Abstract
Background: Blood pressure level is associated with the risk of clinical Alzheimer disease (AD), yet the underlying mechanisms are unclear. High blood pressure levels may cause cerebral small-vessel pathology, which contributes to cognitive decline in patients with AD. Alternatively, in persons with high blood pressure, increased numbers of neurofibrillary tangles and amyloid plaques at autopsy have also been observed, suggesting direct links between blood pressure and AD.
Objective: To investigate the association of blood pressure and markers of small-vessel disease (white matter lesions [WMLs] on MRI) with hippocampal and amygdalar atrophy on MRI—potential in vivo indicators of Alzheimer pathology.
Methods: In 1995 to 1996, 511 nondemented elderly subjects (age 60 to 90) underwent MRI. The extent of WMLs was assessed, and volumes of the hippocampus and amygdala were measured. Blood pressure levels were assessed at the time of MRI and 5 years before the MRI.
Results: Higher diastolic blood pressure 5 years before MRI predicted more hippocampal atrophy in persons untreated for hypertension (per SD increase −0.10 mL [95% CI −0.19 to −0.02, p = 0.02]). Conversely, in persons treated for hypertension, a low diastolic blood pressure was associated with more severe atrophy. Persons with more WMLs on MRI more often had severe atrophy of the hippocampus and amygdala.
Conclusion: Blood pressure and indicators of small-vessel disease in the brain may be associated with atrophy of structures affected by Alzheimer pathology.
Although Alzheimer disease (AD) is generally considered to be a nonvascular disease, this view has been challenged by observations that vascular factors may contribute to the development of late-onset AD.1 The most frequently investigated vascular factor is blood pressure level, and findings have been mixed.2 Most long-term longitudinal studies have shown that persons with a high blood pressure have an increased risk to develop clinical AD.3,4 Conversely, cross-sectional studies5,6 or studies with a short follow-up7,8 report that a low blood pressure is a risk factor for AD. It is unclear whether and which structural brain changes could underlie the associations between blood pressure and clinical AD. High blood pressure levels may cause cerebrovascular damage such as white matter lesions (WMLs) and small brain infarcts. This damage may lead to cognitive decline in a patient who receives a clinical diagnosis of AD.9,10 Alternatively, more direct links between blood pressure and AD are suggested by the observation that persons with hypertension have increased neurofibrillary tangles and brain atrophy at autopsy.11,12 To explore the latter possibility in vivo, we studied the relation between blood pressure and hippocampal and amygdalar atrophy on MRI in nondemented elderly subjects. The hippocampus and amygdala are greatly affected by amyloid plaques and neurofibrillary tangles, even in the earliest stage of the development of AD.13 Histopathologic studies show that neuronal loss, neurofibrillary tangles, and amyloid plaques at autopsy are highly correlated to atrophy visible on MRI.14,15 If the association between blood pressure and clinical AD is (partly) mediated through effects on the development of Alzheimer neuropathology in the medial temporal lobe, one would expect to find an association between blood pressure levels and atrophy of the hippocampus and amygdala on MRI. We additionally examined whether markers of small-vessel disease in the brain (WMLs) or large-vessel disease (carotid atherosclerosis) are associated with atrophy of the hippocampus and amygdala on MRI and modify the association between blood pressure and atrophy on MRI.
Methods.
Participants.
The Rotterdam Study is a large population-based cohort study in the Netherlands designed to investigate the prevalence, incidence, and determinants of diseases in the elderly.16 Baseline examinations were done in 1990 to 1993. In 1995 to 1996, we randomly selected 965 living members (ages 60 to 90) of the cohort in strata of sex and age (5 years) for participation in the Rotterdam Scan Study designed to study age-related brain changes on MRI.17 As part of the eligibility criteria, we excluded from this selection people with dementia (n = 17)18 or MRI contraindications (n = 116). Thus, 832 persons were eligible and invited. Among these, 563 participants gave their written informed consent to participate in the study, which included undergoing an MRI scan of the brain (response rate 68%). Complete MRI data were available for 511 participants.19 Participants were in general healthier than nonparticipants.20 The study protocol was approved by the Medical Ethics Committee of the Erasmus Medical Center.
