STUDY: Higher brain volume loss equals worse disease outcome

[ActiveMSers]

This bears repeating and repeating. If you've got multiple sclerosis, which I presume you do because you are reading this, it is paramount to do everything in your power to prevent brain volume loss. The two key elements that have shown to do this in repeated trials: disease modifying medication and exercise (in particular aerobic). Don't let up. - Dave

The effect of MRI inflammatory activity and age on the association of brain volume loss with disability progression: per-quartile subgroup analysis

D. Jeffery1, T. Vollmer2, S. Ritter3, E. Verdun Di Cantogno4, D. Piani Meier4, E.-W. Radue5
1Piedmont Healthcare, Mooresville, NC, 2University of Colorado Denver, Denver, CO, 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States, 4Novartis Pharma AG, Basel, Switzerland, 5Medical Image Analysis Centre, University of Basel, Basel, Switzerland

Background: Brain volume loss (BVL) reflects both diffuse and focal damage in relapsing MS and correlates with disability progression. Previously, we reported that the quartile of patients with the highest BVL at month (M) 24 experienced the most disability progression at M24 and M48.

Objective: To investigate whether age and MRI inflammatory activity affects concomitant correlation of BVL with disability progression over 24 months and/or its prognostic value over 48 months in RRMS patients.

Methods: Patients (N=1841) from the pooled phase 3 FREEDOMS/FREEDOMS II core (M24) and extension (M48) studies were categorised (post hoc) into quartiles by total percent BV change (PBVC) from baseline (BL) to M24 as assessed by the SIENA method. Mean annualised PBVC was determined for each quartile. Patients were further stratified into subgroups: age (< />40 y, n=1299) at BL, presence/absence of Gd+ lesions at BL (n=1477), or new/enlarging T2 lesions over 24 months (n=819). The proportion of patients at M24 and M48 with 6M-confirmed disability progression (CDP6) and time to EDSS≥6.0 is reported. Odds ratios (OR) and p-values are derived by logistic regression with Q4 as a reference.

Results: PBVC quartile ranges at M24 were: Q1 (n=455), −13.5% to −1.7%; Q2 (n=458), −1.7% to −0.77%; Q3 (n=467), −0.77% to −0.13%; and Q4 (n=461), −0.13% to +4.34%. Within Q1, patients with MRI activity had higher annual BVL than those without; no difference was seen within the other quartiles, and for age. Across all subgroups patients in Q1 were at higher risk for CDP6 compared to those in Q4 and the difference between Q1 and Q4 was similar regardless of lesion activity (OR range: 1.51-2.45) or age (1.81-2.18) over both M24 and M48. During the same time period, correlation of BVL with time to EDSS≥6 was more pronounced (Q1 vs Q4, OR 2.54-5.45). In patients with/without lesion activity (Q1 vs Q4), OR was 3.77-5.45/2.82-4.26, for age < />40 y, OR was 2.54-2.92/3.69-5.24. P< 0.05 for the majority of the comparisons. Over 48 months, patients >40 y had the highest progression rates across Q1 and Q4 for CDP6 (29% and 19%) and time to EDSS≥6 (23% and 7%). Baseline parameters and other outcomes to be presented.

Conclusion: Regardless of baseline or ongoing measures of disease activity, patients with the highest BVL had the worst disease outcome. Lesion activity and age did not have a major impact on the correlation between BVL and disability progression further supporting the clinical relevance of BVL.

[ActiveMSers]

And another study...

A serial 10-year follow-up study of early relapsing-remitting MS patients: exploring long-term value of different MRI brain volumetric outcomes in predicting disability progression

R. Zivadinov1,2, T. Uher1,3, J. Hagemeier1, M. Vaneckova4, D.P. Ramasamy1, M. Tyblova4, N. Bergsland1,5, Z. Seidl4, M.G. Dwyer1, J. Krasensky4, E. Havrdova3, D. Horakova3
1Buffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, 2MR Imaging Clinical Translational Research Center, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States, 3Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, First Faculty of Medicine and General University Hospital, Prague, 4Department of Radiology, 1st Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic, 5IRCCS “S.Maria Nascente”, Don Gnocchi Foundation, Milan, Italy

Background: We previously showed in a study cohort with serial yearly MRI that cortical, central and thalamic atrophy were associated with development of confirmed disability progression (CDP) over a period of 5 years. However, no studies have explored the evolution of brain atrophy in relation to development of CDP on serial yearly MRI scans over a longer 10-year period.
Objectives: We explored the association of different MRI brain volumetric measures and CDP development.

Methods: 180 RRMS patients, who started treatment with intramuscular interferon beta-1a (30 µg/week) received yearly clinical and 1.5T assessments on the same MRI scanner over 10 years. At 10-year follow-up, they were divided into those with (100) or without (76) CDP (48 weeks), by standard treatment trial criteria. The number of available MRI scans at various time points were: baseline (178), months 12 (176), 24 (155), 36 (160), 48 (158), 60 (161), 72 (157), 84 (154), 96 (157), 108 (154) and 120 (152). Changes in whole brain (WB), cortical, gray matter (GM), white matter (WM), and lateral ventricle (LV) volumes were calculated via a direct method on 3D-T1 scans between all available time points. Longitudinal linear mixed effect and regression models, adjusted for age, sex and treatment change, were fit to the data in order to describe the temporal association between development of CDP and evolution of brain volume measures.

