Measuring MS

[cheerleader]

1eye,
Everything I recommended to improve gray matter health has published reseearch behind it.
I will copy over all the lnks, because I know you don't like going to other pages, like the one Iinked but I don't make it up. I merely compile research...never claim to be anything more than an interested layperson who has been looking at the connection of MS to gray matter atrophy for a few years now....

1. eat fish or take an omega 3 supplement
http://www.ncbi.nlm.nih.gov/pubmed/17574755
2. exercise. walk if you can, swim, practice seated yoga, dance, bike, move.
http://www.ncbi.nlm.nih.gov/pubmed/19560443
3. discover a new interest-- a foreign language, knitting, oil painting, floral arranging, cooking, juggling.
http://journals.plos.org/plosone/articl ... ne.0002669
4. get vitamin D from sun and/or supplement
http://yaledailynews.com/blog/2015/11/1 ... -patients/
5. meditate
http://newsroom.ucla.edu/releases/how-t ... rain-91273
6. get plenty of good sleep, and take naps
http://www.ncbi.nlm.nih.gov/pubmed/24346259
7. listen to music...even better, sing along or play an instrument.
http://www.medicalnewstoday.com/articles/246675.php
8. read a book or join a book club
http://www.ncbi.nlm.nih.gov/pubmed/25203270
9. eat Indian food, or take a curcumin supplement. If curcumin is contraindicated for you, you can skip this one
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2527619/
10. hug often. A pet, a grandkid, a spouse, a tree, a friend--yourself
http://opinionator.blogs.nytimes.com/20 ... love/?_r=0

What if there is no "fix"? What if the "cure mentality" keeps us from addressing the things we can change today?
http://ccsviinms.blogspot.com/2014/06/t ... ality.html

Preserving and enhancing gray matter is real. Neuroplasticity is real. It may well be "the fix." Read Norman Doidge's new book, The Brain's Way of Healing...be encouraged and inspired. http://www.normandoidge.com/?page_id=1042 Outlive that solar contract!!! Outlive the fix!
xoxox,
cheer

[1eye]

Proposed method for measuring dRA, or delta Rate of Atrophy:

http://sullivanweb.me/pdfdocs/atrophy-3.pdf

[cheerleader]

Proposed method for measuring dRA, or delta Rate of Atrophy:
http://sullivanweb.me/pdfdocs/atrophy-3.pdf

Looks great, Chris!!! (Although it involves math, and is w-a-a-y over my head) I'll share with some of the imaging folks at next ISNVD. Would be great to have an ongoing meaurement for atrophy that didn't need special equipment.
J

[1eye]

Only if the MRI machine, or one of the doctors, or the patient, is taller than you, is anything way over your head. People tend to turn their brains off when anything involving an operation as challenging as arithmetic is involved.

Nothing in my post is more complicated than subtraction, except atrophy itself, which is length divided by time. Length divided by time, divided by time again, gives the delta I wrote about, the final quantity we are looking for.

t1 t2 and t3 are the time of day of each of the three MRIs.

Difference in length after interval a (t1 to t2), divided by the time between the first two MRIs gives atrophy in interval a.

Difference in length after interval b (t2 to t3), divided by the time between the second two MRIs gives atrophy in interval b.

Subtract the second atrophy from the first, and you have measured how much the atrophy has changed. This change happened some time in interval b, which ends at the time the final, third MRI is done. So your change of length is divided again by interval b. This is a measure of worsening (length is even shorter), or improving (length is longer, so atrophy has reversed).

Is that still too complicated? It's way easier with a picture.

[1eye]

So here's a picture:

http://sullivanweb.me/pdfdocs/atrophy-4.pdf

This hypothetical patient shows -8.3 um atrophy per day in the first interval, and the atrophy changes such that the first interval's atrophy is partly reversed at a dRA of +0.85 um/day/month.

This measurement represents partial regrowth of brain matter at the third MRI at t3, which had previously deteriorated by the time of the second MRI at t2.

[1eye]

So here's a picture:

http://sullivanweb.me/pdfdocs/atrophy-4.pdf

This hypothetical patient shows -8.3 um atrophy per day in the first interval, and the atrophy changes such that the first interval's atrophy is partly reversed at a dRA of +0.85 um/day/month.

This measurement represents partial regrowth of brain matter at the third MRI at t3, which had previously deteriorated by the time of the second MRI at t2.

OK, so I did the unthinkable: I bumped and re-posted on my own thread. But I just wanted to say: the result of this measurement is a direct quantitative measurement, which at least is an analog to, and at best measures MS directly, puts a number to a patient's either improvement or worsening. Healthy controls should show dRA (delta Rate of Atrophy) = 0.

This measurement verifies with counting lesions, black holes, EDSS, and any other measure of MS. It can be done as a sanity check to every purported treatment improvement. A good treatment either reverses, slows down, or stops the disease. This one measurement can put a number on any of those changes, or show very clearly that there has been no change. Qualitative descriptions of these conditions is not good enough, when we are using machines that cost upwards of $30 million, with modern imaging, storage, and computing power.

