research: sleep

Kaminska M et al. Obstructive sleep apnea is associated with fatigue in multiple sclerosis.Mult Scler. 2011 Dec 19. [Epub ahead of print]

Background: Multiple sclerosis (MS) patients often suffer from fatigue.

Objective: We evaluated the relationship of obstructive sleep apnea to fatigue and sleepiness in MS patients.Methods: Ambulatory MS patients without known sleep disorders and healthy controls underwent diagnostic polysomnography and a multiple sleep latency test (objective sleepiness measure). Fatigue was measured with the Fatigue Severity Scale (FSS) and the Multidimensional Fatigue Inventory (MFI), and subjective sleepiness by Epworth Sleepiness Scale. Covariates included age, sex, body mass index, Expanded Disability Status Scale (EDSS), depression, pain, nocturia, restless legs syndrome, and medication.

Results: OSA (apnea-hypopnea index ≥15) was found in 36 of 62 MS subjects and 15 of 32 controls. After adjusting for confounders, severe fatigue (FSS ≥5) and MFI-mental fatigue (>group median) were associated with OSA and respiratory-related arousals in MS, but not control subjects. Subjective and objective sleepiness were not related to OSA in either group. In a multivariate model, variables independently associated with severe fatigue in MS were severe OSA [OR 17.33, 95% CI 2.53-199.84], EDSS [OR 1.88, 95% CI 1.21-3.25], and immunomodulating treatment [OR 0.14, 95% CI 0.023-0.65].

Conclusions: Obstructive sleep apnea was frequent in MS and was associated with fatigue but not sleepiness, independent of MS-related disability and other covariates.

Sleep Apnea are pauses in breathing or shallow breaths while you sleep. The most common type of sleep apnea is obstructive sleep apnea. This most often means that the airway has collapsed or is blocked during sleep. The blockage may cause shallow breathing or breathing pauses. When you try to breathe, any air that squeezes past the blockage can cause loud snoring. Obstructive sleep apnea is more common in people who are overweight, but it can affect anyone. The conclusions say it all.

MS life 2012

MS Life (UK MS Society meeting) will be heading to Manchester Central for 14-15 April 2012. Make it a Date for Your Diary

Come and See Familiar & New Faces and the Science Trilogy From Holland

Meet the Scientists and Members of Team G. Hopefully the T shirts won't be such a tight fit.

Don't forget to Register

Cost of Neurological Disease in Europe

Olesen J et al. The economic cost of brain disorders in Europe.Eur J Neurol. 2012 Jan;19(1):155-162.

Background and purpose:  In 2005, we presented for the first time overall estimates of annual costs for brain disorders (mental and neurologic disorders) in Europe. This new report presents updated, more accurate, and comprehensive 2010 estimates for 30 European countries.

Methods:  One-year prevalence and annual cost per person of 19 major groups of disorders are based on 'best estimates' derived from systematic literature reviews by panels of experts in epidemiology and health economics. Our cost estimation model was populated with national statistics from Eurostat to adjust to 2010 values, converting all local currencies to Euros (€), imputing cost for countries where no data were available, and aggregating country estimates to purchasing power parity-adjusted estimates of the total cost of brain disorders in Europe in 2010.

Results:  Total European 2010 cost of brain disorders was €798 billion, of which direct health care cost 37%, direct non-medical cost 23%, and indirect cost 40%. Average cost per inhabitant was €5.550. The European average cost per person with a disorder of the brain ranged between €285 for headache and €30,000 for neuromuscular disorders. Total annual cost per disorder (in billion € 2010) was as follows: addiction 65.7; anxiety disorders 74.4; brain tumor 5.2; child/adolescent disorders 21.3; dementia 105.2; eating disorders 0.8; epilepsy 13.8; headache 43.5; mental retardation 43.3; mood disorders 113.4; multiple sclerosis 14.6; neuromuscular disorders 7.7; Parkinson's disease 13.9; personality disorders 27.3; psychotic disorders 93.9; sleep disorders 35.4; somatoform disorder 21.2; stroke 64.1; and traumatic brain injury 33.0.

Conclusion:  Our cost model revealed that brain disorders overall are much more costly than previously estimated constituting a major health economic challenge for Europe. Our estimate should be regarded as conservative because many disorders or cost items could not be included because of lack of data.

Long-acting interferon beta

Epub ahead of print:  Kieseier  & Calabresi. PEGylation of Interferon-β-1a: A Promising Strategy in Multiple Sclerosis. CNS Drugs. 2011 Dec 23.

Biological therapies, such as interferon beta, can be hindered by the rapid clearance of the drug requiring frequent dosing. One strategy for addressing this problem is drug modification through PEGylation, a well established process by which one or more molecules of polyethylene glycol (PEG) are attached to a biological or small-molecule drug, effectively transforming it into a therapy with improved properties (pharmacokinetic and pharmacodynamic) that increase its life in the body and hence its duration of action. 

A pegylated protein

Numerous PEGylated therapeutics are currently available, all of which have at least comparable efficacy, safety and tolerability to their unmodified forms. 

A PEGylated form of interferon-β-1a (PEG-IFNβ-1a) is being developed for MS. 

Phase I study data suggest that PEG-IFNβ-1a should provide MS'ers with a first-line therapy with a more convenient dosing regimen (once  a month or twice a month injections) while maintaining the established efficacy, safety and tolerability of presently available IFNβ-1a. 

The ongoing global ADVANCE phase III study will determine the clinical efficacy of PEG-IFNβ-1a in MS'ers with relapsing MS.

"This is what you call life-cycle management of a drug or class of drugs for MS. Some MS'ers who respond to IFN-beta may find the option of a once monthly or twice monthly injection preferable to a weekly injection. If the drug gets through the pipeline I wonder what it will cost?"

