Wallerian Degeneration And Axonal Loss

Previous imaging studies have suggested that there is substantial Axonal loss in the Normal-Appearing White Matter (NAWM) of Brains from Multiple Sclerosis patients and that this Axonal loss may be an important determinant of Disability.

Recently, substantial Axonal loss in the NAWM has been confirmed directly in post-mortem tissue. Whether the NAWM changes occur as a consequence of damage to Axons traversing lesions or to a more diffuse injury process is uncertain.

Using formalin-fixed Brains of eight Multiple Sclerosis patients and eight age-matched controls, we examined the relationship between DeMyelinating lesion load in three volumes of the Cerebral White Matter.

And the loss of Axons in NAWM of the corresponding three projection regions (Anterior, Middle, Posterior) in the Corpus Callosum (CC).

There was a significant loss of calculated total number of Axons crossing the CC in each of the three regions relative to the Non-Multiple Sclerosis controls.

Strong correlations were found between the regional lesion load and both the Axonal density (r = -0.673, P: = 0.001) and the total estimated number of Axons crossing the corresponding projection area in the CC (r = -0.656, P: = 0.001) for the patients.

This suggests that Wallerian Degeneration of Axons transected in the DeMyelinating Lesions makes a major contribution to the substantial, diffuse loss of Axons in the NAWM in Multiple Sclerosis.

These findings emphasize the need to consider the consequences of Multiple Sclerosis lesions in terms of both local and distant effects in functionally connected regions of the Brain.

Axonal loss and degeneration in Multiple Sclerosis (MS) and Experimental Allergic EncephaloMyelitis (EAE) have been suggested by Brain imaging, pathological and Axonal transport studies.

Further elucidation of the processes and mechanisms of Axonal degeneration in DeMyelinating Diseases is therefore of potential importance in order to alleviate the permanent disabilities of MS patients.

However, detailed studies in this area are impeded by the small number of reliable models in which the onset and location of DeMyelination can be well-controlled.

In this study, micro-injection of PolyClonal rabbit Anti-GalactoCerebroside (Anti-Gal C) AntiBody and guinea pig Complement was used to induce local DeMyelination in the rat Optic Nerve.

We found that treatment with appropriate volumes of the AntiBody and Complement could induce local DeMyelination with minimal pressure- or trauma-induced damage.

Local changes in NeuroFilaments (NFs) and MicroTubules (MTs) were examined with both ImmunoHistoChemistry (IHC) and Electron Microscopy (EM).

On day 1 after micro-injection, we observed moderate NF and MT disassembly in the local DeMyelinated area, although in most cases, no apparent Inflammatory Cell infiltration was seen.

The NF and MT changes became more apparent on days 3, 5, 7 after micro-injection, along with gradually increased Inflammatory Cell infiltration.

These results suggested that acute DeMyelination itself may induce local CytoSkeleton changes in the DeMyelinated Axons, and that the ensuing local inflammation may further enhance the Axonal damage.

When the lesions were stained with specific AntiBodies for T-Lymphocytes, Macrophages, and Astrocytes, we found that most of the cells were Macrophages.

Suggesting that Macrophages may play a greater role in inflammation-related Axonal degeneration and Axonal loss.

These results were confirmed and further characterized on the ultrastructural level.

Copyright 1999 Elsevier Science B.V.

The PathoGenesis of Neuropathic Pain states is influenced by inflammatory factors associated with Nerve injuries and may be mediated in part by the Macrophage-dependent process of Wallerian Degeneration.

Macrophages play a dominant role in the Wallerian (Axonal) Degeneration that characterizes the painful chronic constriction injury model of Neuropathy by liberating ProInflammatory Cytokines at the site of Nerve Injury.

These Cytokines directly affect the structural integrity of Neural Systems and have been implicated in the development of Hyperalgesic States.

We hypothesized that interference with the pathologic process of Wallerian Degeneration would alter the development of the Neuropathic Pain state.

To test this hypothesis, we studied the development of thermal Hyperalgesia in the chronic constriction injury model of Neuropathy using normal mice and mice of the WLD strain in which recruitment of Macrophages to the site of Nerve injury and Wallerian Degeneration are delayed.

We compared the onset and magnitude of the Hyperalgesia with quantitative measures of Nerve Injury including the Phagocytic Cellular activity associated with Wallerian Degeneration.

In C57BL/6J (6J) mice, Hyperalgesia peaked 3-10 days after placement of the ligatures, qualitatively matching the response previously reported for rats.

In C57BL/WLD (WLD) mice, there was reduced Hyperalgesia temporally associated with reduced numbers of Phagocytic Cells in the injured nerve.