MRI procedures.
Standard T1-, T2-, and proton density–weighted axial MR images and a custom-made three-dimensional MRI sequence covering the whole brain were made using a 1.5 T MR unit (Vision MR; Siemens, Erlangen, Germany). The MRI acquisition parameters have been described.19,21
MRI assessment of hippocampal and amygdalar volumes.
We constructed a series of coronal brain slices (contiguous 1.5-mm slice thickness) from the three-dimensional MRI, aligned to be perpendicular to the long axis of the hippocampus. We manually traced the boundaries of the hippocampus and amygdala on both sides on each slice with a mouse-driven cursor.19 The summed surface was multiplied by slice thickness to yield estimates of the hippocampal and amygdalar volume (mL). The left- and right-sided volumes were summed to yield the total hippocampal and amygdalar volume. As a proxy for head size, we measured on the middle sagittal MRI slice the intracranial cross-sectional area.19 We corrected for head size differences across individuals by dividing the uncorrected volumes by the participant's calculated head size area and subsequently multiplying this ratio by the average head size area (men and women separately).22 The total 511 scans were equally divided between two raters. Intra- and interreader studies based on 14 random scans showed good reproducibility. Intrarater intraclass correlation coefficients were r = 0.93 for the left hippocampus and r = 0.90 for the right, and interrater intraclass correlation coefficients were r = 0.87 for the left hippocampus and r = 0.83 for the right. The intrarater intraclass correlation coefficients were r = 0.82 for the left amygdala and r = 0.78 for the right, and the interrater intraclass correlation coefficients were r = 0.80 for the left amygdala and r = 0.77 for the right.
Assessment of blood pressure and vasculopathy.
At baseline and time of MRI, we assessed blood pressure with a random zero sphygmomanometer.23 Participants were asked to bring all prescribed medications to the research center, where a physician recorded the use. At baseline and time of MRI, participants underwent ultrasonography of the carotid arteries.24 The presence of atherosclerotic plaques was determined at six locations (common carotid artery, carotid bifurcation, and internal carotid artery at the left and right side) and summed (range 0 to 6). The intima–media thickness was measured by longitudinal two-dimensional ultrasound of the anterior and posterior wall of both common carotid arteries. We calculated the mean of these four locations. Cerebral WMLs on MRI were assessed on proton density– and T2-weighted axial MR images and were scored in the periventricular regions (range 0 to 9) and the subcortical regions (approximated volume).21 We defined a group with severe WMLs on MRI similar to previous analyses25 as having either a subcortical WML score or periventricular WML score in the upper quintile of the distribution. Brain infarcts were defined as focal hyperintensities on T2-weighted images and, if present in the white matter, with corresponding prominent hypointensity on T1-weighted images.26
Other measurements.
Body mass index (BMI) was calculated as weight divided by the square of height. A physician assessed participants' smoking habits with a structured questionnaire, and we categorized this into never, former, or current smoking. Serum total cholesterol and high-density lipoprotein (HDL) were determined with an automated enzymatic procedure.
Data analysis.
We assessed the relation between blood pressure continuously and in categories at baseline or at time of MRI and atrophy with multiple linear regression. As preliminary analysis and previous studies on AD or cognitive impairment4,27,28 suggest differences in relations between persons with or without antihypertensive medication, we stratified for antihypertensive medication use. With multiple linear regression, we investigated the association between WMLs, carotid atherosclerosis, and atrophy. Analyses were adjusted for age and sex and additionally for other cardiovascular factors. Finally, we repeated the analyses on blood pressure and atrophy in strata of severity of WMLs on MRI. Assumptions of the model were verified by residual diagnostics.
Results.
Table 1 gives several characteristics of the study sample both at baseline and at time of MRI.
