Inactive Plaques Research Articles

Atherosclerotic plaque imaging by PET/CT; can inactive, active and mixed plaques be discerned?

Atherosclerosis is one of the leading causes ofmorbidity and mortality in the world. Rupture ofatherosclerotic plaques and formation of thrombi arethe primary mechanisms of myocardial infarction orcerebrovascularaccidents.Atherosclerosisisthereforea dynamic inflammatory disorder and the biologicalcomposition and inflammatory state of an atheroscle-rotic plaque, rather than the degree of stenosis or itssize, are the major determinants of acute clinicalevents [1, 2]. Noninvasive techniques to detectvulnerable atherosclerotic plaque are criticallyneeded. In recent years, radionuclide imaging [3–6],magnetic resonance imaging (MRI) [7–13], and com-puted tomography (CT) have been put forward as themost relevant imaging modalities to identify athero-sclerotic vascular disease and the vulnerable plaque[14–30]. Positron emission tomography with fluoro-deoxyglucose (FDG-PET) has become one of theadvanced imaging approaches for the detection ofvulnerable plaques [31]. Ogawa et al. [32] showed thatmacrophages are responsible for the accumulation ofFDG in atherosclerotic lesions whereby FDG uptake iscorrelated with macrophage density. Because vulner-able plaques are rich in macrophages, FDG imagingshould be useful for selective detection of suchplaques. In recent years, multislice CT has been shownto provide excellent anatomical and morphologicalimages both of the large vessels and the coronaryarteries [18]. In addition, differences in plaque com-position and distribution—both in acute coronarysyndromes and stable coronary artery disease—canadequately be visualized with multislice-CT [29, 30].Hybrid imaging with both PET and CT, being acombined functional and structural whole-body imagingmodality, could therefore offer the optimal potentialto characterize plaque composition [33, 34]. Tatsumiet al. [35] showed in 85 patients who underwent FDGPET/CT imaging that FDG uptake was commonlydepicted in the thoracic aortic wall. The FDG uptakesite was mostly distinct from the calcification site andwas located in areas of metabolic activity (i.e.,macrophages) of atherosclerotic changes. Ben-Haimet al. [36] evaluated FDG uptake in atheroscleroticplaques in 50 asymptomatic patients. Repeat PET/CTstudies were performed to assess changes in patternsof FDG uptake and CT calcifications. FDG-avid focirepresent a dynamic process of transient inflamma-tion, whereas CT calcifications indicate stableatherosclerosis. Hybrid imaging with PET/CT createstherefore incremental value over both imagingmodalities alone. Rudd et al. [37] showed thatatherosclerosis imaging with FDG-PET/CT wasuseful for tracking inflammation within plaques.

Assessment of inactive, active and mixed atherosclerotic plaques by 18F-FDG-PET; an age group-based correlation with cardiovascular risk factors

The aim of this study was to assess the atherosclerotic plaques in a large asymptomatic population stratified based on age and sex. [18F]-2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT of 100 men and 100 women, divided in four age groups were examined to assess FDG-accumulating active, calcified inactive and mixed atherosclerotic plaques in eight defined vessel segments. There was a high correlation between the total number of cardiovascular risk factors and the number of FDG-accumulating active plaques as well as the number of calcified inactive plaques. There was a significant difference in the number of plaques between all age-groups except for active plaques in age groups 60-70 and 80-90 years. There is a correlation between the number of cardiovascular risk factors and the number of FDG-accumulating atherosclerotic lesions in this patient material. Statin-treatment was associated with significantly lower numbers of active plaques.

Cannabinoid CB1and CB2Receptors and Fatty Acid Amide Hydrolase Are Specific Markers of Plaque Cell Subtypes in Human Multiple Sclerosis

