Annika Lekman

Gangliosides and allied glycosphingolipids in human peripheral nerve and spinal cord

Glycosphingolipids were determined in human spinal cord, cauda equina and femoral nerve of 10 subjects aged 20-70 years and in dorsal and ventral roots of four subjects aged 17-60 years. Myelin was isolated from corresponding tissue. Axons were isolated from the four specimens of dorsal and ventral roots. The concentration (mean and standard error of mean) of gangliosides in spinal cord was 0.80 +/- 0.03 mumol sialic acid/g fresh tissue, in cauda equina 0.40 +/- 0.02 mumol/g and in femoral nerve 0.23 +/- 0.01 mumol/g. In spinal cord only trace amounts of glycosphingolipids of the lacto series were found, and the ganglioside pattern differed from that in cerebral white matter by a relatively high proportion of GD3 and a low proportion of GD1a. The ganglioside patterns were almost identical in cauda equina and femoral nerve--the major ganglioside being 3-LM1, 0.07 and 0.04 mumol/g respectively. Another ganglioside of the lacto series, 3-HexLM1, was 25% of 3-LM1. Peripheral nerve also contained three acidic glycosphingolipids in addition to sulfatide--LK1 and HexLK1 belonging to the glycosphingolipid lacto series and containing glucuronyl-3-sulfate instead of sialic acid, and inositolphosphoryl galactosylceramide. The dorsal (sensory) and ventral (motor) roots had the same major membrane lipid composition but the ganglioside concentration was 30% higher in sensory than motor nerve and myelin. The patterns of gangliotetraose gangliosides were, however, the same in motor and sensory myelin and axons. The ceramide composition of the gangliosides is also reported.

CSF biomarkers in the evaluation of idiopathic normal pressure hydrocephalus

Backgroundu2002–u2002 To evaluate cerebrospinal fluid (CSF) markers for neuronal degeneration and demyelination in idiopathic normal pressure hydrocephalus (INPH), subcortical arteriosclerotic encephalopathy (SAE), and neurologically healthy subjects.

Alzheimer disease - effect of continuous intracerebroventricular treatment with GM1 ganglioside and a systematic activation programme.

Five patients with the early-onset form of Alzheimer disease (AD) received GM1 ganglioside by continuous injection into the frontal horns of the lateral ventricles for a period of 12 months. The optimal GM1 dose varied between 20 and 30 mg/24 h. The patients were trained twice a week for 4–5 h with an individually designed cognitive programme, which included the use of a word processor. Neurological, neuropsychological, psychiatric and neurochemical examinations were performed a week before surgery and on days 30, 90, 180, 270 and 365 after surgery. The cerebrospinal fluid levels of the monoamine metabolites homovanillic acid and 5-hydroxyindoleacetic acid and the neuropeptide somatostatin increased. The regional cerebral blood flow showed a tendency to increase. The progression of deterioration was stopped, and motor performance and neuropsychological assessments improved. The patients became more active and felt safer in relation to other people and performing various activities. They had improved reading comprehension and a better feeling for language. They were able to write reports and short letters on a word processor. When interviewed at the end of the study, all 5 patients stated that they felt better, and their relatives reported that they had regained integrity and their joie de vivre.

Rett syndrome: Biogenic amines and metabolites in postmortem brain

The biogenic amines, dopamine, serotonin, and noradrenaline, and their respective metabolites, homovanillic acid, 5-hydroxyindoleacetic acid, and hydroxymethoxyphenylglycol, were measured in selected brain regions obtained at postmortem examination from 4 patients, ages 12-30 years, with typical features of Rett syndrome. A 50% or greater reduction in each compound, except hydroxymethoxyphenylglycol, was observed in the substantia nigra from the 2 older patients, while the youngest patient had normal or nearly normal levels. These results correspond with the most consistent neuropathologic finding in Rett syndrome, reduced melanin content in neurons of the substantia nigra.

Significance of decreased lumbar CSF levels of HVA and 5-HIAA in alzheimer's disease

The monoamine metabolites homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA) and 4-hydroxy-3-methoxy-phenylglycol (HMPG) were determined in lumbar cerebrospinal fluid (CSF) of 123 patients with Alzheimers disease (AD) and 57 healthy controls. Despite CSF sampling under strictly standardized conditions, a wide variability in values among both patients and controls was found, as well as fluctuations in repeated samples from individual patients. This suggests that several unknown factors influence the lumbar CSF levels of monoamine metabolites. The AD group showed significantly lower mean levels of HVA (p less than 0.0001) and 5-HIAA (p less than 0.0001) than the control group. A relation between severity of disease and HVA was also found. The widespread neurotransmitter disturbance in AD, together with the nonspecificity of reduced lumbar HVA and 5-HIAA levels, suggests that the changes are nonspecific, secondary to the cerebral degeneration in AD.

