Spinal Cord Multiple Sclerosis Research Articles

Normalization of the Spinal Cord in Multiple Sclerosis (P06.106)

Normalization of the Spinal Cord in Multiple Sclerosis (P06.106)

Perfil descritivo de esclerose múltipla com início até os 16 anos nos pacientes de um centro de referência do estado de São Paulo

OBJETIVO: Descrever o perfil de pacientes com esclerose múltipla iniciada até os 16 anos de idade no litoral do estado de São Paulo, Brasil. DESCRIÇÃO DOS CASOS: Análise retrospectiva das características dos pacientes que tiveram o episódio inicial de esclerose múltipla até os 16 anos. Nesta situação encontravam-se nove meninas e quatro meninos (7,1% da população total de esclerose múltipla da região). A idade média por ocasião do diagnóstico foi de 13,9 anos (variação entre 8 e 16), sendo a média atual de 19,5 anos (12 a 28). A apresentação inicial da doença foi: ataxia (quatro casos), neurite óptica (dois), motora cortical (dois), sensitiva cortical (dois), distonia (dois) e esclerose múltipla medular (um). Todos os pacientes iniciaram com a forma remitente-recorrente da esclerose múltipla e dois deles, atualmente, apresentam a forma progressiva secundária. COMENTÁRIOS: A esclerose múltipla com início até os 16 anos precisa ser adequadamente registrada e discutida entre pediatras, neurologistas e neuropediatras. Poucos médicos têm bom conhecimento desta condição e a demora no diagnóstico e no tratamento pode ter consequências devastadoras para essas crianças e adolescentes.

A pilot MRI study of white and grey matter involvement by multiple sclerosis spinal cord lesions

ObjectivesSpinal cord pathology is a major cause of disability in multiple sclerosis (MS) and pathology studies show multifocal demyelinating lesions in white matter (WM) tracts and central grey matter (GM). Better localisation of cord lesions by in vivo MRI may help to understand the structural–functional effects of spinal cord pathology in MS. MethodsThree-Tesla MRI was performed on upper cervical cord in 15 MS patients and one clinically isolated syndrome. Axial 3D gradient-echo fast field echo (3D-FFE) and phase sensitive inversion recovery sequences (3D-PSIR) were acquired. Two readers reviewed images to detect and classify lesions: WM-only, mixed WM–GM or GM-only. Location of the WM component was classified: anterior (AC), lateral (LC) or posterior (PC) column. ResultsFifty one lesions were identified: 32 (63%) mixed WM–GM, 19 (37%) WM-only, no GM-only. Most were in LC (n=30, 59%), followed by PC (n=18, 35%) and AC (n=3, 6%). Mean lesion areas: AC 4.3mm2, LC 8.5mm2, PC 11.3mm2, corresponding to 6.1%, 12% and 16.1% of mean cord area, respectively. Mean lesion lengths: 18.3mm in AC, LC 17.6mm and PC 24.8mm. ConclusionsWhile there was good depiction of WM tract involvement by cord lesions, involvement of central grey matter was not as clear. Noting the important effects of spinal cord pathology in MS, further work to better depict cord lesions by in vivo imaging is warranted.

Functional MRI, Diffusion Tensor Imaging, and MR Spectroscopy of the Spinal Cord in Multiple Sclerosis

Functional MRI, Diffusion Tensor Imaging, and MR Spectroscopy of the Spinal Cord in Multiple Sclerosis

Biplanar MRI for the assessment of the spinal cord in multiple sclerosis

Objective: To investigate the entire spinal cord (SC) of multiple sclerosis (MS) patients with biplanar MRI and to relate these MRI findings to clinical functional scores. Methods: Two hundred and two patients (140 women, 62 men 24–74 years, Expanded Disability Status Scale (EDSS) scores 0–7.5) were investigated clinically and with biplanar MRI. Sagittal and axial proton density weighted (PDw) and T2 weighted (T2w) images of the whole SC were obtained employing parallel imaging. Data were analyzed by consensus reading using a standardized reporting scheme. Different combinations of findings were compared to EDSS scores with Spearman’s rank correlation coefficient (ρ). Results: The combined analysis of sagittal and axial planes demonstrated slightly differing results in 97/202 (48%) patients. There were 9% additional lesions identified, leading to a higher lesion count in 28% of these patients, but also rejection of equivocal abnormality leading to a lower lesion count in 11% of patients. Considering both sagittal and axial images, SC abnormalities were found in 167/202 (83%) patients. When compared with EDSS scores, the combination of focal lesions, signs of atrophy and diffuse abnormalities showed a moderate correlation (ρ=0.52), that precludes its use for individual patient assessment. Conclusion: Biplanar MRI facilitates a comprehensive identification, localization, and grading of pathological SC findings in MS patients. This improves the confidence and utility of SC imaging.

