairment including dementia.[26–28] As it is modifiable, it represents an important interventional target against a leading cause of disability and death in modernized societies. SPRINT has previously shown that intensive BP control to a goal of <120 mm Hg, as compared with a target of <140 mm Hg, significantly reduced the risk of MCI,[10] a precursor to dementia, and was associated with smaller increases in white matter hyperintensities based on magnetic resonance imaging.[29] This study extends those findings with two primary observations. First, the protective effect of intensive BP treatment on MCI was largely reflected in amnestic and multi-domain subtypes of MCI, subtypes that generally exhibit higher risk of progression to dementia.[2] This signals that the response to other treatments also may not be consistent across subtypes. Second, following an adjudication of MCI of any subtype, the risk of transitioning to probable dementia or death greatly increased compared with normal cognitive function. Although the increased risk of progression associated with MCI is well established for Alzheimer's dementia,[8] these results suggest that the risk may be similar among individuals with significant cardiovascular risk.

Our findings are consistent with prior studies showing that amnestic and multi-domain MCI are the most prevalent subtypes in persons being assessed for cognitive decline.[30–32] In the longitudinal Sydney Memory and Aging Study, 84% of participants who were diagnosed with incident dementia were previously diagnosed with MCI, most commonly the amnestic and multi-domain subtypes.[24] Similarly, in the Framingham Heart Study and Mayo Clinic Study of Aging, the risk of progression from MCI to dementia was higher for amnestic compared to non-amnestic MCI, and for multi-domain compared with single-domain MCI.[2] The finding that intensive treatment provided benefit for these high-risk subtypes suggests it may ultimately help to prevent or delay more severe cognitive impairment including dementia. SPRINT did not show a significant effect of intensive treatment on probable dementia (HR = 0.83; 95% CI, 0.67–1.04),[10] however, the relative effect was very similar to the significant estimated treatment effect reported for MCI (HR = 0.81; 95% CI, 0.69–0.95). Although we cannot rule out that we may have been underpowered, it appears that the protective effect of intensive treatment may occur most strongly at a place on the continuum of cognitive impairment beyond relatively minor cognitive deficits (i.e., single domain), and more in the range of broader, more severe deficits (i.e., multi-domain), especially in the presence of memory deficits.

We also observed that an adjudication of MCI conferred increased risk of progressing to probable dementia or death, further suggesting that intensive treatment not only prevents clinically meaningful MCI, but could also ultimately prevent or delay the onset of dementia, an hypothesis that is also supported by recent meta-analyses of blood pressure lowering trials.[9,33] These results suggest that MCI should be considered a primary clinical outcome in care settings as well as in future prevention trials of cognitive impairment as it likely represents an earlier stage in disease progression.

Although the results from SPRINT support the choice of MCI as a clinical target, they also raise a number of questions about how best to operationalize it. We observed, as others have, that a sizable proportion of persons initially adjudicated with MCI subsequently did not meet criteria for adjudication, or were classified in cross-section as having normal cognitive function.[8,24,34,35] This was not unexpected given that MCI represents an early stage in the progression of cognitive impairment; the boundaries between preclinical deficits and evident mild impairment often blur. Using cognitive test thresholds designed to be more sensitive for MCI and repeated cognitive testing to demonstrate persistent cognitive impairment for defining MCI, as was done in SPRINT, could reduce misclassifications. It is worth noting, individuals with more variable cognitive status (i.e., intermittent MCI) exhibited consistently lower MoCA scores compared with participants with normal cognition in SPRINT (Figure S4), and are known to be at higher risk for developing more severe impairment.[24]

Strengths and Limitations

There are several limitations to this study. First, loss to follow-up with the extended follow-up visits, although not different for each treatment group, could have been related to cognitive status and led to under-ascertainment of cognitive outcomes. Second, the trial did not adjudicate baseline cognitive status; therefore, we cannot exclude nor examine the influence of prevalent MCI at the time of randomization. Third, we only observed a significant association between treatment and the transition between normal cognitive function and MCI. The lack of associations with other specific transitions likely reflects, to some extent, a lack of statistical power. Multistate models naturally reflect more complex outcomes, with greater data requirements for observing specific transitions between states as compared with analyses of time to the first event, that is, time to event analyses do not typically differentiate between transitioning to probable dementia from normal cognitive function versus MCI. A similar observation with respect to physical activity was made in the Lifestyle Interventions and Independence for Elders trial. Although a structured physical activity program reduced the incidence of the first occurrence of major mobility disability, the intervention was not significantly associated with specific transitions between mobility states.[36] The strengths of this study are the large sample size, the use of multiple measures for cognitive domains, blinded adjudication, length of participant follow-up, and the trial's stringent protocol definition of MCI.

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