If their physician won't do it, patients can actually do that same measurement for themselves, using whatever measuring tools (a ruler of some kind) are at their disposal. All you need are three time-separated MRIs. These are available: in most cases, the patient owns them.

See also http://sullivanweb.me/pdfdocs/atrophy-3.pdf
and http://sullivanweb.me/pdfdocs/atrophy-4.pdf

The Ottawa Hospital has some of my MRIs. In the one I had in 1997 the radiologist reported an atrophic corpus callosum. Along with the one I had in 1996, that forms a complete baseline RA measurement. I would like to see the dRA at my corpus callosum from every MRI I have had since (there have been many).

[1eye]

More info on measurement of atrophy is in this paper: http://www.medscape.com/viewarticle/759837_4.

You need to give Medscape an email and password: for those who can't:

Imaging Normal-appearing Tissue in MS

Longitudinal studies have suggested that the correlation between T2 lesion burden and clinical disability is modest,[9] and that this relationship plateaus as disability progresses.[11] This suggests the presence of pathology outside of the white matter lesions seen with conventional MRI, in the so-called 'normal-appearing tissue'.

Magnetization Transfer Imaging

Magnetization transfer (MT) is based on the interactions of protons in water with protons that are bound in macromolecules in nearby tissue. When an off-resonance pulse is applied, the bound protons become saturated and the magnetization is transferred to the nearby free protons in water, thus decreasing the tissue signal. The efficiency of this exchange, also known as the MT ratio (MTR), is decreased when tissue is damaged.[43] Postmortem studies have shown that the degree of reduction in the MTR correlates with the severity of tissue injury, both in myelin and in axons.[44] MTR is abnormal when applied to lesions that are visible on conventional MRI, particularly in T1 hypointense lesions. MTR is sensitive to tissue destruction as early as the initial presentation of CIS, and the MTR abnormality tends to worsen as the disease progresses. MTR has been shown to correlate with clinical disability,[43] cognitive impairment[45] and brain atrophy.[46]

MT imaging has been increasingly used in Phase III clinical trials for agents in the therapeutic pipeline. Because MT data are easy to acquire from most clinical MRI scanners, MT is currently the most practical nonconventional MRI technique. However, final validation as a clinical metric and lack of standardization in acquisition protocols preclude its clinical use at the present time.
Diffusion Imaging

Diffusion imaging is based on diffusion, or the random movement of molecules through a fluid. Because of cell membranes and organelles, the diffusivity in brain tissue is lower than that of free water. It is known as the apparent diffusion coefficient. Processes that restrict diffusion cause an increase in apparent diffusion coefficient values. Fractional anisotropy and mean diffusivity can be derived quantitatively from a diffusion tensor.[47] Similar to MT, diffusion tensor imaging (DTI) is sensitive to tissue injury and is abnormal in T2-visible lesions, normal-appearing gray matter and normal-appearing white matter (NAWM).[48] Abnormal gray matter diffusivity has been associated with disease progression[49] and cognitive impairment.[50]

Diffusion tractography tracks the principle direction of diffusion of water along axons and allows segmentation of the different functional white matter structures, such as the corticospinal tracts and the corpus callosum. This provides an opportunity to investigate functional correlates with structural white matter disease. Several studies examined DTI of the corpus callosum and found that abnormal DTI parameters correlate with fine motor impairment,[51] disability[52] and disease progression.[53] Tractography, a postprocessing method derived from DTI maps, can delineate specific white matter fiber tracks, including lesional thalamocortical projections, as shown in Figure 1.[17] However, this specific postprocessing technique remains a research tool in experienced hands, since whole brain tracking without careful attention to white matter lesions can lead to nonanatomical tracks and inaccurate measurements.
Click to zoom
(Enlarge Image)

Figure 1.

Example of two thalamocortical fiber tracks (red) seeded through white matter lesions (blue) connecting the thalamus (green) and the cortex (not shown).
Reproduced with permission from [76].

Overall, DTI (which is different to diffusion-weighted imaging) is generally harder to implement in nonresearch settings and can be unreliable if images are not carefully obtained. Studies using DTI tend to be small and cross-sectional, and it has not been validated as a clinical metric. At this point, we would recommend avoiding the use of DTI in routine clinical care. Studies correlating histopathology findings with DTI are forthcoming and will be of interest.
Detecting Cortical Lesions

Although gray matter lesions in MS were described as early as 1916, they have proved to be challenging to image and are frequently missed by conventional MRI sequences. Postmortem MRI and pathologic studies have indicated that conventional T2 spin-echo and fluid-attenuated inversion recovery (FLAIR) sequences detect only 3 and 5% of intracortical lesions, respectively,[54] and that MRI visibility may be a function of intracortical lesion size.[55] Cortical lesions are present as early as CIS and are seen more frequently in patients with progressive forms of MS.[56] Current cortical lesion burden measures already appear to be a clinically relevant MRI metric and have been associated with progression of disability[57] and with cognitive impairment.[58]

