Research: Axonal Loss and disability

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It is not possible to determine exactly how many nerves can be lost before their absence is noted, but this will depend on which areas of the CNS are affected. For MS we can only link precise nerve content to disability at post-mortem so it hard to say. However imaging studies suggest that there may be loss of 1% a year compared to 0.1% with normal aging. 

Bjartmar C, Kidd G, Mörk S, Rudick R, Trapp BD. Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol. 2000;48:893-901.

Axonal
degeneration has been proposed as a cause of irreversible neurological
disability in multiple sclerosis (MS) patients. The purpose of this
study was to quantify axonal loss in spinal cord
lesions from 5 paralyzed (Expanded Disability Status Scale score >
or =7.5) MS patients and to determine if axonal number or volume
correlated with levels of the neuronal marker N-acetyl aspartate (NAA).
Axonal loss in MS lesions ranged from 45 to 84% and averaged 68%. NAA
levels were significantly reduced (>50%) in cross sections of spinal
cords containing MS lesions. Reduced NAA correlated with reduced axonal
numbers within lesion areas. In addition, NAA levels per axonal volume
were significantly reduced in demyelinated axons (42%) and in myelinated
axons in normal-appearing white matter (30%). The data support axonal
loss as a major cause of irreversible neurological disability in
paralyzed MS patients and indicate that reduced NAA as measured by
magnetic resonance spectroscopy can reflect axonal loss and reduced NAA
levels in demyelinated and myelinated axons.

 

This study shows that paralysis can be associated with about 50-70% nerve loss in the spinal cord

Miller DH, Barkhof F, Frank JA, Parker GJ, Thompson AJ. Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain. 2002 Aug;125(Pt 8):1676-95

MRI methods are widely used to follow the pathological evolution of multiple sclerosis
in life and its modification by treatment. To date, measures of the
number and volume of macroscopically visible lesions have been studied
most often. These MRI outcomes have demonstrated clear treatment effects
but without a commensurate clinical benefit, suggesting that there are
other aspects of multiple sclerosis pathology that warrant investigation. In this context, there has been considerable interest in measuring tissue loss (atrophy) as a more global marker of the adverse outcome of multiple sclerosis
pathology, whether it arises in macroscopic lesions or in the normal
appearing tissues. An International Workshop recently considered the
measurement of atrophy in multiple sclerosis and provided the basis for this review. Brain white matter bulk consists predominantly of axons (46%) followed by myelin (24%), and progressive atrophy implies loss
of these structures, especially axons, although variable effects on
tissue volumes may also arise from glial cell proliferation or loss,
gliosis, inflammation and oedema. Significant correlations found
between brain volume and other putative MR neuronal markers also
indicate that atrophy reflects axonal loss.
Numerous methods are available for the measurement of global and
regional brain volumes and upper cervical cord cross-sectional area that
are highly reproducible and sensitive to changes within 6-12 months. In
general, 3D-T(1)-weighted acquisitions and largely automated
segmentation approaches are optimal. Whereas normalized volumes are
desirable for cross-sectional studies, absolute volume measures are
adequate for serial investigation. Atrophy is seen at all clinical stages of multiple sclerosis,
developing gradually following the appearance of inflammatory lesions.
This probably reflects both inflammation-induced axonal loss
followed by Wallerian degeneration and post-inflammatory
neurodegeneration that may be partly due to failure of remyelination.
One component of atrophy appears to be independent of focal lesions.
Existing immunomodulatory therapies have had limited effects on
progressive atrophy, concordant with their modest effects on progressive
disability. Atrophy provides a sensitive measure of the
neurodegenerative component of multiple sclerosis and should be measured in trials evaluating potential anti-inflammatory, remyelinating or neuroprotective therapies.

 Progression is associated with increasing nerve loss.

Bjartmar C, Wujek JR, Trapp BD. Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J Neurol Sci. 2003;206:165-71

