Serum Anticholinergic Activity Research Articles

Anticholinergic burden of medications is associated with dry mouth and reflected in minor labial gland secretion

ObjectiveMedications with anticholinergic potential inhibit saliva secretion. Polypharmacy potentiates anticholinergic burden, causing dry mouth symptoms and chronic deterioration of oral health. Patients of any age can be affected by anticholinergic medication-triggered hyposalivation (the objective measure of dry mouth); therefore, seeking predictions of hyposalivation to screen dry mouth is needed. DesignIn our prospective, cross-sectional clinical study, 55 middle-aged adult patients participated. We examined whether the anticholinergic burden calculated from anticholinergic medications (anticholinergic drug score; ADS) and blood serum anticholinergic activity (SAA; the gold standard measure of anticholinergic burden) is associated with hyposalivation. As no prior studies measured minor salivary glands regarding the quantifiable anticholinergic burden, we assessed hyposalivation by the minor saliva flow (MSF) and unstimulated whole saliva (UWS) secretion. ResultsOur data showed a negative linear relationship between SAA and UWS (p < 0.05); when SAA increases by one pmol/ml unit, the saliva flow decreases by 0.058 ml/min. MSF showed a linear correlation (p < 0.005) with UWS. In a multivariate logistic regression model (including age, gender, race, smoking status, xerostomia severity, ADS, and BMI), we identified SAA and age as predictors of hyposalivation (p < 0.05). ConclusionsWe provide evidence for the significant relationship between measurable anticholinergic burden and saliva flow. The correlation between UWS and MSF suggests that both saliva flow rate measurement methods could reflect anticholinergics-induced changes in salivary health.

Cell-based serum anticholinergic activity assay and working memory in cognitively healthy older adults before and after scopolamine: An exploratory study.

A new cell-based serum anticholinergic activity (cSAA) assay that measures anticholinergic activity specifically at muscarinic M1 receptors and eliminates many of the drawbacks of the existing assay was developed by our team. We aimed to study the relationship between changes in working memory and executive function with changes in cSAA using the new assay in cognitively healthy older adults. Cognitively healthy participants aged 50 years and above, received a single dose of 0.4 mg of intravenous scopolamine. Cognition and cSAA levels were measured before and 30 min after receiving scopolamine. Cognition was measured using the Cambridge Neuropsychological Test Automated Battery. Ten participants were recruited, and nine (mean age = 69.8, SD = 9.5, range 59-86 years) completed the study. Following scopolamine, participants experienced an increase in cSAA (cSAA pre = 0.90 ± 0.97 vs cSAA post = 12.0 ± 3.70 pmol/L; t-test (df = (8) = -9.5, p < 0.001). In addition, there was an association between change in cSAA and changes in working memory (Spearman's ρ = 0.68, p = 0.042) and executive function (Spearman's ρ = 0.72, p = 0.027). In our sample of cognitively healthy older adults, the new cSAA assay was able to quantify the scopolamine induced increase in anticholinergic load which correlated significantly with the observed decline in working memory and executive function.

Validating a New Serum Anticholinergic Activity Assay in Cognitively Healthy Older Adults

