Evaluation of serum miR-191-5p, miR-24-3p, miR-128-3p, and miR-376c-3 in multiple sclerosis patients.

BACKGROUND: Biomarkers that could be used in early diagnosis of multiple sclerosis (MS), segregation of disease subtypes, and discrimination of the aggressive disease course from the benign one are urgently needed. OBJECTIVE: The aim of this study was to investigate the specificity of circulating microRNAs: miR-191-5p, miR-128-3p, miR-24-3p, and miR-376c-3p in MS and evaluate their association with disease activity and disability progression. METHODS: The expressions of circulating miRNAs were studied in serum of 100 subjects (53 relapsing-remitting (RRMS), 20 primary progressive (PPMS), and 27 controls), using miScript serum miRNA RT-PCR assay techniques. RESULTS: In comparison with controls, miR-191-5p and miR-24-3p were overexpressed in RRMS and PPMS, with no differences between the subtypes. miR-24-3p correlated positively with the disability progression index in the combined group of all patients with MS. miR-128-3p showed tendency toward the predominant expression in PPMS and correlated positively with the annual relapse rate in RRMS. miR-376c-3p expression levels did not differ between the groups, and no associations were found to clinical parameters. CONCLUSION: This study highlighted the connection of circulating miRNAs to MS. miR-24-3p and miR-128-3p showed a tendency of association with disability accumulation and disease activity, respectively. Further studies should evaluate their suitability for clinical use.

Anti-JC virus seroprevalence in a Finnish MS cohort.

BACKGROUND: The risk of progressive multifocal leukoencephalopathy (PML) caused by the JC virus (JCV) is increased in patients with multiple sclerosis receiving biological therapies. OBJECTIVES: To determine the seroprevalence of anti-JCV antibodies in Finnish patients with multiple sclerosis (MS) and clinically isolated syndrome and to assess the clinical risk factors for JCV seropositivity. METHODS: The JCV seroprevalence was analyzed in 503 patients using a second-generation two-step ELISA. Sixty-seven patients underwent longitudinal serological evaluation over 4.5 years. RESULTS: The overall seroprevalence of JCV was 57.4%. The seropositivity was higher in men than in women, tended to increase with age, and was not affected by different immunomodulatory therapies. However, in patients with ongoing natalizumab treatment (n = 72), the anti-JCV antibody screening index was lower than in patients without such therapy [median 0.3 (range 0.1-3.1) vs 0.6 (0.1-3.1), respectively, P = 0.01]. Over 4.5 years, 4/19 (21%) initially seronegative patients converted to seropositivity, whereas 4/48 (8.3%) initially seropositive patients reverted to seronegativity. Fluctuations in serostatus were observed in 3/67 patients. CONCLUSION: The study confirmed a high anti-JCV antibody prevalence in patients with MS and its association with age and male gender but not with disease-modifying therapies. Our data suggest that therapy with natalizumab may cause a decrease in anti-JCV antibody levels, suggesting an immunosuppressive effect of natalizumab without an impact on JCV seroprevalence. The results of studies performed until now confirm the predictive value of anti-JCV antibody measurement in the assessment of PML risk; however, changes in serostatus need to be considered.

The mid-M1 segment of the middle cerebral artery is a cutoff clot location for good outcome in intravenous thrombolysis.

BACKGROUND AND PURPOSE: We studied the impact of the location of the thrombus (internal carotid artery, proximal M1 segment, distal M1 segment, M2 segment, and M3 segment of the middle cerebral artery) in predicting the clinical outcome of patients treated with intravenous thrombolytic therapy (<3 h) in a retrospective cohort. METHODS: Anterior circulation thrombus was detected with computed tomography angiography in 105 patients. Baseline clinical and radiological information was collected and entered into logistic regression analysis to predict favorable clinical outcome (3-month modified Rankin Scale from 0 to 2 was a primary outcome measure). RESULTS: Three months after stroke, there was a significant increase in mortality (32% vs. 3%, P < 0.001) and functional dependency (82% vs. 29%, P < 0.001) in patients with internal carotid artery or proximal M1 segment of the middle cerebral artery thrombus compared to a more distal occlusion. In the regression analysis, after adjusting for National Institutes of Health Stroke Scale, age, sex, and onset-to-treatment time, the clot location was an independent predictor of good clinical outcome (P = 0.001) and exhibited dose-response type behavior when moving from a proximal vessel position to a more distal one. When the location was dichotomized, a cutoff between the proximal and the distal M1 segments best differentiated between good and poor clinical outcome (OR = 16.0, 95% CI 3.9-66.2). CONCLUSIONS: The outcome of acute internal carotid artery or proximal M1 segment of the middle cerebral artery occlusion is generally poor even if treated with intravenous thrombolysis. Alternative revascularization strategies should be considered. Vascular imaging at the admission is required to guide this decision.