Increasing evidence supports the idea of a beneficial effect of cannabinoid compounds for the treatment of multiple sclerosis (MS). However, most experimental data come from animal models of MS. We investigated the status of cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase (FAAH) enzyme in brain tissue samples obtained from MS patients. Areas of demyelination were identified and classified as active, chronic, and inactive plaques. CB1 and CB2 receptors and FAAH densities and cellular sites of expression were examined using immunohistochemistry and immunofluorescence. In MS samples, cannabinoid CB1 receptors were expressed by cortical neurons, oligodendrocytes, and also oligodendrocyte precursor cells, demonstrated using double immunofluorescence with antibodies against the CB1 receptor with antibodies against type 2 microtubule-associated protein, myelin basic protein, and the platelet-derived growth factor receptor-alpha, respectively. CB1 receptors were also present in macrophages and infiltrated T-lymphocytes. Conversely, CB2 receptors were present in T-lymphocytes, astrocytes, and perivascular and reactive microglia (major histocompatibility complex class-II positive) in MS plaques. Specifically, CB2-positive microglial cells were evenly distributed within active plaques but were located in the periphery of chronic active plaques. FAAH expression was restricted to neurons and hypertrophic astrocytes. As seen for other neuroinflammatory conditions, selective glial expression of cannabinoid CB1 and CB2 receptors and FAAH enzyme is induced in MS, thus supporting a role for the endocannabinoid system in the pathogenesis and/or evolution of this disease.

Inflammatory demyelination is not central to the pathogenesis of multiple sclerosis

Multiple sclerosis is a disease of the central nervous system that destroys myelin, oligodendrocytes, neurons and axons. Historically considered to be caused by an autoimmune process mainly affecting myelin and oligodendrocytes in the white matter, recent data provide evidence that a generalized, diffuse neurodegenerative process plays an important role in the pathogenesis of MS. There is a high density of axonal transections in active demyelinating lesions, but also persistent low-level axonal damage in inactive plaques and diffuse axonal and neuronal loss throughout the nervous system. Initial axonal injury appears to be closely related to inflammation, but is not restricted to the lesions themselves. Damage may be propagated throughout the nervous system by anterograde Wallerian, retrograde or transynaptic degeneration. Cumulative tissue loss in the grey and white matter, especially of axons, is important and probably the principal determinant of accumulation of irreversible neurological disability and of conversion to a progressive disease course.

Up‐regulation of osteopontin and αΒ‐crystallin in the normal‐appearing white matter of multiple sclerosis: an immunohistochemical study utilizing tissue microarrays

Tissue microarrays assembled from control and multiple sclerosis (MS) brain tissue have been used to assess the expression patterns and cellular distribution of two antigens, the proinflammatory cytokine osteopontin and the inducible heat shock protein alphaBeta-crystallin, which have previously been implicated in MS pathogenesis. Tissue cores were taken from paraffin-embedded donor blocks containing chronic active or chronic inactive plaques and normal-appearing white matter (NAWM) in seven MS cases, and white matter (WM) in five control cases. Expression patterns of both proteins were assessed against myelin density and microglial activation in the different tissue categories. Both proteins showed increased expression in all categories of MS tissue compared with control WM. The results indicate progressive up-regulation of expression of osteopontin with increased plaque activity, while elevation of alphaBeta-crystallin expression in MS tissue was independent of demyelination. In MS NAWM a significant correlation was observed between high levels of expression of osteopontin and alphaBeta-crystallin. Osteopontin expression was predominantly confined to astrocytes throughout MS tissues. alphaBeta-crystallin was expressed on astrocytes, oligodendrocytes and occasionally on demyelinated axons. Taken together, these data indicate a wider distribution of osteopontin and alphaBeta-crystallin in MS tissues than previously described and support their proposed role in MS pathogenesis.

The adhesion molecule P-selectin and cardiovascular disease.

The adhesion molecule P-selectin (CD62P) is of interest because of its role in modulating interactions between blood cells and the endothelium, and also because of the possible use of the soluble form as a plasma predictor of adverse cardiovascular events. Although present on the external cell surface of both activated endothelium and activated platelets, it now seems clear that most, if not all, of the measured plasma P-selectin is of platelet origin. P-selectin is partially responsible for the adhesion of certain leukocytes and platelets to the endothelium. Animal models have also shown the important role of P-selectin in the process of atherogenesis. For example, increased P-selectin expression has been demonstrated on active atherosclerotic plaques; in contrast, fibrotic inactive plaques lack P-selectin expression, and animals lacking P-selectin have a decreased tendency to form atherosclerotic plaques. Increased levels of soluble P-selectin in the plasma have also been demonstrated in a variety of cardiovascular disorders, including coronary artery disease, hypertension and atrial fibrillation, with some relationship to prognosis. The objective of this review is to provide an overview of the current literature on this molecule and thus present a concise view of its potential in dissecting the pathophysiology of atherosclerosis. In doing so we shall focus primarily on human biology but will note a small number of excellent lessons provided by non-human work.

Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood-brain barrier leakage and active demyelination.

Blood-brain barrier (BBB) hyperpermeability in multiple sclerosis (MS) is associated with lesion pathogenesis and has been linked to pathology in microvascular tight junctions (TJs). This study quantifies the uneven distribution of TJ pathology and its association with BBB leakage. Frozen sections from plaque and normal-appearing white matter (NAWM) in 14 cases were studied together with white matter from six neurological and five normal controls. Using single and double immunofluorescence and confocal microscopy, the TJ-associated protein zonula occludens-1 (ZO-1) was examined across lesion types and tissue categories, and in relation to fibrinogen leakage. Confocal image data sets were analysed for 2198 MS and 1062 control vessels. Significant differences in the incidence of TJ abnormalities were detected between the different lesion types in MS and between MS and control white matter. These were frequent in oil-red O (ORO)(+) active plaques, affecting 42% of vessel segments, but less frequent in ORO(-) inactive plaques (23%), NAWM (13%), and normal (3.7%) and neurological controls (8%). A similar pattern was found irrespective of the vessel size, supporting a causal role for diffusible inflammatory mediators. In both NAWM and inactive lesions, dual labelling showed that vessels with the most TJ abnormality also showed most fibrinogen leakage. This was even more pronounced in active lesions, where 41% of vessels in the highest grade for TJ alteration showed severe leakage. It is concluded that disruption of TJs in MS, affecting both paracellular and transcellular paths, contributes to BBB leakage. TJ abnormality and BBB leakage in inactive lesions suggests either failure of TJ repair or a continuing pathological process. In NAWM, it suggests either pre-lesional change or secondary damage. Clinically inapparent TJ pathology has prognostic implications and should be considered when planning disease-modifying therapy.

Proliferating oligodendrocytes are present in both active and chronic inactive multiple sclerosis plaques.

The proliferation marker Ki-67 labels cell nuclei in the G(1), S, M, and G(2) phases of the cell cycle. We used Ki-67 immunohistochemistry to quantify proliferating glial cells in brain tissue sections from twenty-four patients, comprised of multiple sclerosis, normal brains, and other neurological disease controls. Glial proliferation was greatly increased in MS lesions when compared with control brain white matter. Both actively demyelinating/early remyelinating plaques and chronic inactive plaques of long standing often displayed large numbers of glial cells in the proliferative cycle. The bulk of these proliferating cells were of oligodendroglial lineage in the MS plaques. Ki-67 positive macrophage/microglial lineage cells were largely restricted to acute lesions. The finding of increased numbers of proliferating oligodendroglia in most MS plaques, regardless of disease duration or activity state, indicates that the MS brain is capable of recruiting unexpectedly large numbers of new oligodendrocytes over long periods of time. The factors within the MS plaque microenvironment that provoke new oligodendrocyte generation and their subsequent loss still need to be identified.

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.

Astrocytes in multiple sclerosis lack beta-2 adrenergic receptors.

In MS, T cells reactive to myelin proteins can cross the blood-brain barrier and release proinflammatory cytokines, such as interferon gamma. These can induce glial cells to express class II major histocompatibility complex (MHC) molecules, which are required to present myelin antigens to the T cells in order to mount a proper autoimmune response. Both microglia and astrocytes can function as antigen-presenting cells. In contrast to microglia, endogenous suppressors, including norepinephrine, regulate astrocytic class II MHC expression. The effects of norepinephrine are mediated through activation of P2 adrenergic receptors. To investigate P, adrenergic receptors in astrocytes in MS. Immunocytochemical techniques were applied in postmortem brain tissue from 10 patients with MS, three patients with a cerebral infarction, and six controls, and in spinal cord from three patients with ALS. beta2 adrenergic receptors were visualized on astrocytes in white matter of controls, and they were prominently expressed in reactive astrocytes at the boundary of cerebral infarctions and in the lateral corticospinal tract in ALS. In MS, beta2 adrenergic receptors could neither be visualized on astrocytes in normal-appearing white matter nor in reactive astrocytes in chronic active and inactive plaques, whereas they were normally present on neurons. MHC class II-positive astrocytes were only visualized in chronic active plaques. Because astrocytic beta2 adrenergic receptors are involved in suppressing inducibility of MHC class II molecules, we suggest that their lack of expression may play an important role in the induction or perpetuation of autoimmune reactions in MS.

