Table 2. Quantitative summary of included study characteristics between serum anticholinergic activity and cognitive and functional outcomes.
SAA = Serum Anticholinergic Activity; MMSE = Mini Mental State Examination; IQCODE = Informant questionnaire on Cognitive Decline in the Elderly; SPMSQ = Short Portable Mental Status Questionnaire; SIB = Severe Impairment Battery; CAM = Confusion Assessment Method; BI = Barthel Index; AD = Alzheimer’s disease; FAST = Functional Assessment Staging; BEHAVE-AD = Behavioural Pathology in Alzheimer’s Disease Rating Scale; BARS = Brief Agitation Rating Scale; POCD = Postoperative cognitive decline; CAM-ICU = Confusion Assessment Method for critically ill patients in Intensive Care Unit; MCI = Mild Cognitive Impairment; DI = Delirium Index; SDM = Symbol Digit Modalities; IQR = Interquartile range; PGDRS = Psychogeriatric Dependency Rating Scale; DRS = Dementia Rating Scale; WMH = White Matter Hyperintensities; ICU = Intensive care unit; RCT = Randomised Controlled Trial; ADL = Activities of Daily Living; IADL = Instrumental Activities of Daily Living; CERAD = Consortium to Establish a Registry for Alzheimer Disease; GDS = Geriatric Depression Scale; CI = Cognitive impairment; MANCOVA = Multivariate Analysis of Covariance; ANOVA = Analysis of Variance; ANCOVA = Analysis of Covariance; N.S = Not Significant; pmol = Picomol
| Studies used SAA | Study design | Outcome measure | Sample size (n) | Mean SAA (pmol/mL) | Outcome of interest | Statistical test | p value | |||
|---|---|---|---|---|---|---|---|---|---|---|
| Control group | Intervention group | Control/ Pre | Intervention/ Post | Control/pre | Intervention/post | |||||
| RCTs | ||||||||||
| Kersten et al., Norway 2013 [41] | RCT, single-blinded | CERAD | 31 | 37 | 3.80 (2.29–8.0) (median), (n = 26) | 4.27 (2.19–6.39) (median), (n = 35) | 13.06 ± 6.26 | 14.46 ± 5.92 | ANCOVA | .48 |
| MMSE | 30 | 34 | 3.80 (2.29–8.0) (median), (n = 26) | 4.27 (2.19–6.39) (median), (n = 35) | 19.7 ± 5.21 | 20.68 ± 5.18 | ANCOVA | .57 | ||
| saliva flow (g/min) | 27 | 34 | 3.80 (2.29–8.0) (median), (n = 26) | 4.27 (2.19–6.39) (median), (n = 35) | 0.27 (0.16–0.49) | 0.25 (0.09–0.60) | ANCOVA | .34 | ||
| Lackner et al., USA 2008 [40] | RCT, double-blinded | MMSE | 24 | 26 | 1.15 (0.0–5.05) (median), (n = 24) | 0.95 (0.0–6.20) (median), (n = 26) | 13.7 ± 0.9 | 15.2 ± 0.8 | Correlation analysis | .25 |
| SIB | 24 | 26 | 1.15 (0.0–5.05) (median), (n = 24) | 0.95 (0.0–6.20) (median), (n = 26) | 87.0 ± 1.6 | 87.1 ± 1.6 | Correlation analysis | .72 | ||
| CAM | 24 | 26 | 1.15 (0.0–5.05) (median), (n = 24) | 0.95 (0.0–6.20) (median), (n = 26) | 1.8 ± 0.3 | 2.0 ± 0.3 | Correlation analysis | .96 | ||
| BARS | 24 | 26 | 1.15 (0.0–5.05) (median), (n = 24) | 0.95 (0.0–6.20) (median), (n = 26) | 16.1 ± 1.8 | 16.9 ± 1.9 | Correlation analysis | .75 | ||
| Miller et al., Canada 1988 [11] | RCT, double blinded | MMSE | 16 | 16 | 11.6 ± 18.2 (n = 16) | 121.1 ± 85.5 (n = 14) | 28.3 ± 2.2 | 26.7 ± 3.5 | ANCOVA | N.S |