DARS2 mutations in mitochondrial leucoencephalopathy and multiple sclerosis.

BACKGROUND: Leucoencephalopathy with brain stem and spinal cord involvement and high brain lactate (LBSL) was first defined by characteristic magnetic resonance imaging and spectroscopic findings. The clinical features include childhood or juvenile onset slowly progressive ataxia, spasticity, and dorsal column dysfunction, occasionally accompanied by learning difficulties. Mutations in DARS2, encoding mitochondrial aspartyl-tRNA synthetase, were recently shown to cause LBSL. The signs and symptoms show some overlap with the most common leucoencephalopathy of young adults, multiple sclerosis (MS). OBJECTIVE: To clarify the molecular background of LBSL patients in Finland, and to look for DARS2 mutations in a group of MS patients. METHODS: Clinical evaluation of LBSL patients, DARS2 sequencing and haplotype analysis, and carrier frequency determination in Finland. RESULTS: All eight LBSL patients were compound heterozygotes for DARS2 mutations: all carried R76SfsX5 change, seven had M134_K165del, and one had C152F change. Axonal neuropathy was found in five of the eight patients. The carrier frequencies of the R76SfsX5 and M134_K165del mutations were 1:95 and 1:380, respectively. All patients shared common European haplotypes, suggestive of common European LBSL ancestors. No enrichment of the two common DARS2 mutations was found in 321 MS patients. CONCLUSION: All LBSL patients were compound heterozygotes, which suggests that DARS2 mutation homozygosity may be lethal or manifest as a different phenotype. The authors show here that despite identical mutations the clinical picture was quite variable in the patients. Axonal neuropathy was an important feature of LBSL. DARS2 mutations cause childhood-to-adolescence onset leucoencephalopathy, but they do not seem to be associated with MS.

High human T cell lymphotropic virus type 1 (HTLV-1)-specific precursor cytotoxic T lymphocyte frequencies in patients with HTLV-1-associated neurological disease.

The frequencies of human T cell lymphotropic virus type 1 (HTLV-1)-specific CD8+ precursor cytotoxic T lymphocytes (pCTL) were quantitated from lymphocytes obtained from the peripheral blood and cerebrospinal fluid (CSF) of infected individuals with and without HTLV-1-associated neurological disease. An estimate of the pCTL was obtained by separating CD8+ cells, plating these cells in limiting dilution, and testing wells for HTLV-1 specific lysis. Targets consisted of autologous lymphoblastoid cell lines (LCL) infected with vaccinia constructs expressing HTLV-1 gene products or LCL pulsed with HTLV-1 synthetic peptides. In patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), the frequency of HTLV-1 p40X-specific pCTL was at least 40-280-fold higher than in asymptomatic HTLV-1-infected individuals. All HAM/TSP patients (five of five) predominantly recognized HTLV-1 products encoded within the pX region. Lower pCTL to env were demonstrated in three patients, and only one of five HAM/TSP patients had pCTL to gag. A synthetic peptide corresponding to the tax region of HTLV-1 (peptide 11-19, amino acid sequence LLFGYPVYV) was recognized in association with human histocompatibility leukocyte antigen (HLA)-A2 in two HLA-A2 HAM/TSP patients with a high CD8+ pCTL frequency of 1/325 and 1/265, respectively. A second immunodominant region of HTLV-1 tax (peptide 90-55, amino acid sequence VPYKRIEEL) was identified to be restricted by HLA-B14 in two HLA-B14 HAM/TSP patients with a CD8+ pCTL frequency of 1/640 and 1/1,125, respectively. Lymphocytes from the CSF of a patient with HAM/TSP also showed a pCTL frequency against p40X of similar magnitude to that demonstrated from peripheral blood lymphocytes (PBL). The HLA-A2-mediated CSF pCTL activity to the immunodominant tax-specific peptide 11-19 was also comparable to pCTL from PBL. These results indicate that an extremely high pCTL frequency to HTLV-1 tax-encoded peptides may be related to pathogenesis of myeloneuropathy associated with HTLV-1.

Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Glatiramer acetate, approved for the treatment of relapsing-remitting multiple sclerosis, reduces relapses and disease activity and burden monitored by MRI. We assessed the efficacy of early treatment with glatiramer acetate in delaying onset of clinically definite multiple sclerosis. METHODS: In this randomised, double-blind trial, undertaken in 80 sites in 16 countries, 481 patients presenting with a clinically isolated syndrome with unifocal manifestation, and two or more T2-weighted brain lesions measuring 6 mm or more, were randomly assigned to receive either subcutaneous glatiramer acetate 20 mg per day (n=243) or placebo (n=238) for up to 36 months, unless they converted to clinically definite multiple sclerosis. The randomisation scheme used SAS-based blocks stratified by centre, and patients and all personnel were masked to treatment assignment. The primary endpoint was time to clinically definite multiple sclerosis, based on a second clinical attack. Analysis was by intention to treat. A preplanned interim analysis was done for data accumulated from 81% of the 3-year study exposure. This study was registered with ClinicalTrials.gov, number NCT00666224. FINDINGS: All randomly assigned participants were analysed for the primary outcome. Glatiramer acetate reduced the risk of developing clinically definite multiple sclerosis by 45% compared with placebo (hazard ratio 0.55, 95% CI 0.40-0.77; p=0.0005). The time for 25% of patients to convert to clinically definite disease was prolonged by 115%, from 336 days for placebo to 722 days for glatiramer acetate. The most common adverse events in the glatiramer acetate group were injection-site reactions (135 [56%] glatiramer acetate vs 56 [24%] placebo) and immediate post-injection reactions (47 [19%] vs 12 [5%]). INTERPRETATION: Early treatment with glatiramer acetate is efficacious in delaying conversion to clinically definite multiple sclerosis in patients presenting with clinically isolated syndrome and brain lesions detected by MRI. FUNDING: Teva Pharmaceutical Industries, Israel.

Elevated cerebrospinal fluid adiponectin and adipsin levels in patients with multiple sclerosis: a Finnish co-twin study.

BACKGROUND AND PURPOSE: The aim of this study was to investigate the levels of three adipocytokines: leptin, adiponectin and adipsin, in serum and cerebrospinal fluid (CSF) of twins discordant for multiple sclerosis (MS). Adipose tissue is an important component connecting immune system and several tissues and organs including CNS. Fat cells produce adipocytokines, which seem to have a role in various autoimmune disorders including MS. METHODS: Plasma samples were collected from twelve twins and CSF samples from four twins discordant for MS. The concentrations of interleukine (IL)-6, adiponectin, adipsin and leptin in plasma and CSF samples were determined by enzyme immuno assay. RESULTS: A significant difference was seen in the adipocytokine levels in CSF samples. Twins with MS had higher concentrations of adiponectin (P = 0.039) and adipsin (P = 0.039), than their asymptomatic co-twins. CONCLUSION: As adiponectin and adipsin levels in CSF did not correlate with their levels in plasma, it seems that there could be a secondary intrathecal synthesis of these adipocytokines in MS.

Can we face the challenge of expanding use of intravenous immunoglobulin in neurology?

The use of high-dose polyclonal intravenous immunoglobulin (IVIG) in the treatment of autoimmune neurological diseases has expanded over the last decade. Based on controlled clinical trials IVIG can be considered currently as the first-line treatment in Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy, and it may be used as a rescue therapy in worsening myasthenia gravis. IVIG is a second-line therapy in dermatomyositis, stiff-person syndrome and pregnancy-associated or postpartum relapses of multiple sclerosis. Although the biological efficacy of IVIG is due to multiple effects on the immune system, many mechanisms are still unknown. The awareness of risks and complications of IVIG therapy has increased, but severe side effects are still considered rare. Due to increasing costs of this treatment, careful selection of patients who will benefit from IVIG is extremely important.