Endothelial Cell Integrin Laminin Receptor Expression in Multiple Sclerosis Lesions

Laminin, a major glycoprotein component of vessel basement membranes, is recognized by beta1- and beta3-integrins expressed on endothelial cells. To determine how endothelial cell integrins might function in multiple sclerosis (MS) lesions, integrin laminin receptors and laminin were analyzed in central nervous system samples from MS patients and controls by immunohistochemistry. In active MS lesions, endothelial cell VLA-6 and beta1 subunits were decreased compared to controls whereas alpha(v) subunit and VLA-1 were increased. In chronic inactive lesions beta1, VLA-6 and alpha(v) were the same as controls but VLA-1 remained increased. Alpha3 subunit was constant in all samples. By immunoelectron microscopy VLA-1, VLA-6, beta1, and laminin were distributed throughout endothelial cells; alpha(v) was adjacent to and on luminal surfaces; alpha(v) and VLA-1 were on intercellular junctions. These results indicate distinct regulation and functions of these integrins in different lesion stages. In active lesions decreased endothelial cell beta1/VLA-6 could result in their detachment from laminin thereby facilitating leukocyte transvascular migration and blood-brain barrier breakdown. Alpha(v) and VLA-1 on intercellular junctions may participate in re-establishing vessel integrity after leukocyte migration. Luminal surface alpha(v) also likely binds intraluminal ligands and cells. In chronic inactive plaques persistently elevated endothelial cell VLA-1 correlates with long-standing endothelial cell and blood-brain barrier dysfunction.

The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis. Identification and characterization of the primary demyelinating lesion.

Tissues from 13 exceptionally early cases of multiple sclerosis were studied to identify and characterize the primary demyelinating lesion, using a variety of histological and immunocytochemical methods. Multifactorial cluster analysis identified five significantly distinct lesion groups, which showed histological progression from simple microglial lesions, predominating in tissues from the earliest cases, to complex hypercellular fully demyelinated plaques, chiefly associated with cases of intermediate duration. Quiescent lesions showing evidence of remyelination were found at all stages of the disease studied, but hypocellular inactive plaques, were associated with older cases. Evidence is presented that initial demyelination is effected by activated resident microglia. Undegraded myelin is initially enveloped by membranes bearing fixed complexes of immunoglobulin and complement. In contrast with perivenous encephalomyelitis, in which demyelination was dominated by T-cell infiltration, multiple sclerosis lesions of comparable duration and maturity exhibited humoral immune reactions. Parenchymal CD4+ T-cell infiltration developed in association with subsequent plaque maturation. These results emphasize the need for lesion staging when multiple sclerosis tissues are being used in the investigation of pathogenic mechanisms, and suggest that further analysis of the oligoclonal B-cell response may be productive in the search for primary provoking antigens.

High resolution proton MR spectroscopy of cerebrospinal fluid in MS patients. Comparison with biochemical changes in demyelinating plaques

