Micro-diffusely abnormal white matter: An early multiple sclerosis lesion phase with intensified myelin blistering.

OBJECTIVE: Multiple sclerosis (MS) is a chronic central nervous system disease whose white matter lesion origin remains debated. Recently, we reported subtle changes in the MS normal appearing white matter (NAWM), presenting with an increase in myelin blisters and myelin protein citrullination, which may recapitulate some of the prodromal degenerative processes involved in MS pathogenesis. Here, to clarify the relevance of these changes for subsequent MS myelin degeneration we explored their prevalence in WM regions characterized by subtly reduced myelination (dubbed as micro-diffusely abnormal white matter, mDAWM). METHODS: We used an in-depth (immuno)histochemistry approach in 27 MS donors with histological presence of mDAWM and 5 controls. An antibody panel against degenerative markers was combined and the presence of myelin/axonal aberrations was analyzed and compared with the NAWM from the same cases/slices/regions. RESULTS: mDAWM-defined areas exhibit ill-defined borders, no signs of Wallerian degeneration, and they associate with visible veins. Remarkably, such areas present with augmented myelin blister frequency, enhanced prevalence of polar myelin phospholipids, citrullination, and degradation of myelin basic protein (MBP) when compared with the NAWM. Furthermore, enhanced reactivity of microglia/macrophages against citrullinated MBP was also observed in this tissue. INTERPRETATION: We report a new histologically defined early phase in MS lesion formation, namely mDAWM, which lacks signs of Wallerian pathology. These results support the prelesional nature of the mDAWM. We conceptualize that evolution to pathologically evident lesions comprises the previously documented imbalance of axo-myelinic units (myelin blistering) leading to their degeneration and immune system activation by released myelin components.

The cognitive relevance of non-lesional damage to cortical networks in people with multiple sclerosis.

BACKGROUND: Cognitive impairment, a common and debilitating symptom in people with multiple sclerosis (MS), is especially related to cortical damage. However, the impact of regional cortical damage remains poorly understood. Our aim was to evaluate structural (network) integrity in lesional and non-lesional cortex in people with MS, and its relationship with cognitive dysfunction. METHODS: In this cross-sectional study, 176 people with MS and 48 healthy controls underwent MRI, including double inversion recovery and diffusion-weighted scans, and neuropsychological assessment. Cortical integrity was assessed based on fractional anisotropy (FA) and mean diffusivity (MD) within 212 regions split into lesional or non-lesional cortex, and grouped into seven cortical networks. Integrity was compared between people with MS and controls, and across cognitive groups: cognitively-impaired (CI; ≥ two domains at Z ≤ - 2 below controls), mildly CI (≥ two at - 2 < Z ≤ - 1.5), or cognitively-preserved (CP). RESULTS: Cortical lesions were observed in 87.5% of people with MS, mainly in ventral attention network, followed by limbic and default mode networks. Compared to controls, in non-lesional cortex, MD was increased in people with MS, but mean FA did not differ. Within the same individual, MD and FA were increased in lesional compared to non-lesional cortex. CI-MS exhibited higher MD than CP-MS in non-lesional cortex of default mode, frontoparietal and sensorimotor networks, of which the default mode network could best explain cognitive performance. CONCLUSION: Diffusion differences in lesional cortex were more severe than in non-lesional cortex. However, while most people with MS had cortical lesions, diffusion differences in CI-MS were more prominent in non-lesional cortex than lesional cortex, especially within default mode, frontoparietal and sensorimotor networks.

Isolated cognitive impairment in people with multiple sclerosis: frequency, MRI patterns and its development over time.

OBJECTIVES: To study the frequency of isolated (i.e., single-domain) cognitive impairments, domain specific MRI correlates, and its longitudinal development in people with multiple sclerosis (PwMS). METHODS: 348 PwMS (mean age 48 ± 11 years, 67% female, 244RR/52SP/38PP) underwent neuropsychological testing (extended BRB-N) at baseline and at five-year follow-up. At baseline, structural MRI was acquired. Isolated cognitive impairment was defined as a Z-score of at least 1.5 SD below normative data in one domain only (processing speed, memory, executive functioning/working memory, and attention). Multi-domain cognitive impairment was defined as being affected in ≥ 2 domains, and cognitively preserved otherwise. For PwMS with isolated cognitive impairment, MRI correlates were explored using linear regression. Development of isolated cognitive impairment over time was evaluated based on reliable change index. RESULTS: At baseline, 108 (31%) PwMS displayed isolated cognitive impairment, 148 (43%) PwMS displayed multi-domain cognitive impairment. Most PwMS with isolated cognitive impairment were impaired on executive functioning/working memory (EF/WM; N = 37), followed by processing speed (IPS; N = 25), memory (N = 23), and attention (N = 23). Isolated IPS impairment was explained by a model of cortical volume and fractional anisotropy (adj. R2 = 0.539, p < 0.001); memory by a model with cortical volume and hippocampal volume (adj. R2 = 0.493, p = 0.002); EF/WM and attention were not associated with any MRI measure. At follow-up, cognitive decline was present in 11/16 (69%) of PwMS with isolated IPS impairment at baseline. This percentage varied between 18 and 31% of PwMS with isolated cognitive impairment in domains other than IPS at baseline. CONCLUSION: Isolated cognitive impairment is frequently present in PwMS and can serve as a proxy for further decline, particularly when it concerns processing speed. Cortical and deep grey matter atrophy seem to play a pivotal role in isolated cognitive impairment. Timely detection and patient-tailored intervention, predominantly for IPS, may help to postpone further cognitive decline.

