Association Between Microinfarcts and Blood Pressure Trajectories

Key Points

Question  Are blood pressure slopes associated with the development of microinfarcts?

Findings  In this population-based study of 303 patients who underwent autopsy, those with microinfarcts did not differ on baseline blood pressure compared with those with no microinfarcts. Yet, participants with subcortical microinfarcts had a greater annual decline of blood pressure.

Meaning  Subcortical microinfarcts were associated with declining blood pressure, and the presence of microinfarcts is associated with cognitive decline, which is an important consideration when setting blood pressure targets in elderly individuals.

Importance  Cerebral microinfarcts are associated with increased risk of cognitive impairment and may have different risk factors than macroinfarcts. Subcortical microinfarcts are associated with declining blood pressure (BP) in elderly individuals.

Objective  To investigate BP slopes as a risk factor for microinfarcts.

Design, Setting, and Participants  From the population-based Mayo Clinic Study of Aging, 303 of 1158 individuals (26.2%) in this cohort study agreed to have an autopsy between November 1, 2004, and March 31, 2016. Cerebral microinfarcts were identified and classified as cortical or subcortical. Baseline and BP trajectories were compared for groups with no microinfarcts, subcortical microinfarcts, and cortical microinfarcts. A secondary logistic regression analysis was performed to assess associations of subcortical microinfarcts with midlife hypertension, as well as systolic and diastolic BP slopes.

Main Outcomes and Measures  The presence of cerebral microinfarcts using BP slopes.

Results  Of the 303 participants who underwent autopsy, 297 had antemortem BP measurements. Of these, 177 (59.6%) were men; mean (SD) age at death was 87.2 (5.3) years. The autopsied individuals and the group who died but were not autopsied were similar for all demographics except educational level with autopsied participants having a mean of 1 more year of education (1.06; 95% CI, 0.66-1.47 years; P < .01). Among 297 autopsied individuals with antemortem BP measurements, 47 (15.8%) had chronic microinfarcts; 30 (63.8%) of these participants were men. Thirty (63.8%) had cortical microinfarcts, 19 (40.4%) had subcortical microinfarcts, and 4 (8.5%) had only infratentorial microinfarcts. Participants with microinfarcts did not differ significantly on baseline systolic (mean difference, −1.48; 95% CI, −7.30 to 4.34; P = .62) and diastolic (mean difference of slope, −0.90; 95% CI, −3.93 to 2.13; P = .56) BP compared with those with no microinfarcts. However, participants with subcortical microinfarcts had a greater annual decline (negative slope) of systolic (mean difference of slope, 4.66; 95% CI, 0.13 to 9.19; P = .04) and diastolic (mean difference, 3.33; 95% CI, 0.61 to 6.06; P = .02) BP.

Conclusions and Relevance  Subcortical microinfarcts were associated with declining BP. Future studies should investigate whether declining BP leads to subcortical microinfarcts or whether subcortical microinfarcts are a factor leading to declining BP.

High blood pressure (BP) is prevalent in the elderly population^1,2 and is associated with cerebrovascular pathology³ and cognitive impairment, particularly when onset occurs in midlife.⁴ However, it has been shown that low BP in older adults is associated with cognitive impairment and dementia, perhaps due to pathology related to cerebral hypoperfusion.⁵ Microinfarcts are the most common vascular brain pathology identified in older adults at autopsy and contribute to cognitive impairment as much as macroscopic infarcts.^6-8A previous association has been shown between a global burden of more than 2 microinfarcts and higher systolic BP in adults aged 65 to 80 years who underwent autopsy, with no association in adults older than 80 years.⁹ Similarly, in the very old (≥90 years) population, microinfarcts were not associated with traditional vascular risk factors, such as high BP, high cholesterol level, and diabetes.¹⁰ Although microinfarcts are not typically visible on magnetic resonance imaging (MRI), the presence of macroinfarcts, white matter hyperintensity volume, and hemorrhages correlate with the presence of microinfarcts at autopsy.¹¹ The associations of risk factors for microinfarcts differ according to age and microinfarct location. At autopsy, cortical microinfarcts are associated with amyloid angiopathy, and subcortical microinfarcts are associated with arteriolosclerosis and atherosclerosis.¹²

Prior studies have focused on the presence or absence of hypertension or single-visit BP measures. We present a population-based study investigating systolic and diastolic BP slopes utilizing BP measurements at multiple visits and their associations with subcortical and cortical microinfarcts at autopsy.