Proton magnetic resonance spectroscopy (1H-MRS) investigation was performed on CSF samples of patients with neurological inflammatory diseases including 53 cases of multiple sclerosis (MS), 12 acute idiopathic polyneuropathies, 20 acute meningitides (10 viral and 10 bacterial). Spectra were compared with those acquired in 18 neurological controls. High CSF lactate levels were found in MS patients during clinical exacerbation of relapsing-remitting course (p = 0.036 vs. neurological controls). In MS patients with MRI evidence of Gd-enhanced plaques CSF lactate was higher than in patients with MRI inactive plaques (p = 0.017). CSF lactate positively correlated with number of CSF mononuclear cells in MS patients with clinical activity (p = 0.05) as well as in MS patients with MRI enhancement (p = 0.003). A comparative 1H-MRS investigation in vivo on localized demyelinating areas confirmed an elevated lactate signal in Gd-enhanced (61%) more frequently than in unenhanced (22%) plaques (p = 0.03). MS patients with high lactate signal in active plaques showed high lactate levels in CSF. Increased CSF lactate was found also in patients with acute meningitis and idiopathic polyneuropathy. These data suggest that changes in lactate levels may depend on anaerobic glycolytic metabolism in activated leukocytes during inflammatory diseases. A decrease of CSF formate levels was found in MS patients during active and inactive clinical phase (p = 0.037, p = 0.05 vs. neurological controls respectively). Formate changes might be related to a disorder of choline-glycine cycle in MS. 1H-MRS in vivo showed significant increase of choline in acute plaques, whereas a decrease of N-acetyl aspartate was found in chronic plaques; these metabolites are undetectable in CSF. CSF glucose levels were lower in bacterial than in viral meningitis (p = 0.014) and in neurological controls (p = 0.05). These observations suggest that 1H-MRS may be able to detect CSF metabolic impairment in neurological inflammatory diseases. In MS some CSF findings reflect metabolic changes occurring in brain demyelinating areas, and they could be useful for evaluation of disease activity in different stages of disease evolution.

Herpes Simplex Virus in Postmortem Multiple Sclerosis Brain Tissue

Herpes simplex virus (HSV) is a common neurotropic virus that is capable of long latencies. It can cause focal demyelination in animals. To test for the presence of HSV-1 and -2 in postmortem brain samples from patients with multiple sclerosis (MS) and controls using polymerase chain reaction and Southern blot hybridization. Dissected plaque tissue classified as active or inactive and unaffected white matter (WM) and gray matter (GM) from 37 cases of MS were screened for HSV using polymerase chain reaction and Southern blot hybridization. White matter and GM from 22 cases of Alzheimer's disease, 17 cases of Parkinson's disease, and 22 cases without neurologic disease served as controls. Forty-six percent (17/37) of the MS cases and 28% (17/61) of the control cases had samples that were positive for HSV (P = .11). Forty-one percent (9/22) of active plaques and 20% (6/30) of inactive plaques were positive for HSV. Twenty-four percent (9/37) and 14% (5/37) of MS cases and 23% (14/61) and 13% (8/61) of non-MS cases had HSV in WM and GM, respectively. No significant differences were found among all subgroups (P = .10). Herpes simplex virus was present in more MS cases than control cases and in more active plaques than inactive plaques. The presence of HSV in WM and GM in cases of MS as well as in control cases makes an etiologic association to the MS disease process uncertain, but cellular localization of HSV and its relationship to oligodendrocytes and latency may reveal such an association in future studies.

Detection of herpesviridae in postmortem multiple sclerosis brain tissue and controls by polymerase chain reaction.

To test for the presence of herpesviruses in postmortem brain samples from multiple sclerosis patients and controls using polymerase chain reaction. Herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, and human herpesvirus-6 are common viruses capable of persistence and latency. All have been detected in the CNS. Active and inactive plaque tissue, unaffected white matter (WM) and gray matter (GM) from MS cases, and WM and GM controls (Alzheimer's disease, Parkinson's disease and non-neurological disease) were screened for the herpesvirus by PCR. (1) 37% of the MS cases were positive for herpes simplex virus (HSV). Twenty-eight percent of controls cases were positive for HSV. Forty-one percent of active plaques were positive for HSV in contrast to only 20% of inactive plaques (Sanders et al, 1996). (2) 57% of the MS cases and 43% of the control cases were positive for HHV-6. Thirty-two percent of the active plaques contained HHV-6 compared to 17% of inactive plaques. (3) 43% of the MS cases and 32% of the control cases were positive for VZV. Fourteen percent of the active plaques and 10% of the inactive plaques were positive for VZV. (4) 27% of MS cases and 38% of control cases were positive for EBV. Five percent of the active plaques were positive for EBV and 10% of the inactive plaques were positive. (5) 16% of the MS cases and 22% of the controls were positive for CMV. Nine percent of the active plaques and 10% of the inactive plaques were positive. We also compared MS WM and GM with controls and found no significant difference. HSV, HHV-6, and VZV were present in a greater frequency of MS cases compared to controls; however, no statistical differences were noted. The presence of herpesvirus in all tissue makes an etiologic association to MS uncertain. Cellular localization of virus and its relationship to pathology and latency may reveal an association.