Research: Fingolimod in Volunteers

Epub: Boulton C et al. Pharmacodynamic Effects of Steady-State Fingolimod on Antibody Response in Healthy Volunteers: A 4-Week, Randomized, Placebo-Controlled, Parallel-Group, Multiple-Dose Study. J Clin. Pharmacol 2011 Dec.

Fingolimod (Gilenya) , a first-in-class oral sphingosine 1-phosphate receptor (S1PR) modulator, is approved in many countries for relapsing-remitting multiple sclerosis, at a once-daily 0.5-mg dose. A reduction in peripheral lymphocyte count is an expected consequence of the fingolimod mechanism of S1PR modulation.


This study investigated if this pharmacodynamic effect impacts humoral (antibodies and B cells) and cellular (T cell) immunogenicity. In this double-blind, parallel-group, 4-week study, 72 healthy volunteers were randomized to steady state, fingolimod 0.5 mg, 1.25 mg, or to placebo.


The authors compared T-cell dependent and independent responses to the neoantigens, keyhole limpet hemocyanin (KLH. Limpet blood protien), and pneumococcal (pneumonia bacteria) polysaccharides vaccine (PPV-23), respectively, and additionally recall antigen response (tetanus (lockjaw) toxoid [TT]) and delayed-type hypersensitivity (DTH) to KLH, TT, and Candida albicans (Thrust, yeast).


Fingolimod caused mild to moderate decreases in antibody response to anti-KLH and anti-PPV-23 IgG and IgM antibody levels versus placebo. Responder rates were identical between placebo and 0.5-mg groups for anti-KLH IgG (both greater than 90%) and comparable for anti-PPV-23 IgG (55% and 41%, respectively). Fingolimod did not affect anti-TT immunogenicity, and DTH response did not differ between placebo and fingolimod 0.5-mg groups. Expectedly, lymphocyte count reduced substantially in the fingolimod groups versus placebo but reversed by study end. Fingolimod was well tolerated, and the observed safety profile was consistent with previous reports.

DTH Skin Test (Reddening and swelling)

Generalised immunosuppression results in inhibtion of T cell and cell immune responses that could leave you succeptible to infections and tumours and may inhibit your response to infections that you have been vaccinated against. Gilenya traps immune cells in lymph glands and prevents them entering the blood. Whilst this may be good for stopping MS, it may not be good for fighting infections. However Gilenya is not supposed to cause a blanket inhibition of cell function and leaves some white blood cell subsets unaffected. These subsets are thought to deal with infection and so the hope is that you can deal with MS, whilst still having the capacity to fight infection.

The study indicated that there was a modest reduction in antibody responses, which would equate to some reduced capacity to deal with infections but T cell responses as tested using DTH skin swelling response to infections to which we have immunity was unaffected. This is good because it means Gilenya is not completely removing our protective immunity, however we should expect some infection issues as there were some in clinical trials.

Planning MS: It just takes a little longer

Denney DR et al. Deficits in Planning Time but not Performance in Patients with Multiple Sclerosis.Arch Clin Neuropsychol 2011 Dec 15. [Epub ahead of print]

Studies of planning ability typically involve some version of the Tower of Hanoi or Tower of London tests. When these tests are administered to patients with multiple sclerosis (MS), the findings pertaining to planning "performance" have been conflicting.

Possible reasons for failures to find deficits in planning performance among MS patients are: (a) the patients typically have relapsing-remitting MS (RRMS) of mild severity and short duration and thus little cognitive impairment relative to those with more advanced disease; (b) the problems composing the tests are too simple and differences between patients and controls are therefore obscured by ceiling effects; and (c) the scoring system typically used permits participants to earn points for successful solutions on later trials after failing the initial attempt on each problem, thereby further diluting the difference between patients and controls.

The present study compared the performance of patients with both relapsing-remitting and secondary progressive disease with that of healthy controls on a more challenging version of the Tower of London test. Patients exhibited lengthier planning times on the test, greater disparity in their average planning times from those of controls as the difficulty level increased, and greater individual variability in their planning times across the full set of problems. However, no differences in planning performance were found between patients and controls or between RRMS and secondary progressive MS patients. Performance differences in other studies may be attributable in part to the imposition of time limits for solving each problem and the disproportionately adverse effect such time limits have on patients' performance.


Tower of Hanoi. The objective of the puzzle is to move the entire stack to another rod, obeying the following rules: Only one disk may be moved at a time. Each move consists of taking the upper disk from one of the rods and sliding it onto another rod, on top of the other disks that may already be present on that rod and No disk may be placed on top of a smaller disk.

The results say it all, it means that sometimes you may need a little longer to do things. This sort of shows that the brain can be plastic (abilty of nerve circuitary to adapt to change) during MS. For example whilst there may damage to some circuits to get message (nerve impulses) from say A to B, it adapts to go from A to C to D to B so it gets there in the end but may be abit slower.

Kick-Boxing

Jackson et al. Feasibility and effects of a group kickboxing program for individuals with multiple sclerosis: A pilot report. J Bodyw Mov Ther. 2012 Jan;16(1):7-13.

BACKGROUND AND PURPOSE: Balance and mobility impairments are common in MS'ers. The primary purpose of this pilot program was to evaluate the feasibility and the effects of group kickboxing on balance and mobility in individuals with MS.

METHODS: Four individuals with relapsing-remitting or secondary progressive MS participated in a group kickboxing program two times per week for 8 weeks. Outcome measures included the Berg Balance Scale (BBS), Dynamic Gait Index (DGI), Timed Up and Go (TUG), walking speed and the Activities Specific Balance Confidence Scale (ABC).

RESULTS: Following training, 3 of 4 participants had improvements in BBS performance. All participants demonstrated improvements in the DGI. Changes in the TUG, ABC, and walking speed were more variable.

