Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the <scp>INFORMS</scp> study

Miller, David H.; Lublin, Fred; Sormani, Maria Pia; Kappos, Ludwig; Yaldizli, Özgür; Freedman, Mark S.; Cree, Bruce A.C.; Weiner, Howard L.; Lubetzki, Catherine; Hartung, Hans‐Peter; Montalbán, Xavier; Uitdehaag, Bernard M. J.; MacManus, David; Yousry, Tarek; Wheeler-Kingshott, C; Li, Bingbing; Putzki, Norman; Merschhemke, Martin; Häring, Dieter A.; Wolinsky, Jerry S.

doi:10.1002/acn3.534

Cited by 18 publications

(20 citation statements)

References 27 publications

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“…Patients with high NfL at BL had a higher on-study PBVC for up to 120 months. This is clinically relevant because NBV has been shown to predict long-term outcomes in MS. [24][25][26][27] The prognostic value of BL NfL for on-study BVL observed in the current study was broadly in line with recently published work, partly using the same data from FREEEDOMS and TRANS-FORMS. 10 Furthermore, the present results are largely consistent with the Comprehensive Longitudinal Investigations in MS at Brigham and Women's Hospital (CLIMB) 22 and Expression, Proteomics, Imaging, Clinical (EPIC) 28 studies.…”

Section: Discussionsupporting

confidence: 91%

Long-term prognostic value of longitudinal measurements of blood neurofilament levels

Häring

Kropshofer

Kappos

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo assess the long-term prognostic value of an integral of longitudinal measurements of plasma neurofilament light chain levels (NfLlong) over 12 and 24 months vs single neurofilament light chain (NfL) measurements in patients with relapsing-remitting MS (RRMS) and its additional value when combined with clinical and MRI measures.MethodsThis analysis included continuously fingolimod-treated patients with RRMS from the 24-month FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS)/12-month Trial Assessing Injectable Interferon vs FTY720 Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS) phase 3 trials and their long-term extension, LONGTERMS. Patients were classified into high (≥30 pg/mL, n = 110) and low (<30 pg/mL, n = 164) NfL categories based on the baseline (BL) NfL value or the geometric mean NfLlong calculated over 12 and 24 months to predict disability-related outcomes and brain volume loss (BVL). The additional prognostic value of NfL was quantified using the area under the receiver operating characteristic (ROC) curve.ResultsA single high (vs low) NfL measure at BL was prognostic of a higher risk of reaching Expanded Disability Status Scale (EDSS) score ≥4 earlier (hazard ratio [HR] = 2.19; 95% CI = 1.21–3.97) and higher BVL over 120 months (difference: −1.12%; 95% CI = −2.07 to −0.17). When NfLlong was measured over 24 months, high NfL was associated with a higher risk of reaching EDSS score ≥4 (HR = 7.91; 95% CI = 2.99–20.92), accelerated 6-month confirmed disability worsening (HR = 3.14; 95% CI = 1.38–7.11), and 20% worsening in the Timed 25-Foot Walk Test (HR = 3.05; 95% CI = 1.38–6.70). Area under the ROC curve was consistently highest in models combining NfL with clinical and MRI measures.ConclusionsNfLlong had a higher prognostic value than single NfL assessments on long-term outcomes in RRMS. Combining it with clinical and MRI measures increased sensitivity and specificity to predict long-term disease outcomes.Classification of evidenceThis study provides Class I evidence that NfLlong was more strongly associated with long-term outcomes than single NfL assessments in patients with RRMS.

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Section: Discussionsupporting

confidence: 91%

Long-term prognostic value of longitudinal measurements of blood neurofilament levels

Häring

Kropshofer

Kappos

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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“…Miller et al . investigated the relationship between brain volume and disability worsening over ≥3 years in PP‐MS and found that the rate of brain volume loss was most rapid in the severe subgroup who experienced clinical progression and least rapid in the stable subgroup who did not experience confirmed progression.…”

Section: Discussionmentioning

confidence: 99%

“…A few relatively recent studies attempted to identify measures able to predict the clinical outcome in patients with progressive MS and found that lower baseline EDSS scores and short-term changes are associated with a higher risk of subsequent clinical worsening [19,20]. Miller et al [5] investigated the relationship between brain volume and disability worsening over ≥3 years in PP-MS and found that the rate of brain volume loss was most rapid in the severe subgroup who experienced clinical progression and least rapid in the stable subgroup who did not experience confirmed progression.…”

