Repeat concussions (or repetitive mild traumatic brain injury [rmTBI]) are complex pathological processes consisting of a primary insult and long-term secondary complications and are also a prerequisite for chronic traumatic encephalopathy (CTE). Recent evidence implies a significant role of autophagy-mediated dysfunctional mitochondrial clearance, mitophagy, in the cascade of secondary deleterious events resulting from TBI. C18-ceramide, a bioactive sphingolipid produced in response to cell stress and damage, and its synthesizing enzyme (CerS1) are precursors to selective stress-mediated mitophagy. A transporter, p17, mediates the trafficking of CerS1, induces C18-ceramide synthesis in the mitochondrial membrane, and acts as an elimination signal in cell survival. Whether p17-mediated mitophagy occurs in the brain and plays a causal role in mitochondrial quality control in secondary disease development after rmTBI are unknown. Using a novel repetitive less-than-mild TBI (rlmTBI) injury paradigm, ablation of mitochondrial p17/C18-ceramide trafficking in p17 knockout (KO) mice results in a loss of C18-ceramide–induced mitophagy, which contributes to susceptibility and recovery from long-term secondary complications associated with rlmTBI. Using a ceramide analog with lipid-selenium conjugate drug, LCL768 restored mitophagy and reduced long-term secondary complications, improving cognitive deficits in rlmTBI-induced p17KO mice. We obtained a significant reduction of p17 expression and a considerable decrease of CerS1 and C18-ceramide levels in cortical mitochondria of CTE human brains compared with age-matched control brains. These data demonstrated that p17/C18-ceramide trafficking is an endogenous neuroprotective mitochondrial stress response following rlmTBI, thus suggesting a novel prospective strategy to interrupt the CTE consequences of concussive TBI.

Oculomotor dysfunction identified within the first 10 days of sport-related concussion (SRC) is a risk factor for Persisting Post-Concussion Symptoms (PPCS). Oculomotor rehabilitation is the recommended treatment for oculomotor dysfunction from the subacute period onwards. However, there are delays in initiating rehabilitation due to a limited number of specialized providers and associated healthcare costs. Delays in initiating treatment are associated with worse outcomes. We performed a retrospective, quasi-experimental trial to evaluate whether providing instructions for self-guided oculomotor rehabilitation in adolescents with 3 or more abnormal oculomotor findings after SRC (Experimental Arm, n = 27, mean age = 15.50 ± 1.53 years, 63.0% male, 5.74 ± 2.43 days since injury) reduced the number of persisting impairments at 4 weeks compared to a wait-and-see approach (Standard Care Arm, n = 106, mean age = 14.98 ± 1.87 years, 59.4% male, 5.69 ± 2.78 days since injury). A small difference was seen in the incidence of neck tenderness but there were no differences between groups in symptom severity or number of abnormal oculomotor findings at initial presentation. Overall, 50 out of 106 (47.2%) participants in the Standard Care Arm had PPCS compared to 7 out of 27 (25.9%) in the Experimental Arm, which was significantly different (Chi-squared = 3.966, p = 0.046). This corresponds to an absolute risk reduction of 21.3%. Results from our pilot study suggest these treatment guidelines are feasible to incorporate into a busy outpatient practice in a cost-effective manner. Prospectively designed randomized controlled trials are warranted to validate the effectiveness of this treatment.

Diabetes increases the risk of vascular contributions to cognitive impairment and dementia (VCID). Using a microemboli (ME) model, we found that diabetic rats experience more severe white matter damage and progressive cognitive decline than controls. Moreover, the restoration of endothelial function before ME injection prevents VCID in diabetes. Given that diabetes mediates early endothelial dysfunction, activates the endothelin (ET) system, and the post-mortem brain (b) ET-1 levels correlate with tissue hypoxia in dementia patients, this study investigated the relationship between ET system, hypoxia, and neuroinflammation in this clinically relevant VCID model. While there were no ME-mediated changes or differences between control and diabetic groups in plasma and bET-1 levels, bET-1 levels correlated with hypoxia markers. ET _A R expression was reduced by the ISMN (75 mg/kg/day) and cilostazol (60 mg/kg/day) treatment. On the other hand, ET _B R expression was lower in the sham diabetic group compared to the sham controls, and ME injection did not have further effect. The treatment restored ET _B R expression to comparable levels in the control sham group. These findings suggest a link between the ET system, hypoxia, and neuroinflammation in diabetic VCID. Modulating the ET system may be a viable therapeutic strategy to improve vascular function and prevent VCID.

Background: Mild traumatic brain injuries (mTBIs) are a significant public health concern in the US. Understanding incidence and demographic patterns is essential for developing targeted prevention and intervention strategies. The most recent study using national healthcare records to examine incidence utilized data from 2016, highlighting the need for updated estimates that reflect current trends. Methods: The MarketScan^® Database was used for this study which includes person-specific clinical utilization, expenditures, and enrollment across different services. A query for mTBIs (S06.0x.xx) or post-concussion syndrome (F07.89) from January–December 2023 was performed for patients aged 0–64. Patients with the same diagnosis codes for the prior 12 months (i.e., chronic diagnosis), moderate to severe TBIs (S06.2–9), skull fractures (S02.xx), and/or brain hemorrhages (S06.3x) were excluded. Results: Out of 11,737,855 insured members with data in 2023, 43,213 new mTBIs were recorded (incidence rate = 0.37%), with the highest rate in adolescents (incidence rate = 1.27%). From the ages of 0–14 years, males had a higher incidence of concussion, but from 15 to 65 years, females had a higher incidence. Minimal differences were seen between urban and rural zip codes. Conclusions: Concussion incidence in adolescents is higher than other age groups, which may reflect increased participation in sports or heightened vulnerability during development. Males had a higher incidence than females during childhood, but females did later in life. These differences may reflect true disparities in injury risk, variations in reporting patterns, or a combination of both. Further research is warranted to understand the underlying mechanisms and to inform age- and sex-specific prevention efforts.