Diffusion Tensor and Magnetization Transfer Imaging Correlates of Motor Dysfunction in the Spinal Cord in Multiple Sclerosis (S21.002)

Diffusion Tensor and Magnetization Transfer Imaging Correlates of Motor Dysfunction in the Spinal Cord in Multiple Sclerosis (S21.002)

Immune Complex-Induced Inflammation as a Mechanism of Inhibition of Peripheral Nerve Regeneration (IN1-2.002)

Objective: To investigate if immune complex formation and Fc gamma receptors (FcγRs) participate in anti-ganglioside antibody-mediated inhibition of axon regeneration. Background Anti-ganglioside antibodies (Abs) are the most commonly recognized autoimmune markers in all forms of Guillain-Barre syndrome (GBS) and these Abs are associated with poor recovery. Extent of axonal injury and failure of axonal regeneration are critical determinants of recovery after GBS. In this clinical context, we have shown that anti-ganglioside Abs adversely affect axon regeneration after peripheral nerve injury in an animal model, in complement-independent fashion. Therefore, we asked whether immune complexe formation and Fc gamma receptors (FcγRs)-induced inflammation participates in this Ab-mediated inhibition of axon regeneration. Design/Methods: A well characterized antibody passive transfer and sciatic nerve crush model was used to study the anti-ganglioside Ab-mediated inhibition of axon regeneration in wild type and various transgenic mice lacking specific FcγRs. Outcome measures included electrophysiology, morphometry, immunocytochemistry, quantitative real-time PCR, and western blotting. Results: We found that there was a highly significant upregualtion of FcγRs with nerve crush/injury. Notably, anti-ganglioside Ab-mediated inhibition of axon regeneration was entirely dependent on the expression of specific activating FcγRs as transgenic mice lacking specific FcγRs were completely immune to Ab-mediated inhibition of axon regeneration. Conclusions: Our results demonstrate that immune complex formation and engagement of specific FcγRs leads to inhibition of peripheral nerve regeneration. The current studies are relevant not only to acute and chronic immune neuropathies but to other neurological conditions including multiple sclerosis and traumatic spinal cord and brain injuries as recent studies have emphasized the role of anti-neural Abs and FcγRs in secondary central nervous system injury in experimental models. Supported by: NIH/NINDS (NS42888 and NS54962) and GBS/CIDP Foundation. Disclosure: Dr. Sheikh has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Bogdanova has nothing to disclose. Dr. Gao has nothing to disclose. Dr. Guo has nothing to disclose. Dr. Massaad has nothing to disclose. Dr. Kotha has nothing to disclose.

Clinico-Radiologic Profile of Spinal Cord Multiple Sclerosis in Adults

MRI is extremely useful for the assessment of initial disease burden and to identify the dissemination of the multiple sclerosis (MS) in time and space. Though MRI of the spinal cord is not used to establish the diagnosis of MS, spinal cord is frequently involved in this disease and there has been increasing emphasis of the spinal imaging in making clinical decision in the management of MS. We undertook a retrospective study of patients with diagnosed MS: 1) to identify radiologic pattern of spinal cord involvement in MS and 2) to correlate radiologic findings with clinical presentation. We reviewed radiologic records from 2004 to 2009 of patients with abnormal T2 signal intensity of the spinal cord with radiologic concern of demyelinating disease. Patients in this cohort who met the Revised McDonald MS Diagnostic Criteria were included in this study. 166 patients were included in the study. There was preference for cervical spinal cord particularly posterior aspect of the spinal cord. Enhancement of the lesions was rare (4.1%). Mean lesion length was 18.2 mm. The average number of lesions per patient was 2.04. Sensory symptoms were predominating and most of the patients had relapsing-remitting course. Patients with sensory symptoms, bladder and bowel involvement and motor symptoms had almost equally distributed lesions among anterior, posterior and central spinal cord. However, all of the patients presented with posterior column signs and gait abnormality had involvement of the posterior spinal cord. Radiologic manifestation of spinal cord MS is extremely variable and can involve the entire length of the spinal cord. Clinical symptoms may or may not be associated with radiologic presentation of the lesions.

