1. Composite MRI scores improve correlation with EDSS in multiple sclerosis by Poonawalla et al. Review by Jason Su

2. Introduction and Methods Looking for a composite measure that correlates well with EDSS – North American Linomide Trial used volume of Gd lesions, T1 lesion volume, total lesion volume, and CSF volume fraction: distinguishes groups at 3 months but poor correlation (r = 0.146) Build new composite based on T2 relaxation mapping – 3T, N=126 RRMS (101:25 F:M), aged 2-64, EDSS 0-6.5 – dFSE for T2 mapping – FLAIR and T1-weighted SE pre and post Gd – 256x256 in-plane, 3mm slice

3. Methods: Processing Auto image segmentation for WM, GM, T2 lesions, T1 lesions, and enhancing lesions – Based on Texas Medical School papers Normalized each feature to 0 mean and unit variance (“z-transformation”) Searched for combination of 2-4 features with good correlation to EDSS, equal weighting/no regression – Want individual high correlation with EDSS – Low cross-correlation between features

4. Results

6. BH and BOD correlate the most with EDSS – But seem to carry same information, low improvement together Normalized CSF has low cross-correlation Volumetric composite does well and when combined with T2 mapping T2 values alone do poorly T2 values in black hole seem more diverse than T2 lesions

7. Results

8. Discussion Correlation may be limited because EDSS is discrete valued and non-cognitive based RR-only population may also have an effect, limited EDSS range Perhaps a different composite for each subtype is a good idea Authors have previously shown that correlation decreases with population study size – r=0.344 is better than any other study of similar size and seemed more robust with size Black hole volume and T2 values were most important Working on multicenter, longitudinal, and MSFC next

9. Criticisms Really would have liked to see regression, i.e. weighting of the variables – Makes little sense to treat them as all having an equal effect F-tests to show significant improvement in nested models Built composites using (cross-)correlation tables as a guide, but could have done something more thorough – Stepwise or exhastive model selection

10. Imaging Biomarkers in Multiple Sclerosis by Filippi and Agosta

11. Introduction Conventional MR has limited specificity to look at all the processes involved: edema, demyelination, remyelination, gliosis and axonal loss – Atrophy measures – MT – DTI – H-MRS – fMRI T2 hyperintense lesions, T1 hypointense and/or enhancing, and cervical spinal cord lesions typically studied

12. MS Criteria McDonald – Dissemination in space: 9 T2 lesions can include spinal cord – Dissemination in time: new lesions within 30 days Swanton – more lax – A T2 lesion in at least 2 of 4 major regions (juxtacortical, periventricular, infratentorial, and cord) – Any new T2 lesion in a follow up, time scale doesn’t matter – More sensitive and still specific compared to McDonald

13. Biomarkers

14. Lesion Imaging T2-weighted imaging cannot see GM lesions – Dual inversion recovery to suppress CSF and WM improves visibility of WM and GM lesions

15. Pre-MS # and extent of T2 and T1 lesions relevant at onset, predict disability 6 months later MTR lower in NAWM for CIS, correlated with MSFC and Paced Auditory Serial Addition Task but not predictive DTI not predictive but tractography shows increased MD in corticospinal tract with motor impairment – Similar observations for optic neuritis and optic nerve H-MRS shows NAA lower than in control – Increased myoinositol (mI) and creatine in NAWM, meaning early widespread axonal pathology and increase in cell turnover is common – Not much longitudinal correlation

16. Pre-MS GM – MTR has mixed results – MD increases with time but no associated clinical disability – Increased iron in left caudate reducing T2 signal but not associated with progression to MS – GM atrophy seems greater than WM over 3 yrs. Optic neuritis – FSE T2w and SE T1 with Gd imaging can usually find the causative lesion – MTR useful for tracking changes, starts high (inflammation) then becomes low as more damage vs. normal – DTI has strong correlation with visual acuity and predictive

17. Definite MS - Lesions T2 lesion load higher in SPMS, only some correlation for low EDSS < 4.5 PPMS more diffuse involvement of cortical and subcortical regions Higher probability of lesions in PP vs. RR in age and duration matched study Enhancing – Less enhancing lesions in SP than RR – Increase associated with relapse, predicts MRI activity – SP accumulate more cortical lesions than CIS or RR, also associated with PP and epilepsy, but need more sensitive sequences

