Cerebrospinal fluid cholinergic biomarkers are associated with postoperative delirium in elderly patients undergoing Total hip/knee replacement: a prospective cohort study.

BACKGROUND: Postoperative delirium (POD) is a frequent complication after surgery and its occurrence is associated with poor outcomes. The neuropathology of this complication is unclear, but it is important to evaluate relevant biomarkers for postoperative status. The purpose of this study is to explore the relationship between expression levels of cholinergic biomarkers in cerebrospinal fluid (CSF) and the occurrence and development of POD in elderly patients. METHODS: Four hundred and ninety-two elderly patients aged 65 years old or older with elective total hip/knee replacement received combined spinal-epidural anesthesia. Preoperative baseline cognitive function was assessed using the Mini-Mental State Examination (MMSE) before surgery. Each patient was interviewed in post-anesthesia care unit (PACU) and on the first, second, third and seventh (or before discharge) postoperative days. POD was diagnosed using the Confusion Assessment Method (CAM), and POD severity was measured using the Memorial Delirium Assessment Scale (MDAS). Preoperative CSF and plasma choline acetyltransferase (ChAT), acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels were determined by ELISA. The levels of ChAT, AChE and BuChE activities were determined by spectrophotometry. RESULTS: POD was detected in 11.4% (51/447) of the patients. AChE, BuChE, ChAT, TNF-α and IL-6 concentrations in CSF and plasma have higher consistency. In preoperative CSF and preoperative and postoperative plasma, down-regulation of the concentration and activity of AChE and BuChE as well as up-regulation of the concentration and activity of ChAT and the concentrations of IL-6 and TNF-α were observed in patients who developed POD, and the decrease in BuChE was the most obvious. Logistic analysis showed the activities of ChAT, AChE and BuChE in CSF were still related to POD after adjusting for related factors such as sex, age, years of education, height, weight, body mass index (BMI), and American Society of Anesthesiologists (ASA) class. Receiver Operating Characteristic (ROC) curve analysis was conducted to determine the Area Under Curve (AUC) of AChE, BuChE and ChAT activity in CSF was 0.679 (P < 0.01), 0.940 (P < 0.01) and 0.819 (P < 0.01) respectively and found that BuChE activity had the most accurate diagnostic value. CONCLUSION: The changes in preoperative activity of AChE, BuChE and ChAT in CSF were associated with the development of POD in elderly patients, and BuChE activity had the greatest diagnostic value, which may be related to central cholinergic degradation. These cholinergic biomarkers might participate in the neuropathology of POD, pending further investigations. TRIAL REGISTRATION: This study was registered at Chictr.org.cn (NO. ChiCTR1900023729 ) June 9th, 2019. (Retrospectively registered).

Highly sensitive GQDs-MnO2 based assay with turn-on fluorescence for monitoring cerebrospinal acetylcholinesterase fluctuation: A biomarker for organophosphorus pesticides poisoning and management.

In this study, we demonstrated an assay with turn-on fluorescence for monitoring cerebrospinal acetylcholinesterase (AChE) fluctuation as a biomarker for organophosphorus pesticides (OPs) poisoning and management based on single layer MnO2 nanosheets with graphene quantum dots (GQDs) as signal readout. Initially, the fluorescence of GQDs was quenched by MnO2 nanosheets mainly due to the inner filter effect (IFE). However, with the presence of reductive thiocholine (TCh), the enzymatic product, hydrolyzed from acetylthiocholine (ATCh) by AChE, the redox reaction between MnO2 and TCh occurred, leading to the destruction of the MnO2 nanosheets, and thereby IFE was diminished gradually. As a consequence, the turn-on fluorescence of GQDs with the changes in the spectrum of the dispersion constituted a new mechanism for sensing of cerebrospinal AChE. With the method developed here, we could monitor cerebrospinal AChE fluctuation of rats exposed to OPs before and after therapy, and could thereby open up the pathway to a new sensing platform for better understanding the mechanism of brain dysfunctions associate with OPs poisoning.

Complement component C3 and butyrylcholinesterase activity are associated with neurodegeneration and clinical disability in multiple sclerosis.

Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear. In a recent large rat genome-wide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects. We here determined levels of neurofilament-light (NFL), a marker for ongoing nerve injury, C3 and activity of the two main ACh hydrolyzing enzymes, acetylcholinesterase (AChE) and BuChE, in cerebrospinal fluid (CSF) from patients with MS (n = 48) and non-inflammatory controls (n = 18). C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in patients with ≥9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease. BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples. In conclusion, we show that CSF C3 correlates both to a marker for ongoing nerve injury and degree of disease disability. Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation. These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.