Is the modulatory effect of pregnancy in multiple sclerosis associated with changes in blood apoptotic molecules?

OBJECTIVE: We examined whether the modulatory effect of pregnancy on multiple sclerosis (MS) is associated with changes in the apoptotic molecules in sera. SUBJECTS AND METHODS: The serum levels of tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL), sFas, Fas ligand (sFasL) and macrophage migration inhibitory factor were analyzed from 19 MS patients and 14 controls during late pregnancy and post-partum. The obtained results were related to disease activity and the progression of MS. RESULTS: Disease activity decreased during pregnancy. The levels of sTRAIL and sFasL increased from late pregnancy to post-partum situation in both MS patients and controls, but in MS patients the changes in the levels of sTRAIL from late pregnancy to post-partum were smaller than in controls. CONCLUSIONS: Post-partum upregulation of TRAIL and FasL seems to be caused by physiologic reactivation of the mother's immune system after pregnancy. An increased risk of relapses in MS post-partum may be associated with changes in the immunomodulatory potential of these apoptotic molecules.

Interferon regulatory factor 5 (IRF5) gene variants are associated with multiple sclerosis in three distinct populations.

BACKGROUND: IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis (MS). METHODS: We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case-control cohorts from Spain and Sweden, and a set of MS trio families from Finland. RESULTS: Two single nucleotide polymorphism (SNPs) (rs4728142, rs3807306), and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with values of p<0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel. CONCLUSION: These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.

Immunoregulatory factors in multiple sclerosis patients during and after pregnancy: relevance of natural killer cells.

Multiple sclerosis (MS) ameliorates typically during pregnancy but after the delivery the relapse rate often increases. Our study was conducted to understand the immunoregulatory mechanisms accompanying this phenomenon. MS patients were followed-up prospectively during pregnancy and 6 months postpartum, with immunological characterization of the peripheral blood. Groups of age- and parity-matched healthy pregnant women, and age- and sex-matched non-pregnant women and non-pregnant MS patients were studied as controls. In our patient cohort, the annualized relapse rate was 1.0 +/- 1.0 relapses/woman/year (mean +/- standard deviation) during the year before pregnancy, but dropped to 0.2 +/- 0.9 during the third trimester (P = 0.02). After the delivery the relapse rate increased again to 1.4 +/- 1.9 (1-3 months postpartum versus third trimester P = 0.003). While percentages of peripheral blood CD3, CD4, CD8 and CD19 immune cell subsets were unchanged over the observation period, reduced disease activity during the last trimester was associated with a significant increase in the percentage of circulating CD56(bright) natural killer (NK) cells. Simultaneously, the proportion of circulating CD56(dim) NK cells was clearly reduced. No alteration was noted in CD4+ CD25(high) forkhead box P3+ regulatory T cells. Production of interferon-gamma by peripheral blood lymphocytes was down-regulated significantly during pregnancy in comparison to the postpartum period, resulting in an increased T helper type 2 (Th2) : Th1 ratio during pregnancy. In conclusion, pregnant state in MS patients is characterized by an increase in the percentage of CD56(bright) NK cells and by enhanced Th2 type cytokine secretion. Our findings suggest a potential role for CD56(bright) regulatory NK cells in the control of autoimmune inflammation during pregnancy in MS.

Concordance and heritability of multiple sclerosis in Finland: study on a nationwide series of twins.

OBJECTIVES: To evaluate the changes in the multiple sclerosis (MS) concordance in twins, and the contribution of genetic and environmental factors to the aetiology of MS in Finland. BACKGROUND: Both genes and the environment contribute to the development of MS. A well-conducted twin study is an excellent means to assess the relative contribution of heritability and environmental factors. METHODS: Multiple sclerosis concordance was assessed for 10 Monozygotic and 14 dizygotic twin pairs using pairwise and probandwise concordance rates. The tetrachoric correlations in liability to disease for twin pairs were computed and a polygenic multifactorial model was used to estimate heritability. RESULTS: The pairwise concordance for MZ twins was 30% and for the DZ twins 14.3%, compared with 30% for MZ and 0% for DZ 20 years ago. The corresponding probandwise concordance rates were 46.2% and 25%. The genetic variance (heritability) was 15.3% (95% Cl 0.0-77.6), the common environmental variance 73.7% (95% Cl 14.1-93.9) and the unique environmental variance 11.1% (95% Cl 2.3-30.0). CONCLUSIONS: As the concordance of MS in DZ twins has increased during the past two decades and the heritability estimate is low, it seems that the reported increase in MS incidence in Finland is mainly caused by environmental factors.

EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases: EFNS task force on the use of intravenous immunoglobulin in treatment of neurological diseases.

Despite high-dose intravenous immunoglobulin (IVIG) is widely used in treatment of a number of immune-mediated neurological diseases, the consensus on its optimal use is insufficient. To define the evidence-based optimal use of IVIG in neurology, the recent papers of high relevance were reviewed and consensus recommendations are given according to EFNS guidance regulations. The efficacy of IVIG has been proven in Guillain-Barré syndrome (level A), chronic inflammatory demyelinating polyradiculoneuropathy (level A), multifocal mononeuropathy (level A), acute exacerbations of myasthenia gravis (MG) and short-term treatment of severe MG (level A recommendation), and some paraneoplastic neuropathies (level B). IVIG is recommended as a second-line treatment in combination with prednisone in dermatomyositis (level B) and treatment option in polymyositis (level C). IVIG should be considered as a second or third-line therapy in relapsing-remitting multiple sclerosis, if conventional immunomodulatory therapies are not tolerated (level B), and in relapses during pregnancy or post-partum period (good clinical practice point). IVIG seems to have a favourable effect also in paraneoplastic neurological diseases (good practice point) [corrected],stiff-person syndrome (level A), some acute-demyelinating diseases and childhood refractory epilepsy (good practice point).

Magnetic resonance imaging of the brain used to detect early post-partum activation of multiple sclerosis.

Post-partum relapses are a frequent phenomenon in multiple sclerosis (MS). The purpose of this study was to evaluate the timing and extent of new or growing T2-lesions after delivery in a cohort of Finnish MS patients. In addition to serial magnetic resonance imaging (MRI), the patients were followed up clinically with determination of relapse rate and expanded disability status scale. The annualized relapse rate was decreased during the last trimester of pregnancy [mean 0.14, standard deviation (SD) 0.14] when compared with the time before pregnancy (mean 0.64, SD 0.14; P = 0.04) and to time post-partum (mean 1.50, SD 0.45; P = 0.0002). New or enlarging lesions were detected in the post-partum images in 14 of 28 patients. Gadolinium-enhancing lesions in post-partum MRI were present in eight of 13 patients. There was a significant increase in the number of T2-lesions (P = 0.0009), in the total volume of MS-lesions measured from fluid-attenuated inversion recovery images (P = 0.0126) and in the number of diffusion weighted imaging hyperintense lesions (P = 0.0098) in the post-partum images. The clinical results support the earlier findings of decreased disease activity in late pregnancy. The clinical and MRI findings indicate that post-partum activation is an early and common phenomenon amongst mothers with MS.

Asymptomatic subjects differ less from their twin siblings with MS than from healthy controls in cognitive functioning. A Finnish Twin Cohort study.

BACKGROUND: Cognitive impairment develops in some MS patients at any time during the course of the disease regardless of whether the patients have neurological disability or not. Underlying causes for the MS related cognitive decline are yet poorly understood but both genetic and environmental risk factors have been proposed. OBJECTIVES: To assess whether the cognitive performance differs between subjects with multiple sclerosis (MS) and their asymptomatic co-twins. METHODS: Nineteen twin pairs discordant for MS recruited from the Finnish Twin Cohort were studied neurologically and with a comprehensive neuropsychological test battery. Control group included twenty age and education matched healthy subjects. RESULTS: Compared with the control subjects, the asymptomatic co-twins of MS patients performed significantly less well in tests of naming, verbal reasoning, visuospatial performance, processing speed, attention, verbal memory and learning. The twins with MS performed significantly less well than their co-twins in the SDMT evaluating processing speed, in visual learning and in word fluency. CONCLUSIONS: The lack of significant difference in majority of neuropsychological tests between the MS patients and their co-twins as well as considerable differences between asymptomatic co-twins and healthy controls may suggest that the cognitive performance may be partly developmental and regulated both by genes and shared environmental factors.

