Prediction of Cognitive Decline Using Heart Rate Fragmentation Analysis: The Multi-Ethnic Study of Atherosclerosis

Background: Heart rate fragmentation (HRF), a new non-invasive metric quantifying cardiac neuroautonomic function, is associated with increasing age and cardiovascular disease. Since these are risk factors for cognitive decline and dementia, in the Multi-Ethnic Study of Atherosclerosis (MESA), we investigated whether disrupted cardiac neuroautonomic function, evidenced by increased HRF, would be associated with worse cognitive function assessed concurrently and at a later examination, and with greater cognitive decline. Methods: HRF was derived from the ECG channel of the polysomnographic recordings obtained in an ancillary study (n = 1,897) conducted in conjunction with MESA exam 5 (2010-2012). Cognitive function was assessed at exam 5 and 6.4 ± 0.5 years later at exam 6 (2016-2018) with tests of global cognitive performance (the Cognitive Abilities Screening Instrument, CASI), processing speed (Digit Symbol Coding, DSC) and working memory (Digit Span). Multivariable regression models were used to quantify the associations between HRF indices and cognitive scores. Results: The participants' mean age was 68 ± 9 years (54% female). Higher HRF at baseline was independently associated with lower cognitive scores at both exams 5 and 6. Specifically, in cross-sectional analyses, a one-standard deviation (SD) (13.7%) increase in HRF was associated with a 0.51 (95% CI: 0.17-0.86) points reduction in CASI and a 1.12 (0.34-1.90) points reduction in DSC. Quantitatively similar effects were obtained in longitudinal analyses. A one-SD increase in HRF was associated with a 0.44 (0.03-0.86) and a 1.04 (0.28-1.81) points reduction in CASI and DSC from exams 5 to 6, respectively. HRF added predictive value to the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE-APOE-ε4) risk score and to models adjusted for serum concentration of NT-proBNP, an analyte associated with cognitive impairment and dementia. Conclusion: Increased HRF assessed during sleep was independently associated with diminished cognitive performance (concurrent and future) and with greater cognitive decline. These findings lend support to the links between cardiac neuroautonomic regulation and cognitive function. As a non-invasive, repeatable and inexpensive probe, HRF technology may be useful in monitoring cognitive status, predicting risk of dementia and assessing therapeutic interventions.