CONCLUSION: Group kickboxing appears to be a feasible exercise activity for individuals with MS and may lead to improvement in select measures of balance. Further investigation is warranted.

"The creativity of the research community never ceases to amaze me. I have seen similar work done using software and hardware available on the Wii, PSP3 and XBox360. The message is exercise, particularly if it challenges your balance centres, is good for you. Before embarking on any activity please get professional advice from your physiotherapist."

Cognitive testing for all

Epub ahead of print:  Langdon et al. Recommendations for a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). Mult Scler. 2011 Dec 21. 

Background: Cognitive impairment in MS impacts negatively on many MS'ers at all disease stages and in all subtypes. Full clinical cognitive assessment is expensive, requiring expert staff and special equipment. Test versions and normative data are not available for all languages and cultures.

Objective: To recommend a brief cognitive assessment for MS that is optimized for small centers, with one or few staff members, who may not have neuropsychological training and constructed to maximize international use.

Methods: An expert committee of twelve members representing the main cultural groups that have so far contributed considerable data about MS cognitive dysfunction was convened. Following exhaustive literature review, peer-reviewed articles were selected to cover a broad spectrum of cultures and scales that targeted cognitive domains vulnerable to MS. Each was rated by two committee members and candidates scales were rated on psychometric qualities (reliability, validity, and sensitivity), international application, ease of administration, feasibility in the specified context, and acceptability to patients.

Results: The committee recommended the Symbol Digit Modalities Test, if only 5 minutes was available, with the addition of the California Verbal Learning Test - Second Edition and the Brief Visuospatial Memory Test - Revised learning trials if a further 10 minutes could be allocated for testing.

Conclusions: A brief cognitive assessment for MS has been recommended. A validation protocol has been prepared for language groups and validation studies have commenced.

"This initiative is an attempt to get cognitive testing adopted into routine clinical practice. How do you know if you are cognitively impaired if you are not tested for it?"

Research: Spinal Lesions at First neurological signs increase risk of MS

Patrucco L, Rojas JI, Cristiano E Assessing the value of spinal cord lesions in predicting development of multiple sclerosis in patients with clinically isolated syndromes.
J Neurol. 2011 Dec [Epub ahead of print]


The purpose of this study was to determine the value of spinal cord lesions as a predictive factor for conversion in clinically isolated syndrome (CIS) patients.


Patients with CIS and without immunomodulatory treatment were prospectively included. Age at onset, sex, clinical syndrome at onset, oligoclonal bands, and presence, number and location of lesions on brain and spinal MRI were analyzed. Conversion to multiple sclerosis (MS) was the primary endpoint.


A total of 75 patients were included: 53 (71%) women, mean age at onset 32.7 years (SD ± 7.5), mean follow-up time 72.5 months (SD ± 9; range 17-104 months). There were 11 (14.6%) patients with one focal spinal cord lesion, while 13 (17%) patients had two or more spinal cord lesions at the first scan during the onset of the disease. Of the 23 patients (30.6%) who converted to clinically definite MS (CDMS), 2 had a normal spinal cord MRI, 8 patients had one spinal cord lesion, and 13 had more than one lesion on MRI (p < 0.001).


In multivariable analyses, one focal spinal cord lesion was significantly associated with increased risk of conversion to MS (p = 0.01, Hazard ratio (HR) 3.5, CI 95% 2.1-6.9), while the presence of two or more focal spinal cord lesions was independently associated with a higher risk of conversion to MS (p < 0.001, HR 5.9, CI 95% 3.2-10.8). CIS patients with an abnormal baseline spinal cord MRI have a higher risk for developing clinically definite MS, independent of brain lesions as well as the presence of cerebrospinal fluid oligoclonal banding

MRI lesion in the spinal cord.

This adds further confirmation that additional MRI lesions in the CNS during the development of the first signs of neurological disease increases the risk of developing MS......but you know this already.

Research: Predicting MS from Genes

Jafari N et al. Perspectives on the Use of Multiple Sclerosis Risk Genes for Prediction. Plos One 2011;6(12):e26493.

OBJECTIVE: A recent collaborative genome-wide association study replicated a large number of susceptibility loci and identified novel loci. This increase in known multiple sclerosis (MS) risk genes raises questions about clinical applicability of genotyping. In an empirical set we assessed the predictive power of typing multiple genes. Next, in a modelling study we explored current and potential predictive performance of genetic MS risk models.

MATERIALS AND METHODS: Genotype data on 6 MS risk genes in 591 MS patients and 600 controls were used to investigate the predictive value of combining risk alleles. Next, the replicated and novel MS risk loci from the recent and largest international genome-wide association study were used to construct genetic risk models simulating a population of 100,000 individuals. Finally, we assessed the required numbers, frequencies, and odds ratios of risk SNPs for higher discriminative accuracy in the future.

RESULTS: Individuals with 10 to 12 risk alleles (genetic variants) had a significantly increased risk compared to individuals with the average population risk for developing MS (Odds Ratio 2.76 (95% CI 2.02-3.77)). In the simulation study we showed that the area under the receiver operating characteristic curve (AUC) for a risk score based on the 6 single nucleotide polymorphism (SNPs pronounced snips) was 0.64. The area under the curve increases to 0.66 using the well replicated 24 and to 0.69 when including all replicated and novel Single nucleotide polymorphism (n = 53) in the risk model. An additional 20 SNPs with allele frequency 0.30 and Odd ratios of 1.1 would be needed to increase the AUC to a slightly higher level of 0.70, and at least 50 novel variants with allele frequency 0.30 and Odds ratios of 1.4 would be needed to obtain an AUC of 0.85.

CONCLUSION: Although new MS risk SNPs emerge rapidly, the discriminatory ability in a clinical setting will be limited.

