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.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Most patients undergo an initial relapsing-remitting (RR-MS) course that transforms into a ...relentless neurodegenerative disorder, termed secondary progressive (SP)-MS. Reversible inflammation and demyelination account readily for the pattern of RR-MS but provide an unsatisfactory explanation for irrevocable decline in SP-MS. Axon loss is thought to be responsible for progressive, non-remitting neurological disability during SP-MS. There is considerable potential for neuroprotective therapies in MS, but their application awaits animal models in which axonal loss correlates with permanent neurological disability. In this report, we describe quantitative immunohistochemical methods that correlate inflammation and axonal loss with neurological disability in chronic-relapsing experimental autoimmune encephalomyelitis (EAE). At first attack, CNS inflammation, but not axon loss, correlated with the degree of neurological disability. In contrast, fixed neurological impairment in chronic EAE correlated with axon loss that, in turn, correlated with the number of symptomatic attacks. As proposed for MS, these observations imply a causal relationship between inflammation, axon loss, and irreversible neurological disability. This chronic-relapsing EAE model provides an excellent platform for 2 critical objectivesinvestigating mechanisms of axon loss and evaluating efficacy of neuroprotective therapies.
Brain imaging studies detect abnormalities in normal-appearing white matter in patients with MS.
To investigate the histopathologic basis for these changes in autopsy tissue from a patient with MS ...with 9 months' disease duration and a terminal brain stem lesion.
The brain stem and spinal cord were analyzed ultrastructurally and immunocytochemically for axons, myelin, and activated microglia/macrophages.
Pathologic findings were consistent with a terminal inflammatory demyelinated lesion at the cervicomedullary junction. The ventral spinal cord column, containing descending tracts, exhibited 22% axonal loss at segment C7, but grossly normal immunostaining for myelin. Confocal and electron microscopy revealed myelin sheaths without axonal content and initial stages of myelin degradation by activated microglia/macrophages among intact myelinated axons. Axonal number and appearance was normal in ascending sensory tracts.
These studies confirm axonal degeneration in the absence of myelin loss as one histopathologic correlate to abnormal MR findings in patients with MS.
Clearance of lysosomal glycogen has been shown after treatment with ERT (alglucosidase alfa) in LOPD patients. However, there is little data assessing glycogen clearance in ERT-treated LOPD patients. ...This Phase 4, controlled, prospective study evaluated skeletal muscle pathology and ERT response in ERT-naïve LOPD patients. Methods: 15 LOPD patients received alglucosidase alfa 20 mg/kg bi-weekly for 24 weeks. Quadriceps and deltoid biopsies were taken at baseline and week 26. Biopsies were prepared by HRLM and electron microscopy and assessed for glycogen accumulation and secondary pathology. Results: Evaluable baseline and 6-month quadriceps and deltoid biopsies were available for 13 and 10 patients, respectively. Baseline total glycogen (lysosomal plus cytoplasmic glycogen) levels were consistently higher in quadriceps than deltoid muscles. Total glycogen levels in most post-treatment quadriceps and deltoid biopsies were reduced or stable at 6 months vs. baseline. Baseline biopsy examination showed that glycogen was present within lysosomes and in cytoplasm. Post-treatment biopsies revealed that remaining glycogen was overwhelmingly extra-lysosomal and lysosomal glycogen was qualitatively reduced. Secondary changes included occasional foci of autophagic debris. No fibrosis, inflammation or fatty replacement was observed. Conclusions: This is the first proof-of-concept assessment of the histopathologic effects of ERT in LOPD patients. ERT reduced lysosomal glycogen; extra-lysosomal, cytoplasmic glycogen remained in biopsies after 6 months of ERT. This extra-lysosomal glycogen may evolve from the disruption of the lysosomal membrane and leakage of glycogen into the cytoplasm by the repetitive biomechanical forces of muscle contraction which occur in LOPD patients, but less so in IOPD patients. Early diagnosis and treatment of LOPD may translate into lysosomal glycogen clearance and prevention of further accumulation of cytoplasmic glycogen and cellular damage.