| SDM | 17 | 16 | 11.6 ± 18.2 (n = 16) | 121.1 ± 85.5 (n = 14) | 36 ± 12.1 | 28.4 ±13.3 | ANCOVA | N.S | ||
| Delirium | 17 | 16 | 11.6 ± 18.2 (n = 16) | 121.1 ± 85.5 (n = 14) | 37 ± 2.7 | 33.3 ± 4.1 | ANCOVA | .02 | ||
| Rey audio-verbal learning test | 16 | 16 | 11.6 ± 18.2 (n = 16) | 121.1 ± 85.5 (n = 14) | 4.4 ± 0.7 | 3.2 ± 2.0 | ANCOVA | < .01 | ||
| Tollefson et al., USA 1991 [13] | RCT, parallel-arm | MMSE | 19 | 15 | 2.49 ± 3.9 | 1.89 ± 3.4 | 22.59 ± 4.76 | 23.03 ± 4.92 | Correlation analysis | < .01 |
| Longitudinal cohort | ||||||||||
| Golinger et al., USA 1987 [46] | Longitudinal cohort | drug-risk number for delirium | 16 | 9 | 0.81 ± 1.0 (delirium) | 4.67 ± 3.3 (no delirium) | 12.0 ± 9.2 (delirium) | 8.3 ± 6.4 (no delirium) | t-test | .3 (N.S) |
| Kashyap et al., Canada 2014 [48] | Longitudinal cohort | change in cognition (SAA) | 68 | 21, 20, 12 | 1.03 ± 0.75 | 0.08 ± 1.2 | 0.83 (median) | 0.65, 0.76, 0.50 (median) | Kruskal-Wallis one-way ANOVA | .87 |
| van Munster et al., Netherlands 2012 [47] | Longitudinal study | effect of delirium onset on SAA level as effect size, adjusted for CI | 70 | 72 | 3.4 | 4.2 | 28.8 (SD not reported) | Mixed-model regression | < .05 | |
| Cross-sectional | ||||||||||
| Chew et al., USA 2005 [8] | Cross-sectional | Correlation study; MMSE and SAA | 25 in total | 1.06 ± 1.2 (overall) | r = -0.398 | Spearman correlation | .049 | |||
| SIB and SAA | 28 in total | r = -0.405 | Spearman correlation | 095 | ||||||
| Flacker et al., USA 1998 [51] | Cross-sectional | ADL | 47 | 20 | 0.7 ± 0.8 | 1.8 ± 1.6 | 1.5 ± 2.2 | 4.0 ± 2.6 | t-test | < .001 |
| Flacker et al., USA 1999 [52] | Cross-sectional | changes in SAA level in individuals with febrile illness between study entry and at one-month follow-up | 14 | 8 | 0.65 ± 0.51 (entry, delirium) | 0.69 ± 0.85 (entry, no delirium) | 0.08 ± 0.12 (follow-up, delirium) | 0.10 ± 0.16 (follow-up, no delirium) | ANOVA | < .01 for overall change |
| Hori et al., Japan 2011 [57] | Cross-sectional | MMSE | 50 | 26 | <1.95 | 4.14 ± 2.70 | 13.16 ± 8.27 | 8.89 ± 8.40 | Student t-test | .0367 |
| FAST | 50 | 26 | <1.95 | 4.14 ± 2.70 | 4.78 ± 0.98 | 5.46 ± 1.21 | Student t-test | .0096 | ||
| BEHAVE-AD: delusion | 50 | 26 | <1.95 | 4.14 ± 2.70 | 1.2 ± 1.7 | 3.4 ± 1.3 | Student t-test | < .0001 | ||
| BEHAVE-AD: hallucination | 50 | 26 | <1.95 | 4.14 ± 2.70 | 0.7 ± 1.0 | 1.9 ± 1.0 | Student t-test | < .0001 | ||
| BEHAVE-AD: activity disturbance | 50 | 26 | <1.95 | 4.14 ± 2.70 | 2.1 ± 2.2 | 2.3 ± 2.2 | Student t-test | .7162 | ||
| BEHAVE-AD: aggressiveness | 50 | 26 | <1.95 | 4.14 ± 2.70 | 1.1 ± 1.7 | 1.9 ± 2.1 | Student t-test | .0714 | ||
| BEHAVE-AD: rhythm disturbance | 50 | 26 | <1.95 | 4.14 ± 2.70 | 0.6 ± 0.8 | 1.7 ± 0.7 | Student t-test | < .0001 | ||
| BEHAVE-AD: affection | 50 | 26 | <1.95 | 4.14 ± 2.70 | 1.0 ± 1.2 | 0.6 ± 0.8 | Student t-test | .1590 | ||