Introduction We developed a new serum anticholinergic activity (SAA) assay that measures anticholinergic activity specifically at muscarinic M1 receptors and eliminates many of the drawbacks of the existing SAA assay. We aimed to study the relationship between changes in working memory and executive function with changes in SAA using the new assay in cognitively healthy older adults. Methods Cognitively healthy participants aged 50 years or above, received a single dose of 0.4 mg of intravenous scopolamine. Cognition and SAA were measured before, and 30 minutes after receiving scopolamine. Cognition was measured using the Cambridge Neuropsychological Test Automated Battery (CANTAB) (See Figure 1 for details). Results Ten participants were recruited, and nine (mean age = 69.8 years, SD = 9.5, range 59-86 years) completed the study and were analyzed. The one participant who did not complete the study experienced severe nausea after the scopolamine dose and was withdrawn. Following scopolamine, participants experienced increase in SAA (SAA pre = 0.90 ± 0.97 vs. SAA post = 12.0 ± 3.70; t-test (df = 8) = - 9.6, p < 0.001). In addition, there was a decline in working memory (t-test(df=8) = - 2.350, p=0.047). Finally, there was an association between change in SAA and change in working memory (Spearman's rho = 0.68, p = 0.042), and executive function (Spearman's rho = 0.72, p = 0.027). Conclusions In our sample of cognitively healthy older adults, the new SAA assay was able to detect the scopolamine induced increase in anticholinergic load which correlated significantly with the observed decline in working memory and executive function. This research was funded by Internal Chart: https://apps.aagponline.org/abstracts/uploads/2022/xeztdk55pd2t91n.pdf We developed a new serum anticholinergic activity (SAA) assay that measures anticholinergic activity specifically at muscarinic M1 receptors and eliminates many of the drawbacks of the existing SAA assay. We aimed to study the relationship between changes in working memory and executive function with changes in SAA using the new assay in cognitively healthy older adults. Cognitively healthy participants aged 50 years or above, received a single dose of 0.4 mg of intravenous scopolamine. Cognition and SAA were measured before, and 30 minutes after receiving scopolamine. Cognition was measured using the Cambridge Neuropsychological Test Automated Battery (CANTAB) (See Figure 1 for details). Ten participants were recruited, and nine (mean age = 69.8 years, SD = 9.5, range 59-86 years) completed the study and were analyzed. The one participant who did not complete the study experienced severe nausea after the scopolamine dose and was withdrawn. Following scopolamine, participants experienced increase in SAA (SAA pre = 0.90 ± 0.97 vs. SAA post = 12.0 ± 3.70; t-test (df = 8) = - 9.6, p < 0.001). In addition, there was a decline in working memory (t-test(df=8) = - 2.350, p=0.047). Finally, there was an association between change in SAA and change in working memory (Spearman's rho = 0.68, p = 0.042), and executive function (Spearman's rho = 0.72, p = 0.027). In our sample of cognitively healthy older adults, the new SAA assay was able to detect the scopolamine induced increase in anticholinergic load which correlated significantly with the observed decline in working memory and executive function.

Relationships Between a New Cultured Cell-Based Serum Anticholinergic Activity Assay and Anticholinergic Burden Scales or Cognitive Performance in Older Adults

Anticholinergic burden has been associated with deleterious effects on cognition particularly in those with an underlying brain disorder. We developed a new assay based on cultured cells to measure serum anticholinergic activity (cSAA). We report on its relationships with established anticholinergic burden rating scales and cognitive assessments in older patients with mild cognitive impairment (MCI) or major depressive disorder (MDD) in remission or both. The study was cross sectional in nature. This was a five-centre study conducted in Toronto, Canada. Serum samples were collected and cSAA levels were measured in 311 participants aged 60 years or older (154 with MCI, 57 with MDD, and 100 with MCI + MDD). The cSAA assay uses radio-ligand binding to cultured cells stably expressing the muscarinic M1 receptors, with an added procedure to remove potential confounds associated with serum proteins. Lists of medications were used to calculate Anticholinergic Burden and Anticholinergic Drug Scale total scores. Participants also completed a comprehensive cognitive battery. Higher cSAA levels were associated with higher anticholinergic burden and anticholinergic drug scale scores, and also with lower performance on executive function tests, after adjusting for age, gender, education, and diagnosis. These results support the use of the cSAA assay as a laboratory measure of anticholinergic burden.

Serum anticholinergicity is associated with reduced prefrontal brain function in early course schizophrenia

Increased anticholinergic activity resulting from pharmacotherapies used to treat schizophrenia is associated with poorer cognition. However the neural mechanisms underlying this effect are unknown. In this study of 39 early course schizophrenia outpatients, we demonstrate that increased serum anticholinergic activity is associated with reduced activation across the prefrontal cortex, including the dorsolateral, anterior, and medial prefrontal cortices, during two tasks of cognitive control. Lower activation in the dorsolateral and anterior prefrontal cortices mediated the association between increased anticholinergicity and poorer neurocognitive function. Such findings provide preliminary insight into how anticholinergic medications may impact cognition through reduced prefrontal cortical function in schizophrenia.