Acid-sensing ion channel 1 is involved in both axonal injury and demyelination in multiple sclerosis and its animal model

Although there is growing evidence for a role of excess intracellular cations, particularly calcium ions, in neuronal and glial cell injury in multiple sclerosis, as well as in non-inflammatory neurological conditions, the molecular mechanisms involved are not fully determined. We previously showed that the acid-sensing ion channel 1 which, when activated under the acidotic tissue conditions found in inflammatory lesions opens to allow influx of sodium and calcium ions, contributes to axonal injury in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. However, the extent and cellular distribution of acid-sensing ion channel 1 expression in neurons and glia in inflammatory lesions is unknown and, crucially, acid-sensing ion channel 1 expression has not been determined in multiple sclerosis lesions. Here we studied acute and chronic experimental autoimmune encephalomyelitis and multiple sclerosis spinal cord and optic nerve tissues to describe in detail the distribution of acid-sensing ion channel 1 and its relationship with neuronal and glial damage. We also tested the effects of amiloride treatment on tissue damage in the mouse models. We found that acid-sensing ion channel 1 was upregulated in axons and oligodendrocytes within lesions from mice with acute experimental autoimmune encephalomyelitis and from patients with active multiple sclerosis. The expression of acid-sensing ion channel 1 was associated with axonal damage as indicated by co-localization with the axonal injury marker beta amyloid precursor protein. Moreover, blocking acid-sensing ion channel 1 with amiloride protected both myelin and neurons from damage in the acute model, and when given either at disease onset or, more clinically relevant, at first relapse, ameliorated disability in mice with chronic-relapsing experimental autoimmune encephalomyelitis. Together these findings suggest that blockade of acid-sensing ion channel 1 has the potential to provide both neuro- and myelo-protective benefits in multiple sclerosis.

Radial diffusivity predicts demyelination in ex vivo multiple sclerosis spinal cords

ObjectiveCorrelation of diffusion tensor imaging (DTI) with histochemical staining for demyelination and axonal damage in multiple sclerosis (MS) ex vivo human cervical spinal cords. BackgroundIn MS, demyelination, axonal degeneration, and inflammation contribute to disease pathogenesis to variable degrees. Based upon in vivo animal studies with acute injury and histopathologic correlation, we hypothesized that DTI can differentiate between axonal and myelin pathologies within humans. MethodsDTI was performed at 4.7 T on 9 MS and 5 normal control fixed cervical spinal cord blocks following autopsy. Sections were then stained for Luxol fast blue (LFB), Bielschowsky silver, and hematoxylin and eosin (H&E). Regions of interest (ROIs) were graded semi-quantitatively as normal myelination, mild (<50%) demyelination, or moderate–severe (>50%) demyelination. Corresponding axonal counts were manually determined on Bielschowsky silver. ROIs were mapped to co-registered DTI parameter slices. DTI parameters evaluated included standard quantitative assessments of apparent diffusion coefficient (ADC), relative anisotropy (RA), axial diffusivity and radial diffusivity. Statistical correlations were made between histochemical gradings and DTI parameters using linear mixed models. ResultsWithin ROIs in MS subjects, increased radial diffusivity distinguished worsening severities of demyelination. Relative anisotropy was decreased in the setting of moderate–severe demyelination compared to normal areas and areas of mild demyelination. Radial diffusivity, ADC, and RA became increasingly altered within quartiles of worsening axonal counts. Axial diffusivity did not correlate with axonal density (p=0.091). ConclusionsIncreased radial diffusivity can serve as a surrogate for demyelination. However, radial diffusivity was also altered with axon injury, suggesting that this measure is not pathologically specific within chronic human MS tissue. We propose that radial diffusivity can serve as a marker of overall tissue integrity within chronic MS lesions. This study provides pathologic foundation for on-going in vivo DTI studies in MS.

