Thank you Christopher  for the detailed answer. And I do appreciate your suggestions on giving a background to the question posted here. I probably need to be more specific on the kind of axonal degeneration that I am referring to, and its association with the deficits of specific neurocognitive functions.

I do agree with you that, most of the time, patients with mild TBI are not necessarily followed up, let alone being subjected to further assessment or medical evaluation, especially when you have a normal CT finding. Most of the time, they are discharged at the ED, without being seen by the neurosurgeons.  This is due to the assumption that a normal CT means no injury. Such assumption however have been proven to be erroneous as symptoms and outcomes in the mTBI patients are quite heterogenous and unpredictable. While many mild TBI patients report lesser impairments and symptoms after an average of 3-6 months post trauma, a subset of these patients continue to experience various aspects post concussive syndrome and cognitive deficits for much longer periods, These symptoms in the past have been thought to be of psychogenic in origin. This flawed assumption is again slowly being eroded/ or proven wrong by various advanced imaging studies (DTI to be specific) in the recent time (Croall et al, 2014, Mayer et al 2010, Yuh et al, 2013, Bazarian et al, 2007, to name a few). Microstructural changes of the white matter (WM) have been widely associated with the deficits seen both functionally or cognitively. 

Just as you stated and what I do believe, the demyelination of the axons are not necessarily seen acutely due to the various recovery/ healing parameters (hence the scarring).  The demyelinating process therefore should kick in much later, especially in mild TBI. Similar observation were also noted by Kossman, Ragupathi & Maas (2012) in their book. They noted that there were no loss/ reduction in myelin basic proteins in mTBI at 1 week post trauma, despite the presence of axonal swelling and diminished axonal conduction.

Vigneswaran, in regard to reported experience of prolonged cognitive complaints, are you referring to "the miserable minority"?  This term was proposed by Ruff and colleagues back in the mid-90's, though it was later disproven. Ruff and colleagues proposed that there exist a sub-set of patients who reported ongoing cognitive symptoms far past what is to be expected in cases of concussion. These patients were the ones who they believed still suffered from cognitive symptoms directly related to the concussion. Subsequent research showed that the subjective reports of cognitive complaints were not representative of actual cognitive deficiencies due to the concussion. Alternative factors such as depression, secondary gain factors, and similar should be considered instead.

Rohling, M.L., Larrabee, G.J., Millis, S.R. (2012). The “Miserable Minority” following mild traumatic brain injury: Who are they and do meta-analyses hide them? The Clinical Neuropsychologist. 26(2):197-213.

general definition mTBI:

http://www.medicalnewstoday.com/articles/158876.php

Some experts define concussion as a head injury with temporary loss of brain function, which can cause cognitive, physical and emotional symptoms. Concussion may also be defined as an injury to the brain generally caused by a jolt or blow to the head - in the majority of cases the individual does not lose consciousness.

Specific definition:

http://www.internationalbrain.org/mild-traumatic-brain-injuries-were-prev-undiagnosable-therefore-treatment-uncertain-and-damages/

The American Congress of Rehabilitation Medicine defines a mild traumatic brain injury as a patient “who has had a traumatically induced physiological disruption of brain function, as manifested by at least one of the following:

any period of loss of consciousness;

any loss of memory for events immediately before or after the accident;

any alteration in mental state at the time of the accident (eg, feeling dazed, disoriented, or confused); and

focal neurological deficit(s) that may or may not be transient;

but where the severity of the injury does not exceed the following:

loss of consciousness approximately 30 minutes or less;

after 30 minutes, an initial Glasgow Coma Scale (GCS) of 13-15; and

post-traumatic amnesia (PTA) not greater than 24 hours.”[3]

NOT SURE BUT IT MAY NOT BE PURE DEMYELINATION, BUT A COMBINATION OF injury to MYELIN AND AXONAL.

DTI/PET/SPECT from Imaging, and BIOMARKERS in serum and CSF have been found to prognosticate:

http://www.archives-pmr.org/article/S0003-9993(02)00243-5/abstract

http://informahealthcare.com/doi/abs/10.1080/02699050801888816

More terminologies here, but could not find DE-MYELINATION!

Although this article says CHRONIC TRAUMATIC ENCEPHALOPATHY can resemble ALS or other neuro-degenerative process:

http://www.bu.edu/cte/files/2012/05/Baugh_Chronic-Traumatic-Encephalopathy_2012.pdf

Histopathologically glial scar would involve, astrocytes, microglia, endothelium, fibroblasts. Although this scar helps with integrity of the axons, it can block axonal sprouting to occur the desired direction...

http://en.wikipedia.org/wiki/Glial_scar

Dear Timothy Shea,

The "miserable minority" are those patients with mild traumatic brain injury who continue to experience prolonged cognitive deficits even after months and years, way beyond the average cutoffs (which is about 3-6 months post trauma).

You were absolutely right that one should consider preexisting comorbidities/(maybe even age) factors and as well as neurobehavioral/ neuropsychiatric condition arising from the trauma that could adversely influence the cognitive performance of these patients. Having said that, there are many studies (Ref 1-5) that has proven that even when all these factors are accounted for, and removed from the analysis, these individuals continue to exhibit deficits in their neurocognitive functions. So what then would best explain these manifesting derangements/ impairments ?

