Friday, 18 April 2014

Hot microglia: innate inflammation is a part of progressive MS

How hot, is hot, when it comes to microglia in progressive MS? #MSBlog #MSResearch

"Hot microglia the new buzz word in progressive MS. It is hypothesised by a large number of us in the field is that these cells are driving the progressive phase of the disease. The activated or hot mricoglia produce a range of factors that damage axons and neurones. There is now a race on to develop and test drugs that switch these cells off. Hot microglia are not unique to MS and may play a role in other neurodegenerative diseases, for example Alzheimer's disease, therefore there are potentially rich pickings for drugs that work in one disease. Have we found drugs that target these cells? Literally hundreds; laquinimod is the one that is showing the most promise in MS. Interestingly, there is some evidence that BG12, or dimethyl fumarate, may do the same. Sodium channel blocker also down regulate hot microglia. This group of drugs includes oxcarbazepine the drug we are testing in the PROXIMUS trial."

PK11195 imaging in MS

"The study below, using an imaging technique to detect hot microglia, shows what a problem this is in SPMS. This imaging technique will be very useful to test potential therapeutic compounds that target microglia. Now that we have a tool box and many targets let's hope that these insights will lead to a treatment for progressive MS."

Epub: Rissanen et al. In Vivo Detection of Diffuse Inflammation in Secondary Progressive Multiple Sclerosis Using PET Imaging and the Radioligand 11C-PK11195. J Nucl Med. 2014 Apr 7.

BACKGROUND: SPMSers lack efficient medication to slow down the progression of their disease. PET* imaging holds promise as a method to study, at the molecular level and in vivo, the central nervous system pathology of SPMS. 

*PET = positron emission tomography; PET is a nuclear medicine, functional imaging technique that produces a 3D image of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide(tracer), which is introduced into the body on a biologically active molecule. Three-dimensional images of tracer concentration within the body are then constructed by computer analysis. 

PET might thus help to elucidate potential therapeutic targets and be useful as an imaging biomarker in future treatment trials of progressive MS. The objective of this study was to evaluate whether translocator protein (TSPO)** imaging could be used to visualize the diffuse inflammation located in the periplaque area and in the normal-appearing white matter (NAWM) in the brains of patients with SPMS.

**Translocator protein (TSPO); TSPO is a protein found on the outer mitochondrial membrane. It was first described as peripheral benzodiazepine receptor (PBR), a secondary binding site for diazepam, but subsequent research has found the receptor to be expressed throughout the body and brain. It is upregulated in microglial cells and macrophages in the brain of MSers.

METHODS: This was an imaging study using MR imaging and PET with 11C-PK11195 binding to TSPO, which is expressed in activated, but not in resting, microglia. Ten SPMSers with a mean expanded disability status scale score of 6.3 (SD, 1.5) and eight age-matched healthy controls were studied. The imaging was performed using High-Resolution Research Tomograph PET and 1.5-T MR imaging scanners. Microglial activation was evaluated as the distribution volume ratio (DVR) of 11C-PK11195 from dynamic PET images. DVR estimations were performed with special interest in NAWM and gray matter using region-of-interest and parametric image-based approaches.

RESULTS: The DVR of 11C-PK11195 was significantly increased in the periventricular and total NAWM (P = 0.016 and P < 0.001, respectively) and in the thalamic ROIs (P = 0.027) of SPMSers, compared with the control group. Similarly, parametric image analysis showed widespread increases of 11C-PK11195 in the white matter of SPMSers, compared with healthy controls. Increased perilesional TSPO uptake was present in 57% of the chronic T1 lesions in MR imaging.

CONCLUSION: The finding of increased 11C-PK11195 binding in the NAWM of SPMSers is in line with the neuropathologic demonstration that activated microglial cells are the source of diffuse NAWM inflammation. Evaluating microglial activation with TSPO-binding PET ligands provides a unique tool to assess diffuse brain inflammation and perilesional activity in progressive multiple sclerosis in vivo.

