Elevated interleukin-6 levels in cerebrospinal fluid of vascular dementia patients

OBJECTIVES: To investigate a possible implication of inflammatory processes in the development of dementia in cerebrovascular disease. PATIENTS AND METHODS: We examined the levels of interleukin-6 (IL-6) in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) (n = 26), ischemic cerebrovascular disease without dementia (CVD) (n = 11), vascular dementia (VD) (n = 11), and other neurological disorders (n = 21) using sensitive enzyme-linked immunosorbent assay. RESULTS: The CSF concentrations of IL-6 were significantly elevated in patients with VD compared with those of patients with AD or CVD. CONCLUSION: The CSF IL-6 levels are increased in patients with VD, suggesting that inflammatory mechanisms may be involved in the development of cognitive decline in some patients with cerebrovascular disease. CSF IL-6 may be a biological marker for dementia in cerebrovascular disease.     

Decreased soluble interleukin-6 receptor in cerebrospinal fluid of patients with Alzheimer''s disease

The function of the cytokine interleukin-6 (IL-6) is augmented by soluble IL-6 receptors (sIL-6R). We investigated cerebrospinal fluid sIL-6R concentrations in patients with Alzheimer's disease (AD) compared to age-matched healthy subjects and individuals with at least one first degree relative with AD. We found a statistically significant decrease in sIL-6R levels in the AD group compared to controls. Complete analysis of the IL-6R complex seems crucial to better understand the impact of IL-6 in AD pathophysiology.     

Nitric oxide metabolites and interleukin-6 in cerebrospinal fluid from multiple sclerosis patients

Interleukin-6 (IL-6) and nitric oxide (NO) are implicated in the pathology of multiple sclerosis (MS). We have investigated the levels of these mediators in the cerebrospinal fluid (CSF) from 50 patients with MS and 23 control subjects. Mean CSF IL-6 level was higher in the total MS group in comparison with controls, but not significantly, whilst the difference between patients with stable MS and controls reached the level of statistical significance. Mean CSF nitrite/nitrate level was significantly higher in the total MS group compared with the control group, as well as in active MS patients versus controls. There was significant difference neither in the mean CSF IL-6 nor in nitrite/nitrate levels between active and stable MS patients. Interestingly, we observed a significant negative correlation between IL-6 and nitrite/nitrate levels in the CSF in the total MS group. Such a trend existed in both subgroups with active and stable MS, but without reaching the level of statistical significance. Our data further support the involvement of IL-6 and NO in ongoing pathological processes in MS, suggesting their potential interplay within the central nervous system in this disease.     

Intra vitam lumbar cerebrospinal fluid and serum and postmortem ventricular immunoreactive apolipoprotein E in patients with Alzheimer''s disease.

Using a specific enzyme linked immunosorbent assay (ELISA) method, total apolipoprotein E immunoreactivity (tApoE-IR) was measured in premortem lumbar CSF and serum of patients with "probable" Alzheimer's disease and in postmortem ventricular CSF of patients with Alzheimer's disease confirmed by necropsy. Concentrations were compared with those from patients with other neurological diseases and controls. The mean serum:lumbar CSF ratio of ApoE-IR was 15.9 suggesting that the main portion of lumbar ApoE-IR is synthesised intrathecally. No significant differences in ApoE-IR between patients with Alzheimer's disease and the other groups were detected in either CSF compartment. In lumbar CSF, there was no correlation between ApoE-IR of patients with Alzheimer's disease and their mini mental state scores. These results suggest that the diagnostic value of ApoE-IR measurements in CSF of patients with Alzheimer's disease as a single determination is less than that of other markers, in particular tau protein. On the other hand, ApoE determinations could be useful as part of a neurochemical profile of Alzheimer's disease.     

