Diffusion Tensor Imaging Along Perivascular Spaces (DTI-ALPS) to Assess Effects of Age, Sex, and Head Size on Interstitial Fluid Dynamics in Healthy Subjects.

Diffusion tensor imaging along perivascular spaces (DTI-ALPS) is a novel MRI method for assessing brain interstitial fluid dynamics, potentially indexing glymphatic function. Failed glymphatic clearance is implicated in Alzheimer's disease (AD) pathophysiology. We assessed the contribution of age and female sex (strong AD risk factors) to DTI-ALPS index in healthy subjects. We also for the first time assessed the effect of head size. In accord with prior studies, we show reduced DTI-ALPS index with aging, and in men compared to women. However, head size may be a major contributing factor to this counterintuitive sex difference.

Comparisons of electrophysiological markers of impaired executive attention after traumatic brain injury and in healthy aging.

Executive attention impairments are a persistent and debilitating consequence of traumatic brain injury (TBI). To make headway towards treating and predicting outcomes following heterogeneous TBI, cognitive impairment specific pathophysiology first needs to be characterized. In a prospective observational study, we measured EEG during the attention network test aimed at detecting alerting, orienting, executive attention and processing speed. The sample (N = 110) of subjects aged 18-86 included those with and without traumatic brain injury: n = 27, complicated mild TBI; n = 5, moderate TBI; n = 10, severe TBI; n = 63, non-brain-injured controls. Subjects with TBI had impairments in processing speed and executive attention. Electrophysiological markers of executive attention processing in the midline frontal regions reveal that, as a group, those with TBI and elderly non-brain-injured controls have reduced responses. We also note that those with TBI and elderly controls have responses that are similar for both low and high-demand trials. In subjects with moderate-severe TBI, reductions in frontal cortical activation and performance profiles are both similar to that of controls who are ∼4 to 7 years older. Our specific observations of frontal response reductions in subjects with TBI and in older adults is consistent with the suggested role of the anterior forebrain mesocircuit as underlying cognitive impairments. Our results provide novel correlative data linking specific pathophysiological mechanisms underlying domain-specific cognitive deficits following TBI and with normal aging. Collectively, our findings provide biomarkers that may serve to track therapeutic interventions and guide development of targeted therapeutics following brain injuries.

Glymphatic clearance estimated using diffusion tensor imaging along perivascular spaces is reduced after traumatic brain injury and correlates with plasma neurofilament light, a biomarker of injury severity.

The glymphatic system is a perivascular fluid clearance system, most active during sleep, considered important for clearing the brain of waste products and toxins. Glymphatic failure is hypothesized to underlie brain protein deposition in neurodegenerative disorders like Alzheimer's disease. Preclinical evidence suggests that a functioning glymphatic system is also essential for recovery from traumatic brain injury, which involves release of debris and toxic proteins that need to be cleared from the brain. In a cross-sectional observational study, we estimated glymphatic clearance using diffusion tensor imaging along perivascular spaces, an MRI-derived measure of water diffusivity surrounding veins in the periventricular region, in 13 non-injured controls and 37 subjects who had experienced traumatic brain injury ∼5 months previously. We additionally measured the volume of the perivascular space using T2-weighted MRI. We measured plasma concentrations of neurofilament light chain, a biomarker of injury severity, in a subset of subjects. Diffusion tensor imaging along perivascular spaces index was modestly though significantly lower in subjects with traumatic brain injury compared with controls when covarying for age. Diffusion tensor imaging along perivascular spaces index was significantly, negatively correlated with blood levels of neurofilament light chain. Perivascular space volume did not differ in subjects with traumatic brain injury as compared with controls and did not correlate with blood levels of neurofilament light chain, suggesting it may be a less sensitive measure for injury-related perivascular clearance changes. Glymphatic impairment after traumatic brain injury could be due to mechanisms such as mislocalization of glymphatic water channels, inflammation, proteinopathy and/or sleep disruption. Diffusion tensor imaging along perivascular spaces is a promising method for estimating glymphatic clearance, though additional work is needed to confirm results and assess associations with outcome. Understanding changes in glymphatic functioning following traumatic brain injury could inform novel therapies to improve short-term recovery and reduce later risk of neurodegeneration.