Wallace W. Tourtellotte

Antibodies to myelin-associated glycoprotein (MAG) in the cerebrospinal fluid of multiple sclerosis patients.

Cerebrospinal fluids (CSF) and sera from patients with multiple sclerosis (MS), other neurological diseases (ONDs) and healthy controls were tested for antibodies to myelin-associated glycoprotein (MAG) by several different assays. Using a very sensitive, solid-phase radioimmunoassay with radioiodinated protein A, a statistically significant elevation of anti-MAG antibodies was detected in MS CSFs in comparison to those from ONDs and healthy controls. The antibodies reacted with human MAG, but not with rat MAG, and appeared to be directed towards carbohydrate determinants in the glycoprotein. The CSFs from high IgG producers had significantly greater anti-MAG antibody levels than those from low IgG producers, even though the assays were done on CSF samples that had been normalized to the same IgG concentration. The elevated antibodies were not detected when the same samples were tested with a liquid-phase radioimmunoassay or an enzyme-linked immunosorbent assay, and the antibodies in the MS CSF also could not be detected by Western blotting. An elevated level of antibodies was not found in sera from MS patients by any of the assays, possibly because these samples gave higher and more variable background. The results suggest that there is a low level of humoral immunity to MAG in MS patients that can only be detected by the most sensitive assays. This weak immune response to MAG may be secondary to the demyelinating process, but could play a role in the progression of the disease.

Myelin‐associated glycoprotein in multiple sclerosis lesions: A quantitative and qualitative analysis

Myelin‐associated glycoprotein (MAG), myelin basic protein (MBP), and proteolipid protein (PLP) were quantitated by immunoassays in nine plaque, inner periplaque, outer periplaque, and normal‐appearing white matter regions from brains of five multiple sclerosis patients and compared with the levels found in white matter samples of control subjects matched for age, postmortem time, and brain region. In plaque and inner periplaque regions, all three proteins were substantially reduced due to extensive myelin loss. In outer periplaque regions, MBP and PLP were close to control levels, but MAG was significantly reduced to a mean of 57% of control. All three proteins were close to control levels in the normal‐appearing white matter samples. MAG in the various regions was qualitatively examined on Western blots by binding of lectins and by immunostaining with polyclonal and monoclonal antibodies against carbohydrate and protein epitopes of MAG. Densitometric scanning of these blots did not reveal any qualitative differences in the oligosacharide or polypeptide moieties of MAG between samples from control subjects and those from multiple sclerosis patients. However, a high proportion of the MAG in the multiple sclerosis samples was often in the form of dMAG, a proteolytic derivative of MAG that is formed by a myelin‐associated, Ca2+‐activated, neutral protease. The preferential loss of MAG at the periphery of multiple sclerosis plaques may be initiated by its proteolytic conversion to dMAG.

Measurement of complement components in cerebral spinal fluid by radioimmunoassay in patients with multiple sclerosis.

Abstract Evidence for active immune processes occurring within the central nervous system (CNS) and involving complement has been found both in experimental animals and in humans. To examine the possible role of complement in the pathogenesis of multiple sclerosis (MS), we measured complement components C3 and C4 in cerebral spinal fluid (CSF) by the radioallergosorbent test (RAST). The method was found to be reproducible and specific. The effects of incubation time, temperature, pH of diluent, concentration of antibody used for coupling, and that of labeled anti-C3 and anti-C4 were studied. The normal range (mean ± 2 standard deviations) for CSF C4 and C3 were 0.09–0.4 and 0.46–1.4 mg/dl, respectively. The mean value of CSF C4 in neurologically normal control subjects did not differ from 45 patients; in contrast, the mean value of CSF C3 was significantly higher in MS patients. After measuring serum and CSF albumin, IgG, C3, and C4 on 20 neurologically normal subjects and on 102 coded specimens from 11 patients with MS, we calculated the rate of de novo CNS IgG, C3, and C4 synthesis. Synthesis of IgG was elevated in all patients. The measured increase in CSF C3 found in some MS patients appears in some instances to be due to an altered blood-brain barrier, and in other instances to increased CNS de novo synthesis of C3 in a manner analogous to that previously documented for CSF IgG.