Recent advances in imaging techniques have allowed for improved detection of cortical lesions in vivo. Both double-inversion recovery (DIR) and T1-weighted 3D-spoiled gradient-recall echo sequences have been shown to detect cortical lesions better than conventional FLAIR sequences.[59,60] High-field MRI improves detection of cortical lesions compared with conventional magnet strengths.[61] Although these techniques afford a higher signal-to-noise ratio, some technical challenges still exist; for example, artifacts and blood vessels can mimic cortical lesions on DIR sequences. Heterogeneous DIR protocols have been used across the literature, making comparisons of published data difficult. A recent consensus statement by the Magnetic Imaging in Multiple Sclerosis (MAGNIMS) group sought to formulate recommendations for scoring cortical lesions. A full discussion of the recommendations is outside the scope of this review, and the reader is referred to the original paper for further details.[62]
Iron-sensitive Imaging

Ultra-small particles of iron oxide, also known as supra-paramagnetic iron particles of oxide, are under investigation in preclinical studies through being tagged to peripheral macrophages and T cells to monitor sites of inflammation.[63] Studies have shown that by using both GAD and ultra-small particles of iron oxide, there is heterogeneous contrast enhancement perhaps suggesting the ability to track peripheral macrophages and areas of blood–brain barrier breakdown. However, before proceeding further with iron oxide agents in vivo, the safety (and clearance) of introducing iron particles into the human CNS must be ascertained.

Another imaging method recently implemented in the evaluation of MS plaques is susceptibility-weighted imaging (SWI). SWI uses the paramagnetic susceptibility effect of iron to demonstrate susceptibility differences between tissues.[64] It has previously been observed that iron accumulation is associated with MS through the role of free iron in oxidative damage and subsequent inflammation. With SWI and phase imaging, veins associated with MS plaques and areas of iron deposition can be visualized. Grabner et al. demonstrated that by combining FLAIR and SWI, there can be visualization of the hypertintense definition of MS lesions, iron deposition and the presence of veins. By observing these key features of iron in relation to MS plaques, the future goal will be to better understand the pathogenesis of MS lesions.[65]

Clinically, SWI still does not provide enough specificity to distinguish between MS versus small-vessel disease-associated white matter lesions. Its predictive value to monitor disease progression (especially in the deep gray nuclei) has great potential clinically, but definitive multicenter trials have yet to be performed.
Perfusion MRI

Perfusion MRI is an imaging method that uses the technique of bolus tracking of exogenous tracers or arterial spin labeling to analyze brain tissue perfusion. Normal white and gray matter have relative decreased perfusion and active MS lesions have increased perfusion.[66] The goal of perfusion MRI is to be able to track development of active MS lesions, as well as patients' responses to therapy. Although perfusion MRI is not currently used clinically in MS patients, there are multiple areas of research aimed at using this technique to better characterize disease activity.

Recent research by Holland et al. aimed to characterize the differences in regional white matter perfusion changes in RRMS and SPMS. They determined that white matter regions with lower relative perfusion correlated with chronic plaques and more highly perfused lesions were seen in RRMS.[67] One of the future goals of perfusion MRI in MS is to evaluate the process of white matter lesion development, as it is unclear based on current research whether changes in perfusion precede the development of lesions or are a direct consequence of the subsequent repair processes. By using magnetic resonance (MR) perfusion, we may be better able to characterize the stage of the lesion and this could have a direct effect on disease management. Holland et al. also stated that if a relationship can be determined between higher relative brain perfusion and improved lesion repair that it could be a new focus for future MS therapy.[67]
MR Spectroscopy

MR spectroscopy (MRS) is an imaging method that measures signals from different metabolites when water is suppressed. It is both highly sensitive and specific when used with high field strength and can detect multiple metabolites pertinent to MS. Traditional metabolites for MRS include N-acetylaspartate (NAA), choline (Cho), creatine (Cr) and myo-inositol (mI). NAA is synthesized in neuronal mitochondria and a decrease in NAA is seen in areas of neuronal/axonal damage. Cho is seen in compounds associated with membrane synthesis and breakdown and is thus increased in the presence of myelin breakdown, synthesis and inflammation. Cr is a marker of cell energy metabolism and is increased when there are an increased number of cells. mI is a marker of glial cells and is usually present in low amounts in neuronal processes but, if elevated, can indicate glial proliferation and astrogliosis.[68]

For MS, MRS is important because it allows the ability to measure these biochemical markers within the MS lesions and normal-appearing gray/white matter. In active MS lesions there is increased Cr, Cho, mI and glutamate, and a decrease in NAA. In chronic, nonenhancing lesions NAA is decreased, mI is increased and glutamate is normal.[66] There are novel MRS metabolites under investigation, including γ-amino butyric acid, ascorbic acid and glutathione, as well as macromolecular signal detection of valine, alanine, leucine and threonine. These macromolecular signals comprise a significant percentage of myelin content and future studies using these detectors may help further understanding of lesion progression, oxidative stress, neurodegeneration, tissue repair and antioxidant therapy in MS.[63,66,69]

NAA levels (mainly NAA/Cr ratio) correlates with physical and cognitive impairment in MS, and has been shown to improve following disease-modifying therapy.[70] Long-term clinical validation of metabolites of interest is underway in MS. Metabolite changes could reveal tissue suffering years before actual loss occurs.
Multicomponent T2 Relaxometry

