Background: Chronic heart failure (CHF) is one of the most prevalent internal conditions and about half of patients develop cognitive deficits over time. Within the frame of the Cognition.Matters-HF study, we recently could show that impairment of reaction time and verbal memory relate to medial temporal lobe atrophy (Eur Heart J. 2021, PMID: 33496311). Quantification of serum neurodegenerative biomarkers, corresponding to axonal and neuronal loss, brain atrophy and cognitive dysfunction, has recently gained attention across a broad spectrum of neurodegenerative disorders. However, little is known about the influence of comorbidities and biometric factors on serum concentrations of these biomarkers.

Methods: We investigated all participants of the Cognition.Matters-HF prospective cohort study. These were patients suffering from chronic, stable systolic or diastolic heart failure, but were clinically unapparent with regard to history or signs/symptoms of cerebrovascular accidents. All patients underwent extensive neurological, cardiological and neuropsychological testing (five domains of cognition: intensity of attention, selectivity of attention, visual/verbal memory, working memory and visual/verbal fluency), blood sampling, and brain magnetic resonance imaging. Cerebral atrophy was visually rated on a scale from 1 to 8, medial temporal lobe atrophy by Schelten’s score ranging from 0 (normal) to 4 (severe atrophy). Serum levels of neurofilament light chain (NfL), an axonal marker for neuronal damage, and phosphorylated tau (pTau), related to Alzheimer disease, were quantified using ultra-sensitive bead-based single molecular immunoassays. Descriptive statistics and uni- and multivariable regression was used to identify independent variables influencing serum levels of NfL and pTau.

Results: Serum markers (Nfl, pTau) could be analyzed in all n=146 study participants: age range 32 to 85 years, 15.1 % female. NfL serum levels ranged from 5.4 to 215.0 pg/ml (mean 34.0 pg/ml), pTau levels from 0.51 to 9.22 pg/ml (mean 1.96 pg/ml). Age significantly correlated with both NfL (r=0.57, p<0.001) and pTau (r=0.47, p<0.011), as did estimated glomerular filtration rate (eGFR) (r=-0.53, p<0.001 for NfL; r=-0.47, p<0.001 for pTau). NfL (r=0.40, p<0.001) and pTau (r=0.30, p=0.010) correlated to serum NT-proBNP levels, while left ventricular ejection fraction did not significantly relate to NfL (r=-0.03, p=0.689) and pTau (r=-0.11; p=0.201). Serum levels of NfL and pTau were not affected by sex (both p=n.s.). Both serum NfL and pTau were inversely correlated with performance in the domain visual and verbal memory: r=-0.252, p=0.002 (NfL); r=-0.253, p=0.002 (pTau). Further, both Nfl and pTau were correlated with severity of cerebral atrophy (r=0.445, p<0.001; r=0.001, p<0.001, respectively) and hippocampal atrophy (r=0.177, p=0.036; r=0.275, p=0.001, respectively). As independent factors influencing the serum level of both NfL and pTau emerged age and eGFR, while NT-proBNP was an additional independent predictor of serum NfL levels.

Discussion: In chronic heart failure, analysis of NfL and pTau from serum may help identifying those patients at risk for cognitive deficits and cerebral atrophy. However, our findings raise the caveat that these neurodegenerative markers must be interpreted within the clinical context because they are determined by age, renal function and, in the case of NfL, severity of heart failure.