| BEHAVE-AD: anxiety | 50 | 26 | <1.95 | 4.14 ± 2.70 | 1.4 ± 1.8 | 1.7 ± 1.8 | Student t-test | .6278 | ||
| Kersten et al., Norway 2013 [58] | Cross-sectional | MMSE | 72 (EM, extensive metaboliser) | 8 (PM, poor metaboliser) | 4.2 (2.4, 7.0) for EM | 10.3 (5.7, 39.9) for PM | 19.5 (17,22) | 24 (16,25.5) | Mann-Whitney test | N.S |
| CERAD | 72 (EM, extensive metaboliser) | 8 (PM, poor metaboliser) | 4.2 (2.4, 7.0) for EM | 10.3 (5.7, 39.9) for PM | 12 (9,14) | 9.5 (7.25,14.3) | Mann-Whitney test | N.S | ||
| ADL | 72 (EM, extensive metaboliser) | 8 (PM, poor metaboliser) | 4.2 (2.4, 7.0) for EM | 10.3 (5.7, 39.9) for PM | 4 (3,5) | 4 (3,5) | Mann-Whitney test | N.S | ||
| mouth dryness (whole mouth resting salivary flow) | 72 (EM, extensive metaboliser) | 8 (PM, poor metaboliser) | 4.2 (2.4, 7.0) for EM | 10.3 (5.7, 39.9) for PM | 0.7 (0.4,1.2) (EM) | 1.34 (0.1,2.3) (PM) | Mann-Whitney test | N.S | ||
| Konishi et al., Japan 2010 [55] | Cross-sectional | MMSE | 50 | 26 | <1.95 | 4.14 ± 2.7 | 13.16 ± 8.27 | 8.89 ± 8.40 | t-test | .0367 |
| FAST | 50 | 26 | <1.95 | 4.14 ± 2.7 | 4.78 ± 0.98 | 5.46 ± 1.21 | t-test | .0096 | ||
| Lampela et al., Finland 2013 [17] | Cross-sectional | MMSE, GDS, ADL, IADL, short distance vision | 12/609 with and without dementia | median 9.3 (2.27–82.7) Overall | numerical data not shown | Kruskall-Wallis one-way ANOVA | N.S | |||
| Mangoni et al., Netherlands 2013 [59] | Cross-sectional | Regression analysis: SAA vs ADL | 71 in total | median 2.8 (Range 1.1–4.9) | β = 0.39 | Linear regression and Cox regression | 0.001 | |||
| 3-month mortality vs SAA | 71 in total | median 2.8 (Range 1.1–4.9) | HR = 0.07 | Linear regression and Cox regression | 0.07 | |||||
| 1-year mortality vs SAA | 71 in total | median 2.8 (Range 1.1–4.9) | HR = 1.10 | Linear regression and Cox regression | 0.11 | |||||
| Mulsant et al., USA 2003 [7] | Cross-sectional | MMSE (≤24) | n = 21 with undetectable SAA | n = 159 with low SAA; n = 21 with high SAA | <0.25 (undetectable) | 0.25–2.79 (detectable); ≥2.80 (high) | 4.8% | 7.6%; 28.6% | Pearson χ2 test | .006 |
| Mussi et al., Italy 1999 [53] | Cross-sectional | SAA level for delirious and non-delirious individuals | 49 | 12 | 3.9 ± 8.4 | 23.0 ± 15.5 | 3.9 ± 8.4 | 23.0 ± 15.5 | t-test | < .004 |
| Nebes et al., USA 1997 [50] | Cross-sectional | DRS | 17 | 19 | 0.0 | 0.28 ± 0.26 | 138.6 ± 3.0 | 135.6 ± 3.6 | ANOVA | N.S |
| total immediate recall | 17 | 19 | 0.0 | 0.28 ± 0.26 | 26.1 ± 7.2 | 21.9 ± 7.1 | ANOVA | .24 | ||
| delayed recall | 17 | 19 | 0.0 | 0.28 ± 0.26 | 6.5 ± 2.5 | 4.2 ± 2.5 | ANOVA | < .05 | ||
| percent retention | 17 | 19 | 0.0 | 0.28 ± 0.26 | 86% ± 35% | 58% ± 25% | ANOVA | < .05 | ||
| Nebes et al., USA 2005 [54] | Cross-sectional | cognitive decrements based on WMH volume | n = 35, no SAA | n = 69, moderate; SAA; n = 30, high SAA | 0.0 | 1.96 ± 1.0; 6.1 ± 1.7 | 6.2 ± 7.7 | 6.3 ± 11.9; 9.2 ± 15.2 | ANOVA | < .005 (high SAA group correlated with WHM volume) |
