CF is a simultaneous state of physical weakness and cognitive dysfunction. The pathogenesis of CF is related to changes in brain structure. Our previous study found that the volumes of certain subcortical nuclei in CF was smaller than those in healthy controls, indicating that the brain structure in CF has indeed changed. The current study showed that there was an obvious decrease in the volume of 6 hippocampal subregions, including the left presubiculum, parasubiculum, molecular layer of the HP, and HATA and the right CA1 and presubiculum. Furthermore, the volumes of the left molecular layer of the HP and HATA and the right presubiculum were positively correlated with MQ score, the volumes of the left presubiculum, molecular layer of the HP, and HATA and the right CA1 and presubiculum were positively correlated with the MoCA score, and the volumes of the left parasubiculum, molecular layer of the HP and HATA were negatively correlated with the frailty index. We also found that the CF group showed a decreased proportion of brain parenchyma and total number of white matter fibers. These findings suggest that atrophy in some hippocampal subregions may be a potential mechanism underlying cognitive frailty.
To our knowledge, this is the first study to compare changes in hippocampal subfield volumes between CF and HC. Anatomically, atrophied structures, including the presubiculum and parasubiculum, were situated at the medial portions of the hippocampus, while the molecular layer of the HP, CA1 and HATA were situated at the lateral portions. In fact, the volume of the presubiculum or parasubiculum, which is related to cognitive level, has been found to be decreased in many diseases, such as Parkinson's disease, diabetes and Alzheimer's disease[24–26]. The presubiculum and parasubiculum play an important role in cognitive processing and visual spatial function. The volume of the presubiculum is considered to be a promising marker of imminent memory in Alzheimer's disease. Additionally, the left presubiculum volume is positively correlated with MoCA score in MCI patients, which is in line with our study. The connection between the presubiculum and the retrosplenial cortex is the primary site of lesions in most forms of amnesia, and stimulation in this region is reported to enhance memory. Information transfer from the parasubiculum and presubiculum to the medial entorhinal cortex is key to controlling spatial navigation, an important cognitive function. Due to atrophy of the presubiculum and parasubiculum damaging these pathways, cognitive function might be weakened. Although we were unable to find any research on the relationship between the decline in physical function and the subiculum, some studies claimed that exercise could improve the functional connectivity or structural brain health of the parahippocampal gyrus and dentate gyrus of the hippocampus with areas related to motor, sensory integration and mood regulation[31, 32]. The parasubiculum might affect physical function through the above brain areas in CF.
The hippocampal CA1 region is an important part of the medial temporal lobe memory circuit. It is selectively vulnerable to attack in the process of cognitive decline, which can also predict episodic memory impairment[33, 34]. Anatomical and physiological studies confirm that CA1 regulates hippocampal circuitry function and cognitive behavior by interacting with the entorhinal cortex, CA3, subiculum and dentate gyrus. The results of animal experiments also showed that improvement in neuronal inactivation and apoptosis in the hippocampal CA1 area was significantly positively correlated with an improvement in cognitive function. The CA1 region has been highlighted in most studies as a focal atrophy subfield in the early stages of AD. Our study shows that compared with that of HCs, the CA1 region of CF patients was smaller and related to cognitive dysfunction, which was consistent with previous studies. As mentioned above, the CA1 region is an important node of information input and output. The results of this study showed that atrophy of the CA1 region in the CF group was closely related to lower MoCA scores, which may be the secondary result of a decline in information processing ability stemming from this atrophy.
The HATA is located in the medial region of the hippocampus and is the transitional area between the hippocampus and amygdala. A study suggested that in Parkinson's disease subjects with cognitive impairment, the volume of the left fimbria, right CA1, and right HATA were decreased compared with those in normal cognition subjects, the volumes of the left parasubiculum and HATA were predictive of the conversion from normal cognition to mild cognitive impairment, and the CA1 area was associated with baseline attention. The atrophy of the parasubiculum and HATA might destroy the integrity of the hippocampal-amygdala network, which is in charge of information processing. In research on memory recall across the adult lifespan, it has been proposed that HATA is closely related to memory function, which is consistent with our study. In addition, the HATA plays an important role in fear regulation, the underlying mechanism of situational learning and emotional memory. Atrophy of the HATA might be related to a decline in the adaptability of elderly CF adults to new environments, but further research is needed to confirm this hypothesis.
The molecular layer of the HP is located above the subiculum and underneath the fissure, which includes part of the subiculum and CA fields. A study on the development of hippocampal subregion volumes across adolescence found that CA1 and molecular layer of the HP were nonlinear developmental trajectories in early volume increases, and global cognitive ability was positively associated with molecular layer of the HP development, while the numbers of synapses in the molecular layer of the HP showed a significant correlation with cognitive ability in subjects with early Alzheimer's disease, mild cognitive impairment, or no cognitive impairment. Additionally, the loss of synapses might be an early event in the disease process, and this structural loss was correlated with cognitive function. The current study found for the first time that the volume of the molecular layer of the HP was not only related to cognitive function but also negatively correlated with the frailty index. The reason for the negative correlation between the molecular layer of the HP and physical frailty is not clear and needs further study.
In terms of global brain parameters, we found that compared with that in the HC group, brain parenchyma atrophy was more severe and the total number of white matter fibers was smaller in the CF group. These findings indicate that the degree of aging and complexity of the brain in elderly CF patients are decreased from the overall level. In our study, the left side of the hippocampus lost more volume than the right side, which was different from previous work on Alzheimer's disease. This might mean that physical frailty may be more associated with changes in the left side of the hippocampus.