812-21 Angiographic Progression of Inactive Unstable Plaque versus Stable Plaque in Patients with Stable Angina

The angiographic progression of ischemia-related stenoses (IRS) and non-IRS stenoses was prospectively assessed in 256 patients (pts) with stable angina (stable symptoms for at least 3 months) using computerized angiography. IRS were categorized as inactive unstable plaque (IRS which was responsible for a previous (&gt;3 months) episode of unstable angina) in 76 pts (Group 1) and stable plaque (IRS which was not associated with a previous acute episode) in the remaining 180 pts (Group 2.). Following diagnostic angiography, pts were put on a waiting list for PTCA and restudied (8 ± 3 months after first angiogram) immediately preceding PTCA (230 pts) or soon after occurrence of coronary events (MI in 9 pts, unstable angina in 17 pts). IRS were complex (irregular borders, overhanging edges or introcoronary thrombus) in 40 of 76 (55%) inactive unstable plaques and 25 of 180 (21%1 stable plaques (p &lt; 0.001). Stenosis progression (&gt;20% diameter reduction or new total occlusion) and coronary events occurred more frequently in Group 1 than in Group 2 (26% vs. 11%, p = 0.01 and 17% vs. 7%, p = 0.02, respectively). IRS progressed in 14 pts of Group 1 and 9 pts of Group 2 (18% vs. 5%, p = 0.001). Progression of non-IRS (15 of 404 (4%)) was similar in Groups 1 and 2 (5% vs. 5%). Pts of Group 1 were younger than patients of Group 2 (55 ± 8 vs. 59 ± 10 (years). p = 0.002). Pts gender, risk factors, multivessel disease, baseline severity of IRS were not associated with IRS progression. Multiple regression analysis showed that inactive unstable plaque, angiographic complex morphology, and coronary events independently predicted IRS progression (p = 0.03, p = 0.02, and p = 0.0001, respectively). Change of percent stenosis (%) and minimal stenosis diameter (mm) in different subgroups were as following: 1st angio (%) 2nd angio (%) Δ (%) 1st angio (mm) 2nd angio (mm) Δ (mm) IRS in G1 66.3 ± 6.9 72.3 ± 15.3 * 6.0 ± 14.7 1.14 ± 0.26 0.88 ± 0.49* 0.26 ± 0.46 IRS in G2 65.6 ± 17.5 66.6 ± 11.0 † 1.0 ± 9.4 § 1.14 ± 0.28 1.10 ± 0.37 * 0.04 ± 0.28§ non-IRS in Gl 44.3 ± 12.2 46.6 ± 13.8 * 2.3 ± 95 1.69 ± 045 1.59 ± 0.48 * 0.10 ± 0.32 non-IRS in G2 44.1 ± 13.2 46.3 ± 12.6 * 2.2 ± 10.1 1.71 ± 0.45 1.63 ± 0.50 * 0.08 ± 0.31 Data are mean ± SD. G = Group, Angio = angiogram * p &lt; 0.01 † p &lt; 0.05 vs 1st angio by paired t-test § p &lt; 0.001 vs IRS in Gl by unpaired t-test In pts with stable angina, inactive unstable plaques, and stenoses with complex morphology are predictors of rapid progression. Our results may be of clinical and pathophysiological relevance.

Macrophage populations associated with multiple sclerosis plaques.

The macrophage population within and outside plaques from eight cases of multiple sclerosis (MS) (two clinically acute, four chronic progressive and two chronic non-progressive) has been examined in fresh frozen sections with a panel of monoclonal antibodies of macrophage, monocyte and MHC class II specificity. The majority of cells in active, hypercellular plaques, and at active borders, reacted with macrophage- and class II MHC-specific antibodies, and such cells extended beyond the border between demyelinated and myelinated parenchyma. In inactive plaques such cells that reacted with macrophage-specific antibodies were sparse and reacted only inconstantly with class II MHC-specific antibodies. Macrophage heterogeneity was evident in as much as one macrophage antibody, RFD7, reacted only with perivascular and not parenchymal macrophages in most plaques, but reacted with a variable proportion of parenchymal macrophages in active plaques. It is suggested that the RFD7 antibody may identify a sub-population of acute plaques, and that its use may clarify interpretation of findings related to other inflammatory cell populations by providing greater precision of classification of active plaques.