Suppressor CD19 B cells

de Andrés C, Tejera-Alhambra M, Alonso B, Valor L, Teijeiro R, Ramos-Medina R, Mateos D, Faure F, Sánchez-Ramón S. New regulatory CD19+, CD25+ B-cell subset in clinically isolated syndrome and multiple sclerosis relapse. Changes after glucocorticoids. J Neuroimmunol. 2014 Feb 14. pii: S0165-5728(14)00034-4. doi: 10.1016/j.jneuroim.2014.02.003. [Epub ahead of print]

In multiple sclerosis (MS), the immune damage to the central nervous system results from the net balance between self-reactive and immunoregulatory cells, among other factors. We identified novel perforin-expressing regulatory B-cells (BReg) in patients with clinically isolated syndrome, significantly enriched within the cerebrospinal fluid when compared to peripheral blood, of memory B cell phenotype (CD19+CD25+, CD19+CD25+FoxP3+ and CD19+FoxP3+, p=0.007, p=0.06 and p=0.03, respectively). These BReg subsets were also higher in relapsing-remitting MS during relapse symptoms than in non-clinically active MS patients. Suppressive effects by CD19+CD25+hi BReg on CD4+ T cell proliferation seem to be mediated at least in part by perforin/granzyme pathway. To our knowledge, this is the first report that shows cytolytic perforin/granzyme granule storage in B cells; the interesting point is its involvement on BReg cell immunosuppressive mechanisms, similarly to that in TReg cells. Our data may extend the understanding of pathophysiological processes in MS immunoregulation.

Depleting CD19 antibodies are on the table for MS, what will happen? The same as depleting CD20 B cells, or will it be the disaster of atacicept, I doubt it as the studies are in full swing so the balance will be good I expect.

Clinic Speak: what is the risk of you not being treated with a DMT?

What is benign MS? Can we call it? #ClinicSpeak #MSBlog #MSResearch

"The main argument against taking a population, rather than an individual, approach to treating all MSers with highly-active treatment early on is that we would over treating MSers destined to have benign MS. In other words exposing a large number of people, who are destined to have benign MS, to ‘unacceptable risks’. The unacceptable risks is the big issue that drives this debate and is why regulatory authorities, particularly in Europe and recently in the US, have put their foot down and have rejected drugs or severely curtailed their use by licensing them as second or third-line agents.

These unacceptable risks of highly-effective treatments need to be weighed against the risks of not treating MS. The following infographic, which I developed for ECTRIMS last year, tries to capture the consequences of untreated MS. What it does not capture very well is the ‘time is brain’ concept. In other words once damage has occurred to the brain and spinal cord we can’t go backwards and repair that damage; at least not yet. What can happen early on in the course of MS is that the undamaged parts of the nervous system can compensate for the damaged areas and allow functional recovery. This ability for compensatory recovery is time and age dependent; hence the term ‘window of opportunity’.

I try not to use the term ‘benign MS’. Benign MS is a retrospective diagnosis that can only be made many years into the disease and even then it is a hard call to make. For example, our current definition of benign MS is someone who has the disease for 15 years and has no disability, i.e. an EDSS of 3.0 or less. An EDSS of 3.0 implies the presence of neurological impairments (subtle deficits detected on neurological examination) and not overt disability. In other words someone with an EDSS of 3.0 would look normal to the untrained eye; the person in question would have to be examined by a neurologist to detect the neurological dysfunction or interrogated using detailed questionnaires to detect subtle problems. What you have to remember is that you have to pass through EDSS 3.0 to get to EDSS 4.0 and beyond. In natural history studies the majority of MSers who get to EDSS 4.0 become secondary progressive.

When you interrogate MSers with benign disease as defined above they have hidden symptoms. Approximately half of MSers with so called benign MS have cognitive impairment, depression or fatigue. Is this really benign MS? The problem with the field has is that we view MS through EDSS spectacles and we don’t take into account the hidden symptoms that can be very disabling.

In populations of MSers followed in hospital clinics about 30% fulfil the 15 year definition of having benign MS. However, if you follow this population for a further 10 years the figure drops to 15%, and at 30 years only 1 in 20 or 5% of MSers have benign disease. A recent long term follow-up of benign MSers in Gothenburg, Sweden, showed that 50% of MSers with benign MS at 40 years did not have benign MS at 50 years after the onset of the disease. The bottom line is benign MS is a moving target and depends on how you define it.

Hospital studies underestimate the true prevalence of benign MS, because MSers without problems tend to drop-out of long-term follow-up. In community studies the prevalence of benign MS is in the order of 45% at 15 years. This more optimistic community figure of having benign MS does not help you if you have regular follow-up at a hospital. The latter implies that you have more active MS or MS-related problems requiring regular follow-up by a neurological team.

A treatment strategy that I support is to convert every MSers clinical course to that of someone with benign MS, which is the aim of adopting the early effective treatment paradigm of treating-2-target of NEDA (no evidence of disease activity).