Butyrylcholinesterase in lumbar and ventricular cerebrospinal fluid

OBJECTIVES: This study establishes reference data for human lumbar CSF butyrylcholinesterase (E.C.3.1.1.8.) activity and investigates the enzyme activity in ventricular CSF. We comment on the relationship between CSF butyrylcholinesterase activity and other laboratory parameters. Subjects and Methods: We investigated 64 lumbar CSF samples obtained from a clinically healthy population and 169 ventricular CSF samples collected from 90 neurosurgical patients. RESULTS: The reference range we recommend for lumbar CSF butyrylcholinesterase activity is 5.4 to 17.0 nmol/min x ml. The majority of ventricular butyrylcholinesterase activities in our patient subset ranged up to 5 nmol/min x ml. CONCLUSIONS: We established the relative influence of serum and CNS components on total CSF butyrylcholinesterase activity. The CNS fraction predominates the total butyrylcholinesterase activity in normal lumbar CSF. In ventricular CSF enzyme influx from serum outweighs the CNS component.     

Cerebrospinal fluid levels of insulin in patients with Alzheimer's disease

OBJECTIVES: Some previous reports suggested a potential role of insulin in memory and in the pathophysiology of Alzheimer's disease (AD). We assessed the cerebrospinal fluid (CSF) levels of insulin in patients with AD and in age and sex-matched controls trying to elucidate whether this value could be related with the risk or severity of AD. PATIENTS AND METHODS: We measured the CSF insulin levels in 27 patients with AD and 16 matched controls using a RadioImmunoanalysis method. RESULTS: CSF insulin levels did not differ significantly between AD-patient and control groups. These values were not correlated with age, age at onset, duration of the disease, and scores of the MiniMental State Examination in the AD group. CONCLUSION: These results suggest that CSF insulin concentrations are not related with the risk or severity of AD.     

Cholinesterases in the cerebrospinal fluid,plasma, and erythrocytes of patients with Alzheimer's disease

Summary In patients with probable Alzheimer's disease and in controls, acetyl- and butyrylcholinesterase activities were studied in cerebrospinal fluid (CSF) and plasma, and acetylcholinesterase activity of erythrocytes was determined. In addition, the molecular forms of acetylcholinesterase were measured in CSF. Severely demented patients had significantly lower acetylcholinesterase (p<0.01) and butyrylcholinesterase (p<0.05) activities in CSF than the controls had, but the activities of these enzymes in plasma and erythrocytes were within the same range in both groups. Acetylcholinesterase and butyrylcholinesterase activities in the CSF of mildly demented patients did not differ from control values. The ratio of the intermediate molecular form of acetylcholinesterase to the light molecular form of the enzyme did not differ significantly between patients with Alzheimer's disease and controls. According to our results, AChE levels were lower in the CSF of severely demented patients, but both light and intermediate molecular forms were affected.     

Neurotransmitter amino acids in cerebrospinal fluid of patients with Alzheimer's disease

Summary. We measured the CSF and plasma levels of glutamate, glutamine, aspartate (only in plasma), asparagine, glutamine, glycine and GABA in 37 patients with Alzheimer's disease and in 32 matched controls. We used an ion-exchange chromatography method. When compared to controls, AD patients had higher CSF glutamate and glycine levels, higher plasma levels of aspartate and glycine, and lower plasma levels of asparagine and GABA. When expressed relative to CSF proteins, CSF levels of glutamate and glycine remained higher, and CSF asparagine levels were lower in AD patients than in controls. The CSF levels of the amino acids measured were not correlated with the clinical features of AD with the exception of plasma GABA levels with duration of the disease. Our results might suggest a possible pathogenetic role of neurotransmitter amino acids in AD. Accepted December 2, 1997; received August 30, 1997     

Serum interleukin-6 levels correlate with the severity of dementia in Down syndrome and in Alzheimer's disease

Introduction - Inflammatory processes are suspected in the pathomechanism of Alzheimer's dementia (AD) but the serum and cerebrospinal fluid (CSF) levels of inflammatory cytokines are not yet determined in the different forms of the disorder. Subjects and methods - Interleukin-6 (IL-6) levels were examined in the sera and CSF of patients with mild-moderate and severe stage of late onset sporadic type of AD and in the sera of demented Down syndrome (DS) probands with similar stages of AD and compared with data of age-matched healthy controls. Results - Normal serum IL-6 levels were found in the mild-moderate stage, but significantly increased levels were found in the severe stage of both dementia groups. The CSF concentrations remained within the normal range in all groups. Positive correlations between the serum IL-6 levels and age and the severity of the disease were present. Conclusion - These findings suggest a disease stage dependent general activation of the immune system both in sporadic AD and in DS with AD.     