Changes in CSF cholinergic biomarkers in response to cell therapy with NGF in patients with Alzheimer's disease.

INTRODUCTION: The extensive loss of central cholinergic functions in Alzheimer's disease (AD) brain is linked to impaired nerve growth factor (NGF) signaling. The cardinal cholinergic biomarker is the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT), which has recently been found in cerebrospinal fluid (CSF). The purpose of this study was to see if EC-NGF therapy will alter CSF levels of cholinergic biomarkers, ChAT, and acetylcholinesterase. METHOD: Encapsulated cell implants releasing NGF (EC-NGF) were surgically implanted bilaterally in the basal forebrain of six AD patients for 12 months and cholinergic markers in CSF were analyzed. RESULTS: Activities of both enzymes were altered after 12 months. In particular, the activity of soluble ChAT showed high correlation with cognition, CSF tau and amyloid-ß, in vivo cerebral glucose utilization and nicotinic binding sites, and morphometric and volumetric magnetic resonance imaging measures. DISCUSSION: A clear pattern of association is demonstrated showing a proof-of-principle effect on CSF cholinergic markers, suggestive of a beneficial EC-NGF implant therapy.

Pharmacodynamics of cholinesterase inhibitors suggests add-on therapy with a low-dose carbamylating inhibitor in patients on long-term treatment with rapidly reversible inhibitors.

Despite three decades of intensive research in the field of Alzheimer's disease (AD) and numerous clinical trials of new therapeutic agents, cholinesterase inhibitors (ChEIs) are still the mainstay of therapeutics for AD and dementia with Lewy bodies. Pharmacodynamic analyses of ChEIs provide paradoxical observations. Treatment with the rapidly reversible, noncarbamylating ChEIs (donepezil, galantamine, and tacrine) increases acetylcholinesterase (AChE) protein expression, whereas the carbamylating agent, rivastigmine, produces sustained inhibition with no significant change in AChE protein expression. Still, the symptomatic clinical efficacies of all these agents are similar. We report here for the first time that treatment with phenserine, another carbamylating ChEI, produces a sustained but mild inhibition of AChE in cerebrospinal fluid (CSF) of AD patients. We also show that phenserine treatment reverses donepezil-induced elevation of AChE expression. Further analyses on CSF of another larger patient cohort treated with donepezil revealed that, in addition to its main mode of action, donepezil produced two other pharmacodynamics with potentially contradictory outcomes. Donepezil-induced AChE expression favored an AChE-driven amyloid-ß peptide (Aß) aggregation, whereas donepezil itself concentration-dependently counteracted the AChE-induced Aß aggregation, most likely by competing with the Aß peptides for peripheral anionic site on the AChE protein. The reduction of AChE protein expression in the donepezil-treated patients by concomitant administration of the carbamylating agent, phenserine, could allow the donepezil molecule to only prevent interaction between Aß and AChE. The current study suggests that an add-on therapy with a low-dose formulation of a carbamylating agent in patients on long-term donepezil treatment should be explored as a strategy for enhancing the clinical efficacy of these agents in dementia disorders.

Cerebrospinal fluid (CSF) 25-hydroxyvitamin D concentration and CSF acetylcholinesterase activity are reduced in patients with Alzheimer's disease.

BACKGROUND: Little is known of vitamin D concentration in cerebrospinal fluid (CSF) in Alzheimer's disease (AD) and its relation with CSF acetylcholinesterase (AChE) activity, a marker of cholinergic function. METHODS: A cross-sectional study of 52 consecutive patients under primary evaluation of cognitive impairment and 17 healthy controls. The patients had AD dementia or mild cognitive impairment (MCI) diagnosed with AD dementia upon follow-up (n = 28), other dementias (n = 12), and stable MCI (SMCI, n = 12). We determined serum and CSF concentrations of calcium, parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), and CSF activities of AChE and butyrylcholinesterase (BuChE). FINDINGS: CSF 25OHD level was reduced in AD patients (P < 0.05), and CSF AChE activity was decreased both in patients with AD (P < 0.05) and other dementias (P < 0.01) compared to healthy controls. None of the measured variables differed between BuChE K-variant genotypes whereas the participants that were homozygous in terms of the apolipoprotein E (APOE) ε4 allele had decreased CSF AChE activity compared to subjects lacking the APOE ε4 allele (P = 0.01). In AD patients (n=28), CSF AChE activity correlated positively with CSF levels of total tau (T-tau) (r = 0.44, P < 0.05) and phosphorylated tau protein (P-tau) (r = 0.50, P < 0.01), but CSF activities of AChE or BuChE did not correlate with serum or CSF levels of 25OHD. CONCLUSIONS: In this pilot study, both CSF 25OHD level and CSF AChE activity were reduced in AD patients. However, the lack of correlations between 25OHD levels and CSF activities of AChE or BuChE might suggest different mechanisms of action, which could have implications for treatment trials.