Multicenter Evaluation of AI-generated DIR and PSIR for Cortical and Juxtacortical Multiple Sclerosis Lesion Detection.

Background Cortical multiple sclerosis lesions are clinically relevant but inconspicuous at conventional clinical MRI. Double inversion recovery (DIR) and phase-sensitive inversion recovery (PSIR) are more sensitive but often unavailable. In the past 2 years, artificial intelligence (AI) was used to generate DIR and PSIR from standard clinical sequences (eg, T1-weighted, T2-weighted, and fluid-attenuated inversion-recovery sequences), but multicenter validation is crucial for further implementation. Purpose To evaluate cortical and juxtacortical multiple sclerosis lesion detection for diagnostic and disease monitoring purposes on AI-generated DIR and PSIR images compared with MRI-acquired DIR and PSIR images in a multicenter setting. Materials and Methods Generative adversarial networks were used to generate AI-based DIR (n = 50) and PSIR (n = 43) images. The number of detected lesions between AI-generated images and MRI-acquired (reference) images was compared by randomized blinded scoring by seven readers (all with >10 years of experience in lesion assessment). Reliability was expressed as the intraclass correlation coefficient (ICC). Differences in lesion subtype were determined using Wilcoxon signed-rank tests. Results MRI scans of 202 patients with multiple sclerosis (mean age, 46 years ± 11 [SD]; 127 women) were retrospectively collected from seven centers (February 2020 to January 2021). In total, 1154 lesions were detected on AI-generated DIR images versus 855 on MRI-acquired DIR images (mean difference per reader, 35.0% ± 22.8; P < .001). On AI-generated PSIR images, 803 lesions were detected versus 814 on MRI-acquired PSIR images (98.9% ± 19.4; P = .87). Reliability was good for both DIR (ICC, 0.81) and PSIR (ICC, 0.75) across centers. Regionally, more juxtacortical lesions were detected on AI-generated DIR images than on MRI-acquired DIR images (495 [42.9%] vs 338 [39.5%]; P < .001). On AI-generated PSIR images, fewer juxtacortical lesions were detected than on MRI-acquired PSIR images (232 [28.9%] vs 282 [34.6%]; P = .02). Conclusion Artificial intelligence-generated double inversion-recovery and phase-sensitive inversion-recovery images performed well compared with their MRI-acquired counterparts and can be considered reliable in a multicenter setting, with good between-reader and between-center interpretative agreement. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Zivadinov and Dwyer in this issue.

Artificial double inversion recovery images can substitute conventionally acquired images: an MRI-histology study.

Cortical multiple sclerosis lesions are disease-specific, yet inconspicuous on magnetic resonance images (MRI). Double inversion recovery (DIR) images are sensitive, but often unavailable in clinical routine and clinical trials. Artificially generated images can mitigate this issue, but lack histopathological validation. In this work, artificial DIR images were generated from postmortem 3D-T1 and proton-density (PD)/T2 or 3D-T1 and 3D fluid-inversion recovery (FLAIR) images, using a generative adversarial network. All sequences were scored for cortical lesions, blinded to histopathology. Subsequently, tissue samples were stained for proteolipid protein (myelin) and scored for cortical lesions type I-IV (leukocortical, intracortical, subpial and cortex-spanning, respectively). Histopathological scorings were then (unblinded) compared to MRI using linear mixed models. Images from 38 patients (26 female, mean age 64.3 ± 10.7) were included. A total of 142 cortical lesions were detected, predominantly subpial. Histopathology-blinded/unblinded sensitivity was 13.4/35.2% for artificial DIR generated from T1-PD/T2, 14.1/41.5% for artificial DIR from T1-FLAIR, 17.6/49.3% for conventional DIR and 10.6/34.5% for 3D-T1. When blinded to histopathology, there were no differences; with histopathological feedback at hand, conventional DIR and artificial DIR from T1-FLAIR outperformed the other sequences. Differences between histopathology-blinded/unblinded sensitivity could be minified through adjustment of the scoring criteria. In conclusion, artificial DIR images, particularly generated from T1-FLAIR could potentially substitute conventional DIR images when these are unavailable.