In injured WLD nerves there was a reduced rate of Axonal degeneration compared to similarly injured 6J nerves.

Regeneration was correspondingly delayed in the WLD animals. The results suggest that the process of Wallerian Degeneration is a key factor in the PathoGenesis of Hyperalgesia.

Continued development of mouse models of Neuropathic Pain will be important in exploring the molecular basis of Neuropathic Pain.

Interference with the cellular mediators of Wallerian Degeneration may be a useful therapeutic strategy that might modulate the onset and magnitude of Hyperalgesia following Nerve Injury.

Purpose
To describe the MR manifestations and temporal course of Wallerian Degeneration that occurs above and below a Spinal Cord Injury, and to compare the MR findings with postmortem HistoPathology.

METHOD
Twenty-four postmortem Spinal Cords from patients with Cervical (n = 14), Thoracic (n = 6), and Lumbar (n = 4) Cord injuries were studied with Axial T₁- and T₂-weighted Spin-Echo MR imaging. Injury-to-death intervals varied from 8 days to 23 years.

The images were examined for alteration of signal above and below the injury site. Histologic studies of these Cords with Axon, Myelin, and connective tissue stains were performed at levels equivalent to the MR sections.

ImmunoHistoChemical analysis using AntiBodies to Glial Fibrillary Acetic protein was also performed on 19 Cords. Pathologic-imaging comparisons were made.

Results
MR images showed increased signal intensity in the Dorsal Columns above the injury level and in the Lateral CorticoSpinal Tracts below the injury level in all cases in which Cord injury had occurred 7 or more weeks before death.

In early post injury survival times (8 days and 12 days) MR findings were normal; histologically there was early Wallerian Degeneration in only the Dorsal Columns at 8 days and in both the lateral and Dorsal Columns at 12 days.

MR showed Wallerian Degeneration in all cases examined at 7 weeks after injury and thereafter.

Conclusions
Wallerian Degeneration was demonstrated by histology and MR in all specimens in which the injury-to-death interval was greater than 7 weeks.

Recognition of Wallerian Degeneration on MR allows complete analysis of the injury, explains abnormal MR signals at sites remote from the epicenter of the injury, and may be useful in the future in the timing and planning of therapeutic interventions.

We studied the effects of Wallerian Degeneration in the Cerebral Peduncle shown by Magnetic Resonance Imaging (MRI) following a SupraTentorial Vascular lesion, to identify the Somatotopic localization of the Descending Cortical Tracts.

Patients with a lesion involving a large area of a Cerebral Hemisphere had an area of abnormal signal intensity in the whole Cerebral Peduncle, suggesting Wallerian Degeneration of all the whole Descending Cortical Tracts.

With a small lesion confined to the PreCentral Gyrus, Corona Radiata, or Posterior Limb of the Internal Capsule there was an abnormal signal at the center of the Peduncle, suggesting degeneration of the PreCentroSpinal Tract.

Those with a small lesion confined to the Paracentral Gyrus had an abnormal area slightly lateral to the center of the Peduncle, suggesting degeneration of the ParietoSpinal Tract.

Patients with a lesion of the Parietal or Temporal Lobes, not including the ParaCentral or PreCentral Gyri, Corona Radiata, or the Posterior Limb of the Internal Capsule, had an abnormal area laterally in the Peduncle, suggesting degeneration of the ParietoPontine or TemporoPontine Tract.

Four cases of severe acute Guillain-Barre Syndrome (GBS) characterized by severe Axonal degeneration are presented. All had electrically inexcitable Motor Nerves as early as 4 days after onset.

The disease was rapid in onset and the residual disability was severe. Two different types of pathology were seen. Nerve biopsies in 3 cases showed severe Axonal degeneration without Inflammation or DeMyelination.

Autopsy in one of these cases showed that the Dorsal and Ventral Roots were also significantly affected.

These cases illustrate the primary Axonal form of GBS. Nerve biopsy in the fourth case at day 15 showed marked inflammation and DeMyelination with Axonal degeneration.

ContraLateral Nerve biopsy at day 75 showed almost complete loss of Axons. This case illustrates another type of Axonal degeneration, that which occurs secondary to Inflammation and DeMyelination.

We reported a 55-year-old man, whose T₂-weighted MR images disclosed abnormal high signal band along the left Pyramidal Tract 6 months after Cerebral Infarction of the Left Centrum Semiovale.

Brain CT revealed low intensity areas in the Centrum Semiovale, the Posterior Limb of the Internal Capsule on left side.

On T₂-weighted MR images, there were an irregular high signal area on the Left Centrum Semiovale, a high signal band from the Left Centrum Semiovale to the Medullary Pyramid, and a high signal band from the Left Centrum Semiovale to the Cerebral Cortex.

