Dear Angelique,
I have now had the opportunity to read your paper. I should state from the outset that I have no background in biology, so I leave the review of the more densely biological sections of your paper to those better qualified. Overall, I found your hypothesis interesting, but several things undermine my confidence in it. I list some of these below, but for those who don’t want to read the whole thing, my main issues are what appears to be a very selective choice of citations, a lack of empirical support, no consideration of the heterogeneity of MS and no suggestions about how your hypothesis might be tested. I will, however, be very interested in reading the results of any follow-up research you may do on the topic and wish you the best of luck with it.
Yours sincerely,
Karen.
General (in no particular order!)
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You make no reference to the heterogeneity of MS. Can your hypothesis explain the different types of MS (e.g. benign, RRMS, SPMS, PPMS, PRMS, Marburg’s Variant, etc)? And the different severities found within these diagnoses? And the fact that some MSers find that their disease progression naturally plateaus at some point?
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Can your hypothesis explain the increasing incidence of paediatric MS? Children as young as two years old have been diagnosed in the UK.
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You consistently refer to the “acute phase” – how does this relate to progressive forms of MS?
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You refer to “trauma” as a potential trigger, but this is not defined, nor evidence provided to support its importance in the development of MS.
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You offer no suggestions as to how your hypothesis could be tested.
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You propose that the same process leads to atherosclerosis in men and MS in women. There must be data already available with which to explore this proposal, however you have not provided any, nor made any suggestions about how these data may be gathered if necessary.
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Can your hypothesis account for the distribution of MS lesions (e.g. the preference for the periventricular area) and the variability of numbers and locations of lesions between MSers (e.g. those with lesions only in their spinal cord versus those with lesions only in their brain; those with numerous lesions versus those with very few lesions)?
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You do not properly address the growing, very strong evidence of a specific link between EBV and MS. Can your hypothesis account for this?
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Why, if lipid metabolism underlies MS, do statins and fibrates not do a better job?
Specifics (in no particular order!):
“the relatively high incidence of MS in regions where populations can obtain Vitamin D both through UV synthesis and/or diet, such as Iran or Japan (Yamasaki et al. 1996; Niino et al. 2002; Maghzi et al. 2010)." (p288)
- Japan actually has a low incidence of MS
- Maghzi et al suggest that the increasing rates of MS in Iran is linked to a lack of Vitamin D
- Yamasaki et al propose two different types of MS: “Asian MS” (no link to Vitamin D), “Western MS” (link to Vitamin D): how does this fit with your hypothesis?
- Niino et al is about Asian MS
- Asian MS is sometimes likened to NMO instead of MS (see, e.g., Polman et al, 2011)
“For example, a strong association of alleles of the major histocompatibility complex, such as HLA DRB1*1501, with the disease has not been confirmed for all MS patients (Yamasaki et al. 1996; Schreiber et al. 2002).” (p288)
- Yamasaki et al suggest two different forms of MS (Asian and Western). It is hardly surprising, therefore, that these would have different genetic profiles.
- Schreiber et al suggest that not all MSers have the same genotype (which may be linked to severity). How does your hypothesis account for this?
“Atherosclerosisspecific drugs, such as statins and, more recently, PPARs agonists, are currently used to treat MS symptoms (Assmann and Gotto 2004; Rubic et al. 2004; DeAngelis and Lublin 2008; Heinecke 2009; Mandosi et al. 2010; Chrast et al. 2011; Mirabelli-Badenier et al. 2011; Rinaldi et al. 2011), highlighting the shared pathways underlying inflammatory events in the two diseases.” (p300)
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None of these citations are studies of MS! (Instead we have stroke, diabetes, organ failure, etc.)
“This framework explains why statins and PPAR agonists (fibrates) have shown so much promise in treating MS (Stuve et al. 2003; Sena et al. 2007; Xu et al. 2007; Drew et al. 2008; Goldman and Cohen 2008; Malchiodi-Albedi et al. 2008).” (p312)
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None of these papers are studies. Where are the citations that demonstrate that statins and fibrates help MS?
- Where is the exploration of the studies that have reported no effect or even a negative effect of statins on MSers (e.g. Birnbaum et al, 2008; Togha et al, 2010; Sorensen et al, 2011)?
“Statins and PPAR agonists taken separately can successfully treat specific symptoms (Brown and Plutzky 2007).” (p300)
“the current approach of treating the disease as a collection of symptoms to be relieved (Brown and Plutzky 2007).” (p301)
- How does Brown & Plutsky relate to MS?
- Disease modifying treatments for MS focus on reducing relapse rates and progression. They are not symptomatic treatments. Which disease are you referring to here?
“MS patients have severe vascular abnormalities that reduce brain blood flow.” (p306)
- Evidence? The only citation given in that paragraph (Duan et al, 2008) has nothing to do with MS.
“Dysregulation of PPAR functions would result in less serine, and more homocysteine, both phenomena observed in MS patients” (p310)
- Evidence? No citation provided.
“Muscle atrophy, weakness, and spasticity, all major pathophysiological consequences of MS… MS patients improve their motor ability through resistance-training exercises” (p309)
- Muscle atrophy is not generally considered to be a symptom of MS. When it does occur in MS, it is usually caused by lack of use (in which case, it is unsurprising that exercise improves mobility).
“This new framework explains the origins of all the symptoms of MS studied here, from restenosis, neurological disorders, and muscle spasticity to weight loss at the onset of the disease and shift of lipid metabolism throughout the course of the disease and during acute relapses.” (p312)
- Where is the evidence that restenosis is a symptom of MS?
- Where is the evidence that weight loss occurs at the onset of MS? (Incidentally, this is the first mention of weight loss in your paper.)
- You have covered a tiny proportion of MS symptoms in your paper. What about optic neuritis, incontinence, paresthesia, tinnitus, neuralgia, ataxia, tremor, etc?