Cervical spinal cord multiple sclerosis: evaluation with 2D multi-echo recombined gradient echo MR imaging

Objective: The two-dimensional multi-echo recombined gradient echo (MERGE) technique automatically acquires and sums multiple gradient echoes at various echo times in cervical spine magnetic resonance (MR) imaging. This technique increases the grey–white matter contrast within the spinal cord and should also improve the depiction of cervical cord lesions. The aim of this study was to qualitatively and quantitatively evaluate MERGE imaging compared with T2-weighted fast spin-echo (T2WFSE) imaging for depicting multiple sclerosis (MS) lesions in the cervical cord.Methods: Nineteen consecutive patients (10 males and 9 females; age range 22–62 years, mean age 43.6 years) with clinically diagnosed MS were examined with cervical spinal cord MR imaging at 3 T including both MERGE and T2WFSE imaging. Qualitative evaluation for MS lesion conspicuity was performed. The quantitative criterion utilized to compare MERGE imaging with T2WFSE imaging was the lesion-to-background contrast-to-noise ratio (CNR).Results: MERGE imaging showed 79 lesions and missed 1 that was depicted on T2WFSE imaging. T2WFSE imaging showed 46 lesions and missed 34 that were depicted on MERGE imaging. MERGE imaging was markedly superior to T2WFSE imaging in rendering greater lesion conspicuity. In the quantitative evaluation, the lesion-to-background CNR upon MERGE imaging was significantly higher than that upon T2WFSE imaging (P < 0.001, paired t-test).Conclusions: MERGE imaging in the cervical spinal cord increases detection and conspicuity of MS lesions. Strong consideration should be given to utilizing axial MERGE images in the diagnosis and follow-up study of cervical cord MS.

Spinal cord involvement in multiple sclerosis: A correlative MRI and high-resolution HLA-DRB1 genotyping study

Background There have been few magnetic resonance imaging (MRI) studies of the spinal cord in large multiple sclerosis (MS) patient cohorts and little is known about correlations between cord lesions and human leukocyte antigen (HLA) alleles. Objective To investigate the spectrum of MRI changes in the spinal cord in MS and associations with the HLA-DRB1 genotype. Methods Two hundred and fifty two consecutive MS patients from the Perth Demyelinating Diseases Database had MRI of the spinal cord and brain and high-resolution HLA-DRB1 genotyping. The numbers, locations, shape and segmental extent of cord lesions were analysed and were correlated with carriage of individual HLA-DRB1 alleles and diplotypes. Results Focal cord lesions were present in 82.9% of cases, with numbers being maximal in the cervical cord and increasing with disease duration. Focal lesions were usually round or oval in shape but in 35% of cases subpial wedge-shaped lesions were present. Diffuse cord involvement was present in 10% of cases and correlated with carriage of HLA-DRB1*1501 and with higher disability. Carriage of the minor allele HLA-DRB1*0701 was significantly associated with numbers of wedge-shaped lesions and lesions in the cervical cord, while HLA-DRB1*1104 and DRB1*0103 were significantly associated respectively with higher and lower numbers of thoracic cord lesions. HLA-DRB1*1501 and the HLA-DRB1*11 sub-alleles DRB1*1101 and DRB1*1104 were significantly associated with the segmental length of cord lesions. Conclusions Our study is the first to investigate the frequency of subpial wedge-shaped lesions in the cord in vivo and has provided preliminary evidence that HLA-DRB1 alleles may play a role in determining the severity and extent of spinal cord involvement in MS.

The Role of Osteopontin in Experimental Autoimmune Encephalomyelitis (EAE) and Multiple Sclerosis (MS)

Osteopontin (OPN) is an extracelluar matrix protein with chemokine, cytokine and intergrin properties. It has multiple immunological functions and is secreted by activated macrophages, leukocytes and activated T lymphocytes. It is present in extracellular fluids and is up-regulated at sites of inflammation. OPN has intracellular and secreted isoforms. It has been shown to be involved in inflammation and autoimmune disorders, including multiple sclerosis. Multiple sclerosis (MS) is an immune mediated inflammatory disease of the central nervous system (CNS) in which autoreactive T cells attack the myelin-oligodendrocyte complex. Experimental autoimmune encephalomyelitis (EAE) is a widely used experimental model for MS. This review presents updated evidence for the role of OPN in MS and EAE, starting with the data provided by microarray analysis showing elevated levels of OPN transcripts in MS brain lesions and spinal cords of rats with EAE. This plausible target has since been validated in EAE, by showing that OPN knockout mice are protected from severe EAE. Increased levels of OPN were reported in plasma and CSF of MS patients in comparison to healthy controls. Potential mechanisms of OPN involvement in inflammatory demyelination are discussed. The involvement of OPN, in part via non-immune effects, in remyelination and its neuroprotective potential need to balanced against its pro-inflammatory properties.