| Nebes et al., USA 2007 [23] | Cross-sectional | gait speed | n = 29, low SAA | n = 33, medium SAA; n = 26, high SAA | 0.36 ± 0.34 | 1.36 ± 0.31 | 4.32 ± 0.78 | 4.77 ± 1.06; 5.08 ± 0.88 | MANCOVA | .0109 |
| simple response time | n = 29, low SAA | n = 33, medium SAA; n = 26, high SAA | 0.36 ± 0.34 | 3.42 ± 2.33 | 244.4 ± 40.0 | 276.4 ± 56.2; 285.7 ± 63.4 | MANCOVA | .0078 | ||
| Nebes et al., USA 2011 [56] | Cross-sectional | processing-speed (n = 75); perceptual comparison | n = 76, low-paraxanthine | n = 76, high-paraxanthine | 1.72 ± 2.03 | 1.35 ± 1.37 | 781.4 ± 158.9 | 755.2 ± 133.5 | Pearson correlation | < .009 |
| processing-speed (n = 75); conceptual comparison | n = 76, low-paraxanthine | n = 76, high-paraxanthine | 1.72 ± 2.03 | 1.35 ± 1.37 | 799.5 ± 147.3 | 795.6 ± 134.1 | Pearson correlation | < .017 | ||
| processing-speed (n = 75); working-memory (N Back) | n = 76, low-paraxanthine | n = 76, high-paraxanthine | 1.72 ± 2.03 | 1.35 ± 1.37 | 32.6 ± 13.5 | 34.1 ± 12.6 | Pearson correlation | N.S | ||
| Rovner et al., USA 1988 [14] | Cross-sectional | MMSE | 11 | 11 | <0.83 | >0.83 | 6.3 ± 9.6 | 5.2 ± 2.1 | t-test | .7 |
| self-care capacity (PGDRS) | 11 | 11 | <0.83 | >0.83 | 13.2 ± 8.3 | 20.1 ± 1.5 | t-test | .03 | ||
| Thomas et al., Germany 2008 [18] | Cross-sectional | delirium (DI) | n = 15, cognitively unimpaired | n = 31, with dementia; n = 15, delirium with dementia | 9.33 ± 4.44 | 11.03 ± 6.15; 12.25 ± 10.53 | 2.5 ± 0.7 | 6.2 ± 4.0; 8.7 ± 4.5 | ANOVA and Duncan’s post-hoc-tests | < .02 |
| MMSE | n = 15, cognitively unimpaired | n = 31, with dementia; n = 15, delirium with dementia | 9.33 ± 4.44 | 11.03 ± 6.15; 12.25 ± 10.53 | 28.8 ± 1.8 | 16.7 ± 7.5; 14.4 ± 6.0 | ANOVA and Duncan’s post-hoc-tests | < .001 | ||
| IQCODE | n = 15, cognitively unimpaired | n = 31, with dementia; n = 15, delirium with dementia | 9.33 ± 4.44 | 11.03 ± 6.15; 12.25 ± 10.53 | 3.1 ± 0.2 | 4.2 ± 0.6; 4.2 ± 0.7 | ANOVA and Duncan’s post-hoc-tests | < .004 | ||
| SPMSQ | n = 15, cognitively unimpaired | n = 31, with dementia; n = 15, delirium with dementia | 9.33 ± 4.44 | 11.03 ± 6.15; 12.25 ± 10.53 | 0.6 ± 0.9 | 4.7 ± 2.8; 6.4 ± 2.7 | ANOVA and Duncan’s post-hoc-tests | < .001 | ||
| BI | n = 15, cognitively unimpaired | n = 31, with dementia; n = 15, delirium with dementia | 9.33 ± 4.44 | 11.03 ± 6.15; 12.25 ± 10.53 | 62.5 ± 31.2 | 33.7 ± 24.3; 45.0 ± 18.1 | ANOVA and Duncan’s post-hoc-tests | < .005 | ||
| Tune et al., USA 1993 [49] | Cross-sectional | SAA level for delirious and non-delirious individuals | 16 | 9 | 5.0 ± 2.41 | 7.09 ± 2.10 | 5.0 ± 2.41 | 7.09 ± 2.10 | t-test | .045 |
| Case-control | ||||||||||
| Mach Jr et al., USA 1995 [10] | Case-control | MMSE | 11 | 11 | 3.38 ± 2.49 | 6.05 ± 2.97 | 28 ± 1.3 | 26 ± 2.7 | paired t-test | < .05 |
