Grey matter atrophy is associated with disability increase in natalizumab-treated patients

Background: Brain volume loss (BVL) is a key outcome in multiple sclerosis (MS) trials. Natalizumab is highly effective on inflammation with moderate impact on atrophy. Objective: To explore BVL in patients receiving natalizumab with an emphasis on grey matter (GM). Methods: We performed a retrospective post hoc analysis of BVL in 38 patients receiving natalizumab for 3 years using longitudinal voxel-based morphometry (VBM) and FreeSurfer. Results: Significant BVL was observed during first year: brain parenchymal fraction (BPF): −1.12% ( p < 0.001); white matter fraction (WMF): −0.9% ( p = 0.001); grey matter fraction (GMF): −1.28% ( p = 0.002). GM loss was found using VBM in bilateral cerebellum, cingulum, left > right fronto-parietal cortex, right > left hippocampus and left caudate. FreeSurfer showed significant volume losses in subcortical GM, brainstem and cerebellum, and cortical thinning in the left insula. In the second year, only WMF decrease (−0.6%; p = 0.015) was observed with no VBM changes, although FreeSurfer detected significant volume loss in thalamus, hippocampus and cerebellum. Baseline gadolinium enhancement influenced WMF and BPF changes during the first year, but not GMF. Patients with confirmed Expanded Disability Status Scale (EDSS) worsening at 3 years had lower baseline GMF and left thalamus volume and greater BVL over follow-up. Conclusion: BVL develops mainly during the first year of natalizumab therapy. GM changes are independent of baseline inflammation and correlate with disability.

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Clinical impact of early brain atrophy in clinically isolated syndromes

Multiple Sclerosis Journal ◽

10.1177/1352458513488231 ◽

2013 ◽

Vol 19 (14) ◽

pp. 1878-1886 ◽

Cited By ~ 61

Author(s):

F Pérez-Miralles ◽

J Sastre-Garriga ◽

M Tintoré ◽

G Arrambide ◽

C Nos ◽

...

Keyword(s):

Brain Atrophy ◽

Grey Matter ◽

Brain Volume ◽

First Year ◽

Grey Matter Volume ◽

Volume Loss ◽

Mcdonald Criteria ◽

Brain Volume Loss ◽

Clinical Onset ◽

The Impact

Background: The impact of global and tissue-specific brain atrophy on conversion to multiple sclerosis (MS) after a clinically isolated syndrome (CIS) is not fully gauged. Objectives: We aimed to determine the magnitude and clinical relevance of brain volume dynamics in the first year after a CIS. Methods: We assessed 176 patients with CIS within 3 months of onset, clinically and by conventional magnetic resonance imaging (MRI) scans, at baseline and 1 year after clinical onset. We determined the percentage of brain volume change (PBVC) and the brain parenchymal (BPF), grey matter (GMF) and white matter (WMF) fractions. Results: The mean follow-up time was 53 months (SD = 16.8): 76 patients (43%) experienced a second attack, 32 (18%) fulfilled MRI-only 2005 McDonald criteria and 68 (39%) remained as CIS. Statistically significant decreases in the volume measures tested were observed in patients with a second attack, for BPF and PBVC; in both MS groups for GMF; whereas in all groups, the WMF was unchanged. Patients with a second attack had larger PBVC decreases (− 0.65% versus + 0.059%; p < 0.001). PBVC decreases below − 0.817% independently predicted shorter times to a second attack. Conclusions: Global brain and grey matter volume loss occurred within the first year after a CIS; brain volume loss predicted conversion to MS.

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Brain Volume Loss During the First Year of Interferon-Beta Treatment in Multiple Sclerosis: Baseline Inflammation and Regional Brain Volume Dynamics

Journal of Neuroimaging ◽

10.1111/jon.12337 ◽

2016 ◽

Vol 26 (5) ◽

pp. 532-538 ◽

Cited By ~ 16

Author(s):

Angela Vidal-Jordana ◽

Jaume Sastre-Garriga ◽

Francisco Pérez-Miralles ◽

Deborah Pareto ◽

Jordi Rio ◽

...

