An inflammatory process (neuroinflammation) almost certainly plays a major role in the development of many neurological diseases. Andrew Lloyd has pointed out that the symptoms in chronic fatigue syndrome (and fibromyalgia) are “brain symptoms”‘; i.e. they are flu-like symptoms produced by the brain when we get ill. That suggests, of course, that neuroinflammatory processes are at work.
The search for the inflammatory basis of fibromyalgia never really got off first base, but the search for the inflammatory component that many felt must be in chronic fatigue syndrome (ME/CFS), has never died. The tie-in between the infectious onset that many people experience and the flu-like symptoms that have dogged many for decades has simply been too strong to give up on the idea that the immune system plays a huge role in ME/CFS.
Now, technology is giving researchers a deeper look at inflammation. The Lipkin/Hornig cytokine study was comprehensive enough and large enough to uncover a strong inflammatory component occurring earlier in the disease. The Stanford ME/CFS Initiative will soon be publishing gene expression results that strongly implicate inflammation. In Jarred Younger’s intense Good Day/Bad Day study, leptin – an immune factor able to sensitize the microglia in the brain – jumped to the front of the line.
The ability to finally uncover strong evidence of inflammation in the body is gratifying, but it may pale next to what researchers will find when they get into the most heavily guarded area of the body – the brain.
The ability to “see’ the immune activity in the brain is coming and it’s coming fast. The barriers to accessing the brain are falling.
Neuroinflammation in Chronic Fatigue Syndrome and Fibromyalgia
Thus far one neuroinflammation ME/CFS study has been done. The small Nakatomi study found evidence of neuroinflammation in the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons regions of the brain. The fact that the degree of the widespread neuroinflammation was strongly correlated with the severity of the fatigue, pain, cognitive problems and depression found in the ME/CFS group was encouraging.
The areas seemed to fit what we know about ME/CFS. One inflamed area regulates the reticular activating system which determines how awake or aroused one is. Several others are involved in pain sensitivity, cognitive impairment and mood.
Nakatomi proposed two possible causes for the neuroinflammation.
- (1) damage to one of part of brain is causing other parts of the brain to overwork leading to N-methyl-D-aspartate receptor overload and the production of factors that produce inflammation
- (2) the immune response to an initial infection remains active
Other causes are surely possible. Younger has proposed that infection, stress, diet, trauma, etc. plus other factors have caused the microglial cells/astrocytes to become hyperactive to stimulus.
Assessing Inflammation in the Brain
The sophisticated brain imaging techniques that have been developed can do many things. Until recently, though, they’ve never been aimed at assessing the level of immune activity in the brain.
The recognition that the microglia and the inflammation they cause may play a major role in many neurological disorders changed that. We now know that the microglial cells produce dozens of immune factors and other mediators that can produce pain, fatigue, sleeplessness, mood changes and other symptoms.
That understanding prompted the development – years in the making now – of scanning techniques that can assess microglial activity/inflammation in the brain. Those scanning techniques are coming to fruition now. For neurologists 2015 may be the year they finally start getting a good, close look at the levels of inflammation in the brain.
The Race Is On
This is a competitive area of research. Whoever develops the best scanning technique is going to not only get big chops in the research community, but will, if they’re allied with a company, see the cash rolling in. Being able to better understand the biggies, or track treatment efficacy in the biggies, like Multiple Sclerosis (MS), Alzheimer’s, Parkinson’s, etc. is a big deal. That means the race is on. Dozens of competitors are involved.
The remarkable variety of techniques being developed is all to the better. Neuroinflammation is a complex topic that effects numerous aspects of the brain. It appears that someone, somewhere is attempting to image virtually every aspect of the brain – from immune cells to oxidative stress to neuron health – involved in neuroinflammation.
The rich broth of techniques that will result should allow researchers to better analyze and understand neuroinflammation. That’s very good news for anyone with a neurological disorder. This is what it looks like when the research community gets excited about a topic.
A Dec. 2014 review article (possibly already outdated) looked at and assessed the various technologies emerging. Sit back and check out the rather wild world of neuroinflammation imaging.