Can you identify MSers who are more likely to end-up with benign MS? The short answer is no. We do try and pigeonhole MSers into prognostic groups using the following favourable prognostic factors, but more often than not we get it wrong.
  1. Younger age at onset
  2. Female sex
  3. Initial presentation being isolated sensory symptoms or optic neuritis
  4. Complete recovery from first attack
  5. Long interval between the first and second relapse (>2 years)
  6. No disability after 5 years
  7. Normal MRI or low lesion load at baseline
  8. Negative CSF (no oligoclonal IgG bands)
What this list does not address is good or bad luck. What causes a focal MS lesion to present with symptoms is whether or not it is located in an eloquent site, for example the optic nerve (visual loss), brain stem (double-vision or unsteadiness of gait) or the spinal cord (sensory loss or limb weakness). Lesions that occur in ineloquent sites don’t cause overt symptoms because they typically affect cognition and ability of the nervous system to compensate for these lesions means you simply cope with the lesions. However, we know that all lesions cause damage to a greater or lesser extent - this is based on pathological and imaging studies in MSers. If you accumulate enough of these so called asymptomatic lesions you reduce your brain’s reserve capacity and are more likely to run into trouble in the future. Therefore someone who’s 20th lesion causes their first clinical attack will have acquired much more damage than someone who’s 2nd lesion caused their first clinical attack; the former has simply had the disease longer. In my opinion the person whose second lesion causes a clinical attack is lucky in that they presented before the next 18 lesions could cause irreversible damage. Hence the MSers with 2 lesions is more likely to do well that the person with 20 lesions. What I am trying to say is that having a low lesion load should be viewed as good news as it allows you a greater window of opportunity to prevent damage. In contrast the MSer who presents with a high lesion load has a narrower window as they have lost reserve capacity.

Similarly, being young means you will have the disease slightly longer before you become disabled compared to an older person. However, the younger person will still reach disability milestones at a younger age than MSers presenting at an older age. Because of this age of onset is not really a prognostic factor.

I prefer to focus on defining whether or not your disease is active. This can be done clinically, i.e. have you had a recent relapse in the last 12 or 24 months, or has your lesion load on MRI increased over the same period. An easier metric is the presence of gadolinium-enhancing lesions on a single scan; this is the MRI equivalent of a relapse. Enhancement tells us that the lesion is actively inflamed and that the inflammation is relatively new, usually with the last 2-4 weeks. Having active disease indicates that you are more likely to respond to DMTs. MSers with inactive disease are less likely to respond, but need to monitored closely so that if their disease flares-up they can be treated.

I don’t differentiate between types of lesions; i.e. whether or not the lesion causes severe or mild attacks, or no attacks at all (asymptomatic lesions). What causes a lesions to cause symptoms is it location and size; a tiny strategic lesion is a specific pathway can cause symptoms whereas a large lesion a silent area may go unnoticed. What matters to me, and hopefully to you, is whether or not you have MS lesions coming and going, either new or enlarging old lesions. The aim of our treatment is to prevent this from happening to protect your brain and spinal cord from further damage so that we can delay or prevent the onset of progressive MS.

The other treatment aim that is rarely discussed is ‘brain protection’; to prevent brain damage so that you have enough reserve capacity to allow you to age normally. The concept of reserve brain capacity has emerged from the Alzheimer’s and dementia fields; increased brain reserve protects you from the ravages of ageing. Why shouldn’t MSers expect to age normally?

With regard to NEDA; at the moment we define it using clinical and standard MRI metrics. These include relapses, disease progression, new and enlarging T2 (bright lesions) and new enhancing lesions. I suspect the current NEDA metric is only recording the tip of the MS disease activity iceberg and we will need to adapt it as new technologies become available. For example, gray matter lesions that are not visible on standard MRI scans, brain atrophy and spinal fluid neurofilament levels. Some of us also support including a patient-related outcome measure or PROM and cognitive testing in the definition. All of these are not ready for prime time as they need to be validated and tested in prospective studies. What is important is that we are clearly moving to individualised treatment with close monitoring to define outcomes and treatment targets. This is something rheumatologists did decades ago in rheumatoid arthritis. Treat-2-target is something we have stolen from them. Hopefully, we will be as successful as rheumatologists when it comes to treating MS. The big difference between them and us is that if their treatments fail they can always ask their orthopaedic colleagues to replace the joint in question. Unfortunately, as neurologists we don’t have this luxury; we simply can’t replace your brain and spinal cord nor can we fix them at present. That is why having the option of offering early highly-effective treatment with the hope of preventing damage is so important. Prevention is really our only strategy at present. You can ignore this window of opportunity at your own peril. Please don’t forget time is brain."

CoI: multiple