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.     

Subgroups of Alzheimer's disease based on cerebrospinal fluid molecular markers

Alzheimer's disease, the most common cause of dementia, is multifactorial and heterogeneous; its diagnosis remains probable. We postulated that more than one disease mechanism yielded Alzheimer's histopathology, and that subgroups of the disease might be identified by the cerebrospinal fluid (CSF) levels of proteins associated with senile (neuritic) plaques and neurofibrillary tangles. We immunoassayed levels of tau, ubiquitin, and Abeta(1-42) in retrospectively collected CSF samples of 468 clinically diagnosed Alzheimer's disease patients (N = 353) or non-Alzheimer's subjects (N = 115). Latent profile analysis assigned each subject to a cluster based on the levels of these molecular markers. Alzheimer's disease was subdivided into at least five subgroups based on CSF levels of Abeta(1-42), tau, and ubiquitin; each subgroup presented a different clinical profile. These subgroups, which can be identified by CSF analysis, might benefit differently from different therapeutic drugs.     

Decreased plasma and cerebrospinal fluid levels of stem cell factor in patients with early Alzheimer's disease

Alzheimer's disease (AD) is characterized by massive neuronal cell loss in the brain. Stem cell factor (SCF) is a hematopoietic growth factor (HGF) that promotes neuroprotective effects and supports neurogenesis in the brain. In the present study, we found significantly lower SCF plasma levels in 30 early AD patients (908.5 +/- 181.7 pg/ml) in comparison with 30 age-matched healthy controls (1058.3 +/- 221.5 pg/ml; p = 0.006). SCF plasma levels in AD patients showed a significant inverse correlation with dementia severity as measured by ADAS-Cog (r = -0.289; p = 0.037). AD patients showed significantly lower SCF levels in cerebrospinal fluid (CSF) (131.60 +/- 43.03 pg/ml) in comparison with 15 age- and gender-matched patients with other non-inflammatory neurological disease (NIND) (166.03 +/- 42.5 pg/ml; p = 0.017). In addition, we found significant positive correlations between SCF and CXCL12 (also known as SDF-1) plasma levels in healthy controls (r = 0.341; p = 0.008) and between SCF and CXCL12 CSF levels in AD patients (r = 0.487; p < 0.001). In conclusion, decreased SCF plasma and CSF levels in early AD patients may contribute to a deficient hematopoietic brain support with putative pathogenic and clinical relevance. Further studies are needed to examine whether a manipulation of HGFs such as SCF could be a promising new therapeutic strategy for AD.     

beta-Endorphin-like immunoreactivity in cerebrospinal fluid of patients with Alzheimer's disease and Parkinson's disease

beta-Endorphin-like immunoreactivity (beta-EP-LI) in cerebrospinal fluid (CSF) was measured in 42 patients with Alzheimer's disease (AD), 36 patients with Parkinson's disease (PD), and 35 controls. Values for patients with Alzheimer's disease (10.9 +/- 2.8 pmol/l) seemed to be lower than those for controls (12.9 +/- 2.5 pmol/l) (P less than 0.05). In addition, the severely demented patients had lower values than the moderately demented (P less than 0.01). In patients with Parkinson's disease no significant difference in beta-EP-LI values was observed compared to the controls. The data suggest, that processing of pro-opiomelanocortin, precursor of beta-endorphin, and the mechanism of cognitive impairment may differ in Alzheimer's disease and Parkinson's disease.     

Increased lipid peroxidation in cerebrospinal fluid and plasma from patients with Creutzfeldt-Jakob disease

Oxidative pathomechanisms play an important role in neurodegenerative diseases like Alzheimer's disease (AD). It has been shown that lipid peroxidation in cerebrospinal fluid (CSF) and plasma is increased in AD. To assess the role of oxidative stress in Creutzfeldt-Jakob disease (CJD), we investigated the oxidizability of lipids, the lipid composition and the levels of the antioxidants ascorbate and alpha-tocopherol in CSF and plasma of 15 CJD patients and 12 neurologically healthy controls. CSF and plasma lipid peroxidation was increased in CJD patients and polyunsaturated fatty acids were reduced in CSF of these patients. Ascorbate levels were lower in CSF and plasma of CJD patients, while alpha-tocopherol was found to be decreased in CSF but not in plasma. These results support the hypothesis that oxidative mechanisms are involved in the pathogenesis of CJD and provide a rationale for the use of antioxidants in the therapy of this disease.     