Artificial double inversion recovery images for (juxta)cortical lesion visualization in multiple sclerosis.

BACKGROUND: Cortical lesions are highly inconspicuous on magnetic resonance imaging (MRI). Double inversion recovery (DIR) has a higher sensitivity than conventional clinical sequences (i.e. T1, T2, FLAIR) but is difficult to acquire, leading to overseen cortical lesions in clinical care and clinical trials. OBJECTIVE: To evaluate the usability of artificially generated DIR (aDIR) images for cortical lesion detection compared to conventionally acquired DIR (cDIR). METHODS: The dataset consisted of 3D-T1 and 2D-proton density (PD) T2 images of 73 patients (49RR, 20SP, 4PP) at 1.5 T. Using a 4:1 train:test-ratio, a fully convolutional neural network was trained to predict 3D-aDIR from 3D-T1 and 2D-PD/T2 images. Randomized blind scoring of the test set was used to determine detection reliability, precision and recall. RESULTS: A total of 626 vs 696 cortical lesions were detected on 15 aDIR vs cDIR images (intraclass correlation coefficient (ICC) = 0.92). Compared to cDIR, precision and recall were 0.84 ± 0.06 and 0.76 ± 0.09, respectively. The frontal and temporal lobes showed the largest differences in discernibility. CONCLUSION: Cortical lesions can be detected with good reliability on artificial DIR. The technique has potential to broaden the availability of DIR in clinical care and provides the opportunity of ex post facto implementation of cortical lesions imaging in existing clinical trial data.

Histopathology-validated recommendations for cortical lesion imaging in multiple sclerosis.

Cortical demyelinating lesions are clinically important in multiple sclerosis, but notoriously difficult to visualize with MRI. At clinical field strengths, double inversion recovery MRI is most sensitive, but still only detects 18% of all histopathologically validated cortical lesions. More recently, phase-sensitive inversion recovery was suggested to have a higher sensitivity than double inversion recovery, although this claim was not histopathologically validated. Therefore, this retrospective study aimed to provide clarity on this matter by identifying which MRI sequence best detects histopathologically-validated cortical lesions at clinical field strength, by comparing sensitivity and specificity of the thus far most commonly used MRI sequences, which are T2, fluid-attenuated inversion recovery (FLAIR), double inversion recovery and phase-sensitive inversion recovery. Post-mortem MRI was performed on non-fixed coronal hemispheric brain slices of 23 patients with progressive multiple sclerosis directly after autopsy, at 3 T, using T1 and proton-density/T2-weighted, as well as FLAIR, double inversion recovery and phase-sensitive inversion recovery sequences. A total of 93 cortical tissue blocks were sampled from these slices. Blinded to histopathology, all MRI sequences were consensus scored for cortical lesions. Subsequently, tissue samples were stained for proteolipid protein (myelin) and scored for cortical lesion types I-IV (mixed grey matter/white matter, intracortical, subpial and cortex-spanning lesions, respectively). MRI scores were compared to histopathological scores to calculate sensitivity and specificity per sequence. Next, a retrospective (unblinded) scoring was performed to explore maximum scoring potential per sequence. Histopathologically, 224 cortical lesions were detected, of which the majority were subpial. In a mixed model, sensitivity of T1, proton-density/T2, FLAIR, double inversion recovery and phase-sensitive inversion recovery was 8.9%, 5.4%, 5.4%, 22.8% and 23.7%, respectively (20, 12, 12, 51 and 53 cortical lesions). Specificity of the prospective scoring was 80.0%, 75.0%, 80.0%, 91.1% and 88.3%. Sensitivity and specificity did not significantly differ between double inversion recovery and phase-sensitive inversion recovery, while phase-sensitive inversion recovery identified more lesions than double inversion recovery upon retrospective analysis (126 versus 95; P < 0.001). We conclude that, at 3 T, double inversion recovery and phase-sensitive inversion recovery sequences outperform conventional sequences T1, proton-density/T2 and FLAIR. While their overall sensitivity does not exceed 25%, double inversion recovery and phase-sensitive inversion recovery are highly pathologically specific when using existing scoring criteria and their use is recommended for optimal cortical lesion assessment in multiple sclerosis.