Methods

The Framingham Offspring Study design and selection criteria have been described elsewhere. From 1971 to 1975, 5,124 participants were recruited and have been examined every 4 to 8 years since. Details on the derivation of the current sample are provided in Figure 1 . The protocol was approved by the local institutional review board. Participants provided written informed consent before assessments.

Participant enrollment and exclusion details.

Participants completed the following cognitive protocol, which was selected a priori to represent different cognitive systems: (1) delayed memory: Logical Memory Delayed Recall and Visual Reproduction Delayed Recall; (2) language: Boston Naming Test–30 Item; (3) executive functioning: a difference score of Trail Making Test Part B − Part A; (4) verbal reasoning: Similarities; and (5) visuoperceptual abilities: Hooper Visual Organization Test.

For brain imaging acquisition, images were obtained using a Siemens 1-T magnetic resonance machine (Siemens Medical Systems, Erlangen, Germany) using a T2-weighted double spin-echo coronal imaging sequence. Digital information was postprocessed by a central laboratory blinded to demographic and clinical information. A custom-written, semiautomatic segmentation protocol was used to quantify total cranial, total brain, frontal lobar, temporal horn, and hippocampal volumes and WMH segmentation. Interrater reliabilities for these methods have been published elsewhere. For this study, intra- and interrater reliabilities were consistently >0.90. Hippocampal data were available for a subset of participants (n = 423). For cardiac MRI acquisition, images were obtained with participants in the supine position using a Philips 1.5-T MR system (Philips Medical Systems, Andover, Massachusetts) with a 5-element (3 anterior, 2 posterior) surface coil. Images were acquired at end-tidal breath hold and analyzed by a single, experienced, blinded reviewer using a commercial workstation (EasyVision 4.0; Philips Medical Systems). End-systolic phase was determined as the minimal cross-sectional area of a midventricular slice. The time delay from the QRS complex (phase) was analyzed for each contiguous slice, and endocardial borders were segmented. End-diastolic volume and end-systolic volume were computed by summation of disks (i.e., modified Simpson’s rule) to derive the LVEF ([end-diastolic volume − end-systolic volume]/end-diastolic volume). Intra- and interobserver coefficients of variation for these methods have been published elsewhere. For this study, interrater reliabilities were consistently >0.92.

Total brain, frontal lobe, temporal horn, and hippocampal volumes and WMH were expressed as percentages of total cranial volume. WMH, Trail Making Test Part B − Part A, and Hooper Visual Organization Test were natural log–transformed to normalize distributions. As previously described, neuropsychological scores were adjusted for age and education, separately by sex, to enable comparison across measures. Resulting values were standardized, separately by gender, to a mean of 0 and a standard deviation of 1 (i.e., values were transformed to represent standard deviation units from the mean).

We used regression to assess linear relations between the LVEF and each brain aging variable. Next, we compared brain aging variables among participants classified by LVEF quintile and noted U-shaped associations. We therefore compared the lower (quintile 1) and upper (quintile 5) quintiles to the referent (quintiles 2 to 4) for each brain aging variable. On the basis of previous work, we adjusted for covariates defined at the seventh examination cycle, including age, sex, systolic blood pressure, smoking status, diabetes mellitus (i.e., history of fasting blood glucose ≥126 mg/dl or use of oral hypoglycemic or insulin), hypertension treatment, atrial fibrillation, and prevalent cardiovascular disease (CVD), including coronary heart disease, heart failure, and intermittent claudication. Secondary analyses were performed (1) excluding prevalent CVD (n = 77); (2) using the categorical LVEF variable (i.e., quintile 1, quintile 5, and referent quintiles 2 to 4) assessing effect modification by sex, age (<60 vs ≥60 years), and APOE-ε4 status (ε4− vs ε4+) and stratifying analyses by subgroups as indicated. Significance was set at p <0.05 for all models. Data were analyzed using SAS version 9.1 (SAS Institute Inc., Cary, North Carolina).

Results

Clinical characteristics are listed in Table 1 . Cardiac MRI, brain MRI, and neuropsychological descriptive variables are listed in Table 2 . As a continuous variable, the LVEF was unrelated to any brain MRI or neuropsychological variable ( Table 3 ). Findings were not altered when participants with CVD were excluded ( Table 4 ).

Table 4

Left ventricular ejection fraction, brain magnetic resonance imaging, and neuropsychological regression data excluding cardiovascular disease

Variable	LVEF (n = 1,037)		LVEF Quintiles (n = 1,037)
			Quintile 1 (Lowest)		Quintiles 2–4 (Middle)	Quintile 5 (Highest)
	β ± SE	p Value	β ± SE	p Value		β ± SE	p Value
Brain MRI data
WMH	0.01 ± 0.03	0.768	0.10 ± 0.08	0.193	Referent	0.02 ± 0.08	0.805
Total brain volume	0.01 ± 0.03	0.808	0.13 ± 0.24	0.594	Referent	0.20 ± 0.24	0.410
Frontal lobar volume	−0.04 ± 0.03	0.164	0.14 ± 0.22	0.514	Referent	−0.22 ± 0.22	0.333
Temporal horn volume	0.01 ± 0.03	0.690	−0.01 ± 0.06	0.930	Referent	−0.03 ± 0.06	0.574
Hippocampal volume (n = 391)	0.07 ± 0.05	0.151	−0.002 ± 0.01	0.841	Referent	0.01 ± 0.01	0.425
Neuropsychological data
Logical Memory Delayed Recall	−0.02 ± 0.03	0.495	−0.11 ± 0.09	0.213	Referent	−0.20 ± 0.09	0.020 ⁎
Visual Reproduction Delayed Recall	0.05 ± 0.03	0.129	−0.24 ± 0.08	0.003 ⁎	Referent	−0.14 ± 0.08	0.073
Boston Naming Test–30 Item	−0.03 ± 0.03	0.377	−0.003 ± 0.08	0.973	Referent	−0.06 ± 0.09	0.465
Trail Making Test Part B − Part A	−0.01 ± 0.04	0.806	−0.12 ± 0.10	0.202	Referent	−0.24 ± 0.10	0.017 ⁎
Similarities	0.03 ± 0.03	0.425	−0.15 ± 0.08	0.069	Referent	−0.10 ± 0.08	0.203
Hooper Visual Organization Test	0.01 ± 0.03	0.886	−0.27 ± 0.08	0.001 ⁎	Referent	−0.15 ± 0.08	0.078

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