Three-decade neurological and neurocognitive follow-up of HIV-1-infected patients on best-available antiretroviral therapy in Finland.

OBJECTIVES: Is it possible to live without neurocognitive or neurological symptoms after being infected with HIV for a very long time? These study patients with decades-long HIV infection in Finland were observed in this follow-up study during three time periods: 1986-1990, in 1997 and in 2013. SETTING: Patients from greater Helsinki area were selected from outpatient's unit of infectious diseases. PARTICIPANTS: The study included 80 HIV patients. Patients with heavy alcohol consumption, central nervous system disorder or psychiatric disease were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: The patients underwent neurological and neuropsychological examinations, MRI of the brain and laboratory tests, including blood CD4 cells and plasma HIV-1 RNA. Neuropsychological examination included several measures: subtests of Wechsler Adult Intelligence Scale, Wechsler Memory Scale-Revised, list learning, Stroop and Trail-Making-B test. The Beck Depression Inventory and Fatigue Severity Scale were also carried out. The obtained data from the three time periods were compared with each other. RESULTS: Owing to high mortality among the original 80 patients, eventually, 17 participated in all three examinations performed between 1986 and 2013. The time from the HIV diagnosis was 27 (23-30) years. Blood CD4 cells at the diagnosis were 610 (29-870) cells/mm(3), and the nadir CD4 168 (4-408) cells/mm(3). The time on combined antiretroviral treatment was 13 (5-17) years. 9 patients suffered from fatigue, 5 had polyneuropathy and 3 had lacunar cerebral infarcts. There was a subtle increase of brain atrophy in 2 patients. Mild depressive symptoms were common. The neuropsychological follow-up showed typical age-related cognitive changes. No HIV-associated dementia features were detected. CONCLUSIONS: Polyneuropathy, fatigue and mild depression were common, but more severe neurological abnormalities were absent. These long-term surviving HIV-seropositive patients, while on best-available treatment, showed no evidence of HIV-associated neurocognitive disorder in neuropsychological and neuroradiological evaluations.

Abundant expression of HIV Nef and Rev proteins in brain astrocytes in vivo is associated with dementia.

OBJECTIVE: To relate the expression of HIV regulatory proteins and HIV-specific mRNA in the brain cells of infected individuals with clinical neurological disease. DESIGN: Formalin-fixed postmortem brain tissue from 14 HIV-infected adult patients, with previous repeated neurological and neuroradiological examinations, was studied by immunohistochemical and molecular biological methods. Samples from non-infected brains served as controls. METHODS: Immunohistochemistry with monoclonal antibodies (MAb) was combined with in situ RNA hybridization. Target cells were identified with MAb to glial fibrillary acidic protein (GFAP; astrocytes), CD68 (activated macrophages) and Ricinus communis agglutinin (RCA-1; microglia, endothelial cells). For HIV, a panel of MAb against HIV Nef, Tat, Rev and Env proteins or probes specific for all classes of mRNA (nef), for singly or non-spliced mRNA (env) and for non-spliced mRNA (gag/pol) were used. RESULTS: Nef protein was detected in subcortical or subpial astrocytes in seven out of 14 samples, and in multinucleated giant cells in two cases. Gag/pol or env mRNA-expressing astrocytes were detected in four cases. In four out of five cases studied, HIV Rev, but not Tat, was also expressed in astrocytes. Six out of the seven patients with Nef-positive astrocytes had suffered from moderate to severe dementia. The patient with most rapidly progressing severe dementia showed extensive HIV mRNA expression together with Nef and Rev expression in astrocytes. CONCLUSION: In adult human brain, astrocytes are infected by HIV and preferentially express HIV Nef and Rev proteins but are also sometimes productively infected. Astrocyte infection is associated with moderate to severe dementia which agrees with recent knowledge on the housekeeping activities of astrocytes and their eventual role in learning and memory.

Adhesion molecules in multiple sclerosis: relation to subtypes of disease and methylprednisolone therapy.

