Chronic hypometabolism in striatum and hippocampal network after traumatic brain injury and their relation with memory impairment - [18F]-FDG-PET and MRI 4 months after fluid percussion injury in rat.

Hippocampal and thalamo-cortico-striatal networks are critical for memory function as well as execution of a variety of learning strategies. In subjects with memory impairment as a sequel of traumatic brain injury (TBI), the contribution of late metabolic depression across these networks to memory deficit is poorly understood. We used [18F]-FDG-PET to measure chronic post-TBI glucose uptake in the striatum and connected brain areas (septal and temporal hippocampus, thalamus, entorhinal cortex, frontoparietal cortex and amygdala) in rats with lateral fluid-percussion injury (LFPI). Then we assessed a link between network hypometabolism and memory impairment. At 4 months post TBI, glucose uptake was decreased in ipsilateral striatum (10%, p = 0.027), frontoparietal cortex (17%, p = 0.00009), and hippocampus (22%, p = 0.027) as compared to sham operated controls. Thalamic uptake was 6% lower ipsilaterally than contralaterally, p = 0.00004). At 5 months, Morris water maze (MWM) showed memory impairment in 83% of the rats with TBI. The lower the hippocampal or striatal [18F]-FDG uptake, the poorer the MWM performance (hippocampus: r = -0.471, p < 0.05; striatum: r = -0.696, p < 0.001). Striatal [18F]-FDG-PET identified the injured animals with memory impairment with 100% specificity and sensitivity (AUC = 1.000, p = 0.009). Interestingly, the low striatal glucose uptake was a better diagnostic biomarker for memory impairment than the reduced hippocampal (AUC = 0.806, p = 0.112) or entorhinal (AUC = 0.528, p = 0.885) glucose uptake. The volumetric atrophy assessed in T2 weighted MRI or the gliotic area in Nissl staining did not correlate with glucose uptake. Arterial spin labeling did not indicate any reduction in the striatal blood flow. Our study suggests that TBI-induced chronic hypometabolism in striatum contributes to the cognitive deficits.

Post-injury ventricular enlargement associates with iron in choroid plexus but not with seizure susceptibility nor lesion atrophy-6-month MRI follow-up after experimental traumatic brain injury.

Ventricular enlargement is one long-term consequence of a traumatic brain injury, and a risk factor for memory disorders and epilepsy. One underlying mechanisms of the chronic ventricular enlargement is disturbed cerebrospinal-fluid secretion or absorption by choroid plexus. We set out to characterize the different aspects of ventricular enlargement in lateral fluid percussion injury (FPI) rat model by magnetic resonance imaging (MRI) and discovered choroid plexus injury in rats that later developed hydrocephalus. We followed the brain pathology progression for 6 months and studied how the ventricular growth was associated with the choroid plexus injury, cortical lesion expansion, hemorrhagic load or blood perfusion deficits. We correlated MRI findings with the seizure susceptibility in pentylenetetrazol challenge and memory function in Morris water-maze. Choroid plexus injury was validated by ferric iron (Prussian blue) and cytoarchitecture (Nissl) stainings. We discovered choroid plexus injury that accumulates iron in 90% of FPI rats by MRI. The amount of the choroid plexus iron remained unaltered 1-, 3- and 6-month post-injury. During this time, the ventricles kept on growing bilaterally. Ventricular growth did not depend on the cortical lesion severity or the cortical hemorrhagic load suggesting a separate pathology. Instead, the results indicate choroidal injury as one driver of the post-traumatic hydrocephalus, since the higher the choroid plexus iron load the larger were the ventricles at 6 months. The ventricle size or the choroid plexus iron load did not associate with seizure susceptibility. Cortical hypoperfusion and memory deficits were worse in rats with greater ventricular growth.

MRS Reveals Chronic Inflammation in T2w MRI-Negative Perilesional Cortex - A 6-Months Multimodal Imaging Follow-Up Study.

Sustained inflammation in the injured cortex is a promising therapeutic target for disease-modification after traumatic brain injury (TBI). However, its extent and dynamics of expansion are incompletely understood which challenges the timing and placement of therapeutics to lesioned area. Our aim was to characterize the evolution of chronic inflammation during lesion expansion in lateral fluid-percussion injury (FPI) rat model with focus on the MRI-negative perilesional cortex. T2-weighted MR imaging (T2w MRI) and localized magnetic resonance spectroscopy (MRS) were performed at 1, 3, and 6 months post-injury. End-point histology, including Nissl for neuronal death, GFAP for astrogliosis, and Prussian Blue for iron were used to assess perilesional histopathology. An additional animal cohort was imaged with a positron emission tomography (PET) using translocator protein 18 kDa (TSPO) radiotracer [18F]-FEPPA. T2w MRI assessed lesion growth and detected chronic inflammation along the lesion border while rest of the ipsilateral cortex was MRI-negative (MRI-). Instead, myo-inositol that is an inflammatory MRS marker for gliosis, glutathione for oxidative stress, and choline for membrane turnover were elevated throughout the 6-months follow-up in the MRI- perilesional cortex (all p < 0.05). MRS markers revealed chronically sustained inflammation across the ipsilateral cortex but did not indicate the upcoming lesion expansion. Instead, the rostral expansion of the cortical lesion was systematically preceded by a hyperintense band in T2w images months earlier. Histologic analysis of the hyperintensity indicated scattered astrocytes, incomplete glial scar, and intracellularly packed and free iron. Yet, the band was negative in [18F]-FEPPA-PET. [18F]-FEPPA also showed no cortical TSPO expression within the MRS voxel in MRI- perilesional cortex or anywhere along glial scar when assessed at 2 months post-injury. However, [18F]-FEPPA showed a robust signal increase, indicating reactive microgliosis in the ipsilateral thalamus at 2 months post-TBI. We present evidence that MRS reveals chronic posttraumatic inflammation in MRI-negative perilesional cortex. The mismatch in MRS, MRI, and PET measures may allow non-invasive endophenotyping of beneficial and detrimental inflammatory processes to aid targeting and timing of anti-inflammatory therapeutics.