We have known for many years that an allele of HLA-DR (common in white Northern Europeans) has been associated with a risk of development of MS. However, even without HLA-DR there was an increased, but small, risk for developing MS in people with 8 to 10 risk alleles. This underlines the current insight that multiple genes exert a small effect on developing MS on top of the major influence of HLA-DR.

However by investigating more and more of these risk alleles, using such models, it does not dramatically increase the ability to predict whether one will get MS and so simply adding in more and more low risk alleles into the equation does not make it more useful in clinical practice.

Therefore the genetic analysis has so far cost considerable funds but has yet to provide valuable practical information that has therapeutic application.

Another approach to improve MS prediction could be combining genetic with nongenetic risk factors such as infection with Epstein-Barr virus (EBV), smoking, and serum vitamin D concentrations but I'll leave this for Prof G to discuss.

Predicting disability in MS on DMTs

Epub ahead of print:  Goodin et al. Relationship between early clinical characteristics and long term disability outcomes: 16 year cohort study (follow-up) of the pivotal interferon β-1b trial in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2011 Dec 21.


Background: Evaluating the long term benefit of DMTs in MS is challenging. Although randomised controlled trials (RCTs) demonstrate therapeutic benefits on short term outcomes, the relationship between these outcomes and late disability is not established.

Methods: In a patient cohort from the pivotal interferon β-1b trial, the value of clinical and MRI measures were analysed, both at baseline and during the RCT, for predicting long term physical and cognitive outcome.

Results: Baseline disability correlated with both physical (R(2)=0.22; p<0.0001) and cognitive (R(2)=0.12; p<0.0001) outcome after 16 years. Accrual of disability during the RCT (R(2)=0.12; p<0.0001) and annualised relapse rates during the trial correlated with physical outcome (R(2)=0.12; p<0.0001) but not with cognition. In contrast, baseline MRI measures of atrophy and lesion burden correlated with cognitive (R(2)=0.21; p<0.0001), but not with physical, outcome. Accumulation of plaque burden measured by MRI did not correlate with late physical disability or with cognitive outcome. Multivariate regression analysis using stepwise elimination demonstrated that baseline variables contributed independently to predicting long term outcomes while trial outcome variables contributed little. Overall, and considerably dependent on baseline measures, the models developed by this method accounted for approximately half of the variance in long term cognitive and disability outcome.

Conclusions: Although on-trial change in some short term clinical measures correlated with long term physical and disability outcomes, the proportion of the variance explained by single commonly employed on-study variables was often small or undetectable. Better correlations were observed for several baseline measures, suggesting that long term outcome in MS may be largely determined early in the disease course.

"The results of this analysis are very important and have major implications for how we do trials and interpret the results of short-term DMT studies. It is clear from this study, and other data, that disability be-gets disability, both physical and cognitive. Therefore we need  to prevent the acquisition of disability in MS early on; I sincerely hope that aggressive early treatments will achieve this aim." 

Happy Holiday

What Every Your Religion,
Whether it be: Atheist, Agnostic, Christian, Jewish, Muslim, Hindu or CCSVI and Others

Prof G, the MouseDoc & Team G Wish You Happy Holidays.
Hoping SantaMouse Delivers Effective Treatments to You

Research:EBV activating the Immune Response

Tzartos JS, Khan G, Vossenkamper A, Cruz-Sadaba M, Lonardi S, Sefia E, Meager A, Elia A, Middeldorp JM, Clemens M, Farrell PJ, Giovannoni G, Meier UC. Association of innate immune activation with latent Epstein-Barr virus in active MS lesions.Neurology 2011 Dec [Epub]

OBJECTIVE: To determine whether the activation of innate immune responses, which can be elicited by pathogenic and endogenous triggers, is associated with the presence of Epstein-Barr virus (EBV) infection in the multiple sclerosis (MS) brain.

METHODS: White matter postmortem MS (n = 10) and control tissue (n = 11) was analyzed for the expression of the proinflammatory cytokine interferon α (IFNα) by immunohistochemistry and for EBV by using the highly sensitive method of EBV-encoded RNA (EBER) in situ hybridization.

RESULTS: We detected overexpression of IFN alpha (an immune protein that prevents replication of viruses) in active areas of white matter MS lesions but not in inactive MS lesions, normal-appearing white matter, or normal brains. The presence of IFNα in macrophages and microglia is suggestive of local production as part of an acute inflammatory process. Interestingly, EBERs were also specifically detected in areas where IFNα was overexpressed in these preselected active MS lesions. EBER+ cells were also found in CNS lymphoma (white blood cell tumor) and stroke cases, but were absent in other control brains. We next addressed a potential mechanism for a role of EBERs in eliciting IFNα production, and transfected EBERs into human embryonic kidney (HEK) cells. We used HEK cells that stably expressed Toll-like receptor-3, which recognizes double-stranded RNAs, associated with many viral infections. EBERs elicited IFNα production in vitro.

CONCLUSION: These findings suggest that latent EBV infection may contribute to the inflammatory milieu in active MS lesions by activating innate immune responses, such as IFNα production. Unraveling the underlying mechanisms may help in uncovering causal pathways and developing better treatment strategies for MS and other neuroinflammatory diseases.




The conclusions say it all, yet more evidence from Team G, implicating a role of EBV in the disease process.

24 MS Research Day Advent Calendar

Please remember to register your interests for the Open Day, You can do this if you Click Here.

NativityMice say come to our Research Day and...

• Meet and Talk to Members of Team G
• Hear the Trials & Tribulations of MS Drugs 2012?
• Review Stem Cells Trials for 2012 and Beyond
• Talk the walk about symptomatic therapy
• Speak to Prof G and the Other Neuros
• See who the MouseDoctors Really Are
• Hear About New trials for Progressive MS..Stopping MS?
• Enjoy the Lunchtime Food
• What's Beyond Cannabis for Treatment of Spasticity
• Image the Brain to Help Explain..MS
• Expose Bad Science
• Talk about Sex and MS
• Find Out What's new with CCSVI
• Digest Science with Coffee & Tea(m G)
• Can you Prevent MS?...the Risk factors
• Think about High Risk, High Gain Drugs
• Research MS
• Turn off the Immune Response & Avoid Side Effects
  
• Hear about the Charcot Project....What's that?
  