Table 1 Characteristics of study sample at baseline (1990–1993) and time of MRI (1995–1996)
People using antihypertensive medication at both baseline and follow-up (n = 288) had on average smaller hippocampal (age- and sex-adjusted difference −0.15 mL [95% CI −0.32 to 0.02, p = 0.09]) and amygdalar (−0.20 mL [95% CI −0.34 to −0.06, p = 0.005]) volumes than people without antihypertensive medication (n = 136). A higher diastolic blood pressure at baseline in persons untreated for hypertension was related to smaller hippocampal volumes (figure 1). Per SD increase in diastolic blood pressure at baseline, we found in untreated persons a 0.10-mL smaller hippocampal volume (95% CI −0.19 to −0.02, p = 0.02). Diastolic blood pressure at time of MRI was not associated with hippocampal or amygdalar volume in persons without antihypertensive treatment (see figure 1). Conversely, in persons using antihypertensive medication, a lower diastolic blood pressure at time of MRI was related to smaller volumes, which was significant for the amygdala (see figure 1). Per SD increase in diastolic blood pressure at time of MRI, 0.10-mL (95% CI 0.00 to 0.20, p = 0.05) larger amygdalar volumes were found. These associations did not change after adjusting for the cholesterol/HDL ratio, BMI, or smoking. No associations were found with systolic blood pressure levels (figure 2).
Figure 1. Association between diastolic blood pressure levels at baseline (top) or at time of MRI (bottom) and volumes of the hippocampus (left) and amygdala (right), adjusted for age and sex and normalized to head size. *p < 0.05 compared with diastolic blood pressure of <70 mm Hg.
Figure 2. Association between systolic blood pressure levels at baseline (top) or at time of MRI (bottom) and volumes of the hippocampus (left) and amygdala (right), adjusted for age and sex and normalized to head size.
People with more carotid atherosclerosis at either baseline (data not shown) or time of MRI did not have smaller volumes on MRI (table 2). People with more WMLs had smaller hippocampal or amygdalar volumes (see table 2). This relation did not disappear after adjusting for blood pressure levels, antihypertensive medication use, cholesterol/HDL ratio, BMI, or smoking. People with infarcts on MRI did not have smaller hippocampal or amygdalar volumes (age- and sex-adjusted difference in hippocampal volume −0.10 ml [95% CI −0.27 to 0.07, p = 0.24] and in amygdalar volume −0.01 mL [95% CI −0.15 to 0.13, p = 0.89]).
Table 2 Cross-sectional associations between markers of vasculopathy and hippocampal and amygdalar volumes on MRI, n = 511
The association found in persons without antihypertensive treatment between a high diastolic blood pressure at baseline and hippocampal atrophy on MRI remained when excluding persons with severe WMLs on MRI (per SD increase in 0.13-mL smaller hippocampal volume [95% CI 0.03 to 0.23, p = 0.02]). The association between concurrent low diastolic blood pressure level and more atrophy in persons using antihypertensive medications was, however, restricted to people with coexistent severe WMLs on MRI (table 3).
Table 3 Cross-sectional association between diastolic blood pressure level and volumes of hippocampus and amygdala on MRI according to WML severity on MRI
Discussion.
We found that a high diastolic blood pressure in persons not treated for hypertension was associated with more hippocampal atrophy on MRI. Higher severity of WMLs coexisted with atrophy of the hippocampus and amygdala. Finally, in persons using antihypertensive medications, a low diastolic blood pressure was related to more hippocampal and amygdalar atrophy.
The clinical distinction between vascular dementia and AD is sometimes difficult, hampering studies investigating vascular risk factors in relation to clinically diagnosed AD.29 In elderly people, dementia symptoms are due mostly to mixed disease; that is, both cerebrovascular damage and AD pathology contribute to the cognitive symptoms.30 We had the opportunity to assess hippocampal and amygdalar atrophy on MRI, which can be regarded as preclinical MRI markers of AD.14,15,31 These assessments in vivo may help us clarify whether vascular factors influence AD pathology in the medial temporal lobe. However, a drawback of our study is that indication of a smaller hippocampal or amygdalar volume on MRI is not always due to AD pathology. For some persons, a small brain volume on MRI will be innate, or other pathology such as hippocampal sclerosis can also be recognized as a smaller hippocampal volume on MRI.