One possible explanation may lie in the structural changes. Patients with visible injuries -complicated mild TBI (radiologically visible lesions  i.e hematoma, contusion, edema, etc) and the corresponding functional and cognitive deficits are findings that are widely accepted by scientific community. How about the wider group of mild TBI patients whose radiological findings are usually negative and discharged from the ED without even being seen by neurosurgeons and without any subsequent follow-ups? Does normal CT/ MRI in the acute stage means there isn't any injury to start with with?

Many advances imaging protocols have proven otherwise. Diffusion Tensor Imaging (DTI) studies (reference to which I will give at the end of this reply) for example are able to pick up changes to the microstructure like the axons or the white matter tracts which are usually missed by the CT/ conventional MRI sequences. Could these structural anomalies/injuries then  explain the neurocognitive impairments experienced by the "miserable minority"? I guess the answer would be affirmative (see ref 5-8). With all these new evidences of microstructural abnormalities (even at the earliest hours post trauma), we can no longer reject the patient experiences as purely psychogenic in origin, ensuring we do our due diligence. 

1.  Stapert et al 2006 http://arnop.unimaas.nl/show.cgi?fid=4933

2. Silver et al, 2009 http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2009.08111676

3. Bigler, 2013a http://journal.frontiersin.org/article/10.3389/fnhum.2013.00395/abstract

4. Le et al 2008 http://online.liebertpub.com/doi/abs/10.1089/neu.2008.0566

5.Spencer et al 2010 http://online.liebertpub.com/doi/abs/10.1089/neu.2008.0566

6. Shenton et al 2012 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3803157/

7. Bigler , 2013b http://www.mccauslandcenter.sc.edu/CRNL/sw/tbi/7/2013_BiglerA.pdf

8. Mayor et al, 2010 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2830922/

9. Irimia et al 2012 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757727/

10. Croall et al, 2014 http://www.neurology.org/content/early/2014/07/16/WNL.0000000000000666

11. Lo et al, 2009 http://www.ncbi.nlm.nih.gov/pubmed/19346863

Chandramouli Balasubramaniam, if I understood you correctly , I believe you do concur that demyelination does not start in the early stages (acute) of mild neurotrauma. It is usually the other processes that kicks in including increased vascular permeability, edema, derangement of blood brain barrier homeostasis, neuroinflammation (astrogliosis/ microgliosis), glial scarring.  Did I get you right?

Besides Kossman et al, I believe there are few others who have suggested that the demyelinating process in mild TBI does not start at least until some later stages (Ref 1-4).

In our current work, we found similar results (hopefully accepted for publication in coming months). Through cutting age DTI post scan processing methods (combination of ROI and TBSS), we found interesting patterns of change in the DTI parameters which are better explained by vasogenic and cytotoxic edema and as well as astrogliosis than the demyelination (the scans were acquired at 10 hours post trauma on average).

1. Creed et al 2011 https://www.researchgate.net/publication/49815588_Concussive_brain_trauma_in_the_mouse_results_in_acute_cognitive_deficits_and_sustained_impairment_of_axonal_function

2. Staal and Vickers, 2011 http://www.ncbi.nlm.nih.gov/pubmed/21235329

3. Bramlett and Dietrich, 2002 http://www.ncbi.nlm.nih.gov/pubmed/12012093

4. Liu et al, 2006 http://www.ncbi.nlm.nih.gov/pubmed/16893416

Article Concussive Brain Trauma in the Mouse Results in Acute Cognit...

I am not sure if injury to myelin is same as eating up of myelin by immune cells that have gone "mad" against their own body proteins! because traditionally de-myelination is used for a systemic (blood borne) process and not a central or peripheral nervous SYSTEM  process (mTBI) !

Injury to myelin doesn't equate demyelination. The assertion here is that the injury to the axons or the myelin sheath can trigger off demyelinating process. Inflammatory process or ischemic events in traumatic brain injury is not a new concepts being discussed. Both events  are known to lead to degeneration of the white matter microstructures.

this article does not assert much on the association of MS and head injury........

We found no significant association between head injury and MS overall, or in patients with severe injury (as estimated by the proxy of length of hospital stay), or at any time interval between injury and MS. Our findings add weight to the evidence that head trauma does not contribute to the aetiology or precipitation of MS.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2077695/

great discussion !

Well, Chandramouli. I am pretty sure that you are aware of the fact that demyelination ≠ MS., although the former is the trademark of MS and is often wrongly equated as MS. The term in itself is generic and is in reference to the loss of normal myelin surrounding the axons in CNS. There are few well known cause factors to demyelination besides inflammatory process (again inflammation is not limited to MS, and is also seen in TBI). Among the other known factors to cause or lead to demyelination are : infective disease (PML, HIV encephalitis ), toxic (chemotherapy, central pontine myelinolysis), metabolic/genetic (leukodystrophies) and ischemia.

TALKING OF ISCHEMIC DEMYELINATION....

http://www.ncbi.nlm.nih.gov/pubmed/16687062

A particularly relevant clinical model for white matter disease is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) which combines the potential components of small vessel disease, resulting in progressive neurological deficit, with a common association with migraine which can also be associated with white matter lesions.

However, the most common pathogenic factor associated with the microangiopathy, which appears to be at the heart of ischemic demyelination, continues to be hypertension.

How well we are able to tie in the various pathological mechanisms associated with this end organ damage of the brain will determine how well we can arrive at effective interventions for a common contributor to neurological deficits in the elderly.