• Novel trials against the Cause of MS
• Aims to be the Cure

It's Free but Can you Afford Not to Be there?

Press the Link Click Here.

Research: Damaging Microglia

Huizinga R, van der Star BJ, Kipp M, Jong R, Gerritsen W, Clarner T, Puentes F, Dijkstra CD, Valk PV, Amor S. Phagocytosis of neuronal debris by microglia is associated with neuronal damage in multiple sclerosis. Glia. 2011 . doi: 10.1002/glia.22276. [Epub]

Neuroaxonal degeneration is a pathological hallmark of multiple sclerosis (MS) contributing to irreversible neurological disability. Pathological mechanisms leading to axonal damage include autoimmunity to neuronal antigens.

In actively demyelinating lesions, myelin is phagocytosed by microglia and blood-borne macrophages, whereas the fate of degenerating or damaged axons is unclear. Phagocytosis (engulfing by cells such as macrophages) is essential for clearing neuronal debris to allow repair and regeneration. However, phagocytosis may lead to antigen presentation and autoimmunity, as has been described for neuroaxonal antigens. Despite this notion, it is unknown whether phagocytosis of neuronal antigens occurs in MS.

Here, we show using novel, well-characterized antibodies to axonal antigens, that axonal damage is associated with HLA-D/ MHC class II (a protien that is used to activate T cells) expressing microglia/macrophages engulfing axonal bulbs, indicative of axonal damage. Neuronal proteins were frequently observed inside HLA-DR(+) cells in areas of axonal damage. In vitro, phagocytosis of neurofilament light (NF-L. A nerve scaffolding protein), present in white and gray matter, was observed in human microglia. The number of NF-L or myelin basic protein (MBP) positive cells was quantified using the mouse macrophage cell line J774.2. Intracellular colocalization of NF-L with the lysosomal membrane protein LAMP1 was observed using confocal microscopy confirming that NF-L is taken up and degraded by the cell. In vivo, NF-L and MBP was observed in cerebrospinal fluid cells from patients with MS, suggesting neuronal debris is drained by this route after axonal damage.

In summary, neuroaxonal debris is engulfed, phagocytosed, and degraded by HLA-DR(+) cells. Although uptake is essential for clearing neuronal debris, phagocytic cells could also play a role in augmenting autoimmunity to neuronal antigens.

Axonal bulb in MS occurs when axons are cut and molecules being transported down the axon accumulate in the bulb. Abit like a ballooon blowing-up as air is pushed down the spout.

We know that microglia and macrophages are vital in clearing up the debris that occurs during attack. This is important for repair and remyelination and there appearto be good-microglia. But they have the potential to be bad microglia and can act as antigen presenting cells to stimulate damaging white blood cell responses. When neural antigens are damaged they can be taken up by macrophages/microglia by a process called phagocytosis. In the cell the neural proteins are digested in the lysosome and then loaded into MHC class I/II to stimulate T cell responses. If they are stimulated in the brain they can cause damage to nerves, as we can show experimentally. They could also help generate damaging antibodies that could contribute to progression.

There are other ways that progressive nerve damage can occur.

CoI Prof Amor and Dr Puentes are part of Team G

23 MS Research Day Advent Calendar

Please remember to register your interests for the Research Day, You can do this if you Click Here.

ThreewiseMice (Did you know that the United Colours of Team G come from 5 continents? ) say come to our Open Day sorry Research Day and...

• Meet and Talk to Members of Team G
• Hear the Trials & Tribulations of MS Drugs 2012?
• Review Stem Cells Trials for 2012 and Beyond
• Talk the walk about symptomatic therapy
• Speak to Prof G and the Other Neuros
• See who the MouseDoctors Really Are
• Hear About New trials for Progressive MS..Stopping MS?
• Enjoy the Lunchtime Food
• What's Beyond Cannabis for Treatment of Spasticity
• Image the Brain to Help Explain..MS
• Expose Bad Science
• Talk about Sex and MS
• Find Out What's new with CCSVI
• Digest Science with Coffee & Tea(m G)
• Can you Prevent MS?...the Risk factors
• Think about High Risk, High Gain Drugs
• Research MS
• Turn off the Immune Response & Avoid Side-Effects
  
• Hear about the Charcot Project....What's that?
  
• Novel trials against the Cause of MS
  

TeamG: Yule-Tide Greetings

Team G are Scattering Round the Globe
for the Festive Season

Thank You for Viewing & Commenting in 2011,
We're off until 2012.
See you in the New Year

For those in Need of a Daily Blog-Fix
You will get a trickle of Posts on AutoPilot
and the End of the Advent Calendar but,

We will probably not be answering any comments until 2012.
MouseDoc is escaping the internet &
Prof G will be misbehaving if he posts.
He has been misbehaving already!

December:Unrelated Blogger Comments

Sometimes You want to post a comment that is Unrelated to the thread.

Therefore I have Created this Spot for You
I'll move it so that it is Visible &
Start a New One Every So Often

If you want a one-one with a Neuro,
Private Consultation is the Best Place For This

ADVERTS will be DELETED!

Basic Science: Forming B cell follicles in the CNS

Peters A et al. Th17 Cells Induce Ectopic Lymphoid Follicles in Central Nervous System Tissue Inflammation. Immunity. 2011 Dec [Epub ahead of print]

Ectopic lymphoid follicles (place where antibody producing B cells are generated) are hallmarks of chronic autoimmune inflammatory diseases such as multiple sclerosis (MS), rheumatoid arthritis, Sjögren's syndrome, and myasthenia gravis. However, the effector cells and mechanisms that induce their development are unknown.

