Lower Left Ventricular Ejection Fraction Relates to Cerebrospinal Fluid Biomarker Evidence of Neurodegeneration in Older Adults

Article type: Research Article

Authors: Kresge, Hailey A.^a | Liu, Dandan^b | Gupta, Deepak K.^c | Moore, Elizabeth E.^a | Osborn, Katie E.^a | Acosta, Lealani Mae Y.^a | Bell, Susan P.^{a; c; d} | Pechman, Kimberly R.^a | Gifford, Katherine A.^a | Mendes, Lisa A.^c | Wang, Thomas J.^c | Blennow, Kaj^{e; f} | Zetterberg, Henrik^{e; f; g; h} | Hohman, Timothy J.^{a; i} | Jefferson, Angela L.^{a; c; *}

Affiliations: [a] Vanderbilt Memory & Alzheimer’s Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA | [b] Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA | [c] Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA | [d] Center for Quality Aging, Division of General Internal Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA | [e] Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden | [f] Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden | [g] Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK | [h] UK Dementia Research Institute at UCL, London, UK | [i] Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA

Correspondence: [*] Correspondence to: Angela L. Jefferson, Vanderbilt Memory & Alzheimer’s Center, 1207 17th Avenue South, Suite 204, Nashville, TN 37212, USA. Tel.: +615 322 8676; Fax: +615 343 1302; E-mail: [email protected].

Abstract: Background:Subclinical cardiac dysfunction is associated with decreased cerebral blood flow, placing the aging brain at risk for Alzheimer’s disease (AD) pathology and neurodegeneration. Objective:This study investigates the association between subclinical cardiac dysfunction, measured by left ventricular ejection fraction (LVEF), and cerebrospinal fluid (CSF) biomarkers of AD and neurodegeneration. Methods:Vanderbilt Memory & Aging Project participants free of dementia, stroke, and heart failure (n = 152, 72±6 years, 68% male) underwent echocardiogram to quantify LVEF and lumbar puncture to measure CSF levels of amyloid-β42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau). Linear regressions related LVEF to CSF biomarkers, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive diagnosis, and apolipoprotein E ɛ4 status. Secondary models tested an LVEF x cognitive diagnosis interaction and then stratified by diagnosis (normal cognition (NC), mild cognitive impairment (MCI)). Results:Higher LVEF related to decreased CSF Aβ42 levels (β= –6.50, p = 0.04) reflecting greater cerebral amyloid accumulation, but this counterintuitive result was attenuated after excluding participants with cardiovascular disease and atrial fibrillation (p = 0.07). We observed an interaction between LVEF and cognitive diagnosis on CSF t-tau (p = 0.004) and p-tau levels (p = 0.002), whereas lower LVEF was associated with increased CSF t-tau (β= –9.74, p = 0.01) and p-tau in the NC (β= –1.41, p = 0.003) but not MCI participants (p-values>0.13). Conclusions:Among cognitively normal older adults, subclinically lower LVEF relates to greater molecular evidence of tau phosphorylation and neurodegeneration. Modest age-related changes in cardiovascular function may have implications for pathophysiological changes in the brain later in life.

Keywords: Aging, Alzheimer’s disease, atrophy, cerebrospinal fluid proteins, echocardiography, tau proteins

DOI: 10.3233/JAD-190813

Journal: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 965-974, 2020