Emile-Christian Laterre

Assessment of damage to the central nervous system by determination of S-100 protein in the cerebrospinal fluid.

S-100 protein was determined by Particle Counting ImmunoAssay in the CSF of patients with various neurological disorders. With a limit of sensitivity of 2.5 micrograms/l this brain-specific protein was detected only in samples from patients with acute damage of the central nervous system, particularly in compression of the spinal cord by tumour, ischaemic disorders, subarachnoïd bleeding and haematoma, and viral or suspected viral infections. Our results support the assumption that S-100 is a reliable index of central nervous system damage and that changes in its concentration could have a prognostic value.

The concentration of IgM in the cerebrospinal fluid of neurological patients.

The level of IgM was determined by Particle Counting Immunoassay in the cerebrospinal fluid. In non-neurological patients (N = 20) the mean was 97.5 micrograms/l with the upper reference limit at 380 micrograms/l. The mean IgM index was 0.021 with the upper reference limit at 0.071. Of 21 patients with stroke, 5 had an IgM index exceeding the reference limit. High levels and indices of IgM were observed in most patients (N = 27) with infectious meningo-encephalitis. In this group, the IgM index was abnormal in about 30% of cases with a normal total protein content, and was more often increased than the IgG index. In multiple sclerosis patients (N = 80), the IgM index was increased in 32%. In this disease very high values of IgM index (greater than 0.13) were never associated with very high values of IgG index (greater than 1.8). A significantly higher proportion of males was found in the group of patients with very high values of IgM index (N = 11). No significant influence of the age of onset, the interval between onset and sampling and clinical state was observed. However, of 10 patients with a multiple sclerosis history exceeding 15 years none had an IgM index exceeding the upper reference limit. Four patients with multiple sclerosis had a high IgM index without either an increase of the IgG index or the presence of oligoclonal bands.

Oligoclonal free kappa and lambda bands in the cerebrospinal fluid of patients with multiple sclerosis and other neurological diseases: An immunoaffinity-mediated capillary blot study

We describe an affinity-mediated capillary blotting technique for the detection of free kappa or lambda light chains in native cerebrospinal fluid (CSF) after isoelectric focusing in agarose gel. Interferences by light chains bound to immunoglobulins were carefully excluded. An absolute amount of 20-50 ng of free kappa or lambda Bence-Jones proteins were detectable by this method, under the form of several discrete bands with isoelectric points between 5 and 8.5. No free light chains were observed in CSF and sera from patients without neurological disorders (n = 26). Such bands were present in most CSF samples in the case of central nervous system (CNS) infections, except in aseptic meningitis. In a group of 48 multiple sclerosis (MS) patients, 44 (92%) displayed oligoclonal free kappa bands restricted to the CSF; oligoclonal IgG bands were observed in 40 cases, and oligoclonal free lambda bands in 33. In this group, the presence of CSF free light chain bands was highly correlated with their absolute levels (p less than 0.001). In other neurological diseases (n = 44), oligoclonal free kappa and free lambda bands were detected much more rarely, in seven (16%) and four (9%) cases respectively. Surprisingly, the CSF from three unrelated patients with Huntingtons disease (out of five tested) contained both oligoclonal IgG and free kappa bands.

The clinical relevance of ferritin concentration in the cerebrospinal fluid.

By means of a new technique (Particle Counting Immunoassay), we have determined the level of ferritin in 470 samples of cerebrospinal fluid of patients with various neurological disorders. The median value obtained in a control group was 2.3 ng/ml with an upper limit at 5.5 ng/ml. the concentrations in the serum and cerebrospinal fluid were independent, but that in cerebrospinal fluid correlated with its total protein content. High values of ferritin were found in infectious meningo-encephalitis, in vascular diseases of the central nervous system, and, unexpectedly, in several cases of dementia without obvious vascular pathology.

Cholinergic Neurotransmission Has Different Effects on Cerebral Glucose Consumption and Blood Flow in Young Normals, Aged Normals, and Alzheimer's Disease Patients

Cerebral blood flow (CBF) and glucose consumption (GC) are both tracers of brain metabolic activity used to image the human brain in vivo. To know if both tracers reacted in the same manner when brain cholinergic neurotransmission was activated, CBF and GC were measured in young normals (YN), aged normals (AN), and Alzheimers Disease patients (AD) using positron emission tomography (PET), H2 15O, and 18F-FDG. Each subject was studied twice, under placebo and physostigmine, in randomized order and blind fashion using the maximal tolerated dose of physostigmine individually determined. Under physostigmine CBF increased significantly (P = 0.0007) in posterior regions of the cerebral cortex and in the subcortical structures. Inversely, GC was decreased significantly in most regions. The largest decrease was seen in the prefrontal region of the cerebral cortex (P < 0.0001). Significant regional decreases were registered in all three groups of subjects, but were larger in AD than in controls. Looking at the absolute values of prefrontal cortex metabolism we found no correlation (r = 0.04) between the responses of CBF and GC. After normalization of the regional values for the mean we found a significant positive correlation between the responses of CBF and GC (r = 0.71, P < 0.0001). These findings suggest two components in the CBF response to physostigmine: one metabolic, depressive, and regional which follows the GC response; and one vascular, larger, diffuse, and opposite in direction to the metabolic component. These results have implications for the interpretation of CBF values as tracer of brain metabolic activity when brain cholinergic neurotransmission is manipulated.