Here we showed that in experimental autoimmune encephalomyelitis (EAE), the animal model of MS, Th17 ( a subset of white blood cell that produces interleukin 17 that is thought to drive autoimmunity) cells specifically induced ectopic (In this context not in the lymphoid organs) lymphoid follicles in the central nervous system (CNS). Development of ectopic lymphoid follicles was partly dependent on the cytokine interleukin 17 (IL-17) and on the cell surface molecule Podoplanin , which was expressed on Th17 cells, but not on other effector T cell subsets. Podoplanin was also crucial for the development of secondary lymphoid structures: Podoplanin-deficient mice lacked peripheral lymph nodes and had a defect in forming normal lymphoid follicles and germinal centers in spleen and lymph node remnants. Thus, Th17 cells are uniquely endowed to induce tissue inflammation, characterized by ectopic lymphoid follicles within the target organ.

The B cell that make the antibodies are found in structures called "ectopic lymphoid follicle-like structures" in the coverings of the brain and spinal cord; the covering are called the meninges.

Grey matter (4) - Meningeal B-cell follicles in secondary progressive ...

06 Jun 2011

Multiple Sclerosis Research: Gray matter and B cells

07 Oct 2011

Multiple Sclerosis Research: Research: antibody production

30 Aug 2011

To date there is limited evidence that true B cell follicles, as opposed to B cell rich accumulations that are a normal component of EAE, occur in EAE and their role and occurrance in (progressive) MS is contentious. However some people think that they are important in driving progressive MS (so why does rixtuimab not appear to inhibit non-enhancing, progressive MS?), where many B cell rich aggregates accumulate in the sulci (foldings of the brain) of the brain, which mice lack.

Whilst it is known that some immune molecules such a lymphotoxin can influence B cell follicle formation and lymph gland development, this study implicates Th17 and a molecule called Podoplanin in this process. Podoplanin is expressed by lymphoid endothelium and importantly follicle dendritic cells in B cell follicles and so would be in a good location to influence ectopic follicles generation. Looking at the pictures presented in the paper they appear to be more B cell rich aggreates rather than true B cell follicles , but the same could be said for many of the claims in MS. These aggregates appear at the earliest stages of disease rather than something that seems to accumlate with progression. When similar studies were done by the same authours/pathologists two years ago they were only called the infiltrates aggreates and not follicles. However if this process is important to progression then this study is very interesting and this study starts to highlight a new target to inhibit this aspect and the "B cell hypothesis of progressive MS" may become more testable.

Whilst, I suspect this will turn out to be abit of EAEology (Science of EAE rather than MS) let us hope that it opens a new avenue that allows us to investigate B cell follicles....If correct then some people will need a rethink, as there is no Epstein-Barr Virus (doesn't infect mice) in sight.

There is an ongoing trial of inhibitors of Th17 cells that are recruiting in mainly Eastern Europe (NCT01051817) that would target this pathway. I suspect the result will be very interesting.

I am sure we will see and hear more on this aspect in the future as people try to recreate and explore this. Let us hope someone does this quick before Dogma sets in.

22 MS Research Day Advent Calendar

Please remember to register your interests for the Research Day, You can do this if you Click Here.

FlockMice say come to our Research Day and...

• Meet and Talk to Members of Team G
• Hear the Trials & Tribulations of MS Drugs 2012?
• Review Stem Cells Trials for 2012 and Beyond
• Talk the walk about symptomatic therapy
• Speak to Prof G and the Other Neuros
• See who the MouseDoctors Really Are
• Hear About New trials for Progressive MS..Stopping MS?
• Enjoy the Lunchtime Food
• What's Beyond Cannabis for Treatment of Spasticity
• Image the Brain to Help Explain..MS
• Expose Bad Science
• Talk about Sex and MS
• Find Out What's new with CCSVI
• Digest Science with Coffee & Tea(m G)
• Can you Prevent MS?...the Risk factors
• Think about High Risk, High Gain Drugs
• Research MS
• Turn off the Immune Response
  
• Hear about the Charcot Project...What's that?
  

Guest Post: John Prineas

In relation to a heated Thread on Pathology

You wrote: "I wonder how your Prof Prineas wouls react to the manner in which you are using his work"

So as you want posts from Guest Experts I decided to ask "How Prof Prineas would react to the manner in which his work was being used"

so I wrote

"Dear Professor Prineas
I hope that you don't mind this intrusion but the reason I am writing to you is that I ( a basic scientist. We met in Cambridge once) contribute to a research BLOG for MS patients and their families. One of the things that often occurs in comments about postings is that your previous research on the findings that early lesions of MS appear to have oligodendrocytes damage and few immune cells, is often used as support for the concept of CCSVI or a (structural) vascular deficit. I was wondering if you have a few moments to write a few (lay words) words in support of or against the above thought. I am know that our readers would really appreciate your views on this topical matter.

Hoping to Hear from You".

John Prineas is one of the World's Most Respected MS Pathologists and Sends his comments from Australia

John Prineas wrote

"I apologise for not replying sooner to your email re path studies of MS that have been used by some to support CCSVI and the possibility of a vascular structural defect in MS.

If oligodendrocyte injury with few inflammatory cells present was the only or main feature characterizing the MS lesion, perhaps such a possibility might be worth discussing.

However there is absolutely nothing else about the very complex pathology of the evolving MS lesion that even remotely could be considered to support the sort of vascular pathology that has been proposed.