The study cohort comprised participants in the population-based Mayo Clinic Study of Aging (MCSA)^13,14 who died from November 1, 2004, through March 31, 2016, including both autopsied and nonautopsied participants (Figure 1). The study enrolled individuals without dementia from Olmsted County, Minnesota. Full details of the study design have been published.¹³ Study participants undergo annual clinical and neuropsychological examinations. The Short Test of Mental Status (score range, 0-38, with 38 indicating the highest level)¹⁵ was administered as a global cognitive screen at each visit. The presence and location of microinfarcts were abstracted from the autopsy reports. Participants with chronic microinfarcts identified at autopsy were included in the study, but participants with acute and subacute microinfarcts were excluded from the study to avoid potential confounding effects of the terminal illness. In addition, participants with only infratentorial microinfarcts (n = 4) were not used in primary analyses because of the small number. A participant with microinfarcts secondary to intravascular metastasis also was excluded.

The study protocols were approved by the Mayo Clinic and Olmsted Medical Center institutional review boards. All individuals provided written informed consent to participate in the study and in the imaging protocols. Participants received financial compensation.

Neuropathologic sampling followed recommendations of the Consortium to Establish a Registry for Alzheimer’s Disease.¹⁶ Regions sampled included anterior cingulate, posterior cingulate, anterior hippocampus, posterior hippocampus (sampled at the level of the lateral geniculate nucleus), primary motor cortex, middle frontal gyrus, inferior parietal lobule, superior temporal gyrus, primary visual/visual association cortices, nucleus basalis, amygdala, basal ganglia, caudate, thalamus, cerebellum, midbrain, pons, medulla, pituitary, optic nerve, and olfactory bulb.

Microinfarcts were identified by board-certified neuropathologists (D.W.D., R.R.R., and J.E.P.). The microinfarcts were defined according to the National Institute of Neurologic Disorders and Stroke–Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards¹⁷ as infarcts not visible on gross pathology or antemortem MRI that are identified on hematoxylin-eosin–stained histologic sections, which contrasts with lacunar infarcts that are grossly visible. Microinfarcts in cortical gray matter regions (frontal, temporal, parietal, occipital, and hippocampus) were classified as cortical, while those in the deep gray and white matter structures were classified as subcortical. Microinfarcts in the brainstem and cerebellar cortex (infratentorial) were not included in the analysis. Six participants had both subcortical and cortical microinfarcts and were classified as mixed. Braak neurofibrillary tangle stage was used to assess Alzheimer disease burden, and the presence of Lewy body pathology was recorded.

At each research visit, brachial BP was measured twice approximately 2 minutes apart with the participant in a seated position. The second measurement from each visit was used in our analysis. A subset of participants (n = 2) had only 1 measurement during a visit. One participant was in the no-microinfarct group and 1 was in the cortical infarct group used for analysis. Blood pressure slopes over time were calculated for each of the participants except the 47 with only 1 time point. For the 48 participants with 2 two time points, the slope for each was the difference in measurements divided by the increase in time. For the 198 participants with more than 2 measurements, the slope for each was extracted from a simple linear regression. Times between measurements were fairly consistent: for the no-microinfarct group, the mean (SE) time between BP measurements was 1.37 (0.01) years, and for the microinfarct group, the mean time between BP measurements was 1.39 (0.03) years.

At each visit, participants self-reported their current medications. The medication name was recorded.

