Background

In multiple sclerosis (MS), a subset of chronic active white matter lesions are identifiable on MRI by their paramagnetic rims, and increasing evidence supports their association with clinical disease severity.

Objectives

To assess the prevalence and MS-specificity of paramagnetic rim lesions (PRL) on 3-tesla susceptibility-based MR brain images in MS vs non-MS cases in a multicenter sample drawn from 5 academic research hospitals at sites in Europe (Brussels, Lausanne, Milan) and the United States (NIH and JHU).

Methods

On submillimetric 3D T2*-segmented EPI brain MRI, the presence of PRL and central vein sign (CVS) were evaluated in the supratentorial brain of adults with MS (n=329) and non-MS neurological conditions (n=83). Non-MS cases were grouped as follows: (1) other-inflammatory neurological diseases (n=41); (2) HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP; n=10); (3) HIV-infected (n=10); (4) non-inflammatory neurological diseases (n=22).

ROC curve analysis, with diagnosis as dependent variable (MS vs non-MS), was applied to examine the diagnostic accuracy for each biomarker (PRL and CVS). Youden’s index method was used to obtain the optimal cutoff value for each biomarker.

Results

PRL were detected in 172/329 (52%) of MS cases vs. 6/83 non-MS cases (7%).

In MS, 58% of progressive cases had at least one PRL, compared to 50% of relapsing cases. MS cases with more than 4 PRL were more likely to have higher disability scores (EDSS, MSSS and ARMSS), but not significantly longer disease duration or older age.

In non-MS cases, PRL were seen exclusively in only a few inflammatory/infectious neurological conditions, including Susac syndrome (3 cases), neuromyelitis optica spectrum disorder (1 case), Sjögren disease (1 case) and HAM/TSP (1 case). Unlike in MS, PRL in non-MS cases were not associated with a high frequency of CVS+ lesions.

The identification of at least one PRL (optimal cutoff) was associated with high diagnostic specificity (93%), but relatively low sensitivity (52%) and accuracy (area under ROC curve=0.77), whereas CVS detection alone (optimal cutoff 35.5-38%) could better discriminate MS from non-MS cases with high specificity (96%), sensitivity (99%), and accuracy (area under ROC curve=0.99). The combination of the two biomarkers further improved the specificity (99%), but sensitivity remained low (59%).

Conclusions

PRL yielded high specificity for MS lesions. Future prospective multicenter studies should further validate its role as a diagnostic biomarker.

Background

Advanced diffusion-weighted MRI (DW-MRI) sequences, in combination with biophysical models, provide new information on the microstructural properties of the tissue.

Objectives

To investigate the differences in intra-axonal signal fraction (IASF) between perilesional normal-appearing white matter (pl-NAWM), white matter lesions (WML) without (rim-) and with paramagnetic rim (rim+) comparing eight biophysical diffusion models.

Methods

The study included 102 MS patients: RRMS: 66%, SPMS: 18%, PPMS: 16%, mean age 46±14; female 64%, disease duration 12.16±18.18 yrs, median EDSS: 2.5.

DW-MRI data were acquired with 1.8mm isotropic resolution and b-values [0, 700, 1000, 2000, 3000] s/mm².

Lesion masks were generated with a deep-learning-based method and manually corrected if required; pl-NAWM was defined as a region of 3-voxels around each WML; 225 paramagnetic rim lesions were manually identified based on 3D EPI and 2330 were labelled as rim-.

The following microstructural models were applied: Ball and Stick, Ball and Rockets, AMICO-NODDI, SMT-NODDI, MCMDI, NODDIDA, CHARMED, Microstructure Bayesian approach.

Delta (WML - pl-NAWM) was calculated for each WML, and one-side Mann Whitney U was used to compare the delta between models, followed by Bonferroni to correct for multiple testing.

Mean difference and Cohen's d was used to assess differences between lesions with extensive axonal damage (rim+) and other WML (rim-).

Results

All models applied in this study reported low IASF in rim+ WML, medium IASF in rim- WML and relatively high IASF in pl-NAWM. However, a broad spectrum of IASF values was identified from the different models: relatively simple models such as Ball and Stick and CHARMED, showed low delta IASF within lesions, while MCMDI models reported the highest significant difference compared to other models (p<0.0001). The comparison between WML and pl-NAWM mean IASF across models showed that MCDMI exhibited the highest difference (mean 0.13, Cohen’s d 1.34). AMICO-NODDI and SMT-NODDI showed close results (mean difference 0.12/0.12 and Cohen’s d 1.46/1.51).

The models best discriminating IASF between rim+ and rim- lesions were MCMDI and NODIDDA (mean 0.08/0.07, Cohen’s d -0.69/-0.70).

Conclusions

We compared eight WM diffusion models for assessment of intralesional axonal damage in MS patients. The comparison between WML and pl-NAWM showed that robustness of the method, identified with SMT-based and NODDI-based models, it is crucial. For the comparison between lesions with a high level of damage (rim +) and other WML, the diffusivity estimation appeared to play an important role. The method which appeared both robust and able to estimate the diffusivity of the tissue was MCMDI, which performed best in both cases.

Background

In multiple sclerosis (MS), a subset of chronic active white matter lesions are identifiable on MRI by their paramagnetic rims, and increasing evidence supports their association with clinical disease severity.

Objectives

To assess the prevalence and MS-specificity of paramagnetic rim lesions (PRL) on 3-tesla susceptibility-based MR brain images in MS vs non-MS cases in a multicenter sample drawn from 5 academic research hospitals at sites in Europe (Brussels, Lausanne, Milan) and the United States (NIH and JHU).

Methods

On submillimetric 3D T2*-segmented EPI brain MRI, the presence of PRL and central vein sign (CVS) were evaluated in the supratentorial brain of adults with MS (n=329) and non-MS neurological conditions (n=83). Non-MS cases were grouped as follows: (1) other-inflammatory neurological diseases (n=41); (2) HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP; n=10); (3) HIV-infected (n=10); (4) non-inflammatory neurological diseases (n=22).

ROC curve analysis, with diagnosis as dependent variable (MS vs non-MS), was applied to examine the diagnostic accuracy for each biomarker (PRL and CVS). Youden’s index method was used to obtain the optimal cutoff value for each biomarker.

Results

PRL were detected in 172/329 (52%) of MS cases vs. 6/83 non-MS cases (7%).

In MS, 58% of progressive cases had at least one PRL, compared to 50% of relapsing cases. MS cases with more than 4 PRL were more likely to have higher disability scores (EDSS, MSSS and ARMSS), but not significantly longer disease duration or older age.

In non-MS cases, PRL were seen exclusively in only a few inflammatory/infectious neurological conditions, including Susac syndrome (3 cases), neuromyelitis optica spectrum disorder (1 case), Sjögren disease (1 case) and HAM/TSP (1 case). Unlike in MS, PRL in non-MS cases were not associated with a high frequency of CVS+ lesions.

The identification of at least one PRL (optimal cutoff) was associated with high diagnostic specificity (93%), but relatively low sensitivity (52%) and accuracy (area under ROC curve=0.77), whereas CVS detection alone (optimal cutoff 35.5-38%) could better discriminate MS from non-MS cases with high specificity (96%), sensitivity (99%), and accuracy (area under ROC curve=0.99). The combination of the two biomarkers further improved the specificity (99%), but sensitivity remained low (59%).

Conclusions

PRL yielded high specificity for MS lesions. Future prospective multicenter studies should further validate its role as a diagnostic biomarker.