The vascular pathology in MS is quite typical of inflammation as it occurs in any solid organ i.e. with respect to structural changes and upregulation of all of the mediators expected in an immune mediated disease. Also there is no experimental or naturally occurring type of vascular lesion known that can cause the extraordinarily selective and permanent loss of myelin typical of some inflammatory demyelinating diseases.

Also important is the fact that veins of all sizes in and around MS lesions look absolutely normal, or show changes only of a type seen as mentioned above in any inflammatory disease.

I must say that instead of supporting the idea that there is a structural change in veins anywhere that could contribute to lesion genesis in MS, the pathology of MS argues very strongly against such an idea.

Again , sorry for not replying sooner.

John Prineas"

Research MS

So the Mouse Doc has been diligently posting the Advent Calendar with tantalizing tidbits about the next Research Day. Yesterday Jack Frost Mouse mentioned Research.ms. What is Research.ms??

Research.ms is a project that Shift.ms and Prof G and Mouse Doc's teams are working on, to bring research to a younger audience of MSers and create a two-way conversation between the community and the researchers.

We've got research videos and articles on the Shift.ms Magazine, and we're working together to make the next Research Day more engaging and accessible for those who don't have a scientific background.

We want to get MSers' questions answered, for their ideas to inform the researchers and for researchers to be able to communicate their work in a brilliantly engaging way.

Have you watched any of the Research.ms videos (all on the Shift.ms Youtube channel)? Are you coming to the next Research Day? Let us know!

21 MS Research Day Advent Calendar

Please remember to register your interests for the Research Day, You can do this if you Click Here.

StarMouse leading the way says come to our Research Day, it's free and in Central London, and...
Today's Star is approriate to reflect the Post from a StarScientist

• Meet and Talk to Members of Team G
• Hear the Trials & Tribulations of MS Drugs 2012?
• Review Stem Cells Trials for 2012 and Beyond
• Talk the walk about symptomatic therapy
• Speak to Prof G and the Other Neuros
• See who the MouseDoctors Really Are
• Hear About New trials for Progressive MS..Stopping MS?
• Enjoy the Lunchtime Food
• What's Beyond Cannabis for Treatment of Spasticity
• Image the Brain to Help Explain..MS
• Expose Bad Science
• Talk about Sex and MS
• Find Out What's new with CCSVI
• Digest Science with the Tea(m G)
• Can you Prevent MS?...the Risk factors
• Think about High Risk, High Gain Drugs
• Research MS
• Turn Off the Immune Response to avoid side-efffects
  

MS in the Media: Scotland and Vitamin D

Prof E from Oxford wants to give Prof G a Christmas a present and has caught the media limelight with their desire to try and prevent MS by treating with vitamin D.

Prof E believes that the rates of multiple sclerosis are so "dire" in Scotland that essential foods should be fortified with vitamin D. According to the British Broadcasting Corporation (should we really believe this?) he says the Scottish government could face legal action from people who go on to develop MS in future.

Prof Ebers' efforts to convince the Scottish government and its top health advisor, Sir Harry Burns, that the whole population needs to take vitamin D has so far come to nothing .

As Scotland has the highest levels of MS and the cost of giving enough vitamin D supplementation is a few pence a person a day. Surely it must be worth it to invest in this health issue, if only to just shut Prof E and Prof G up!

Cautious parents treating MS in Children

Waldman AT, Shumski MJ, Jerrehian M, Liu GT. Parent and Medical Professional Willingness to Enroll Children in a Hypothetical Pediatric Optic Neuritis Treatment Trial. Front Neurol. 2011;2:75.

The optic neuritis treatment trial (ONTT) and subsequent studies have had a tremendous impact on the treatment and prognosis of optic neuritis and multiple sclerosis in adults. The results of these studies have been extrapolated to children; however, pediatric data are sparse.

Using the method of prospective preference assessment, the willingness of parents and medical professionals to enroll children in a hypothetical Pediatric ONTT was assessed using a mock consent form and questionnaire. A three-arm trial was proposed: (1) intravenous corticosteroids, (2) high-dose oral corticosteroids, and (3) an oral placebo. The forms were completed by 198 parents and 49 physicians.

After reviewing the hypothetical scenario, trial design, risks and benefits, and alternatives to the study, 21% of parents would enroll their children in the trial whereas 98% of medical professionals would enroll their patients. With medical professional recommendation, 43% of parents would enroll their children.

The manner in which this hypothetical trial was presented to parents, specifically with respect to the recommendation of their child's health care team, influenced a parent's willingness to participate.

Whilst steroids are often used in Optic Neuritis in adults, people can still have vision problems even if they are given steroids. As such optic neuritis (inflammation of the optic nerve) has been targeted for a number of innovative trials for new MS drugs aimed at targeting problems in relapsing remitting and progressive MS.

Prof G and Friends will be doing one of these studies in adults in the New Year. It will be interesting to see how this recruits, however it is clear that we will need to properly inform if we are to recruit a reasonable rate. It is clear that parents are cautious when issues relate to their children (or are they?).

Prof G may comment on this

Research: Memantine is Neuroprotective

Esfahani MR et al. Memantine for axonal loss of optic neuritis. Graefes Arch Clin Exp Ophthalmol 2011 Dec 16. [Epub ahead of print]

BACKGROUND: To determine the effect of memantine on axonal loss and visual function during the course of optic neuritis (ON).

METHODS: Sixty optic neuritis patients in a single-center, institutional setting were randomly assigned to the memantine or placebo groups. Patients with first attack of acute unilateral optic neuritis, with visual symptoms of 8 days duration or less were enrolled in this trial.

No patient had known multiple sclerosis, and none had taken immunomodulatory agent prior to or at the time of presentation. For all patients, the following characteristics were recorded and compared at initial presentation and 3 months afterward: visual acuity (sight), retinal nerve fiber layer thickness (measure of nerve (retinal ganglion cell) content in the retina, that can reflect changes in the optic nerve btween the eye and the brain), visual field parameters, visual evoked potential (measure of electrical signalling between eye and brain and shows nerve loss and demyelination), and contrast sensitivity (MSers have more problem seeing grey eye charts than black eye charts).