Keyword(s):

Multiple Sclerosis ◽

Interferon Beta ◽

Brain Volume ◽

First Year ◽

Volume Loss ◽

Brain Volume Loss ◽

Regional Brain ◽

Regional Brain Volume

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Brain volume loss precedes cognitive decline in the first year after ischaemic stroke

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2017-316074.6 ◽

2017 ◽

Vol 88 (5) ◽

pp. e1.59-e1

Author(s):

Emilio Werden ◽

Toby Cumming ◽

Laura Bird ◽

Mohamed Khlif ◽

Amy Brodtmann

Keyword(s):

Cognitive Decline ◽

Ischaemic Stroke ◽

Brain Volume ◽

First Year ◽

Volume Loss ◽

Brain Volume Loss

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Early brain pseudoatrophy while on natalizumab therapy is due to white matter volume changes

Multiple Sclerosis Journal ◽

10.1177/1352458512473190 ◽

2013 ◽

Vol 19 (9) ◽

pp. 1175-1181 ◽

Cited By ~ 55

Author(s):

Angela Vidal-Jordana ◽

Jaume Sastre-Garriga ◽

Francisco Pérez-Miralles ◽

Carmen Tur ◽

Mar Tintoré ◽

...

Keyword(s):

White Matter ◽

Brain Volume ◽

Corticosteroid Treatment ◽

First Year ◽

Volume Loss ◽

White Matter Volume ◽

Volume Changes ◽

Brain Volumes ◽

Matter Volume ◽

Brain Volume Loss

Background: Investigation of atrophy data from a pivotal natalizumab trial has demonstrated an increased rate of volume loss, compared to placebo, after the first year of therapy. It was considered to be probably due to a pseudoatrophy effect. Objective: To assess grey and white matter volume changes and their relation to global brain volume changes and to baseline inflammation, for patients under natalizumab therapy. Methods: We selected 45 patients on natalizumab therapy for at least 24 months, with magnetic resonance imaging (MRI) scans at baseline, 12 and 24 months. We calculated the percentage brain volume change (PBVC) for the first and second year, using SIENA software. Grey and white matter fractions (GMF and WMF, respectively) for the first year were calculated with SPM5, using lesion masks. After quality checks, six patients were excluded. We studied the predictive variables of change in brain volumes. Results: The PBVC decrease was faster during the first year (−1.10% ± 1.43%), as compared to the second (−0.51% ± 0.96%) ( p = 0.037). These differences were more marked in patients with baseline gadolinium-enhancing lesions ( p = 0.005). Mean GMF and WMF changes during the first year of treatment were +1.15% (n.s.) and −1.72% ( p = 0.017), respectively. The presence of active lesions at baseline MRI predicted PBVC ( p = 0.022) and WMF change ( p = 0.026) during the first year of treatment, after adjusting for age and corticosteroid treatment. No predictors were found for GMF volume changes. Conclusion: Early brain volume loss during natalizumab therapy is mainly due to WMF volume loss and it is related to the inflammatory activity present at the onset of therapy. We found that the pseudoatrophy effect is mostly due to white matter volume changes.

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PARTIAL INDEPENDENCE OF FINGOLIMOD EFFECT ON DIFFUSE VS. FOCAL DAMAGE

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2015-312379.112 ◽

2015 ◽

Vol 86 (11) ◽

pp. e4.16-e4

Author(s):

C Constantinescu ◽

N De Stefano ◽

L Kappos ◽

EW Radue ◽

T Sprenger ◽

...

Keyword(s):

Regression Analysis ◽

Regression Model ◽

Volume Change ◽

Treatment Effect ◽

Brain Volume ◽

Volume Loss ◽

T2 Lesions ◽

Brain Volume Loss ◽

Intent To Treat ◽

Post Hoc

ObjectiveTo investigate if the effects of fingolimod 0.5mg on brain volume loss are mediated through effects on focal disease activity (FD) or independent-reduction of diffuse damage (DD).MethodsFREEDOMS and FREEDOMS-II data was pooled and analyzed post-hoc. Assessment of the percent brain volume change (PBVC) at M12 and 24, in patients with no evidence of FD, (absence of new Gd+ T1-lesions and/or new/enlarging T2-lesions) and clinical relapses. Regression analysis of the intent-to-treat (ITT) population to quantified whether the extent of the treatment effect was maintained for patients with new/active lesions and relapsesResultsOf the 1383 patients included, 808 patients (placebo=142; fingolimod=666) showed no FD at M12 and 573 patients (placebo=79; fingolimod=494) at M24 showed no FD. Fingolimod significantly reduced PBVC by 52% and 42% vs. placebo, over 12M and 24M respectively. In the pooled ITT population, fingolimod reduced 49% of PBVC (p<0.001)vs placebo over 24M. This effect was still evident when adjusting for new-active lesions and relapse activity (28% reduction vs placebo, p<0.001). The regression model suggests 57% of fingolimod effect on PBVC is FD-independent. Fingolimod effect on DD is partly independent of its treatment effect on FD, suggesting fingolimod impacts both inflammatory and neurodegenerative components.