Myelinated nerve fibres in the CNS Hildebrand, C; Remahl, S; Persson, H ...
Progress in neurobiology,
03/1993, Letnik:
40, Številka:
3
Journal Article
Recenzirano
(1) Lamellated glial sheaths surrounding axons, and electrogenetically active axolemmal foci have evolved independently in widely different phyla. In addition to endowing the axons to conduct trains ...of impulses at a high speed, myelination and node formation results in a remarkable saving of space and energy. This is particularly important in the CNS, where space is restricted. Unlike the PNS, most CNS axons are myelinated, and several axons may be myelinated by a single cell. This adds further economy of space and energy. On the other hand the high level of complexity of the CNS white matter makes it vulnerable. There are several different kinds of disease affecting myelinated fibre tracts, particularly with respect to CNS white matter. (2) The CNS node of Ranvier presents a more complex structure the larger the fibre. The constricted nodal axon is encircled by perinodal astrocytic processes which contain large gliosomes and emit delicate processes towards the nodal axolemma. One astrocyte may project to several nodes. The node gap contains a polyanionic extracellular material. (3) Lamellated myelinoid bodies are frequent along paranodes of large myelinated CNS fibres. These bodies probably form through budding off from the paranodal myelin sheath. Similar bodies are seen inside astrocytes and microglia. The observation that these bodies are Marchi-positive and argyrophilic, and the presence of acid phosphatase activity around myelinoid bodies inside microglia suggests that they might represent degenerating myelin quanta, involved in the turnover of large myelin sheaths. This putative quantal release and breakdown of myelin material must be compensated for by a production of new myelin at other sites. Therefore, myelination may be viewed as a process that continues throughout life. (4) Biochemical analysis of a sub-cellular fraction enriched in myelinoid bodies shows that these bodies have a composition basically similar to that of myelin. However, breakdown products of myelin constituents, as well as exotic high molecular substances, not present in conventional myelin, can also be found. In addition, the myelinoid body fraction contains proteolytic activity. Studies using isotope labelling of myelin proteins show a source-product relation between myelin and myelinoid bodies. Altogether these data strongly support the hypothesis that myelinoid bodies reflect the catabolic side of myelin turnover. (5) Axons in the nerve fibre layer of the adult rat retina are all unmyelinated, although their diameters range up to over 2 microns. These axons exhibit focally differentiated axolemmal areas. At these sites the axolemma presents a dense undercoating with externally associated Müller cell processes or astrocytic processes.
Renewed interest in axonal injury in multiple sclerosis has significantly shifted the focus of research into this disease toward neurodegeneration. During the past year magnetic resonance and ...morphologic studies have continued to confirm and extend the concept that axonal transection begins at disease onset, and that cumulative axonal loss provides the pathologic substrate for the progressive disability that most long-term MS patients experience. Although inflammation and chronic demyelination are probable causes of axonal transection, little is known about the molecular mechanisms that are involved. The view that MS can also be considered an inflammatory neurodegenerative disease has important clinical implications for therapeutic approaches, monitoring of patients, and future treatment strategies.
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 ≥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. Ann Neurol 2000;48:893–901
Axonal pathology is a major cause of neurological disability in multiple sclerosis. Axonal transection begins at disease onset but remains clinically silent because of compensatory brain mechanisms. ...Noninvasive surrogate markers for axonal injury are therefore essential to monitor cumulative disease burden in vivo. The neuronal compound N‐acetylaspartate, as measured by magnetic resonance spectroscopy, is currently the best and most specific noninvasive marker of axonal pathology in multiple sclerosis. The possibility has been raised, however, that N‐acetylaspartate is expressed also by oligodendroglial lineage cells. In order to investigate N‐acetylaspartate specificity for white matter axons, transected rat optic nerves were analyzed by high‐performance liquid chromatography and immunohistochemistry. In transected adult nerves, N‐acetylaspartate and N‐acetyl aspartylglutamate decreased in concordance with axonal degeneration and were undetectable 24 days posttransection. Nonproliferating oligodendrocyte progenitor cells, oligodendrocytes, and myelin were abundant in these axon‐free nerves. At 24 days posttransection, N‐acetylaspartate was increased (42%; p = 0.02) in nontransected contralateral nerves. After transection at postnatal day 4, total N‐acetylaspartate decreased by 80% (P14; p = 0.002) and 94% (P20; p = 0.003). In these developing axon‐free nerves, 25 to 33% of oligodendrocyte progenitor cells were proliferating. These data validate magnetic resonance spectroscopy measurements of N‐acetylaspartate as an axon‐specific monitor of central nervous system white matter in vivo. In addition, the results indicate that neuronal adaptation can increase N‐acetylaspartate levels, and that 5 to 20% of the N‐acetylaspartate in developing white matter is synthesized by proliferating oligodendrocyte progenitor cells.