Acetylcholinesterase activity in the cerebrospinal fluid of dogs with seizures.

Recent studies in animal models have focused on the role of cholinergic elements, mainly acetylcholinesterase (AChE) and the 'readthrough' acetylcholinesterase isoform (AChE-R), in seizures. A prospective double-masked study was conducted to assess the activity of AChE and AChE-R in cerebrospinal fluid (CSF) of 26 dogs post-seizure, 28 dogs with intervertebral disc disease (IVDD) and 16 healthy dogs. AChE was also measured in the serum in the post-seizure and IVDD groups. The results showed no significant differences in CSF AChE among the three groups. AChE-R was not detected in any dog and AChE in the serum was similar between groups. This preliminary study provides new information on AChE and AChE-R in the CSF and sera of dogs following naturally-occurring seizures.

Regulated Extracellular Choline Acetyltransferase Activity- The Plausible Missing Link of the Distant Action of Acetylcholine in the Cholinergic Anti-Inflammatory Pathway.

Acetylcholine (ACh), the classical neurotransmitter, also affects a variety of nonexcitable cells, such as endothelia, microglia, astrocytes and lymphocytes in both the nervous system and secondary lymphoid organs. Most of these cells are very distant from cholinergic synapses. The action of ACh on these distant cells is unlikely to occur through diffusion, given that ACh is very short-lived in the presence of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), two extremely efficient ACh-degrading enzymes abundantly present in extracellular fluids. In this study, we show compelling evidence for presence of a high concentration and activity of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT) in human cerebrospinal fluid (CSF) and plasma. We show that ChAT levels are physiologically balanced to the levels of its counteracting enzymes, AChE and BuChE in the human plasma and CSF. Equilibrium analyses show that soluble ChAT maintains a steady-state ACh level in the presence of physiological levels of fully active ACh-degrading enzymes. We show that ChAT is secreted by cultured human-brain astrocytes, and that activated spleen lymphocytes release ChAT itself rather than ACh. We further report differential CSF levels of ChAT in relation to Alzheimer's disease risk genotypes, as well as in patients with multiple sclerosis, a chronic neuroinflammatory disease, compared to controls. Interestingly, soluble CSF ChAT levels show strong correlation with soluble complement factor levels, supporting a role in inflammatory regulation. This study provides a plausible explanation for the long-distance action of ACh through continuous renewal of ACh in extracellular fluids by the soluble ChAT and thereby maintenance of steady-state equilibrium between hydrolysis and synthesis of this ubiquitous cholinergic signal substance in the brain and peripheral compartments. These findings may have important implications for the role of cholinergic signaling in states of inflammation in general and in neurodegenerative disease, such as Alzheimer's disease and multiple sclerosis in particular.

Biological markers in cerebrospinal fluid for axonal impairment in multiple sclerosis: acetylcholinesterase activity cannot be considered a useful biomarker.

An impairment of the cholinergic system activity has been demonstrated in multiple sclerosis (MS). The correlation between the cholinergic system and the cognitive dysfunction in MS has led to studies on the use of acetylcholinesterase inhibitors (AChEI). The acetylcholinesterase (AChE), essential enzyme for the regulation of turnover of acetylcholine, can be considered the most important biochemical indicator of cholinergic signaling in the nervous system. Besides its catalytic properties, AChE has a crucial role in the regulation of the immune function. Based on the role of the AChe in the regulation of cholinergic signaling in the nervous system, the aim of the present study is to evaluate the activity of AChE in different pathological conditions: MS, other inflammatory neurological disorders (OIND) and non-inflammatory neurological disorders (NIND). We measured AChE activity in CSF samples obtained from 34 relapsing-remitting MS patients and, as controls, 40 patients with other inflammatory neurological disorders (OIND) and 40 subjects with other non-inflammatory neurological disorders (NIND). Fluorimetric detection of the AChE in MS patients and in the controls showed no statistically significant differences: 1.507 ± 0.403 nmol/ml/min in MS patients, 1.484 ± 0.496 nmol/ml/min in OIND and 1.305 ± 0.504 nmol/ml/min in NIND. Similar results were obtained in another recent study, using a different method. Further studies must be conducted on a larger number of patients, with different degrees of cognitive impairment. However, AChE measured in CSF can probably not be considered a useful biomarker for the assessment of the functional alterations of cholinergic system in pathological conditions.