Multicomponent T2 relaxometry is a method that is used to further characterize tissue by assessment of myelin water fraction (MWF). MWF is determined by a T2 decay curve, which indicates water trapped within layers of myelin.[71] In healthy human brain tissue, the MR-visible proton signal can be separated into three components based on length of relaxation time: very long T2 (>2 s), which correlates with cerebrospinal fluid; intermediate T2 (~80 ms), which indicates intra- and extra-cellular water; and short T2 (~20 ms), which indicates water trapped in myelin bilayers.[69,72] T2 relaxometry has been used in MS patients to determine if there is damage in NAWM that is undetectable using more conventional MR methods. Studies have shown that in MS, MWF is decreased in NAWM by 7–15% and by 30–50% in MS lesions. The future goal is to use the differences in MWF time to better characterize the timing of lesions as acute, chronically active or chronically inactive, thereby acting as a direct marker of disease activity and tissue repair.[66] Large multicenter trials are underway, which will provide necessary validation of this imaging method. This work is particularly important, as this MRI modality is likely to represent our most specific tool to assess myelin content and integrity in vivo.'

Expert Commentary

MRI and other advanced imaging techniques have shaped diagnostic criteria for MS, greatly influenced the outcomes of key clinical trials and can increase our understanding of MS. Throughout this article, we have mentioned our personal views on the clinical relevance of current imaging modalities in MS. The large meta-analyses that have shown strong correlation, including Sormani et al.'s work, supports the clinician's use of MRI in clinical practice and validates MRI metrics as an outcome measure in clinical trials.[3,4] MRI is attractive as a measurement strategy since it is a safe imaging modality that may be repeated serially. We think that this has daily practical considerations for clinicians monitoring MS patients. We recommend acquiring a 6-month brain MRI scan following the initiation of any new disease-modifying therapy, with a GAD-enhancing lesion on that 6-month scan to represent suboptimal response. New or enlarging T2 lesions on the 6-month MRI may have formed before the treatment was fully effective, thus a second scan at 12 months may be compared with the 6-month scan for new or enlarging T2 lesions, and also for GAD-enhancing lesions. As such, the finding of GAD-enhancing lesions on a 6- or 12-month scan, or two or more new or enlarging T2 lesions on the 12-month scan compared with the 6-month scan, should lead to consideration of change in the disease-modifying therapy. Manipulation of MRI data to yield coregistered highly reproducible images ready for subtraction may eventually allow for more quantitative and accurate evaluation of treatment effect and disease activity. This in turn may increase power to find a treatment effect and thus decrease required enrollment for clinical trials with primary MRI outcomes.

Measurement of brain volume loss is now incorporated into all major Phase III MS trials. The specificity of whole brain (white plus gray) volume measures is being challenged, as discussed previously, because of the potential confounding effect of 'pseudo-atrophy' in short-term studies. The field of research is now moving towards measurement of gray matter volume and cortical thinning. They can both potentially serve as outcome measures for trials in progressive MS. However, it still remains unclear whether the importance of gray matter atrophy predominates over white matter in progressive MS, as shown by Fisher et al.[26] It may be that, in later stages of MS when the white matter has sustained extensive damage, the percent change in white matter volume per year is lower than that of gray matter because there is not as much white matter left to lose. This could actually suggest that there has been extensive white matter disease that took place for years and that gray matter still has some tissue to lose or the tissue loss started later.

Furthermore, although novel imaging contrast strategies (DIR, SWI and phase-sensitive inversion recovery) have the potential to illuminate cortical disease activity, MS cortical lesions remain largely undetected using clinical or research MRI methods. Their relevance to clinical symptoms, disease worsening and a better understanding of MS is undeniable at this point. This is currently a serious challenge, despite significant effort, mainly because of their size (resolution), the difficulty to generate enough contrast (demyelinating areas in poorly myelinated regions) and the paucity of inflammatory cells surrounding these lesions, while increasing water content (MRI being a water-based method).

Five-year View

Current conventional imaging will continue to impact our daily care of MS patients for years to come. Better guidelines related to undesirable disease activity seen on MRI will need to be developed for clinicians to help them decide about suboptimal treatment response and switching therapeutic agents. It is likely that several MS clinics will start using volumetric measures (lesion and brain volumes) in their routine imaging practice even before the creation of a 'gold-standard' method. Large datasets of normative values can be collected and made available along with standardized acquisition parameters and postprocessing methods, which will provide additional large-scale validation. Most quantitative imaging techniques (nonconventional) will continue to improve and accumulate validation, while the most informative and robust methods may add to volumetric measurements.

Advancement in MRI will certainly involve the use of ultra-high-field magnet strengths (>3T). However, this is still going to be limited to clinical research over the next few years. Imaging at 7T affords advantages in signal-to-noise ratio, image contrast and resolution. It was already demonstrated to be safe, well tolerated and able to provide high-resolution anatomical images, allowing visualization of structural abnormalities localized near to or within the cortical layers (Figure 2A). Phase maps at 7T showed an increased local field in the deep gray nuclei of MS patients relative to controls, suggesting increased pathological iron content, which was strongly correlated with disease duration (Figure 2B). More importantly, phase images can display distinct peripheral rings and a close association with vasculature. The clearly defined vessels penetrating MS lesions should increase our specificity to perivenular demyelinating processes (Figure 2C).