T CELL SUBSETS IN MULTIPLE SCLEROSIS

This report provides a quantitative analysis of the distribution of helper-inducer T cells (H-I, LEU3A+) and cytotoxic-suppressor T cells (C-S, OKT8+) performed in a standardized fashion on material from 10 cases of multiple sclerosis. Particular attention was paid to cells at the plaque edge and to normal appearing white matter adjacent to plaques. Numbers of both the C-S and the H-I subset peaked directly at the edges of plaques, whether histopathologically active or inactive (P less than 0.01). Normal appearing areas outside active plaques had fewer C-S cells than equivalent areas outside inactive plaques (P less than 0.05). A study of three whole plaques showed that the sum of the two T cell subsets was significantly greater than the number of cells bearing the pan-T cell marker in two plaques and in two border regions. The present results support a crucial role for the balance of T cell subsets in the evolution of plaque margins. When taken together with similar findings in experimental allergic encephalomyelitis, they suggest that helper-inducer cell dominance at the border is necessary for plaque expansion while C-S dominance in non plaque areas is associated with controlled disease. In addition, they suggest either modulation of the OKT3 surface antigen or the presence of a non-T cell bearing OKT8 in association with the site of histopathological change.

Blood-brain barrier in chronic relapsing experimental allergic encephalomyelitis: a correlative study between cerebrospinal fluid protein concentrations and tracer leakage in the central nervous system.

Blood-brain barrier (BBB) permeability in chronic relapsing experimental allergic encephalomyelitis was studied morphologically in tracer studies with horseradish peroxidase (HRP) as well as by quantitative determination of HRP, albumin, and IgG in serum and cerebrospinal fluid (CSF). BBB damage was found to be localized in demyelinating plaques and in blood vessels with vasculitis. Actively demyelinating lesions showed massive increase in BBB permeability, whereas in inactive or remyelinated lesions BBB damage was either minimal or absent. Determination of serum proteins in the CSF of animals with severe disease and a high incidence of actively demyelinating lesions showed evidence of BBB damage (reduction of Q-albumin) and an IgG-index in the normal range. In animals with only inactive lesions the Q-albumin was normal, the IgG index, however, was elevated. This finding indicates intrathecal IgG synthesis. A correlation between morphologically visualized tracer leakage in the central nervous system (CNS) with serum protein concentrations in the CSF revealed that elevated CSF albumin is a reliable indicator for BBB damage in lesions, located near the inner or outer surface of the brain and spinal cord. However, singular focal lesions with BBB damage located in the depth of the CNS parenchyma may not be accompanied by CSF protein alterations. The invariable presence of BBB damage in active inflammatory demyelinating lesions and its absence in inactive plaques or in the unaffected nervous tissue may be important in therapy, not only in experimental allergic encephalomyelitis but also in multiple sclerosis (MS).

Schwann cell remyelination of demyelinated axons in spinal cord multiple sclerosis lesions.

To investigate remyelination in multiple sclerosis lesions, we immunostained spinal cord sections from patients with multiple sclerosis and neurological normal (control) patients with antisera to P0 protein, a major constituent of peripheral nervous system myelin, and myelin basic protein, which is found in both central and peripheral nervous system myelin. In sections from five of the eight patients with no clinical or pathological evidence of neurological disease, P0 immunostaining was confined to peripheral myelin sheaths in dorsal and ventral roots. They were intensely stained, and peripheral--central nervous system transition zones were clearly demarcated. Sections from the other three control patients contained a few P0-stained sheaths in the central nervous system near root entry zones or among marginal glia near the dorsal sulcus. Spinal cord sections from six of the ten patients with multiple sclerosis contained clusters of myelin sheaths immunostained by P0 antiserum. These regenerating sheaths of peripheral nervous system origin were most numerous in large lesions and were commonly located in central areas or peripherally near root entry zones. The sheaths were observed frequently in areas of active demyelination and appeared morphologically normal even when surrounded by debris-filled macrophages. Near margins of small inactive plaques were a few basic protein--stained oligodendroglia extending processes to thin basic protein--stained sheaths.(ABSTRACT TRUNCATED AT 250 WORDS)