The results of studies on the association between blood pressure and AD are determined by the time period between blood pressure level assessment and AD diagnosis.2,32 Longitudinal population studies with a long follow-up have shown high blood pressure levels in people who develop clinically overt AD several years later.3,4,33 Especially in persons not using antihypertensive medications, a higher blood pressure is a risk factor for clinical AD4 and cognitive impairment.27,28 High blood pressure levels may lead to a spectrum of brain changes, which all could, separately or in combination, cause cognitive decline. Generalized brain atrophy,34–36 WMLs,20,35,36 and infarcts on MRI26 are observed in persons with hypertension and are associated with cognitive decline and dementia.9 Another potential structural intermediate in the association between high blood pressure and clinical AD is damage to hippocampal neurons, as suggested by an autopsy study showing more neurofibrillary tangles and amyloid plaques in hippocampi of persons with a high blood pressure.12 How exactly pathologic changes in the hippocampus develop as a result of high blood pressure is unclear. Long-standing hypertension and chronic brain hypoperfusion in rats may up-regulate levels of nitric oxide in the hippocampus, which leads to amyloid accumulation and memory loss.37 Recent observations in Alzheimer patients show that severe WMLs, medial temporal lobe atrophy,38,39 and global brain atrophy40 frequently coexist. One possible explanation for these observations could be that WMLs and atrophy share similar risk factors such as high blood pressure. However, as adjusting for blood pressure levels did not change the relation we found between WMLs and atrophy, microangiopathy might also reduce cerebral blood flow to the hippocampus41 and induce loss of hippocampal neurons.42 Infarcts on MRI and large-vessel disease (carotid atherosclerosis) were not associated with the degree of atrophy of the hippocampus and amygdala on MRI, suggesting that these factors are independent of Alzheimer pathology in the medial temporal lobe.
Studies in which blood pressure is assessed shortly before or at time of diagnosis of AD showed patients to have lower blood pressure levels than control subjects.5–8,43,44 Two hypotheses have been postulated to explain these associations with low blood pressure: 1) A low blood pressure is a secondary phenomenon of the dementia process, or 2) a low blood pressure primarily contributes to development of dementia. Regarding the first hypothesis, the hippocampus and amygdala have a role in blood pressure regulation,45,46 and atrophy of these structures due to AD pathology could result in a decrease of blood pressure level. However, this being true, we would expect similar associations between atrophy and low blood pressure levels in all persons, whereas in our study, the association was strongest in those using antihypertensive medication. This is in line with the stronger association found between a low blood pressure and AD in persons on antihypertensive treatment.7,8,44 According to the second hypothesis, a too-low blood pressure level can be detrimental to the brain.47 Under normal conditions, cerebral autoregulatory mechanisms will keep up adequate cerebral blood flow despite a low systemic blood pressure level.48 This is achieved by vasodilatation of the arterioles of the brain.49 In persons with chronic hypertension and microangiopathy,50,51 the ability to vasodilate is reduced and a low systemic blood pressure might lead to hypoperfusion and ischemia of the brain, particularly the sensitive hippocampus and amygdala. Our finding that a low diastolic blood pressure level was particularly associated with atrophy in persons with antihypertensive medication (most likely with a history of chronic hypertension) and severe WMLs may fit this hypothesis.
Footnotes
-
Supported by the Netherlands Organisation for Scientific Research (NWO) and the Health Research and Development Council (ZON-MW).
Received July 8, 2004. Accepted in final form October 7, 2004.
References
Letters: Rapid online correspondence
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Topics Discussed
Alert Me
Recommended articles
Association of peripheral blood pressure with gray matter volume in 19- to 40-year-old adults
Joint effect of mid- and late-life blood pressure on the brain
Focal atrophy on MRI and neuropathologic classification of dementia with Lewy bodies
Association of higher diastolic blood pressure levels with cognitive impairment