Figure 2.

Ultra-high field in vivo imaging of multiple sclerosis. (A) Enlarged axial T2*-weighted image (195 × 260 µm) at 7 T of an MS patient, demonstrating fine details of a putative intracortical demyelinating lesion (yellow arrow). (B) Magnitude (grayscale) and local field shift (color inset) images of an MS patient (left) and age- and gender-matched control (right). The cool (blue) spectrum of the basal ganglia in the MS patient shows an increased field, indicating the local presence of paramagnetic compounds such as iron. The hot (red) spectrum of the calcified choroid plexus shows a decreased field, indicating the local presence of diamagnetic compounds such as calcium. (C) Representative magnitude (left) and phase (right) images of a phase ring lesion showing a putative perivenular area of demyelination associated with a phase contrast rim consistent with intracellular iron or deposits. MS: Multiple sclerosis.
Reproduced from [78] with permission from Wiley.

Lastly, the next few years are likely to focus on combining high-resolution MR images or metabolite maps with PET, a neuroimaging technique that complements traditional MRI by using specific molecular markers to identify cellular and metabolic processes.[73] Traditionally, PET has been used in MS to evaluate metabolism in the setting of specific symptoms, such as fatigue and cognitive decline.[74] However, the goal of using PET in MS would be to better understand the role of specific neurotransmitters or detect the presence of inflammatory cells. For example, translocator protein ligands (i.e., PK11195 and PBR28) are potential markers of activated macrophages and microglial cells with different binding affinities. High-resolution PET scanners and improved quantitative modeling methods are likely to increase our imaging specificity to test individual pathways, develop markers of activity or treatment responses, and finally to better characterize the pathophysiology of MS.[49,73,75]
References

Polman C, Reingold S, Banwell B et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann. Neurol. 69, 292–302 (2011).
•• These revised criteria for the diagnosis of multiple sclerosis (MS) simplify the imaging requirements for diagnosis, while maintaining sensitivity and specificity.

Polman C, Reingold S, Edan G et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the 'McDonald criteria'. Ann. Neurol. 58(6), 840–846 (2005).

Sormani MP, Bonzano L, Roccatagliata L et al. Magnetic resonance imaging as a potential surrogate for relapses in multiple sclerosis: a meta-analytic approach. Ann. Neurol. 65, 268–275 (2009).
•• This large meta-analysis establishes the link between treatment effect on MRI and relapse frequency in MS.

Sormani MP, Bonzano L, Roccatagliata L et al. Surrogate endpoints for EDSS worsening in multiple sclerosis: a meta-analytic approach. Neurology 75, 302–309 (2010).
•• This meta-analysis significantly correlates MRI with disability progression in MS, a key clinical outcome.

Cotton F, Weiner HL, Jolesz FA, Guttmann CR. MRI contrast uptake in new lesions in relapsing–remitting MS followed at weekly intervals. Neurology 60(4), 640–646 (2003).

Río J, Rovira A, Tintoré M et al. Relationship between MRI lesion activity and response to IFN-β in relapsing–remitting multiple sclerosis patients. Mult. Scler. 14, 479–484 (2008).

Río J, Castilló J, Rovira, A et al. Measures in the first year of therapy predict the response to interferon β in MS. Mult. Scler. 15, 848–853 (2009).

Prosperini L, Gallo V, Petsas N, Borriello G, Pozzilli C. One-year MRI scan predicts clinical response to interferon β in multiple sclerosis. Eur. J. Neurol. 16, 1202–1209 (2009).

Fisniku LK, Brex PA, Altmann DR et al. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain 131, 808–817 (2008).
•• Disability at 20 years was predicted by T2 lesion volume change in the first 5 years of follow-up for these 107 clinically isolated syndrome patients who were followed prospectively for a mean of 20.2 years.

Weiner H, Guttmann C, Khoury S et al. Serial magnetic resonance imaging in multiple sclerosis: correlation with attacks, disability and disease stage. J. Neuroimmunol. 104, 164–173 (2000).

Li DKB, Held U, Petkau J et al. MRI T2 lesion burden in multiple sclerosis: a plateauing relationship with clinical disability. Neurology 66, 1384–1389 (2006).

Liguori M, Meier D, Hildenbrand P et al. One year activity on subtraction MRI predicts subsequent 4 year activity and progression in multiple sclerosis. J. Neurol. Neurosurg. Psychiatr. 82(10), 1125–1131 (2011).

Moraal B, Meier D, Poppe P et al. Subtraction MR images in a multiple sclerosis multicenter clinical trial setting. Radiology 250(2), 506–514 (2009).

Moraal B, van den Elskamp IJ, Knol DL et al. Long-interval T2-weighted subtraction magnetic resonance imaging: a powerful new outcome measure in multiple sclerosis trials. Ann. Neurol. 67, 667–675 (2010).