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     

Proteomic studies of potential cerebrospinal fluid protein markers for Alzheimer's disease

By comparing the cerebrospinal fluid (CSF) proteome between Alzheimer's disease (AD) patients and controls, it may be possible to identify proteins that play a role in the disease process and thus to study the pathogenesis of AD. Two-dimensional gel electrophoresis (2-DE), SYPRO Ruby staining and mass spectrometry were used for clinical screening of disease-influenced CSF proteins in AD patients compared to controls. In order to increase the detection of CSF proteins and to improve the separation of protein isoforms in a 2-D gel, micro-narrow range IPG strips were used. The levels of eight proteins and their isoforms, including apolipoprotein A1, apolipoprotein E, apolipoprotein J, beta-trace, retinol-binding protein, kininogen, alpha-1 antitrypsin, cell cycle progression 8 protein, and alpha-1beta glycoprotein were significantly altered in CSF of AD patients compared to controls. Furthermore, we also used liquid-phase IEF, as a prefractionation step, prior to 2-DE for comparison of CSF proteins between individual AD patients and controls. The levels of 37 proteins spots were altered in AD patients. One of the identified proteins, alpha-2-HS glycoprotein, has not previously been linked to AD. Our study shows that several glycoproteins are altered in AD.     

Dimethylarginines, homocysteine metabolism, and cerebrospinal fluid markers for Alzheimer's disease

Dimethylarginine and homocysteine metabolism are closely linked and alterations of both were observed in plasma and cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD). CSF parameters of homocysteine metabolism have recently been found to be associated with the CSF level of the AD biomarker phosphorylated tau (ptau) in AD patients. To investigate possible relationships between homocysteine and dimethylarginine metabolism and the AD CSF biomarkers ptau181 and amyloid-β 1-42 (Aβ42), we assessed parameters of homocysteine metabolism (CSF homocysteine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), 5-methyltetrahydrofolate (5-MTHF)) and dimethylarginine metabolism (plasma and CSF asymmetric dimethylarginine (ADMA), symmetric dimethylarginine, L-arginine) as well as CSF Aβ42 and ptau181 in 98 controls and 51 AD patients. Multivariate linear regression analyses were performed to assess associations between the considered parameters. SAH concentrations show significant associations to CSF ADMA levels, and CSF ADMA and L-arginine to ptau181, but not to Aβ42 concentrations in AD patients. When including concentrations of homocysteine, 5-MTHF, SAM, and SAH into the analysis, CSF ADMA concentrations independently predicted ptau181 levels in AD patients but homocysteine-related metabolites were associated with ptau181 only when ADMA was removed from the analysis model. These results suggest that CSF ADMA may interact with CNS homocysteine metabolism and may contribute to neurodegeneration and accumulation of phosphorylated tau in AD. Functional and interventional studies are needed to further proof this hypothesis.     

Age-dependent decline in the apolipoprotein E level in cerebrospinal fluid from control subjects and its increase in cerebrospinal fluid from patients with Alzheimer's disease

