Highlights
- High-sensitivity cardiac troponin I (hs-cTnI) and natriuretic peptides (NT-proBNP, MR-proANP) are independently associated with MRI-defined markers of brain aging.
- Elevated NT-proBNP is a significant predictor of reduced cortical thickness and impaired verbal memory.
- Structural brain changes, particularly in network connectivity and white matter integrity, mediate the relationship between cardiac health and cognitive performance.
- Monitoring cardiac biomarkers may serve as a low-invasive screening tool for early neurocognitive risk assessment in subclinical populations.
Background: The Heart-Brain Axis and Cognitive Longevity
The intricate relationship between cardiovascular health and cognitive preservation has become a focal point of modern geriatric and preventive medicine. As the global burden of dementia rises, identifying early, accessible, and reliable indicators of cognitive decline is a public health priority. Traditionally, cardiovascular disease has been linked to an increased risk of dementia through mechanisms involving overt clinical events such as stroke or heart failure. However, there is growing evidence that subclinical cardiac dysfunction, even in the absence of symptomatic heart disease, may contribute to structural brain changes and subsequent cognitive impairment.
Biomarkers such as high-sensitivity cardiac troponin I (hs-cTnI), midregional pro-atrial natriuretic peptide (MR-proANP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are well-established in clinical cardiology for diagnosing myocardial injury and wall stress. Emerging research now suggests these markers might reflect a broader systemic vascular and hemodynamic state that directly impacts the brain’s structural integrity. The Hamburg City Health Study (HCHS) sought to clarify these associations in a large, population-based cohort, specifically examining whether these biomarkers relate to MRI markers of neurodegeneration and vascular damage, and whether such structural changes mediate cognitive deficits.
Study Design and Methodology
The study utilized data from the Hamburg City Health Study (NCT03934957), a large-scale, prospective, population-based study in Hamburg, Germany. The researchers included 2,553 participants aged 45 to 74 years. This cohort represents a critical demographic for early intervention, as it captures individuals in the transition from midlife to early late-life when subclinical changes often begin to manifest.
Biomarker Assessment
Blood samples were analyzed for three key cardiac markers:
1. High-sensitivity cardiac troponin I (hs-cTnI): A marker of chronic or acute myocardial injury.
2. Midregional pro-atrial natriuretic peptide (MR-proANP).
3. N-terminal pro-B-type natriuretic peptide (NT-proBNP): Markers of atrial and ventricular wall stress and hemodynamic load.
Neuroimaging and Cognitive Evaluation
Participants underwent comprehensive brain MRI to quantify markers of brain health across three domains:
1. Neurodegeneration: Total brain volume and cortical thickness.
2. Vascular Brain Damage: White matter hyperintensity (WMH) volume and the peak width of skeletonized mean diffusivity (PSMD), the latter being a highly sensitive marker for small vessel disease.
3. Structural Network Organization: Measures of brain network integration and segregation using diffusion tensor imaging (DTI).
Cognitive function was assessed using the CERAD-Plus battery, focusing on verbal memory (word list recall) and executive function (verbal fluency). The researchers employed multivariable-adjusted linear regression and structural equation modeling (SEM) to adjust for cardiovascular risk factors and investigate mediation pathways.
Key Findings: Linking the Heart to Brain Structure
The study population had a median age of 64 years, with 44% being women. The results provided robust evidence that cardiac biomarkers are closely tied to the brain’s structural and functional status, even after adjusting for traditional cardiovascular risk factors like hypertension, diabetes, and smoking.</n
Natriuretic Peptides and Neurodegeneration
Elevated levels of NT-proBNP and MR-proANP were consistently associated with markers of both neurodegeneration and vascular damage. Specifically, higher NT-proBNP concentrations correlated with lower cortical thickness (β = -0.081; 95% CI [-0.127 to -0.034]). This suggests that chronic cardiac wall stress may be a marker for, or a contributor to, the thinning of the cerebral cortex, a hallmark of early neurodegenerative processes including Alzheimer’s disease.
Cardiac Troponin and Vascular Injury
In contrast to the natriuretic peptides, hs-cTnI showed a more specific association with markers of vascular brain damage rather than general neurodegeneration. Higher hs-cTnI levels were significantly associated with increased PSMD (β = 0.103; 95% CI [0.060-0.146]), indicating that even subclinical myocardial injury is reflective of widespread cerebral small vessel disease. This finding underscores the concept that the microvasculature of the heart and the brain may share common pathological pathways.
Structural Connectivity and Network Integrity
One of the most striking findings was that all three studied biomarkers were associated with alterations in the brain’s structural network organization. Specifically, higher biomarker levels were linked to a shift toward less integration and more segregation within the brain’s white matter networks. This “de-integrated” network state is often associated with reduced cognitive efficiency and lower resilience to aging-related changes.
Cognitive Performance and Mediation
Elevated NT-proBNP was significantly associated with lower scores in verbal memory (β = -0.054) and verbal fluency (β = -0.054). Importantly, the structural equation modeling revealed that the effect of NT-proBNP on cognitive function was largely mediated by the observed structural brain changes. This provides a clear mechanical link: cardiac stress leads to structural brain alterations (both vascular and neurodegenerative), which in turn result in measurable cognitive deficits.
Expert Commentary: Mechanistic Insights and Clinical Implications
The findings from the Hamburg City Health Study provide a compelling argument for the “heart-brain axis.” The differential associations observed—where natriuretic peptides relate to neurodegeneration and troponins relate to vascular damage—suggest multiple pathways of injury. One potential mechanism is chronic cerebral hypoperfusion; subclinical cardiac dysfunction may lead to subtle reductions in cardiac output or blood pressure variability, depriving the metabolically demanding cerebral cortex of adequate oxygenation, leading to thinning. Another pathway involves shared microvascular pathology, where systemic inflammation or endothelial dysfunction affects both coronary and cerebral microvessels simultaneously.
Strengths and Limitations
The study’s primary strength lies in its large sample size and the use of sophisticated MRI metrics like PSMD and network analysis, which offer a more nuanced view than simple volume measurements. However, being a cross-sectional analysis, the study cannot definitively establish causality. It remains possible that common systemic factors drive both cardiac and cerebral deterioration in parallel. Additionally, while the population-based nature of the study is a strength, the results may predominantly reflect a relatively healthy subclinical cohort rather than patients with advanced clinical heart failure.
Conclusions and Future Directions
The research concludes that blood-based cardiac biomarkers, especially NT-proBNP, represent a low-invasive and widely available method to identify individuals at higher risk for structural brain damage and cognitive decline. In a clinical setting, an elevated NT-proBNP in a patient without overt heart failure might serve as a “red flag” for underlying cerebral small vessel disease or incipient neurodegeneration.
Future longitudinal studies are essential to determine if aggressive management of subclinical cardiac stress—perhaps through more stringent blood pressure control or the use of cardioprotective medications—can slow the progression of structural brain changes and preserve cognitive function. For now, clinicians should view these cardiac biomarkers not just as indicators of heart health, but as windows into the aging brain.
Funding and Clinical Trial Information
The Hamburg City Health Study is supported by various grants and institutional funding. The study is registered at ClinicalTrials.gov with the number NCT03934957.
References
Jensen M, Vettorazzi E, Weber P, et al. Association of Cardiac Biomarkers With Structural Brain Changes and Cognitive Impairment: Results From the Hamburg City Health Study. Neurology. 2025 Aug 12;105(3):e213865. doi: 10.1212/WNL.0000000000213865.