Section: Discussionmentioning

confidence: 99%

“…Findings from clinical trials suggest that the risk of disability progression and treatment effects in progressive multiple sclerosis (MS) depends not only on the presence of Gd + lesions at baseline but also on brain volume loss . In addition to the well‐recognized role of gray matter (GM) pathology , histopathological studies from post‐mortem samples of patients with PP‐MS have demonstrated that normal‐appearing white matter (NAWM) shows extensive and diffuse pathology .…”

Section: Introductionmentioning

confidence: 99%

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Axonal water fraction as marker of white matter injury in primary‐progressive multiple sclerosis: a longitudinal study

Margoni

Petracca

Schiavi

et al. 2019

Euro J of Neurology

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Background and purpose Diffuse white matter (WM) injury is prominent in primary‐progressive multiple sclerosis (PP‐MS) pathology and is a potential biomarker of disease progression. Diffusion kurtosis imaging allows the quantification of non‐Gaussian water diffusion, providing metrics with high WM pathological specificity. The aim of this study was to characterize the pathological changes occurring in the normal‐appearing WM of patients with PP‐MS at baseline and at 1‐year follow‐up and to assess their impact on disability and short‐term disease progression. Methods A total of 26 patients with PP‐MS and 20 healthy controls were prospectively enrolled. Diffusion kurtosis imaging single‐shot echo‐planar imaging (EPI) was acquired on a 3‐T scanner (Philips Achieva, Best, The Netherlands) (voxel size, 2 × 2 × 2 mm3, 30 directions for each b‐value = 1000, 2000 s/mm2 and one b = 0 s/mm2). A two‐compartment biophysical model of WM tract integrity was used to derive spatial maps of axonal water fraction (AWF), intra‐axonal diffusivity, extra‐axonal axial and radial diffusivities (De,axial, De,radial) and tortuosity from the following WM tracts: corpus callosum (CC), corticospinal tract (CST) and posterior thalamic radiation (PTR). Results At baseline, patients with PP‐MS showed a widespread decrease of AWF, tortuosity and De,axial and an increase of De,radial in CC, CST and PTR (P ranging from 0.001 to 0.036). At 1‐year follow‐up, a significant AWF decrease was detected in the body of CC (P = 0.048), PTR (P = 0.008) and CST (P = 0.044). Baseline AWF values in CST significantly discriminated progressed from non‐progressed patients (P = 0.021; area under the curve, 0.854). Conclusion Based on its change over time and its relationship with disease progression, among the analyzed metrics, AWF seems the most sensitive metric of WM tissue damage in PP‐MS and therefore it could be considered as a marker for monitoring disease progression.

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“…1), although care must be taken before applying this threshold as a marker of ther apeutic efficacy owing to the phenomenon of pseudo atrophy (see Brain volume as an outcome measure in randomized clinical trials) 25,26 . Multiple studies have shown that short term changes (over as little as 1 year) in brain volume are predictive of clinical status (diagnosis of MS or disability status) at various follow up times in clinically isolated syndromes 27,28 , relapsing-remitting MS (RRMS) 29 and primary progressive MS [30][31][32] , either in isolation or together with lesion related parameters 33,34 .…”

Section: Global Brain Volume Measures To Define and Predict Ms Severitymentioning

confidence: 99%

MAGNIMS consensus recommendations on the use of brain and spinal cord atrophy measures in clinical practice

et al. 2020

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Early evaluation of treatment response and prediction of disease evolution are key issues in the management of people with multiple sclerosis (MS). In the past 20 years, MRI has become the most useful paraclinical tool in both situations and is used clinically to assess the inflammatory component of the disease, particularly the presence and evolution of focal lesions — the pathological hallmark of MS. However, diffuse neurodegenerative processes that are at least partly independent of inflammatory mechanisms can develop early in people with MS and are closely related to disability. The effects of these neurodegenerative processes at a macroscopic level can be quantified by estimation of brain and spinal cord atrophy with MRI. MRI measurements of atrophy in MS have also been proposed as a complementary approach to lesion assessment to facilitate the prediction of clinical outcomes and to assess treatment responses. In this Consensus statement, the Magnetic Resonance Imaging in MS (MAGNIMS) study group critically review the application of brain and spinal cord atrophy in clinical practice in the management of MS, considering the role of atrophy measures in prognosis and treatment monitoring and the barriers to clinical use of these measures. On the basis of this review, the group makes consensus statements and recommendations for future research.

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Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the INFORMS study

Cited by 18 publications

References 27 publications

Long-term prognostic value of longitudinal measurements of blood neurofilament levels

Long-term prognostic value of longitudinal measurements of blood neurofilament levels

Axonal water fraction as marker of white matter injury in primary‐progressive multiple sclerosis: a longitudinal study

MAGNIMS consensus recommendations on the use of brain and spinal cord atrophy measures in clinical practice

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