18. Definite MS - Lesions New contrast agents like ultra small particles of iron oxide to track macrophages MTR higher in homogenously enhancing vs. ring and triple vs. single dose of Gd DTI less clear, FA lower in enhancing but MD mixed results – Tracking lesions over 3 months: only a subgroup had increasing MD, MD correlated with T1 hypointensity H-MRS shows increased choline and lactate – Glutamate also elevated, ineffective removal due to oligodenrocyte loss – NAA significant decrease for RR, SP, and PP, inversely correlated with lesions – Lac returns to normal over a week, Cho and NAA over months Relative proportion of T2 lesions with severe intrinsic damage probably relevant to disability Lesion MTR lower in RR than CIS, similarly for SP and PP vs. RR even for new lesions – Average lesion MTR change after 12 months predicts disability over next 8 yrs.

19. Definite MS – NAWM & NABT Reduced MTR, increased MD, and lower NAA before lesions appear on T2w MTR NAWM more correlated with cognitive disability than lesions – Predictive of disability over 5 yrs. DTI more sensitive for later stages – Lower NAWM FA correlated with GM atrophy – Tractography more difficult in patients, pathology makes uncertainty in primary eigenvector of DT – Corticospinal tracts different for patients – Higher MD in CC for cognitively impaired – FA useful in optic radiation damage NAA drops more in NAWM for SP and PP

20. Definite MS – GM Lower MTR in GM for progressive patients – Lower for cognitively impaired in benign MS – Predictive of disability in relapsing-onset MS – MTR decline reflected rate of clinical deterioration – Regional correlations with EDSS and PASAT SP more severe DTI changes than PP – GM diffusivity predictive of disability for PP – Abnormalities in thalamus for RR and SP Lower NAA and Cho, increased mI especially for progressive – NAA lower in thalamus for SP and RR and cortex for PP – Lower Glu-glutamine in PP cortex, correlated with EDSS Iron deposition may be cause of T2 hypointense regions and lower T2 times GM damage only partially correlated with WM lesions

21. Definite MS – Atrophy Important for later stages 0.5-1% brain volume loss per year vs. 0.1-0.3% in control Significant brain volume loss in all definite MS but rate seems independent of subtype Frontal, temporal, and parietal lobes most atrophic GM regions, involved in progressive disability – Atrophy as a result of demyelination still not known Volume loss at early stages predicts disability at follow up Greater GM atrophy rate in RR, RR who progress, and SP, 8-14x normal WM atrophy same in these groups, 3x normal Better correlated with cognitive impairment than lesions, esp. cortical Thalamus atrophy in pediatric MS

22. Definite MS – Functional Consistent natural course for functional reorganization of cortex in MS – Recruiting larger areas for later stages of disease – Less recruitment in recovering patients Movement and cognitive fMRI correlated with NAWM, GM, and cervical cord injury Measures of functional connectivity and tract damage to improve understanding of connection between structural and functional abnormalities

23. Definite MS – Spinal Cord Lesions in 90% of cases Seems independent of brain atrophy Correlates better with EDSS than lesion load MTR in cord correlates with relapse rate and EDSS change over 18 months Value of DTI and MT in long follow-ups not yet established FA decreased and MD increased in 2.4 yr. follow up

24. Future Biomarkers New contrast agents – Target inflammation or neuronal dysfunction – Myeloperoxidase to image inflammation – Gado-fluorine M accumulates in Wallerian degeneration 7T+ MR – Some lesions show distinct rings on phase images – Cortical lesions more visible 3 types have been established in imaging, comparable to histology – Increased susceptibility in caudate, putamen, and globus pallidus, correlated with disease duration MRS, new metabolites under study

25. Future Biomarkers Myelin imaging – MWF loss in NAWM dominated by myelin integrity loss, not edema or inflammation Perfusion – Changes in lesions, NAWM, and deep GM – Findings in CC of RRMS looks more like primary ischemia than Wallerian degeneration Spinal cord – Quantitative methods being applied here – MT shows damage in GM of cord for RR

26. Take Away Message Cognitive tests like MSFC and PASAT are seeing more use Predicting progression to MS or SP remains a challenge Understanding and imaging all the physical processes at play is vital It is becoming more apparent that GM degeneration has a large effect on disability