| Plaschke et al., Germany 2010 [60] | Case-control | cognitive function (neuropsychological tests), cortisol and SAA correlation | 23, low SAA group | 7, high SAA group | 3.3 ± 2.2 | 6.1 ± 3.9 | not reported | not reported | ANOVA | N.S for both studies |
| Plaschke et al., Germany 2013 [61] | Case Control | IQCODE | n = 87, no POCD | n = 30, with POCD | 4.5 ± 3.9 | 1.6 ± 1.7 | 86 (98.9) | 28 (93.3) | χ2 test | .099 |
| subjective memory complaints | n = 87, no POCD | n = 30, with POCD | 4.5 ± 3.9 | 1.6 ± 1.7 | 76 (87.4) | 22 (73.3) | χ2 test | .073 | ||
| Thienhaus et al., USA 1990 [12] | Case-control | MMSE | 18 | 18 | 4.09 ± 4.83 | 6.66 ± 6.23 | 27.7 ± 1.2 | 27.9 ± 1.9 | Paired t-test | N.S |
| Digit Retention Span | 18 | 18 | 4.09 ± 4.83 | 6.66 ± 6.23 | 6.2 ± 2.1 | 6.1 ± 1.7 | Paired t-test | N.S | ||
| word recognition | 18 | 18 | 4.09 ± 4.83 | 6.66 ± 6.23 | 12.4 ± 5.3 | 14.0 ± 6.1 | Paired t-test | N.S | ||
| category retrieval | 18 | 18 | 4.09 ± 4.83 | 6.66 ± 6.23 | 10.4 ± 4.0 | 10.5 ± 4.9 | Paired t-test | N.S | ||
| self-rated Memory | 18 | 18 | 4.09 ± 4.83 | 6.66 ± 6.23 | 26.0 ± 38.4 | 27.2 ± 43.3 | Paired t-test | N.S | ||
| Prospective cohort | ||||||||||
| Plaschke et al., Germany 2007 [44] | Prospective, cohort | Correlation of SAA and cerebral spinal fluid anticholinergic activity. | n = 20 | n = 17, with delirium | 2.6 ± 2.3 | 2.8 ± 2.5 | r = 0.861 | Correlation between two numerical variables | >.05 | |
| Remillard, Canada 1994 [43] | Prospective cohort | MMSE | 23, non-detectable SAA | 8, detectable SAA | <1.8 | >1.8 | 23.9 ± 3.7 | 25.2 ± 3.8 | unpaired t-test | N.S |
| SDM | 23, non-detectable SAA | 8, detectable SAA | <1.8 | >1.8 | 15.2 ± 6.4 | 24.2 ± 8.7 | unpaired t-test | < .001 | ||
| Rossi et al., Switzerland 2014 [45] | Prospective cohort | MMSE | n = 38, no POCD | n = 32, with POCD | 0.97 (.65, 1.83) | 1.32 (.68, 2.59) | 29 (28, 30) | 27.5 (25, 29) | χ2 test | .004 |
| CERAD | n = 38, no POCD | n = 32, with POCD | 0.97 (.65, 1.83) | 1.32 (.68, 2.59) | 99 (93, 105) | 93 (85, 101) | t-test | .007 | ||
| Tune et al., USA 1981 [42] | Prospective cohort | Correlation between delirium (MMSE) and SAA level. | 19 controls | 10 patients with delirium | Not clearly mentioned, but a SAA level >1.5 pmol is defined as high-SAA | r = -0.83 | Correlation between two numerical variables | < .001 | ||
| Watne et al., Norway & UK 2014 [16] | Prospective cohort | IQCODE | 32, no delirium (Edinburg) | 20, with delirium | 1.62 (0.81–2.45) (IQR) | 1.35 (0.76–2.46) (IQR) | 0 | 5 | Mann-Whitney test/ Chi-square test | .01 |
| Katz ADL | 32, no delirium (Edinburg) | 20, with delirium | 1.62 (0.81–2.45) (IQR) | 1.35 (0.76–2.46) (IQR) | 31 | 16 | Mann-Whitney test/ Chi-square test | .07 | ||
| IQCODE | 44, no delirium (Oslo) | 52, with delirium | 6.08 (4.08–9.86) (IQR) | 7.02 (4.24–9.73) (IQR) | 10 | 42 | Mann-Whitney test/ Chi-square test | < .001 | ||
| Barthel ADL | 44, no delirium (Oslo) | 52, with delirium | 6.08 (4.08–9.86) (IQR) | 7.02 (4.24–9.73) (IQR) | 29 | 11 | Mann-Whitney test/ Chi-square test | < .001 | ||