Quantification of Hand Tremor in the Clinical Neurological Examination

A compensatory tracking task using a visual display and augmented auditory feedback and requiring subjects to maintain a 500-gm force on a control stick has been modified for clinical use. Integrated absolute values of the subjects force error/second (tremor scores) have been used as a measure of steadiness, and power spectra of the force error have been used to establish the predominant tremor frequencies. Twenty parkinsonian patients, 7 age-matched controls, and 20 young controls have been evaluated, and representative tremor-time records, tremor scores, and tremor-power spectra are presented. The quantitative measures have proven sensitive to individual differences among normals, yet having a dynamic range sufficient to include the most severely afflicted patient tested. Normative values of both tremor scores and predominant tremor frequencies have been established and are significantly different from the parkinsonian values, the parkinsonian patients having a higher average tremor score [8.31 versus 3.76 (gram . seconds/second)] and a lower mean predominant tremor frequency (6.6 Hz versus 7.9 Hz). Representative tremor-power spectra have proven useful in describing physiological and parkinsonian tremors. Reevaluation over 1-3-week intervals indicates that the quantitative measures of tremor scores are reliable (r= 0.83, p < 0.01 for control subjects; r = 0.87, p < 0.01 for parkinsonian patients). In addition, the predominant tremor frequency as measured from the tremor-power spectra is found to be independent of learning effects. It is emphasized that such tests are not designed as diagnostic tools in themselves.

AIDS dementia complex complicated by cytomegalovirus encephalopathy

We have studied longitudinally ten patients with AIDS encephalopathy with respect to pathogenetic roles of human immunodeficiency virus (HIV) and cytomegalovirus (CMV). Three patients manifested typical AIDS dementia complex (ADC) (initially without retinitis and with slowly progressive cognitive, motor and behavioral abnormalities which were zidovudine-responsive, and relatively preserved CD4 + T cells), and seven patients presented with AIDS dementia complex complicated by CMV encephalopathy (ACE) (with CMV retinitis, peripheral neuropathy, altered sensorium, and rapidly declining clinical and immunological status). Whereas only HIV antibody was elevated in the spinal fluid of patients with ADC, both virus infections were active in the central nervous system of patients with ACE as shown by HIV p24 antigenemia and antigenrrhachia, elevated HIV and CMV antibody in the spinal fluid, disseminated CMV infection with retinitis, and basilar ventriculoencephalitis with multinucleated cytomegalic cells containing CMV and HIV proteins and CMV DNA. The recognition of ADC and ACE is important, since some patients with ACE may respond to ganciclovir or foscarnet.

JC virus in urine of chronic-progressive multiple sclerosis patients and control individuals

The o~ectrve of the research IS rhe study of clm~cs and unmunolo~ m pattents wth muittple sclerosis in acute paiod (30 pat.) and during rermssmn (17 pat.). axed 20-35. Tw~cal cfimcal wmutoms m acute Mod: wtlcal. se&ive; pyramidal a& vcstibular&&lhun disclubanccs. T~#cal mmmnological changes in ttus peiod: immunode#iiiency of T systw. deuease of Ig A, muease of 1~ M and level of cuculzv ~XIUIK complexa. actwatron of phagocytes. high level of antiDNA antibody. adwalmn of components of ;Uicr~-kynine system and pr ocesss of peroude oxygenation of llpnis. renusaon neurologul sympmms decreased. disturbances of movements and muscular coordination xrgressed. sensitivity restored. The positive mummological dynamics took place though T~mmunodeficrmcy was presaved. Thus the prcwnce of parallelisms m cluucs and mmmnology in various stages of the bsease was drscovered.

Measurement of Intra-Blood-Brain-Barrier IgG Synthesis in Multiple Sclerosis. A Review

AbstractSince synthesis of IgG inside the blood-brain-barrier (BBB) is the cardinal feature of the cerebrospinal fluid (CSF) profile indicative of multiple sclerosis (MS), a number of methods to detec