This study evaluated regional brain volumes in retired athletes with a history of rmTBI and found that TBV-adjusted brain volumes of the MBs and CC were lower than those in HCs. In addition, the TBV-adjusted MB volume correlated with scores of the ROCFT and LM for delayed recall, and the TBV-adjusted CC volume didn’t correlate with any cognitive assessment results in rmTBI participants. Furthermore, the excellent interobserver agreement suggested that MRI-based evaluation methods for regional brain volumes using ITK–SNAP are applicable for individualized assessment of rmTBI. To the best of our knowledge, this is the first report to demonstrate MB atrophy and its association with the severity of memory impairment on an individual basis in rmTBI participants.
The MBs form a vital link in a putative memory system, comprising projections from the hippocampus to the MBs, connecting to the anterior thalamic nuclei14 through the mammillothalamic tract. Recent studies describing the role of the MBs in memory emphasize the importance of the hippocampal inputs to the region; the MBs are often referred to as part of an “extended hippocampal system”.14 The presence of MB atrophy has been reported in various conditions, including Korsakoff’s syndrome,18 postresection of colloid cysts in the third ventricle,19 Alzheimer’s disease (AD),20 schizophrenia,21 heart failure,22 and sleep apnea.23 Furthermore, recent evidence suggests that the MBs are important for memory highlights the memory problems associated with these conditions and the need to accommodate such problems. 24
CTE is a persistent condition caused by rmTBI. The gross pathological findings of CTE include ventricular enlargement, cavum septum pellucidum or cavum vergae, frontal and temporal atrophy, thinning of the hypothalamic floor and the CC, and shrinkage of the MBs.12,13 Particularly, shrinkage of the MBs is a characteristic finding for CTE and is one of the supportive neuropathological findings in the consensus criteria.25 Furthermore, MB dysfunction is suggested to play a significant role in producing memory loss, cognitive impairment, and eventual dementia.26 However, the exact mechanism underlying MB shrinkage in CTE is unknown.
One hypothesis for the cause of MB atrophy in rmTBI is a direct traumatic injury to the hypothalamus, including the MBs. The hypothalamus is one of the brain regions vulnerable to injury from head trauma. A report based on 15 cases of severe TBI identified four anatomical lesions by examining serial histological sections of the hypothalamus: (1) lesions of the supraoptic and paraventricular nuclei, (2) lesions of the infundibulum, (3) lesions in and around the third ventricle, and (4) lesions of the MBs. Lesions in all four areas were consistently found in all TBI patients.27 Furthermore, infarction and hemorrhage were less frequently observed in the MBs, but gliosis and loss of neurons were observed, especially in longstanding cases.27 In previous MR imaging analyses, detected disruption of fornical fibers after TBI, including the MBs, using diffusion tensor imaging with anisotropy measures and tractography.28–30 In addition, a reduction in the volume of the fornix and atrophy elsewhere, including the CC and hippocampus, were observed in a long-term course after TBI.31,32 These neuropathological and neuroimaging results may help explain the cause of the rmTBI-related MB atrophy in our study.
Another potential mechanism for MB atrophy in rmTBI participants is neurodegeneration. Axonal injury and rmTBI might trigger molecular pathways that result in the aggregation of proteins prone to pathological accumulation in neurodegenerative disease, including phosphorylated tau (p-tau), TAR DNA-binding protein 43 kDa, α-synuclein, and amyloid-ß, thereby increasing the likelihood of frontotemporal lobar degeneration, Lewy body disease, or AD.26,28 Multiple epidemiological studies have shown that trauma is a risk factor for dementia, especially AD.28 Among neuropathological findings in patients with early-stage AD, only 60% of the patients had senile plaques and/or NF neurofibrillary tangles in the MBs.20 In addition, age and dementia are accompanied by a loss of MB volume without neuronal loss29 or neuronal atrophy.30 Furthermore, abnormal p-tau immunoreactive neuronal and astrocytic aggregates in subcortical nuclei, including the MBs, are a supportive neuropathological feature in the Preliminary National Institute of Neurological Disorders and Stroke criteria for the pathologic diagnosis of CTE.26 However, not a single study to date has succeeded in demonstrating that MB atrophy is directly linked to TBI-induced tau accumulation or other TBI-related neurodegenerative changes. Thus, these data suggest that MB atrophy in rmTBI may not only be affected by neurodegenerative disease, but may also be produced by direct traumatic injury or by lesions coexisting in other memory-related areas, such as the medial thalamus, mammillothalamic tract, descending columns of the fornix, amygdalofugal pathways, or by other neuronal pathologies.
The current study showed that, in rmTBI participants, MB atrophy occurs, and the MBs-volume/TBV ratio correlates with delayed recall on the ROCFT and LM tests. To the best of our knowledge, this is the first study to quantitatively evaluate the relationship between the MBs volume and memory performance in rmTBI participants. Our findings suggest that MB atrophy may serve as an index for the severity of visual and verbal memory impairment in rmTBI participants. Furthermore, memory impairment may be attributed to a disconnection between the MBs and the anterior nuclei of the thalamus, which are a part of the Papez circuit. Previous reports on retired National Football League (NFL) players with a history of concussions demonstrated significant reductions in hippocampal volumes and deficits in episodic memory.33 In addition, after the late 50s, atrophy of the hippocampus was more pronounced in the players than in HCs.33 In our study, 85% of the rmTBI participants were aged < 55 years; the hippocampal volume was not significantly different from that of the HC group in the NFL study.33 It should be noted that our results suggest that the MB atrophy in rmTBI precedes the volume reduction of the hippocampus and may be related to memory impairment in the early stage.
The present study also revealed atrophy of the CC in rmTBI participants, as measured by volumetric analysis. The CC is particularly vulnerable to shearing forces or rotation of the brain due to trauma.31 Our results are consistent with those of previous studies on CC injury in concussion or mild TBI.32 The CC is crucial for the normal interhemispheric transfer of sensory, motor, attentional, and executive information.34 Anterior callosal regions, such as the genu, contain fibers from the prefrontal cortex, whereas the body (proceeding from front to back) contains fibers from the premotor, motor, somatosensory, parietal, and temporal cortices.35 Previous studies suggested that trauma-induced atrophy of the CC likely occurs as a consequence of complex neuropathological features. These features involve both direct trauma to the CC36 and secondary Wallerian degeneration occurring because of diffuse damage elsewhere in the brain, disrupting the integrity of white matter tracts.37 Other studies have reported an association between white matter alterations (e.g., volume and microstructure) and cognitive function in TBI.38 However, Our study showed that the CC volume/TBV ratio was not correlated with age, duration since the first injury, or any cognitive assessment results. This result may reflect the heterogeneity of CC damage and widespread white matter alternation in rmTBI participants.
This study had some limitations. First, the relatively small sample size represents a sampling bias. Second, only Japanese participants were evaluated; thus, the results should be interpreted cautiously because post-TBI outcomes differ according to genetic associations among Caucasians, African-Americans, Hispanic, and Asians.39 In addition, racial variations in physique may contribute to the extent of brain trauma. Third, the sports professions varied. A previous study found differences in impact velocity and head injury criteria between boxing and American football.40 Therefore, differences in MB or CC atrophy in rmTBI should be examined by sport. Future research should investigate the longitudinal associations between MB atrophy and the prognosis of behavioral or cognitive impairment in rmTBI to determine whether MB atrophy can be used as an imaging marker.
In conclusion, retired athletes with a long history of rmTBI have MB atrophy, and this may be related to memory impairment associated with disconnection of the MBs from the Papez circuit.