Meningeal T cells associate with diffuse axonal loss in multiple sclerosis spinal cords

A link between diffuse axonal loss and diffuse inflammation has been established in the brain of patients with progressive multiple sclerosis (MS). In the present paper, we sought to determine whether such a link could be similarly demonstrated in the spinal cord of patients with progressive MS. A neuropathological quantitative assessment of inflammation and axonal loss was performed in the cervical spinal cord of 18 patients with progressive MS and 5 control subjects. As previously reported, we found a mean 25% decrease of axonal density in the normal-appearing white matter (NAWM) of MS versus control spinal cords. T-cell perivascular infiltrates were rare, but a robust diffuse inflammation was observed in both the normal-appearing parenchyma and the meninges. The extent of diffuse axonal loss in the NAWM correlated with both the density of major histocompatibility complex (MHC) class II(+) microglia in the NAWM and, surprisingly, the density of CD3(+) T cells in the meninges. Interestingly, close interactions between T cells and MHC class II(+) macrophages were observed in the meninges of spinal cords from MS patients. Recent studies assigned a major role to meningeal B-cell follicles in the pathophysiology of secondary progressive MS. The present work also emphasizes the link between meningeal inflammation and parenchymal lesions and points to a specific role exerted by both meningeal T cells and activated microglia in diffuse axonal loss in the spinal cord.

CNS-Resident Glial Progenitor/Stem Cells Produce Schwann Cells as well as Oligodendrocytes during Repair of CNS Demyelination

After central nervous system (CNS) demyelination-such as occurs during multiple sclerosis-there is often spontaneous regeneration of myelin sheaths, mainly by oligodendrocytes but also by Schwann cells. The origins of the remyelinating cells have not previously been established. We have used Cre-lox fate mapping in transgenic mice to show that PDGFRA/NG2-expressing glia, a distributed population of stem/progenitor cells in the adult CNS, produce the remyelinating oligodendrocytes and almost all of the Schwann cells in chemically induced demyelinated lesions. In contrast, the great majority of reactive astrocytes in the vicinity of the lesions are derived from preexisting FGFR3-expressing cells, likely to be astrocytes. These data resolve a long-running debate about the origins of the main players in CNS remyelination and reveal a surprising capacity of CNS precursors to generate Schwann cells, which normally develop from the embryonic neural crest and are restricted to the peripheral nervous system.

Substantial early, but nonprogressive neuronal loss in multiple sclerosis (ms) spinal cord

Research in multiple sclerosis (MS) has recently been focusing on the extent of neuroaxonal damage and its contribution to disease outcome. In the present study, we examined spinal cord tissue from 30 clinically well-characterized MS patients. MS, amyotrophic lateral sclerosis (ALS), and control spinal cord tissue were subjected to morphometric analysis and immunohistochemistry for markers of cell damage and regeneration. Data were related to disease duration and age at death. Here, we present evidence for substantial, nonprogressive neuronal loss on the cervical and lumbar levels early in the disease course of MS. Chromatolytic neurons and immunoreactivity for c-Jun and GAP43 were observed in the ventral gray matter in and adjacent to actively demyelinating lesions, pointing toward neuronal damage and regeneration as an early response to lesion formation.

Spinal Cord Neuronal Pathology in Multiple Sclerosis

The objective of this study was to assess neuronal pathology in the spinal cord in multiple sclerosis (MS), both within myelinated and demyelinated tissue. Autopsy material was obtained from 38 MS cases and 21 controls. Transverse sections were taken from three spinal cord levels and stained using Luxol Fast Blue/Cresyl Violet and myelin protein immunohistochemistry. Measurements of neuronal number and size were made for all neurons within the anterior horns of the gray matter. Neurons were classified as motoneurons or interneurons according to size criteria. In comparison with controls, both motoneuron and interneuron number were reduced in MS cases at the upper cervical (interneuron P = 0.0549; motoneuron P = 0.0073) and upper thoracic (interneuron P = 0.0507; motoneuron P = 0.0144), but not the lumbar level. Interneuron cross-sectional area was reduced in MS cases at all levels (upper cervical, P = 0.0000; upper thoracic, P = 0.0002; lumbar, P = 0.0337). Neuronal loss appears to be predominantly related to local gray matter plaques, whereas interneuron atrophy occurs in both myelinated and demyelinated areas.