In order to address the significance of apolipoprotein E (apoE) in the pathogenesis as well as the clinical diagnosis of Alzheimer's disease (AD), we measured its level in cerebrospinal fluid (CSF) from randomly selected Japanese control subjects at various ages (n = 36), which included 14 age-matched controls, and from AD patients including early-onset (n = 11, EOAD) and late-onset (n = 14, LOAD) cases. The CSF apoE level in controls linearly decreased during aging to over 80 years (r(2) = 0.323, p < 0.0001). The CSF apoE level in AD patients was 31.9% elevated compared to the age-matched controls (n = 14, p < 0.05) and linearly increased with a decrement of the patients' Mini Mental State Examination scores. Moreover, the CSF apoE level of EOAD patients (n = 11) was higher than that of LOAD patients (n = 14, p < 0.05), whose APOE epsilon4 allele frequency was significantly higher than that of controls (chi(2) = 7. 16, p < 0.03). Two-dimensional gel electrophoretic analysis of the heparin-Mn(2+)-precipitable lipoprotein fraction in CSFs showed that the ratio between the level of CSF apoA-I and that of CSF apoE of controls was significantly higher than those of all AD and LOAD subjects (p < 0.01, p < 0.05), while the CSF apoA-I-to-apoE ratios of the two AD groups were not significantly different. These results suggest that overproduction of apoE protein may be a consequence of astroglial response to neurodegeneration in AD and that the determination of CSF apoliprotein levels serves as a clinical marker for monitoring the progression of AD.     

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.     

Acetylcholinesterase activity in cerebrospinal fluid of patients with Alzheimer's disease and senile dementia

Acetylcholinesterase (AChE) in the cerebrospinal fluid (CSF) from patients with Alzheimer-type dementia and control subjects was analyzed by centrifugation on a sucrose density gradient, and by column chromatography on Sephadex G-200. The sedimentation coefficient and molecular weight of CSF AChE were calculated as 10S and 380,000, respectively, which corresponded to those of G4 isozyme in the brain. Other isozymes of AChE were not detected in the CSF of either patients with Alzheimer-type dementia or the controls. Sufficient activity of AChE was observed in the CSF of a patient with familial pseudocholinesterase deficiency, although the pseudocholinesterase activity was not found either in the serum or in the CSF. CSF AChE activity in control subjects increased with advancing age (P less than 0.02). AChE activity in the CSF was significantly lower in patients with presenile dementia (Alzheimer's disease), compared with age-matched control subjects (P less than 0.001). However, AChE activity in the CSF showed a wide variation among patients of Alzheimer-type dementia with a late onset (senile dementia).     

Inflammatory biomarkers in Alzheimer's disease plasma

IntroductionPlasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a “Holy Grail” of AD research and intensively sought; however, there are no well-established plasma markers.MethodsA hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed.ResultsTen analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOε4 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71).DiscussionPlasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation.     

Remarkable increase in the concentration of 8-hydroxyguanosine in cerebrospinal fluid from patients with Alzheimer's disease

To investigate the possible role of oxidative RNA damage in the pathogenesis of Alzheimer's disease (AD), the concentrations of the oxidative stress marker 8-hydroxyguanosine (8-OHG) were measured in the cerebrospinal fluid (CSF) and the serum of patients with AD and control subjects. The concentration of 8-OHG in CSF in AD patients was approximately fivefold that in controls (P < 0.001). The concentration of 8-OHG in CSF decreased significantly with the duration of illness (r(s) = -0.48, P < 0.05) and the progression of cognitive dysfunctions (r(s) = 0.67, P < 0.01). However, the concentration of 8-OHG in CSF showed no correlation with that in serum in both the controls and AD patients. In addition, the concentration of 8-OHG in serum was not significantly altered in AD patients compared to that in controls, suggesting that the 8-OHG concentrations in the CSF do not reflect those in serum and may be probably reflect those in brain tissue. These in vivo findings suggest a possible role of 8-OHG and increased oxidative RNA damage in the early stage of the development of AD.     

Altered glycosylation of acetylcholinesterase in lumbar cerebrospinal fluid of patients with Alzheimer's disease

As clinical diagnosis of Alzheimer's disease is only 80%-90% accurate, there is a need to identify biochemical markers of Alzheimer's disease. Previous studies have shown an abnormality in the glycosylation of acetylcholinesterase (AChE) in the CSF collected postmortem from patients with Alzheimer's disease. This abnormality was very specific for Alzheimer's disease, as it was not detected in other illnesses causing dementia. We report here that the glycosylation of AChE is also altered in lumbar CSF collected antemortem. The altered glycosylation was due to increased concentrations of a minor AChE isoform that does not bind to concanavalin A (Con A). Glycosylation of AChE may eventually be of diagnostic value, especially when used in combination with other CSF markers.