Repetitive head impacts and chronic traumatic encephalopathy are associated with TDP-43 inclusions and hippocampal sclerosis.

Hippocampal sclerosis (HS) is associated with advanced age as well as transactive response DNA-binding protein with 43 kDa (TDP-43) deposits. Both hippocampal sclerosis and TDP-43 proteinopathy have also been described in chronic traumatic encephalopathy (CTE), a neurodegenerative disease linked to exposure to repetitive head impacts (RHI). However, the prevalence of HS in CTE, the pattern of TDP-43 pathology, and associations of HS and TDP-43 with RHI are unknown. A group of participants with a history of RHI and CTE at autopsy (n = 401) as well as a group with HS-aging without CTE (n = 33) was examined to determine the prevalence of HS and TDP-43 inclusions in CTE and to compare the clinical and pathological features of HS and TDP-43 inclusions in CTE to HS-aging. In CTE, HS was present in 23.4%, and TDP-43 inclusions were present in 43.3% of participants. HS in CTE occurred at a relatively young age (mean 77.0 years) and was associated with a greater number of years of RHI than CTE without HS adjusting for age (p = 0.029). In CTE, TDP-43 inclusions occurred frequently in the frontal cortex and occurred both with and without limbic TDP-43. Additionally, structural equation modeling demonstrated that RHI exposure years were associated with hippocampal TDP-43 inclusions (p < 0.001) through increased CTE stage (p < 0.001). Overall, RHI and the development of CTE pathology may contribute to TDP-43 deposition and hippocampal sclerosis.

Short-term neurochemical effects of transcutaneous trigeminal nerve stimulation using 7T magnetic resonance spectroscopy.

BACKGROUND AND PURPOSE: The purpose was to explore the effects of transcutaneous trigeminal nerve stimulation (TNS) on neurochemical concentrations (brainstem, anterior cingulate cortex [ACC], dorsolateral prefrontal cortex [DLPFC], ventromedial prefrontal cortex [VMPFC], and the posterior cingulate cortex [PCC]) using ultrahigh-field magnetic resonance spectroscopy. METHODS: This double-blinded study tested 32 healthy males (age: 25.4 ± 7.3 years) on two separate occasions where participants received either a 20-minute TNS or sham session. Participants were scanned at baseline and twice post-TNS/sham administration. RESULTS: There were no group differences in concentration changes of glutamate, gamma-aminobutyric acid, glutamine, myoinositol (mI), total N-acetylaspartate, total creatine (tCr), and total choline between the baseline scan and the first post-TNS/sham scan and between the first and second post-TNS/sham scan in the brainstem, ACC, DLPFC, VMPFC, and PCC. Between the baseline scan and the second post-TNS/sham scan, changes in tCr (mean difference = 0.280 mM [0.075 to 0.485], p = .026) and mI (mean difference = 0.662 mM [0.203 to 1.122], p = .026) in the DLPFC differed between groups. Post hoc analyses indicated that there was a decrease in tCr (mean change = -0.201 mM [-0.335 to -0.067], p = .003) and no change in mI (mean change = -0.327 mM [-0.737 to 0.083], p = .118) in the TNS group; conversely, there was no change in tCr (mean change = -0.100 mM [-0.074 to 0.274], p = .259) and an increase in mI (mean change = 0.347 mM [0.106 to 0.588], p = .005) in the sham group. CONCLUSION: These data demonstrate that a single session of unilateral TNS slightly decreased tCr concentrations in the DLPFC region.

Nonhomogeneous Gadolinium Retention in the Cerebral Cortex after Intravenous Administration of Gadolinium-based Contrast Agent in Rats and Humans.

Background Gadolinium retention after repeated gadolinium-based contrast agent (GBCA) exposure has been reported in subcortical gray matter. However, gadolinium retention in the cerebral cortex has not been systematically investigated. Purpose To determine whether and where gadolinium is retained in rat and human cerebral cortex. Materials and Methods The cerebral cortex in Sprague-Dawley rats treated with gadopentetate dimeglumine (three doses over 4 weeks; cumulative gadolinium dose, 7.2 mmol per kilogram of body weight; n = 6) or saline (n = 6) was examined with antemortem MRI. Two human donors with repeated GBCA exposure (three and 15 doses; 1 and 5 months after exposure), including gadopentetate dimeglumine, and two GBCA-naive donors were also evaluated. Elemental brain maps (gadolinium, phosphorus, zinc, copper, iron) for rat and human brains were constructed by using laser ablation inductively coupled plasma mass spectrometry. Results Gadopentetate dimeglumine-treated rats showed region-, subregion-, and layer-specific gadolinium retention in the neocortex (anterior cingulate cortex: mean gadolinium concentration, 0.28 µg ∙ g-1 ± 0.04 [standard error of the mean]) that was comparable (P > .05) to retention in the allocortex (mean gadolinium concentration, 0.33 µg ∙ g-1 ± 0.04 in piriform cortex, 0.24 µg ∙ g-1 ± 0.04 in dentate gyrus, 0.17 µg ∙ g-1 ± 0.04 in hippocampus) and subcortical structures (0.47 µg ∙ g-1 ± 0.10 in facial nucleus, 0.39 µg ∙ g-1 ± 0.10 in choroid plexus, 0.29 µg ∙ g-1 ± 0.05 in caudate-putamen, 0.26 µg ∙ g-1 ± 0.05 in reticular nucleus of the thalamus, 0.24 µg ∙ g-1 ± 0.04 in vestibular nucleus) and significantly greater than that in the cerebellum (0.17 µg ∙ g-1 ± 0.03, P = .01) and white matter tracts (anterior commissure: 0.05 µg ∙ g-1 ± 0.01, P = .002; corpus callosum: 0.05 µg ∙ g-1 ± 0.02, P = .001; cranial nerve: 0.02 µg ∙ g-1 ± 0.01, P = .004). Retained gadolinium colocalized with parenchymal iron. T1-weighted MRI signal intensification was not observed. Gadolinium retention was detected in the cerebral cortex, pia mater, and pia-ensheathed leptomeningeal vessels in two GBCA-exposed human brains but not in two GBCA-naive human brains. Conclusion Repeated gadopentetate dimeglumine exposure is associated with gadolinium retention in specific regions, subregions, and layers of cerebral cortex that are critical for higher cognition, affect, and behavior regulation, sensorimotor coordination, and executive function. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Kanal in this issue.

Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model.

The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood-brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood-brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.awx350media15713427811001.