Miller DH, Barkhof F, Frank JA, Parker GJ, Thompson AJ. Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 125, 1676–1695 (2002).

Calabrese M, Atzori M, Bernardi V et al. Cortical atrophy is relevant in multiple sclerosis at clinical onset. J. Neurol. 254(9), 1212–1220 (2007).

Henry RG, Shieh M, Okuda D, Evangelista A, Gorno-Tempini ML, Pelletier D. Regional grey matter atrophy in clinically isolated syndromes at presentation. J. Neurol. Neurosurg. Psychiat. 79, 1236–1244 (2008).

Amato MP, Portaccio E, Goretti B et al. Association of neocortical volume changes with cognitive deterioration in relapsing-remitting multiple sclerosis. Arch. Neurol. 64(8), 1157–1161 (2007).

Sanfilipo MP, Benedict RH, Sharma J, Weinstock-Guttman B, Bakshi R. The relationship between whole brain volume and disability in multiple sclerosis: a comparison of normalized grey vs white matter with misclassification correction. Neuroimage 26(4), 1068–1077 (2005).

Mowry EM, Beheshtian A, Waubant E et al. Quality of life in multiple sclerosis is associated with lesion burden and brain volume measures. Neurology 72, 1760–1765 (2009).
• This cross-sectional study found a strong correlation between higher T2 lesion burden and gray matter volume loss, with lower scores on health-related quality-of-life metrics.

Bermel RA, Bakshi R. The measurement and clinical relevance of brain atrophy in multiple sclerosis. Lancet Neurol. 5, 158–170 (2006).

Tedeschi G, Lavorgna L, Russo P et al. Brain atrophy and lesion load in a large population of patients with multiple sclerosis. Neurology 65, 280–285 (2005).

Wegner C, Esiri MM, Chance SA. Neocortical neuronal, synaptic, and glial loss in multiple sclerosis. Neurology 67, 960–967 (2005).

Minagar A, Toledo EG, Alexander JS, Kelley RE. Pathogenesis of brain and spinal cord atrophy in multiple sclerosis. J. Neuroimaging 14(Suppl. 3), 5–10 (2004).

Miller DH, Soon D, Fernando KT et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology 68, 1390–1401 (2007).

Fisher E, Lee JC, Nakamura K, Rudick R. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann. Neurol. 64, 255–265 (2008).
• Gray matter atrophy was shown to be significantly higher in clinically isolated syndrome patients who convert to clinically definite MS, and higher still in relapsing–remitting MS patients who convert to secondary-progressive MS.

Fisniku LK, Chard DT, Jackson JS et al. Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann. Neurol. 64, 247–254 (2008).

Roosendaal SD, Bendfeldt K, Vrenken H et al. Grey matter volume in a large cohort of MS patients: relation to MRI parameters and disability. Mult. Scler. 17, 1098–1106 (2011).

Tao G, Datta S, He R et al. Deep grey matter atrophy in multiple sclerosis: a tensor based morphometry. J. Neurol. Sci. 282, 39–46 (2009).

Calabrese M, Rinaldi F, Mattisi I et al. The predictive value of gray matter atrophy in clinically isolated syndromes. Neurology 77, 257–263 (2011).

Filippi M, Rocca M. MR imaging of multiple sclerosis. Radiology 259(3), 659–681 (2011).

Sicotte NL, Kern KC, Giesser BS et al. Regional hippocampal atrophy in multiple sclerosis. Brain 131(Pt 4), 1134–1141 (2008).

Kiy G, Lehmann P, Hahn HK, Eling P, Kastrup A, Hildebrandt H. Decreased hippocampal volume, indirectly measured, is associated with depressive symptoms and consolidation deficits in multiple sclerosis. Mult. Scler. 17(9), 1088–1097 (2011).

Pellicano C, Gallo A et al. Relationship of cortical atrophy to fatigue in patients with multiple sclerosis. Arch. Neurol. 67(4), 447–453 (2010).

Pelletier D, Garrison K, Henry R. Measurement of whole-brain atrophy in multiple sclerosis. J. Neuroimaging 14, S11–S19 (2004).

Rudick RA, Fisher E, Lee JC, Simon J, Jacobs L. Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing–remitting MS. Neurology 53, 1698–1704 (1999).

Udupa JK, Wei L, Samarasekera S et al. Multiple sclerosis lesion quantification using fuzzy-connectedness principles. IEEE Trans. Med. Imaging 16, 598–609 (1997).

Alfano B, Brunetti A, Covelli EM et al. Unsupervised, automated segmentation of the normal brain using a multispectral relaxometric magnetic resonance approach. Magn. Reson. Med. 37, 84–93 (1997).

Smith SM, Zhang Y, Jenkinson M et al. Accurate, robust and automated longitudinal and cross-sectional brain change analysis. Neuroimage 17, 479–489 (2002).

Dade LA, Gao FQ, Kovacevic N et al. Semiautomatic brain region extraction: a method of parcellating brain regions from structural magnetic resonance images. Neuroimage 22, 1492–1502 (2004).

Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis I. Segmentation and surface reconstruction. Neuroimage 9, 179–194 (1999).

Fischl B, Sereno MI, Dale AM. Cortical surface-based analysis II. Inflation, flattening, and a surface-based coordinate system. Neuroimage 9, 195–207 (1999).

Filippi M, Agosta F. Magnetization transfer MRI in multiple sclerosis. J. Neuroimaging 17, S22–S26 (2007).

Schmierer K, Scaravilli F, Altmann DR et al. Magnetization transfer ratio and myelin in postmortem multiple sclerosis brain. Ann. Neurol. 56(3), 407–415 (2004).

Deloire MSA, Ruet A, Hamel D. MRI predictors of cognitive outcome in early multiple sclerosis. Neurology 76, 1161–1167 (2011).

Rovaris M, Bozzali M, Rodegher M et al. Brain MRI correlates of magnetization transfer imaging metrics in patients with multiple sclerosis. J. Neurol. Sci. 166(1), 58–63 (1999).

Rovaris M, Filippi M. Diffusion tensor MRI in multiple sclerosis. J. Neuroimaging 17, S27–S30 (2007).

Henry RG, Oh J, Nelson SJ, Pelletier D. Directional tensor imaging in relapsing–remitting multiple sclerosis: a possible in vivo signature of wallerian degeneration. J. Magn. Reson. Imaging 18, 420–426 (2003).

Rovaris M, Gallo A, Valsasina P et al. Short-term accrual of gray matter pathology in patients with progressive multiple sclerosis: an in vivo study using diffusion tensor MRI. Neuroimage 24, 1139–1146 (2005).

Yu HJ, Christodoulou C, Bhise V et al. Multiple white matter tract abnormalities underlie cognitive impairment in RRMS. Neuroimage doi:10.1016/j.neuroimage.2011.10.053 (2011) (Epub ahead of print).

Kern KC, Sarcona J, Montag M et al. Corpus callosal diffusivity predicts motor impairment in relapsing–remitting multiple sclerosis: a TBSS and tractography study. Neuroimage 55(3), 1169–1177 (2011).

Sigal T, Shmuel M, Mark D, Gil H, Anat A. Diffusion tensor imaging of corpus callosum integrity in multiple sclerosis: correlation with disease variables. J. Neuroimaging 22(1), 33–37 (2012).

Tian W, Zhu T, Zhong J et al. Progressive decline in fractional anisotropy on serial DTI examinations of the corpus callosum: a putative marker of disease activity and progression in SPMS. Neuroradiology doi:10.1007/s00234-011-0885-8 (2011) (Epub ahead of print).

Geurts JJ, Bo L, Pouweis PJ, Castelijns JA, Polman CH, Barkhof F. Cortical lesions in multiple sclerosis: combined postmortem MR imaging and histopathology. AJNR 26(3), 572–577 (2005).

Seewann A, Vrenken H, Kooi EJ et al. Imaging the tip of the iceberg: visualization of cortical lesions in multiple sclerosis. Mult. Scler. 17, 1202 (2011).

Calabrese M, De Stefano N, Atzori M et al. Detection of cortical inflammatory lesions by double inversion recovery magnetic resonance imaging in patients with multiple sclerosis. Arch. Neurol. 64(10), 1416–1422 (2007).

Calabrese M, Rocca MA, Atzori M et al. A 3-year magnetic resonance imaging study of cortical lesions in relapse-onset multiple sclerosis. Ann. Neurol. 67(3), 367–383 (2010).

Roosendaal SD, Moraal B, Pouwels PJ et al. Accumulation of cortical lesions in MS: relation with cognitive impairment. Mult. Scler. 15(6), 708–714 (2009).

Geurts JJ, Pouwels PJ, Uitdehaag BM et al. Intracortical lesions in multiple sclerosis: improved detection with 3D double inversion-recovery MR imaging. Radiology 236, 254–260 (2005).

Bagnato F, Butman JA, Gupta S et al. In vivo detection of cortical plaques by MR imaging in patients with multiple sclerosis. AJNR 27(10), 2161–2167 (2006).

Kollia K, Maderwald S, Putzki N et al. First clinical study on ultra-high-field MR imaging in patients with multiple sclerosis: comparison of 1.5T and 7T. AJNR 30(4), 699–702 (2009).

Geurts JJG, Roosendaal SD, Calabrese M et al. Consensus recommendations for MS cortical lesion scoring using double inversion recovery MRI. Neurology 76, 418–424 (2011).

Ramli N, Rahmat K, Azmi K et al. The past, present and future of imaging in multiple sclerosis. J. Clin. Neurosci. 17(4), 422–427 (2010).

Haacke EM, Xu Y, Cheng YC, Reichenbach JR. Susceptibility weighted imaging (SWI). Magn. Reson. Med. 52(3), 612–618 (2004).

Grabner G, Dal-Bianco A, Schernthaner M, Vass K, Lassmann H, Trattnig S. Analysis of multiple sclerosis lesions using a fusion of 3.0 T FLAIR and 7.0 T SWI phase: FLAIR SWI. J. Magn. Reson. Imaging 33, 543–549 (2011).