Axonal
degeneration has been identified as the major determinant of
irreversible neurological disability in patients with multiple sclerosis
(MS). Axonal injury begins at disease onset and correlates with the
degree of inflammation within lesions, indicating that inflammatory
demyelination influences axon pathology during relapsing-remitting MS
(RR-MS). This axonal loss remains clinically silent for many years, and
irreversible neurological disability develops when a threshold of axonal
loss is reached and compensatory CNS resources are exhausted.
Experimental support for this view-the axonal hypothesis-is provided by
data from various animal models with primary myelin or axonal pathology,
and from pathological or magnetic resonance studies on MS patients. In
mice with experimental autoimmune encephalomyelitis (EAE), 15-30% of spinal cord
axons can be lost before permanent ambulatory impairment occurs.
During
secondary progressive MS (SP-MS), chronically demyelinated axons may
degenerate due to lack of myelin-derived trophic support. In addition,
we hypothesize that reduced trophic support from damaged targets or
degeneration of efferent fibers may trigger preprogrammed
neurodegenerative mechanisms. The concept of MS as an inflammatory
neurodegenerative disease has important clinical implications regarding
therapeutic approaches, monitoring of patients, and the development of
neuroprotective treatment strategies.
The figure of 15-30% loss without noticing ambulatory impairment is perhaps a bit high but with a 15% initial loss, I would expect to be able to see something, but it does show there is capacity to lose a certain amount of nerves
The pathological substrate of progressive disability in multiple sclerosis is hypothesized to be axonal loss. Differences in the demographic, pathological and radiological features of patients with primary progressive compared with secondary progressive multiple sclerosis
raise the question as to whether they actually represent separate
clinical entities. So far, large pathological studies comparing axonal damage between primary progressive and secondary progressive multiple sclerosis
have not been reported. In this clinico-pathological study we examined
the cervical spinal cord in patients with primary and secondary progressive multiple sclerosis. Human cervical spinal cord was derived at autopsy from 54 patients (17 primary progressive, 30 secondary progressive
and 7 controls). Tissue was stained immunohistochemically and examined
to determine: (i) the number of surviving corticospinal tract axons;
(ii) the extent of grey and white matter demyelination; (iii) the degree
of inflammation inside and outside of lesions; and (iv) the
relationship between demyelination and axonal loss.
Associated clinical data was used to calculate expanded disability
status scale for each patient preceding death. Motor disability in the
primary progressive and secondary progressive groups was similar preceding death.
Secondary progressive multiple sclerosis
patients showed considerably more extensive demyelination of both the
white and grey matter of the cervical spinal cord. The total number of
corticospinal axons was equally low in primary progressive and secondary progressive multiple sclerosis groups versus controls.
The reduction of axonal density in demyelinated regions compared to normal appearing white matter was significantly more extensive in primary progressive versus secondary progressive patients (33% reduction versus 16% reduction, P < 0.001). These findings suggest axonal loss is the pathological substrate of progressive disability in both primary progressive and secondary progressive multiple sclerosis with a common plaque-centred mechanism. More extensive axonal loss within areas of demyelination in primary progressive multiple sclerosis could explain high levels of axonal loss observed in these patients despite low levels of demyelination.

Number of axons in the Corticol spinal tract

Growing evidence suggests that axonal degeneration rather than demyelination is the pathological substrate underlying chronic, irreversible disability in multiple sclerosis. However, direct evidence linking clinical disability measured in vivo with corresponding post-mortem measures of axonal
pathology is lacking. Our objective in this study was to investigate
the relationship between motor disability accumulated by patients with multiple sclerosis during life and the degree of axonal loss observed in their descending motor tracts after death. Human spinal cord derived at autopsy from 45 patients with multiple sclerosis was investigated. The medical records of each patient were reviewed by a multiple sclerosis
neurologist to determine the degree of motor disability reached before
death. Spinal cord sections were stained immunohistochemically. The
degree of demyelination and the number of surviving corticospinal tract
axons were measured in each patient. Patients who had accumulated higher
levels of motor disability prior to death demonstrated fewer surviving
corticospinal axons.
Motor disability did not correlate with degree of
demyelination. This study provides for the first time, direct
clinico-pathological evidence that axonal loss is the pathological substrate of established disability in multiple sclerosis.

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MouseDoctor

4 comments

  • Hi All,
    Just trying to find the papers you are discussing, can you tell me the date of the latest one you are referencing?

    Regards Andy Clarke

  • Dear Andy
    This post was in response to a questoion posed on the corpusu callosum post.

    The references posted have dates on them

    if you are asking about references to rate of loss that was based on what I have heard and can not remember the exact reference probably G can enlighten, otherwise it needs a search

  • Thank you for this post. It is very fascinating. I’m surprised to read that there is less demyelination in PPMS compared to SPMS, but the degree of axonal loss in the former is greater than the latter. Does this mean that PPMS is more neuro-degenerative in its pathology than SPMS? If that is the case then that implies PPMS is a direct attack on the nerves. Is it that the nerves are the object of destruction, not necessarily the myelin?

    The evidence outlined here also suggests inflammation is not a recognisable trait of progressive MS, something else is killing the nerves, or the nerve cells are killing themselves. Am I right in my understanding? Why on earth would nerve cells kill themselves?

    The evidence in these papers also highlights that nerve cell death is an early component of MS. It begins as soon as the first attacks happen, even if there is no detectable symptom in the sufferer. This indicates that the real emphasis of MS research should be in the proliferation of sustaining healthy nerve cell development. That is the holy grail of MS treatment. How far away are we from seeing such therapies? Why are nerve cells so difficult to sustain in the CNS?

    Great post MouseDoc. I can’t tell you how much of a difference this blog has made to my life since diagnosis. I am so much better informed. I wish you luck in everything you’re working on and hope you have some good news in the field of treating progressive MS, soon.

  • I think it is always difficult to say more demyelination here and less there, and think the posted studies suggest that there is not a huge difference between PPMS and SPMS in terms of cause.

    I think we have to be very cautious about what we call inflammation. To one person it is lymphocytes, to another it is not. I think there is inflammation in both PPMS and SPMS, but the main culprits are microglia/macrophages.
    maybe with a bit of an assist by astrocytes.

    I think you are right that things are going on from the get-go and the sooner something is down to limit damage the better.

    Likewise I hope that we will get good news on treatment. The next one to report is probably going to be CUPID.

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