Cerebrospinal fluid nitrate levels in patients with Alzheimer's disease

It has been suggested that nitric oxide could be implicated in the pathogenesis of Alzheimer's disease (AD). Recently Kuiper et al. reported decreased CSF nitrate levels (oxidation product that provides an indirect estimation of nitric oxide) in AD patients, assessed with a colorimetric method. However other group, using a microplate version of the Griess reaction, did not confirm these findings. We studied the CSF and plasma levels of nitrate with a kinetic cadmium-reduction method in 32 AD patients and 36 matched controls. The CSF and plasma nitrate levels did not differ significantly between the two study groups. CSF and plasma nitrate levels did not correlate with age at onset and duration in the patient group. These data suggest that CSF and plasma levels of nitrate are apparently unrelated with the risk for AD.     

Cerebrospinal fluid levels of selenium in patients with Alzheimer's disease

Summary. We compared CSF and serum selenium levels, measured by atomic absorption spectrophotometry, in 27 patients with Alzheimer's disease (AD) (13 females, 14 males, mean ± SD age 73.6 ± 7.4 years) without major clinical signs of undernutrition, and 34 matched controls (18 females, 16 males, mean ± SD age 70.7 ± 7.8 years). CSF and serum selenium levels did not differ significantly between AD-patient (11.4 ± 7.8 ng/ml and 28.5 ± 13.0 ng/ml, respectively) and control groups (13.3 ± 7.0 ng/ml and 22.5 ± 17.5 ng/ml). These values were not correlated with age, age at onset, duration of the disease, and scores of the MiniMental State Examination in the AD group. Weight and body mass index were significantly lower in AD patients than in controls. These results suggest that CSF selenium concentrations are apparently unrelated with the reported oxidative stress processes in patients with AD. Received May 5, 1998; accepted September 9, 1998     

Cerebrospinal fluid levels of thiamine in patients with Alzheimer's disease

Summary. Thiamine is an essential cofactor for several important enzymes involved in brain oxidative metabolism, such as the alpha-ketoglutarate dehydrogenase complex (KGDHC), pyruvate-dehydrogenase complex (PDHC), and transketolase. Some investigators reported decreased thiamine-diphosphate levels and decreased activities of KGDHC, pyruvate-dehydrogenase complex and transketolase in the brain tissue of Alzheimer's disease (AD) patients. We measured cerebrospinal (CSF) levels of thiamine-diphosphate, thiamine-monophosphate, free thiamine, and total thiamine, using ion-pair reversed phase high performance liquid chromatography, in 33 patients with sporadic AD and 32 matched controls. The mean CSF levels of thiamine-derivatives did not differ significantly from those of controls, while the mean plasma levels of thiamine-diphosphate, free and total thiamine were significantly lower in the AD-patient group. CSF and plasma thiamine levels were not correlated with age, age at onset, duration of the disease, and scores of the MiniMental State Examination, with the exception of plasma thiamine-diphosphate with MiniMental State Examination (r = 0.41, p < 0.05) in the AD-patients group. CSF and plasma values did not predict dementia progression, assessed with the Minimental State Examination scores. These results suggest that CSF thiamine levels are not related with the risk for and the progression of AD. Received May 19, 2001; accepted January 8, 2002     

Cerebrospinal fluid levels of non-neurotransmitter amino acids in patients with Alzheimer's disease

Summary. We measured the CSF levels of 21 and the plasma levels of 24 amino acids in 37 patients with Alzheimer's disease (AD) and in 32 matched controls. We used an ion-exchange chromatography method. When compared with controls, AD patients had lower CSF levels of phosphoserine, citrulline, alfa-aminobutyric acid, methionine, and ethanolamine; and higher CSF levels of threonine, serine, lysine, histidine and arginine. However, when expressed relative to CSF protein, CSF levels of serine, lysine, histidine, and arginine, were normal. AD patients had higher plasma levels of phosphoserine, threonine, citrulline, hydroxyproline, and proline; and lower plasma levels of alfa-aminobutyric acid, methionine, leucine and ethanolamine. The CSF/plasma ratios of phosphoserine, serine, citrulline, alfa-aminobutyric acid and arginine were significantly lower in AD patients than those of controls. CSF amino acid levels were not related with the duration and severity of the disease. Accepted December 2, 1997; received August 30, 1997     

