Abstract
We sought to determine whether there is any association between a cardiac workload marker, rate pressure product (RPP), working memory, and cortical amyloid-β (Aβ) burden in 63 cognitively normal midlife adults (Mage = 62.8 years; range = 55 to 75 years) at risk for Alzheimer’s disease (AD). The results show a small-to-moderate relationship between increasing cardiac workload (at rest) and neocortical amyloidosis in individuals at the preclinical stage of AD. Moreover, increasing RPP was linearly related to increasing relative impairments on a spatial working memory task (R2 = 0.30), but only for those individuals with neuroimaging evidence suggestive of preclinical AD. These results support a relationship between the aggregation of Aβ protein plaques in the neocortex, increased cognitive impairment, and more inefficient myocardial oxygen use in the absence of significant metabolic demands.
Keywords
INTRODUCTION
Cardiovascular diseases (CVD) are common in older adults and share several important risk factors (e.g., chronic hypertension) with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) [1–3]. CVD can lead to cognitive impairment as a result of a variety of insults that result in oxidative stress and/or neuroinflammatory responses [4, 5]. Moreover, the aggregation of insoluble amyloid-β (Aβ) protein over the course of AD appears to also lead to deleterious changes in the integrity of the cerebrovascular system, resulting in impaired vascular function [6, 7]. This high co-morbidity between AD and CVD is thus both well known [8] and results from a complex bidirectional mechanistic relationship that leads to important considerations for establishing subject inclusion and exclusion criteria for clinical trials, despite the fact that cerebrovascular pathologies can be observed in more than half of AD cases [9].
Previously, we have shown that in healthy older adults who are free of diagnosable cardiovascular diseases or dementia, a simple outpatient measure of cardiac workload (rate pressure product; RPP) is associated with relative impairments in performance on a spatial working memory test, a relationship that is not observed in young [10]. RPP (systolic blood pressure × heart rate/100) represents the maximum pressure in a structurally normal left ventricle when it is ejecting blood based on the number of beats per minute, providing an indirect assessment of myocardial oxygen consumption [11]. During the performance of challenging cognitive and/or physical tasks, such as exercise, psychological stress, and everyday physical activity, RPP will increase to meet required metabolic demands [12, 13]. If RPP is high in the resting state, we could assume that myocardial oxygen use is already elevated in the absence of significant metabolic demands.
Although the relationship between increased cardiac workload and/or increased cardiac risk, and cognitive decline in older adults, has been reasonably well established [14, 15], it is unclear just how strong the relationship is between cardiac function and biomarkers of prodromal disease in cardiovascular healthy individuals at high risk for preclinical AD. In the Honolulu-Asia Aging Study (HAAS), results suggest that midlife elevated diastolic blood pressure may impair Aβ clearance, which can eventually lead to AD and cerebral amyloid angiopathy [16]. It was also observed that raised systolic blood pressure increase the risk of AD in later life [13, 17]. We sought to determine whether there was any association between cardiac workload, working memory, and cortical Aβ burden in 63 cognitively normal older adults. We predicted that increased RPP at rest would be inversely related to performance on the spatial working memory test, but only for individuals with neuroimaging evidence of amyloid aggregation consistent with prodromal AD.
MATERIALS AND METHODS
Subjects
Participants were recruited by serial referrals from two memory disorder centers in Rhode Island, and from broad print advertising to the community. All subjects were cognitively normal midlife adults (N = 63, Mage = 62.8; range = 55 to 75 years old), with first-degree family histories of AD and with complaints of significant subjective memory impairment. All subjects presented with normal neurological exams, had MMSE scores >27, no current Axis I or II psychopathology, no reported significant cardiovascular disease and no current alcohol or substance abuse. All subjects also performed well within-normal limits on episodic memory testing, including a word-list learning test and computer-administered measures of working memory, concentration, and attention [18]. None of the subjects met NIA-AA diagnostic criteria for MCI [19]. Although all subjects denied cardiologic conditions or diagnoses, we could not exclude the possibility of asymptomatic cardiologic conditions or the presence of occult cerebrovascular disease in some individuals.
Subjects were separated into two groups, based on PET amyloid imaging results, with 15 subjects having Florbetapir uptake SUVr scores ≥1.10, and 48 subjects having SUVr scores <1.10. Additionally, all 15 subjects with evidence of significant neocortical amyloid aggregation failed a micro-dose scopolamine “cognitive stress test” [18, 20], suggesting the presence of prodromal cholinergic tone disruption and supporting the prediction of preclinical stage of AD. With respect to genetic risk for AD, eight of 15 individuals (53%) in the amyloid positive group (SUVr scores ≥1.10) had at least one copy of the APOE ɛ4 allele, whereas 20 of 45 individuals (45%) in the amyloid negative group (SUVr scores <1.10) had at least one copy of the APOE ɛ4 allele. Hence, roughly half of the subjects in each group presented with this additional risk factor for AD, but due to small sample sizes, we were not able to further evaluate the specific effect of APOE genetic risk on the relationship between RPP and cognitive performance. Subject demographics are provided in Table 1.
Neuroimaging
A 370 MBq (10 mCi ± 10%) bolus injection of F-florbetapir was administered intravenously [21]. Approximately 50 min post-injection, a 20-min PET scan was performed with head CT scan for attenuation correction purposes. Because this is a study of relatively healthy midlife adults for whom only a minority of subjects present in the preclinical stage of AD, we had no reason to suspect generalized neocortical amyloid deposition and instead focused our attention on the anterior cingulate region-of-interest (ROI) [18]. The PET standardized uptake value (SUV) for the anterior cingulate (ACC) region was summed and normalized to the whole cerebellum SUV, resulting in an ACC-to-cerebellum ratio termed SUV ratio (SUVr). An ACC SUVr threshold of ≥1.1 was used to discriminate between Aβ- and Aβ+, and both the rationale for selection of this specific ROI, and these methods are described by Lim et al. [18]. For all cases, Aβ positivity was confirmed by consensus over-read by two board-certified radiologists who were also board-certified in Nuclear Medicine.