Research on the mechanism of delirium based on related serum biomarkers of the delirium

Delirium is an acute cognitive disorder caused by a variety of factors which lead to cerebral cortical dysfunction. At present the studies on the pathophysiology of delirium is still very few. But studies on serum biomarker of delirium can help to elucidate the pathophysiological mechanism of delirium, and the studies are significant for delirium diagnosis, severity classification and prediction of long-term outcome. This review examines three major groups of delirium related serum biomarkers: ① risk markers: those that are present or elevated prior to disease onset, including serum chemistries, genetic markers and so on; ② disease markers: those markers elevate with delirium onset and fall when delirium recovery, including acetylcholine and serum anticholinergic activity, serotonin, serum amino acids, and melatonin, interleukin, C-reactive protein; and ③ end products: those that rise in proportion to the consequences of disease, including S-100ß and neuron specific enolase. The three markers mentioned above are helpful to further investigate the mechanism of delirium.

An improved, high-efficiency assay for assessing serum anticholinergic activity using cultured cells stably expressing M1 receptors

Assessments of total anticholinergic activity (SAA) in serum are of considerable interest for its potential involvement in cognitive impairment associated with polydrug states in the elderly and other populations. Such estimations have been based on the displacement of radioligand binding in rat brain tissues. The validity of such measurements has been questioned, as a potentially distorting effect of large serum proteins was identified. We sought to develop a modified assay that would be more efficient and free of this potential confound. Cultured CHO cells stably expressing M1 receptors M1WT3 were used. Binding of 3H-radioligands was conducted in 96-well plates and tested in serum containing known amounts of anticholinergic medications. Effects of endogenous serum proteins were assessed by pre-assay filtration and also by deproteinization with perchloric acid (PCA). Binding of [3H]quinuclidinyl benzilate ([3H]QNB) or [3H]N-methyl-scopolamine ([3H]NMS) to M1WT3 cells proved reliable and equally sensitive to varying concentrations of anticholinergic agents. In agreement with previous findings (Cox, Kwatra, Shetty, & Kwatra, 2009), filtration of proteins heavier than 50kDa essentially reduced SAA values to zero. In contrast, PCA preserved more than 70% of the binding seen untreated cell membranes. Cell-based assays also showed significant signal increases compared to the conventional rat brain-based protocol. Further advantages of the cell-based protocol described here include increased sensitivity and reliability, smaller amounts of radioligand needed, and higher throughput. PCA pretreatment eliminates potential artifacts attributable to serum proteins. This step, together with improvements in efficiency, should contribute significantly to the usefulness of the assay.

Comparison of Nine Instruments to Calculate Anticholinergic Load in a Large Cohort of Older Outpatients: Association with Cognitive and Functional Decline, Falls, and Use of Laxatives

A patient's risk for anticholinergic adverse effects is frequently estimated by instruments evaluating the drugs included in his medication profile. It remains unknown, however, which characteristics should be included in such an assessment instrument aiming to reliably predict adverse anticholinergic outcomes. Cross-sectional study. ESTHER cohort (Germany). Home-dwelling participants (N = 2,761) aged between 60 and 87 years. The association between anticholinergic load calculated with nine different instruments and four anticholinergic adverse outcomes was investigated in univariate and multivariate analyses. Therefore, linear models complemented with Kendall's tau rank correlation coefficients (ԏ) were applied for continuous outcomes and generalized linear models were used to derive odds ratios (ORs) with 95% confidence intervals (CIs) for binary endpoints. Based on the respective identification criteria for anticholinergic drugs, the nine instruments identified between 245 (9%) and 866 (31%) anticholinergic drug users (mean age ± SD: 73 ± 6 years; Mini-Mental State Examination [MMSE] score: 28.3 ± 2.07; Barthel Index: 97.1 ± 7.5; 291 reporting falls; 29 taking laxatives [surrogate for constipation]). In the multivariate analysis, only two instruments indicated a significant association between anticholinergic load and all four outcomes. The instrument considering the prescribed dose showed the strongest association with MMSE scores (ԏ = -0.10), falls (OR: 2.30; 95% CI: 1.50-3.52), and the use of laxatives (OR: 3.11; 95% CI: 1.04-9.36). Instruments most reliably predicted anticholinergicadverse events if they were either based on the drugs' serum anticholinergic activity and the suggestions of clinician experts or considered the actual prescribed dose.

