Ischemic stroke and Alzheimer's disease (AD) are leading causes of neurological disability and cognitive decline, respectively. Although traditionally studied as distinct disorders, growing evidence suggests that both conditions can be understood within a brain-heart disease framework characterized by disrupted oxygen and energy homeostasis. Acute cerebral ischemia can provoke secondary cardiac dysfunction, whereas chronic cardiovascular insufficiency may impair cerebral perfusion, disrupt neurovascular homeostasis, and accelerate cognitive decline. These reciprocal interactions support the concept of a bidirectional brain-heart axis that links neural and cardiac vulnerability. Within this cross-organ stress network, hypoxia-responsive signaling, metabolic reprogramming, mitochondrial dysfunction, neurovascular injury, and systemic inflammation contribute to adaptive and maladaptive responses across multiple organ systems. In this Review, we examine how brain-heart interactions shape responses to acute and chronic neurological injury, with particular emphasis on ischemic stroke and AD as representative models of acute and chronic oxygen-energy stress. We discuss mechanisms of metabolic adaptation, neurovascular remodeling, inflammatory activation, and hypoxia-inducible factor (HIF) signaling across the brain-heart axis, while highlighting evidence from experimental studies, single-cell analyses, and human clinical investigations. By integrating these findings, we propose a systems-level framework that may help explain how acute neurological injury, chronic neurodegeneration, and cardiometabolic stress converge over time and guide the development of more integrated therapeutic strategies. 

Ischemic stroke and Alzheimer's disease (AD) are leading causes of neurological disability and cognitive decline, respectively. Although traditionally studied as distinct disorders, growing evidence suggests that both conditions can be understood within a brain-heart disease framework characterized by disrupted oxygen and energy homeostasis. Acute cerebral ischemia can provoke secondary cardiac dysfunction, whereas chronic cardiovascular insufficiency may impair cerebral perfusion, disrupt neurovascular homeostasis, and accelerate cognitive decline. These reciprocal interactions support the concept of a bidirectional brain-heart axis that links neural and cardiac vulnerability. Within this cross-organ stress network, hypoxia-responsive signaling, metabolic reprogramming, mitochondrial dysfunction, neurovascular injury, and systemic inflammation contribute to adaptive and maladaptive responses across multiple organ systems. In this Review, we examine how brain-heart interactions shape responses to acute and chronic neurological injury, with particular emphasis on ischemic stroke and AD as representative models of acute and chronic oxygen-energy stress. We discuss mechanisms of metabolic adaptation, neurovascular remodeling, inflammatory activation, and hypoxia-inducible factor (HIF) signaling across the brain-heart axis, while highlighting evidence from experimental studies, single-cell analyses, and human clinical investigations. By integrating these findings, we propose a systems-level framework that may help explain how acute neurological injury, chronic neurodegeneration, and cardiometabolic stress converge over time and guide the development of more integrated therapeutic strategies. 

Abstract

Background and aims: Post-stroke fatigue (PSF) can independently predict mortality in stroke patients. The effect of PSF on the process of exercise and its nature remains unclear. This study aimed to investigate how motor performance and cortical activity differ between stroke patients with high versus low post-stroke fatigue during exercise.

Materials and Methods: 18 informed patients completed the trial, with 8 individuals in the high PSF group (HFG) and 10 individuals in the low PSF group (LFG). Maximum voluntary contraction was measured using surface electromyogram (sEMG), each participant underwent a fatigue-inducing isometric knee-extension task at 70% maximum voluntary contraction. Cortical neural activity in cortical regions of interest was assessed using near-infrared functional imaging system (fNIRS), while muscle activity was monitored with sEMG. Primary outcomes included the number of knee-extensions performed, and changes in oxygenated hemoglobin (HbO2) in the regions of interest.

Results: No significant difference was observed in the number of knee-extensions between groups (P=0.11). However, significant group differences were found in HbO2 concentration of the right primary motor cortex (P=0.01) and left primary somatosensory cortex (P=0.01). A time effect revealed an increase in HbO2 concentration in the left frontal eye field (P=0.04). MPF values significantly correlated with HbO2 concentration changes in left frontal eye field for both groups (HFG, P=0.01; LFG, P=0.047).

Conclusions: The endurance of patients in LFG and HFG after stroke is comparable. Patients with high PSF have the characteristics of increased neural activity in the left primary somatosensory cortex and the right primary motor cortex during exercise.

Abstract

Background and aims: Post-stroke fatigue (PSF) can independently predict mortality in stroke patients. The effect of PSF on the process of exercise and its nature remains unclear. This study aimed to investigate how motor performance and cortical activity differ between stroke patients with high versus low post-stroke fatigue during exercise.

Materials and Methods: 18 informed patients completed the trial, with 8 individuals in the high PSF group (HFG) and 10 individuals in the low PSF group (LFG). Maximum voluntary contraction was measured using surface electromyogram (sEMG), each participant underwent a fatigue-inducing isometric knee-extension task at 70% maximum voluntary contraction. Cortical neural activity in cortical regions of interest was assessed using near-infrared functional imaging system (fNIRS), while muscle activity was monitored with sEMG. Primary outcomes included the number of knee-extensions performed, and changes in oxygenated hemoglobin (HbO2) in the regions of interest.

Results: No significant difference was observed in the number of knee-extensions between groups (P=0.11). However, significant group differences were found in HbO2 concentration of the right primary motor cortex (P=0.01) and left primary somatosensory cortex (P=0.01). A time effect revealed an increase in HbO2 concentration in the left frontal eye field (P=0.04). MPF values significantly correlated with HbO2 concentration changes in left frontal eye field for both groups (HFG, P=0.01; LFG, P=0.047).

Conclusions: The endurance of patients in LFG and HFG after stroke is comparable. Patients with high PSF have the characteristics of increased neural activity in the left primary somatosensory cortex and the right primary motor cortex during exercise.