Bakshi R, Thompson AJ, Rocca MA et al. MRI in multiple sclerosis: current status and future prospects. Lancet Neurol. 7(7), 615–625 (2008).

Holland CM, Charil A, Csapo I et al. The relationship between normal cerebral perfusion patterns and white matter lesion distribution in 1,249 patients with multiple sclerosis. J. Neuroimaging doi:10.1111/j.1552-6569.2011.00585.x (2011) (Epub ahead of print).

Fisher SK, Novak JE, Agranoff BW. Inositol and higher inositol phosphates in neural tissues: homeostasis, metabolism and functional significance. J. Neurochem. 82, 736–754 (2002).

Filippi M, Agosta F. Imaging biomarkers in multiple sclerosis. J. Magn. Reson. Imaging 31(4), 770–788 (2010).

Khan O, Shen Y, Caon C et al. Axonal metabolic recovery and potential neuroprotective effect of glatiramer acetate in relapsing–remitting multiple sclerosis. Mult. Scler. 11(6), 646–651 (2005).

Neema M, Goldberg-Zimring D, Guss ZD et al. 3 T MRI relaxometry detects T2 prolongation in the cerebral normal-appearing white matter in multiple sclerosis. Neuroimage 46(3), 633–641 (2009).

Laule C, Vavasour IM, Kolind SH et al. Long T2 water in multiple sclerosis: what else can we learn from multi-echo T2 relaxation? J. Neurol. 254(11), 1579–1587 (2007).

Owen DR, Piccini P, Matthews PM. Towards molecular imaging of multiple sclerosis. Mult. Scler. 17(3), 262–272 (2011).

Kiferle L, Politis M, Muraro PA et al. Positron emission tomography imaging in multiple sclerosis-current status and future applications. Eur. J. Neurol. 18(2), 226–231 (2011).

Oh U, Fujita M, Ikonomidou VN et al. Translocator protein PET imaging for glial activation in multiple sclerosis. J. Neuroimmune Pharmacol. 6(3), 354–361 (2011).

Henry RG, Shieh M, Amirbekian B, Chung SW, Okuda DT, Pelletier D. Connecting white matter injury to thalamic atrophy in clinically isolated syndromes. J. Neurol. Sci. 282(1–2), 61–66 (2009).

Zivadinov R, Reder AT, Filippi M et al. Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis. Neurology 71(2), 136–144 (2008).

Hammond KE, Metcalf M, Carvajal L et al. Quantitative in vivo magnetic resonance imaging of multiple sclerosis at 7 tesla with sensitivity to iron. Ann. Neurol. 64, 707–713 (2008).

Papers of special note have been highlighted as:
• of interest
•• of considerable interest

[vesta]

Proposed method for measuring dRA, or delta Rate of Atrophy:
http://sullivanweb.me/pdfdocs/atrophy-3.pdf

Hello 1 eye: Wonderful information you've provided. Who is the author of the sullivanweb article? Thanks, Vesta

[1eye]

Who is the author of the sullivanweb article?

Sorry. You cannot find that link to sullivanweb.me anywhere (that I know of) except right here in this thread. There might be something close on my computer. Chris Sullivan is apparently the alter ego of 1eye, when he is at home. It's not really for publication anywhere, just a post to TiMS that ran astray; however the picture shows what the dRA is, and how you might use it to assess how one is doing after some kind of intervention. Atrophy is either worse, the same, or better, and dRA says how much, if it's not 0. If it is, you are young and healthy.

The clue is in the units: the hypothetical patient is getting better (just because of the sign), and the speed of the improvement is increasing, by as much as 0.85 um per day, every month since the intervention.


P.S. Sullivan is Gaelic for "one-eye".

Chris Sullivan

[vesta]

Who is the author of the sullivanweb article?

Sorry. You cannot find that link to sullivanweb.me anywhere (that I know of) except right here in this thread. There might be something close on my computer. Chris Sullivan is apparently the alter ego of 1eye, when he is at home. It's not really for publication anywhere, just a post to TiMS that ran astray; however the picture shows what the dRA is, and how you might use it to assess how one is doing after some kind of intervention. Atrophy is either worse, the same, or better, and dRA says how much, if it's not 0. If it is, you are young and healthy.

The clue is in the units: the hypothetical patient is getting better (just because of the sign), and the speed of the improvement is increasing, by as much as 0.85 um per day, every month since the intervention.


P.S. Sullivan is Gaelic for "one-eye".

Chris Sullivan

Hello Chris:
I'm impressed and think your papers should be posted directly. Anyway, I quoted one on my site as well as much of the above discussion. So as to not butt in on your post, I'm sending a PM to identify my site so you can see what has been posted. Also
in keeping with the subject see my blog post March 2, 2015 and article dated April 2012. http://www.msdiscovery.org/news/news_sy ... -meets-eye) which discusses the advances in MRI technology for MS drug research, researchers have experienced “the recent epiphany that MS also ravages gray matter” so that “the full scope of the damage is emerging.” Wow. I guess they had to see it to believe it. So will the CCSVI epiphany come anytime soon?

Best regards, Vesta