A systematic review and meta-analysis on serum anticholinergic activity and adverse outcomes in older people

A systematic review and meta-analysis on serum anticholinergic activity and adverse outcomes in older people

Serum Anticholinergic Activity and Cognitive and Functional Adverse Outcomes in Older People: A Systematic Review and Meta-Analysis of the Literature.

IntroductionStudies have reported associations between serum anticholinergic activity (SAA) and decline in cognitive performance, delirium, and functional impairment. The aim of this meta-analysis was to explore and quantify associations between SAA and adverse cognitive and functional outcomes in older people.Materials and MethodsA literature search in Ovid MEDLINE, EMBASE, PsycINFO and IPA from 1946–2014 was completed. The primary outcomes of interest were cognitive and functional adverse outcomes associated with SAA in older people aged 55 years and above. The Cochrane Risk-Bias assessment tool was used to assess bias in randomised controlled trials (RCTs). The Newcastle-Ottawa Scale was used to assess the quality of non-RCTs. Meta-analyses were conducted for RCTs and cohort studies separately. Heterogeneity was assessed using I2 tests.ResultsThe primary electronic literature search identified a total of 1559 records in the 4 different databases. On the basis of full-text analysis, 33 studies that met the inclusion criteria. The review included 4 RCTs, 5 prospective cohort studies, 3 longitudinal cohort studies, 17 cross-sectional studies, and 4 case-control studies. Twenty-four of the retrieved studies examined an association between SAA and cognitive outcomes, 2 studies examined an association with SAA and functional outcomes and 8 studies examined associations between SAA and both cognitive, and functional outcomes. The meta-analysis on 4 RCTs showed no association with higher SAA and cognitive performance (I2 = 89.38%, H2 = 25.53 and p-value = <0.05) however, the pooled data from 4 observational studies showed elevated SAA was associated with reduced cognitive performance (I2 = 0.00%, H2 = 3.37 and p-value = 0.34).ConclusionThis systematic review summarises the limitations of the SAA on predicting cognitive and functional outcomes in older people. SAA measured by receptor bioassay is flawed and its use in older people with multimorbidity and polypharmacy is questionable.

Erratum

Erratum

Serum Anticholinergic Activity as an Index of Anticholinergic Activity Load in Alzheimer's Disease

We reported a procedure of serum anticholinergic activity (SAA) measurement and the reliability and reproducibility of the receptor binding assay, and we also described the usefulness of SAA measurement reflecting the anticholinergic activity (AA) in the central nervous system (CNS). According to the results of a 10 times repeated measurement of standard atropine binding, the relative error was between -5.5 and +3.7%, and we considered that measurement of SAA in our studies is accurate and validated. Downregulation of acetylcholine activates inflammation in both CNS and peripheral tissue, which causes AA in both sites. Therefore, changes of AA in the CNS link with SAA in the peripheral system even if a substance having AA does not penetrate through the blood-brain barrier. Then we redescribe issues that require attention in the measurement of SAA. It is generally defined that any SAA greater than the detection limit of a quantitative atropine equivalent level (≥1.95 n<smlcap>M</smlcap> in our study) is positive. According to previous studies, SAA is considered to be positive when its atropine equivalent is ≥1.95 n<smlcap>M</smlcap> and undetectable when this is <1.95 n<smlcap>M</smlcap>. Nevertheless, as a low SAA can act as AA in the CNS, we should assume that SAA might also be positive if its marker concentration is between 0 and 1.95 n<smlcap>M</smlcap>. In addition, SAA should be measured around 11 a.m. or somewhat later because of the diurnal rhythm of cortisol in humans.

Prediction of working memory performance in schizophrenia by plasma ratio of clozapine to N-desmethylclozapine.