A highly sensitive gold-nanoparticle-based assay for acetylcholinesterase in cerebrospinal fluid of transgenic mice with Alzheimer's disease.

A highly sensitive, selective, and dual-readout (colorimetric and fluorometric) assay for acetylcholinesterase (AChE) based on Rhodamine B-modified gold nanoparticle is reported. Due to its good sensitivity and selectivity, the assay can be used for monitoring AChE levels in the cerebrospinal fluid of transgenic mice with Alzheimer's disease.

A systematic literature review of cerebrospinal fluid biomarkers in delirium.

BACKGROUND: Cerebrospinal fluid (CSF) analysis has great potential to advance understanding of delirium pathophysiology. METHODS: A systematic literature review of CSF studies of DSM or ICD delirium was performed. RESULTS: In 8 studies of 235 patients, delirium was associated with: elevated serotonin metabolites, interleukin-8, cortisol, lactate and protein, and reduced somatostatin, ß-endorphin and neuron-specific enolase. Elevated acetylcholinesterase predicted poor outcome after delirium and higher dopamine metabolites were associated with psychotic features. CONCLUSIONS: No clear conclusions emerged, but the current literature suggests multiple areas for further investigation with more detailed studies.

Changes in CSF acetyl- and butyrylcholinesterase activity after long-term treatment with AChE inhibitors in Alzheimer's disease.

OBJECTIVES: To measure cerebrospinal fluid (CSF) activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in patients with Alzheimer's disease (AD) participating in randomized clinical trials from three European centers, before and after long-term treatment with different AChE inhibitors (AChEIs). MATERIALS AND METHODS: Of the 144 patients included in the study, 104 were treated with donepezil, 15 with galantamine, 16 with rivastigmine, and nine with placebo. CSF AChE and BChE activities were measured at baseline and after 1- year treatment. RESULTS: Donepezil and galantamine groups showed a significant increase in CSF AChE activity at follow-up, while no changes for BChE activity were observed; in donepezil group, a positive correlation between plasma concentration and AChE activity was documented. Conversely, in rivastigmine group, a decrease in CSF activity of both enzymes was observed. CSF AChE and BChE activities were not correlated with the clinical outcome in any group considered. CSF biomarkers did not show any change after treatment. CONCLUSIONS: AChEIs differently influence the activity of target enzymes in CSF independent of their pharmacodynamic effects.

Different cholinesterase inhibitor effects on CSF cholinesterases in Alzheimer patients.

BACKGROUND: The current study aimed to compare the effects of different cholinesterase inhibitors on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities and protein levels, in the cerebrospinal fluid (CSF) of Alzheimer disease (AD) patients. METHODS AND FINDINGS: AD patients aged 50-85 years were randomized to open-label treatment with oral rivastigmine, donepezil or galantamine for 13 weeks. AChE and BuChE activities were assayed by Ellman's colorimetric method. Protein levels were assessed by enzyme-linked immunosorbent assay (ELISA). Primary analyses were based on the Completer population (randomized patients who completed Week 13 assessments). 63 patients were randomized to treatment. Rivastigmine was associated with decreased AChE activity by 42.6% and decreased AChE protein levels by 9.3%, and decreased BuChE activity by 45.6% and decreased BuChE protein levels by 21.8%. Galantamine decreased AChE activity by 2.1% and BuChE activity by 0.5%, but increased AChE protein levels by 51.2% and BuChE protein levels by 10.5%. Donepezil increased AChE and BuChE activities by 11.8% and 2.8%, respectively. Donepezil caused a 215.2% increase in AChE and 0.4% increase in BuChE protein levels. Changes in mean AChE-Readthrough/Synaptic ratios, which might reflect underlying neurodegenerative processes, were 1.4, 0.6, and 0.4 for rivastigmine, donepezil and galantamine, respectively. CONCLUSION: The findings suggest pharmacologically-induced differences between rivastigmine, donepezil and galantamine. Rivastigmine provides sustained inhibition of AChE and BuChE, while donepezil and galantamine do not inhibit BuChE and are associated with increases in CSF AChE protein levels. The clinical implications require evaluation.