Because a subset of participants underwent autopsy, characteristics of the autopsy cohort were compared with the group of those who died but did not undergo autopsy to confirm the similarity of cohorts and, therefore, representativeness of the sample. Participant characteristics were compared between the no-microinfarct and any-microinfarct, no-microinfarct and cortical microinfarct groups, and no-microinfarct and subcortical microinfarct groups using 2-tailed, unpaired t tests for differences in the continuous measures and χ² tests for differences in proportions for categorical variables. A secondary logistic regression analysis was performed to assess associations of cortical and subcortical microinfarcts (present/absent) excluding mixed cases with midlife hypertension, systolic BP slope, and diastolic BP slope while adjusting for time between last BP measurement and death. Time was square root transformed to improve model diagnostics. Because neither age nor sex was significant when included in any of the models and adjusting for age and sex made no qualitative difference to the results of interest, we report results without adjustment for those 2 variables. SAS, version 9.4 (SAS Institute) and R statistical software, version 3.1.1 (R Foundation) were used for data analysis.

The autopsy cohort (n = 303) and the group of individuals who died but were not autopsied (n = 855) were similar for all characteristics except educational level, with autopsied participants having a mean of 1 year more of education (1.06; 95% CI, 0.66-1.47 years; P < .001) (eTable in the Supplement). Among the autopsy cohort, 177 (59.6%) were men; mean (SD) age at death was 87.2 (5.3) years.

In the MCSA autopsy cohort with antemortem blood pressure measurements (n = 297), 47 (15.8%) had chronic microinfarcts (Figure 1). Thirty (63.8%) of these participants were men. Thirty (63.8%) had cortical microinfarcts, 19 (40.4%) had subcortical microinfarcts, and 4 (8.5%) had only infratentorial microinfarcts. The mean (SD) number of microinfarcts detected was 1.5 (0.80).

Among participants with no microinfarcts, 43 (17.2%) had 1 BP measurement, 39 (15.6%) had 2 BP measurements, and 168 (67.2%) had 3 or more BP measurements. In the participant group with only chronic cortical microinfarcts, 2 (6.7%) had 1 BP measurement, 6 (20.0%) had 2 BP measurements, and 22 (73.3%) had 3 or more BP measurements. In the participant group with chronic subcortical microinfarcts, 2 (10.5%) had 1 BP measurement, 3 (15.8%) had 2 BP measurements, and 14 (73.7%) had 3 or more BP measurements. More than 80% of participants had more than 1 BP measurement (208 [83.2%] in the no-microinfarct group, 28 [93.3%] in the chronic cortical microinfarct group, and 17 [89.5%] in the chronic subcortical infarct group).

Characteristics by microinfarct status (none, any, cortical, or subcortical) are reported in Table 1. Participants with mixed microinfarcts were included in both the cortical and subcortical groups. The study group with cortical microinfarcts had a trend for a higher proportion of apolipoprotein E (APOE) ε4 carriers than the group with no microinfarcts (mean difference, 16%; 95% CI, −2% to 35%; P = .05). All other characteristics were similar across the study groups. We investigated pathologic differences in Alzheimer disease likelihood and the presence of Lewy body pathology across the study groups and found no associations.

Participants with any microinfarcts (subcortical, cortical, and/or infratentorial) did not differ significantly on baseline systolic (mean difference, −1.48; 95% CI, −7.30 to 4.34; P = .62) and diastolic (mean difference, −0.90; 95% CI, −3.93 to 2.13; P = .56) BP compared with the group with no microinfarcts. Furthermore, those with no microinfarcts did not differ significantly on baseline systolic BP from those with subcortical microinfarcts (mean difference, −4.24; 95% CI, −12.86 to 4.39; P = .33) or cortical microinfarcts (mean difference, 3.27; 95% CI, −3.83 to 10.36; P = .37). Similarly, those with no microinfarcts did not differ significantly on baseline diastolic BP from those with subcortical microinfarcts (mean difference, 0.03; 95% CI, −4.46 to 4.51; P = .99) or cortical microinfarcts (mean difference, 2.18; 95% CI, −1.50 to 5.87; P = .24) (Table 2, Figure 2). However, participants with subcortical microinfarcts had significantly greater annual decline (ie, negative slopes) for both systolic BP (mean difference, 4.66; 95% CI, 0.13 to 9.19; P = .04) and diastolic BP (mean difference, 3.33; 95% CI, 0.61 to 6.06; P = .02) (Table 2, Figure 2).

