Biomedical subjects

C Lucchinetti

Publications and source records attributed to C Lucchinetti.

10 recordsLinked to original sources

PubMed2001

A longitudinal MRI study of histopathologically defined hypointense multiple sclerosis lesions.

Severe tissue destruction is the presumed histopathological correlate of hypointense multiple sclerosis (MS) lesions. In this study we correlated changes of lesion hypointensity over time with initial histopathological features in 14 biopsied MS lesions. The extent of hypointensity increased in initially demyelinated plaques and decreased in remyelinating lesions. The initial axonal loss determined the increase of hypointensity over time. In conclusion, both axonal loss and demyelinating activity determine the evolution of hypointensity over time.

Adult↗

PubMed2001

Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy.

Multiple sclerosis is a chronic inflammatory disease of the nervous system in which a T-cell-mediated inflammatory process is associated with destruction of myelin sheaths. Although demyelination is the primary event, axons are also destroyed in the lesions, and the loss of axons correlates with permanent functional deficit. Here, we discuss evidence that demyelination and axonal destruction follow different pathogenetic pathways in subgroups of patients. This might, at least in part, explain the heterogeneity in genetic susceptibility, clinical presentation and response to treatment observed between individuals.

Genetic Heterogeneity↗

PubMed2001

Multiple sclerosis: recent developments in neuropathology, pathogenesis, magnetic resonance imaging studies and treatment.

The cause of multiple sclerosis is generally considered to be entirely T cell mediated. However, recent reports of studies in a variety of animal models of inflammatory demyelinating disease, coupled with detailed pathological analysis and neuroimaging studies of multiple sclerosis patients, indicate that the events involved in the formation of the multiple sclerosis lesion may be more complicated. This complex pathogenesis is reflected in the variable response of multiple sclerosis patients to immunomodulatory therapy.

Axons↗

PubMed2000

Multiple sclerosis.

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Disease Progression↗

PubMed2000

Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination.

Multiple sclerosis (MS) is a disease with profound heterogeneity in clinical course, neuroradiological appearance of the lesions, involvement of susceptibility gene loci, and response to therapy. These features are supported by experimental evidence, which demonstrates that fundamentally different processes, such as autoimmunity or virus infection, may induce MS-like inflammatory demyelinating plaques and suggest that MS may be a disease with heterogeneous pathogenetic mechanisms. From a large pathology sample of MS, collected in three international centers, we selected 51 biopsies and 32 autopsies that contained actively demyelinating lesions defined by stringent criteria. The pathology of the lesions was analyzed using a broad spectrum of immunological and neurobiological markers. Four fundamentally different patterns of demyelination were found, defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction, and the immunopathological evidence of complement activation. Two patterns (I and II) showed close similarities to T-cell-mediated or T-cell plus antibody-mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity. At a given time point of the disease--as reflected in autopsy cases--the patterns of demyelination were heterogeneous between patients, but were homogenous within multiple active lesions from the same patient. This pathogenetic heterogeneity of plaques from different MS patients may have fundamental implications for the diagnosis and therapy of this disease.

Adolescent↗

PubMed1999

A quantitative analysis of oligodendrocytes in multiple sclerosis lesions. A study of 113 cases.

We studied quantitatively the fate of oligodendrocytes (OGs) during lesion formation in 395 lesion areas from biopsy and autopsy tissue of 113 multiple sclerosis cases. The density of OGs in multiple sclerosis lesions was variable at all stages of demyelinating activity, ranging from nearly complete loss to values exceeding those in the periplaque white matter (range 0-970 OGs/mm2) determine whether there were distinct patterns of OG pathology in different patients, we restricted our analysis to the 56 cases in which the longitudinal extent of the lesion extended from periplaque white matter into the active demyelinating edge and inactive plaque centre. Two major groups of OG pathology were defined by the presence or absence of increased OGs within the lesion. In 70% (39 out of 56) of the cases, OGs were variably reduced during active stages of myelin destruction, but reappeared within inactive or remyelinating areas. In inactive areas, an increased number of OGs expressing proteolipid protein (PLP) mRNA compared with those expressing myelin oligodendrocyte glycoprotein (MOG) suggested these cells may have been derived from the progenitor pool. In the remaining 30% (17 out of 56) of the cases, extensive destruction of myelinating cells at active sites of demyelination was observed, but OGs were absent in inactive plaque areas without remyelination. In all lesions from a given patient the pattern of OG pathology remained consistent. A highly significant negative correlation was observed between number of macrophages in lesions and number of MOG- and PLP mRNA-labelled OGs (MOG: r = -0.32, P < 0.0000118; PLP mRNA: r = -0.23, P < 0.00238). OG density did not correlate with T-cell and plasma cell inflammation, or axonal loss. The profound heterogeneity in extent and topography of OG destruction in active demyelinating lesions suggests that in subsets of multiple sclerosis patients, myelin, mature OGs and possibly OG progenitors are differentially affected.