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A.03 Durable clinical and MRI efficacy of alemtuzumab over 6 years in CARE-MS II patients with RRMS who relapsed between Courses 1 and 2

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2018.84 ◽

2018 ◽

Vol 45 (s2) ◽

pp. S10-S10

Author(s):

MS Freedman ◽

S Broadley ◽

A Chinea ◽

G Izquierdo ◽

J Lycke ◽

...

Keyword(s):

Disease Activity ◽

Inadequate Response ◽

Hyperintense Lesion ◽

Prior Therapy ◽

Brain Volume Loss ◽

Disease Modifying Therapy ◽

Core Study ◽

Brain Parenchymal Fraction ◽

Brain Parenchymal ◽

Relative Change

Background: In RRMS patients with inadequate response to prior therapy, 2 alemtuzumab courses (12 mg/day; baseline: 5 days; 12 months later: 3 days) significantly improved outcomes over 2 years (y) versus SC IFNB-1a (CARE-MS II [NCT00548405]), with durable efficacy over a 4-y extension (NCT00930553). We present 6-y efficacy (2-y core study plus 4-y extension) in patients with relapse (relapsers) between Courses (C) 1 and 2. Methods: Annualized relapse rate (ARR); 6-month confirmed disability worsening (CDW); MRI disease activity (Gd-enhancing lesions; new/enlarging T2 hyperintense lesions); brain volume loss (BVL; derived by relative change in brain parenchymal fraction). Results: 105/435 (24%) patients relapsed between C1 and C2; 33% (relapsers) versus 55% without relapse (non-relapsers) received neither alemtuzumab retreatment nor another disease-modifying therapy through Y6. ARR (Y1: 1.2) declined post-C2 (0.5), remaining low through Y6 (0.2 [0.1, non-relapsers]; 10/105 [10%] relapsed). Through Y6, patients remained CDW-free (60% [relapsers]; 75% [non-relapsers]), Gd-enhancing lesion-free (94% [relapsers]; 90% [non-relapsers]), new/enlarging T2 hyperintense lesion-free (68% [relapsers]; 69% [non-relapsers]), and MRI disease activity-free (68% [relapsers]; 69% [non-relapsers]). Alemtuzumab slowed median percent yearly BVL (Y6: -0.13% [relapsers]; -0.10% [non-relapsers]). Conclusions: Patients relapsing between C1 and C2 improved post-C2 through Y6. These findings support administering 2 alemtuzumab courses to achieve optimal and durable benefit.

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Pathological cut-offs of global and regional brain volume loss in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458517742739 ◽

2017 ◽

Vol 25 (4) ◽

pp. 541-553 ◽

Cited By ~ 14

Author(s):

Tomas Uher ◽

Manuela Vaneckova ◽

Jan Krasensky ◽

Lukas Sobisek ◽

Michaela Tyblova ◽

...

Keyword(s):

Corpus Callosum ◽

Grey Matter ◽

Brain Volume ◽

Healthy Controls ◽

Volume Loss ◽

Whole Brain ◽

Brain Volume Loss ◽

Regional Brain ◽

Mri Scans ◽

Regional Brain Volume

Background: Volumetric MRI surrogate markers of disease progression are lacking. Objective: To establish cut-off values of brain volume loss able to discriminate between healthy controls and MS patients. Methods: In total, 386 patients after first demyelinating event suggestive of MS (CIS), 964 relapsing-remitting MS (RRMS) patients, 63 secondary-progressive MS (SPMS) patients and 58 healthy controls were included in this longitudinal study. A total of 11,438 MRI scans performed on the same MRI scanner with the same protocol were analysed. Annualised percentage changes of whole brain, grey matter, thalamus and corpus callosum volumes were estimated. We investigated cut-offs able to discriminate between healthy controls and MS patients. Results: At a predefined specificity of 90%, the annualised percentage change cut-off of corpus callosum volume (−0.57%) was able to distinguish between healthy controls and patients with the highest sensitivity (51% in CIS, 48% in RRMS and 42% in SPMS patients). Lower sensitivities (22%−49%) were found for cut-offs of whole brain, grey matter and thalamic volume loss. Among CIS and RRMS patients, cut-offs were associated with greater accumulation of disability. Conclusion: We identified cut-offs of annualised global and regional brain volume loss rates able to discriminate between healthy controls and MS patients.

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