Clozapine's potent antagonism of muscarinic M1 receptors is thought to worsen working memory deficits associated with schizophrenia. In contrast, its major metabolite, N-desmethylclozapine (NDMC), is thought to enhance working memory via its M1 receptor agonist activity. The authors hypothesized that the ratio of serum clozapine and NDMC concentrations would be inversely associated with working memory performance in schizophrenia. Thirty patients with schizophrenia or schizoaffective disorder who were receiving clozapine monotherapy at bedtime completed the MATRICS Consensus Cognitive Battery (MCCB) on the day their blood was collected to assess concentrations of clozapine and NDMC as well as serum anticholinergic activity. The clozapine/NDMC ratio was significantly and negatively associated with working memory performance after controlling for age, gender, education, and symptom severity. No significant associations were found between individual clozapine and NDMC concentrations and working memory performance. Serum anticholinergic activity was significantly associated with clozapine concentration, but not with working memory performance or NDMC concentration. No significant associations were found between any pharmacological measure and performance on other MCCB cognitive domains. This hypothesis-driven study confirms that clozapine/NDMC ratio is a strong predictor of working memory performance in patients with schizophrenia. This finding suggests that manipulating the clozapine/NDMC ratio could enhance cognition in patients with schizophrenia treated with clozapine. It also supports the study of procholinergic agents, such as M1 receptor-positive allosteric modulators, to enhance cognition in schizophrenia.

Effect of anticholinergic drugs on cognitive impairment in the elderly

The use of anticholinergic drugs is common in the elderly, even in people with cognitive impairment. A systematic search was conducted in PubMed (anticholinergic effects, anticholinergic and dementia) to define the effects of anticholinergic drugs in the elderly. We emphasised the search in patterns of use, the combined use with AChEIs, the measurement of the Serum Anticholinergic Activity, and the short-term and long-term cognitive effects. The conclusions are that the use of anticholinergic drugs is common in the elderly, even more so than the medical prescription of AChEIs in Alzheimer's disease. The use of anticholinergic drugs may result in cognitive impairment. In long-term use it may generate a worsening of cognitive functions. It can lead to a wrong diagnosis of mild cognitive impairment or dementia, and they can also initiate signs of dementia. Greater cognitive effects appear when there is a previous deficit, but cognitive effects from anticholinergic drugs disappear in severe dementia. The presence of ApoE-ɛ4 increases the vulnerability for cognitive impairment when these drugs are employed.

Small longitudinal study of serum anticholinergic activity and cognitive change in community-dwelling older adults.

The discriminative ability of serum anticholinergic activity (SAA) to differentiate between older individuals with stable versus deteriorating cognition remains undetermined. We examined the relationship between SAA changes, the presence or absence of a mild neurocognitive disorder, age and anticholinergic medication over a one-year time period. SAA at baseline and one-year follow-up was measured for 121 older adults without dementia. Participants were classified at both timepoints as being cognitively intact or meeting the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for a mild neurocognitive disorder. Medications were assessed according to the Anticholinergic Cognitive Burden (ACB) scale. SAA changes did not discriminate between individuals whose cognition remained stable versus those with improvement or decline (H[3]=0.725, p=0.867). SAA change did not vary between age groups, and could not reliably differentiate between individuals on ACB medication or not. While SAA does not appear to be a valid biomarker for cognitive decline, longitudinal studies with a larger sample size and longer duration are required to confirm this finding.

Effect of anticholinergic drugs on cognitive impairment in the elderly

The use of anticholinergic drugs is common in the elderly, even in people with cognitive impairment. A systematic search was conducted in PubMed (anticholinergic effects, anticholinergic and dementia) to define the effects of anticholinergic drugs in the elderly. We emphasized the search in patterns of use, the combined use with AChEIs, the measurement of the Serum Anticholinergic Activity, and the short-term and long-term cognitive effects. The conclusions are that the use of anticholinergic drugs is common in the elderly, even more so than the medical prescription of AChEIs in Alzheimer's disease. The use of anticholinergic drugs may result in cognitive impairment. In long-term use it may generate a worsening of cognitive functions. It can lead to a wrong diagnosis of mild cognitive impairment or dementia, and they can also initiate signs of dementia. Greater cognitive effects appear when there is a previous deficit, but cognitive effects from anticholinergic drugs disappear in severe dementia. The presence of ApoEɛ4 increases the vulnerability for cognitive impairment when these drugs are employed.

