The contribution of gliosis to diffusion tensor anisotropy and tractography following traumatic brain injury: validation in the rat using Fourier analysis of stained tissue sections

Abstract

Diffusion tensor imaging is highly sensitive to the microstructural integrity of the brain and has uncovered significant abnormalities following traumatic brain injury not appreciated through other methods. It is hoped that this increased sensitivity will aid in the detection and prognostication in patients with traumatic injury. However, the pathological substrates of such changes are poorly understood. Specifically, decreases in fractional anisotropy derived from diffusion tensor imaging are consistent with axonal injury, myelin injury or both in white matter fibres. In contrast, in both humans and animal models, increases in fractional anisotropy have been suggested to reflect axonal regeneration and plasticity, but the direct histological evidence for such changes remains tenuous. We developed a method to quantify the anisotropy of stained histological sections using Fourier analysis, and applied the method to a rat controlled cortical impact model to identify the specific pathological features that give rise to the diffusion tensor imaging changes in subacute to chronic traumatic brain injury. A multiple linear regression was performed to relate the histological measurements to the measured diffusion tensor changes. The results show that anisotropy was significantly increased (P < 0.001) in the perilesioned cortex following injury. Cortical anisotropy was independently associated (standardized β = 0.62, P = 0.04) with the coherent organization of reactive astrocytes (i.e. gliosis) and was not attributed to axons. By comparison, a decrease in white matter anisotropy (P < 0.001) was significantly related to demyelination (β = 0.75, P = 0.0015) and to a lesser extent, axonal degeneration (β = -0.48, P = 0.043). Gliosis within the lesioned cortex also influenced diffusion tensor tractography, highlighting the fact that spurious tracts in the injured brain may not necessarily reflect continuous axons and may instead depict glial scarring. The current study demonstrates a novel method to relate pathology to diffusion tensor imaging findings, elucidates the underlying mechanisms of anisotropy changes following traumatic brain injury and significantly impacts the clinical interpretation of diffusion tensor imaging findings in the injured brain.

Thalamic Fractional Anisotropy Predicts Accrual of Cerebral White Matter Damage in Older Subjects with Small-Vessel Disease

“…In recent animal experiments of traumatic brain injury a similar DTI pattern has been associated with gliosis at the histopathologic level. 24 Unlike FA, AD did not provide added predictive value with regard to WMH accrual, compared with a regression model that included only baseline WMH volume (Table 4). Future studies using more sophisticated DTI techniques employing multiple or higher b-values compared with the standard DTI, such as high angular resolution diffusion imaging 25 or composite hindered and restricted model of diffusion, 26 as well as DTI-pathology combination studies may provide meaningful information to better understand the histopathologic substrate of DTI changes in the GM.…”

A Longitudinal Diffusion Tensor Imaging Study Assessing White Matter Fiber Tracts after Sports-Related Concussion

“…For example, a recent controlled cortical impact (CCI) study on rats 80 showed significantly increased RD and decreased FA in WM. RD may also be selectively sensitive to alterations of the myelin sheath, 81 as shown in the mouse model 22,82 and, more recently, in optic neuritis.…”

A prospective study of gray matter abnormalities in mild traumatic brain injury

“…Additionally, recent animal models indicate increased anisotropy within the thalamus and hippocampus during acute and more chronic injury phases. 6,7 Although evidence of atrophy has been found as early as 1 to 3 weeks postinjury in moderate to severe TBI,8,9 it becomes more prevalent at 6 to 12 months, 10-13 even in the absence of macroscopically detectable lesions.…”

“…Additionally, recent animal models indicate increased anisotropy within the thalamus and hippocampus during acute and more chronic injury phases. 6,7 Although evidence of atrophy has been found as early as 1 to 3 weeks postinjury in moderate to severe TBI, 8,9 it becomes more prevalent at 6 to 12 months, [10][11][12][13] even in the absence of macroscopically detectable lesions. 14,15 Studies of patients with complicated 16 and symptomatic mild to moderate 17 TBI indicate atrophy as a function of disease progression approximately 6 months 16 or 1 year 17 postinjury.…”