Contributions
Abstract: 147
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - 21 Imaging
Introduction: Thalamic atrophy occurs early in multiple sclerosis (MS) and is associated with cognitive impairment and fatigue. We sought to determine characteristics of extrathalamic injury that may have lead to thalamic atrophy.
Objectives: To examine MRI characteristics predictive of thalamic atrophy and investigate pathological correlates of thalami with extremes in atrophy.
Methods: We used a rapid autopsy program with in situ post-mortem MRI followed by brain fixation. Thalami were excised from fixed coronal slices and 30µm free floating sections were stained for myelin, neurons, activated microglia, and axons/dendrites. We acquired T1 MPRAGE, T2, and FLAIR. A semi-automated technique was to calculate volumes: T1 and T2 lesion (T1LV, T2LV), brain parenchymal fraction (BPF), total grey matter fraction (GMF), and thalamic (TV). Thalamic pathology was recorded for subjects with the most and least TV loss by MRI.
Results: Ninety five subjects with MS had MRI and tissue available and 25 (26%) had grossly apparent thalamic lesions. Mean TV was 13.5 mL ± 2.7. MRI thalamic lesion burden did not correlate with thalamic atrophy [Spearman rho (ρ) -0.15, p = 0.15] but did correlate with BPF (ρ = 0.61, p < 0.001), T2LV (ρ = -0.65, p < 0.001), and T1LV (ρ = - 0.48, p < 0.001). T2LV strongly correlated with T1LV (ρ = 0.76) and with TV (ρ = - 0.65) more than total grey matter fraction (GMF; ρ = 0.44) or BPF (ρ = - 0.54); all p < 0.001. Most had progressive courses: 74 (72%) secondary progressive, 14 (15%) primary progressive, and 7 (7%) relapsing. The mean disease duration was 25 ± 11.8 years and mean age at death was 59 ± 12 years.
Histologically, neuronal density was reduced and neurons were less polygonal in demyelinated lesions compared to normal appearing grey matter. Activated microglia were present in normal appearing thalamic tissue but were increased in lesions and lesional borders. Axonal density was decreased in perilesional and lesional areas. Histopathologic data for TV extremes (10th-percentile) will be presented.
Conclusions: Thalamic atrophy correlates with BPF, GMF, T1LV and T2LV but not thalamic lesions. Gross thalamic lesions corresponding to MRI lesions are demyelinated, have dysmorphic neurons, increased number of activated microglia, and reduced axonal density. These findings suggest that thalamic atrophy in MS results more from Wallerian or transsynaptic degeneration than from intra-thalamic lesions and reflects global white matter disease burden.
Disclosure:
Kedar Mahajan has nothing to disclose.
Kunio Nakamura has received personal compensation for speaking: Sanofi Genzyme. License fee payment: Biogen Idec. Research support to institution: Biogen Idec, Sanofi Genzyme.
Jacqueline Chen has nothing to disclose.
Bruce Trapp has received personal compensation for activities with Renovo Neural, Teva, Biogen Idec, Endece, Merck, EMD Serono, and Novartis as a consultant, speaker, or advisory board member.
Jeffrey Cohen received personal compensation for serving as a consultant or speaker from Merck, Novartis, and Receptos. Editor of Multiple Sclerosis Journal - Experimental, Translational and Clinical.
Daniel Ontaneda has received personal compensation for consulting with Genentech, Biogen Idec. Research Support from Genzyme and Novartis.
Abstract: 147
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - 21 Imaging
Introduction: Thalamic atrophy occurs early in multiple sclerosis (MS) and is associated with cognitive impairment and fatigue. We sought to determine characteristics of extrathalamic injury that may have lead to thalamic atrophy.
Objectives: To examine MRI characteristics predictive of thalamic atrophy and investigate pathological correlates of thalami with extremes in atrophy.
Methods: We used a rapid autopsy program with in situ post-mortem MRI followed by brain fixation. Thalami were excised from fixed coronal slices and 30µm free floating sections were stained for myelin, neurons, activated microglia, and axons/dendrites. We acquired T1 MPRAGE, T2, and FLAIR. A semi-automated technique was to calculate volumes: T1 and T2 lesion (T1LV, T2LV), brain parenchymal fraction (BPF), total grey matter fraction (GMF), and thalamic (TV). Thalamic pathology was recorded for subjects with the most and least TV loss by MRI.
Results: Ninety five subjects with MS had MRI and tissue available and 25 (26%) had grossly apparent thalamic lesions. Mean TV was 13.5 mL ± 2.7. MRI thalamic lesion burden did not correlate with thalamic atrophy [Spearman rho (ρ) -0.15, p = 0.15] but did correlate with BPF (ρ = 0.61, p < 0.001), T2LV (ρ = -0.65, p < 0.001), and T1LV (ρ = - 0.48, p < 0.001). T2LV strongly correlated with T1LV (ρ = 0.76) and with TV (ρ = - 0.65) more than total grey matter fraction (GMF; ρ = 0.44) or BPF (ρ = - 0.54); all p < 0.001. Most had progressive courses: 74 (72%) secondary progressive, 14 (15%) primary progressive, and 7 (7%) relapsing. The mean disease duration was 25 ± 11.8 years and mean age at death was 59 ± 12 years.
Histologically, neuronal density was reduced and neurons were less polygonal in demyelinated lesions compared to normal appearing grey matter. Activated microglia were present in normal appearing thalamic tissue but were increased in lesions and lesional borders. Axonal density was decreased in perilesional and lesional areas. Histopathologic data for TV extremes (10th-percentile) will be presented.
Conclusions: Thalamic atrophy correlates with BPF, GMF, T1LV and T2LV but not thalamic lesions. Gross thalamic lesions corresponding to MRI lesions are demyelinated, have dysmorphic neurons, increased number of activated microglia, and reduced axonal density. These findings suggest that thalamic atrophy in MS results more from Wallerian or transsynaptic degeneration than from intra-thalamic lesions and reflects global white matter disease burden.
Disclosure:
Kedar Mahajan has nothing to disclose.
Kunio Nakamura has received personal compensation for speaking: Sanofi Genzyme. License fee payment: Biogen Idec. Research support to institution: Biogen Idec, Sanofi Genzyme.
Jacqueline Chen has nothing to disclose.
Bruce Trapp has received personal compensation for activities with Renovo Neural, Teva, Biogen Idec, Endece, Merck, EMD Serono, and Novartis as a consultant, speaker, or advisory board member.
Jeffrey Cohen received personal compensation for serving as a consultant or speaker from Merck, Novartis, and Receptos. Editor of Multiple Sclerosis Journal - Experimental, Translational and Clinical.
Daniel Ontaneda has received personal compensation for consulting with Genentech, Biogen Idec. Research Support from Genzyme and Novartis.