Accumulating data support axonal degeneration as the major determinant of irreversible neurological disability in patients with multiple sclerosis (MS). The extent of axonal injury correlates with ...the degree of inflammation in active MS lesions and occurs at early stages of disease, indicating that inflammatory demyelination is an important factor behind axon pathology at the relapsing-remitting stage of MS. Axonal loss from disease onset can remain clinically silent for many years, and permanent neurological disability develops when a threshold of axonal loss is reached and the CNS compensatory resources are exhausted. Lack of myelin-derived trophic support due to long term demyelination may cause continuous axonal degeneration in chronic inactive lesions at the secondary-progressive stage of MS. Axonal pathology is not limited to demyelinated lesions, but also extends into normal appearing white matter. The concept of MS as a neurodegenerative disorder has important clinical implications: First, proactive anti-inflammatory and immunomodulatory treatment should prevent or delay chronic disability since inflammation influences axonal injury. Second, the pathophysiological mechanisms underlying axonal degeneration in MS need to be clarified in order to develop novel neuroprotective therapeutics. Finally, surrogate markers of axonal pathology, such as N-acetyl aspartate, can be used to monitor axonal dysfunction, axonal loss and treatment efficiency in patients with MS.
Clearance of lysosomal glycogen has been shown after treatment with ERT (alglucosidase alfa) in LOPD patients. However, there is little data assessing glycogen clearance in ERT-treated LOPD patients. ...This Phase 4, controlled, prospective study evaluated skeletal muscle pathology and ERT response in ERT-naïve LOPD patients. Methods: 15 LOPD patients received alglucosidase alfa 20mg/kg bi-weekly for 24weeks. Quadriceps and deltoid biopsies were taken at baseline and week 26. Biopsies were prepared by HRLM and electron microscopy and assessed for glycogen accumulation and secondary pathology. Results: Evaluable baseline and 6-month quadriceps and deltoid biopsies were available for 13 and 10 patients, respectively. Baseline total glycogen (lysosomal plus cytoplasmic glycogen) levels were consistently higher in quadriceps than deltoid muscles. Total glycogen levels in most post-treatment quadriceps and deltoid biopsies were reduced or stable at 6months vs. baseline. Baseline biopsy examination showed that glycogen was present within lysosomes and in cytoplasm. Post-treatment biopsies revealed that remaining glycogen was overwhelmingly extra-lysosomal and lysosomal glycogen was qualitatively reduced. Secondary changes included occasional foci of autophagic debris. No fibrosis, inflammation or fatty replacement was observed. Conclusions: This is the first proof-of-concept assessment of the histopathologic effects of ERT in LOPD patients. ERT reduced lysosomal glycogen; extra-lysosomal, cytoplasmic glycogen remained in biopsies after 6months of ERT. This extra-lysosomal glycogen may evolve from the disruption of the lysosomal membrane and leakage of glycogen into the cytoplasm by the repetitive biomechanical forces of muscle contraction which occur in LOPD patients, but less so in IOPD patients. Early diagnosis and treatment of LOPD may translate into lysosomal glycogen clearance and prevention of further accumulation of cytoplasmic glycogen and cellular damage.
PDF