The logistic regression model for the probability of a subcortical microinfarct, adjusted for time from last BP measurement to death, showed significant associations with systolic and diastolic slopes. For every 1 unit of positive change in the systolic or diastolic slopes, the predicted odds of a subcortical microinfarct were reduced (odds ratio [OR], 0.94; 95% CI, 0.89-0.99; OR, 0.90; 95% CI, 0.82-0.98, respectively). These correspond to ORs of 0.57 (95% CI, 0.35-0.94) and 0.54 (95% CI, 0.33-0.89) for each SD increase in the systolic and diastolic slopes. Conversely, for every unit of negative change in systolic or diastolic slopes, the odds of a subcortical microinfarct increased (OR, 1.06; 95% CI, 1.01-1.12; OR, 1.1; 95% CI, 1.02-1.22, respectively). These values correspond to ORs of 1.76 (95% CI, 1.07-2.89) and 1.87 (95% CI, 1.13-3.07) for each SD decrease in the systolic and diastolic slopes. For example, we would estimate that an individual whose systolic BP is decreasing by 10.59 mm Hg per year would have an odds of a subcortical microinfarct that is 1.76 times greater than one whose systolic BP is decreasing by 1.31 mm Hg per year. The rate of systolic BP decrease in the first participant is 1 SD below that of the second. Midlife hypertension, however, did not indicate the presence of subcortical microinfarcts at autopsy (Table 3).

We found an association between a steeper decline in BP in older adults and the presence of subcortical microinfarcts at autopsy. We were unable to demonstrate a cross-sectional difference in baseline BP measurements between those with subcortical or cortical microinfarcts and those without cerebral microinfarcts. An advantage of our study was the ability to use 2 or more BP measurements to assess change in BP on microinfarct presence at autopsy in contrast to existing reports, which have focused on cross-sectional BP measurements or hypertension diagnosis.^8,9,18 Because BP varies significantly during life¹⁹ and orthostatic hypotension becomes more common with advancing age, a single snapshot may be insufficient to understand the association between BP and microinfarcts.

In addition, we investigated microinfarcts by subcortical or cortical location. Only cortical microinfarcts demonstrated a trend for an association with the presence of the APOE ε4 allele. Since subcortical and cortical infarcts may be etiologically distinct,¹² combining them into a global measure would have obscured the associations with specific predictors. This separation by location of the microinfarct allowed us to show the association between subcortical microinfarcts and decreasing BP.

Aging and high BP lead to vessel-wall remodeling,²⁰ targeting arteries and arterioles in particular that supply the deep white matter and basal ganglia (subcortical regions). This vessel-wall remodeling has important implications for cerebral autoregulation, which is the mechanism that maintains cerebral blood flow relatively constantly in the face of changing BP. In response to high pressure, the blood vessel constricts, and in response to low pressure, the blood vessel dilates. With a drop in BP, the damaged blood vessel is unable to dilate. Damage from high BP and aging causes a shift of the pressure-flow curve to the right, so higher pressures are needed to maintain the same level of cerebral perfusion. Consequently, drops in BP can no longer be compensated and may result in ischemia.²¹ Impaired cerebral autoregulation is associated with periventricular white matter damage,²² and white-matter lesions on MRI are associated with pathologic markers of hypoxia.²³ This mechanism has not been studied in microinfarcts, but microinfarcts have been shown to be associated with atrophy in the border zones between vascular territories independent of Alzheimer disease pathology.²⁴

Aortic stiffness increases with age, particularly after 60 years, leading to transmission of excessive pulsatility to the brain and the kidney. This increase causes microvascular remodeling to protect the capillaries from the effects of increased pulsatility, which, however, limits the autoregulatory response and exposes the brain to repeated episodes of ischemia when the BP drops.²⁵

The results of this study are timely as the optimal targets for BP control are being reassessed.²⁶ Although we did not find evidence that antihypertensive treatment was associated with the development of microinfarcts in our cohort, information on antihypertensive treatment in our study was limited.

Prior studies have shown an association between cortical microinfarcts and amyloid angiopathy.^12,27 In congruence with these findings, cortical microinfarcts were associated with the presence of an APOE ε4 allele but not with BP.