Analysis of cerebrospinal fluid of Alzheimer patients. Biomarkers and toxic properties.

Alzheimer's disease (AD) is a severe, progressive and chronic disorder with strong cognitive deficits. Diagnosis of probable AD can be performed by measuring biomarkers in cerebrospinal fluid (CSF). The aim of the present study was to measure CSF levels of nerve growth factor (NGF), the anti-NGF auto-antibody, and the cholinesterases AChE and BChE, and to correlate them with beta-amyloid, tau and phospho-tau-181. We could show that NGF-like immunoreactivity, but not anti-NGF auto-antibody, was significantly enhanced in AD patients compared to healthy subjects, while both cholinesterases were not changed. beta-Amyloid(1-42) was decreased, while tau and phospho-tau-181 were increased. The commercial Promega NGF ELISA detected mature NGF but not wild-type-human-pro-NGF. Using a bioassay of brain slices, we showed that recombinant mature NGF enhanced survival of cholinergic neurons, while wild-type human pro-NGF displayed a less pronounced effect. The addition of CSF to brain slices exhibited strong toxic effects on the survival of cholinergic neurons. We conclude that in CSF of AD patients (at least partly) mature NGF-like immunoreactivity is enhanced, and is masked in a bioassay by the toxic properties of CSF.

Association between acetylcholinesterase and beta-amyloid peptide in Alzheimer's cerebrospinal fluid.

The altered expression of acetylcholinesterase (AChE) in the brains of patients with Alzheimer's disease (AD) has raised much interest of late. Despite an overall decrease in the AD brain, the activity of AChE increases around beta-amyloid plaques and indeed, the beta-amyloid peptide (Abeta) can influence AChE levels. Such evidence stimulated our interest in the possibility that the levels of AChE and amyloid might vary together in AD. We previously found that the different AChE forms present in both the brain and in the cerebrospinal fluid (CSF) of AD patients varied in conjunction with abnormal glycosylation. Thus, the alterations in glycosylation are correlated with the accumulation of a minor subspecies of AChE monomers. We also recently analysed whether long-term exposure to the cholinesterase inhibitor (ChE-I) donepezil influences the AChE species found in AD CSF. The marked increase in CSF-AChE activity in AD patients following long-term treatment with donepezil was not paralleled by a rise in this subset of light variants. Hence, the correlation with the levels of CSF-Abeta is unique to these AChE species in patients receiving such treatment. The aim of this report is to review the links between AChE and beta-amyloid, and to discuss the significance of the responses of the distinct AChE species to ChE-I during the treatment of AD.

Inhibition of acetylcholinesterase in CSF versus brain assessed by 11C-PMP PET in AD patients treated with galantamine.

The relationship between acetylcholinesterase (AChE) activity in the CSF and brain of patients with Alzheimer's disease (AD) was investigated in 18 mild AD patients following galantamine treatment. The first 3 months of the study had a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16-24 mg/day) and six patients placebo. This was followed by 9 months galantamine treatment in all patients. Activities and protein levels of both the "read-through" AChE (AChE-R) and the synaptic (AChE-S) variants in CSF were assessed in parallel together with the regional brain AChE activity by (11)C-PMP and PET. The AChE-S inhibition was 30-36% in CSF, which correlated well with the in vivo AChE inhibition in the brain. No significant AChE inhibition was observed in the placebo group. The increased level of the AChE-R protein was 16% higher than that of AChE-S. Both the AChE inhibition and the increased level of AChE-R protein positively correlated with the patient's performance in cognitive tests associated with visuospatial ability and attention. In conclusion, AChE levels in CSF closely mirror in vivo brain AChE levels prior to and after treatment with the cholinesterase inhibitors. A positive cognitive response seems to dependent on the AChE inhibition level, which is balanced by an increased protein level of the AChE-R variant in the patients.

Cerebrospinal fluid acetylcholinesterase changes after treatment with donepezil in patients with Alzheimer's disease.

We analyzed whether donepezil differently influences acetylcholinesterase (AChE) variants from cerebrospinal fluid (CSF) in patients with Alzheimer's disease (AD) after long-term treatment. Overall CSF-AChE activity in AD patients before treatment was not different from controls, but the ratio between the major tetrameric form, G(4), and the smaller G(1) and G(2) species was significantly lower. AChE levels at study outset were found to correlate positively with beta-amyloid (1-42) (Abeta42). When patients were re-examined after 12 months treatment with donepezil, there was a remarkable increase in both the G(4) and the lighter species of CSF AChE. As compared with placebo, donepezil caused decreases in the percentage of AChE that failed to bind to the lectin concanavalin A and the antibody AE1. These non-binding species comprised primarily a small subset of G(1) and G(2) forms. In treated patients, these light variants were the only subset of CSF AChE that correlated with CSF-Abeta42 levels. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis showed that a 77-kDa band, attributed in part to inactive AChE, was lower in AD patients than in controls. Unlike enzyme activity, the intensity of this band did not increase after donepezil treatment. The varying responses of different AChE species to ChE-I treatment suggest different modes of regulation, which may have therapeutic implications.