RESULTS: Fifty-four patients completed the 3-month follow up. There were no significant differences between the placebo and memantine groups for any of the characteristics at initial presentation. After 3 months, the only statistically significant difference between the two groups was in RNFL thickness. Memantine group subjects had higher thickness in nasal (P = 0.01), superior (P = 0.006), inferior (P = 0.01) quadrants and average (P = 0.01). However, temporal quadrant thickness was not different between two groups (P = 0.35). (Back of the eye [Fundus) is divided into quarters of a diagonal cross (nasal=towards nose temporal towards the temple/ears. Superior top and inferior bottom. The temporal and nasal regions have less nerve content than superior and inferior quadrants)

Nerve fibre layer is the top red layer

CONCLUSION: Memantine was effective in reduction of RNFL thinning, although this structural difference was not associated with improved visual function

Memantine (marketed under a variety of trade names) is an glutamate (excitory neurotransmitter) receptor antagonist that is used in Alzheimers Disease, where it has a small positive effect on cognition. To date there is no evidence for an influence of memantine on memory in clinical trials in MS, although it may have some influence as a symptom control in conditions such as nystagmus.

Whilst it is perhaps disappointing that there was no obvious clinical improvement, this study is interesting because it supports some of our experimental findings for a neuroprotective (as RNFL thickness is correlated with nerve content) potential for memantine and importantly supports the thought that studies in optic neuritis may help to identify neuroprotective compounds that may useful for (progressive) MSers. So good news for Prof G & Friends (See comments on todays other research post) and the EyeDoctor.

20 MS Research Day Advent calandar

Please remember to register your interests for the Research Day, You can do this if you Click Here.

JackFrost Mouse says come to our Research Day and...

• Meet and Talk to Members of Team G
• Hear the Trials & Tribulations of MS Drugs 2012?
• Review Stem Cells Trials for 2012 and Beyond
• Talk the walk about symptomatic therapy
• Speak to Prof G and the Other Neuros
• See who the MouseDoctors Really Are
• Hear About New trials for Progressive MS..Stopping MS?
• Enjoy the Lunchtime Food
• What's Beyond Cannabis for Treatment of Spasticity
• Image the Brain to Help Explain..MS
• Expose Bad Science
• Talk about Sex and MS
• Find Out What's new with CCSVI
• Digest Science with Coffee & Tea(m G)
• Can you Prevent MS?...the Risk factors
• Think about High Risk, High Gain Drugs
• Research MS

Health Tourism: It is Not always Safe

Some of you have been commenting on interesting stuff such as the New York Stem Stem Foundation and so you know there are lots of others such Harvard Stem Cell Institute the Institute for Stem cell Research as the UK Stem Cell Foundation etc, etc.

However, whilst stem cells do offer massive potential their most challenging use will be in the repair of the nervous system.Therefore it is unrealistic to expect miracles too quickly, as there are many hurdles to climb.

In the New Year maybe we can expand on Stem Cell Research, but it is a field that has huge public interest...which can lead to alot of "in my opinion" unhelpful media spin. This is also not always helped by claims of researchers about the significance of the studies.

Whilst there has been progress in stem cell research there are many unknowns and it is our opinion that people recieving stem cell treatments should do so as part of registered clinical trials in reputatble places, until they are shown to work and be safe.

Stem cell is a a term used that can describe a number of things and whilst some stem cells have the ability to re-create every one of the individual cell types in the body. However, without understanding the biology of these stem cells they can sometimes become cancers or act as a buzz word on which to hang some unproven treatments/procedures by some unscrupulous individuals, who will often locate themselves to places where regulations controlling health care are lax. With this in mind I report on this new case study

Alderazi YJ, Coons SW, Chapman K Catastrophic Demyelinating Encephalomyelitis After Intrathecal and Intravenous Stem Cell Transplantation in a Patient With Multiple Sclerosis. J Child Neurol. 2011 Dec [Epub ahead of print]

Stem cell transplantation is an investigational therapy for multiple sclerosis. This study describe a case of catastrophic demyelinating encephalomyelitis following stem cell transplantation in a 17-year-old girl. Nine months after an initial diagnosis of multiple sclerosis, she underwent stem cell transplantation in Costa Rica.

Subsequently, she deteriorated and was transported back to the United States with headache and vomiting progressing to quadriparesis (movement of all limbs affected), locked-in syndrome (awake/aware but unable to communicate) and superimposed encephalopathy (Damge to brain) Magnetic resonance imaging and brain biopsy were consistent with fulminant demyelinating encephalomyelitis (EAE in human) with MRI enhancing lesions, with white blood cells in the cerebrospinal fluid. The protracted illness required tracheostomy and gastrostomy. After methyleprednisone, intravenous immunoglobulin, and cyclophosphamide, she improved during 2.5 months to an ambulatory, functionally independent state. Subsequently, typical less severe multiple sclerosis relapses occurred.

This case demonstrates that stem cell transplantation may provoke life-threatening encephalomyelitis in patients with multiple sclerosis. This highlights the need to restrict transplantation to trials with appropriate safety controls.

Although it is difficult to know what triggered the attack and whether it was the stem cells and/or the procedure that caused the encephalomyetitis. As the cells were put in intrathecally (directly into the brain) there is a reasonable chance that they were causally related. It appears that unprorven procedures can go wrong with dramatic consequences and shows the dangers of travel to countires for reasons of health tourism.

This highlights the need to restrict transplantation to trials with appropriate safety controls. Whilst we all want stem cell therapy to work invariably these rogue treatments usually lack real science that provides a rationale for them to work.

Prof G may want to add to this.