This study has several limitations. Since sampling was restricted to certain regions of the brain, we may have missed microinfarcts in other regions, likely underestimating the microinfarct burden. The frequency of microinfarcts (15.8%) in this study is slightly lower than that in other studies on microinfarcts, such as the Baltimore Longitudinal Study on Aging (21.8%)⁸and the study from the Rush Memory and Aging Project and the Religious Orders Study (28.1%).¹² Although the difference could be related to sampling, the MCSA is a population-based cohort and only enrolls participants without dementia, which could bias the sample toward a lower frequency of microinfarcts. In addition, this study relied on brachial measures of BP; measures of aortic BP, if available, might have provided important alternative mechanistic information. This study reported associations between microinfarcts and BP and, therefore, does not imply causation. It is possible that subcortical microinfarcts or another factor associated with them contribute to declining BP. Recent studies have demonstrated that a subset of microinfarcts may be detected on 7T and 3T MRI.²⁸ Future studies evaluating BP trajectories in these patients will be of interest.

Our study suggests that hypoperfusion from declining BP is associated with subcortical microinfarcts. Purely cortical microinfarcts may be related to a degenerative vasculopathy independent of BP.

Accepted for Publication: August 25, 2017.

Corresponding Author: Jonathan Graff-Radford, MD, Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (graffradford.jonathan@mayo.edu).

Published Online: December 4, 2017. doi:10.1001/jamaneurol.2017.3392

Author Contributions: Drs Graff-Radford and Raman contributed equally to the study and shared co–senior authorship. Dr Graff-Radford had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Graff-Radford, Raman, Rabinstein, Petersen.

Acquisition, analysis, or interpretation of data: Graff-Radford, Raman, Przybelski, Boeve, Lesnick, Murray, Dickson, Reichard, Parisi, Knopman, Petersen, Jack Jr, Kantarci.

Drafting of the manuscript: Graff-Radford, Raman, Lesnick, Parisi.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Graff-Radford, Raman, Przybelski, Lesnick, Kantarci.

Obtained funding: Petersen, Jack, Kantarci.

Administrative, technical, or material support: Boeve, Murray, Kantarci.

Study supervision: Petersen, Jack, Kantarci.

Conflict of Interest Disclosures: Dr Graff-Radford receives funds from the Myron and Jane Hanley Career Development Award and National Institute on Aging of the National Institutes of Health (NIH). Dr Boeve has served as an investigator for clinical trials sponsored by Cephalon Inc, Allon Pharmaceuticals, and GE Healthcare; receives royalties from the publication of a book entitled Behavioral Neurology of Dementia (Cambridge Medicine; 2009), has received honoraria from the American Academy of Neurology; serves as a paid member of the Scientific Advisory Board of the Tau Consortium; and receives research support from the National Institute on Aging and the Alzheimer's Association. Dr Knopman serves as a paid consultant for the data safety monitoring board for Lundbeck Pharmaceuticals and for the DIAN study; is an investigator in clinical trials sponsored by TauRX Pharmaceuticals, Lilly Pharmaceuticals, and the Alzheimer’s Disease Cooperative Study; and receives research support from the NIH. Dr Petersen receives a consultant fee overseen by Mayo Clinic for Roche Inc, Merck Inc, Genentech Inc, Biogen Inc, and Eli Lilly and Company; receives publishing royalties for Mild Cognitive Impairment (Oxford University Press, 2003); and receives research support from the NIH. Dr Jack receives research funding from the NIH and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Foundation. The Mayo Clinic receives compensation for Dr Kantarci’s participation as a member of the data safety monitoring board for Pfizer Inc and Takeda Global Research & Development Center Inc and is funded by the NIH and Minnesota Partnership for Biotechnology and Medical Genomics. No other disclosures are reported.

Funding/Support: This study received funding through grants U01 AG006786 (Mayo Clinic Study on Aging) (Dr Peterson), R01-AG040042 (Dr Kantarci), R01-AG011378 (Dr Peterson), R01-AG041851 (Dr Jack), P50AG044170 (Specialized Centers of Research) (Dr Kantarci), R01AG034676 (Rochester Epidemiology Project), and Robert H and Clarice Smith and Abigail van Buren Alzheimer Disease Research Program.

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Michael Joyner, MD (Mayo Clinica, Rochester, Minnesota), performed critical review and editing; there was no financial compensation.