OBJECTIVES: To determine levels of adhesion molecules in blood and cerebrospinal fluid (CSF) samples from patients with different subtypes and activities of multiple sclerosis (MS) and to assess the effect of intravenous methylprednisolone sodium succinate treatment on the levels of soluble adhesion molecules. DESIGN: The expressions of very late activation antigen 4 (VLA-4), lymphocyte function associated antigen 1 (LFA-1), vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) were determined immunocytochemically, and levels of soluble VCAM-1, ICAM-1, and E-selectin, by means of enzyme immunoassay technique. The volumes of T2- and T1-weighted MS plaques and brain atrophy were determined by means of the semiautomatic magnetic resonance imaging (MRI) segmentation technique. SETTING: A university hospital in Finland. PATIENTS: One hundred subjects (71 patients with MS and 29 healthy control subjects). The subtypes of MS were relapsing-remitting (RRMS [n = 26]), secondary progressive (SPMS [n = 20]), and primary progressive (PPMS [n = 25]). RESULTS: In patients with RRMS and SPMS, the expressions of VLA-4 and LFA-1 on immune cells from blood were at least 1.5- to 3-fold higher than in controls (RRMS, P = .002 and P<.001, respectively; SPMS, P = .03 and P =.001, respectively). In RRMS, LFA-1 and ICAM-1 expression in blood was more up-regulated than in SPMS (P = .03 and P = .01, respectively). The expressions of adhesion molecules on CSF lymphocytes in RRMS and SPMS were of similar magnitude, but the proportions of CSF VLA-4- and LFA-1-expressing lymphocytes were 3- to 4-fold higher than in controls (P = .04 and P = .008, respectively). The levels of serum soluble VCAM-1 were higher in SPMS than in RRMS (P = .005) or PPMS (P = .04). Intravenous methylprednisolone treatment of patients with RRMS in exacerbation caused a significant reduction in the serum levels of soluble VCAM-1 and E-selectin (P<.001). In SPMS, the volumes of T2-weighted plaques correlated with the serum level of soluble ICAM-1 (r = 0.64; P = .03). CONCLUSIONS: Up-regulated adhesion molecules in blood and CSF indicate sustained potential for inflammation in the CNS throughout the clinical spectrum of MS. Therapies interfering with cell adhesion may be of key importance in suppressing MS.

Zidovudine reduces intrathecal immunoactivation in patients with early human immunodeficiency virus type 1 infection.

OBJECTIVE: To evaluate the effect of zidovudine on human immunodeficiency virus type 1 (HIV-1)-associated central nervous system infection in Centers for Disease Control and Prevention stage II or III disease. DESIGN: In an open-ended trial, patients received 500 mg of zidovudine twice a day for 12 months. Lumbar punctures, neurological, neuropsychological, and neuroradiological examinations were repeatedly performed during the trial period and were compared with pretrial values. In 11 patients post-trial neurological follow-up of 10 to 20 months was performed. PATIENTS: Initially, 14 volunteers with stage II or III disease and intrathecal synthesis of HIV-1-specific antibodies were enrolled. Additionally, patients had slight neuropsychological disturbance or brain atrophy unrelated to other agents than HIV-1. Two patients dropped out because of poor compliance. MAIN OUTCOME MEASURES: Intrathecal and systemic immune and virological responses, cognitive performance, and brain images were repeatedly monitored. RESULTS: After 6 weeks of zidovudine therapy, initial low-grade pleocytosis and elevated levels of beta 2-microglobulin, both in cerebrospinal fluid and in serum samples, declined. Intrathecal HIV-1 antibody synthesis could no longer be detected in half of the patients after 12 months of zidovudine therapy. Patients with defective cognition transiently improved cognitive speed and flexibility after 6 months of therapy. Slight atrophic brain changes, however, remained unchanged. CONCLUSIONS: Zidovudine reduces intrathecal immuno-activation and transiently improves cognitive functioning in HIV-1-infected subjects who show evidence of central nervous system involvement by HIV-1 but are otherwise asymptomatic.

Increased nitric oxide products in CSF in primary progressive MS may reflect brain atrophy.

Because nitric oxide (NO) is a putative mediator of oligodendrocyte damage in the primary progressive form of MS (PPMS), the authors analyzed the levels of NO oxidation products in CSF and plasma from 25 patients with PPMS and 15 controls. The levels of nitrite + nitrate (NOx) in CSF were fourfold higher in patients with PPMS than in controls (p < 0.001), whereas the concentrations in plasma were similar. These data suggests involvement of NO in nervous tissue damage in PPMS.