Study of IgA in the cerebrospinal fluid of neurological patients with special reference to size, subclass and local production.

IgA was assayed by particle counting immunoassay in cerebrospinal fluid (CSF) from non-neurological and neurological patients. Reference values had a logarithmic normal distribution with a mean of 1.54 mg/l and an upper limit of 5 mg/l. To estimate the possible intra-blood-brain barrier (BBB) production of IgA we have calculated an IgA index: CSF-IgA/serum-IgA: CSF-albumin/serum-albumin. Values higher than the upper reference limit of 0.41 were found in 12 out of 67 patients with multiple sclerosis (18%), in 5 out of 11 with aseptic meningitis, in 7 out of 8 with herpetic encephalitis, in 1 out of 8 with Guillain-Barré syndrome and in 2 cases of tuberculous meningitis. However, this index does not take into account the relative proportions of monomeric and polymeric IgA in CSF and serum. We therefore ultracentrifuged 17 paired CSF and serum samples and determined the relative proportions of monomeric and dimeric IgA and calculated the indices for monomeric and dimeric IgA. In controls the proportion of dimeric IgA in CSF was below 5% of total IgA whereas this proportion was increased up to 53.9% in the case of intra-BBB production of IgA, which is thus characterized by a very high dimeric IgA index. In all cases IgA1 remained the predominant subclass. These results had to be compared with those observed in cultures of peripheral blood lymphocytes, which secrete about equal proportions of monomeric and polymeric IgA pertaining to the IgA1 subclass.

Neuroleptic binding to sigma receptors: Possible involvement in neuroleptic-induced acute dystonia

Several antipsychotic drugs, belonging to various chemical classes, were compared for their affinity for the sigma, dopamine-D2, and muscarinic receptors. Many neuroleptic drugs were found to bind with high affinity to sigma 2 receptors, and the binding affinity was clearly different from that observed for dopamine-D2 receptors. The dopaminergic and muscarinic theories for the physiopathology of acute dystonia are not completely satisfactory. Since the sigma receptors were reported to play a role in the control of movement, the high affinity of some neuroleptics for these sites suggests their possible involvement in some side effects, such as drug-induced dystonia. There was a correlation between the clinical incidence of neuroleptic-induced acute dystonia and binding affinity of drugs for the sigma receptor, except for some drugs, with a lower incidence, displaying significant affinity for the cholinergic muscarinic receptor. Therefore, we conclude that the affinity for the sigma receptor might be involved in neuroleptic-induced acute dystonia, but this might be partially corrected by the intrinsic anticholinergic properties of the drug.

Brain glucose metabolism in thalamic syndrome.

Regional brain glucose metabolism was studied in a case of postischaemic thalamic syndrome. Despite a normal density of the thalamus on MRI and CT images, a 17% relative hypometabolism was found in the posterior thalamus on the affected side. This observation of functional anomalies in the posterior thalamic complex in case of thalamic syndrome is compatible with a deregulated processing of pain-related information at this level.

Occurrence of oligoclonal IgM bands in the cerebrospinal fluid of neurological patients: an immunoaffinity-mediated capillary blot study

We developed a highly sensitive and specific immunoaffinity-mediated capillary blot technique for the detection of oligoclonal IgM bands in CSF and sera from patients with various neurological disorders. Pre-treatment of the samples by dithiothreitol was necessary to obtain a migration of the IgM molecule into the gel of isoelectric focusing. IgM was then transferred by immunoaffinity onto a polyvinylidene difluoride sheet previously coated with anti-IgM antiserum. The limit of detection was found to be 6 ng in 15-microliters samples. The presence of CSF-restricted IgM bands was considered the result of an intrathecal synthesis and was observed in 13 out of 46 (28%) patients with MS, more frequently in acute relapses (9 out of 21, 43%), including 6 cases out of 13 presenting the first bout of the disease. Similar IgM bands were also detected in 15 out of 46 (38%) patients with CNS infections, especially in cases of neurosyphilis and neuroborreliosis. The presence of CSF oligoclonal IgM bands was linked to an increase of the IgM index in the MS group, but not in the group of infectious diseases as a whole. The occurrence of CSF-restricted oligoclonal IgM bands seems to be the most specific indicator of an intrathecal synthesis of this isotype.

[3H]MK-801 binding to NMDA glutamatergic receptors in Parkinson's disease and progressive supranuclear palsy.

The interactions existing between glutamatergic and dopaminergic systems, notably in the basal ganglia, suggest that glutamatergic antagonists may have therapeutic interest in extrapyramidal disorders characterized by impaired dopaminergic transmission. The binding of [3H]dizocilpine maleate (MK-801) to glutamate receptors of the N-methyl-D-aspartate (NMDA)-subtype was characterized in temporal and frontal cortex, in hippocampus and in subcortical areas (caudate nucleus and putamen) from controls and patients with Parkinsons disease or progressive supranuclear palsy. The binding affinity (KD) and the maximal specific binding capacity (Bmax) of [3H]MK-801 were unchanged in all the cerebral regions studied in both diseases. This indicates the existence of preserved NMDA glutamate receptors, which is required for potential therapeutic efficacy of specific antagonists.