Serum and cerebrospinal fluid cystatin C levels in vascular and Alzheimer's dementia

INTRODUCTION: Cystatin C, a cysteine protease inhibitor, has been implicated in the neurodegenerative and repair processes of the nervous system, and the deposition of the same protein together with beta amyloid peptide was found as cerebral amyloid angiopathy (CAA) in different types of dementias. OBJECTIVE AND METHODS: Because of the differential diagnostic importance, serum and cerebrospinal fluid (CSF) cystatin C levels of 24 late onset Alzheimer's demented (AD) and 16 ischemic type of vascular demented (VD) probands were compared with 17 aged control (AC) persons. RESULTS: The serum and CSF cystatin levels were found in the normal range in all groups. The ischemic VD probands had the tendency to have higher cystatin C levels than the AD. No correlation has been found with the severity and duration of dementia and with the other measured parameters. CONCLUSION: These results indicate that lower than normal CSF cystatin C level is not a diagnostic marker in ischemic VD and CAA related to AD.     

Increased cerebrospinal fluid cAMP levels in Alzheimer's disease

Since increasing evidence suggests that upregulation of the cAMP-second messenger system may be implicated in Alzheimer's disease neurodegeneration, we have compared the cAMP and cGMP levels in cerebrospinal fluid (CSF) from patients with dementia of the Alzheimer type (DAT, n=10) with those from nondemented age-matched controls (n=10). Our results show that cAMP levels, but not cGMP, are significantly (p<0.01) elevated in CSF from patients with DAT compared to those from nondemented controls. Moreover, a linear regression analysis demonstrated a significant correlation (r=0.62; p<0.01) between cAMP and tau protein levels in CSF when controls and patients with DAT were studied together. These results suggest that upregulation of cAMP-signaling pathway is implicated in Alzheimer's disease physiopathology.     

Increased hepatocyte growth factor level in cerebrospinal fluid in Alzheimer's disease

BACKGROUND & OBJECTIVE: Hepatocyte growth factor (HGF), also known as the scatter factor, is a potent mitogen for mature hepatocytes, and also has multifunctional effects on some cells in various organs. Recently, we have found expression and localization of HGF in white matter astrocytes in human brain tissues. Furthermore, immunohistochemistry using anti-HGF antibody revealed more intense immunolabeling in Alzheimer's disease (AD) than control brains. The aim of the study is to investigate the level of HGF in cerebrospinal fluid (CSF) from patients with AD. MATERIAL AND METHODS: We examined the level of HGF in CSF from 34 AD and 15 age-matched disease control patients by highly sensitive enzyme-linked immunoabsorbent assay (ELISA) system. RESULTS: Consistent with the immunohistochemical data, a significantly higher concentration of HGF in AD CSF was found as compared with controls. A significant correlation was also seen between CSF HGF levels and white matter high-signal foci determined on brain magnetic resonance imaging (MRI) in AD patients. CONCLUSION: These results indicate that CSF HGF levels correspond with the white matter damage in AD brain.     

The relationship of cerebrospinal fluid monoamine metabolites with clinical response to tetrahydroaminoacridine in patients with Alzheimer's disease

Summary The effect of tetrahydroaminoacridine (THA) on the cerebrospinal fluid (CSF) monoamine metabolites was studied in 22 patients with Alzheimer's disease in an open treatment trial. The CSF monoamine metabolites were assayed at baseline and after 4 weeks' active THA treatment with 100 mg/d. A statistically significant increase in the CSF homovanillic acid (HVA) and in 5-hydroxyindoleacetic acid (5-HIAA) content was found. The increase of the CSF 5-HIAA level correlated significantly with improvement in cognitive tests and in the Instrumental Activities of Daily Living Scale. We conclude that besides its anticholinesterase activity THA enhances also the monoaminergic neurotransmission in the brain and that the clinical improvement during THA treatment may be partly mediated through the monoaminergic system.     

