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.     

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.     

Plasma and cerebrospinal fluid alpha1-antichymotrypsin levels in Alzheimer's disease: correlation with cognitive impairment

alpha-1-Antichymotrypsin (ACT) is present in neuritic plaques in which it participates in the inflammatory cascade of Alzheimer's disease (AD). Reports of blood ACT levels in AD, and its usefulness as a disease biomarker, have been conflicting. In an effort to clarify this, we measured plasma ACT levels in 516 white subjects including 359 subjects with probable or possible AD, 44 subjects with other late-life dementias, and 113 nondemented people. Subjects with systemic inflammatory diseases or who were taking antiinflammatory medications were excluded. All patients underwent extensive medical and detailed neuropsychological examinations at the time their blood was drawn. We found that plasma ACT levels were elevated in AD patients compared with the control group (p = 0.01) and were associated with severity of AD dementia; there was a negative association with the Mattis Dementia Rating Scale (a global measure of cognition) and a positive association with the Clinical Dementia Rating Scale (a global functional assessment). These relationships remained significant after controlling for demographic and genetic variables. When AD subjects were stratified into subgroups by dementia severity, matched by age, education, and gender, increased serum ACT correlated with Clinical Dementia Rating Scale (p = 0.0041) or Mattis Dementia Rating Scale (p = 0.0031) scores. ACT measurements in cerebrospinal fluid from an additional 34 AD cases and 16 controls showed elevated levels (p = 0.02) in AD. There was a negative correlation (p = 0.037) between cerebrospinal fluid ACT levels and clinical severity as measured by the Mini-Mental State Examination. Our results demonstrate that peripheral ACT levels are elevated in AD, but not in dementias other than AD, and they increase with progression of AD dementia. Although not useful as a diagnostic biomarker, ACT may reflect disease severity and may be helpful as a within subject biomarker in interventions (particularly with antiinflammatory agents) directed at slowing or halting progression of disease.     

Plasma and cerebrospinal fluid neurochemical pattern in Menkes disease

Menkes disease is a neurodegenerative disorder of copper metabolism. Because the enzyme dopamine-b?-hydroxylase requires copper to catalyze the conversion of dopamine to norepinephrine, we reasoned that patients with Menkes disease would have a neurochemical pattern similar to that seen in patients with congenital absence of dopamine-b?-hydroxylase, i.e., high levels of dopamine, the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), and the catecholamine precursor dihydroxyphenylalanine (DOPA), and low levels of norepinephrine and its neuronal metabolite dihydroxyphenylglycol (DHPG). We measured plasma and cerebrospinal fluid (CSF) levels of catechols in 10 patients ranging in age from 9 days to 27 months. In contrast to patients with congenital absence of dopamine-b?-hydroxylase, norepinephrine levels were normal in plasma of 4 Menkes patients and in CSF of all 10 patients. However, the ratios of DOPA : DHPG and DOPAC : DHPG in plasma and CSF of Menkes patients were invariably increased beyond the ranges of control values. These neurochemical findings indicate partial deficiency of dopamine-b?-hydroxylase in Menkes patients, with compensatory increases in catecholamine biosynthesis in sympathetic nerves and in the brain. Increased tyrosine hydroxylation and increased exocytotic release of norepinephrine may be responsible for preservation of plasma and CSF norepinephrine levels in Menkes patients. The abnormal neurochemical pattern, including high ratios of DOPA : DHPG and DOPAC : DHPG, may serve as a biochemical marker for Menkes disease and provide a baseline against which the influence of proposed therapies can be judged.     

Novel ventriculo-peritoneal shunt in Alzheimer's disease cerebrospinal fluid biomarkers

Alzheimer's disease is an age-related dementia and its incidence is rising in developed countries as the population ages. Amyloid plaques and tau-rich neurofibrillary tangles are pathologic hallmarks of the disease. Treatment is symptomatic, consisting of compounds that block enzymatic acetylcholine degradation (acetylcholinesterase inhibitors). Cognitive benefits of the four approved antidementia drugs are typically modest and limited in duration. While Alzheimer's disease is undoubtedly multifactorial in cause, advancing age is the most important risk factor. Any robust theory of pathogenesis must account for the profound influence of age on the emergence of Alzheimer's disease. There is evidence that senescent changes in cerebrospinal fluid production, circulation, turnover and clearance of amyloid beta-peptides may be a key factor in the onset and progression of Alzheimer's disease. The effect of increasing cerebrospinal fluid circulation and turnover in Alzheimer's disease patients by implanting a novel, low-flow drainage system (COGNIshunt) has been studied and promising trends in cognitive stabilization and improvement in cerebrospinal fluid biomarkers have been found.     

