Margareta A Clarke1, Dhairya A Lakhani2, Sijin Wen3, Si Gao3, Seth A Smith4, Richard Dortch5, Junzhong Xu5, Francesca Bagnato6. 1. Neuroimaging Unit, Neuro-immunology Division, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA. 2. Neuroimaging Unit, Neuro-immunology Division, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Radiology, West Virginia University, Morgantown, WV, USA. 3. Department of Biostatistics, West Virginia University, Morgantown, WV, USA. 4. Department of Electrical Engineering and Computer Science, Vanderbilt University, Nashville, TN, USA; Vanderbilt University Institute of Imaging Sciences, Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA. 5. Vanderbilt University Institute of Imaging Sciences, Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA. 6. Neuroimaging Unit, Neuro-immunology Division, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Neurology, VA Hospital, TN Valley Healthcare System, Nashville, TN, USA. Electronic address: francesca.r.bagnato@vanderbilt.edu.
Abstract
BACKGROUND: Axonal injury is the primary source of irreversible neurological decline in persons with multiple sclerosis (pwMS). Identifying and quantifying myelin and axonal loss in lesional and perilesional tissue in vivo is fundamental for a better understanding of multiple sclerosis (MS) outcomes and patient impairment. Using advanced magnetic resonance imaging (MRI) methods, consisting of selective inversion recovery quantitative magnetization transfer imaging (SIR-qMT) and multi-compartment diffusion MRI with the spherical mean technique (SMT), we conducted a cross-sectional pilot study to assess myelin and axonal damage in the normal appearing white matter (NAWM) surrounding chronic black holes (cBHs) and how this pathology correlates with disability in vivo. We hypothesized that lesional axonal transection propagates tissue injury in the surrounding NAWM and that the degree of this injury is related to patient disability. METHODS: Eighteen pwMS underwent a 3.0 Tesla conventional clinical MRI, inclusive of T1 and T2 weighted protocols, as well as SIR-qMT and SMT. Regions of interests (ROIs) were manually delineated in cBHs, NAWM neighboring cBHs (perilesional NAWM), distant ipsilateral NAWM and contra-lateral distant NAWM. SIR-qMT-derived macromolecular-to-free pool size ratio (PSR) and SMT-derived apparent axonal volume fraction (Vax) were extracted to infer on myelin and axonal content, respectively. Group differences were assessed using mixed-effects regression models and correlation analyses were obtained by bootstrapping 95% confidence interval. RESULTS: In comparison to perilesional NAWM, both PSR and Vax values were reduced in cBHs (p < 0.0001) and increased in distant contra-lateral NAWM ROIs (p < 0.001 for PSR and p < 0.0001 for Vax) but not ipsilateral NAWM (p = 0.176 for PSR and p = 0.549 for Vax). Vax values measured in cBHs correlated with those in perilesional NAWM (Pearson rho = 0.63, p < 0.001). No statistically relevant associations were seen between PSR/Vax values and clinical and/or MRI metrics of the disease with the exception of cBH PSR values, which correlated with the Expanded Disability Status Scale (Pearson rho = -0.63, p = 0.03). CONCLUSIONS: Our results show that myelin and axonal content, detected by PSR and Vax, are reduced in perilesional NAWM, as a function of the degree of focal cBH axonal injury. This finding is indicative of an ongoing anterograde/retrograde degeneration and suggests that treatment prevention of cBH development is a key factor for preserving NAWM integrity in surrounding tissue. It also suggests that measuring changes in perilesional areas over time may be a useful measure of outcome for proof-of-concept clinical trials on neuroprotection and repair. PSR and Vax largely failed to capture associations with clinical and MRI characteristics, likely as a result of the small sample size and cross-sectional design, however, longitudinal assessment of a larger cohort may unravel the impact of this pathology on disease progression.
BACKGROUND: Axonal injury is the primary source of irreversible neurological decline in persons with multiple sclerosis (pwMS). Identifying and quantifying myelin and axonal loss in lesional and perilesional tissue in vivo is fundamental for a better understanding of multiple sclerosis (MS) outcomes and patient impairment. Using advanced magnetic resonance imaging (MRI) methods, consisting of selective inversion recovery quantitative magnetization transfer imaging (SIR-qMT) and multi-compartment diffusion MRI with the spherical mean technique (SMT), we conducted a cross-sectional pilot study to assess myelin and axonal damage in the normal appearing white matter (NAWM) surrounding chronic black holes (cBHs) and how this pathology correlates with disability in vivo. We hypothesized that lesional axonal transection propagates tissue injury in the surrounding NAWM and that the degree of this injury is related to patient disability. METHODS: Eighteen pwMS underwent a 3.0 Tesla conventional clinical MRI, inclusive of T1 and T2 weighted protocols, as well as SIR-qMT and SMT. Regions of interests (ROIs) were manually delineated in cBHs, NAWM neighboring cBHs (perilesional NAWM), distant ipsilateral NAWM and contra-lateral distant NAWM. SIR-qMT-derived macromolecular-to-free pool size ratio (PSR) and SMT-derived apparent axonal volume fraction (Vax) were extracted to infer on myelin and axonal content, respectively. Group differences were assessed using mixed-effects regression models and correlation analyses were obtained by bootstrapping 95% confidence interval. RESULTS: In comparison to perilesional NAWM, both PSR and Vax values were reduced in cBHs (p < 0.0001) and increased in distant contra-lateral NAWM ROIs (p < 0.001 for PSR and p < 0.0001 for Vax) but not ipsilateral NAWM (p = 0.176 for PSR and p = 0.549 for Vax). Vax values measured in cBHs correlated with those in perilesional NAWM (Pearson rho = 0.63, p < 0.001). No statistically relevant associations were seen between PSR/Vax values and clinical and/or MRI metrics of the disease with the exception of cBH PSR values, which correlated with the Expanded Disability Status Scale (Pearson rho = -0.63, p = 0.03). CONCLUSIONS: Our results show that myelin and axonal content, detected by PSR and Vax, are reduced in perilesional NAWM, as a function of the degree of focal cBH axonal injury. This finding is indicative of an ongoing anterograde/retrograde degeneration and suggests that treatment prevention of cBH development is a key factor for preserving NAWM integrity in surrounding tissue. It also suggests that measuring changes in perilesional areas over time may be a useful measure of outcome for proof-of-concept clinical trials on neuroprotection and repair. PSR and Vax largely failed to capture associations with clinical and MRI characteristics, likely as a result of the small sample size and cross-sectional design, however, longitudinal assessment of a larger cohort may unravel the impact of this pathology on disease progression.
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