Adult↗

PubMed1999

Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients.

Chemokines direct tissue invasion by specific leukocyte populations. Thus, chemokines may play a role in multiple sclerosis (MS), an idiopathic disorder in which the central nervous system (CNS) inflammatory reaction is largely restricted to mononuclear phagocytes and T cells. We asked whether specific chemokines were expressed in the CNS during acute demyelinating events by analyzing cerebrospinal fluid (CSF), whose composition reflects the CNS extracellular space. During MS attacks, we found elevated CSF levels of three chemokines that act toward T cells and mononuclear phagocytes: interferon-gamma-inducible protein of 10 kDa (IP-10); monokine induced by interferon-gamma (Mig); and regulated on activation, normal T-cell expressed and secreted (RANTES). We then investigated whether specific chemokine receptors were expressed by infiltrating cells in demyelinating MS brain lesions and in CSF. CXCR3, an IP-10/Mig receptor, was expressed on lymphocytic cells in virtually every perivascular inflammatory infiltrate in active MS lesions. CCR5, a RANTES receptor, was detected on lymphocytic cells, macrophages, and microglia in actively demyelinating MS brain lesions. Compared with circulating T cells, CSF T cells were significantly enriched for cells expressing CXCR3 or CCR5. Our results imply pathogenic roles for specific chemokine-chemokine receptor interactions in MS and suggest new molecular targets for therapeutic intervention.

Acute Disease↗

PubMed1999

Bcl-2-expressing oligodendrocytes in multiple sclerosis lesions.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system leading to selective destruction of myelin sheaths and/or oligodendrocytes. The immunological mechanisms responsible for myelin destruction and the primary target of the immune response have not yet been identified. Prior studies have reported a variable degree of oligodendrocyte preservation in actively demyelinating lesions. We have previously demonstrated that oligodendrocyte survival is heterogenous and varies between individual MS patients. Bcl-2 belongs to the group of apoptosis-associated proteins that protects cells from cell death. The purpose of the present study was to determine whether bcl-2 expression is associated with oligodendrocyte preservation observed in some early MS lesions. Double immunocytochemistry was performed with antibodies against bcl-2 and myelin oligodendrocyte glycoprotein (MOG) to identify bcl-2-expressing oligodendrocytes within MS lesions from 43 patients. The number of bcl-2-positive oligodendrocytes was determined depending on the lesion demyelinating activity and the disease course of the patients. The number of bcl-2-expressing oligodendrocytes increased within demyelinating lesions compared to the periplaque white matter, with highest numbers in remyelinating lesions. There was a significant association between the presence of bcl-2-positive oligodendrocytes and the presence of remyelination. The highest proportion of bcl-2-positive oligodendrocytes was observed in a subgroup of patients with relapsing-remitting disease course. The expression of apoptosis-associated proteins may contribute to oligodendrocyte preservation or loss in MS lesions.

Adolescent↗

PubMed1997

Remyelination in multiple sclerosis.

Stimulation of remyelination in multiple sclerosis lesions may be one possible therapeutic approach. However, since the pathology and pathogenesis of multiple sclerosis may be heterogeneous, it is important to analyze in what patients and at what stages of the disease such a therapy can be reasonable and feasible. Spontaneous remyelination is pronounced in some MS patients. The extent of remyelination correlates well with the presence of oligodendrocytes in the lesions. Yet, the source and origin of the remyelinating cells is still unclear. These may be derived from either undifferentiated progenitor cells or, in part from mature oligodendrocytes, that have escaped destruction during lesional activity. Complete remyelination of plaques is possible, leading to the formation of 'shadow plaques'. No reliable data are available at present on the frequency of remyelination in different forms of MS. However, most studies agree that remyelination is especially prominent at the early stages of the disease, whereas it is sparse after several years of disease duration. In addition, very little remyelination is found in cases of primary progressive MS.

Brain↗

PubMed1992

Electrical field effects on crushed nerve regeneration.

The delivery of an electrical field to a transected nerve has been shown to enhance the regeneration. This study examined the effects of such fields on the regeneration of crushed rat sciatic nerve during the first postoperative month. The treated (T) nerve group received a battery implant delivering 10 microA with the cathode at the distal stump. The recovery was compared to an untreated (UT) group and unoperated controls (C). The loss of locomotion behavior and partial recovery (SFI) was identical for the T and UT groups. The index of motor recovery (twitch tension) was also similar (T/C = 48%, UT/C = 53%), but a "window" of enhancement occurred 2-4 days earlier in the T group. Qualitative histology at 28 days suggested a more healthy and normal-appearing nerve in the T group. Morphometric analysis indicated that the nerve area, fiber density, and fiber number in the T group were more similar to those in the control group than to those in the UT group. There were no group differences in the number of HRP-labeled motoneurons, but the enlarged endoneurial space was significantly reduced in the T group compared to the UT group. In conclusion, electrical fields appeared to have a small effect on some aspects of nerve regeneration following crush injury.

Analysis of Variance↗