Altered glycosylation of cerebrospinal fluid butyrylcholinesterase in Alzheimer's disease

Our previous studies have shown that a minor isoform of acetylcholinesterase (AChE) is increased in the cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients. In the present study, the glycosylation of butyrycholinesterase (BuChE) was found to be altered in AD CSF. By combining an analysis of CSF AChE and BuChE glycosylation, it is possible to identify cases of AD with more than 90% sensitivity and specificity.     

Differential expression of microRNAs in Alzheimer's disease brain,blood, and cerebrospinal fluid

IntroductionSeveral microRNAs (miRNAs) have been implicated in Alzheimer's disease pathogenesis, but the evidence from individual case-control studies remains inconclusive.MethodsA systematic literature review was performed, followed by standardized multistage data extraction, quality control, and meta-analyses on eligible data for brain, blood, and cerebrospinal fluid specimens. Results were compared with miRNAs reported in the abstracts of eligible studies or recent qualitative reviews to assess novelty.ResultsData from 147 independent data sets across 107 publications were quantitatively assessed in 461 meta-analyses. Twenty-five, five, and 32 miRNAs showed studywide significant differential expression (α < 1·08 × 10⁻⁴) in brain, cerebrospinal fluid, and blood-derived specimens, respectively, with 5 miRNAs showing differential expression in both brain and blood. Of these 57 miRNAs, 13 had not been reported in the abstracts of previous original or review articles.DiscussionOur systematic assessment of differential miRNA expression is the first of its kind in Alzheimer's disease and highlights several miRNAs of potential relevance.     

Alzheimer's disease: paired helical filament immunoreactivity in cerebrospinal fluid

Summary A competitive enzyme-linked immunosorbent assay with high sensitivity has been developed for measuring ubiquitin reactivity of paired helical filaments (PHF). Using the assay, ubiquitin immunoreactivity was estimated in the cerebrospinal fluid (CSF) of 44 patients who had been clinically diagnosed as having Alzheimer's disease (AD) and of 38 control patients, including 20 neurological cases. Monoclonal antibody (mAb) 5–25 to isolated paired helical filaments was used. This mAb recognizes amino acids 64–76 of ubiquitin. The levels of ubiquitin immunoreactivity measured in CSF (twice diluted) were significantly higher in the AD (p<0.001) than in the control group. In only a minority of instances were values for ubiquitin levels the same in AD and control groups: on PHF-coated plates, immunoreactivity values for 77% of the AD CSF specimens were higher than those for 92% of the controls, and on ubiquitin-coated plates, values for 85% of the AD CSF specimens were higher than those for 88% of the controls. On immunoblots of both AD and control CSF, mAb 5-25 stained a series of protein bands. The free ubiquitin that is also present in the CSF was not labeled. No striking differences were detected in the immunoblot pattern of AD and control CSF. This study demonstrastes the presence of quantitative differences in the conjugated ubiquitin in AD and control CSF.Supported in part by the NYS Office of Mental Retardation and Developmental Disabilities; NIH grants NS18105, AG05892, and AG04220; and a grant from Senetek PLCA preliminary report on part of these findings was presented at The First International Conference on Alzheimer Disease & Related Disorders (Alzheimer Disease Assoc. Disord. 2:175, 1988)     