Inhibition of acetyl- and butyryl-cholinesterase in the cerebrospinal fluid of patients with Alzheimer's disease by rivastigmine: correlation with cognitive benefit

Cholinesterase (ChE) inhibition represents the most efficacious treatment approach for Alzheimer's disease (AD) to date. This multiple-dose study has examined the relationship between inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities in the cerebrospinal fluid (CSF) and cognitive change (measured by the Computerised Neuropsychological Test Battery [CNTB]) following administration of the ChE inhibitor, rivastigmine (Exelon). In 18 patients with mild to moderate AD, CNTB scores, activities of AChE and BuChE in the CSF, and plasma BuChE activity were determined prior to treatment with rivastigmine. Doses of rivastigmine were then titrated (1 mg b.i.d./week) to final doses of 1, 2, 3, 4, 5 or 6 mg b.i.d. (n = 3 per dose). Following treatment with the target dose of rivastigmine for at least 3 days, CNTB scores were re-determined. CSF samples were continuously collected together with plasma samples prior to and for 12 hours after the final dose of rivastigmine, and AChE and BuChE activities determined.AChE in CSF and BuChE in plasma were dose-dependently inhibited by rivastigmine treatment. The inhibition of BuChE in CSF was not clearly dose-dependent. A statistically significant correlation was observed between the change in CNTB summary score and inhibition of AChE activity (r = -0.56, p < 0.05) and BuChE activity (r = -0.65, p < 0.01) in CSF. Improvement in speed-, attention- and memory-related subtests of the CNTB correlated significantly with inhibition of BuChE but not AChE activity in CSF. Weak or absent correlation with change in cognitive performance was noted for inhibition of plasma BuChE. These results indicate that cognitive improvement with rivastigmine in AD is associated with central inhibition of ChEs and support a role for central BuChE in addition to AChE inhibition in modulating cholinergic function in AD.     

L-Glutamate, L-arginine and L-citrulline levels in cerebrospinal fluid of Parkinson's disease, multiple system atrophy, and Alzheimer's disease patients

Summary. Alterations in neuronal nitric oxide (NO) production may play a role in the pathophysiology of Parkinson's disease (PD) Alzheimer's disease (AD), and multiple system atrophy (MSA). The biosynthesis of NO is dependent on the availability of L-arginine, the substrate for NO-synthase (NOS), and on L-glutamate, which stimulates NO synthesis via the NMDA receptor. In this process L-citrulline is formed. We measured the levels of these amino acids in cerebrospinal fluid (CSF) of 108 PD patients, 12 AD patients, 15 MSA patients and 21 healthy subjects. A slight but statistically significant elevation of CSF L-citrulline was found in MSA patients, while CSF L-glutamate was found to be significantly decreased in AD patients. We found no significant changes in L-arginine levels. Although the relation between the CSF levels of these amino acids and neuronal NO production is still unclear, our findings suggest that AD is associated with a decrease in NO synthesis. Received November 2, 1998; accepted October 26, 1999     

Neurochemical markers in the cerebrospinal fluid of patients with Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis and normal controls

Summary Several neurotransmitter markers were investigated in the cerebrospinal fluid (CSF) from patients with Alzheimer's disease (AD) (n=27), Parkinson's disease (PD) (n=35) and ALS (n=26) and from control subjects (n=34) to compare the possible alterations in the biochemical profiles of these different neurodegenerative diseases. The main proportion of the patients represented an early phase of the illness at the time of the diagnosis. Correlations of the degree of dementia and the stage of the disease with CSF measures were evaluated. The CSF levels of somatostatin like-immunoreactivity (SLI) were significantly reduced in AD patients when compared with those of normals and ALS patients. The CSF concentrations of homovanillic acid (HVA) were significantly decreased for PD patients and the decrease focused on the nondemented patients. A trend of decreasing HVA values towards the most advanced stage of Parkinson's disease assessed by Webster's scale was also displayed. The content of 3-methoxy-4-hydroxyphenylglycol (MHPG) in the CSF was higher for ALS patients than for other groups. The lowest 5-hydroxy-indoleacetic acid (5HIAA) levels were observed in the PD group and the lowest acetylcholinesterase (AChE) activities were found in the PD patients with the most severe disease. Changes in CSF measures were too subtle to be beneficial for diagnostic purposes, but adequate for reflecting the different neurochemical profiles of these three degenerative neurological disorders.