Establishing pathological cut-offs of brain atrophy rates in multiple sclerosis

Stefano, Nicola De; Stromillo, Maria Laura; Giorgio, Antonio; Bartolozzi, Maria Letizia; Battaglini, Marco; Baldini, Mariella; Portaccio, Emilio; Amato, Maria Pia; Sormani, Maria Pia

doi:10.1136/jnnp-2014-309903

Cited by 189 publications

(258 citation statements)

References 38 publications

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“…These values translate to a loss of 0.68%, 0.57%, and 0.45% per year, respectively. Only in the subgroup with no on‐study inflammatory activity and no confirmed progressions (28% of the placebo population) did the annualized rate of brain volume loss (0.38%) approach the proposed cutoff that separates pathologic from physiologic rates of brain volume loss (0.37% per year) 16. All the other disease course subgroups had higher rates of brain volume loss.…”

Section: Resultsmentioning

confidence: 99%

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

Miller

Lublin

Sormani

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo investigate the relationship between brain volume and disability worsening over ≥3 years in the natural history of primary progressive multiple sclerosis using data from the placebo group of the INFORMS trial (n = 487; clinicaltrials.gov NCT00731692).MethodsMagnetic resonance imaging scans were collected annually. Brain volume loss was determined using SIENA. Patients were stratified by baseline normalized brain volume after adjusting for demographic and disease‐burden covariates.ResultsBaseline normalized brain volume was predictive of disability worsening: Risk of 3‐month confirmed disability progression was reduced by 36% for high versus low baseline normalized brain volume (Cox's model hazard ratio 0.64, P = 0.0339; log‐rank test: P = 0.0297). Moreover, on‐study brain volume loss was significantly associated with disability worsening (P = 0.012) and was evident in patients with or without new lesions or relapses. Brain volume loss depended significantly on baseline T2 lesion volume (P < 0.0001). Despite low inflammatory activity at baseline (13% of patients had gadolinium‐enhancing lesions) and throughout the study (mean 0.5 new/enlarging T2 lesions and 172 mm3 T2 lesion volume increase per year), baseline T2 lesion volume was substantial (mean 10 cm3). Lower normalized brain volume at baseline correlated with higher baseline T2 volume and older age (both P < 0.0001).InterpretationBaseline brain volume and the rate of ongoing brain atrophy are significantly associated with disability worsening in primary progressive multiple sclerosis. Brain volume loss is significantly related to baseline T2 lesion volume, but partially independent of new lesion activity, which might explain the limited efficacy of anti‐inflammatory treatment.

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Section: Resultsmentioning

confidence: 99%

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

Miller

Lublin

Sormani

et al. 2018

Ann Clin Transl Neurol

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“…Over time, brain volume declines more rapidly in MS patients when compared to age‐matched healthy controls (HCs) 3, 4, 5, 6. Across MS phenotypes, SPMS shows the fastest annual rate of brain atrophy, which is estimated to be 0.6% (compared to around 0.2% in age‐matched HCs) 5.…”

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confidence: 99%

Deep gray matter volume loss drives disability worsening in multiple sclerosis

Eshaghi

Prados

Brownlee

et al. 2018

Annals of Neurology

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ObjectiveGray matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS.MethodsWe analyzed 3,604 brain high‐resolution T1‐weighted magnetic resonance imaging scans from 1,417 participants: 1,214 MS patients (253 clinically isolated syndrome [CIS], 708 relapsing‐remitting [RRMS], 128 secondary‐progressive [SPMS], and 125 primary‐progressive [PPMS]), over an average follow‐up of 2.41 years (standard deviation [SD] = 1.97), and 203 healthy controls (HCs; average follow‐up = 1.83 year; SD = 1.77), attending seven European centers. Disability was assessed with the Expanded Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem, and cerebral white matter. Hierarchical mixed models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time‐to‐EDSS progression.ResultsSPMS showed the lowest baseline volumes of cortical GM and DGM. Of all baseline regional volumes, only that of the DGM predicted time‐to‐EDSS progression (hazard ratio = 0.73; 95% confidence interval, 0.65, 0.82; p < 0.001): for every standard deviation decrease in baseline DGM volume, the risk of presenting a shorter time to EDSS worsening during follow‐up increased by 27%. Of all longitudinal measures, DGM showed the fastest annual rate of atrophy, which was faster in SPMS (–1.45%), PPMS (–1.66%), and RRMS (–1.34%) than CIS (–0.88%) and HCs (–0.94%; p < 0.01). The rate of temporal GM atrophy in SPMS (–1.21%) was significantly faster than RRMS (–0.76%), CIS (–0.75%), and HCs (–0.51%). Similarly, the rate of parietal GM atrophy in SPMS (–1.24‐%) was faster than CIS (–0.63%) and HCs (–0.23%; all p values <0.05). Only the atrophy rate in DGM in patients was significantly associated with disability accumulation (beta = 0.04; p < 0.001).InterpretationThis large, multicenter and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS. The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions. Ann Neurol 2018;83:210–222

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“…Indeed, while WM volume shows a mild reduction during the course of disease, GM volume significantly and progressively decreases [5][6][7][8][9][10][11][12][13]. Recently, a parenchymal loss of ≥0.4% per year was proposed as "pathological atrophy rate" in MS patients [14].…”

Section: Introductionmentioning

confidence: 99%

Effects of disease modifying therapies on brain and grey matter atrophy in relapsing remitting multiple sclerosis

Favaretto

Lazzarotto

Margoni

et al. 2018

Mult Scler Demyelinating Disord

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Background: Progressive brain atrophy is a major feature of multiple sclerosis (MS) pathology and is actually considered a major determinant of the progressive accumulation of physical and cognitive disability in MS patients. Although brain atrophy may have different pathological substrates, several lines of evidence suggest that in disease modifying drug (DMD)-treated MS patients, the higher is the anti-inflammatory effect of the DMD the lower is the progression of brain volume loss, grey matter atrophy and the accumulation of disability. Areas covered: Magnetic resonance imaging (MRI)-based measurements of inflammation (focal white matter and grey matter lesions) and neurodegeneration (decrease in brain volume, cortical and deep grey matter atrophy) are currently included among the primary or secondary end-points of Phase II and III randomized clinical trials (RCT). This review summarizes literature data on the effects of DMDs on either whole brain or grey matter atrophy emerged from RCT and from post-marketing studies.

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Establishing pathological cut-offs of brain atrophy rates in multiple sclerosis

Cited by 189 publications

References 38 publications

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

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

Deep gray matter volume loss drives disability worsening in multiple sclerosis

Effects of disease modifying therapies on brain and grey matter atrophy in relapsing remitting multiple sclerosis

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