Cardiac measures and cognitive assessment
Blood pressure and heart rate data were collected while subjects were at rest, with all assessments occurring between 0800 and 0900. Subsequent to the collection of these measures, all subjects completed the Groton Maze Learning Test (GMLT; http://www.cogstate.com). The GMLT is a computer-administered hidden maze test that differentially measures both spatial working memory and reasoning/problem solving cognitive functions [22]. For the purpose of this study, the total errors score was relied on as the principal measure of spatial working memory. In addition, the number of rule-break errors was obtained as an additional measure of executive functioning [23]. Rule-break errors are made when subjects fail to adhere to any of three very simple rules (e.g., not to move diagonally) that, when followed, facilitate performance on the test. Finally, we chose to also look at the timed-chase test of the GMLT [24, 25], as a measure of simple visuomotor speed. The GMLT, and these three component scores, has been described previously both in terms of performance within the context of studies with healthy elderly adults [24–27], as well as in MCI [23]. All subjects completed an initial practice run of the GMLT, to allow for initial task familiarity; and after a 10-min break, all subjects repeated the GMLT as a baseline assessment.
RESULTS
A moderate relationship was found between increasing cardiac workload (at rest) and increasing impairments on the GMLT measure of spatial working memory (total errors score) for the 15 subjects with evidence of substantial neocortical amyloid aggregation (Florbetapir PET imaging); however, after adjustment for multiple comparisons the effect approached but was not statistically significant (p = 0.0429, adj. p = 0.0858). This association was nonetheless significantly different than was observed for the other 48 subjects (interaction p = 0.0307), in whom no association was evident (p = 0.3974, adj. p = 0.3974). This relationship remained significant, after statistical control for education (p = 0.0354), gender (p = 0.4708), body mass index (p = 0.3668), and age (p = 0.9425).
The effect of Aβ moderation was more apparent with regards to the relationship between RPP and increasing impairments on the GMLT measure of reasoning/problem-solving (rule-break errors score). Here, RPP increased by approximately 11.2 mmHg*bpm (95% , CI 3.5–18.8 mmHg*bpm; p = 0.0014, adj. p = 0.0028) for the 15 Aβ positive subjects (see Fig. 1). This relationship was significantly stronger than for the 48 subjects (interaction p = 0.0017) without any evidence of cortical Aβ plaque burden, in whom no association was evident (p = 0.6230, adj. p = 0.6230). This relationship remained significant, after statistical control for education (p = 0.0256), gender (p = 0.9586), body mass index (p = 0.3999), and age (p = 0.9727). By comparison, the correlation between systolic blood pressure alone and the GMLT rule-break errors score, for the Aβ positive group, was comparatively modest but still significant (Adj. R2 = 0.21, p < 0.05), and there was no such correlation observed for the Aβ negative group (Adj. R2 = –0.02, NS).
Finally, no significant relationship between RPP and the GMLT measure of simple visuomotor speed (timed chase test) were observed, regardless of Aβ status.
With all 63 subjects considered together, there is a small-to-moderate relationship between neocortical Aβ burden and RPP (p = 0.0329), with increasing cardiac workload at rest associated with greater neocortical amyloidosis. This relationship remained significant, after statistical control for education (p = 0.2011), gender (p = 0.0476), body mass index (p = 0.1846), and age (p = 0.8548).
DISCUSSION
This study may be the first to demonstrate that increased cardiac workload, as a surrogate of myocardial oxygen use, at rest, has a small to moderate correlation with neocortical amyloidosis in midlife adults with preclinical AD; with approximately one-quarter of the sample (n = 15) meeting neuroimaging criteria for pre-clinical stage of the disease. This relationship is modest, and RPP does not have the potential to serve as a biomarker of cortical Aβ burden in preclinical AD. Rather, we were impressed by finding a significant relationship at all, given that our study subjects are all relatively young, healthy, living independently, and free of any diagnosable cardiological or neurological diseases. Limitations of this current study and report include the small sample sizes (particularly for the amyloid positive group, n = 15) and the cross-sectional design of these plannedcomparisons.
We have shown previously that, in older adults, elevated resting state RPP is associated with relatively poorer cognitive performance on a modified version of the GMLT, but this prior cohort was not specifically screened for possible occult disease [10]. These current results corroborate that initial report, as we observed a strong linear correlation between RPP and performance on both the spatial working memory and reasoning/problem-solving measures of the GMLT, with increasing cardiac workload at rest associated with greater impairment on the spatial working memory measure of this test, but only for those subjects with PET amyloid imaging evidence of likely preclinical AD. By comparison, this association was not observed for the GMLT measure of simple visuomotor speed, suggesting that this relationship might only be observed for cognitive measures that require executive functions (including working memory).
Taken together, these results support a relationship between at least one major neuropathologic pathway for the disease (the aggregation of Aβ protein plaques in the neocortex) and more inefficient myocardial oxygen use in the absence of significant metabolic demands, which appears related to a relative decrement in cognitive function. We are currently re-evaluating the subject cohort described in this report, to determine whether indices of phasic vagal cardiac control, such as their resting sinus arrhythmia and heart rate variability measures, are also related to cortical amyloidosis in preclinical AD, since both cardiac phenomena are directly modulated by muscarinic cholinergic and nicotinic autonomic neurotransmission.