CSF and urine biogenic amine metabolites in Rett syndrome

The metabolites of dopamine (homovanillic acid ‐ HVA), noradrenaline (4‐hydroxy‐3‐methoxy‐phenylglycol ‐ HMPG), and serotonin (5‐hydroxyindoleacetic acid ‐ 5‐HIAA) were measured in cerebrospinal fluid (CSF) from 38 patients and urine from 36 patients with typical Rett syndrome (RS) and compared with controls of similar age. CSF metabolite concentrations were the same in the patients and controls. Urinary metabolites expressed per mol creatinine were significantly higher in older RS patients. This difference is partly explained by lower urinary creatinine levels in older RS patients, due to their known reduction in muscle mass. Alterations in CSF or urine biogenic amine metabolite concentrations do not appear to represent the primary abnormality in RS, and their measurement cannot be regarded as a reliable means of diagnosis.

Intracerebroventricular Administration of GM1 Ganglioside to Presenile Alzheimer Patients

We have conducted a preliminary study of the optimum conditions for a therapeutic effect of ganglioside GM1 in Alzheimers disease. Five patients with the early onset form of Alzheimers disease (AD type I) received the ganglioside by intracerebroventricular administration for 12 months. Bilateral stereotactic punction of the frontal horns of the ventricular system was performed, and shunt catheters were implanted and connected to a programmable pump. The optimum GM1 dose varied between 20 and 30 mg/24 h. Neurological neuropsychological, psychiatric and neurochemical examinations were performed 7 days before surgery and on days 30, 90, 180 and 360. No patient found the surgery difficult and no patient or relative regretted that they participated in the study. The patients became more active and safer in relation to others and to performance of various activities from day 90. The cerebrospinal fluid level of the monoamine metabolites homovanillic acid and 5-hydroxyindoleacetic acid and the neuropeptide somatostatin increased.

Monoamine metabolites in cerebrospinal fluid and behavioral ratings in patients with early and late onset of alzheimer dementia

Patients with Alzheimer disease (AD, onset <65 years of age, n = 13) and senile dementia of the Alzheimer type (SDAT, onset ≥65 years of age, n = 28) were investigated for cerebrospinal fluid (CSF) content of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxy-phenylglycol (MHPG) and compared with a group of controls (n = 26). A geriatric rating scale, the Gottfries-Bråne-Steen scale, was used to assess impairment of motor performance, intellectual and emotional functioning, and symptoms common in dementia disorders. The HVA levels in CSF were significantly lower in the AD group than in the SDAT group and controls. MHPG was slightly but significantly increased in the SDAT group when compared with the controls. The HVA and 5-HIAA concentrations were correlated negatively with impairment of motor performance in the SDAT group; 5-HIAA correlated positively with impaired performance in the AD group; and 5-HIAA/HVA ratios were correlated positively with the performance variables. HVA correlated significantly and negatively with “impaired wakefulness” and “inability to increase tempo” in the SDAT group. 5-HIAA and the ratio 5-HIAA/HVA correlated significantly and positively with some items measuring intellectual and emotional impairment. In the AD group, “anxiety” and “fear-panic” correlated positively with 5-HIAA and “restlessness” with MHPG. The data indicate qualitative differences in the CSF monoamine pattern between AD and SDAT.

Glycosphingolipids as Potential Diagnostic Markers and/or Antigens in Neurological Disorders

Glycosphingolipids are most abundant in the nervous system within which there are developmental, regional, structural and cellular differences regarding their composition. They are shedded to the cerebrospinal fluid and thus potential markers for pathogenic alterations in the brain, such as developmental abnormalities, demyelination, gliosis, neuronal cell destruction. The glycosphingolipids have also been found to be antigens in autoimmune processes involving the nervous system, in particular in peripheral neuropathies like Guillain Barré syndrome, multifocal motor neuropathy etc. The immune response might have been triggered by infectious agents with an antigen epitope which mimic the glycosphingolipid or by a primary nerve tissue damage leading to release of glycosphingolipids. There is a series of support for a clinical significance of cerebrospinal fluid glycosphingolipid determinations and the presence of anti-glycosphingolipid antibodies but this has to be further explored. This paper is a mini review of the state of the art and discuss methodological aspects and improvements that might help to explore the relevance of glycosphingolipids in neurological disorders.

Membrane cerebral lipids in Rett syndrome.

The lipid membrane composition of cerebral tissue from 5 patients with classic Rett syndrome, ages 12-30 years, and from 14 age-matched controls was studied. The results demonstrated a selective loss of myelin-associated lipids and an enrichment of gangliosides in temporal white matter. The ganglioside pattern revealed an increase of astroglial cell-associated gangliosides and reduced proportions of gangliosides GD1a and GT1b. This latter finding may be crucial in synaptic function. The fatty acid compositions of ethanolamine phosphoglyceride, choline phosphoglyceride, and galactosylceramide were normal.