Association Between Inherited CYP2D6/2C19 Phenotypes and Anticholinergic Measures in Elderly Patients Using Anticholinergic Drugs

To compare measures of anticholinergic activity between metabolic phenotypes of the polymorphic enzymes cytochrome P450 2D6 (CYP2D6) and CYP2C19 in the elderly patients exposed to anticholinergic agents. Long-term nursing home patients (n = 80) with an anticholinergic drug scale (ADS) score ≥3 were recruited from 22 nursing homes in Norway. Based on pharmacogenetic analyses of mutations encoding absent CYP2D6 or CYP2C19 metabolism, patients were divided into subgroups of poor metabolizers (PMs) (n = 8) and extensive metabolizers (n = 72). Serum anticholinergic activity (SAA) was determined by a validated, 96-well format radio receptor assay and adjusted for ADS score. Unadjusted and adjusted SAAs, mouth dryness, and cognitive function (Mini-Mental State Examination and verbal recall tests from Consortium to Establish a Registry for Alzheimer Disease) were compared between the subgroups with Mann-Whitney tests. The study population was represented by 78% women, 68% had mild to moderate dementia, and mean age was 86 years. More than 80% used more than 1 anticholinergic agent, and their median ADS score was 4. The subpopulation of PMs had significantly higher median SAA than the extensive metabolizers (10.3 versus 4.2 pmol atropine equivalents per milliliter, P = 0.012). This difference remained significant after adjusting for ADS score (P = 0.013). No significant differences in mouth dryness and cognitive function were observed between the subgroups (P > 0.3). These preliminary findings suggest that elderly CYP2D6/CYP2C19 PMs with a high anticholinergic drug burden are at increased risk of elevated SAA. Whether PMs are also more prone to experience anticholinergic side effects needs to be further studied in larger patient populations.

Serum Anticholinergic Activity: A Possible Peripheral Marker of the Anticholinergic Burden in the Central Nervous System in Alzheimer’s Disease

We review the utility of serum anticholinergic activity (SAA) as a peripheral marker of anticholinergic activity (AA) in the central nervous system (CAA). We hypothesize that the compensatory mechanisms of the cholinergic system do not contribute to SAA if their system is intact and that if central cholinergic system deteriorates alone in conditions such as Alzheimer's disease or Lewy body dementia, CAA and SAA are caused by way of hyperactivity of inflammatory system and SAA is a marker of the anticholinergic burden in CNS. Taking into account the diurnal variations in the plasma levels of corticosteroids, which are thought to affect SAA, it should be measured at noon or just afterward.

Anticholinergic Activity in Cerebrospinal Fluid and Serum in Individuals with Hip Fracture with and without Delirium

To examine whether anticholinergic activity (AA) in cerebrospinal fluid (CSF) and serum is associated with risk of delirium in individuals with hip fracture. Prospective cohort study. Two university hospitals in Oslo, Norway, and Edinburgh, UK. Individuals admitted with acute hip fracture (N = 151). Participants were assessed daily for delirium using the Confusion Assessment Method (preoperatively and postoperative days 1-5 (all) or until discharge (participants with delirium)). Prefracture cognitive function was assessed using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Serum was collected preoperatively and CSF at the onset of spinal anesthesia. AA in serum (SAA) and CSF samples was determined according to a muscarinic radio receptor bioassay. The association between AA measures and delirium was evaluated using logistic multivariate analyses. Fifty-two (54%) of the participants in Oslo and 20 (39%) in Edinburgh developed delirium. There was no statistically significant difference in AA between participants with and without delirium in Oslo (serum: 7.02 vs 6.08 pmol/mL, P = .54; CSF: 0.39 vs 0.48 pmol/mL, P = .26) or in Edinburgh (serum: 1.35 vs 1.62 pmol/mL, P = .76; CSF: 0.36 vs 0.31 pmol/mL, P = .93). Nor was there any difference in SAA (Oslo, P = .74; Edinburgh, P = .51) or CSF AA (Oslo, P = .21; Edinburgh, P = .93) when participants were subdivided into prevalent, incident, subsyndromal, and never delirium. Stratifying participants according to prefracture cognitive status (IQCODE) gave the same results. This is the first study of AA in CSF of individuals with and without delirium. The study does not support the hypothesis that central (CSF) or peripheral (serum) AA is an important mechanism of delirium in individuals with hip fracture.

The Relationship Between the Perioperative Transition of Serum Anticholinergic Activity and Postoperative Delirium in Patients Undergoing Esophagectomy and Gastrectomy

The Relationship Between the Perioperative Transition of Serum Anticholinergic Activity and Postoperative Delirium in Patients Undergoing Esophagectomy and Gastrectomy