Changes in brain 11C-nicotine binding sites in patients with mild Alzheimer's disease following rivastigmine treatment as assessed by PET.

RATIONALE: Marked reduction in the cortical nicotinic acetylcholine receptors is observed in the brain of patients suffering from Alzheimer's disease (AD). Although cholinesterase inhibitors are used for symptomatic treatment of mild to moderate AD patients, numerous long-term treatment studies indicate that they might stabilize or halt the progression of the disease by restoring the central cholinergic neurotransmission. Thus, we used positron emission tomography (PET) technique as a sensitive approach to assess longitudinal changes in the nicotine binding sites in the brains of patients with AD. OBJECTIVE: To evaluate changes in brain nicotinic binding sites in relation to inhibition level of cholinesterases in cerebrospinal fluid (CSF) and plasma and changes in cognitive performance of the patients in different neuropsychological tests after rivastigmine treatment. MATERIALS AND METHODS: Ten mild AD patients received rivastigmine for 12 months. A dual-tracer PET model with administration of (15)O-water and (S)(-)(11)C-nicotine was used to assess (11)C-nicotine binding sites in the brain at baseline and after 3 and 12 months of the treatment. Cholinesterase activities in CSF and plasma were assessed colorimetrically. RESULTS: The (11)C-nicotine binding sites were significantly increased 12-19% in several cortical brain regions after 3 months compared with baseline, while the increase was not significant after 12 months of the treatment. After 3 months treatment, low enzyme inhibition in CSF and plasma was correlated with higher cortical (11)C-nicotine binding. The (11)C-nicotine binding positively correlated with attentional task at the 12-month follow-up. CONCLUSION: Changes in the (11)C-nicotine binding during rivastigmine treatment might represent remodeling of the cholinergic and related neuronal network.

Altered glycosylation of acetylcholinesterase in the Creutzfeldt-Jakob cerebrospinal fluid.

Several neurodegenerative disorders present deficiencies in the cholinergic system. Scarce research on prion encephalopathies has examined the levels of cholinergic pathway-related enzymes. Acetylcholinesterase (AChE) is expressed as several molecular forms. The potential importance of these variants is increased by the possibility that AChE has roles other than acetylcholine hydrolysis. We investigated the levels of AChE, its molecular forms, and glycosylation in the cerebrospinal fluid (CSF) from Creutzfeldt-Jakob disease (CJD) patients.

Changes in the activity and protein levels of CSF acetylcholinesterases in relation to cognitive function of patients with mild Alzheimer's disease following chronic donepezil treatment.

OBJECTIVES: To evaluate long-term changes in acetylcholinesterase (AChE) activity in CSF and blood following donepezil treatment in relation to the concentration of donepezil and cognition in AD patients. METHODS: CSF or blood (or both) samples of a total of 104 patients with mild AD were used [MMSE score 23 +/- 0.4; age 75 +/- 1 years (mean +/- SEM); n=53 for CSF and n=51 for plasma/red blood cell (RBC) samples]. The patients were treated with 5 or 10 mg/day donepezil and clinically followed for 2 years. The CSF and RBC AChE activities were measured by the Ellman's direct colorimetric assay. Protein levels of two variants of AChE ("read-through" AChE-R and synaptic AChE-S) were determined by an ELISA-like method. RESULTS: The plasma donepezil concentration was dose-dependent (between 30 and 60 ng/mL in the 5-mg and 10-mg group, respectively). The CSF donepezil concentration was 10 times lower than the plasma level and showed dose- and time-dependent kinetics. The RBC AChE inhibition was moderate (19-29%). CSF AChE-S inhibition was estimated to 30-40% in the 5-mg and 45-55% in the 10-mg group. Positive correlations were observed between the CSF AChE inhibition, an increased protein level of the AChE-R variant and MMSE examination. Patients with high AChE inhibition (>or=45%) showed a stabilized MMSE test result after up to two years, while a significant decline was observed in AD patients with lower AChE inhibition (