These lesions were observed as high signal areas on Proton weighted images and low signal areas on T₁-weighted MR images.

Diffusion coefficient perpendicular to the Pyramidal Tract in the patient, which was calculated from Diffusion weighted images at the Posterior Limb of the Internal Capsule, was higher than that in normal individuals.

Diffusion Anisotropy at the lesion, which is the rate between the Diffusion coefficient parallel and perpendicular to Nerve Fiber, was higher than that of normal individuals.

Macrophages are important Effector Cells in Immune-mediated DeMyelination. Current concepts regarding their entry and activation focus on the effects of T-Cell-derived Cytokines.

This presentation describes the responses of Macrophages and Microglia to a non-inflammatory, non-Immune injury, Wallerian Degeneration.

During Wallerian Degeneration in the Peripheral Nervous System (PNS), Macrophages are promptly and abundantly recruited from the circulation, and Myelin clearance is prompt.

In the Central Nervous System (CNS), the appearance of Macrophages is markedly slower, and entry from the circulation is modest or absent. Myelin clearance is similarly delayed.

The nature of the factors promoting Macrophage entry and activation in Wallerian Degeneration, and the bases for the differences between PNS and CNS, are relevant to current issues in Immune-mediated DeMyelination.

Increased Blood-Brain Barrier (BBB) permeability, important in the PathoGenesis of MS, may be demonstrated as lesion enhancement with High-Volume Delayed CT (HVDCT).

We studied 40 MS patients with history, Neurologic Examination, HVDCT, and MRI. In addition, 7 of the patients with enhancing CT lesions were followed with serial MRI for up to 3 years and 7 months. In 3 of these patients we repeated the HVDCT.

Patients with enhancing lesions on CT were younger, had shorter duration of disease, and had more frequent clinical relapses than did patients without enhancement.

More than half (56%) of the enhancing CT lesions were in the deep White Matter, 23% were PeriVentricular, and 21% were at the Gray/White Matter junction.

Half the CT enhancing lesions, when followed by serial MRI, showed significant changes in Lesion size.

Although the majority (59%) of these lesions faded, some remained actively changing (25%) or became confluent with adjacent lesions (16%).

In 48% of the MRI examinations that showed activity, some lesions were increasing in size while others were simultaneously decreasing in size.

This study confirms that MS is a dynamic process in which recurrent episodes of BBB disruption and inflammation play a major role.

Recurrent episodes of inflammation may well be a prelude to the largely irreversible changes of DeMyelination and Gliosis.

Twenty-three patients who underwent routine Magnetic Resonance (MR) Imaging of the Brain were found to have signal or structural abnormalities corresponding to White Matter Tracts.

Images were evaluated for anatomic and MR signal characteristics of the involved tract, associated primary lesions, and, when possible, changes in MR signal and anatomic structures with time.

Images from 20 patients demonstrated a thin band of abnormal signal contiguous with the primary lesion and conforming to the known anatomic pathway of a White Matter Tract. Cerebral Infarction was the most common associated primary disorder (n = 17).

Neoplasms (n = 2), DeMyelinating (n = 1) and PostheMorrhagic (n = 2) conditions, and an Idiopathic Movement Disorder (n = 1) were associated with White Matter Tract signal abnormalities that were indistinguishable from those seen with Infarction.

Signal abnormality corresponding to the CorticoSpinal Tract was the type most commonly seen. No change in signal characteristics was seen with time (six cases) or following contrast material administration (two cases).

The authors conclude that MR imaging provides a sensitive method of evaluating Wallerian Degeneration in the living human Brain.

Wallerian Degeneration was investigated to determine whether Axonal changes occur progressively in a SomatoFugal or SomatoPetal direction or simultaneously along the length of the Axon.

MicroTubule density was used as a measure of the extent of Axonal degeneration and was assessed by a computer-aided analysis of electron micrographs.

The left Sural Nerves of ten rats were crushed and 30 hours later Axonal areas and Axonal MicroTubule numbers were recorded from a large sample of Axons at two sites 1 cm and 3 cm distal to the crush.

The same recordings were made from the right unoperated Nerve at two comparable sites. Statistical analysis of all the data provided no evidence for a SomatoFugal or reverse direction of degeneration.

It is concluded therefore that in Wallerian Degeneration Axonal changes, as indicated by MicroTubule dissolution, occur simultaneously along the length of the Axon.

It is proposed that to interpret the conflicting published data on the direction of Fiber degeneration, Schwann Cell changes (e.g. Myelin ovoid formation) and Axonal changes (e.g. MicroTubule dissolution) should be considered independently.

Since, they have different Etiological mechanisms which may account for the differing experimental results reported.