Heightened intrathecal release of axonal cytoskeletal proteins in multiple sclerosis is associated with progressive disease and clinical disability

Semra, Y K; Seidi, Osheik; Sharief, Mohammed

doi:10.1016/s0165-5728(01)00455-6

Cited by 119 publications

(90 citation statements)

References 40 publications

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“…Immune responses to these glycolytic enzymes might, therefore, damage these organelles and reduce energy production. Reports of decreased function of the neuronal mitochondrial respiratory chain in the motor cortex of MS patients [61] and increased intrathecal release of the axonal cytoskeletal protein tubulin [62] are consistent with this hypothesis. Other studies have shown that binding of inhibitors to GAPDH and TPI causes decreased ATP production in neurons, leading to progressive neuronal degeneration and apoptosis [63].…”

supporting

confidence: 52%

Mechanisms of injury in multiple sclerosis: involvement of antineuroaxonal humoral autoimmunity

Qin¹,

Sobel

2007

Expert Review of Clinical Immunology

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supporting

confidence: 52%

Mechanisms of injury in multiple sclerosis: involvement of antineuroaxonal humoral autoimmunity

Qin¹,

Sobel

2007

Expert Review of Clinical Immunology

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“…NFs are released from damaged axons during transection, Wallerian degeneration and ''die-back'' of neurons. These cytoskeletal components are degraded and are detectable in CSF of MS patients after relapse [16,26], during the progressive phase of the disease [21] and in all types of MS courses [17,20]. Cytoskeletal and myelin debris, released by damaged axons, are removed by macrophages which may be able to reach the periphery, e.g.…”

Section: Discussionmentioning

confidence: 99%

Elevated intrathecal antibodies against the medium neurofilament subunit in multiple sclerosis

et al. 2007

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Neurofilaments are cytoskeletal proteins localized within axons, which may interact with the immune system during and following tissue destruction in multiple sclerosis (MS). Antibodies against the medium neurofilament subunit synthesized intrathecally may reflect axonal damage in MS patients. Both immunoglobulin G (IgG) and M (IgM) responses against the purified native medium subunit of neurofilaments (NFM) using enzyme-linked immunosorbent assay (ELISA) were determined in paired serum and cerebrospinal fluid samples obtained from 49 MS patients, 16 normal controls (CN), 21 control patients with miscellaneous diseases (CD) and 14 patients with neurodegenerative disorders (CDEG). Intrathecal production of IgM and IgG antibodies to NFM were elevated in MS patients compared with the CN or CD groups (p<0.04 for IgM, p<0.01 for IgG). The increase was present in all the MS courses (relapsing-remitting, primary and secondary progressive). Similar local anti-NFM IgG and IgM synthesis occurred in the MS and CDEG groups. MS patients with short and long disease duration did not differ in terms of their anti-NFM IgM and IgG responses. Repeated examinations showed stable intrathecal anti-NFM production. Intrathecal IgG and IgM antibodies against NFM were increased in MS patients and may serve as a potential marker for axonal pathology. The extent of anti-NFM levels did not correspond to any individualized clinical profiles of MS patients.

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“…Although multiple sclerosis (MS) is considered an autoimmune disease, there is accumulating evidence that degenerative processes participate in the pathogenesis of MS. Neurodegeneration seems to be the most prominent feature of MS progression, and is often accompanied by extensive axonal loss [30], atrophy [7,10], and gliotic scar formation of chronic lesions [5]. The major intermediate astrocytic cytoskeletal protein, glial fibrillary acidic protein (GFAP), is considered the morphological basis of astrogliosis and the dominant protein constituent of chronic MS lesions [4].…”

Section: Introductionmentioning

confidence: 99%

“…Increased NFL levels, indicating damage of myelinated axons, have been found in neurodegenerative diseases [1,3,9,25], CNS infections [23,31], and inflammatory CNS diseases [21], including MS [8,14,15,20,30,32]. High NFL levels have been associated with clinical relapses [14,15,20] and increased disability [14,20,30,32] and may have prognostic value [20,29]. Augmented GFAP levels have been observed in the CSF in patients with relapsing-remitting MS (RRMS) [26], and a strong correlation between CSF GFAP concentrations and the degree of neurological disability during MS, especially in secondary progressive MS (SPMS), has been reported [15].…”

Section: Introductionmentioning

confidence: 99%

Glial fibrillary acidic protein: a potential biomarker for progression in multiple sclerosis

et al. 2011

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The major intermediate cytoskeletal protein of astrocytes, glial fibrillary acidic protein (GFAP), and that of axons, neurofilament light protein (NFL), may both be released into the cerebrospinal fluid (CSF) during pathological processes in the central nervous system (CNS). We investigated GFAP and NFL levels in CSF as possible biomarkers for progression in multiple sclerosis (MS). Patients with relapsing-remitting MS (RRMS, n = 15) or secondary progressive MS (SPMS, n = 10) and healthy control subjects (n = 28) were examined twice with an interval of 8-10 years apart. Neurological deficits were scored with the Expanded Disability Status Scale (EDSS). GFAP and NFL levels were determined in CSF by enzyme-linked immunosorbent assay (ELISA). GFAP levels and NFL levels correlated with age (r and r (s) = 0.50, p = 0.006). Adjusting for age, MS patients had increased GFAP levels compared with controls (p = 0.03) and GFAP levels correlated with neurological disability (EDSS, r = 0.51, p < 0.05) and disease progression [Multiple Sclerosis Severity Score (MSSS), r = 0.47, p < 0.05]. The mean annual increase of GFAP was 6.5 ng/L for controls, 8.1 ng/L for RRMS patients, and 18.9 ng/L for SPMS patients. GFAP level at the first examination had predictive value for neurological disability 8-10 years later (EDSS, r = 0.45, p < 0.05) but not for EDSS increase between the examinations. NFL levels were not significantly increased in MS patients compared with controls and had no relationship to disability or progression and no prognostic value for disability development. GFAP, a marker for astrogliosis, is a potential biomarker for MS progression and may have a role in clinical trials for assessing the impact of therapies on MS progression.

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Heightened intrathecal release of axonal cytoskeletal proteins in multiple sclerosis is associated with progressive disease and clinical disability

Cited by 119 publications

References 40 publications

Mechanisms of injury in multiple sclerosis: involvement of antineuroaxonal humoral autoimmunity

Mechanisms of injury in multiple sclerosis: involvement of antineuroaxonal humoral autoimmunity

Elevated intrathecal antibodies against the medium neurofilament subunit in multiple sclerosis

Glial fibrillary acidic protein: a potential biomarker for progression in multiple sclerosis

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