Regional variations in the extent and pattern of grey matter demyelination in multiple sclerosis: a comparison between the cerebral cortex, cerebellar cortex, deep grey matter nuclei and the spinal cord

Background:Substantial grey matter (GM) demyelination occurs in both the cerebral cortex and spinal cord in multiple sclerosis (MS). GM demyelination also occurs in the cerebellar cortex and the deep GM...

Poster Abstract #15: MRI Measurement of Whole Spinal Cord Volume at 3T: Reproducibility and Relevance to Multiple Sclerosis

Objective Determine the reproducibility and clinical relevance of measuring whole spinal cord volume in healthy controls and patients with multiple sclerosis (MS) using 3T MRI. Background Spinal cord atrophy may be especially relevant to disability in MS. The advent of 3T MRI brings the potential to assess spinal cord volume more precisely than conventional platforms. Design/Methods Eight patients with MS and five healthy subjects underwent 3T MRI of the whole spinal cord using axial fast spin-echo T2-weighted images. The upper cervical cord volume was calculated at C2–3. The cord volume was acquired using an edge-finding tool based on local thresholding and was normalized by the craniocaudal extent of the cord. Results The whole spinal cord volume in the MS group was 8.2% lower vs. healthy subjects ( p = 0.13; effect size, Cohen's d = 0.89). Whole spinal cord volume normalized by number of slices was 5% lower in patients with MS ( p = 0.16; d = 0.79) and whole spinal cord volume normalized by intracranial volume (ICV) was lower by 4.7% in MS vs. controls ( p = 0.16; d = 0.63). Normalizing the whole cord volume with number of slices and ICV showed a 1.5% difference in MS vs. controls ( p = 0.79; d = 0.50). Upper cervical spinal cord volume was 7% lower in MS vs. controls ( p = 0.33; d = 0.51). The whole cord volume scan–rescan, intrarater, and inter-rater coefficient of variation ranged from 0.5% to 0.7%; those for upper cervical cord cross-sectional volume ranged from 1.3% to 3.8%. Conclusions In this pilot study, whole spinal cord volume shows larger effect sizes than upper cervical cord volume in differentiating mildly disabled patients with MS from normal controls. Normalization of spinal cord volume by intracranial volume reduced such effect sizes and therefore may not be desirable. Whole spinal cord volume showed higher reproducibility than measurement of upper cervical cord volume. Study supported by: National Multiple Sclerosis Society (RG3705A1; RG3798A2); National Institutes of Health (NINDS 1R01NS055083-01).

Phosphorylation and compactness of neurofilaments in multiple sclerosis: Indicators of axonal pathology

AimsAxonal pathology extends to the axonal cytoarchitecture leaving its signature on axoskeletal proteins. This study investigated whether neurofilament (NfH) phosphorylation would relate to the dynamics of axonal pathology in multiple sclerosis (MS). MethodsNfH phosphoforms (SMI32, SMI34, SMI35) were quantified by ELISA from microdissected samples of control and MS brain and spinal cord. Individual axons were analysed by electron microscopy, densitometrically and morphologically in adjacent tissue sections. Experiments were carried out pre- and post enzymatic dephosphorylation. ResultsIn control tissue a rostro-caudal gradient of NfH indicated an increase in axonal density from the brain gray matter towards the spinal cord. The highest levels of phosphorylated and hyperphosphorylated NfH were found in acute lesions of brain and spinal cord, in contrast to chronic lesions where levels were lower than in white matter, consistent with axonal loss. Dephosphorylated NfH was higher, but less densly packed in MS white matter axons compared to control tissue. ConclusionsThe findings suggest that a less organised/compact axoskeleton or impaired axonal transport may represent an early sign of axonal pathology within the normal appearing white matter in MS. Subsequently a proportional increase of dephosphorylated NfH, aberrant phosphorylation and/or aggregation may occur whilst the protein is transported through the white matter towards the MS plaque, where hyperphosphorylated NfH dominates.