Imaging Neuroinflammation – from Bench to Bedside Benjamin Pulli and John W Chen* Center for Systems Biology and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, USA. J Clin Cell Immunol. 2014 ; 5: . doi:10.4172/2155-9899.1000226
Imaging Inflammation in the Brain
Attempts have been made to adapt major scanning techniques: MRI, positron emission tomography (PET), single photon emission computed tomography (SPECT) and optical imaging to assess inflammation in the brain.
Targeting Immune Cells and Immune Activity
Adhesion molecules such as VCAM-1 and CD62 open the doors, so to speak, that allow immune cells to get into inflamed area. Studies suggest that magnetic resonance (MR) techniques that track adhesion molecule activity are subtle enough to detect small levels of neuroinflammation. Another technique tracks the levels of myeloperoxidase – a proinflammatory enzyme secreted by neutrophils and monocytes in inflamed tissues. Another approach is looking at COX-1 and 2 enzyme levels. These are enzymes that convert arachidonic acid to prostaglandins – a major player in inflammation.
Markers of Neuronal Damage
Matrix metalloproteinases (MMP’s) are substances that damage tissues in response to microglial and other immune activity. They’re associated with excitotoxicity, nerve damage and gaps in the blood-brain barrier. At least four different markers of MMP activity are being assessed.
Translocator protein (TSPO)
Translocator Proteins have been the most extensively studied neuroinflammation imaging technique. This technique targets a receptor that appears on activated microglial and astrocyte cells. Watanable used the PET ligand 11C-PK11195 to find evidence of neuroinflammation in ME/CFS.
In one small study a TSPO scan picked up increased microglial activity 17 years after a group of patients had experienced a traumatic brain injury. In multiple sclerosis this technique picked up evidence of increased microglial activation in areas of the brain that appeared normal otherwise. It’s been used to assess neuroinflammation in a variety of animal models and in humans.
The 11C-PK11195 ligand that was first developed, however, had several drawbacks. It’s not particularly specific (precise) and has a poor signal-to-noise ratio and its very short half-life (20 minutes) restricts its use.
Second generation TSPO markers are more precise. One called 11C-DAA1106 appears to be five times more specific than 11C-PK11195. Two others (11C-CLINME, PBR111) appear to have higher binding potential and at the time the article was written were undergoing tests in humans. At least two other ligands for the TSPO are being tested.
Other markers of neuroinflammation that have been developed include scanning for cannabinoid receptor, radioactively labeling white blood cells, tagging cells with iron oxide, tracking cells that take in iron oxide, fluorine 19F-MR imaging and imaging specific immune cells. Some of thse techniques have received multiple studies and are viable alternatives.
MRI’s have been used to identify areas where inflammation has broken down the myelin covering of the nerves. This technique, however, has been hampered by low specificity. Probes are being developed now though, that are much more precise. At least eight different compounds have been developed for use with MR, PET or FRI scans.
Tracking Neuronal Death
The most severe consequences of neuroinflammation are lots of dead neurons. Inevitable disease progression and/or irreversible damage appears to be associated with the death of neurons in MS and stroke. Techniques to scan seven different factors associated with neuronal death (receptors, proteins) are being tested.
It’s not clear what the future will bring but it will certainly bring many more ways of assessing and ultimately understanding the immune status of the brain. Whether they are directly tracking micoglial and astrocyte activity, neuron damage or death, oxidative stress, or accumulations of immune cells or cytokines, or other factors, methods are being developed that will tell us much.
Already researchers recognize microglial activation, and more subtle forms of damage can take place in parts of the brain far removed from the center of damage. (A recent autopsy study of traumatic brain injury patients found that virtually their entire brains had been affected.) Expect many more revelations as this technology matures.
In the last month studies using new PET imaging techniques examining people with epilepsy, Alzheimer’s, schizophrenia and dementia have been published and the efficacy of three new inflammation tracers have been reported on.
Given the strong sense among many that ME/CFS and FM are neuroinflammatory disorders the development of this new technology is good news indeed. At least three neuroinflammation studies (Nakatomi followup, Andrew Lloyd, Jarred Younger) are underway in ME/CFS.