Effect of statins on Alzheimer's disease biomarkers in cerebrospinal fluid

BACKGROUND: Treatment with HMG-CoA reductase inhibitors ("statins") has been variably associated with a reduced risk of Alzheimer's disease (AD) in epidemiologic studies and reduced amyloid-beta (Abeta) deposition in animal models of AD. Putative neuroprotective effects of statins may vary in relation to their ability to penetrate into the central nervous system (CNS). METHODS: We measured levels of cerebrospinal fluid (CSF) AD biomarkers following 14 weeks of treatment with simvastatin (a CNS permeant statin; n=10) at 40 mg/day or pravastatin (a CNS impermeant statin; n=13) at 80 mg/day in hypercholesterolemic subjects without dementia. RESULTS: Simvastatin, but not pravastatin, reduced CSF levels of phospho-tau-181 (p-tau181) in all subjects. There were no differences in CSF levels of total tau, Abeta42, Abeta40, soluble amyloid beta protein precursor (sAbetaPP) alpha or beta, or F2-isoprostanes. CONCLUSIONS: Statins may modulate the phosphorylation of tau in humans and this effect may depend on the CNS availability of the statin. These results suggest another mechanism by which statins may act to reduce the risk of AD.     

Long-term stability of Alzheimer's disease biomarker proteins in cerebrospinal fluid

The quantitative analysis of peptides in human cerebrospinal fluid (CSF) has become an important step in the early diagnosis of dementia, e.g., Alzheimer's disease. In search of new biomarkers for early detection and differential diagnosis of chronic neurodegenerative diseases, "biobanking" and long-term storage of human samples is increasingly important. The German Dementia Competence Network (DCN) has accomplished one of the largest biomaterial banks in this field, comprising CSF from several hundreds of patients. Since little is known about long-term stability of biomarker proteins in frozen CSF, we investigated the reliability of quantitative analysis in a total of 56 CSF samples that had been frozen for up to six years. Here, we compare a second quantitative analysis of Aβ40, Aβ42, and the total-tau protein after several years of storage at -80 °C with initial results obtained within six months after lumbar puncture. The second analysis was done using standard ELISAs or the newly developed Mesocale System. We found that regarding Aβ42 and total-tau, the results highly correlate with correlation coefficients of c = 0.73 and c = 0.82 respectively, while for Aβ40 the correlation coefficient was lower (c = 0.53), suggesting that Aβ40 is more vulnerable to degradation. We conclude that the quantitative analysis of the concentration of Aβ42, as well as for total-tau, in CSF in samples that have been stored for years is reliable. The determination of these biomarkers and potentially new biomarkers in CSF samples stored in large biomaterial banks assembled over many years is feasible.     

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.     

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.     

Normal cerebrospinal fluid glutathione concentrations in Parkinson's disease, Alzheimer's disease and multiple system atrophy.

We measured total glutathione concentrations in the cerebrospinal fluid (CSF) of non-demented Parkinson's disease patients (PD; n=71), demented PD patients (PDD; n=13), multiple system atrophy patients (MSA; n=10), Alzheimer's disease patients (AD; n=17) and age-matched controls (n=21). No statistically significant differences in the mean total CSF glutathione concentrations were found between groups and dopaminomimetic treatment was not found to have any effect on total CSF glutathione levels. Our main conclusion is that total glutathione is not useful as a CSF marker for assumed oxidative stress in patients with PD, MSA or AD.     

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.     

Decreased somatostatin-like immunoreactivity in cerebral cortex and cerebrospinal fluid in Alzheimer's disease

To investigate changes in the somatostatinergic neurons of patients with Alzheimer's disease (AD), we determined the somatostatin-like immunoreactivity (SLI) in post-mortem brain tissue of histopathologically confirmed AD patients and in CSF of probable AD patients (according to DSM III). The CSF values were then correlated with psychological test scores. In 6 AD patients the SLI values were decreased 42% (P less than 0.005) in the frontal cortex, 28% (P less than 0.05) in the temporal cortex and 42% (P less than 0.01) in the parietal cortex but not in the thalamus and putamen compared to 11 control patients. In some brain areas there were statistical correlations between SLI values and cholinergic markers, choline acetyltransferase and acetylcholine esterase activities, suggesting a relationship between these two neurotransmitter systems. In the CSF among 75 AD patients SLI was 35% lower (P less than 0.001) than in controls. Severely demented power (P less than 0.001) than in controls. Severely demented patients showed lower SLI values than moderately demented individuals, but this difference was not significant. There was a weak but statistically significant correlation between SLI values in CSF and neuropsychological test scores. This study further confirms the involvement of somatostatinergic neurons in AD and suggests that this involvement may be related to the progression of dementia symptoms.