Results: At 10 years, the greatest effect size on percentage decreases from baseline, in MS patients with CDP compared to those without, was detected for WB (d=0.55, -7.5% vs. -5.2%, p < 0.001), LV (d=0.51, +40.5% vs. +21.8%, p < 0.001), cortical (d=0.49, -7.7% vs. -6.2%, p = 0.001) and GM (d=0.40, -7.1% vs. -5.8%, p = 0.006) volumes. In patients who developed CDP at 10 years and those who did not, mixed effect models showed significant interactions between CDP status and percentage changes over time for WB and LV (p < 0.001), cortical (p = 0.02) and GM (p = 0.04) volumes. LV volume was the best independent predictor of changes in GM (R2 = 0.43, p < 0.001), cortical (R2 = 0.38, p < 0.001) and WB (R2 = 0.21, p < 0.001) volumes.

Conclusions: Whole brain atrophy and enlargment of lateral ventricles are strongly associated with development of CDP on serial yearly MRI assessments over a period of 10 years. Given the simplicity of LV assessment on lower quality images, assesment of LV may become a useful brain atrophy outcome for clinical routine.

Disclosure: The study is an investigator-initiated study that was supported by Czech Ministries of Education and Health [NT13237-4/2012, PRVOUK-P26/

[Suebee]

I'm wondering if anyone has been impressed by their brain MRI radiologist? I was surprised to find out many radiologists are off site, even out of the country. My personal experience is that it is almost possible to get a radiologist to compare a current MRI with anything other than the immediately prior film. In my case, it would be informative to my disease process to have a comparison to initial lesion and analysis if brain atrophy is present based on prior 20 years. My neurologists have agreed comparison to aggressive 10 yr old lesion would be helpful, but even specific orders by neuro to compare haven't worked and only comparison to recent MRI, which is not changed. I am also told atrophy has to be grossly apparent to be remarked upon. But this article says the lateral ventrical is representative of the atrophy and should be measured. One would think it would be a simple excercise by radiologists to Compare. I'll also note that sometimes the radiologist will broadly specific the location of a lesion, letting the neurologist sort out the exact structures affected. I think that is lame.

[Cvfactor]

I'm happy with the radiologist that looks at my scans. He noted that my brain atrophy rate has stabilized since I started on Copaxone.

I don't think it is usual protocol for atrophy to be looked at but at the center I go this seems to be a subject that they look closely at.

Here is a paper that my doctor was an author on regarding a brain atrophy study and I think they use this methods when looking at MRI's:

http://www.ncbi.nlm.nih.gov/pubmed/21920559

[Suebee]

Thanks CV! I am glad your experience has been different. But I find it curious that my experience has been so different. I've gone to top notch faculties in several big urban areas. I think you are right about brain volume not top issue when reviewing films. In 10 years I have not been able to get a comparison either way. I think because I had such an aggressive attack and improved so much clinically over the years, it wasn't a big enough concern for my neuros to get it. Of course, it is becoming better understood now that brain volume is effected early on and is part of disease process. Your doc is at the forefront! Suebee

[Cvfactor]

Suebee,

I think the problem is there is no consensus on how brain volume is measured (there is no standards for software, etc.).

Until there is a standard set and it is widely accepted that this is a measurement that needs to be done, most places won't do this because insurance is not going to pay for the analysis time. Hopefully in the near future there will be some agreement.

[Suebee]

Ah Cvfactor, that makes a lot of sense. Even my neuros didn't explain this pt as good as you. It's better explanation than radiologist is dropping ball. I will Also point out that there are different strengths of mris. They currently range from 1 T (I think it stands for tessler) to 3 T. The higher T gets better resolution but also heats the body more and can be warm. If it is a 3T, be sure to dress lightly, and maybe keep feet bare without blanket. I also wonder if all neuros are good with the MRI software. I had one neuro who pulled my aggressive lesion up on the computer monitor and made it a 3D image we were able to look at zoomed up and turning in circles. The only way to explain it was that it was truly awesome to be able to see the cause of all my problems. It was incredible to see and I use it to visualize my fight against ms. No other neuro has done that for me. I'm glad some scientists are trying to standardize MRI review of ms brains! Suebee

[Cvfactor]

Yes, there is a lot of difficulties trying to measure brain atrophy. Even comparing scans taken from different machines can cause errors in the results. I don't think it is a perfected science at this point.

[Suebee]

Consensus on how measure for brain volume loss?!?

Update: my radiologist in Houston medical center did a brain volume measurement with my recent MRI. This is my first volume measure ever. Finally, I think there is starting to be consensus on how to measure MS patient's brains for atrophy.
The method used was "Postcontrast
volumetric T1 FS obtained in the coronal plane reconstructed in the axial and sagittal planes."
Not surprisingly I had some mild disproportionate volume loss, not age related. Hopefully this measurement will allow my neuro to see in the future how my DMD is working.

If you are on the follow up MRI circuit, look for this new measurement tool. Every little bit helps inform our treatment!